CZ20003126A3 - Indole derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

Indole derivatives of the general formula I, wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group, Y represents a hydroxy group or a pivaloyloxy group and the carbon atom designated (R) represents a carbon atom in the (R)-configuration, or pharmaceutically acceptable salts thereof, are described, which have a potent and long-lasting effect on reducing intraocular pressure and are useful as agents for reducing intraocular pressure.

Description

Indole derivatives and pharmaceutical compositions containing them

Field of the invention

The invention relates to novel indole derivatives and their pharmaceutically acceptable salts which are useful as pharmaceuticals.

State of the art

Heretofore, for example, timolol maleate and isopropyl unoprostone are known as compounds that are useful as intraocular pressure lowering agents.

Recently, bunazosin hydrochloride, which has a cg-adrenoceptor blocking effect (hereinafter referred to as cg-blocking effect) completely different from that of these compounds, has been developed as an agent for treating glaucoma and has attracted public interest. However, bunazosin hydrochloride was primarily developed as an agent for treating hypertension. Since bunazosin hydrochloride is very effective on blood pressure, there is concern that it may cause side effects such as hypotension and orthostatic hypotension.

In general, the majority of intraocular pressure-lowering agents are applied topically in the form of eye drops. Even in this case, the active substance is distributed throughout the body via the bloodstream and can be expected to have a systemic effect. It is therefore desirable that these systemic side effects are minimized even with topical applications.

Compounds that are absorbed into the eyes immediately after application and have a long-lasting effect are most advantageous because they act as topically as possible. ^! φφ φ φ • · • φ φ φφ

-2ΦΦ ' φ φφφφ • φ ♦ φφφ

Φ··· φφφ φφ ' • φ φ φ φ · ·' ·.

• φφφ φ • φ· « φ

Therefore, compounds that have a strong intraocular pressure-lowering effect with minimized occurrence of side effects such as hypotension and orthostatic hypotension, are rapidly absorbed into the eyes after instillation and have a long-lasting effect, and are mainly recommended as intraocular pressure-lowering agents.

The essence of the invention

The present invention relates to indole derivatives of the general formula I

(I) (wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group, Y represents a hydroxy group or a pivaloyloxy group, with the proviso that when R represents a 2,2,2-trifluoroethyl group, Y represents a pivaloyloxy group, and the carbon atom designated (R) represents a carbon atom in the (R)-configuration) or pharmaceutically acceptable salts thereof.

The present invention also relates to a pharmaceutical composition comprising an indole derivative of the general formula I

(I) ·· ··>· ·* ·♦ . ·· ·· • · · * 9 9 · 4 » · 9 • 999 9 9 9 9 9 9 9 9 9 • · · · · ·! · « * · · • · · · .·'· »·.·· 9 9 9 ······· ·* ·· ·· ·· (wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group, Y represents a hydroxy group or a pivaloyloxy group, with the proviso that when R represents a 2,2,2-trifluoroethyl group, Y represents a pivaloyloxy group, and the carbon atom designated (R) represents a carbon atom in the (R)-configuration) or a pharmaceutically acceptable salt thereof.

The present invention further relates to a substance for reducing intraocular pressure, which contains as an active ingredient an indole derivative of the general formula I

(wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group, Y represents a hydroxy group or a pivaloyloxy group, and the carbon atom designated (R) represents a carbon atom in the (R)-configuration) or a pharmaceutically acceptable salt thereof.

The present invention further relates to a substance for the prevention or treatment of glaucoma or ocular hypertension, which contains as an active ingredient an indole derivative of the general formula I

(wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group, Y represents a hydroxy group or a pivaloyloxy group, and ·· *··* 00 0« .-.:--..-99 ··

0 0 · · 0 · .0 · · 0

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0000 000 0« 00 00 0« the carbon atom designated (R) means a carbon atom in the (R)-configuration) or a pharmaceutically acceptable salt thereof.

The present invention further relates to a method of preventing or treating glaucoma or ocular hypertension, which comprises administering a therapeutically effective amount of an indole derivative of general formula I

(I) (wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group, Y represents a hydroxy group or a pivaloyloxy group, and the carbon atom designated (R) represents a carbon atom in the (R)-configuration) or a pharmaceutically acceptable salt thereof.

The present invention also relates to the use of an indole derivative of the general formula I

(wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group, Y represents a hydroxy group or a pivaloyloxy group, and the carbon atom designated (R) represents a carbon atom in the (R)-configuration) or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the prevention or treatment of glaucoma or ocular hypertension.

♦ · ··*·

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The present invention also includes the use of an indole derivative.

(I) (wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group, Y represents a hydroxy group or a pivaloyloxy group, and the carbon atom designated (R) represents a carbon atom in the (R)-configuration) or a pharmaceutically acceptable salt thereof as an agent for preventing or treating glaucoma or ocular hypertension.

Furthermore, the present invention relates to a method for preparing a pharmaceutical composition for the prevention or treatment of glaucoma or ocular hypertension, which comprises using an indole derivative of the general formula I

(wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group, Y represents a hydroxy group or a pivaloyloxy group, and the carbon atom designated (R) represents a carbon atom in the (R)-configuration) or a pharmaceutically acceptable salt thereof as an active ingredient of said pharmaceutical composition.

The inventors have sought drugs that have a strong and prolonged α-blocking effect with fewer side effects, such as an indole derivative, which treats dysuria having urethral contractions with

- ·· ··«» ·· 44 '.:·· ΦΦ

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- g - ΦΦΦΦ ΦΦΦ ΦΦΦ 44. ΦΦΦ ΦΦ hypotension and orthostatic hypotension, and with higher permeability in the eyes. It has been found that (R)-1-(3-hydroxypropyl)-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1-indole-7-carboxamide (herein referred to as compound A), one of the compounds previously developed as agents for selective suppressive effect on blood pressure with less effect (Japanese Patent Application (Kokai) Publication No. Hei

7-330726) and (R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1-(3-hydroxypropyl)-1,1-indole-7-carboxamide (herein referred to as compound B) hydrochloride, have an extremely potent α-blocking effect, more than seventy times more potent than Bunazosin hydrochloride, with less incidence of side effects such as hypotension and orthostatic hypotension, and are therefore expected to act for a longer period of time because they have a low excretion rate after penetration into the eyes and are useful as advantageous agents for lowering intraocular pressure.

Furthermore, since compounds A and B have low permeability through membranes such as the cornea, the inventors sought derivatives which have high membrane permeability and are rapidly converted after permeation into compounds A or B which have poor membrane permeability. As a result, it was surprisingly found that pivalic acid ester derivatives of the general formula Ia

O (Ia) • 9 »999 • 9 9 '9 9 ·9 • 9

9

9

9 9

I 9 9 9 » 9 9 9 » 9 9 9 9

-Ί9« (wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group and the carbon atom marked (R) represents a carbon atom in the (R)-configuration) have extremely high membrane permeability, are rapidly converted by hydrolase after permeation to compound A or B having low membrane permeability, and are extremely stable in aqueous solution, which is the normal form of eye drops, and thus form the essence of the present invention.

The inventors have found that compounds A and B having a strong _α -blocking effect are advantageous compounds as intraocular pressure lowering agents. However, these compounds have low corneal permeability and their concentration in the aqueous humor of the anterior chamber is quite low when these compounds are topically applied as eye drops. Therefore, the inventors have extensively searched for a way to obtain a full concentration of the drug in the aqueous humor of the anterior chamber after application of eye drops.

