MXPA00008396A - Indole derivatives and medicinal compositions containing the same - Google Patents

Abstract

Indole derivatives represented by general formula (I) or pharmacologically acceptable salts thereof which have a remarkable and long-lasting effect of lowering ocular tension and thus are useful as drugs for lowering ocular tension. In said formula, R represents ethyl or 2,2,2-trifluoroethyl;Y represents hydroxy or pivaloyloxy;and the carbon atom marked with (R) means one having the R-configuration.

Description

INDOL DERIVATIVES AND MEDICINAL COMPOSITIONS THAT CONTAIN THEM TECHNICAL FIELD The present invention relates to novel indole derivatives and their pharmaceutically acceptable salts, which are useful as medicaments DESCRIPTION OF THE PREVIOUS TECHNIQUE To date, for example, it is known that timolol maleate and isopropyl unoprostone are compounds that have been used as agents to reduce intraocular pressure. Recently, bunazosin hydrochloride, which has an α-adrenoreceptor blockade agent, has been used. (hereinafter referred to as et -> or blocker a,) quite different from the actions of these compounds, has been developed as an agentt; -t "-i glaucoma treatment and is of great attraction to the public, However, bunazosin hydrochloride was first developed as an agent for the treatment of hypertension. Therefore, the bunazosin isolate has a potent action on sargonial pressure and it is natural that it can induce such side effects. Stress and orthostatic hypotension Generally, most agents to reduce the intraocular pressure are applied topically as eye drops Even in this case, an active component distributes everything on the body through the bloodstream and is expected to show a systemic action. Therefore, it is desired that the expected systemic side effects be reduced to the minimum even in topical administration Compounds that are absorbed in the eyes immediately after application and act for a long period, are very preferable to act as typically as possible. Consequently, compounds that have a potent reducing effect on infra-ocular pressure With less incidence of lateral effects such as hypotension and orthostatic hypotension, they are quickly absorbed in the eyes after instillation and act for a long period and are highly recommended as agents to reduce infraocular pressure DESCRIPTION OF THE INVENTION The present invention relates to an indole derivative represented by the general formula (I) (wherein R represents an ethyl group or a 2,2,2-tr? fluoroetyl group, Y represents a hydroxy group or a pivaloyloxy group provided that Y represents a pivaloyloxy group when R represents a group 2,2,2- tpfluoroethyl, and the carbon atom marked with (R) represents a carbon atom in the (R) -configuration, or a pharmaceutically acceptable salt thereof. The present invention relates to a pharmaceutical composition comprising an indole derivative represented by the General Formula (wherein R represents an ethyl group or a 2,2,2-tr? fluoroetyl group, Y represents a hydroxy group or a pivaloyloxy group provided that Y represents a pivaloyloxy group when R represents a group 2,2,2- tpfluoroethyl, and the carbon atom labeled with (R) represents a carbon atom in the (R) -configuration, or a pharmaceutically acceptable salt thereof. The present invention relates to an agent for reducing infraocular pressure, which comprises as the active ingredient an mdol derivative represented by the general formula (wherein R represents an ethyl group or a 2,2,2-tr? fluoroetyl group, Y represents a hydroxy group or a pivaloyloxy group, and the carbon atom marked with (R) represents a carbon atom in the configuration (R)), or a pharmaceutically acceptable salt thereof The present invention relates to an agent for the prevention or treatment of glaucoma, or ocular hypertension, which comprises as the active ingredient an indole derivative represented by the general formula (wherein R represents an ethyl group or a 2,2,2-tr? fluoroetyl group, Y represents a hydroxy group or a pivaloyloxy group, and the carbon atom marked with (R) represents a carbon atom in the configuration (R)), or a pharmaceutically acceptable salt of the The present invention relates to a method for the prevention or treatment of glaucoma or ocular hypertension, which comprises administering a therapeutically effective amount of an indole derivative represented by the general formula (wherein R represents an ethyl group or a 2,2,2-tpfluoroetyl group, Y represents a hydroxy group or a pivaloyloxy group, and the carbon atom marked with (R) represents a carbon atom in the configuration ( R)), or a pharmaceutically acceptable salt thereof The present invention relates to the use of an indole derivative represented by the general formula (I) (wherein R represents an ethyl group or a 2,2,2-tr? fluoroetyl group, Y represents a hydroxy group or a pivaloyloxy group, and the carbon atom marked with (R) represents a carbon atom in the configuration (R)) or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the prevention or treatment of glaucoma or ocular hypertension The present invention relates to the use of an indole derivative represented by the general formula (wherein R represents an ethyl group or a 2,2,2-tr? fluoroetyl group, Y represents a hydroxy group or a pivaloyloxy group, and the carbon atom marked with (R) represents a carbon atom in the (R) configuration) or a pharmaceutically acceptable salt thereof, as an agent for the prevention or treatment of glaucoma or ocular hypertension. In addition, the present invention relates to a process for the manufacture of a pharmaceutical composition for the prevention or treatment of glaucoma or ocular hypertension, wherein the use, as an essential constituent of the pharmaceutical composition, of an indole derivative represented by the general formula (wherein R represents an ethyl group or a 2,2,2-tr? fluoroetyl group, Y represents a hydroxy group or a pivaloyloxy group, and the carbon atom marked with (R) represents a carbon atom in the configuration (R)) or a pharmaceutically acceptable salt thereof BEST MODE FOR CARRYING OUT THE INVENTION The inventors of the present have studied in order to find drugs that have a potent and prolonged effect blocker of a, with less side effects such as hypotension and orthostatic hypotension and with a high permeability in the eyes As a result, it has been found that (R) -1- (3-h? Drox? Prop? L) -5- [2 - [[2- [2- (2,2,2-tr? Fluoroethoxy?) Phenoxy ?] et? l] am? no] prop? l] -1H-? ndol-7-carboxamide (hereinafter referred to as compound A), one of the indole derivatives that were previously developed for the treatment of dysuria having a selective suppressive effect on urethral contractions with a blood pressure affectation (Japanese patent application published (Kokai) No Hei 7-330726), and hydrochloride of (R) -5- [2 - [[2- (2 -etox? fenox?) et? l] -am? no] prop? l] -1- (3-hydroxyl propyl) -1H-? ndol-7-carboxamide (hereinafter referred to as the compound B) have a blocking effect to (extremely potent, more than 70 times greater than bunazosin hydrochloride, with less incidence of side effects such as hypotension and orthostatic hypotension and that these compounds are expected to act for a long period, due to the low regimen of Excretion after penetration into the eyes and are useful as preferred agents for reducing infraocular pressure Further, since compounds A and B have a poor permeability of membranes such as cornea, the inventors of the present have studied in order to find derivatives having high membrane permeability and rapidly converting to poorly permeable membrane or A compound after penetration. As a result, it has surprisingly been found that the pyridic acid ester derivatives represented by the general formula (wherein R represents an ethyl group or a 2,2,2-tr? fluoroetyl group, the carbon atom marked with (R) represents an carbon in the (R) configuration) have an extremely high membrane permeability, quickly convert to compound A or B having a poor membrane permeability through hydrolase after penetration, and are extremely stable in aqueous solution, which is a normal form of eye drops, thus forming the basis of the present invention. Primarily, the inventors of the present have found that compounds A and B have a potent blocking effect - , and are preferred compounds as agents for reducing infraocular pressure. However, these compounds have poor corneal permeability and their concentration in aqueous humor is quite low when these compounds are topically applied as eye drops. Therefore, the inventors of the present have studied extensively in order to find a way to obtain a complete drug concentration in aqueous humor even when applied as eye drops. In order to find derivatives of compound A or B, which are easily converted to compound A or B, respectively, in the case of cornea penetration or in aqueous humor and are able to show their effec In this case, the inventors have converted compound A or B into several derivatives and have analyzed their ease of cleavage through endogenous hydrolase by measuring the conversion ratio in compound A or B in the blood with the course of time.

