JP3331048B2 - Indole derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to indole derivatives useful as pharmaceuticals.

More specifically, the present invention has a selective urethral smooth muscle contraction inhibitory action, reduces intraurethral pressure without causing a strong blood pressure lowering action or orthostatic hypotension, and is useful as a therapeutic agent for dysuria. A general formula

[0003]

Embedded image

(Wherein R is an aliphatic acyl group, a hydroxyalkyl group, an aliphatic acyloxyalkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group or a lower group having a mono- or di-lower alkyl-substituted carbamoyl group as a substituent. The alkyl group, R ¹ and R ² are each a hydrogen atom or a lower alkyl group, provided that when R is an aliphatic acyl group, both R ¹ and R ² are hydrogen atoms, and R ³ is a substituent A lower alkyl group which may have one or more halogen atoms) or a pharmaceutically acceptable salt thereof.

[0005]

2. Description of the Related Art The indole derivative represented by the general formula (I) of the present invention is a novel compound which has not been described in the literature. Such a compound has an inhibitory effect on urethral smooth muscle contraction and an effect on lowering urethral pressure. Has not been reported at all. Also, prazosin hydrochloride (1- (4-amino-6,7-dimethoxy-2-quinazolinyl) hydrochloride-4- (2-furoyl) piperazine hydrochloride) is commercially available as a therapeutic agent for dysuria having a urethral pressure lowering effect. Since prazosin hydrochloride also has a blood pressure lowering effect at the same time, for example, side effects of causing orthostatic hypotension and the like have been reported, and there are problems in use such that patients, especially elderly people, need to take cautiously. Has been pointed out.

[0006] As described above, the therapeutic agent for dysuria, which has a main effect of lowering the intraurethral pressure, has a strong blood pressure lowering effect as a side effect. Therefore, it selectively suppresses the contraction of urethral smooth muscle, and has a strong blood pressure lowering effect or standing. There is a strong demand for the development of a new type of therapeutic agent for dysuria that does not cause inflammatory hypotension.

[0007]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a selective urethral smooth muscle contraction inhibitory effect, a small effect on blood pressure, and a strong hypotensive effect or orthostatic hypotension. It is an object of the present invention to provide a novel indole derivative which is useful as a therapeutic agent for dysuria.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies to find a compound which has a selective urethral smooth muscle contraction inhibitory action and is useful as a therapeutic agent for dysuria. It has been found that a certain kind of indole derivative exerts a strong intraurethral pressure lowering effect and furthermore, the blood pressure lowering effect is alleviated, which has led to the present invention.

Here, in the compound represented by the general formula (I) of the present invention, lower alkyl means straight-chain or branched alkyl having 1 to 6 carbon atoms, hydroxyalkyl has a hydroxyl group, However, the hydroxyl group is a straight-chain or branched alkyl having 2 to 6 carbon atoms located at a position other than the α-position,
Lower alkoxy refers to straight-chain and branched alkoxy having 1 to 6 carbon atoms, and aliphatic acyl refers to straight-chain and branched alkyl carboxylic acids having 2 to 7 carbon atoms or 3 to 7 carbon atoms. Linear or branched alkenyl carboxylic acid acyl having the formula: aliphatic acyloxyalkyl has a hydroxyl group substituted by the aliphatic acyl group, provided that the aliphatic acyloxy group is located at a position other than the α-position. Means alkylcarbonyloxyalkyl having 4 to 13 carbon atoms. Further, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom, and the like.

The indole derivative represented by the general formula (I) of the present invention is a novel compound and can be produced as follows.

That is, among the compounds represented by the general formula (I) of the present invention,

[0012]

Embedded image

(Wherein R ⁵ is a hydroxyalkyl group, an aliphatic acyloxyalkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group or a lower alkyl group having a mono- or di-lower alkyl-substituted carbamoyl group as a substituent. , R ¹ , R ² and R ³ have the same meanings as described above);

[0014]

Embedded image

(Wherein R ⁶ is a hydroxyalkyl group, an aliphatic acyloxyalkyl group protected with a protecting group, a lower alkyl group having a lower alkoxy group, a carboxy group, or a lower alkoxycarbonyl group as a substituent, Boc
Is a tert-butoxycarbonyl group, and R ¹ , R ² and R ³ have the same meaning as described above.

NHR ⁷ R ⁸ (III)

(Wherein R ⁷ is a hydrogen atom or a lower alkyl group, and R ⁸ is a lower alkyl group), followed by amidation by reacting with amines.
By removing the hydroxyl-protecting group or hydrolyzing the compound according to a conventional method, the Boc group of the compound obtained with a reagent such as trifluoroacetic acid or concentrated hydrochloric acid is removed to obtain a compound represented by the general formula:

[0018]

Embedded image

(R ¹ , R ² , R ³ and R ⁵ in the formula have the same meanings as described above), and further treated with palladium carbon in the presence of ammonium formate. Can be manufactured.

Among the compounds represented by the general formula (I) of the present invention,

[0021]

Embedded image

(Wherein R ⁹ is an aliphatic acyl group and R ³ has the same meaning as described above).

[0023]

Embedded image

(Wherein R ³ , R ⁹ and Boc have the same meanings as described above), and can be produced by treating the compound with concentrated hydrochloric acid.

The compound represented by the general formula (II) used in the above production method is represented by the general formula:

[0026]

Embedded image

Wherein R ¹ , R ² , R ³ and Boc have the same meanings as described above, and a compound of the general formula

R ¹⁰ -A (VII)

(Wherein R ¹⁰ is a hydroxyalkyl group, an aliphatic acyloxyalkyl group, a lower alkyl group having a lower alkoxy group or a lower alkoxycarbonyl group as a substituent, A is a halogen atom,
4-nitrobenzenesulfonyloxy group or methanesulfonyloxy group), and if necessary, remove the protecting group of the hydroxyl group according to a conventional method or hydrolyze according to a conventional method. O if necessary
-It can be produced by acylation.

Among the compounds represented by the above general formula (VI) used in the above production method,

[0031]

Embedded image

Wherein R ³ , R ⁷ , R ⁸ and Boc have the same meaning as described above,

[0033]

Embedded image

(Wherein R ³ and Boc have the same meanings as described above);

R ⁹ —OH (VIII)

(Wherein R ⁹ has the same meaning as described above) or a reactive functional derivative thereof, if necessary, with 1,3-dicyclohexylcarbodiimide, 1,1'- Reaction in the presence of a condensing agent such as carbonyldiimidazole, phosphorus oxychloride or phosphorus trichloride,
General formula

[0037]

Embedded image

(Wherein R ³ , R ⁹ and Boc have the same meanings as described above), and after treatment with concentrated hydrochloric acid, an amine represented by the general formula (III) And 1,3-dicyclohexylcarbodiimide, 1,1′-
The reaction is carried out in the presence of a condensing agent such as carbonyldiimidazole, phosphorus oxychloride or phosphorus trichloride;

[0039]

Embedded image

(Wherein R ³ , R ⁷ and R ⁸ have the same meanings as described above), and the obtained compound is subjected to Boc conversion using a Boc-forming reagent according to a conventional method. It can be manufactured by forming

In the above-mentioned production method, examples of the reactive functional derivative of carboxylic acid include acid halide, acid anhydride, mixed acid anhydride, active ester, active amide and the like.

Among the compounds represented by the above general formula (VI) used in the above production method,

[0043]

Embedded image

(Wherein R ³ , R ⁸ and Boc have the same meanings as described above) are represented by the general formula (IX)
Reacting the compound represented by in the presence of potassium carbonate,
General formula obtained by ring closure

[0045]

Embedded image

[0046] (R ¹¹ in the formula represents a lower alkyl group, R ³
And Boc have the same meanings as described above),

R ⁸ -X (XII)

(Wherein X is a bromine atom or iodine atom, and R ⁸ has the same meaning as described above), and then, for example, a benzyltrimethylammonium hydroxide methanol solution ( 40%) and treated with a general formula

[0049]

Embedded image

(Wherein R ³ , R ⁸ , R ⁹ and Boc have the same meanings as described above), followed by treatment with caustic soda and the like to deacylate the compound. it can.