In order to find derivatives of compound A or B that would be easily converted to compound A or B when permeating through the cornea or in the aqueous humor of the anterior chamber of the eye and would exhibit a rapid effect, the inventors converted compound A or B into a series of derivatives and determined their ability to be cleaved by endogenous hydrolase by measuring the time-dependent rate of conversion to compound A or B in blood. For example, it was surprisingly found that the conversion rates of some esters of compound A to compound A after 30 minutes in blood were extremely low, about 12% in the case of the corresponding 2-ethyl butyrate, about 4% in the case of the corresponding 2,2-dimethyl valerate, about 2% in the case of the corresponding α,α-dimethyl phenyl acetate and about 6% in the case of the corresponding 2,2-dimethyl butyrate. Whereas the corresponding pivalate was already converted to compound A after 30 minutes in blood to about 67% and almost completely after 2 hours. The inventors have found that the pivalates of general formula la according to the present invention are different from other carboxylates and are specific compounds that are easily converted to compound A or B • fr ··»· frfr frfr frfr ·· «frfr · · · · ·*· • ··♦ a ·· · ' · · · fr • ··· fr frfrfr · · «· · .frfrfr· /· . frfr · _g_ ··· ··· frfr frfr ·',·· frfr by endogenous hydrolase in the cornea or in the aqueous humor of the anterior chamber of the eye.

The inventors measured the time dependence of the drug concentration in the aqueous humor of the anterior chamber of the eye after instillation into the eyes of rabbits to confirm the permeability of this pivalate through the cornea. For example, in the case of instillation of pivalate hydrochloride of compound B into the eyes, the concentration of compound B in the aqueous humor of the anterior chamber of the eye was about 70 times higher after 20 minutes and about 27 times higher after 2 hours than in the case of instillation of hydrochloride of compound B. Therefore, the pivalates of the above general formula la according to the present invention are extremely excellent compounds with corneal permeability and are also long-acting compounds.

In addition, in the above experiment, the pivalate of compound B is rapidly converted to compound B in the case of permeation through the cornea or in the aqueous humor of the anterior chamber of the eye, and cannot be detected at all in the aqueous humor of the anterior chamber of the eye after 20 minutes. Therefore, the pivalates of the above general formula la according to the present invention are permeable quickly and successfully through the cornea and are easily converted to compound A or B. Therefore, they are very advantageous compounds that reveal the effect of compound A or B reliably and quickly. Thus, it is confirmed in the rabbit experiment that the pivalates of the above general formula la have a very strong and prolonged effect of lowering intraocular pressure. Therefore, the pivalates of the above general formula la are excellently usable compounds as eye drops for preventing or treating glaucoma or ocular hypertension.

Furthermore, the pivalates of the above-mentioned general formula Ia according to the present invention hardly decompose at all in the state of eye drops at higher temperatures and are therefore extremely stable compounds. For example, if the pivalate of compound A is left to stand for about 1 month at a temperature of 40°C in the form of an aqueous solution, only about 0.1% of this compound decomposes into

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-9 compound A. Similarly, about 1.1% of this compound decomposes into compound A at 70°C. Thus, the pivalates of the above general formula Ia according to the present invention are extremely stable compounds in the form of aqueous solution, and eye drops containing these compounds are excellently stable during long-term storage. Therefore, the pivalates of the above general formula Ia according to the present invention are very suitable compounds for topical applications as eye drops.

The compounds of the above general formula I according to the present invention can be prepared, for example, by protecting the secondary nitrogen atom of an indoline derivative of the general formula II.

OR (II) (wherein R and the carbon atom designated (R) have the meanings given above), with a protecting group such as a tert-butoxycarbonyl group, in a conventional manner, the indoline ring of the resulting compound is oxidized in the presence of a metal catalyst such as palladium on carbon and ammonium formate to give an indole derivative of the general formula III

OH (III) ·» *··* . · 9 9

9 99 t>9 Ifc ·· • 9 9 :.9 9 9 9 9 9 « 9 9 ·. 9 9 9 9 .9 999 9 999 99 99 · • 9 9 · ·: 9 . 9' 9 9 9 (wherein P represents an amino protecting group, and R and the carbon atom designated (R) have the meanings given above), this derivative is reacted with pivaloyl halide if necessary in the presence of a base and the protecting group is removed in the usual manner.

From the compounds of the above general formula I according to the present invention, pivalates of the general formula Ia can also be prepared by protecting the secondary nitrogen atom of the indoline derivative of the general formula II with a protecting group such as a tert-butoxycarbonyl group in a conventional manner, the resulting compound is reacted with a pivaloyl halide in the presence of a base, thereby preparing an indoline derivative of the general formula IV.

(IV) (wherein P, R and the carbon atom designated (R) have the meanings given above), the indoline ring of the resulting compound is oxidized in the presence of a metal catalyst such as palladium on carbon and ammonium formate, and the protecting group is removed in the usual manner.

The indole derivatives of the general formula I according to the present invention can be converted into their pharmaceutically acceptable salts in a conventional manner. Examples of these salts include salts with mineral acids (for example, hydrochloric acid, hydrobromic acid/hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like)

-1144 ·44· <·· μ ' 44 ·4 • * · 4 4 4 4 4 · · 4 • 444 4 4 4 4 4 4 4 4 • · β 4 4 444 · 4 ·4 4 '4 4 4-4 4/9-44 4 • 444 444 44 ..44. 4 4 44 and salts with organic acids (for example, with formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, salicylic acid, benzoic acid, adipic acid, carbonic acid, glutamic acid, aspartic acid and the like).

When the indole derivatives of the general formula I according to the present invention and their pharmaceutically acceptable salts are used in practical treatment, they are applicable in various application forms. Of these forms, topical administration using eye drops and the like is preferred. Eye drops can be conveniently prepared by conventional methods. For example, eye drops can be prepared by adding the pivalate of the general formula Ia according to the present invention to sterile purified water, dissolving by adding suitable pharmaceutically acceptable additives such as antiseptics, isotonic agents and buffers, if necessary, with heating and filtration to remove dust and/or microbes.

Dosages are determined depending on gender, age, body weight, degree of symptoms, etc. for each patient to be treated. For example, in the case of eye drops, it is preferable to instill a solution in the eye in the range of 0.001 to 0.5% one to three times a day.

Examples.....implementation of the invention

The present invention is further explained in more detail in the following comparative examples, examples and test examples.

Comparative Example 1.·· (R)-3-[7-cyano-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2,3-dihydro-1,1-indol-1-yl]propyl]benzoate

To a solution of potassium carbonate (32.3 g) in distilled water (120 ml) was added ethyl acetate (120 ml), and (R)-3-[5-(2-aminopropyl)-7-cyano-2,3-dihydro-1H-indol-1-yl]propylbenzoate L-tartrate (12.0 g) was added portionwise to the mixture while stirring. After 1 hour of reaction, the reaction mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with 10% aqueous potassium carbonate solution and then with sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give (R)-3-[5-(2-aminopropyl)-7-cyano-2,3-dihydro-1H-indol-1-yl]propylbenzoate (8.98 g) as a brown oil.

