JPH09143182A - New 5-6-dihydropyrrolo(3,2,1-ij)quinazoline-1-one derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound useful as a therapeutic agent for dysuria and an antihypertensive agent due to possession of strong a receptor antagonism and exhibition of excellent urethra and prostate smooth muscle contractile function and hypotensive effect. SOLUTION: This compound is shown by formula I (R is a 1-6C alkyl; R<1> is H or a 1-6C alkoxy which may be replaced with a halogen; A is a 1-6C alkylene) or its salt such as 5,6-dihydroxy-8-[2-[[2-(2-ethoxyphenoxy)-1 ethyl]amino]propyl]-3-methylpyrrolo[3,2,1-ij]quinazolin-1-one. The compound, for example, is obtained by subjecting a compound of formula II to ring formation in the presence of a base substance such as sodium hydrogencarbonate. The starting raw material of formula II, for example, is obtained by reacting a compound of formula III with a compound of formula IV, then subjecting the reaction product to optical resolution, if required, to give an optically active substance and hydrolyzing the cyano group into a carbamoyl group with an acid such as concentrated hydrochloric acid.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a 5,6-dihydropyrrolo [3,2,1-ij] quinazolin-1-one derivative useful as a medicine.

More specifically, the present invention provides a compound of general formula

[0003]

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(In the formula, R is an alkyl group having 1 to 6 carbon atoms, and R ¹ is a hydrogen atom or 1 to 6 carbon atoms which may have one or more halogen atoms as a substituent.
Is an alkoxy group, and A is an alkylene group having 1 to 6 carbon atoms).
It relates to 2,1-ij] quinazolin-1-one and a pharmacologically acceptable salt thereof.

[0005]

2. Description of the Related Art The 5,6-dihydropyrrolo [3,2,1-ij] quinazolin-1-one derivative represented by the general formula (I) of the present invention is a compound having a novel skeleton which has not been described in any literature. However, it is not described at all in the technical literature.

[0006]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a novel 5,6-dihydropyrrolo [3,2,1-ij] quinazolin-1-one derivative having an α receptor antagonistic action. is there.

[0007]

Means for Solving the Problems As a result of intensive studies to develop a compound having an α-receptor antagonistic activity, the present inventors have found that 5,6-dihydropyrrolo [ The 3,2,1-ij] quinazolin-1-one derivative exerts a strong α-receptor antagonistic action and has excellent urethral and prostatic smooth muscle contracting action and blood pressure lowering action, and thus a therapeutic agent for dysuria or The present inventors have found that they are useful as antihypertensive agents and completed the present invention.

Here, the alkyl group having 1 to 6 carbon atoms in the compound represented by the general formula (I) of the present invention means a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group,
sec-butyl group, tert-butyl group, pentyl group,
A linear or branched alkyl group having 1 to 6 carbon atoms such as an isopentyl group, a neopentyl group, a tert-pentyl group, or a hexyl group is shown, and an alkoxy group having 1 to 6 carbon atoms is a methoxy group or an ethoxy group. , Propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert
-C1 to C1 such as pentyloxy group and hexyloxy group
6 represents a linear or branched alkoxy group having 6 carbon atoms, and an alkylene group having 1 to 6 carbon atoms means a methylene group, an ethylene group,
A straight-chain or branched chain having 1 to 6 carbon atoms such as trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, methylmethylene group, propylene group, 1-methyltrimethylene group, 2-methyltrimethylene group. And the halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

5,6-represented by the general formula (I) of the present invention
Dihydropyrrolo [3,2,1-ij] quinazoline-1-
The on derivative has, for example, a general formula

[0010]

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It is prepared by cyclizing a compound represented by the formula (R, R ¹ and A have the same meaning as described above) in the presence of a basic substance such as sodium hydrogen carbonate or potassium carbonate. be able to.

The indoline derivative represented by the above general formula (II), which is the starting material for the above production method, can be produced as follows.