As a result, for example, it has surprisingly been found that conversion ratios of some ester derivatives of compound A to compound A after 30 minutes in the blood were extremely low, about 12% in the case of the butyrate derivative of 2-et? correspondingly, about 4% in the case of the corresponding 2,2-d-methale valerate derivative, about 3% in the case of the corresponding acetate, α-dimethylphenyl derivative and about 6% in the case of the derivative of corresponding 2,2-d-methylated butyrate, respectively Although the corresponding pivalate derivative had already been converted to compound A in the ratio of approximately 67% after 30 minutes and almost compound A after 2 hours In this way , the inventors of the present have found that the pivalate derivatives represented by the above general formula (Ia) of the present invention are different from other carboxylate derivatives and are com specific posts, which are easily converted to compound A or B through endogenous hydrolase in the cornea or aqueous humor. Next, the present inventors have measured the concentration of drug in aqueous humor after instillation in rabbit eyes with the time course in order to confirm the corneal permeability of this pivalate derivative For example, in the case of eye instillation of the pivalate derivative hydrochloride of compound B the drug concentration of compound B in aqueous humor was approximately 70 times greater after minutes and approximately 27 times greater after 2 hours than that in the case of instillation of the hydrochloride of compound B In this manner, the pivalate derivatives represented by the above general formula (Ia) of the present invention are extremely excellent compounds in permeability cornea and long-acting compounds Furthermore, in the previous experiment, the pivalate derivative in compound B was quickly converted to compound B in the case of cornea penetration or in aqueous humor and could not be detected in the aqueous humor at all yet after 20 minutes Accordingly, the pivalate derivatives represented by the above general formula (la) of the present invention are rapidly and favorably permeable through the cornea and have the property of being converted to the compound a or B, rapidly. Therefore, these are extremely preferred compounds to reveal the effect of compound A or B safely and quickly In fact, in an experiment using rabbits, it was confirmed that the pivalate derivatives represented by the above general formula (la) show a prolonged and very potent reducing effect on the infraocular pressure Accordingly, the pivalate derivatives represented by the above general formula ( la) are extremely useful compounds such as eye drops for the prevention or treatment of glaucoma or ocular hypertension In addition, the pivalate derivatives represented by the above general formula (la) of the present invention are hardly decomposed in the state of eye drops under high temperature and are extremely stable compounds. For example, when the pivalate derivative of compound A is allowed to stand for about 1 month at 40 ° C in the aqueous solution state, only about 0.1% of this compound decomposes to compound A. Similarly, about 1.1% of this compound is decomposed to compound A even at 70 ° C. In this manner, the pivalate derivatives represented by the above general formula (la) of the present invention are extremely stable compounds in the state of aqueous solution and eye drops containing the compounds are excellent in long storage stability. Therefore, the pivalate derivatives represented by the above general formula (la) of the present invention are highly suitable compounds for topical application as eye drops. The compounds represented by the above general formula (la) of the present invention, for example, can be prepared by protecting the secondary nitrogen atom of an indoline derivative represented by the general formula: (wherein R and the carbon atom marked with (R) have the same meanings defined above), with a protecting group such as a tert-butoxycarbonyl group in a usual manner, allowing the oxidation of the indole ring of the resulting compound in presence of a metal catalyst, such as palladium-carbon and ammonium formate to prepare the indole derivative represented by the general formula (wherein P represents a protective amino group, and R and the carbon atom marked with (R) has the same meanings defined above), allowing to react with a pivaloyl halide in the presence of a base according to the demands of the occasion and removing the protective group in a usual way Of the compounds represented by the above general formula (I) of the present invention, the pivalate derivatives represented by the above general formula (la) can also be prepared by protecting the secondary nitrogen atom of a mdoline derivative represented by the general formula above (II) with a protecting group such as a tert-butoxycarbonyl group in a usual manner, allowing the resulting compound to react with a pivaloyl halide in the presence of a base to prepare an indoline derivative represented by the following general formula (wherein P, R and the carbon atom marked with (R) have the same meanings above), allowing oxidation of the indoline ring of the resulting compound in the presence of a metal catalyst such as palladium-carbon and ammonium formate and removing the protecting group in the usual manner The indole derivatives represented by the above general formula (I) of the present invention can be converted to their pharmaceutically acceptable salts in the usual manner Examples of said salts include acid addition salts with mineral acids (for example, hydrochloric acid, hydrobromic acid, pregnant hydrocodone, sulfuric acid, nitric acid, phosphoric acid, and the like) and addition salts with organic acids (eg, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-acid). -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 indole derivatives represented by the above general formula (I) of the present invention and their pharmaceutically acceptable salts are used in the practical treatment, various administration forms are applicable. Among the forms, topical administration using eye drops and the like is preferred. the eyes can be conveniently formulated according to conventional methods. For example, eye drops can be prepared by adding the pivalate derivatives represented by the above general formula (Ia) of the present invention to sterile purified water, dissolving through the addition of conveniently pharmaceutical additives such as antiseptic eptics, isotonic agents and pH regulators, if necessary, under heating and filtration to remove dust and / or microbes. The dose is appropriately determined depending on sex, age, body weight, degree of symptoms, and the like, of each patient being treated For example, the instillation in eyes of the solution varying from 00001 to 05%, 1 to 3 times a day, is preferred in the case of eye drops EXAMPLES The present invention is further illustrated in more detail through the following reference examples, examples and test examples. The present invention is not limited thereto.