The resulting (R)-3-[5-(2-aminopropyl)-7-cyano-2,3-dihydro-1-indol-1-yl]propylbenzoate (8.98 g) was dissolved in tert-butanol (43 ml). To the solution were added 2-(2-ethoxyphenoxy)ethyl methanesulfonate (7.02 g) and sodium carbonate (2.86 g), and the mixture was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium bicarbonate solution and then with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate and ethyl acetate/methanol = 100/6). Azeotropic concentration of the resulting oily substance gave (R)-3-[7-cyano-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2,3-dihydro-1H-indol-1-yl]propyl]benzoate (7.46 g) as a brown oil.

^X H-NMR (CDC1 ₃ ) δ ppm: 1.04 (d, J=6.0 Hz, 3H) , 1.41 (t, J=6.9 Hz, 3H) , 2.10-2.20 (m, 2H) , 2.42 (dd, J=13.6, 6.9 Hz, IH) , 2.63 (dd, J=13.6, 6.0 Hz, IH) , 2.80-3.10 (m, 5H) , 3.50-3.60 (m, 2H) , 3.75 (t, J=7.3 Hz, 2H) , 4.00-4.15 (m, 4H) , 4.40-4.50 φ φ

Φ Φ

Φ φ · Φ ;φ .Φ • Φ ♦ · φ φ Φ · · · • ' Φ ' ΦΦ ·· (m, 2Η), 6.85-7.00 (m,

1Η) , 8.00-8.10 (m, 2Η) . Specific rotation: [α] _D ²⁷

Comparative example 2

-136H) , 7.40-7.50 (m, = -14.8° (c = 1.04,

2H), 7.50-7.60 (m, methanol).

(R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1-(3-hydroxypropyl)-2,3-dihydro-1H-indole-7-carbonitrile (R)-3-[7-cyano-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2,3-dihydro-1H-indol-1-yl]propyl]benzoate (7.23 g) was dissolved in methanol (46 ml) and the resulting solution was added to a solution of potassium hydroxide (1.54 g) in distilled water (9.2 ml). After heating to reflux for 1 hour, the reaction mixture was concentrated under reduced pressure. Distilled water (100 ml) was added to the residue and the resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium bicarbonate and brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was dissolved in toluene (30 mL) and the toluene was removed under reduced pressure to give (R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1-(3-hydroxy-

propyl)-2,3-dihydro-1H-indole-7-carbonitrile (6.06g) in the form of light brown oil. ¹ H-NMR (CDCl1) δ ppm: 1.05 (d, J=6.0 Hz, 3H), 1.41 (t, J=6.9 Hz, 3H), 1.50-1.90 (m, 1H), 1.85-2.00 (m, 2H) , 2.43 (dd, J=13.6, 6.9 Hz, 1H), 2.63 (dd, J=13.6, 6, 3 Hz, 1H) , 2.80-3.10 - (m, 5H), 3.50-3.60 (m, 2H), 3.67 (t, J=7, 3Hz, 2H), 3.75-3.85 (m, 2H) , 4.00-4.15 (m, 4H) , 6.85-7.30 (m, 6H) .

Specific rotation: [α] _D ²⁷ = -19.4° (c = 1.06, methanol).

Comparative Example 3 (R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1-(3-hydroxypropyl)-2,3-dihydro-1H-indole-7-carboxamide

• · · · • · · · · 4 • · · · · · · · • · · 4

4· 44 • · · · · · ·14· (R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1-(3-hydroxypropyl)-2,3-dihydro-1H-indole-7-carbonitrile (5.95 g) was dissolved in dimethyl sulfoxide (16.4 ml) and 5 N sodium hydroxide solution (0.25 ml) was added to the solution. 30% hydrogen peroxide (1.55 ml) was added to the mixture while maintaining the internal temperature below 25 °C and the mixture was stirred overnight at an internal temperature of 25 to 30 °C. A solution of sodium sulfite (2.39 g) in distilled water (82 ml) and ethyl acetate were added to the reaction mixture. The ethyl acetate layer was washed with aqueous sodium bicarbonate solution, distilled water and sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from ethyl acetate to give (R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1-(3-hydroxypropyl)-2,3-dihydro-1H-indole-7-carboxamide (4.27 g).

the mixture is extracted and washed with saturated ^X H-NMR (CDCl ₃ ) δ ppm: 1.07 (d, J=6.2 Hz, 3H), 1.37 (t, J=7.0

Hz, 3H) , 1.60-1.85 (m, 3H) , 2.54 (dd, J=13.6, 6.6 Hz, IH) ,

2.68 (dd, J=13.6, 6.4 Hz, IH) , 2.85-3.10 (m, 6H) , 3.19 (t,

J=6.6 Hz, 2H) , 3.35-3.45 (m, 2H) , 3.75 (t, J=5.4 Hz, 2H) ,

3.95-4.20 (m, 4H) , 5.70 (wide s, IH) , 6.66 (wide s, IH) ,

6.80-6.95 (m, 4H), 7.02 (s, 1H), 7.16 (s, 1H).

Specific rotation: [α] _D ²⁷ = -15.3° (c = 0.98, methanol).

Comparative example 4

Tert-butyl-(R)-N-[2-[7-carbamoyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-indol-5-yl]-1-methylethyl]-N-[2-(2-ethoxyphenoxy)ethyl]carbamate (R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1-(3-hydroxypropyl)-2,3-dihydro-1H-indole-7-carboxamide (10.9 g) was dissolved in methylene chloride (100 ml) and a solution of di-tert-butyl dicarbonate (5.87 g) in methylene chloride (25 ml) was added dropwise to the solution with stirring and ice-cooling. The reaction mixture was stirred under the same conditions for 30 minutes and then stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (150 ml). The solution was washed with 10% aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give light brown amorphous tert-butyl-(R)-N-[2-[7-carbamoyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-indol-5-yl]-1-methylethyl]-N-[2-(2-ethoxyphenoxy)ethyl]carbamate (10.2 g).

H-NMR (CDC1 ₃ ) δ ppm: 1.20-1.50 (m, 15H), 1.70-1.85 (m, 2H), 2.50-4.40 (m, 18H), 5.75 (broad s, 1H), 6.63 (broad s, 1H), 6.80-7.20 (m, 6H).

Specific rotation: [α] _D ²⁷ = -50.4° (c = 1.27, methanol).

Example 1 (R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1-(3-hydroxypropyl)-1H-indole-7-carboxamide (Compound B)

Tert-butyl-(R)-N-[2-[7-carbamoyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-indol-5-yl]-1-methylethyl]-N-[2-(2-ethoxyphenoxy)-ethyl]carbamate (4.93 g) was dissolved in methanol (150 ml) and 10% palladium on carbon (490 mg) and ammonium formate (2.96 g) were added to the solution. The mixture was heated to reflux for 36 hours, cooled and the insoluble matter was filtered off. The solvent was removed under reduced pressure and the residue was dissolved in methanol (150 ml). 10% palladium on carbon (490 mg) and ammonium formate (2.96 g) were added to the solution. The mixture was heated to _reflux for 24 hours, cooled and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a white amorphous φφ φφ φφ ·· φ φφφ φ · φ · φ φφ φφ · ••Φ φ φφφ φ φφ φ φφ φφ φφ ·

-16ΦΦ φφφφ φ # φ φφφ tert.Butyl-(R)-Ν-[2-[7-carbamoyl-1-(3-hydroxypropyl)-alpha-indol-5-yl]-1-methylethyl]-N-[2-(2-ethoxyphenoxy)ethyl]carbamate (4.55 g).