The compound represented by the general formula (V) used in the above production method is obtained by treating the compound represented by the general formula (VIb) with palladium carbon in the presence of ammonium formate. , General formula

[0052]

Embedded image

(Wherein R ³ and Boc have the same meanings as described above) by the above-mentioned general formula (VIII)
With a carboxylic acid or a reactive functional derivative thereof, if necessary, in the presence of a condensing agent such as 1,3-dicyclohexylcarbodiimide, 1,1′-carbonyldiimidazole, phosphorus oxychloride or phosphorus trichloride. It can be produced by performing the following reaction. The compound represented by the general formula (VIb) used in the above production method has a general formula

[0054]

Embedded image

The compound represented by the formula (R ³ has the same meaning as described above) can be converted to B
general formula obtained by oc

[0056]

Embedded image

After obtaining a compound represented by the formula (R ³ and Boc have the same meanings as described above), the compound is treated with caustic soda or the like and deacetylated to obtain a compound represented by the general formula

[0058]

Embedded image

(Wherein R ³ and Boc have the same meanings as described above), and then can be produced by treating with hydrogen peroxide in the presence of sodium hydroxide.

The compound represented by the general formula (XV) used in the above production method is represented by the formula

[0061]

Embedded image

After reacting the compound represented by the formula (II) with 2-bromopropionic halide in the presence of a Lewis acid or under the same conditions as described above, the compound is reacted with bromide such as pyrrolidone trihydrobromide. By brominating with an agent, the formula

[0063]

Embedded image

The compound represented by the formula is reacted with potassium phthalimide to obtain a compound represented by the formula

[0065]

Embedded image

By reducing with a reducing agent such as triethylsilane, the compound represented by the formula

[0067]

Embedded image

After conversion into the compound represented by the formula, bromination with a brominating agent such as N-bromosuccinimide

[0069]

Embedded image

A compound represented by the following formula was obtained, and a reaction was carried out using copper cyanide.

[0071]

Embedded image

After obtaining the compound represented by the formula, the compound is treated with hydrazine monohydrate to give a compound of the formula

[0073]

Embedded image

And then converted to a compound of the general formula

[0075]

Embedded image

(Wherein R ³ has the same meaning as described above).

The above general formulas (III), (VII), (VIII) and (XII) used in the above production method
The compounds represented by (XVIII) and (XVIII) can be obtained as commercial products or can be produced by known methods.

The compound represented by the general formula (XXV) used in the above production method may be obtained by decomposing a commercially available product or a corresponding methyl ether derivative with, for example, boron tribromide.

[0079]

Embedded image

A compound represented by the formula (R ³ has the same meaning as described above) is reacted with 2-chloroethanol or 2-bromoethanol to give a compound of the general formula

[0081]

Embedded image

(Wherein R ³ has the same meaning as described above), followed by reaction with methanesulfonyl chloride.

The compound represented by the above general formula (I) of the present invention can be obtained by the test described by Shinichiro Kitada et al. (J. Smooth Muscle Res., 2).
7 (4), 254 (1991)), in an in vivo test using rats, approximately 0.9 to 5 μg / kg
At a dose of phenylephrine (30 μg / kg), it exhibited an activity to inhibit the increase in intraurethral pressure resulting from urethral contraction by 50%. For example, (R) -1- (3-hydroxypropyl)
-5- [2- [2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indole-7-carboxamide at 1.8 μg / kg and 5- [7
-Carbamoyl-5- [2- [2- (2-isopropoxyphenoxy) ethylamino] propyl] indole-
Ethyl 1-yl] pentanoate is 1.4 μg / kg and 4- [5
Ethyl [-[2- [2- (2-butoxyphenoxy) ethylamino] propyl] -7- (N-methylcarbamoyl) indol-1-yl] butyrate at 3.5 μg / kg
[5- [2- [2- (2-isopropoxyphenoxy)
Ethylamino] propyl] -7- (N-methylcarbamoyl) indol-1-yl] butyrate is 1.4 μg / kg
To give 4- [7-carbamoyl-5- [2- [2- (2-
Isopropoxyphenoxy) ethylamino] propyl]
Indole-1-yl] ethyl butyrate is 0.97 μg / kg,
(R) -4- [7- (N, N-dimethylcarbamoyl)
Ethyl-5- [2- [2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indol-1-yl] butyrate at 1.2 μg / kg respectively
It showed 50% inhibitory activity. Similarly, a test was performed on prazosin hydrochloride, which is currently used for the treatment of dysuria, and a similar effect was confirmed at 4.0 μg / kg.

In an in vivo blood pressure measurement test usually performed on rats to which a test compound was intravenously administered through the femoral vein, prazosin hydrochloride showed a 10% blood pressure lowering effect at about 2 μg / kg, whereas the present invention Is about 5 to 11
At 0 μg / kg, a 10% blood pressure lowering effect was exhibited. For example, (R)
-1- (3-hydroxypropyl) -5- [2- [2-
[2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indole-7-carboxamide is about 18 μg / kg and 5- [7-carbamoyl-5- [2- [2- (2 -Isopropoxyphenoxy)
Ethylamino [propyl] indol-1-yl] pentanoate is about 44 μg / kg, and 4- [5- [2-
[2- (2-Butoxyphenoxy) ethylamino] propyl] -7- (N-methylcarbamoyl) indole-
Ethyl 1-yl] butyrate is about 109 μg / kg and 4- [5
Ethyl [-[2- [2- (2-isopropoxyphenoxy) ethylamino] propyl] -7- (N-methylcarbamoyl) indol-1-yl] butyrate is about 45 μg / kg and 4- [7-carbamoyl- 5- [2- [2- (2
Ethyl-isopropoxyphenoxy) ethylamino] propyl] indol-1-yl] butyrate is about 20 μg / kg and is (R) -4- [7- (N, N-dimethylcarbamoyl) -5- [2- [2 Ethyl-[2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indol-1-yl] butyrate exhibited the same action at about 26 μg / kg. As described above, the compound of the present invention has a strong inhibitory action on urethral smooth muscle contraction and generally has a slight effect on lowering blood pressure as compared with the action of lowering intraurethral pressure, The blood pressure lowering effect at a dose that exerts an inhibitory effect is extremely moderate. For example, when compared to prazosin hydrochloride, its action on urethral smooth muscle shows several times better selectivity for blood vessels, and some compounds show excellent selectivity of 10 times to 30 times or more, It is a very useful compound as a therapeutic agent for dysuria that does not cause strong hypotension or orthostatic hypotension.

The compound represented by the above general formula (I) of the present invention has at least one asymmetric carbon, and each of the asymmetric carbons has two stereoisomers of (R) configuration and (S) configuration. Although configurations exist, any configuration of compounds may be used in the present invention, and mixtures thereof may be used.

In the compound represented by the above general formula (I) of the present invention, the corresponding optically active compound is reacted by using the optically active compound as a starting material, or is subjected to an optical resolution according to a conventional method as needed during the production process. Thereafter, the reaction can be carried out in the same manner using the obtained optically active substance, or the corresponding racemate can be optically resolved in the final step by a conventional method. For example, the compound represented by the general formula (XV) is converted into a compound according to a conventional method, for example, using (-) or (+)-
The optically active substance is separated by optical resolution using mandelic acid or the like, and then reacted in the same manner using the obtained optically active substance, whereby the compound represented by the general formula (I) of the present invention is obtained. Optically active form of the compound can be produced.

Among the compounds represented by the above general formula (I) of the present invention, those having an unsaturated bond have geometrical isomers of E and Z. Is also good.

Among the compounds represented by the above general formula (I) of the present invention, compounds having a moderate blood pressure lowering action as compared with an intraurethral pressure lowering action, that is, compounds having high selectivity for urethral smooth muscle are preferred.

As the substituents possessed by the compound of the present invention, the substituent R is an aliphatic acyl group, a hydroxyalkyl group, a lower alkoxy group, a mono-lower alkyl-substituted carbamoyl group or a lower alkyl group having a lower alkoxycarbonyl group as a substituent. preferably, an ethyl group in the substituent R ^3, a propyl group, an isopropyl group, a butyl group,
An alkyl group having 2 to 4 carbon atoms which may have one or more halogen atoms, such as a 2,2,2-trifluoroethyl group, is preferred. Specifically, 1- (3-hydroxypropyl) ) -5- [2- [2- [2- (2,2,2
-Trifluoroethoxy) phenoxy] ethylamino]
Propyl] indole-7-carboxamide, 5- [7
-Carbamoyl-5- [2- [2- (2-isopropoxyphenoxy) ethylamino] propyl] indole-
Ethyl 1-yl] pentanoate, 4- [5- [2- [2-
(2-butoxyphenoxy) ethylamino] propyl]
Ethyl -7- (N-methylcarbamoyl) indol-1-yl] butyrate, 4- [5- [2- [2- (2-isopropoxyphenoxy) ethylamino] propyl] -7-
Ethyl (N-methylcarbamoyl) indol-1-yl] butyrate, 4- [7-carbamoyl-5- [2- [2-
Ethyl (2-isopropoxyphenoxy) ethylamino] propyl] indol-1-yl] butyrate, 4- [7-
(N, N-dimethylcarbamoyl) -5- [2- [2-
[2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indol-1-yl]
Ethyl butyrate, ethyl 4- [5- [2- [2- (2-ethoxyphenoxy) ethylamino] propyl] -7- (N-methylcarbamoyl) indol-1-yl] butyrate,
1- (3-hydroxypropyl) -N, N-dimethyl-
5- [2- [2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] -7-
Indolecarboxamide, 4- [7-carbamoyl-
5- [2- [2- (2-isopropoxyphenoxy) ethylamino] propyl] indol-1-yl] -N-
Methylbutyric amide, 5- [2- [2- (2-ethoxyphenoxy) ethylamino] propyl] -1- (2-methoxyethyl) indole-7-carboxamide, 1-butyryl-5- [2- [2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indole-7-carboxamide and the like.