That is, the general formula

[0014]

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(Wherein R and A have the same meanings as described above) and the general formula

[0016]

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A compound of the general formula obtained by reacting with a compound represented by the formula (wherein R ¹ has the same meaning as described above)

[0018]

[Chemical 6]

A compound represented by the formula (R, R ¹ and A have the same meanings as described above) is optically resolved as necessary to obtain an optically active substance, and then concentrated hydrochloric acid and the like are subjected to a conventional method. It can be produced by hydrolyzing a cyano group to a carbamoyl group with the acid of.

Further, the compound of the general formula (V) in which R is a methyl group is optically resolved as necessary to obtain an optically active substance, and then the amino group is converted to a tert-butoxycarbonyl group by a conventional method. General formula by protecting

[0021]

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(Boc in the formula is a tert-butoxycarbonyl group and R ¹ and A have the same meanings as described above), and then deacetylated with caustic soda or the like according to a conventional method. The general formula obtained

[0023]

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A cyano group is treated with carbamoyl by treating a compound represented by the formula (wherein R ¹ , A and Boc have the same meanings as described above) with hydrogen peroxide in the presence of caustic soda according to a conventional method. Hydrolyzed into a group to give the general formula

[0025]

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After obtaining a compound represented by the formula (wherein R ¹ , A and Boc have the same meanings as described above), the compound of the general formula

R-COOH (IX)

A carboxylic acid represented by the formula (wherein R has the same meaning as described above) or a reactive functional derivative thereof is added, if necessary, to 1,3-dicyclohexylcarbodiimide, 1,1'-carbonyl. By reacting in the presence of a condensing agent such as diimidazole, phosphorus oxychloride or phosphorus trichloride, the general formula

[0029]

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It can also be produced by obtaining a compound represented by the formula (wherein R, R ¹ , A and Boc have the same meanings as described above) and then de-Boc-forming according to a conventional method.

The compound represented by the general formula (III), which is the starting material used in the above-mentioned production method, has the general formula

[0032]

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(Wherein A ¹ is an alkylene group which may have an oxo group having 1 to 6 carbon atoms, X is a chlorine atom or a bromine atom, and R has the same meaning as described above). After reacting the compound to be treated with potassium phthalimide, in the case of a compound having an oxo group, it is further reduced with a reducing agent such as triethylsilane, or

[0034]

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A compound of the general formula obtained by reacting a compound represented by the formula (wherein R and A have the same meanings as described above) with N-carboethoxyphthalimide

[0036]

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The compound represented by the general formula (wherein R and A have the same meaning as described above) is brominated with a brominating agent such as N-bromosuccinimide to give a compound of the general formula

[0038]

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By obtaining a compound represented by the formula (wherein R and A have the same meanings as described above) and further reacting with copper cyanide, a compound of the general formula

[0040]

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It can be produced by obtaining a compound represented by the formula (wherein R and A have the same meanings as described above) and then treating with hydrazine monohydrate.

The compound of the general formula (IV), which is the other starting material in the above production method, is obtained by demethylating a commercially available product or a corresponding methyl ether derivative with, for example, boron tribromide. General formula

[0043]

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A compound represented by the formula (R ¹ has the same meaning as described above) is reacted with 2-chloroethanol or 2-bromoethanol to give a compound of the general formula

[0045]

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It can be produced by obtaining a compound represented by the formula (wherein R ¹ has the same meaning as described above) and then reacting it with methanesulfonyl chloride.

The compounds represented by the above general formulas (XI) and (XII) used in the above production method include novel compounds, but they can be easily produced by a method described in the literature or a method similar thereto. it can.

The compound represented by the above general formula (I) of the present invention can be converted into a pharmaceutically acceptable salt according to a conventional method. Examples of such salts include hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, succinic acid, tartaric acid, 2,4-dimethylbenzenesulfonic acid. ,
2,5-Dimethylbenzenesulfonic acid, 2,4,6-trimethylbenzenesulfonic acid, (+)-camphorsulfonic acid, (-)-camphorsulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 1- Examples thereof include acid addition salts with butanesulfonic acid, fumaric acid, glutamic acid, aspartic acid and the like.

Further, the compound represented by the general formula (I) and the acid addition salt thereof of the present invention include a hydrate and a solvate with a pharmaceutically acceptable solvent such as ethanol.