^-NMR (CDCl1) δ ppm: 1.05-1.50 (m, 15H), 1.90-2.10 (m, 2H), 2.70-3.00 (m, 3H), 3.30-3.75 (m, 4H), 3.80-4.65 (m, 7H), 5.75-5.95 (m, 1H), 6.40-6.65 (m, 2H), 6.75-7.55 (m, 7H).

Specific rotation: [α] _D ³⁰ = -47.8° (c = 1.05, methanol).

Tert-butyl-(R)-N-[2-[7-carbamoyl-1-(3-hydroxypropyl)-1Hindol-5-yl]-1-methylethyl]-N-[2-(2-ethoxyphenoxy)ethyl]carbamate (4.55 g) was dissolved in isopropanol (50 ml), and concentrated hydrochloric acid (25 ml) was added portionwise to the solution under stirring and ice-cooling. The mixture was stirred at room temperature for 3 hours, and saturated aqueous sodium bicarbonate solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by aminopropyl silica gel column chromatography (eluent: methylene chloride/methanol = 20/1) to give white amorphous (R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1-(3-hydroxypropyl)-1H-indole-7-carboxamide (1.27 g). The crude mixture was further purified by aminopropyl silica gel column chromatography (eluent: ethyl acetate/ethanol = 7/1) and the purified product was combined with the previous purified product to give white amorphous (R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1-(3-hydroxypropyl)-1H-indole-7-carboxamide (2.39 g).

¹ H-NMR (CDCl1) δ ppm: 1.11 (d, J=6.3 Hz, 3H), 1.25 (t, J=7.0

Hz, 3H), 1.95-2.10 (m, 2H), 2.70-3.20 (m, 6H), 3.52 (t, J=5.6

Hz, 2H) , 3.93 (q, J=7.0 Hz, 2H) , 4.00-4.20 (m, 2H) , 4.38 (t,

J=7.0 Hz, 2H), 5.90 (broad s, 1H), 6.38 (broad s, 1H), 6.49 (d, J=3.2 Hz, 1H), 6.75-6.95 (m, 4H), 7.11 (d, J=3.2 Hz, 1H), 7.19 (d, J=1.5 Hz, 1H), 7/53 (d, J=1.4 Hz, 1H).

Specific rotation: [α] _D ³⁰ = -15.5° (c = 1.02, methanol).

»0 0 00 0 ·* · ·

0 · 9 0 «

900 9 4

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99 99 99

Example 2 (R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1-(3-hydroxypropyl)-1H-indole-7-carboxamide hydrochloride (Compound B hydrochloride) (R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1-(3-hydroxypropyl)-1H-indole-7-carboxamide (862 mg) was dissolved in ethanol (5 ml) and 2 N hydrochloric acid (985 μΐ) was added to the solution. The solvent was removed under reduced pressure, the residue was dissolved in ethanol (3 ml) and ethyl acetate (12 ml) was added to the solution. The mixture was allowed to stand and the resulting crystals were collected by filtration to give (R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1-(3-hydroxypropyl)-1H-indole-7-carboxamide hydrochloride (821 mg).

¹ H-NMR (CDCl1) δ ppm: 1.19 (d, J=6.4 Hz, 3H) , 1.26 (t, J=7.0 Hz, 3H) , 1.70-1.85 (m, 2H) , 2.65-2.80 (m, IH) , 3.20-3.55 (m,

5H) , 3.64 (broad s, IH) , 4.02 (q, J=7.0 Hz, 2H) , 4.20-4.40 (m, 4H) , 4.55 (t, J=5.0 Hz, IH) , 6.45 (d, J=3.1 Hz, IH) ,

6.85-7.15 (m, 5H) , 7.36 (d, J=3.1 Hz, IH) , 7.49 (d, J=1.3 Hz, IH) , 7.60 (broad s, IH) , 7.99 (broad s, IH) , 9.05-9.30 (m, 2H) .

Specific rotation: [α] _D ³⁰ = -7.8° (c = 1.16, methanol).

Example 3 (R)-3-[7-carbamoyl-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-ΙΗ-indol-1-yl]propyl pivalate (compound C)

Tert-butyl-(R)-N-[2-[7-carbamoyl-1-(3-hydroxypropyl)-2,3dihydro-1H-indol-5-yl]-1-methylethyl]-N-[2-(2-ethoxyphenoxy)ethyl]carbamate (6.24 g) was dissolved in anhydrous pyridine (9.4 ml) and pivaloyl chloride (1.54 ml) was added to the solution. The mixture was stirred at room temperature overnight and a saturated aqueous solution of sodium bicarbonate was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with

-18• 4 4444 · · · · 4.

4444 44

-444.4

4 4 4

4444 444 44

44 44

4 4 4 4 · 4 4 4

444 44 44 4

4 4 4 4

44 44 saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by aminopropyl silica gel column chromatography (eluent: hexane/ethyl acetate = 1/1) to give colorless amorphous (R)-3-[5-[2-[N-(tert-butoxycarbonyl)-N-[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-7-carbamoyl-2,3-dihydro-1H-indol-1-yl]propyl pivalate (4.30 g).

^X H-NMR (CDCl1) 8 ppm: 1.15-1.50 (m, 24H) , 1.85-2.00 (m, 2H) ,

2.55-3.20 (m, 6H), 3.30-3.60 (m, 4H), 3.85-4.40 (m, 7H), 5.52 (broad s, 1H), 6.80-7.40 (m, 7H).

Specific rotation: [α] _D ²⁷ = -38.3° (c = 1.03, methanol).

(R)-3-[5-[2-[N-(tert-butoxycarbonyl)-N-[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-7-carbamoyl-2,3-dihydro-1H-indol-1-yl]propyl pivalate (8.53 g) was dissolved in methanol (280 ml) and 10% palladium on carbon (853 mg) and ammonium formate (3.97 g) were added to the solution. The mixture was heated to reflux for 13 hours and the catalysts were filtered off. The solvent was removed under reduced pressure to give light green amorphous (R)-3-[5-[2-[N-(tert-butoxycarbonyl)-N-[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-7-carbamoyl-1H-indol-1-yl]propyl pivalate (8.20 g).

^X H-NMR (CDCl1) δ ppm: 1.05-1.50 (m, 24H) , 1.90-2.10 (m, 2H) ,

2.70-3.05 (m, 2H), 3.30-3.75 (m, 2H), 3.85-4.70 (m, 9H), 5.66 (broad s, 1H), 6.35-6.50 (m, 2H), 6.75-7.55 (m, 7H).

Specific rotation: [α] _D ²⁷ = -44.5° (c = 1.06, methanol).