Further, a compound in which the substituent R is a 3-ethoxycarbonylpropyl group, a 4-ethoxycarbonylbutyl group or a 3-hydroxypropyl group is particularly preferred. As such a compound, for example, 1- (3-hydroxypropyl) Propyl) -5- [2- [2- [2- (2,
2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indole-7-carboxamide, 5
Ethyl- [7-carbamoyl-5- [2- [2- (2-isopropoxyphenoxy) ethylamino] propyl] indol-1-yl] pentanoate, 4- [5- [2-
[2- (2-Butoxyphenoxy) ethylamino] propyl] -7- (N-methylcarbamoyl) indole-
Ethyl 1-yl] butyrate, 4- [5- [2- [2- (2-
Isopropoxyphenoxy) ethylamino] propyl]
Ethyl-7- (N-methylcarbamoyl) indol-1-yl] butyrate, 4- [7-carbamoyl-5- [2-
Ethyl [2- (2-isopropoxyphenoxy) ethylamino] propyl] indol-1-yl] butyrate, 4
-[7- (N, N-dimethylcarbamoyl) -5- [2
-[2- [2- (2,2,2-trifluoroethoxy)
Phenoxy] ethylamino] propyl] indole-1
-Yl] ethyl butyrate and the like.

The indole derivative represented by the general formula (I) of the present invention can be converted into a pharmacologically acceptable salt according to a conventional method.

As the pharmacologically acceptable salt, for example, a compound having a carboxy group is converted into a salt with an inorganic base such as sodium, potassium, calcium and the like, and a salt with an organic amine such as morpholine and piperidine. be able to. Further, the compound of the present invention can be prepared by using 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,
It can be converted to an acid addition salt with (-)-camphorsulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 1-butanesulfonic acid, fumaric acid, glutamic acid, aspartic acid and the like. These pharmacologically acceptable salts also have a selective inhibitory action on urethral smooth muscle contraction like the free form, and as a therapeutic agent for dysuria without causing a strong blood pressure lowering action or orthostatic hypotension Useful.

When the indole derivative represented by the general formula (I) of the present invention and a salt thereof are used for actual treatment,
It is administered orally or parenterally as a suitable pharmaceutical composition such as tablets, powders, granules, capsules, injections and the like. These pharmaceutical compositions can be prepared by pharmaceutical methods performed in general preparation.

The dose is appropriately determined depending on the sex, age, weight, degree of symptoms, etc. of the subject patient.
In the case of oral administration, the dose is generally in the range of 0.5 to 500 mg per adult per day, and in the case of parenteral administration, the dose is generally in the range of 0.05 to 100 mg per adult per day.

[0095]

The contents of the present invention will be described in more detail in the following Reference Examples and Examples. In addition, the melting points of the compounds in each Reference Example and Examples are all uncorrected.

Reference Example 11 1-acetyl-5- (2-aminopropyl) indoline
7-carbonitrile 1,2-dichloroethane 500 ml of aluminum chloride 200
g was suspended, and 140.3 g of 2-bromopropionyl bromide was added with stirring at 0 ° C., followed by stirring for 30 minutes. 80 g of 1-acetylindoline was added to this reaction solution while stirring at 0 ° C.
-A solution dissolved in 500 ml of dichloroethane was added dropwise over 1 hour, followed by stirring at room temperature for 3 hours. 2000 ml of ice water
The mixture was stirred for 30 minutes and the organic layer was separated. Extract the aqueous layer twice with 500 ml of methylene chloride, combine with the previous organic layer and add 2N hydrochloric acid
The mixture was washed twice with 500 ml, twice with 500 ml of water, twice with 500 ml of a saturated aqueous solution of sodium hydrogen carbonate, and 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 remaining crystals to make the crystals fine, 250 ml of hexane was added, and the mixture was collected by filtration and dried.
131.7 g of 1-acetyl-5- (2-bromopropionyl) indoline at 40 DEG-142 DEG C. was obtained.

IR (KBr): νC = O 1675, 1660 cm ^-1 NMR (CDCl ₃ ) δ: 1.89 (3H, d, J = 6.4 Hz), 2.27 (3H, s), 3.26 (2H, t,
J = 8.4Hz), 4.14 (2H, t, J = 8.4Hz), 5.27 (1H, q, J = 6.4H
z), 7.87 (1H, s), 7.89 (1H, d, J = 8.4Hz), 8.26 (1H, d,
J = 8.4Hz)

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

IR (KBr): νC = O 1778, 1708, 1666 cm
^-1 NMR (CDCl ₃ ) δ: 1.71 (3H, d, J = 7.1Hz), 2.21 (3H, s), 3.15 -3.25
(2H, m), 4.07 (2H, t, J = 8.5Hz), 5.61 (2H, q, J = 7.1H
z), 7.63 (1H, d, J = 8.7Hz), 7.65-7.70 (2H, m), 7.75-
7.85 (2H, m), 8.13 (1H, d, J = 8.7Hz)

1-acetyl- was added to 818 g of trifluoroacetic acid.
5- (2-phthalimidopropionyl) indoline 260
g in a solution of ice-cooled triethylsilane 192
g was added. The mixture was stirred at 50 ° C. for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was poured into 1500 ml of ice water with stirring, and 250 ml of ethyl acetate was further added. When hexane (1000 ml) was further added, the mixture began to become cloudy and crystals precipitated. After stirring this mixture for 20 minutes, the crystals were collected by filtration, washed with 500 ml of hexane, and dried under reduced pressure, melting point 204-207 ° C.
229.7 g of 1-acetyl-5- (2-phthalimidopropyl) indoline was obtained.

IR (KBr): νC = O 1708, 1659 cm ^-1 NMR (CDCl ₃ ) δ: 1.51 (3H, d, J = 6.9 Hz), 2.17 (3H, s), 2.90-3.20 (3
H, m), 3.29 (1H, dd, J = 13.8, 9.4Hz), 3.99 (2H, t, J =
8.4Hz), 4.50-4.70 (1H, m), 6.96 (1H, d, J = 8.4Hz), 7.
02 (1H, s), 7.60-7.85 (4H, m), 8.00 (1H, d, J = 7.9Hz)

After 218 g of 1-acetyl-5- (2-phthalimidopropyl) indoline was suspended in 3100 ml of N, N-dimethylformamide, 145.0 g of N-bromosuccinimide was added, and the mixture was reacted at 50 ° C. for 1 hour with stirring. Was. The reaction solution was stirred with sodium sulfite heptahydrate 55.5 g water 560 ml
The solution was added. The mixture was slowly poured into 4000 ml of ice water with stirring, and the precipitated white crystals were collected by filtration, washed twice with 1000 ml of water, dried under reduced pressure, and dried under reduced pressure of 1-acetyl-7-bromo-5- (178-182 ° C). 2-phthalimidopropyl)
228.7 g of indoline were obtained.