The compound represented by the general formula (I) of the present invention may have an asymmetric carbon atom depending on the kind of the substituent A or R ¹ , in which case the configuration is not limited. , (R) arrangement, (S) arrangement or (R),
It may be any of the mixtures in the (S) configuration.

The compound of the general formula (I) of the present invention was tested by Shinichiro Kitada et al. (J. Smooth Muscl).
e Res. , 27 (4), 254 (1991)), in vivo using a rat.
In the study, the compound showed an excellent inhibitory activity of inhibiting the increase in urethral pressure caused by phenylephrine (30 μg / kg) -induced contraction of the urethra by 50% at a dose of about 1 to 150 μg / kg, and was useful as a therapeutic agent for dysuria. is there.

Further, in a blood pressure measurement test which is usually performed in rats in which a test compound is intravenously administered through a femoral vein, the compound of the general formula (I) of the present invention is about 6 to 1500 μg / kg. It is a compound that exhibits a% blood pressure lowering effect and is also useful as an antihypertensive agent.

When the compound of the above-mentioned general formula (I) of the present invention and a salt thereof are used for actual treatment, suitable pharmaceutical compositions such as tablets, powders, granules, capsules,
It is orally or parenterally administered as an injection. These pharmaceutical compositions can be prepared by a pharmaceutical method performed in a general preparation.

The dose is appropriately determined according to the sex, age, weight, degree of symptoms, etc. of the subject patient.
In the case of oral administration, the average adult dose is 0.5 to 500 m per day.
g, In the case of parenteral administration, it is about
It is administered within the range of 100 mg.

[0055]

BEST MODE FOR CARRYING OUT THE INVENTION The contents of the present invention will be described in more detail with reference to the following reference examples, examples and test examples. However, this shows an embodiment, and the present invention is not limited to this. The melting points and boiling points of the compounds in Reference Examples are all uncorrected.

[0056]

【Example】

Reference Example 1 1-Acetyl-5- (2-aminopropyl) indoline-7-carbonitrile 1,2-dichloroethane 500 m
To a liquid obtained by suspending 200 g of aluminum chloride in 1 was added 140.3 g of 2-bromopropionyl bromide with stirring at 0 ° C., and the mixture was stirred for 30 minutes. The reaction solution was stirred at 0 ° C. 1-
80 g of acetylindoline and 5 of 1,2-dichloroethane
The solution dissolved in 00 ml was added dropwise over 1 hour, and the mixture was stirred at room temperature for 3 hours. Pour the reaction mixture into 2000 ml of ice water, and
After stirring for 0 minutes, the organic layer was separated. Water layer is methylene chloride 50
After extracting twice with 0 ml, combine with the previous organic layer and 2N hydrochloric acid 50
The extract was washed twice with 0 ml, twice with 500 ml of water, twice with 500 ml of a saturated aqueous sodium hydrogen carbonate solution, once with 500 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 250 ml of ethyl acetate was added to the residual crystals to finely crystallize, 250 ml of hexane was added, the crystals were collected by filtration and dried, and 1-acetyl-5 having a melting point of 140 to 142 ° C.
13-1.7 g of-(2-bromopropionyl) indoline
I got

[0057]

N, N-dimethylformamide 1700 m
1-acetyl-5- (2-bromopropionyl) indoline (260 g) and potassium phthalimide (163 g) were added to 1 and reacted at 100 ° C. for 40 minutes under stirring. The reaction solution was poured into water (5000 ml), and the precipitated white crystals were collected by filtration, washed with water (1000 ml) and dried to give a melting point of 207 to 210.
273.6 g of 1-acetyl-5- (2-phthalimidopropionyl) indoline having a temperature of ℃ were obtained.