(R)-3-[5-[2-[N-(tert-butoxycarbonyl)-N-[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-7-carbamoyl-1H-indol-1-yl]propyl pivalate (7.81 g) was dissolved in isopropanol (78 ml), and concentrated hydrochloric acid (39 ml) was added dropwise to the solution over 10 minutes under stirring and ice-cooling. The mixture was stirred at room temperature for 4 hours, and then the reaction mixture was adjusted by adding • · · · · ·

19• fr frfr ·· ·· .·..·» · · · frfr · ··.···· · ·· · fr.fr frfrfr fr · frfr fr • · · fr frfr · frfr frfr frfr frfr powdered sodium bicarbonate to pH 8. The mixture is diluted with water (200 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium bicarbonate solution, then with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on aminopropyl silica gel (eluent: ethyl acetate) and recrystallized from a mixture of diethyl ether and hexane (2/1) to give (R)-3-[7-carbamoyl-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1H-indol-1-yl]propyl pivalate (5.21 g) as colorless crystals.

^X H-NMR (CDC1 ₃ ) δ ppm: 1.11 (d, J=6.2 Hz, 3H) , 1.21 (s, 9H) ,

1.27 (t, J=7.0 Hz, 3H) , 1.95-2.10 (m, 2H) , 2.75 (dd, J=13.6,

6.4 Hz, 1H), 2.85 (dd, J=13.6, 6.6 Hz, 1H), 2.95-3.10 (m, 3H), 3.85-4.00 (m, 4H), 4.00-4.20 (m, 2H), 4.35-4.45 (m, 2H), 5.55-5.65 (wide s, 1H) , 6.05-6.20 (broad s, 1H) , 6.47 (d,

J=3.2 Hz, 1H), 6.75-6.95 (m, 4H), 7.06 (d, J=3.2 Hz, 1H), 7.21 (d, J=1.5 Hz, 1H), 7.54 (d, J=1.5 Hz, 1H).

Specific rotation: [α] _D ²⁷ = -15.8° (c = 1.06, methanol).

Example 4

The following compound was prepared in a similar manner as described in Example 3, using tert-butyl-(R)-N-[2-7-carbamoyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-indol-5-yl]-1-methylethyl]-N-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]carbamate instead of tert-butyl-(R)-N-[2-[7-carbamoyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-indol-5-yl]-1-methylethyl]-N-[2-(2-ethoxyphenoxy)ethyl]carbamate.

(R)-3-[7-carbamoyl-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-ΙΗ-indol-1-yl]propyl pivalate (compound D)

^X H-NMR (CDC1 ₃ ) δ ppm: 1.11 (d, J=6.2 Hertz, 3H) , 1, 21 (with, 9H) , 2.00-2.10 (m, 2H), 2.73 (dd, J=13.5, 6.5 Hz, 1H) / 2.84 (dd, J=13.5, 0.8 Hz, 1H), 2.95-3.15 (m, 3H) , 3.90-4, 00 (m, 2H) ,

-·····♦·. .·« . ; · * Φ * • · · · φ · · ··· · »»···♦ • ♦ · • · · · • ·

-20- .ϊ»....*

4.00-4.30 (m, 4H) , 4.35-4.45 (m, 2H) , 5.73 (wide s, ÍH) ,

6.10 (broad s, ÍH) , 6.47 (d, J=3.2 Hz, ÍH) , 6.80-7.05 (m, 4H) , 7.07 (d, J=3.2 Hz, ÍH) , 7.19 (d, J=1.4 Hz, ÍH) , 7.54 (d, J=1.4 Hz, ÍH).

Specific rotation: [α] _D ²⁷ = -17.5° (c = 0.79, methanol).

Example 5 (R)-3-[7-carbamoyl-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1H-indol-1-yl]propyl pivalate hydrochloride (Compound C hydrochloride)

To a solution of (R)-3-[7-carbamoyl-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1H-indol-1-yl]propyl pivalate (6.07 g) in ethanol (58 ml) was added dropwise 1 N hydrochloric acid (11.6 ml) under stirring and ice-cooling, and the mixture was stirred under the same conditions for 15 minutes. The reaction mixture was concentrated under reduced pressure, and ethanol was added to the residue. After azeotropic removal of water, the residue was dissolved in ethanol (6 ml), and ethyl acetate (60 ml) was added to the solution. The mixture was allowed to stand at room temperature for 16 hours to obtain colorless crude crystals (5.14 g). The crystals were combined with other crude crystals obtained in a similar manner, and the combined crystals (8.12 g) were recrystallized from a mixture of ethanol and ethyl acetate (15/1) to give (R)-3-[7-carbamoyl-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1H-indol-1-yl]propyl pivalate hydrochloride (7.46 g) as colorless crystals.

^X H-NMR (CDCl1) δ ppm: 1.21 (s, 9H) , 1.29 (t, J=7.0 Hz, 3H) ,

1.45 (d, J=6.5 Hz, 3H) , 1.95-2.10 (m, 2H) , 3.12 (dd, J=14.0,

7.2 Hz, ÍH), 3.30-3.60 (m, 3H) , 3 .85-4.05 (m, 5H), 4.30-4.50 (m, 4H) , 5.87 (s, ÍH) , 6.40 (d, J =3.2 Hz, H), 6.80-7.00 (m, 4H) , 7.05 (d, J=3.2 Hz, ÍH) , 7.33 (d, J=1.5 Hz, ÍH), 7.36 (s, ÍH) , 7.50 (d, J=1.5 Hz ¹ , ÍH) , 9.10-9.30 (wide s, ÍH),

9.50-9.65 (wide s, ÍH).

-219994 4« 4« 99 99 » · * * 4 » 9 9 4 ·

4 ·· 4 ·· 4 4 .. · 9 4 9 ♦

4 4 9 9 999 · 9 9 4 ·

9 99 · 9 9 9 ·

9999999 44 »4 44 44

Specific rotation: [α] _D ²⁸ = -7.0° (c = 1.22, methanol).

Comparative Example 5 (R)-3-[7-carbamoyl-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-ΙΗ-indol-1-yl]propyl-2-ethylbutyrate (compound a)

To a solution of (R)-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1-(3-hydroxypropyl)-2,3-dihydro-1H-indole-7-carboxamide (3.0 g) in methylene chloride (50 ml) was added ditert-butyl dicarbonate (1.32 g) under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes and then overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 ml). The solution was washed with 10% aqueous citric acid solution, saturated aqueous sodium bicarbonate solution, and then sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give light brown amorphous tert-butyl-(R)-N-[2-[7-carbamoyl-1-(3-hydroxypropyl)-2,3-dihydro-1H-indol-5-yl]-1-methylethyl]-N-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]carbamate (2.99 g).

^X H-NMR (CDCl ₃ ) δ ppm: 1.20-1.50 (m, 12H), 1.70-1.85 (m, 2H), 2.50-4.50 (m, 18H), 5.89 (broad s, IH), 6.69 (broad s, IH), 6.80-7.20 (m, 6H).

Specific rotation: [α] _D ²⁵ = -41.6° (c = 1.12, methanol).

Tert-butyl-(R)-N-[2-[7-carbamoyl-1-(3-hydroxypropyl)-2,3dihydro-1H-indol-5-yl]-1-methylethyl]-N-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]carbamate (12.0 g) and ammonium formate (12.7 g) were dissolved in methanol (300 ml) and 10% palladium on carbon (1.20 g) was carefully added to the solution at reflux overnight and removed under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate.