IR (KBr): νC = O 1701, 1673 cm ^-1 NMR (CDCl ₃ ) δ: 1.51 (3H, d, J = 6.9 Hz), 2.23 (3H, s), 2.90-3.00 (2
H, m), 3.05 (1H, dd, J = 13.9, 7.1Hz), 3.26 (1H, dd, J =
13.9, 8.9Hz), 4.10 (2H, t, J = 7.5Hz), 4.55-4.65 (1H,
m), 7.04 (1H, s), 7.21 (1H, s), 7.65-7.85 (4H, m)

After suspending 215 g of 1-acetyl-7-bromo-5- (2-phthalimidopropyl) indoline in 1200 ml of N, N-dimethylformamide, copper cyanide 4
9.6 g was added and reacted at 70 ° C. for 40 minutes with stirring. Reaction solution
The mixture was poured into a mixture of 177 g of 28% ammonium hydroxide, 8800 ml of a 29% aqueous ammonium chloride solution and 2000 ml of methylene chloride with stirring. After stirring vigorously for 4 hours, insolubles were removed by filtration and the organic layer was separated. The obtained organic layer was washed with 500 ml of saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. After adding 300 ml of ethyl acetate to the remaining crystals and stirring, 250 ml of hexane was added and the crystals were collected by filtration.
Wash with 300 ml and dry under reduced pressure, 1-mp with a melting point of 207-209 ° C.
127.8 g of acetyl-5- (2-phthalimidopropyl) indoline-7-carbonitrile was obtained.

IR (KBr): νCN 2228 cm ^-1 νC = O 1707, 1673 cm ^-1 NMR (CDCl ₃ ) δ: 1.52 (3H, d, J = 6.9 Hz), 2.27 (3H, s), 3.00- 3.15 (3
H, m), 3.35 (1H, dd, J = 13.9, 9.4Hz), 4.09 (2H, t, J =
8.4Hz), 4.50-4.70 (1H, m), 7.27 (1H, s), 7.28 (1H,
s), 7.65-7.85 (4H, m)

1-acetyl-5 in 630 ml of methanol
After suspending 50.0 g of (2-phthalimidopropyl) indoline-7-carbonitrile, hydrazine monohydrate 2
0.1 g was added. The mixture was heated to reflux for 3 hours with stirring,
After cooling, 500 ml of isopropanol was added, and the precipitated crystals were removed by filtration using Celite. The crystals were washed twice with 500 ml of isopropanol, and the filtrates were combined and concentrated under reduced pressure. 300 ml of isopropanol was added to the residue, the insoluble material was removed by filtration using Celite, the insoluble material was washed with 300 ml of isopropanol, and the filtrates were combined and concentrated under reduced pressure. Subsequently, 300 ml of methylene chloride was added to the residue, and the insoluble matter was removed by filtration using Celite, and the insoluble matter was washed with 100 ml of methylene chloride. The filtrates were combined and concentrated under reduced pressure. Further, 300 ml of toluene was 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, and 12.4 g of 1-acetyl-5- (2-aminopropyl) indoline-7-carbonitrile having a melting point of 94-96 ° C.
g.

IR (KBr): νNH 3375 cm ⁻¹ νCN 2220 cm ⁻¹ νC = O 1670 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.11 (3H, d, J = 6.4 Hz), 2.32 (3H, s) , 2.51 (1H, d
d, J = 13.4, 7.9Hz), 2.67 (1H, dd, J = 13.4, 5.4Hz), 3.0
5 -3.25 (3H, m), 4.15 (2H, t, J = 7.9Hz), 7.25 (1H, s),
7.30 (1H, s)

Reference Example 2 93.1 g of 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl 2-methoxyphenol, 105.0 g of 1,1,1-trifluoro-2-iodoethane, and Potassium carbonate 10
3.6 g was added to 1000 ml of N, N-dimethylformamide and reacted at 130 ° C. for 22 hours with stirring. 1000 ml of water was added to the reaction solution with stirring at room temperature, and the mixture was extracted three times with 1000 ml of toluene.
The organic layer was washed twice with 500 ml of 2N aqueous sodium hydroxide solution and
After successively washing twice with 500 ml, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was distilled under reduced pressure to give a light yellow 1-methoxy-benzene having a boiling point of 89 to 93 ° C / 13 mmHg.
2- (2,2,2-trifluoroethoxy) benzene 8
2.7 g were obtained.

NMR (CDCl ₃ ) δ: 3.86 (3H, s), 4.38 (2H, q, J = 8.4 Hz), 6.85-7.10 (4
H, m)

112 g of 1-methoxy-2- (2,2,2-trifluoroethoxy) benzene was added to 230 ml of methylene chloride.
And a mixture of boron tribromide (62 ml) and methylene chloride (110 ml) was added dropwise over 2 hours under ice-cooling with stirring, followed by a reaction for 1 hour. The reaction solution was slowly poured into 1000 ml of ice water, neutralized with about 160 g of sodium hydrogen carbonate, and the insoluble material was removed by filtration. The filtrate was extracted three times with 1000 ml of ethyl acetate, washed twice with 500 ml of water, and dried over anhydrous magnesium sulfate. did. The solvent was distilled off under reduced pressure to obtain 100.5 g of 2- (2,2,2-trifluoroethoxy) phenol having a melting point of 49 to 50 ° C.

IR (KBr): νOH 3310 cm ^-1 NMR (CDCl ₃ ) δ: 4.41 (2H, q, J = 8.1 Hz), 5.52 (1H, s), 6.80-6.90 (2
H, m), 6.95-7.00 (2H, m)

188 g of potassium carbonate and 55 ml of 2-chloroethanol were added to a solution of 100.5 g of 2- (2,2,2-trifluoroethoxy) phenol dissolved in 210 ml of ethanol while stirring at room temperature. The mixture is stirred at 50 ° C
The reaction was performed for 19 hours. 1000 ml of water was added to the reaction solution while stirring at room temperature, and the mixture was extracted twice with 1000 ml of ethyl acetate. Organic layer with water 500
After washing twice with ml, the mixture was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was distilled under reduced pressure to a boiling point of 85 to 87.
C./0.1 mmHg, 115 g of colorless 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethanol was obtained.

IR (neat): νOH 3400 cm ^-1 NMR (CDCl ₃ ) δ: 2.32 (1H, t, J = 6.4 Hz), 3.90-4.25 (4H, m), 4.39 (2
(H, q, J = 8.4Hz), 6.90-7.15 (4H, m)

115 g of 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethanol was added to methylene chloride.
To the solution dissolved in 440 ml was added 74.6 ml of triethylamine under ice-cooling and stirring, and then methanesulfonyl chloride 3
A solution of 9.6 ml of methylene chloride in 50 ml was added dropwise over 30 minutes. After stirring the reaction solution at room temperature for 2 hours, 300 ml of methylene chloride was added.
And 1000 ml of water were added, and the organic layer was separated. The organic layer was washed with 1N hydrochloric acid (200 ml) and saturated aqueous sodium hydrogen carbonate solution (200 ml).
The mixture was washed sequentially with 200 ml of water and 200 ml of water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure.
The resulting mixture was crystallized to obtain 145 g of 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl methanesulfonate having a melting point of 40.5 to 42.0 ° C.

IR (KBr): νSO ₂ 1355, 1130 cm ^-1 NMR (CDCl ₃ ) δ: 3.11 (3H, s), 4.20-4.30 (2H, m), 4.38 (2H, q, J =
8.3Hz), 4.55-4.65 (2H, m), 6.90-7.10 (4H, m)

Reference Example 3 1-acetyl-5- [2- [2- [2- (2,2,2-
18.85 g of trifluoroethoxy) phenoxy] ethylamino] propyl] indoline-7-carbonitrile 1-acetyl-5- (2-aminopropyl) indoline-7-carbonitrile 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 hydrogen carbonate was added, and the mixture was refluxed for 24 hours. After adding 1 l of water to the reaction solution and extracting with diethyl ether,
It was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel flash column chromatography (elution solvent: chloroform / methanol = 10/10).
Purified in 1), 1-acetyl-5- [2
-[2- [2- (2,2,2-trifluoroethoxy)
[Phenoxy] ethylamino] propyl] indoline-7
23.48 g of carbonitrile were obtained.

IR (KBr): νNH 2931 cm ⁻¹ νCN 2221 cm ⁻¹ νC = O 1673 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.06 (3H, d, J = 6.4 Hz), 2.31 (3H, s) , 2.56 (1H, d
d, J = 13.2, 6.9Hz), 2.75 (1H, dd, J = 13.2, 6.4Hz), 2.9
0-3.20 (5H, m), 4.00-4.20 (4H, m), 4.33 (2H, q, J = 8.4H
z), 6.80-7.20 (4H, m), 7.24 (1H, s), 7.30 (1H, s)

Reference Example 4 The compounds shown in the table were prepared in the same manner as in Reference Example 3.