[0059]

1-Acetyl-5- (2-phthalimidopropionyl) indoline 2 was added to 818 g of trifluoroacetic acid.
To a solution prepared by dissolving 60 g, 192 g of triethylsilane was added with stirring under ice cooling. The mixture was stirred at 50 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ice water.
It was poured into 00 ml with stirring, and 250 ml of ethyl acetate was further added. When 1000 ml of hexane was further added, white turbidity began and crystals were deposited. After stirring this mixture for 20 minutes, the crystals were collected by filtration, washed with 500 ml of hexane, and dried under reduced pressure to give 1-acetyl-5-5 having a melting point of 204 to 207 ° C.
(2-phthalimidopropyl) indoline 229.7 g
I got

[0061]

N, N-dimethylformamide 3100 m
l-acetyl-5- (2-phthalimidopropyl)
After suspending 218 g of indoline, 145.0 g of N-bromosuccinimide was added and the mixture was reacted at 50 ° C. for 1 hour with stirring. Sodium sulfite heptahydrate 5 under stirring in the reaction solution
A solution of 5.5 g of water in 560 ml was added. This mixture was slowly poured into 4000 ml of ice water with stirring, the precipitated white crystals were collected by filtration, washed twice with 1000 ml of water, and then dried under reduced pressure to give 1-acetyl-7-bromo-5- (melting point 178-182 ° C. 2-phthalimidopropyl) indoline 22
8.7 g were obtained.

[0063]

N, N-dimethylformamide 1200 m
After suspending 215 g of 1-acetyl-7-bromo-5- (2-phthalimidopropyl) indoline in 1 l, 49.6 g of copper cyanide was added and the mixture was reacted at 70 ° C. for 40 minutes with stirring. The reaction solution was 28% ammonium hydroxide 177 g, 2
The mixture was poured into a mixed solution of 8800 ml of 9% ammonium chloride aqueous solution and 2000 ml of methylene chloride under stirring, and vigorously stirred for 4 hours, then the insoluble matter was filtered off and the organic layer was separated. The obtained organic layer was washed with 500 ml of saturated saline, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. After adding 300 ml of ethyl acetate to the residual crystals and stirring, 250 ml of hexane was added and the crystals were collected by filtration, then 300 ml of methanol
It was washed with water and dried under reduced pressure to obtain 127.8 g of 1-acetyl-5- (2-phthalimidopropyl) indoline-7-carbonitrile having a melting point of 207 to 209 ° C.

[0065]

1-Acetyl-5 in 630 ml of methanol
After suspending 50.0 g of-(2-phthalimidopropyl) indoline-7-carbonitrile, 20.1 g of hydrazine monohydrate was added. This mixture was heated under reflux for 3 hours with stirring, cooled, 500 ml of 2-propanol was added, and the precipitated crystals were filtered off using Celite. The crystals were washed twice with 500 ml of 2-propanol, the filtrates were combined and concentrated under reduced pressure. To the residue was added 2-propanol (300 ml), the insoluble matter was filtered off using Celite, the insoluble matter was washed with 300 ml of 2-propanol, and the filtrates were combined and concentrated under reduced pressure. Then, 300 ml of methylene chloride was added to the residue, the insoluble matter was filtered off using Celite, and the insoluble matter was washed with 100 ml of methylene chloride. The filtrates were combined and concentrated under reduced pressure, 300 ml of toluene was further added to the residue, and the mixture was concentrated to dryness under reduced pressure. The residue was dried at room temperature under reduced pressure for 15 hours to obtain 32.4 g of 1-acetyl-5- (2-aminopropyl) indoline-7-carbonitrile having a melting point of 94 to 96 ° C.

[0067]

Reference Example 2 Chloroacetyl chloride was used in place of 2-bromopropionyl bromide and treated in the same manner as in Reference Example 1 to obtain the following compound.

[0069]

By using 3-chloropropionyl chloride instead of 2-bromopropionyl bromide and treating in substantially the same manner as in Reference Example 1, the following compound was obtained.

[0071]

Reference Example 3 The following compound was obtained by using 1-acetyl-5-phthalimidomethylindoline as a starting material and performing the reaction steps after bromination in the same manner as in Reference Example 1.