Reference Example 1 Benzoate of (R) -3-f7-c? Ano-5-y2 - [[2- (2-ethoxy? Pheno?) Et? Llam? Nol-prop? Ll-2,3-d? H-dro-1 H-? ndol-1-? llpropyl To a solution of potassium carbonate (32 3 g) in 130 ml of distilled water were added 120 ml of ethyl acetateand 12.0 g of (R) -3- [5- (2-aminopropyl) -7-c-ano-2-benzoate L-tartrate were added in portions to the mixture with stirring, 3-hydroquinol-1 H-β-nol-1-ylpropyl After the reaction for 1 hour, the reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with an aqueous solution of ethyl acetate. 10% potassium carbonate and brine subsequently, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give (R) -3- [5- (2-aminopropyl) -7-c benzoate. ? ano-2,3-d? h? dro-1 H-? ndol-1-? l] prop? lo (8 98 g) as a brown oil The benzoate of (R) -3- [5- (2-am? Noprop?) -7-c? Ano-2,3-d? H? Dro-1 H-? Ndol-1-? L] The resulting proprà ³ (8 98 g) was dissolved in 43 of tert-butanol. 7 02 g of 2- (2-ethoxyphenoxy) ethano methanesulfonate and 2 86 g of sodium carbonate were added to the solution, and the The mixture was heated under reflux overnight. The reaction mixture was concentrated in vacuo, a solution of saturated aqueous bicarbonate was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a bicarbonate solution. of saturated aqueous sodium and brine subsequently, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, the residue was purified by column chromatography on silica gel (eluent ethylacetate / methanol = 100/6 ) The azeotropic concentration of the resulting oily material gave (R) -3- [7-c? Ano-5- [2 - [[2- (2-etpxophenoxy?) Et? L] am? No] -prop benzoate. l] 2,3-d? h? dro-1 H-? ndol-1-? l] propylene (7 46 g) as a brown oil 1 H-NMR (CDCl 3) d ppm 1 04 (d, J = 6 OHz, 3H), 1 41 (t, J = 6 9Hz, 3H), 2 10-2 20 (m, 2H), 242 (dd, J = 13 6, 6 9Hz, 1H), 2 63 (dd , J = 13 6, 6 OHz, 1H), 2 80-3 10 (m, 5H), 3 50-3 60 (m, 2H), 3 75 (t, J = 7 3Hz, 2H), 00-4 15 (m, 4H), 440-4 50 (m, 2H), 6 85-7 00 (m, 6H), 740-7 50 (m, 2H), 7 50-7 60 (m, 1H), 8 00-8 10 (m, 2H) Specific rotation [] D2r = -14 8 ° (c = 1 04, ethanol) Reference Example 2 (R) -5-f2-ff2- (2-Etox? Pheno?) Et? Llam? Nolprop? Ll1-1- (3-h? Drox? Prop? L) -2.3-d? H-dro-1H-? ndol-7-carbon? trol was dissolved benzoate of (R) -3- [7-c? ano-5- [2 - [[2- (2-ethoxy? pheno?) et? l] am? no] prop? l] 2,3-d? h? dro-1 H-? ndol-1 -? l] prop? lo (7 32 g) in 46 ml of methanol and the solution added to a solution of 1 54 g of potassium hydroxide in 9 ml of distilled water After heating under reflux for 1 hour, the reaction mixture was concentrated in vacuo. 100 ml of distilled water was added to the residue and the resulting mixture was extracted with ethyl acetate. Ethyl acetate was washed with a saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was dissolved in 30 ml of toluene and the toluene was removed under vacuum. to give 6 06 g of (R) -5- [2 - [[2- (2-ethoxy? pheno?) et? l] am? no] prop? l] -1- (3-h? drox? prop l) -1-3-10 d? h? drox? prop? l) -2,3-d? h? dro-1 H-? ndol-7-carbon? tr? lo as a pale brown oil 'H-NMR (CDCl 3) d ppm 1 05 (d, J = 6 OHz, 3 H), 1 41 (t, J = 6 9 Hz, 3 H), 1 50-1 90 (m, 1H), 1 85-2 00 (m, 2H), 2 43 (dd, J = 13 6, 6 9Hz, 1H), 2 63 (dd, J = 13 6, 6 3Hz, 1H), 2 80-3 10 (, 5H), 3 50-3 60 (m, 2H), 15 3 67 (t, J = 7 3Hz, 2H) , 3 75-3 85 (, 2H), 4 00-4 15 (, 4H), 6 85-7 30 (m, 6H) Specific rotation [a] D27 = -194 ° (c = 1 06, Methanol) Reference Example 3 (R) -5-f2-rr2- (2-etox? Pheno?) Et? Llam? Nol? Rop? Ll-1- (3-h? Drox? Prop? L) -2.3 - d-H? dro-1H-? ndol-7-carboxam? da 5.95 g of (R) -5- [2 - [[2- (2-ethox? pheno?) et? l] am? no] prop? l] -1- (3-hydroxypropyl) -2,3-d? h? dro-1 H-indole-7-carbon? tr? lo in 164 ml of dimethyl sulfoxide , and a solution of 25 N of 5 N sodium hydroxide solution was added to the solution. 1! the mixture was added with 1 55 ml of 30% hydrogen peroxide keeping the internal temperature below 25 ° C and the mixture was stirred overnight at an internal temperature of 25-30 ° C. A solution of 2 39 was added. g of sodium sulfite and 82 ml of distilled water to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate mixture was washed with a saturated aqueous sodium bicarbonate solution, distilled water and subsequently brine. , and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, the residue was recrystallized from ethyl acetate to give (R) -5- [2 - [[2- (2-ethoxyphenoxy) et? L] am? No] prop? L] -1- (3-hydroxy prop ?) -2,3-d? h? dro-1H-? ndol-7-carboxam? da (4 72 g)? -NMR (CDCI3) d ppm 1 07 (d, J = 6 2Hz, 3H), 1 37 (t, J = 7 OHz, 3H), 1 60-1 85 (m, 3H), 2 54 (dd, J = 13 6, 6 5Hz, 1H), 2 68 (dd, J = 13 6, 64Hz, 1H), 2 85-3 10 (m, 6H), 3 19 (t, J = 6 6Hz, 2H), 3 35-345 (m, 2H), 3 75 (t, J = 54Hz, 2H ), 3 95-4 20 (m, 4H), 5 70 (br s, 1H), 6 66 (br s, 1H), 6 80-6 95 (m, 4H), 7 02 (s, 1H), 7 16 (s, 1H) Specific rotation [a] D27 = -15 3 ° (c = 0 98, Methanol) Reference Example 4 (R) -N-f2-r7-carbamo? Lo-1- (3-h? Drox? Prop? L) -2,3-d? H? Dro-1H-? Ndol-5- ? ll-1-met? let? ll-N-l2- (2-ethoxyl-phenoxy) -tert-butylcarbamate 10 9 g of (R) -5- [2 - [[2- 2- (2-ethoxy-phenoxy?) Et? L] am? No] prop? L] -1- (3-hydroxy propylene) -2.3-d? H? Dro-1H-? Ndol- 5-carboxamide in 100 ml of methylene chloride, and drop was added to drop a solution of 5 87 g of di-tert-butyl dicarbonate in 25 ml of methylene chloride to the solution under stirring with ice cooling. After stirring for 30 minutes under the same condition, the reaction mixture was stirred for 10 minutes. hours at room temperature The reaction mixture was concentrated in vacuo, and the residue was dissolved in 150 ml of ethyl acetate. The solution was washed with a 10% aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution and brine. Subsequently, and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to