[0119]

Embedded image

[0120]

[Table 1]

Reference Example 5 (R)-(-)-1-acetyl-5- [2- [2- [2
-(2,2,2-trifluoroethoxy) phenoxy]
Ethylamino] propyl] indoline-7-carbonitrile (±) -1-acetyl-5- [2- [2- [2- (2,
2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indoline-7-carbonitrile 4.4
Dissolve 6 g in ethanol 20 ml and add (+)-mandelic acid
After 1.52 g was added and left at room temperature, the precipitated crystals were collected by filtration. The obtained crystals were subjected to methanol-ethanol (35 ml / 35 ml), methanol-ethanol (28 ml / 14 ml), methanol (15 ml / 15 ml).
ml) and methanol (13 ml).
(-)-1-acetyl-5- [2- [2- [2- (2,
740 mg of a salt of (2-, 2-trifluoroethoxy) phenoxy] ethylamino] propyl] indoline-7-carbonitrile and (+)-mandelic acid were obtained. This salt was added to a mixture of 50 ml of ethyl acetate and 50 ml of a 10% aqueous solution of sodium carbonate, and reacted at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate, washed with a 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 57-59 ° C., and (R)-(−)-1-acetyl-5- [2- [2- [2- (2,2,2-trifluoroethoxy) phenoxy) was used. [Ethylamino] propyl] indoline-7-carbonitrile (494 mg) was obtained.

Specific rotation: [α] _D ²⁵ -21.3 ゜ (c = 1.0
2, MeOH)

The NMR of this product completely coincided with the compound obtained in Reference Example 3.

Reference Example 6 1-acetyl-5- [2- [N-tert-butoxycarbonyl-2- (2-ethoxyphenoxy) ethylamino] propyl] indoline-7-carbonitrile 1-acetyl-5- [2 200 mg of-[2- (2-ethoxyphenoxy) ethylamino] propyl] indoline-7-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 (elution solvent: chloroform / ethyl acetate = 4/1).
Oily 1-acetyl-5- [2- [N-tert-butoxycarbonyl-2- (2-ethoxyphenoxy) ethylamino] propyl] indoline-7-carbonitrile
167 mg were obtained.

IR (neat): νCN 2225 cm ⁻¹ νC = O 1685 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.26 (3H, d, J = 6.4 Hz), 1.43 (12H, brs), 2.31 (3
H, s), 2.65-2.75 (1H, m), 2.90-3.10 (3H, m), 3.40-3.
55 (2H, m), 3.85-4.25 (7H, m), 6.75-6.95 (4H, m), 7.15
-7.30 (2H, m)

Reference Example 7 The compounds shown in the table were prepared in the same manner as in Reference Example 6.

[0127]

Embedded image

[0128]

[Table 2]

Reference Example 8 5- [2- [N-tert-butoxycarbonyl-2-
(2-ethoxyphenoxy) ethylamino] propyl]
Indoline-7-carbonitrile 1-acetyl-5- [2- [N-tert-butoxycarbonyl-2- (2-ethoxyphenoxy) ethylamino] propyl] indoline-7-carbonitrile 167 mg
Was dissolved in 2.2 ml of ethanol, 1.1 ml of a 5N aqueous sodium hydroxide solution was added, and the mixture was reacted at room temperature for 2.5 hours. The reaction solution was neutralized by adding acetic acid, and then extracted with methylene chloride.
After washing with a saturated aqueous solution of sodium hydrogen carbonate, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give oily 5- [2- [N-tert-butoxycarbonyl-2].
133 mg of-(2-ethoxyphenoxy) ethylamino] propyl] indoline-7-carbonitrile were obtained.

IR (neat): νCN 2214 cm ^-1 νC = O 1686 cm ^-1 NMR (CDCl ₃ ) δ: 1.24 (3H, d, J = 6.6 Hz), 1.42 (12H, brs), 2.55-2 .
65 (1H, m), 2.70-2.90 (1H, m), 3.02 (2H, t, J = 8.5Hz),
3.35-3.45 (2H, m), 3.66 (2H, t, J = 8.5Hz), 3.80-4.25
(5H, m), 4.32 (1H, br s), 6.80-7.10 (6H, m)

Reference Example 9 The compounds shown in the table were prepared in the same manner as in Reference Example 8.

[0132]

Embedded image

[0133]

[Table 3]

Reference Example 10 5- [2- [N-tert-butoxycarbonyl-2-
(2-ethoxyphenoxy) ethylamino] propyl]
Indoline-7-carboxamide 5- [2- [N-tert-butoxycarbonyl-2-
(2-ethoxyphenoxy) ethylamino] propyl]
Indoline-7-carbonitrile (120 mg) was dissolved in dimethylsulfoxide (2.5 ml), 30% hydrogen peroxide solution (0.26 ml) was added, the mixture was stirred at room temperature for 15 minutes, 5N sodium hydroxide aqueous solution (0.26 ml) 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 a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain an oily 5
-[2- [N-tert-butoxycarbonyl-2-
(2-ethoxyphenoxy) ethylamino] propyl]
127 mg of indoline-7-carboxamide were obtained.

IR (neat): νC = O 1687, 1659 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.1 Hz), 1.36 (3H, s), 1.41 (9H,
s), 2.50-2.70 (1H, m), 2.80-2.90 (1H, m), 2.95-3.00 (2
H, m), 3.40-3.50 (2H, m), 3.65 (2H, t, J = 8.4Hz), 3.9
0-4.00 (1H, m), 4.05-4.15 (4H, m), 5.20-6.10 (2H, m),
6.24 (1H, br s), 6.80-7.05 (6H, m)

Reference Example 11 The compounds shown in the table were prepared in the same manner as in Reference Example 10.

[0137]

Embedded image

[0138]

[Table 4]

Reference Example 12 1-acetyl-5- [2- [N-tert-butoxycarbonyl-2- (2-ethoxyphenoxy) ethylamino] propyl] indoline-7-carboxamide 5- [2- [N-tert -Butoxycarbonyl-2-
(2-ethoxyphenoxy) ethylamino] propyl]
Indoline-7-carboxamide (50 mg) was dissolved in dry methylene chloride (1 ml), triethylamine (21 mg) and acetic anhydride (21 mg) were added, and the mixture was reacted at room temperature for 3.5 hours. Water 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 to obtain 40 mg of amorphous 1-acetyl-5- [2- [N-tert-butoxycarbonyl-2- (2-ethoxyphenoxy] ethylamino] propyl] indoline-7-carboxamide. Was.

IR (KBr): νNH 3340 cm ^-1 νC = O 1678 cm ^-1 NMR (CDCl ₃ ) δ: 1.20-1.30 (3H, m), 1.41 (12H, brs), 2.22 (3H,
s), 2.65-2.75 (1H, m), 2.90-3.10 (3H, m), 3.35-3.60
(2H, m), 3.95-4.15 (7H, m), 5.40-6.00 (2H, m), 6.85-
7.25 (6H, m)

Reference Example 13 The compound shown in the table was prepared by acylation in the same manner as in Reference Example 12.

[0142]

Embedded image

[0143]

[Table 5]

Reference Example 148- [2- [N-tert-butoxycarbonyl-2-
(2-ethoxyphenoxy) ethylamino] propyl]
-5,6-dihydro-3-methylpyrrolo [3,2,1-
ij] quinazolin-1-one 1-acetyl-5- [2- [N-tert-butoxycarbonyl-2- (2-ethoxyphenoxy) ethylamino] propyl] indoline-7-carboxamide 1.32
g in 13 ml of ethanol and 0.35 g of potassium carbonate
And reacted at 60 ° C. for 2 hours. 60 ml of water was added to the reaction solution, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the melting point was 203-20.
8- [2- [N-tert-butoxycarbonyl-2- (2-ethoxyphenoxy) ethylamino] propyl] -5,6-dihydro-3-methylpyrrolo [3.
[1,2-ij] quinazolin-1-one 1.15 g was obtained.

IR (KBr): νC = O 1694, 1623 cm ^-1 NMR (CDCl ₃ ) δ: 1.20-1.55 (15H, m), 2.47 (3H, s), 2.70-2.95 (1H,
m), 3.00-3.20 (1H, m), 3.25-3.60 (4H, m), 3.85-4.45 (7
H, m), 6.70-6.95 (4H, m), 7.20-7.80 (2H, m)

Reference Example 15 The compounds shown in the table were prepared in the same manner as in Reference Example 14.