Reference Example 4 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl methanesulfonate 93.1 g of 2-methoxyphenol, 1,1,1-trifluoro-2-iodoethane 105. 0 g and potassium carbonate 103.6 g were added to N, N-dimethylformamide 10
It was added to 00 ml, and reacted for 22 hours under stirring at 130 ° C. 1000 ml of water was added to the reaction solution under stirring at room temperature, and the mixture was extracted 3 times with 1000 ml of toluene. The organic layer was washed twice with 500 ml of a 2N aqueous sodium hydroxide solution and twice with 500 ml of water, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was distilled under reduced pressure to give a boiling point of 89-93.
C / 13 mmHg, pale yellow 1-methoxy-2- (2,
82.7 g of 2-2-trifluoroethoxy) benzene was obtained.

[0074]

112 g of 1-methoxy-2- (2,2,2-trifluoroethoxy) benzene was added to 23 methylene chloride.
It was dissolved in 0 ml, and a mixture of 62 ml of boron tribromide and 110 ml of methylene chloride was added dropwise over 2 hours with stirring under ice cooling.
Allowed to react for hours. The reaction solution was slowly poured into 1000 ml of ice water, neutralized with about 160 g of sodium hydrogencarbonate, insoluble matter was removed by filtration, and the filtrate was extracted 3 times with 1000 ml of ethyl acetate.
It was washed twice with 500 ml of water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the melting point was 49 to 50 ° C.
(2,2,2-trifluoroethoxy) phenol 10
0.5 g was obtained.

[0076]

To a solution prepared by dissolving 100.5 g of 2- (2,2,2-trifluoroethoxy) phenol in 210 ml of ethanol was added 188 g of potassium carbonate and 55 ml of 2-chloroethanol while stirring at room temperature. This mixture was reacted at 50 ° C. for 19 hours with stirring. 1000 ml of water was added to the reaction solution with stirring at room temperature, and the mixture was extracted twice with 1000 ml of ethyl acetate. The organic layer was washed twice with 500 ml of water and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue is distilled under reduced pressure to give a boiling point of 85 to 87 ° C / 0.1 mmH.
Thus, 115 g of colorless 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethanol was obtained.

[0078]

To a solution prepared by dissolving 115 g of 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethanol in 440 ml of methylene chloride, 74.6 ml of triethylamine was added with stirring under ice cooling, and then 39.39 of methanesulfonyl chloride was added. 30 ml of 6 ml methylene chloride 50 ml solution
It dripped over minutes. The reaction solution was stirred at room temperature for 2 hours, 300 ml of methylene chloride and 1000 ml of water were added, and the organic layer was separated. The organic layer was washed successively with 200 ml of 1N hydrochloric acid, 200 ml of saturated aqueous sodium hydrogen carbonate solution and 200 ml of water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 500 ml of hexane was added to the residue for crystallization, and methanesulfonic acid 2- [2- (2,2,2-trifluoroethoxy) having a melting point of 40.5 to 42.0 ° C was crystallized. 145 g of phenoxy] ethyl were obtained.

[0080]

Reference Example 5 1-Acetyl-5- [2-[[2- [2- (2,2,2
-Trifluoroethoxy) phenoxy] ethyl] amino] propyl] indoline-7-carbonitrile 1-acetyl-5- (2-aminopropyl) indoline-7-
Carbonitrile 18.85 g and methanesulfonic acid 2-
24.34 g of [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl was dissolved in 155 ml of ethanol, 7.81 g of sodium hydrogencarbonate was added, and the mixture was heated under reflux for 24 hours. Water (1 L) was added to the reaction mixture, the mixture was extracted with diethyl ether, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (eluting solvent: chloroform / methanol = 10/1) to give a 1-melting point of 64-65 ° C.
Acetyl-5- [2-[[2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl] amino] propyl] indoline-7-carbonitrile 23.48 g
I got

[0082]

Reference Example 6 In the same manner as in Reference Example 5, the compounds shown in the following table were produced.