The mixture is heated with the solvent «« «999 99 99 99 ♦· • 9 9 · * ♦ 9 · ♦ · · • · 99 · 9 · · · · · · • 9 9 9 9 999 99 9

9 9 9 9 9999

9999 999 99 99 99 99

-22The solvent was removed under reduced pressure to give amorphous tert-butyl-(R)-N-[2-[7-carbamoyl-1-(3-hydroxypropyl)-1H-indol-5-yl]-1-methylethyl]-N-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]carbamate (12.2 g).

^X H-NMR (CDC1 ₃ ) δ ppm: 1.1-1.4 (m, 12H) , 1.95-2.1 (m, 2H) ,

2.7-3.0 (m, 2H) , 3.25-3.7 (m, 4H) , 3.8-4.2 (m, 3H) , 4.3-4.6 (m, 4H) , 5.91 (broad s, 1H) , 6.45-6.6 (m, 2H) , 6.75-7.6 (m,

7H) .

Specific rotation: [α] _D ²⁷ = -44.5° (c = 1.11, methanol).

Tert-butyl-(R)-N-[2-[7-carbamoyl-1-(3-hydroxypropyl)-1H-indol-5-yl]-1-methylethyl]-N-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]carbamate (2.00 g) was dissolved in anhydrous pyridine (3 ml), and 2-ethylbutyryl chloride (0.54 g) prepared from 2-ethylbutyric acid and oxalyl chloride was added to the solution. The mixture was stirred overnight at room temperature, saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium bicarbonate and then brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 2/1) to give white amorphous (R)-3-[5-[2-[N-(tert-butoxycarbonyl)-N-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-7-carbamoyl-1H-indol-1-yl]propyl]-2-ethylbutyrate (1.66 g).

¹ H-NMR (CDCl3) δ ppm: 0.90 (t, J=7.4 Hz, 6H), 1.10-1.40 (m, 12H), 1.45-1.70 (m, 4H), 1.90-2.10 (m, 2H), 2.15-2.30 (m, ÍH) , 2.70-3.00 (m, 2H) , 3.30-3.70 (m, 2H) , 3.80-4.70 (m, 7H), 4.36 (q, J=8.4 Hz, 2H) , 5.62 (wide with, ÍH) , 6.40-6.50 (m, 2H) , 6.85-7.40 (m, 6H), 7.45-7.55 (m, 1H).

Specific rotation: [α] _D ³¹ = -41.8° (c = 0.99, methanol).

(R)-3-[5-[2-[N-(tert-butoxycarbonyl)-N-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-7-carbamoyl-1H-indol-1-yl]propyl]-2-ethylbutyrate (1.56 g) was dissolved in

-23«· ·»·« · » · · • · · · · · · · · · · · « · » · · ··· · The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol = 20/1) and recrystallized from diethyl ether/hexane mixtures to give (R)-3-[7-carbamoyl-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indol-1-yl]propyl-2-ethylbutyrate (1.10

g) in the form of white crystals.

H-NMR (CDCl1) δ ppm: 0.90 (t, J=7.4 Hz, 6H), 1.11 (d, J=6.2

Hz, 3H), 1.45-1.70 (m, 4H) , 2.00- 2.10 (m, 2H) , 2.15-2.25 (m, IH), 2.65-2.90 (m, 2H) , 2.95- 3.15 (m, 3H) , 3.99 (t, J=6.3 Hz, 2H), 4.00-4.30 (m, 4H) , 4.41 (t, J=6.9 Hz, 2H) , 5.64 (wide

s, IH), 6.07 (broad s, IH), 6.47 (d, J=3.2 Hz, IH), 6.80-7.05 (m, 4H) , 7.08 (d, J=3.2 Hz, IH) , 7.19 (d, J=1.6 Hz, IH) , 7.54 (d, J=1.6 Hz, IH).

Specific rotation: [α] _D ³⁰ = -16.4° (c = 1.00, methanol).

Comparative example 6

The following compounds were prepared in a similar manner to Comparative Example 5 using the corresponding acid halide instead of 2-ethylbutyryl chloride (R)-3-[7-carbamoyl-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indol-1-yl]propyl-2,2-dimethylvalerate (compound b) ¹ H-NMR (CDCl 3 ) δ ppm: 0.90 (t, J=7.3 Hz, 3H), 1.11 (d, J=6.2

Hz, 3H) , 1.18 (S, 9H) , i;i9-1.28 (m, 2H) , 1.49-1.53 (m, 2H) ,

2.03-2.06 (iii, 2H) , 2.73 (dd, J=13.5, 6.5 Hz, IH) , 2.84 (dd, ··

J=13.5, 6.8 Hz, IH) , 3.00-3.10 (m, 3H) , 3.96 (t, J=6.2 Hz, 2H) , 4.07-4.23 (m, 4H) , 4.40 (t, J=6.9 Hz, 2H) , 5.66 (wide s, IH), 6.09 (broad s, IH), 6.47 (d, J=3.2 Hz, IH), 6.84-7.03 (m, 4H) , 7.07 (d, J=3.2 Hz, IH) , 7.19 (d, J=1.6 Hz, IH), 7.54 (d, J=l, 6 Hz, IH) .

Specific rotation: [α] _D ³⁰ = -16.2° (c = 0.82, methanol).

(R)-3-[7-carbamoyl-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-ΙΗ-indol-1-yl]propyl-α,α-dimethylphenylacetate (compound c) 'H-NMR (CDCl ₃ ) δ ppm: 1.10 (d, J=6.2 Hz, 3H), 1.60 (s, 6H),

1.80-1.96 (m, 2H), 2.71 (dd, J=13.7, 6.4 Hz, 1H), 2.82 (dd,

J=13.5, 6.7 Hz, IH), 2.96-3.10 (m, 3H), 3.90 (t, 2H), 4.03-4.28 (m, 6H) , 5.58 (broad s, IH) , 6.00 (broad s, IH) , 6.37 (d, J=3.l Hz, IH) , 6.84-7.03 (m, 4H), 6.68 (d, J=3.2 Hz,

1H), 7.19 (d, J=1.6 Hz, 1H), 7.54 (d, J=1.6 Hz, 1H).

Specific rotation: [α] _D ²⁹ = -13.7° (c = 1.15, methanol).

(R)-3-[7-carbamoyl-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indol-1-yl]propyl-2,2-dimethylbutyrate (compound d) 1H-NMR (CDCl) δ ppm: 0.85 (t, J=7.5 Hz, 3H), 1.12 (d, J=6.2

Hertz, 3H) , 1.17 (s, 6H), 1.57 (q, J=7.5 Hz, 4H) , 2, 00-2.10 (m, 2H) , 2, 70-2.90 (m, 2H), 2.95 -3.15 (m, 3H), 3.97 (t , J=6.2 Hz, 2H) , 4, 00-4.40 (m, 4H) , 4.40 i (t, J=7.0 Hz, 2H) , 5 .70 (wide with, IH) , 6.12 (wide s, IH), 6.47 (d, J=3.2 Hz, IH) , 6.80-7.05 (m, 4H) , 7.07 (d, J=3.2 Hz, IH) , 7.19 (d, J=1.6 Hz , IH) , 7.54

(d, J=1.5 Hz, 1H).

Specific rotation: [α] _D ³¹ = -15.4° (c = 1.00, methanol).