[0147]

Embedded image

[0148]

[Table 6]

Reference Example 16 1-acetyl-5- [2- [N-tert-butoxycarbonyl-2- (2-ethoxyphenoxy) ethylamino] propyl] -N-methyl-7-indolinecarboxamide 8- [2- [N-tert-butoxycarbonyl-2-
(2-ethoxyphenoxy) ethylamino] propyl]
-5,6-dihydro-3-methylpyrrolo [3,2,1-
ij] Dissolve 1.07 g of quinazolin-1-one in 11 ml of N, N-dimethylformamide and add 0.24 ml of methyl iodide
Was added and reacted at 70 ° C. for 2 hours under an argon atmosphere. 1.72 ml of benzyltrimethylammonium methyl alcohol solution (40%) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours, added with 50 ml of water, extracted with ethyl acetate, 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 (eluent: ethyl acetate / methanol = 8/1) to obtain amorphous 1-acetyl-5- [2- [N
-Tert-butoxycarbonyl-2- (2-ethoxyphenoxy) ethylamino] propyl] -N-methyl-
0.89 g of 7-indolinecarboxamide was obtained.

IR (KBr): νNH 3416 cm ^-1 νC = O 1736, 1687, 1659 cm ^-1 NMR (CDCl ₃ ) δ: 1.10-1.50 (15H, m), 2.19 (3H, s), 2.60-2.75 (1H,
m), 2.85-3.10 (6H, m), 3.35-3.60 (2H, m), 3.85-4.40 (7
H, m), 5.80 (1H, br s), 6.88 (4H, s), 7.00-7.20 (2H,
m)

Reference Example 17 The compounds shown in the table were prepared in the same manner as in Reference Example 16.

[0152]

Embedded image

[0153]

[Table 7]

Reference Example 18 5- [2- [N-tert-butoxycarbonyl-2-
(2-ethoxyphenoxy) ethylamino] propyl]
877 mg of -N-methyl-7-indolinecarboxamide 1-acetyl-5- [2- [N-tert-butoxycarbonyl-2- (2-ethoxyphenoxy) ethylamino] propyl] -N-methyl-7-indolinecarboxamide After dissolving in 8 ml of ethanol, 1.63 ml of 5N sodium hydroxide was added and reacted at 60 ° C. for 2.5 hours.
50 ml of water was added to the reaction solution, extracted with ethyl acetate, 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 (eluent: hexane / ethyl acetate = 2/3) to obtain amorphous 5- [2- [N-tert-butoxycarbonyl]. 675 mg of 2- (2-ethoxyphenoxy) ethylamino] propyl] -N-methyl-7-indolinecarboxamide were obtained.

IR (KBr): νNH 3416 cm ^-1 νC = O 1687, 1638 cm ^-1 NMR (CDCl ₃ ) δ: 1.20-1.80 (15H, m), 2.50-3.10 (7H, m), 3.35-3.60
(2H, m), 3.63 (2H, t, J = 8.4Hz), 3.85-4.25 (5H, m), 6.
00-6.40 (2H, m), 6.75-7.10 (6H, m)

Reference Example 19 The compounds shown in the table were prepared in the same manner as in Reference Example 18.

[0157]

Embedded image

[0158]

[Table 8]

Reference Example 20 (R)-(-)-N, N-dimethyl-5- [2- [2-
[2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] -7-indolinecarboxamide (R)-(-)-1-butyryl-5- [2- [N-te
rt-butoxycarbonyl-2- [2- (2,2,2-
3.00 g of trifluoroethoxy) phenoxy] ethylamino] propyl] indoline-7-carboxamide was dissolved in 30 ml of concentrated hydrochloric acid and reacted at 90 ° C. for 2 hours. After the reaction solution was concentrated to dryness, methylene chloride (26 ml) was added and suspended, and triethylamine (3.68 ml), 1,3-dicyclohexylcarbodiimide (2.18 g), and dimethylamine hydrochloride (1.
29 g were sequentially added and reacted at room temperature for 64 hours. The reaction solution was filtered, 100 ml of ethyl acetate was added to the filtrate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel medium pressure liquid column chromatography (elution solvent: chloroform / methanol = 10/10).
Purified in 1), and oily (R)-(-)-N, N-dimethyl-5- [2- [2- [2- (2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl ]-
2.13 g of 7-indolinecarboxamide was obtained.

IR (neat): νNH 3389 cm ^-1 νC = O 1628 cm ^-1 NMR (CDCl ₃ ) δ: 1.06 (3H, d, J = 6.2 Hz), 2.48 (1H, dd, J = 13.5, 7.0
Hz), 2.68 (1H, dd, J = 13.5, 6.4Hz), 2.85-3.15 (11H,
m), 3.57 (2H, t, J = 8.5Hz), 4.00-4.15 (2H, m), 4.33 (2
H, q, J = 8.4Hz), 4.80 (1H, br s), 6.80 (1H, s), 6.85-
7.05 (5H, m) Specific rotation: [α] _D ²⁵ -15.2 ° (c = 1.10, MeOH)

Reference Example 21 (R)-(-)-5- [2- [N-tert-butoxycarbonyl-2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] −N,
N-dimethyl-7-indolinecarboxamide (R)-(-)-N, N-dimethyl-5- [2- [2-
2.12 g of [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] -7-indolinecarboxamide is dissolved in 20 ml of methylene chloride, and 1.22 g of di-tert-butyl dicarbonate in 3 ml of methylene chloride Was added and reacted at room temperature for 13 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel medium pressure liquid column chromatography (elution solvent: ethyl acetate) to obtain amorphous (R)-(-)-5- [2- [N-tert- Butoxycarbonyl-2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl]-
N, N-dimethyl-7-indolinecarboxamide 0.9
6 g were obtained.

IR (KBr): νNH 3396 cm ^-1 νC = O 1690, 1631 cm ^-1 NMR (CDCl ₃ ) δ: 1.15-1.30 (3H, m), 1.42 (9H, s), 2.50-2.65 (1H ,
m), 2.75-3.10 (9H, m), 3.30-3.60 (4H, m), 3.80-4.30 (3
H, m), 4.36 (2H, q, J = 8.4Hz), 4.84 (1H, br s), 6.70-
7.05 (6H, m) Specific rotation: [α] _D ²⁵ -55.2 ° (c = 1.10, MeOH)

Reference Example 22 (R)-(-)-1- (3-benzyloxypropyl)
-5- [2- [N-tert-butoxycarbonyl-2
-[2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indoline-7-carboxamide (R)-(-)-5- [2- [N-tert-butoxycarbonyl-2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indoline-7-carboxamide (179.3 g), 3-benzyloxy-1-bromopropane (80.1 g) and N, N-diisopropylethylamine (61.0 ml) The mixture was heated and stirred at a bath temperature of 115 ° C. for 9 hours under a stream of argon. 550 ml of ethyl acetate was added to the reaction mixture with stirring, and the mixture was stirred for 30 minutes, and the insoluble precipitate was removed by filtration. The filtrate was washed with 700 ml of saturated saline and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure,
Oily (R)-(-)-1- (3-benzyloxypropyl) -5- [2- [N-tert-butoxycarbonyl-2- [2- (2,2,2-trifluoroethoxy)
[Phenoxy] ethylamino] propyl] indoline-7
235.3 g of carboxamide were obtained.

IR (neat): νNH 3350 cm ^-1 νC = O 1675 cm ^-1 NMR (CDCl ₃ ) δ: 1.15-1.30 (3H, m), 1.40 (9H, s), 1.80-1.95 (2H,
m), 2.55-2.70 (1H, m), 2.75-3.00 (3H, m), 3.14 (2H, t,
J = 6.9Hz), 3.35-3.55 (6H, m), 3.85-4.30 (3H, m), 4.36
(2H, q, J = 8.4Hz), 4.47 (2H, s), 5.48 (1H, br s), 6.85
-7.40 (12H, m) Specific rotation: [α] _D ²⁵ -39.2 ° (c = 1.25, MeOH)

Reference Example 23 The compounds shown in the table were prepared in the same manner as in Reference Example 22.