[0084]

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[0085]

[Table 1]

[0086]

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[0087]

[Table 2]

Reference Example 7 (-)-(R) -1-acetyl-5- [2-[[2-
[2- (2,2,2-trifluoroethoxy) phenoxy] ethyl] amino] propyl] indoline-7-carbonitrile (±) -1-acetyl-5- [2-[[2- [2-
4.46 g of (2,2,2-trifluoroethoxy) phenoxy] ethyl] amino] propyl] indoline-7-carbonitrile was dissolved in 20 ml of ethanol, and (+)
-1.52 g of mandelic acid was added and the mixture was allowed to stand at room temperature, and the precipitated crystals were collected by filtration. The crystals obtained were methanol-ethanol (35 ml / 35 ml), methanol-ethanol (2
(-)-(R)-
1-acetyl-5- [2-[[2- [2- (2,2,2
740 mg of the salt of -trifluoroethoxy) phenoxy] ethyl] amino] propyl] indoline-7-carbonitrile and (+)-mandelic acid were obtained. This salt
50 ml of ethyl acetate and 50% aqueous solution of sodium carbonate 50
It was added to the mixed solution of ml and reacted at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate, washed with 10% aqueous sodium carbonate solution and water, and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the melting point was 57 to 59 ° C. (−) −
(R) -1-acetyl-5- [2-[[2- [2-
494 mg of (2,2,2-trifluoroethoxy) phenoxy] ethyl] amino] propyl] indoline-7-carbonitrile was obtained.

[0089]

The NMR of this product was completely consistent with that of the compound obtained in Reference Example 5.

Reference Example 8 (+)-(S) -1-acetyl-5- [2-[[2-
[2- (2,2,2-trifluoroethoxy) phenoxy] ethyl] amino] propyl] indoline-7-carbonitrile (±) -1-acetyl-5- [2-[[2- [2-
From (2,2,2-trifluoroethoxy) phenoxy] ethyl] amino] propyl] indoline-7-carbonitrile (3.86 g) and (−)-mandelic acid (1.27 g),
(+)-With a melting point of 57-59 ° C as in Reference Example 7.
(S) -1-acetyl-5- [2-[[2- [2-
681 mg of (2,2,2-trifluoroethoxy) phenoxy] ethyl] amino] propyl] indoline-7-carbonitrile was obtained.

[0092]

The NMR spectrum of this product was completely identical to that of the compound obtained in Reference Example 5.

Reference Example 9 1-Acetyl-5- [2- [N-tert-butoxycarbonyl-N- [2- (2-ethoxyphenoxy) ethyl] amino] propyl] indoline-7-carbonitrile 1-acetyl- 5- [2-[[2- (2-ethoxyphenoxy) ethyl] amino] propyl] indoline-7-
200 mg of carbonitrile was dissolved in 2 ml of dry methylene chloride, 160 mg of di-tert-butyl dicarbonate was added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (eluting solvent: chloroform / ethyl acetate = 4/1) to give oily 1-acetyl-5- [2- [N-tert.
-Butoxycarbonyl-N- [2- (2-ethoxyphenoxy) ethyl] amino] propyl] indoline-7-
167 mg of carbonitrile was obtained.

[0095]

Reference Example 10 In the same manner as in Reference Example 9, the compounds shown in the following table were produced.

[0097]

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[0098]

[Table 3]

Reference Example 11 5- [2- [N-tert-butoxycarbonyl-N-
[2- (2-Ethoxyphenoxy) ethyl] amino] propyl] indoline-7-carbonitrile 1-acetyl-5- [2- [N-tert-butoxycarbonyl-N- [2- (2-ethoxyphenoxy) ethyl] ] Amino] propyl] indoline-7-carbonitrile 167 mg is dissolved in ethanol 2.2 ml, 5N sodium hydroxide aqueous solution 1.1 ml is added, and it is 2.5 at room temperature.
Allowed to react for hours. After acetic acid was added to the reaction solution for neutralization, it was extracted with methylene chloride, washed with water and a saturated aqueous solution of sodium hydrogen carbonate, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and oily 5- [2- [N-tert-
133 mg of butoxycarbonyl-N- [2- (2-ethoxyphenoxy) ethyl] amino] propyl] indoline-7-carbonitrile were obtained.

[0100]

Reference Example 12 In the same manner as in Reference Example 11, the compounds in the following table were produced.