give 10 2 g of (R) -N- [2- [7-carbamoyl-1- (3-hydroxypropyl) ) -2,3-d? H? Dro-1H-? Ndol-5-? L] -1-met? Let? L] -N- [2 - (- ethoxy? Pheno?) Et? L] carbamate tert-butyl as a pale brown amorphous part 'H-NMR (CDCl 3) d ppm 1 20-1 50 (m, 15H), 1 70-1 85 (m, 2H), 2 50-440 (m, 18H ), 5 75 (br h, 1 H), 6 63 (br s, 1 H), 6 80-7 20 (m, 6 H) Specific Rotation [] D27 = -504 ° (c = 1 27, Meta nol) Example 1 (R) -5-l2-lf2- (2-ethoxy? Pheno?) Et? Llam? Nolprop? Ll-1- (3-h? Drox? Prop? L) -1 H-? Ndol-7-carboxam (Compound B) 4.93 g of (R) -N- [2- [7-carbamo] -1- (3-hydroxypropylene) -2,3-d? h were dissolved. dro-1H-? ndol-5-? l] -1-met? let? l] -N- [2 - (- 2-ethoxy? pheno?) et? l] tert-butyl carbamate in 150 ml of methanol , and 490 mg of 10% palladium on carbon and 2 96 g of ammonium formate were added to the solution. Afterwards, the mixture was heated under reflux for 36 hours and cooled, the insoluble material was filtered The solvent was removed in vacuo, and the residue was dissolved in 150 ml of methanol. 450 mg of palladium on carbon and 2 96 g of ammonium formate were added to the solution. , the mixture was heated under reflux for 24 hours and cooled, the insoluble material was filtered The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate The solution was washed with water and brine, and dried over sodium sulfate Anhydrous The solvent was removed in vacuo to give 4 55 g of (R) -N- [2- [7-carbamoyl-1- (3-hydroxylpropyl) -1 H-? ndol-5 -? l] -1-met? let? l] -N- [2 - (- 2-ethoxy? pheno?) et? lj-amorphous tert-butyl carbamate, white H-NMR (CDCI3) d 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 m, 7H), 5 75-5 95 (m, 1H), 640-6 65 (m, 2H), 6 75-7 55 (m, 7H) Specific rotation [a] D30 = -47 8 ° (c = 1 05, Methanol) 445 g of (R) -N- [2- [7-carbamoyl-1 - (3-hydroxypropylene) -2,3-d? H? Dro-1H-? Ndol- were dissolved. 5-? L] -1-met? Let? L] -N- [2 - (- 2-ethoxypheno?) Et? L] tert-butyl carbamate in 150 ml of isopropanol, and added in portions ml of concentrated hydrochloric acid to the solution under ice-cooling with stirring. After the mixture was stirred for 3 hours at room temperature, a solution of saturated aqueous sodium bicarbonate was added to the reaction mixture under cooling with ice and the mixture was stirred. extracted with ethyl acetate The ethyl acetate layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by column chromatography on aminopropyl silica gel (eluent methylene chloride / methanol = 20/1) to give 1 25 g. of (R) -5- [2 - [[2- (2-ethoxy? pheno?) et? l] am? no] prop? l] -1- (3-h? drox? prop? l) -1H White amorphous -dol-7-carboxamide The unpurified mixture was further purified through column chromatography on aminopropyl silica gel (eluent ethylacetate / ethanol = 7/1) and the purified product was combined with the product previously purified to give 2.39 g of (R) -5- [2 - [[2- (2-ethoxy? pheno?) et? l] am? no] prop? l] -1- (3- hydroxy? propyl) -1H-? ndol-7-carboxamide amorphous white 'H-NMR (CDCl 3) d ppm 1 11 (d, J = 6 3Hz, 3H), 1 25 (t, J = 7 OHz, 3H), 1 95-2 10 (, 2H), 2 70-3 20 (m, 6H), 3 52 (t, J = 5 6Hz, 2H), 3 93 (q, J = 7 OHz, 2H), 4 00-4 20 (m, 2H), 4 38 (t, J = 7 OHz, 2H), 5 90 (br s, 1H), 6 38 (br s, 1H), 649 (d, J = 3 2Hz, 1H), 6 75- 6 95 (m, 4H), 7 11 (d, J = 3 2Hz, 1H), 7 19 (d, J = 1 5Hz, 1H), 7 53 (d, J = 1 4Hz, 1H) Specific rotation [a ] D30 = -15 5th (c = 1 02, Methanol) EXAMPLE 2 (R) -5-L2-ll2- (2-ethoxy? Pheno?) Et? Llam? Nolprop? Ll-1- (3-h? Drox? Prop? L) -1H-? Ndol- hydrochloride 7-carboxamide (Compound B Hydrochloride) 862 mg of (R) -5- [2 - [[2- (2-ethoxy? Pheno?) Et? L] am? No] prop?] - was dissolved 1- (3-hydroxylpropyl) -1H-? Ndol-7-carboxamide in 5 ml of ethanol, and 985 μl was added to the solution of 2N hydrochloric acid The solvent was removed in vacuo, the residue was dissolved in 3 ml of ethanol, and 12 ml of ethyl acetate was added to the solution. Then, the mixture was allowed to stand, the resulting crystals were collected through filtration to give (R) -5- [2 - [[2- (2-ethoxy? pheno?) et? l] am? no] prop? l] -1- (3-hydrox? prop?) hydrochloride l) -1 H-? ndol-7-carboxamide (821 mg) H-NMR (DMSO-d6) d ppm 1 19 (d, J = 6 4Hz, 3H), 1 26 (t, J = 7 OHz , 3H), 1 70-1 85 (m, 2H), 2 65-2 80 (m, 1H), 3 20-3 55 (m, 5H), 3 64 (br s, 1H), 4 02 (q , J = 7 OHz, 2H), 4 20-440 (m, 4H), 4 55 (t, J = 5 OHz, 1H), 645 (d, J = 3 1Hz, 1H), 6 85-7 15 ( m, 5H), 7 36 (d, J = 3 1Hz, 1H), 749 (d, J = 1 3Hz, 1H), 7 60 (br s, 1H), 7 99 (br s, 1H), 9 05 -9 30 (m, 2H) Specific rotation [a] D30 = -7 8o (c = 1 16, Methanol) Example 3 Pivalate of (R) -3-f7-carbamoyl-5-l2-ll2- (2-ethoxyphenoxy) et? Llam? Nol-prop? Ll-1 H-? Ndol-1-propyl propyl ( Compound C) 6 24 g of (R) -N- [2- [7-carbamoyl-1- (3-hydroxyl-propyl) -2,3-d? 1H-? Ndol-5-? L] -1-met? Let? L] -N- [2- (2-ethoxypheno?) Et? L] tert-butyl carbamate in 94 ml of dry pipdine, and 1 54 ml of pivaloyl chloride was added to the solution. The mixture was stirred overnight at room temperature, and a solution of saturated aqueous sodium bicarbonate was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the Ethyl acetate layer with an aqueous sodium bicarbonate solution Saturated and brine, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by column chromatography on aminopropyl silica gel (eluent: hexane / ethyl acetate = 1/1). to give pivalate of (R) -3- [5- [2- [N- (tert-butox? carbon? l) -N- [2- (2-ethoxy? pheno?) et? l] am? no] -prop? l] -7-carbamo? -2,3-d? h? dro-1 H-? ndol-1-? l] colorless, amorphous proprion (4 30 g) 1H-NMR (CDCI3) d 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 85-440 (m, 7H), 5 52 (br s, 1H), 6 80-740 (, 7H) Specific rotation [] D27 = -38 3 ° (c = 1 03, Methanol) 8 53 g of (R) -3- [5- [2- [N- (tert-butoxycarbonyl) -N- [2- (2-ethoxyphenoxy) et? L] pivalate