[0166]

Embedded image

[0167]

[Table 9]

[0168]

[Table 10]

Reference Example 24 5- [2- [N-tert-butoxycarbonyl-2-
(2-ethoxyphenoxy) ethylamino] propyl]
-1- (2-methoxyethyl) indoline-7-carboxamide 5- [2- [N-tert-butoxycarbonyl-2-
(2-ethoxyphenoxy) ethylamino] propyl]
241 mg of indoline-7-carboxamide and 523 mg of 2-methoxyethyl p-nitrobenzenesulfonate were added to 1,4-
Dissolve in 2.5 ml of dioxane and dicyclohexano-18
-Add 93 mg of Crown-6 and 346 mg of potassium carbonate, and add
Reaction was performed at 24 ° C. for 24 hours. 10 ml of water was added to the reaction solution, extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel medium pressure liquid column chromatography (elution solvent: hexane / hexane).
The residue was purified with ethyl acetate = 1/1) to give an oily 5- [2- [N
-Tert-butoxycarbonyl-2- (2-ethoxyphenoxy) ethylamino] propyl] -1- (2-methoxyethyl) indoline-7-carboxamide 184 mg
I got

IR (neat): νNH 3410, 3340 cm ^-1 νC = O 1676 cm ^-1 NMR (CDCl ₃ ) δ: 1.10-1.55 (15H, m), 2.55-3.10 (4H, m), 3.15-3.75
(11H, m), 3.85-4.35 (5H, m), 5.51 (1H, br s), 6.88 (4
H, br s), 6.95-7.40 (3H, m)

Reference Example 25 4- [5- [2- [N-tert-butoxycarbonyl-2- (2-isopropoxyphenoxy) ethylamino] propyl] -7-carbamoylindoline-1-yl] -N-methyl Butyric acid amide methyl 4- [5- [2- [N-tert-butoxycarbonyl-2- (2-isopropoxyphenoxy) ethylamino] propyl] -7-carbamoylindoline-1-yl] butyrate 150 mg to 40% methylamine It was dissolved in 2 ml of a methanol solution and stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel medium pressure liquid column chromatography (elution solvent: methylene chloride / diethyl ether /
(Methanol = 5/5/1) to give oily 4- [5-
[2- [N-tert-butoxycarbonyl-2- (2
-Isopropoxyphenoxy) ethylamino] propyl] -7-carbamoylindolin-1-yl] -N-
135 mg of methylbutyric acid amide was obtained.

IR (neat): νNH 3320 cm ^-1 νC = O 1660 cm ^-1 NMR (CDCl ₃ ) δ: 1.10-1.50 (18H, m), 1.80-2.00 (2H, m), 2.22 (2H,
t, J = 7.1Hz), 2.50-3.70 (13H, m), 3.80-4.20 (3H, m),
4.40-4.60 (1H, m), 5.59 (1H, br s), 6.13 (1H, br s),
6.70-7.30 (7H, m)

Reference Example 26 (R)-(-)-1- (3-benzyloxypropyl)
-5- [2- [2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indoline-7-carboxamide (R)-(-)-1- (3-benzyloxy Propyl) -5
-[2- [N-tert-butoxycarbonyl-2-
To a solution of 235.3 g of [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indoline-7-carboxamide in 400 ml of isopropanol was added 420 ml of concentrated hydrochloric acid under stirring at an internal temperature of 10 ° C. or lower. It was added dropwise over a period of minutes. After the reaction solution was stirred at an internal temperature of 20 ° C. or lower for 3.5 hours, 5400 ml of ion-exchanged water was added, and the mixture was washed with 650 ml of ethyl acetate. After the aqueous layer was neutralized with sodium carbonate, the mixture was stirred overnight at room temperature, and the precipitated crystals were collected by filtration and dried. The obtained crude crystals (crystalline powder) are dissolved in 1400 ml of ethyl acetate and activated carbon
Processed at 5.4g. After evaporating the solvent under reduced pressure, the residue was recrystallized from 530 ml of ethyl acetate-270 ml of hexane to give a melting point of 10%.
(R)-(-)-1- (3-benzyloxypropyl) -5- [2- [2- [2- (2,2,2-
94.9 g of trifluoroethoxy) phenoxy] ethylamino] propyl] indoline-7-carboxamide were obtained.

IR (KBr): νNH 3346 cm ^-1 νC = O 1623 cm ^-1 NMR (CDCl ₃ ) δ: 1.06 (3H, d, J = 6.2 Hz), 1.80-1.95 (2H, m), 2.51 ( 1
H, dd, J = 13.5, 7.0Hz), 2.72 (1H, dd, J = 13.5, 6.3H
z), 2.90-3.20 (7H, m), 3.44 (2H, t, J = 8.2Hz), 3.51 (2
H, t, J = 6.3Hz), 4.05-4.15 (2H, m), 4.31 (2H, q, J = 8.4
Hz), 4.48 (2H, m), 5.42 (1H, br s), 6.85-7.05 (5H,
m), 7.15-7.40 (7H, m) Specific rotation: [α] _D ²⁵ -13.8 ° (c = 0.97, MeOH)

Reference Example 27 The compounds shown in the table were prepared in the same manner as in Reference Example 26.

[0176]

Embedded image

[0177]

[Table 11]

[0178]

[Table 12]

Reference Example 28 (R)-(-)-4- [7- (N, N-dimethylcarbamoyl) -5- [2- [2- [2- (2,2,2-trifluoroethoxy) Phenoxy] ethylamino] propyl] indolin-1-yl] butyrate ethyl (R)-(-)-4- [5- [2- [N-tert-butoxycarbonyl-2- [2- (2,2,2 -Trifluoroethoxy) phenoxy] ethylamino] propyl]
-7- (N, N-dimethylcarbamoyl) indoline-
280 mg of ethyl 1-yl] butyrate was dissolved in 2 ml of methylene chloride, 0.7 ml of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 5 hours. The reaction solution was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel medium pressure liquid column chromatography (elution solvent:
Purified with chloroform / methanol = 20/1), and oily (R)-(-)-4- [7- (N, N-dimethylcarbamoyl) -5- [2- [2- [2- (2, 216 mg of ethyl 2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indolin-1-yl] butyrate were obtained.

IR (neat): νNH 3430 cm ⁻¹ νC = O 1735, 1637 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.05 (3H, d, J = 6.2 Hz), 1.25 (3H, t, J = 7.2) Hz), 1.
75-1.90 (2H, m), 2.33 (2H, t, J = 7.5Hz), 2.40-2.50 (1H,
m), 2.60-2.75 (1H, m), 2.85-3.60 (15H, m), 4.05-4.2
0 (4H, m), 4.34 (2H, q, J = 8.4Hz), 6.71 (1H, s), 6.85-
7.10 (5H, m) Specific rotation: [α] _D ²⁵ -11.1 ° (c = 1.00, MeOH)

Reference Example 29 The compounds shown in the table were prepared in the same manner as in Reference Example 28.

[0182]

Embedded image

[0183]

[Table 13]

Reference Example 30 (R)-(-)-1- (3-hydroxypropyl) -5
-[2- [2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indoline-7-carboxamide (R)-(-)-1- (3-benzyloxypropyl)
70.9 g of -5- [2- [2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indoline-7-carboxamide in 560 ml of ethanol
292 ml of 1N hydrochloric acid and 7.1 g of 10% palladium on carbon were added to the solution dissolved in ice-cooled and stirred, and reacted for 3 hours under a hydrogen stream. After removing the catalyst by filtration and concentrating the filtrate under reduced pressure, 1000 ml of ion-exchanged water was added to the residue, and the mixture was washed with 250 ml of ethyl acetate. The aqueous layer was stirred under ice-cooling and 10% aqueous sodium carbonate solution 2
After adjusting the pH to 8 with 50 ml, the mixture was stirred at room temperature for 18 hours. The precipitated crystals were collected by filtration, dissolved in 1000 ml of ethyl acetate, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was dissolved in ethyl acetate (360 ml) at 70 ° C, and allowed to stand at room temperature to give (R)-(-)-1- (3-hydroxypropyl) having a melting point of 107 to 108 ° C. ) -5- [2- [2- [2- (2,
2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indoline-7-carboxamide 52.
1 g was obtained.