[0102]

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[0103]

[Table 4]

Reference Example 13 5- [2- [N-tert-butoxycarbonyl-N-
[2- (2-Ethoxyphenoxy) ethyl] amino] propyl] indoline-7-carboxamide 5- [2- [N-tert-butoxycarbonyl-N-
[2- (2-Ethoxyphenoxy) ethyl] amino] propyl] indoline-7-carbonitrile (120 mg) was dissolved in dimethylsulfoxide (2.5 ml), 30% hydrogen peroxide solution (0.26 ml) was added, and the mixture was stirred at room temperature for 15 minutes and then treated with 5N. 0.26 ml of an aqueous sodium hydroxide solution was added, and the mixture was reacted at room temperature for 1.5 hours. Acetic acid was added to the reaction solution, diluted with water, extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give an oily 5- [2- [Nt
ert-Butoxycarbonyl-N- [2- (2-ethoxyphenoxy) ethyl] amino] propyl] indoline-7-carboxamide 127 mg was obtained.

[0105]

Reference Example 14 In the same manner as in Reference Example 13, the compounds shown in the following table were produced.

[0107]

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[0108]

[Table 5]

Reference Example 15 5- [2- [N-tert-butoxycarbonyl-N-
[2- (2-Ethoxyphenoxy) ethyl] amino] propyl] -1-butyrylindoline-7-carboxamide 5- [2- [N-tert-butoxycarbonyl-N-
[2- (2-Ethoxyphenoxy) ethyl] amino] propyl] indoline-7-carboxamide (145 mg) was dissolved in dry methylene chloride (0.5 ml) to give pyridine (0.5).
ml and butyryl chloride (47 μl) were added, and the mixture was reacted at room temperature for 1 hour. Water was added to the reaction solution, extracted with chloroform, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel medium pressure liquid column chromatography (eluting solvent: ethyl acetate) to give amorphous 5- [2- [N-tert-butoxycarbonyl-N- [2- (2-Ethoxyphenoxy) ethyl] amino] propyl] -1-butyrylindoline-7
-142 mg of carboxamide are obtained.

[0110]

Reference Example 16 5- [2- [N-tert-butoxycarbonyl-N-
Instead of [2- (2-ethoxyphenoxy) ethyl] amino] propyl] indoline-7-carboxamide,
Using the corresponding 5- [2- [N-tert-butoxycarbonyl-N- [2- (2-alkoxy) ethyl] amino] propyl] indoline-7-carboxamide in the same manner as in Reference Example 15, the compounds in the following table were obtained. Was manufactured.

[0112]

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[0113]

[Table 6]

Reference Example 17 1-Butyryl-5- [2-[[2- (2-ethoxyphenoxy) ethyl] amino] propyl] indoline-7-
Carboxamide 5- [2- [N-tert-butoxycarbonyl-N-
[2- (2-Ethoxyphenoxy) ethyl] amino] propyl] -1-butyrylindoline-7-carboxamide (142 mg) was added to a solution of methylene chloride in 3 ml of trifluoroacetic acid (320 μl) under ice-cooling stirring, and then at room temperature for 1 hour. It was made to react. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, extracted with methylene chloride, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel medium pressure liquid column chromatography (eluting solvent: chloroform / methanol = 9/1),
63 mg of oily 1-butyryl-5- [2-[[2- (2-ethoxyphenoxy) ethyl] amino] propyl] indoline-7-carboxamide was obtained.

[0115]

Reference Example 18 In the same manner as in Reference Example 17, the compounds in the following table were produced.

[0117]

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[0118]

[Table 7]

Reference Example 19 (-)-(R) -1-acetyl-5- [2-[[2-
[2- (2,2,2-trifluoroethoxy) phenoxy] ethyl] amino] propyl] indoline-7-carboxamide (-)-(R) -1-acetyl-5- [2-[[2-
[2- (2,2,2-trifluoroethoxy) phenoxy] ethyl] amino] propyl] indoline-7-carbonitrile To 4.2 ml of 2-propanol solution of 4.2 g of 2-propanol, 4.2 ml of concentrated hydrochloric acid under ice-cooling stirring. Was slowly added dropwise. The reaction mixture was stirred for 40 minutes, neutralized with saturated aqueous sodium hydrogen carbonate solution, and then extracted with methylene chloride. The organic layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the melting point was 144 to 146 ° C (-)-.
(R) -1-acetyl-5- [2-[[2- [2-
1.70 g of (2,2,2-trifluoroethoxy) phenoxy] ethyl] amino] propyl] indoline-7-carboxamide was obtained.