Test example 1

Test to measure the blocking effect of cq-adrenoceptor

The vas deferens (about 1.5 cm from the testicular side) is isolated from male Wistar rats (about ¹³⁰⁰ to 350 g body weight). After removing the blood vessels and connective tissue, each preparation is

00

0 0 0

0 0 *

0 0 0

0 0 0

00

-25•0 0000 • 0 • 000 • 0 0« «0 0 « · ·

0 0 0000

0 0 0 > 00 00 vertically suspended in a Magnus bath containing 10 ml of Krebs-Henseleit solution maintained at 37° C and flushed with a mixture of 95% oxygen and 5% carbon dioxide and adjusted to a voltage of lg. A solution of a mixture containing propranolol and yohimbine (final concentration: propranolol ΙμΜ and yohimbine 0.1 μΜ) is added to the Magnus bath. After 30 minutes, norepinephrine is added to the Magnus bath to a final concentration of 10 μΜ and once the maximum concentration is reached, each preparation is washed. This procedure is repeated several times until the contraction heights are stable. Each preparation is pre-treated for 30 minutes with a solution containing the test compound and then the contractions are measured after the application of 10 μΜ norepinephrine. The contractions of each preparation without pre-treatment with the test compound are expressed as 100%. The α-adrenoceptor blocking effect of the test compound is expressed as the molar concentration of the compound required for 50% inhibition of contraction before the addition of norepinephrine (i.e., IC ₅₀ value). The results are shown in Table 1.

Table 1

test compound _IC50 (nM) compound A 2.7 Compound B hydrochloride 4.3 bunazosin hydrochloride 315

Test example 2

Test for measuring drug concentration in aqueous humor (1) (1) Method

After instillation of a 0.1% solution of (R)-5-[2-[(2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1-(3-hydroxypropyl-1,1-indole-7-carboxamide hydrochloride) (compound B hydrochloride) (50 μΐ) into the eye of Japanese white rabbits (about 3 kg body weight,

99

9 9 9

9 9 9

9 9 9

9 9 9

99 ' 9

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9' • 99 . 9

9

9999 999

99 • *« 9

9 9 · • · ··· • 9 99

Japan SLC), after which the aqueous humor is collected at time intervals. (R)-3-chloro-1-(3-hydroxypropyl)-5-[2-[[2-2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indole-7-carboxamide (10 ng) is added as an internal standard to the collected aqueous humor (0.1 ml), and 0.1 M phosphate buffer (pH 7.6) and sodium chloride (about 1 g) are added to the mixture. The resulting mixture is extracted with diethyl ether (5 ml) and the diethyl ether layer is concentrated under a stream of nitrogen. The resulting residue is dissolved in the mobile phase (200 μϊ), after which 100 μΐ of the solution is injected into a high-performance liquid chromatograph (HPLC) and compound B is determined under the following conditions. The results are shown in Table 2.

(2) HPLC conditions

Analytical column: Inertsil ODS-3 (4.6 x 250 mm)

Mobile phase: acetonitrile/0.1% phosphoric acid + 2 mM sodium lauryl sulfate = l/l

Column temperature: 50° C

Flow rate: 1.0 ml/minute

Fluorometry: excitation wavelength 270 nm, emission wavelength 435 nm

Table 2

tested compound drug concentration (ng/ml) 20 minutes after 2 hours after 6 hours after compound B 2 20 8

Test example 3

Endogenous enzyme hydrolysis rate test (1) Method

Blood ester is always added to whole blood (0.5 ml) collected from male Wistar rats in the form of heparinized blood.

-27(R)-1-(3-hydroxypropyl)-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indole-7-carboxamide, (Compound A) and the internal standard (R)-3-chloro-1-(3-hydroxypropyl)-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indole-7-carboxamide (1 μg) and the mixture was incubated at 37° C. After 15 minutes, 30 minutes, 1 hour and 2 hours, the reaction was stopped by adding 0.7 M aqueous sodium fluoride solution (0.5 ml) to each sample as an esterase inhibitor. 0.1 M phosphate buffer (pH 7.6) and sodium chloride (about 1 g) were added to the mixture, and the resulting mixture was extracted with diethyl ether (5 ml). The diethyl ether phase was then concentrated under a stream of nitrogen. The residue was dissolved in the mobile phase (300 μΐ), 10 μΐ of the solution was injected into a high-performance liquid chromatograph, and the test compound and compound A were determined under the following conditions. The results are shown in Table 3.

(2) HPLC conditions

Analytical column: Inertsil ODS-3 (4.6 x 250 mm)

Mobile phase: acetonitrile/20mM acetate buffer (pH 5.0) = 40/60

Column temperature: 50° C

Flow rate: 1.0 ml/minute

Fluorometry: excitation wavelength 270 nm, emission wavelength 435 nm

Table 3

tested compound decomposition rate (%) 15 minutes after 30 minutes after 1 hour after 2 hours after compound D 54.8 67.1 86.5 98.6 comb. and 8.4 12 12.6 25.2 compound b 2.2 3.8 7.5 10.2 compound c 0.6 1.6 3.2 3.7 conjugation d 2.1 5.6 8.4 21.7

-28• 4 4 9 »9 ·

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44 t · · « 4 4 4 • 4 4 4 4 • 4 4 «4

4 44

4 4 4

4 4 4

4 4 4

4 4 4

44

Test example 4

Aqueous drug concentration measurement test (2) (1) Method

Japanese white rabbits (about 3 kg body weight, Japan SLC) were instilled with a 0.1% solution of (R)-3-[7-carbamoyl-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1H-indol-1-yl]propylpivalate hydrochloride (compound C hydrochloride) into the eyes, and aqueous humor was collected at timed intervals. To the collected aqueous humor (0.1 ml), an internal standard, [(R)-3-chloro-1-(3-hydroxypropyl)-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indole-7-carboxamide], (10 ng) was added, and 0.1 M phosphate buffer (pH 7.6) and sodium chloride (about 1 g) were added. The resulting mixture was extracted with diethyl ether (5 mL) and the diethyl ether layer was concentrated under a stream of nitrogen. The residue was dissolved in mobile phase (200 μΐ) and 100 μΐ of the solution was injected into a high-performance liquid chromatograph and compound C and (R)-5-[2-[[-2(2-ethoxyphenoxy)ethyl]amino]propyl]-1-(3-hydroxypropyl)-1H-indole-7-carboxamide (compound B) were determined under the following conditions. The results are shown in Table 4.

(2) HPLC conditions

Analytical column: Inertsil ODS-3 (4.6 x 250 mm)

Mobile phase: acetonitrile/0.1% phosphoric acid + 2 mM sodium lauryl sulfate = l/l Column temperature: 50 ⁰ C Flow rate: 1.0 ml/minute

Fluorometry: excitation wavelength 270 nm, emission wavelength 435 nm.

-29«9 ··*· ·· ·* ·* • » · « « 9.. · · * · 9

9 99 9 9 9 « 9 · « « • · · 9 9 999 »9 99 · • · 9 * 9 9 9 9 9 9 »««« 999 94 ·'** 99 99

Table 4

tested compound drug concentration (ng/ml) 20 minutes after 2 hours after 6 hours after compound B 140 546 136 compound C <1 <1 <1

Test example 5

Stability test

The test compounds were dissolved in 0.1 M acetate buffer (pH 5.0) and 0.1% solutions were prepared. Each 0.1% solution was left to stand in the dark for 28 days at 40° C, 50° C, 60° C and 70° C. The results are shown in Table 5.