were dissolved. am? no] -prop? l] -7-carbamo? l-2,3-d? h? dro-1 H?? ndol-1-? l] prop? lo in 280 ml of methanol, and were added to the solution 853 mg of 10% palladium on carbon and 3 97 g of ammonium formate The mixture was heated under reflux for 13 hours, and the crystals were filtered The solvent was removed in vacuo to give pivalate of (R) -3- [5- [2- [N- (tert-butox? Carbon? L) -N- [2- (2-ethoxy? Pheno?) Et? L] am? No] -prop? L] -7-carbamo? l-1H-? ndol-1-? l] propylene pale green, amorphous (8 20 g)? -NMR (CDC) d 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 (br s, 1H), 6 35 -6 50 (m, 2H), 6 75-7 55 (m, 7H) Specific rotation [a] D 7 = -44 5 ° (c = 1 06, methanol) 7.81 g of (R) -3- [5- [2- [N- (tert-butoxycarbonyl) -N- [2- (2-ethoxyphenoxy) et? L] pivalate were dissolved. ammonium] -propyl] -7-carbamoyl-1H-β-ddol-1-? l] propylene in 78 ml of isopropanol, and 39 ml of concentrated hydrochloric acid were added dropwise during a 10 minute period to the solution under cooling with ice, with stirring. After, the mixture was stirred for 4 hours at room temperature, the reaction mixture was stirred to a pH of 8 by adding sodium bicarbonate powder under ice cooling with stirring The mixture was diluted with 200 ml of water and extracted with ethyl acetate. The ethyl acetate layer was washed with a solution of saturated aqueous sodium bicarbonate, water and brine subsequently, and dried over anhydrous sodium sulfate. The mixture was removed under vacuum, and the residue was purified through a column on aminopropyl silica gel (eluent ethyl acetate) and recrystallized from diethyl ether / hexane (2/1) to give pivala of (R) -3- [7-carbamo? l-5- [2 - [[2- (2-ethoxy? pheno?) et? l) am? no] -propyl I] - 1 H-? ndol -1-? L) propylene (521 g) as colorless crystals' H-NMR (CDCI3) d ppm 1 11 (d, J = 6 2Hz, 3H), 1 21 (s, 9H), 1 27 (t, J = 7 OHz, 3H), 1 95-2 10 (m, 2H), 2 75 (dd, J = 13 6 , 64Hz, 1H), 2 85 (dd, J = 13 6, 6 6Hz, 1H), 2 95-3 10 (m, 3H), 3 85-400 (, 4H), 4 00-4 20 (m , 2H), 4 35-4 45 (m, 2H), 5 55-5 65 (br s, 1H), 6 05-6 20 (br s, 1H), 6 47 (d, J = 3 2Hz, 1H ), 6 756 95 (m, 4H), 7 06 (d, J = 3 2Hz, 1H), 7 21 (d, J = 1 5Hz, 1H), 7 54 (d, J = 1 5Hz, 1H) Rotation specific [a] D27 = -15 8o (c = 1 06, methanol) EXAMPLE 4 The following compound was prepared according to a similar form to that described in Example 3 using (R) -N- [2- [7- carbamoyl-1- (3-hydroxypropyl)) -2,3-d? H? Dro-1H-? Ndol-5-? L] -1-met? L] -N- [2-5 [2- (2,2,2-tr? Fluoro-etox ?) phenoxy] tert-butyl carbamate in place of (R) -N- [2- [7-carbamo? 1- (3-hydrox? prop?) -2,3-d? h ? d-1H-? ndol-5-? l) -1- met? let? l] -N- [2- (2-ethoxy? pheno?) - et? l] tert-butyl carbamate Pivalate of (R) -3-f7-Carbamo? L-5-f2-fr2-12- (2,2.2-tr? Fluoroethoxy?) - 10 phenoxyl? Llam? Nolprop? Ll-1H-? Ndol-1 -? Compound D) 1 H-NMR (CDCl 3) d ppm 1 11 (d, J = 6 2Hz, 3H), 1 21 (s, 9H), 2 00-2 10 (m, 2H), 2 73 (dd, J = 13 5, 6 5Hz, 1H), 2 84 (dd, J = 13 5, 6 8Hz, 1H), 2 95-3 15 (m, 3H), 3 90-400 (m, 2H), 4 00-4 30 (m, 4H), 15 4 35-445 (m, 2H), 5 73 (br s, 1H), 6 10 (br s, 1H), 647 (d, J = 3 2Hz, 1H), 6 80-7 05 (, 4H), 707 (d, J = 32Hz, 1H), 7 19 (d, J = 1 4Hz, 1H), 7 54 (d, J = 1 4Hz, 1H) Specific rotation [a] D27 = -17 5 ° (c = 0 79, Methanol) Example 5 Pivalate hydrochloride of (R) -3-17-carbamo-l-5-12-rf2- (2-ethoxyphenoxy) et? Llam? Nol-prop? L1-1H-? Ndol-1- • Compound (Compound Cl Clhydrate To a solution of 6 07 g of (R) -3- [7-carbamoyl-5- 5 [2 - [[2- (2-ethoxyphenoxy?) pivalate] et? l] am? no] prop? l] -1 H-? ndol-1 -? l] prop? lo in 58 mi of ethanol were added dropwise 11 6 ml of 1 N hydrochloric acid under ice-cooling, with stirring, and the mixture was stirred for 15 minutes under the same condition. The reaction mixture was concentrated in vacuo, and the residue was Ethanol was added after the azeotropic removal of water, the residue was dissolved in 6 ml of ethanol and 60 ml of ethyl acetate were added to the solution. After the mixture was allowed to stand for 16 hours at room temperature, the residue was obtained. g of resulting colorless crude crystals Afterwards, the crystals were combined with other crude crystals obtained in a similar manner, the reclassification of the combined crystal (8 12 g) to couple of ethanol / ethyl acetate 15/1) gave pivalate hydrochloride ( R) -3- [7-carbamo? L-5- [2 - [[2- (2-ethoxy? Pheno?) Et? L] am? No] prop? L] -1 H-? Ndol-1 - 1 l) pro pi I o (7 46 g), as colorless crystals 1 H-NMR (CDCl 3) d ppm 1 21 (s, 9 H), 1 29 (t, J = 7 OHz, 3 H), 1 45 (d, J = 6 5Hz, 3H), 1 95-2 10 (m, 2H), 3 12 (dd, J = 14 0, 7 2Hz, 1H), 3 30-3 60 (m, 3H), 3 85-4 05 (m, 5H), 4 30-4 50 (m, 4H), 5 87 (s, 1H), 640 (d, J = 3 2Hz, 1H), 6 80-7 00 (m, 4H), 7 05 (d, J = 3 2Hz, 1H), 7 33 (d, J = 1 5Hz, 1H), 7 36 (s, 1H), 7 50 (d, J = 1 5Hz, 1H), 9 10-9 30 (br s, 1H), 9 50-9 65 (br s, 1H) Rotation specific [a] D28 = -7 0 ° (c = 1 22, Methanol) Reference Example 5 2-Et? L-butyrate of (R) -3-r7-Carbamo? L-5-f2-fl2-f2- (2,2,2-tr? Fluoroethoxy?) - phenoxy? Let ? callol nolprop? ll-1 H-? pdol-1-? llpropol (Compound a) To a solution of 3.0 g of (R) -5- [2 - [[2- [2.2.2 -tr? fluoro-ethoxy?) fenox?] et? l] am? no] prop? l] -1- (3-hydro? prop?) -2.3-d? h? dro-1 H -? ndol-7-carboxamide in 50 ml of methylene chloride were added 1 32 g of di-tert-butyl dicarbonate was added under ice cooling, and the mixture was stirred for 30 minutes under ice-cooling and overnight at room temperature. The reaction mixture was concentrated in vacuo, and the residue was dissolved in 50 ml ethyl acetate The solution was washed with a 10% aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution and subsequently brine, and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to give ( R) -N- [2- [2-carbamo? L-1- (3-hydro? Propyl) -2,3-d? H? Dro-1H-? Ndol-5-? L] - 1-met? Let? L] -N- [2- [2- (2,2,2-tr? Fluoroethoxy?) Pheno?] - et? L] tert-butyl carbamate (2 99) amorphous brown pale 1 H-NMR (CDCl 3) d ppm 1 20-1 50 (m, 12H), 1 70-1 85 (m, 2H), 2 50-4 50 (m, 18H), 5 89 (br s, 1H), 6 69 (br s, 1H), 6 80-7 20 (m, 6H) Specific rotation [a] D25 = -41 6 ° (c = 12, methanol) 300 g of methanol were dissolved in 12 g of (R) -N- [2- [2-carbamoyl-1- (3-hydroxylpropyl) -2,3-d? -1H-? Ndol-5-? L] -1-met? Let? L] -N- [2- [2- (2,2,2-tr? Fluoroethoxy?) Phenox?] - et? L] tert-butyl carbamate of ter- butyl and 12 7 g of ammonium formate, and 20 g of 10% palladium on carbon were carefully added to the solution. The mixture was heated overnight under reflux, and the solvent was removed under vacuum. 