IR (KBr): νNH, OH 3388 cm ⁻¹ νNH 3202 cm ⁻¹ νC = O 1637 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.08 (3H, d, J = 6.2 Hz), 1.75-1.85 ( 2H, m), 2.53 (1
H, dd, J = 13.6, 6.7Hz), 2.68 (1H, dd, J = 13.6, 6.6H
z), 2.90-3.10 (5H, m), 3.19 (2H, t, J = 6.7Hz), 3.41 (2
H, t, J = 8.5Hz), 3.75 (2H, t, J = 5.6Hz), 4.05-4.15 (2
H, m), 4.30 (2H, q, J = 8.4Hz), 5.79 (1H, br s), 6.65
(1H, br s), 6.85-7.05 (5H, m), 7.16 (1H, s) Specific rotation: [α] _D ²⁵ -14.0 ° (c = 1.01, MeOH)

Reference Example 31 The following compound was produced in the same manner as in Reference Example 30. (R)-(-)-1- (3-hydroxypropyl)-
N, N-dimethyl-5- [2- [2- [2- (2,2,2
2-trifluoroethoxy) phenoxy] ethylamino] propyl] -7-indolinecarboxamide

IR (neat): νNH, OH 3416 cm ^-1 νC = O 1618 cm ^-1 NMR (CDCl ₃ ) δ: 1.06 (3H, d, J = 6.2 Hz), 1.70-1.80 (2H, m), 2.47 (1
H, dd, J = 13.5, 7.0Hz), 2.67 (1H, dd, J = 13.5, 6.2H
z), 2.85-3.80 (18H, m), 4.05-4.20 (2H, m), 4.33 (2H,
q, J = 8.4Hz), 6.69 (1H, s), 6.85-7.10 (5H, m) Specific rotation: [α] _D ²⁵ -12.6 ° (c = 1.01, MeOH)

Reference Example 32 (R)-(-)-5- [2- [N-tert-butoxycarbonyl-2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] Indole-7-carboxamide (R)-(-)-5- [2- [N-tert-butoxycarbonyl-2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indoline Dissolve 300 mg of -7-carboxamide in 11 ml of methanol, and add 165 mg of ammonium formate and 10% palladium on carbon.
220 mg was added and the mixture was heated under reflux for 3 hours. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure, and the residue was dissolved in methylene chloride.
After washing with water, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain amorphous (R)-(-)-5
[2- [N-tert-butoxycarbonyl-2- [2
-(2,2,2-trifluoroethoxy) phenoxy]
227 mg of [ethylamino] propyl] indole-7-carboxamide were obtained.

IR (KBr): νNH 3445, 3353 cm ^-1 νC = O 1666 cm ^-1 NMR (CDCl ₃ ) δ: 1.20-1.45 (12H, m), 2.75-3.15 (2H, m), 3.30-3.60
(2H, m), 3.75-4.20 (3H, m), 4.35 (2H, q, J = 8.4Hz),
6.49 (1H, s), 6.70-7.45 (6H, m), 7.61 (1H, s), 10.10 (1
H, br s) Specific rotation: [α] _D ²⁵ -47.7 ° (c = 1.03, CHCl ₃ )

Reference Example 33 (R)-(-)-5- [2- [N-tert-butoxycarbonyl-2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] -1-
Butyrylindole-7-carbonitrile (R)-(-)-5- [2- [N-tert-butoxycarbonyl-2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] Propyl] indole-7-carboxamide 500 mg, sodium butyrate 13 m
g and a mixture of 2.0 ml of butyric anhydride were reacted at 130 ° C. for 2 hours. The reaction solution is concentrated under reduced pressure, and the residue is subjected to silica gel medium pressure liquid column chromatography (elution solvent: hexane / hexane).
(Ethyl acetate = 3/1) to give oily (R)-(-)
-5- [2- [N-tert-butoxycarbonyl-2
77 mg of-[2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] -1-butyrylindole-7-carbonitrile were obtained.

IR (neat): νCN 2223 cm ⁻¹ νC = O 1727, 1686 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.09 (3H, t, J = 7.3 Hz), 1.30 (3H, d, J = 6.8 Hz), 1.
41 (9H, s), 1.93 (2H, sext, J = 7.3Hz), 2.75-3.60 (6H,
m), 3.75-4.30 (3H, m), 4.36 (2H, q, J = 8.3Hz), 6.60 (1
H, br s), 6.75-7.05 (4H, m), 7.39 (1H, d, J = 3.4Hz),
7.50-7.70 (2H, m) Specific rotation: [α] _D ²⁵ -60.0 ° (c = 0.98, MeOH)

Example 1 (R)-(-)-1- (3-hydroxypropyl) -5
-[2- [2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indole-7-carboxamide (R)-(-)-1- (3-hydroxypropyl)- 5
-[2- [2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indoline-7-carboxamide 3.51 g and ammonium formate 2.0
Dissolve 8 g in 140 ml methanol and add 10% palladium on carbon 2.
78 g was added and the mixture was heated under reflux for 3 hours. After removing the insoluble matter by filtration, the solution was concentrated under reduced pressure, and the residue was purified by silica gel medium pressure liquid column chromatography (elution solvent: methylene chloride / methanol = 5/1) to obtain oily (R)-(-). -1-
(3-hydroxypropyl) -5- [2- [2- [2-
1.98 g of (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indole-7-carboxamide was obtained.

IR (film): νNH 3346, 3184 cm ⁻¹ νC = O 1652 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.11 (3H, d, J = 6.2 Hz), 1.90-2.10 (2H, m), 2.73 (1
H, dd, J = 13.6,6.4Hz), 2.82 (1H, dd, J = 13.6, 6.9Hz),
2.90-3.15 (3H, m), 3.52 (2H, t, J = 5.7Hz), 4.00-4.25
(4H, m), 4.36 (2H, t, J = 7.0Hz), 6.23 (1H, br s), 6.34
(1H, br s), 6.48 (1H, d, J = 3.2Hz), 6.80-7.05 (4H,
m), 7.11 (1H, d, J = 3.2Hz), 7.15 (1H, d, J = 1.5Hz), 7.5
2 (1H, d, J = 1.5Hz) Specific rotation: [α] _D ²⁵ -14.9 ° (c = 1.10, MeOH)

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

[0195]

Embedded image

[0196]

[Table 14]

[0197]

[Table 15]

[0198]

[Table 16]

Example 3 (R)-(-)-1-butyryl-5- [2- [2- [2
-(2,2,2-trifluoroethoxy) phenoxy]
Ethylamino] propyl] indole-7-carboxamide (R)-(-)-5- [2- [N-tert-butoxycarbonyl-2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl Amino] propyl] -1-
70 mg of butyrylindole-7-carbonitrile was dissolved in 1 ml of isopropanol, 1 ml of concentrated hydrochloric acid was added, and the mixture was reacted at room temperature for 2 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with methylene chloride, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel medium pressure liquid column chromatography (eluent: chloroform / methanol = 20/1),
Oily (R)-(-)-1-butyryl-5- [2- [2
22 mg of-[2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indole-7-carboxamide were obtained.

IR (neat): νNH 3453, 3301 cm ^-1 νC = O 1701, 1672 cm ^-1 NMR (CDCl ₃ ) δ: 1.04 (3H, t, J = 7.4 Hz), 1.12 (3H, d, J = 6.0Hz), 1.
70-1.85 (2H, m), 2.70-3.20 (7H, m), 4.00-4.30 (4H, m),
6.50-6.60 (1H, m), 6.80-7.05 (4H, m), 7.25-7.40 (2H,
m), 7.72 (1H, s), 8.65 (1H, br s), 10.08 (1H, br s) Specific rotation: [α] _D ²⁵ -26.8 ° (c = 1.00, MeOH)

Continued on the front page (72) Inventor Toshikazu Yazaki 5944-95, Ariake, Hotaka-cho, Minamiazumi-gun, Nagano Pref. Field surveyed (Int. Cl. ⁷ , DB name) C07D 209/08 CA (STN) REGISTRY (STN)

Claims (8)

(57) [Claims] 1. A compound of the general formula (Wherein R is an aliphatic acyl group, a hydroxyalkyl group,
An aliphatic acyloxyalkyl group, a lower alkyl group having a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group or a mono- or di-lower alkyl-substituted carbamoyl group as a substituent, and R ¹ and R ² are each a hydrogen atom or a lower alkyl group. However, when R is an aliphatic acyl group, R ¹ and R ² are both hydrogen atoms, and R ³ is a lower alkyl group which may have one or more halogen atoms as a substituent. Or a pharmacologically acceptable salt thereof. 2. A compound of the general formula (Wherein R ⁴ is a 3-ethoxycarbonylpropyl group, 4-
An ethoxycarbonylbutyl group or a 3-hydroxypropyl group, R ¹ and R ² are each a hydrogen atom or a lower alkyl group, and R ³ may have one or more halogen atoms as a substituent The indole derivative according to claim 1, which is a lower alkyl group) or a pharmaceutically acceptable salt thereof. 3. The formula: The indole derivative according to claim 2, which is represented by the formula: or a pharmacologically acceptable salt thereof. 4. The formula: The indole derivative according to claim 2, which is represented by the formula: or a pharmacologically acceptable salt thereof. 5. The formula The indole derivative according to claim 2, which is represented by the formula: or a pharmacologically acceptable salt thereof. 6. A compound of the formula The indole derivative according to claim 2, which is represented by the formula: or a pharmacologically acceptable salt thereof. 7. A compound of the formula The indole derivative according to claim 2, which is represented by the formula: or a pharmacologically acceptable salt thereof. 8. The formula: The indole derivative according to claim 2, which is represented by the formula: or a pharmacologically acceptable salt thereof.