Table 5

tested compound remainder ratio (%) 40°C 50°C 60°C 70°C compound D 99.9 99.7 99.5 98.9 compound A 0.1 0.3 0.5 1.1

Test example 6

Acute toxicity test

Male SD rats, 7 weeks old (n=5, 190-210 g body weight) were fasted for 18 hours. (R)-3-[7-carbamoyl-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1-indol-1-yl]propylpivalate hydrochloride was suspended in 0.5% aqueous methylcellulose to a concentration of 100 mg/ml and administered orally to rats at a dose of 1000 mg/kg. No rats died 24 hours after administration.

Claims (16)

P A T.E NT CLAIMS An indole derivative of the general formula Y 4000-Y 1 (where R is ethyl or 2,2,2-trifluoroethyl, Y is hydroxy or pivaloyloxy, with the proviso that when R is 2,2,2-trifluoroethyl, Y is pivaloyloxy and the carbon atom labeled (R) represents a carbon atom in the (R) -configuration) or a pharmaceutically acceptable salt thereof. An indole derivative according to claim 1, having the general formula CONH ₂ O (wherein R is ethyl or 2,2,2-trifluoroethyl and the carbon atom designated with (R) is a carbon atom in the (R) -configuration) or a pharmaceutically acceptable salt thereof. -31 · · · 31 31 31 31 31 31 31 31 31:::::::::::::: · ············ · 444 44 4 ·· 4 4 « The indole derivative according to claim 1, having the general formula (wherein the carbon atom designated with (R) is a carbon atom in the (R) -configuration) or a pharmaceutically acceptable salt thereof. 4. A pharmaceutical composition comprising an indole derivative of the general formula (wherein R is ethyl or 2,2,2-trifluoroethyl, Y is hydroxy or pivaloyloxy, provided that when R is 2,2, 2-trifluoroethyl, Y is pivaloyloxy, and the carbon atom designated (R) is the carbon atom in the (R) -configuration) or a pharmaceutically acceptable salt thereof. 5. A pharmaceutical composition according to claim 4, characterized ¹ in that an indole derivative of the general formula • • · · · • // Ν CONH ₂ ο O = / (wherein R is ethyl or 2,2,2-trifluoroethyl and the carbon atom designated with (R) is a carbon atom in the (R) -configuration) or a pharmaceutically acceptable salt thereof. 6. A composition according to claim 1, wherein the active ingredient is an indole derivative of the general formula (wherein R is ethyl or 2,2,2-trifluoroethyl, Y is hydroxy or pivaloyloxy and the carbon atom designated ¹ (R)). represents a carbon atom in the (R) -configuration) or a pharmaceutically acceptable salt thereof. ······ · <· • ··· ·. · ·. ··. ···· -33- ....... An intraocular pressure reducing device according to claim 6, characterized in that it contains an indole derivative of the general formula (wherein R represents ethyl or 2,2,2-trifluoroethyl) and the carbon atom marked with (R) represents a carbon atom in the (R) -configuration) or a pharmaceutically acceptable salt thereof. Composition for the prevention or treatment of glaucoma or ocular hypertension, characterized in that it contains an indole derivative of the general formula (wherein R represents an ethyl group or 2,2,2-trifluoroethyl group, Y represents a hydroxy group or a pivaloyloxy group, and The carbon atom marked with (R) means a carbon atom (R) -configuration) or a pharmaceutically acceptable salt thereof. Composition for the prevention or treatment of glaucoma or ocular hypertension according to claim 8, characterized in that it contains an indole derivative of the general formula (wherein R represents an ethyl group or 2,2,2-trifluoroethyl group and a carbon atom marked with (R)) represents a carbon atom in the (R) -configuration) or a pharmaceutically acceptable salt thereof. 10. A method of preventing or treating glaucoma or ocular hypertension, comprising administering a therapeutically effective amount of an indole derivative of the formula: Y ······ 00 '·· ·· ·· · .0 * 0 · 0 * · · ·' '. ·, ·. ·. · · · · * · · · · · 9 · · _ _ 0 - ♦. ····· 0-0 00 0 -35- ······· ♦ ·. (Wherein R is ethyl or 2,2,2-trifluoroethyl, Y is hydroxy or pivaloyloxy and the carbon atom marked with (R) represents a carbon atom in the (R) -configuration) or a pharmaceutically acceptable salt thereof. A method of preventing or treating glaucoma or ocular hypertension according to claim 10, wherein a therapeutically effective amount of an indole derivative of the formula (wherein R is ethyl or 2,2,2-trifluoroethyl and the carbon atom marked with (R)) is administered. represents a carbon atom in the (R) -configuration) or a pharmaceutically acceptable salt thereof. 12. Use of an indole derivative of the general formula Ir (wherein R is ethyl or 2,2,2-trifluoroethyl, Y is hydroxyl or pivaloyloxy, and R · is an alkyl or pivaloyloxy group). Φ · φφ · · · · · · · · · · ·................... · Φ · · φ φ φ φ φ The carbon atom designated with (R) means the carbon atom in the (R) -configuration) or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the prevention or treatment of glaucoma or ocular hypertense. formulas Use of an indole derivative according to claim 12, wherein R is ethyl or 2,2,2-trifluoroethyl and the carbon atom marked with (R) is a carbon atom in the (R) -configuration) or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for preventing or treating glaucoma or ocular hypertension. 14. Use of an indole derivative of the general formula Y ΦΦ · · • • • • • • • • • • • • • • • • • • φ · φ φ ······ • *. · Φφφφ φ · φ -37 (wherein R is ethyl or 2,2,2-trifluoroethyl, Y is hydroxy or pivaloyloxy and the carbon atom designated with (R) is a carbon atom in the (R) -configuration) or a pharmaceutically acceptable salt thereof as a means of preventing or treating glaucoma or ocular hypertension. Use of an indole derivative according to claim 14, of the general formula (wherein R represents ethyl or 2,2,2-trifluoroethyl and the carbon atom marked with (R) represents a carbon atom in the (R) -configuration) or a pharmaceutically acceptable salt thereof as a composition for the prevention or treatment of glaucoma or ocular hypertension. A process for the preparation of a pharmaceutical composition for the prevention or treatment of glaucoma or ocular hypertension, characterized in that an indole derivative of the formula I is used as the active ingredient of the pharmaceutical composition. 9 · ♦ »··· 9 9 9 999 .. -3899 99 99 99 9 9 9 9 9 9 9 · • · * 4. 9 999 9 · 9 9 · • .4 9 '' · ... · · 9 9 9 (Where R is ethyl or 2,2,2-trifluoroethyl, Y is hydroxy or pivaloyloxy and the carbon atom marked with (R) is the carbon atom in (R) 9 9 9 9 9 9 9 9 9 9 9 or a pharmaceutically acceptable salt thereof. A process for the preparation of a pharmaceutical composition for the prevention or treatment of glaucoma or ocular hypertension according to claim 16, characterized in that an indole derivative of the general formula (wherein R represents ethyl or 2,2,2-trifluoroethyl) is used as the active ingredient of the pharmaceutical composition. and a carbon atom marked with (R) is a carbon atom in the (R) -configuration) or a pharmaceutically acceptable salt thereof.