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 solvent was removed under vacuum to give 12.2 g of (R) -N- [2- [7 -carbamo? -1- (3-h? drox? -prop? l) -1H-? ndol-5-? l] -1-met? let? l] -N- [2- [2- (2 , 2,2-tr? Fluoroethoxy?) - phenox?] Et? L] tert-butyl carbamate, amorphous' H-NMR (CDCl 3) d ppm 1 1-1 4 (m, 12H), 1 95-2 1 (m, 2H), 2 7-3 0 (m, 2H), 325-3 7 (m, 4H), 3 8-42 (m, 3H), 43-46 (m, 4H), 591 (br s , 1H), 645-6 6 (m, 2H), 6 75-7 6 (m, 7H) Specific rotation [a] D27 = -44 50 (c = 11, methanol) 2 00 g of R) -N- [2- [7-carbamo? L-1- (3-h? Drox? -prop? L) -1H-? Ndol-5-? L] -1-met were dissolved. ? let? l] -N- [2- [2- (2,2,2-tr? fluoroethoxy?) pheno?] - tert-butyl ethyl-carbamate in 3 ml of dry pipdine, and 0.54 was added to the solution. g of 2-yl chloride Ib uti p lo prepared from 2-et? l-butyric acid and oxahl chloride After the mixture was stirred overnight at room temperature, it was added to the reaction mixture. a solution of saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution and subsequently brine, and dried over anhydrous magnesium sulfate. removed under vacuum, and the residue was purified through column chromatography on silica gel (eluent hexane / ethyl acetate = 2/1) to give 1 66 g of 2-ethylbutyrate of (R) -3- [5- [2- [N- ( ter-butox? carbon? l) -N- [2- [2- (2,2,2-tr? uoro-ethoxy?) pheno?] et? l] am? no] prop? l] -7-carbamo β-1 H- β-ndol-1- l l] propyl H-NMR (CDCl 3) d ppm 0 90 (t, J = 74 Hz, 6 H), 1 10-1 40 (m, 12 H), 1 45-1 70 (m, 4H), 1 90-2 10 (m, 2H), 2 15-2 30 (m, 1H), 2 70-3 00 (m, 2H), 3 30-3 70 (m, 2H), 380-4 70 (m, 7H), 4 36 (q, J = 8 4Hz, 2H), 5 62 (br s, 1H), 6 40-6 50 (m, 2H), 6 85-740 (m, 6H), 7 45-7 55 (m, 1H) Specific rotation [a] D31 = -41 8 ° (c = 099, Methanol) 1 56 g of 2-etylbutyrate of (R) -3- [5- [2- [N- (tert-butoxycarbonyl) -N- [2- [2- (2, 2,2-tr? Uoro-ethoxy?) Pheno?] Et? L] am? No] prop? L] -7-carbamo? L-1 H-? Ndol-1-ylpropyl in 10 ml of isopropanol, and 5 ml of concentrated hydrochloric acid were added dropwise to the solution under cooling with ice, with stirring. After the mixture was stirred for 4 hours at room temperature, a solution of saturated sodium bicarbonate was added to the reaction mixture under cooling. with ice, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the residue was purified through gel column chromatography. of silica (eluent methylene chloride / methanol = 20/1) and recrystallized from diethyl ether / hexane to give 10 g of 2- et I I but of (R) -3- [7-carbamo? l- [5- [2 - [[2- [2- (2,2,2-tr? uoro-ethoxy?) pheno?] et? l] amnot] prop? l] -1H-? ndol-1-? l] propylene as white crystals' HN R (CDC) d ppm 0 90 (t, J = 74Hz, 6H), 1 11 (d, J = 6 2Hz, 3H), 5 1 45-1 70 (m, 4H), 2 00-2 10 (m, 2H), 2 15-2 25 (m, 1H), 2 65-2 90 (m, 2H), 2 95-3 15 (m, 3H), 3 99 (t, J = 6 3Hz, 2H), 4 00-4 30 (m, 4H), 441 (t, J = 6 9Hz, 2H), 5 64 (br s, 1H), 6 07 (br s, 1H), 647 (d, J = 3 2Hz, 1H), 6 80-7 05 (m, 4H), 7 08 (d, J = 3 2Hz, 1H), 7 19 (d, J = 1 6Hz, 1H), 7 54 (d, J = 1 6Hz, 1H) 10 Specific rotation [a] D30 = -164 ° (c = 1 00, Methanol ) Reference Example 6 The following compounds were prepared according to a form similar to that described in Reference Example 5, 15 using the corresponding acid halide in place of 2-ethylenebutyl chloride. 2, 2-D? Methylate (R) -3-f7-carbamo-l-5-l2-fl2-12- (2,2,2-tr? Fluoro-ethoxy?) Fenox? Let? Llam ? nolprop? ll-1H-? ndol-1-? llprop? (Compound b) 'H-NMR (CDCl 3) d ppm 0 90 (t, J = 7 3Hz, 3H), 11 11 (d, J = 6 2Hz, 3H), 1 18 (s, 9H), 1 19-1 28 ( m, 2H), 1 49-1 53 (m, 2H), 2 03-2 06 (m, 2H), 2 73 (dd, J = 13 5, 6 5Hz, 1H), 2 84 (dd, J = 13 5, 6 8Hz, 1H), 3 00-3 10 (m, 3H), 3 96 (t, J = 6 2Hz, 2H), 4 07-4 23 (m, 4H), 440 (t, J = 6 9Hz, 2H), 566 (brs, 1H), 609 (brs, 1H), 647 (d, J = 32Hz, 1H), 6 84-7 03 (m, 4H), 7 07 (d, J = 3 2Hz, 1H), 7 19 (d, J = 1 6Hz, 1H), 7 54 (d, J = 1 6Hz, 1H) Specific rotation [a] D30 = -16 2 ° (c = 0 82, Methanol) a.ct-dimethylphenylacetate of (R) -3-f7-carbamo? -5-l2-lf2-12- (2,2,2-tr? uoro-ethoxy?) pheno? let? lla? nolprop? ll- 1 H-βdol-1-propyl (Compound c) 'H-NMR (CDCl 3) d ppm 1 10 (d, J = 6 2Hz, 3H), 1 60 (s, 6H), 1 80-1 96 (m , 2H), 2 71 (dd, J = 13 7, 64Hz, 1H), 2 82 (dd, J = 13 5, 6 7Hz, 1H), 2 96-3 10 (m, 3H), 3 90 (t , 2H), 4 03-4 28 (m, 6H), 5 58 (br s, 1H), 6 00 (br s, 1H), 6 37 (d, J = 3 1Hz, 1H), 6 84-7 03 (m, 4H), 6 68 (d, J = 3 2Hz, 1H), 7 19 (d, J = 1 6Hz, 1H), 7 54 (d, J = 1 6Hz, 1H) Specific Rotation [a] D 9 = -137 ° (c = 1 15, methanol) 2,2-D? Met? Lbutton of (R) -3-r7-carbamo? -5-f2-ri2-r2- (2,2,2-tr? Fluoro-ethoxy?) Fenox? Let? call? nolprop? ll-1H-? ndol-1-? llprop? (Compound d) 1 H-NMR (CDCl 3) d ppm 0 85 (t, J = 7 5 Hz, 3 H), 1 12 (d, J = 6 2 Hz, 3 H), 1 17 (s, 6 H), 1 57 (q, J = 7 5Hz, 4H), 2 00-2 10 (m, 2H), 2 70-2 90 (, 2H), 2 95-3 15 (m, 3H), 397 (t, J = 6 2Hz, 2H), 4 00-440 (m, 4H), 4 40 (t, J = 7 OHz, 2H), 5 70 (br s, 1H), 6 12 (br s, 1H), 6 47 (d, J = 3 2Hz, 1H), 6 80-7 05 (m, 4H), 7 07 (d, J = 3 