[0120]

Reference Example 20 In the same manner as in Reference Example 19, the compounds shown in the following table were produced.

[0122]

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[0123]

[Table 8]

[0124]

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[0125]

[Table 9]

Example 1 5,6-Dihydro-8- [2-[[2- (2-ethoxyphenoxy) ethyl] amino] propyl] -3-methylpyrrolo [3,2,1-ij] quinazoline-1- One (Compound 1) 1-Acetyl-5- [2-[[2- (2-ethoxyphenoxy) ethyl] amino] propyl] indoline-7-
300 mg of carboxamide was dissolved in 7 ml of ethanol, 60 mg of sodium hydrogen carbonate was added, and the mixture was heated under reflux for 3.5 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, the mixture was extracted with methylene chloride, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give amorphous 5,6-dihydro-8- [2-[[2- (2-ethoxyphenoxy) ethyl] amino] propyl] -3-methylpyrrolo [3,2,1-ij 262 mg of quinazolin-1-one were obtained.

[0127]

Example 2 The compounds in the following table were prepared in the same manner as in Example 1.

[0129]

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[0130]

[Table 10]

[0131]

[Table 11]

[0132]

[Table 12]

[0133]

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[0134]

[Table 13]

Test Example 1 Rat Urethral Pressure Measurement Experiment Male SD rats having a body weight of 250 to 350 g were used. Under urethane (1.5 g / kg, intraperitoneal administration) anesthesia, the animal was incised under the abdomen to expose the pubic symphysis, and the pubic symphysis was cut along the urethra. Urethra (below the prostate)
After being ligated with a thread, the prostate was peeled from the bladder neck. Cut the upper part of the bladder, and then use the Glucosefree t
A cannula filled with the yrode solution was inserted deep into the urethra so that the tip was located in the prostatic urethra, and the bladder neck was ligated to fix the cannula. Urethral pressure was measured from the other end of the cannula via a pressure transducer.
When phenylephrine (30 μg / kg) is infused through the femoral vein (infusion rate: 36 ml / h), the urethra contracts and the urethral pressure rises. The inhibitory activity against this increase was examined for the effect of the drug on the urethral pressure. The test drug was intravenously administered, and after 5 minutes, phenylephrine was infused to measure the increase in urethral pressure. Phe before drug administration
100% increase in urethral pressure due to nylephrine
The value after drug administration was expressed as a percentage and a concentration inhibition curve was drawn to obtain an ID ₅₀ value.

[0136]

[Table 14]

Test Example 2 Rat Blood Pressure Measurement Experiment Male SD rats weighing about 300 g were used. After anesthetizing the animal with urethane (1.5 g / kg, intraperitoneal administration), the common carotid artery was cannulated and blood pressure was recorded via a pressure transducer. The test drug was dissolved in physiological saline, and the dose was increased stepwise and administered intravenously through the femoral vein. Changes in mean blood pressure before and after drug administration were measured. The antihypertensive effect of a drug is ED at a dose that causes a 15% decrease.
_It was expressed as ₁₅ values.

[0138]

[Table 15]

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Motohiro Ozawa 4-28-9 Hongo, Bunkyo-ku, Tokyo Miyako Mansion Room 305 (72) Inventor Toshikazu Yazaki 5944-95 Ariake Hodaka-cho, Minami Azumi-gun, Nagano Prefecture (72) Invention Person Ryoichi Yamagishi 5003, Shimajima, Matsumoto City, Nagano Prefecture Flemish Hope A-101

Claims (1)

[Claims] 1. A compound of the general formula (In the formula, R is an alkyl group having 1 to 6 carbon atoms, and R ¹ is a hydrogen atom or an alkoxy group having 1 to 6 carbon atoms which may have one or more halogen atoms as a substituent. And A is an alkylene group having 1 to 6 carbon atoms) represented by 5,6-dihydropyrrolo [3,2,1-ij]
Quinazolin-1-one and its pharmacologically acceptable salt.