2Hz, 1H), 7 19 (d, J = 1 6Hz, 1H), 7 54 (d, J = 1 5Hz, 1H) Specific rotation [a] D31 = -15 4 ° (c = 1 00, Methanol) Test Example 1 Test to measure the α-adrenoreceptor blocking effect The vas deferens (approximately 1 5 cm from the testicle side) of male Wistar rats (with an approximate body weight of 300 to 350 g) were isolated after the removal of the Blood vessel and connective tissue, each preparation was suspended vertically in a Magnus bath containing 10 ml of a Krebs-Henseleit solution maintained at 37 ° C and gassed with a mixture of 95% oxygen and 5% low carbon dioxide a resting tension of 1 g A solution of a mixture containing propranorol and yohimbine (concentration 1 μM propranorol and 1 μM yohimbine) was added to the Magnus bath After 30 minutes, norepinephrine was added to the final concentration of 10 μM in the bath of Magnus until the maximum concentration was obtained, and each precipitation was washed. This procedure was repeated several times until the concentration heights were stable. was pretreated with a solution containing the test compound 30 minutes before, and the contractile responses were measured through the treatment of 10 μM of norepinephrine. The concentration of each preparation without the pretreatment of the test compound was expressed as 100% The blocking effect The adrenoreceptor of the test compound was evaluated as the molar concentration of the required compound producing a 50% inhibition of the concentration before the addition of norepinephrine (ie, IC50 value). The results were as follows. shown in Table 1 TABLE 1 Test Example 2 Test to measure the concentration of drug in aqueous humor (1) (1) Method After a solution at 0 1% of hydrochloride of (R) -5- [2 - [[2- (ethoxy? -phenoxy? ) et? l] am? no] prop? l] -1- (3-hydroxyl propyl) -1 H-? ndol-7-carboxamide (hydrochloride of Compound B) (50 μl) was instilled in the eye of Japanese white rabbits (weighing about 3lg, Japan SLC), the aqueous humor was collected over time To the collected aqueous humor (0 1 ml) was added 10 ng of (R) -3-chloro -1- (3-hydroxy propylene) -5- [2 - [[2- [2- (2,2,2-tr? Fluoroethoxy?) Phenox]] et? L] amnot] propylene] -1H-? ndol-7-carboxamide as an internal standard, and 0 1 M of phosphate pH regulator (pH 76) and about 1 g of sodium chloride were added to the mixture. The resulting mixture it was extracted with 5 ml of diethyl ether and the diethyl ether layer was concentrated under a stream of nitrogen. After, the residue was dissolved in the mobile phase (200 μl), 100 μl of the solution was injected into the chromate. liquid graph high performance and compound B was determined under the following conditions The results are shown in Table 2 (2) HPLC conditions Intersil ODS-3 analytical column (4 6 x 250 mm) Mobile phase aceton? tr? lo / 0 1% Phosphoric acid + 2mM sodium lauryl sulfate = 1/1 Column temperature 50 ° C Flow rate 1 0 ml / minute Fluorometry excitation wavelength 270 nm, emission wavelength 435 nm TABLE 2 Test Example 3 Test for the hydrolysis regime through endogenous enzyme (3) Method A whole blood (50 mL) collected from male Wistar rats as hepapnized blood was respectively added an ester derivative (1 μg) of (R) -1 - (3-hydroxylpropyl) - 5- [2 - [[2- [2- (2,2,2-tr? Fluoroethoxy?) Pheno?] Et? L] am? No] prop? L] -1H-? Ndol-7-carboxamide (Compound A) and [(R) -3-chloro-1 - (3-h? Drox? Prop? L) -5- [2 - [[2- (2- (2,2,2- tr? fluoroethoxy?] et? l] am? no] prop? l] -1H-? ndol-7-carboxamide] O M9), internal standard, and the mixture was incubated at 37 ° C. After 15 minutes, 30 minutes, 1 hour and 2 hours, 0 7 M of an aqueous sodium fluoride solution (0 5 ml) was added as a stearase inhibitor to each sample to retain the reaction. Phosphate pH (pH 7 6) and about 1 g of sodium chloride, the resulting mixture was extracted with 5 ml of diethyl ether, and the diethyl ether layer was concentrated under a stream of nitrogen. Then, the residue was dissolved in a mobile phase (300 μl), 10 μl of the solution was injected in high performance liquid chromatography, 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 Intersil ODS-3 (4 6 x 250 mm) Mobile phase aceton? Tr? Lo / 20 mM of acetate pH regulator (pH 0) = 40/60 Column temperature 50 ° C Flow rate 1 0 ml / minute Fluorometry excitation wavelength 270 nm, emission wavelength 435 nm TABLE 3 Test Example 4 Test to measure the concentration of drug in aqueous humor (2) 5 (1) Method Then, a 0 1% solution (50 μl of pivalate hydrochloride of (R) -3- [7-carbamoyl] -5- [2 - [[2- [2- ethoxy? Pheno?) Et? L] am? No] prop? L] 1H-? Ndol-1-? L] propyl (hydrochloride of compound C) is instilled over the eye of Japanese white rabbits (weighing approximately 3 kg, Japan SLC), the aqueous humor was collected over time. To the collected aqueous humor (0 1 ml) was added 10 ng of [(R) -3-chloro-1- (3-hydroxy propylene) -5- [2 - [[2- [2- (2,2,2-tr? Fluoroethoxy?) Phenoxy]] et? L] am? No] prop? ] -1H-? Ndol-7-carboxamide] (10 ng) internal standard, and added wing mix 0 1 M phosphate buffer (pH 7 6) and about 1 g sodium chloride The resulting mixture was extracted with 5 ml diethyl ether, and the diethyl ether layer was concentrated under a stream of nitrogen. the residue was dissolved in 200 μl of mobile phase, 100 μl of the solution was injected to chromatography high performance liquid, and compound C and (R) -5- [2 - [[2- (2-ethoxy? pheno?) et? l] am? no] prop? l] -1- (3- H? drox? prop?) -1H-? ndol-7-carboxamide (Compound B) were determined under the following conditions The results are shown in Table 4 (2) HPLC conditions Intersil ODS-3 analytical column (46 x 250 mm) Mobile phase aceton? Tplo / 0 1% phosphorus acid + 2mM sodium lauryl sulfate = 1/1 Column temperature 50 ° C Flow rate 1 0 ml / minute Fluorometry excitation wavelength 270 nm , emission wavelength 435 nm TABLE 4 Test Example 5 Stability test Test compounds were dissolved in 0 1 M acetate buffer (pH 50) to prepare 0 1% solutions Each 0 1% solution was allowed to stand in the dark for 28 days at 40 ° C, 50 ° C, 60 ° C and 70 ° C, respectively The results are shown in Table 5 TABLE 5 Test Example 6 Acute toxicity test They were fasted for 18 hours, male SD rats with an age of 7 weeks (n = 5, body weight 190-210 grams) Pivalate hydrochloride of (R) -3- [ 7-carbamo? L-5- [2 - [[2- (2-ethoxy? Pheno?) Et? L] am? No] prop? L] -1H-? Ndol-1-? L] prop? Lo , which was suspended in an aqueous solution of methylcellulose at 05% at a concentration of 100 mg / ml, was administered orally to the rats at a dose of 1000 mg / kg. Fatal rats were not observed for 24 hours after administration

Claims (1)

1. CLAIMS An indole derivative represented by the general formula: (wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group; Y represents a hydroxy group or a pivaloyloxy group provided that Y represents a pivaloyloxy group when R represents a 2,2,2-trifluoroethyl group; and the carbon atom marked with (R) represents a carbon atom in the (R) -configuration, or a pharmaceutically acceptable salt thereof. 2 - An indole derivative according to claim 1, represented by the general formula: (wherein R represents an ethyl group or a 2,2,2-tpfluoroetyl group, and the carbon atom marked with (R) represents a carbon atom in the (R) -configuration), or a pharmaceutically acceptable salt thereof. same 3 - The indole derivative according to claim 1, represented by the formula (wherein the carbon atom marked with (R) represents a carbon atom in the (R) -configuration) or a pharmaceutically acceptable salt thereof. 4 - A pharmaceutical composition comprising an indole derivative represented by the general formula (wherein R represents an ethyl group or a 2,2,2-tr? fluoroetyl group, Y represents a hydroxy group or a pivaloyloxy group provided that Y represents a pivaloyloxy group when R represents a 2,2,2-tpfluoroethyl group, and the carbon atom marked with (R) represents a carbon atom in the (R) configuration ), or a pharmaceutically acceptable salt thereof - A pharmaceutical composition according to claim 4, comprising an mdol derivative represented by the general formula (wherein R represents an ethyl group or a 2,2,2-tr? fluoroetyl group, and the carbon atom marked with (R) represents a carbon atom in the (R) -configuration), or a pharmaceutically salt acceptable thereof 6 - An agent for reducing infraocular pressure, which comprises, as the active ingredient, an indole derivative represented by the general formula (wherein R represents an ethyl group or a 2,2,2-tr? fluoroetyl group, Y represents a hydroxy group or a pivaloyloxy group, and the carbon atom marked with (R) represents a carbon atom in the configuration (R)), or a pharmaceutically acceptable salt thereof 7 - An agent for reducing infraocular pressure according to claim 6, which comprises, as the active ingredient, an indole derivative represented by the general formula (wherein R represents an ethyl group or a 2,2,2-tr? fluoroetyl group, and the carbon atom marked with (R) represents a carbon atom in the (R) -configuration), or a pharmaceutically salt acceptable thereof 8 - An agent for the prevention or treatment of glaucoma or ocular hypertension, which comprises, as the active ingredient, an mdol derivative represented by the general formula (wherein R represents an ethyl group or a 2,2,2-tr? fluoroetyl group, Y represents a hydroxy group or a pivaloyloxy group, and the carbon atom marked with (R) represents a carbon atom in the configuration (R)) or a pharmaceutically acceptable salt thereof 9 - An agent for the prevention or treatment of glaucoma, or ocular hypertension according to claim 8, which comprises, as the active ingredient, an indole derivative represented by the General Formula (wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group, and the carbon atom marked with (R) represents a carbon atom in the (R) -configuration), or a pharmaceutically acceptable salt thereof. 10. A method for the prevention or treatment of glaucoma or ocular hypertension, which comprises administering a therapeutically effective amount of an indole derivative represented by the general formula: (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 marked with (R) represents a carbon atom in the configuration (R)), or a pharmaceutically acceptable salt thereof 11 - A method for the prevention or treatment of glaucoma or ocular hypertension according to claim 10, which comprises administering a therapeutically effective amount of an indole derivative represented by the General Formula (wherein R represents an ethyl group or a 2,2,2-tr? fluoroetyl group, and the carbon atom marked with (R) represents a carbon atom in the (R) -configuration), or a pharmaceutically salt acceptable thereof 12 - A use of an indole derivative represented by the general formula (wherein R represents an ethyl group or a 2,2,2-tr? fluoroetyl group, Y represents a hydroxy group or a pivaloyloxy group, and the carbon atom marked with (R) represents a carbon atom in the configuration (R)), or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the prevention or treatment of glaucoma or ocular hypertension 13 -. 13 - The use according to claim 12, of an indole derivative represented by the general formula (wherein R represents an ethyl group or a 2,2,2-tr? fluoroetyl group, and the carbon atom marked with (R) represents a carbon atom in the (R) -configuration), or a pharmaceutically salt acceptable thereof, for the manufacture of a pharmaceutical composition for the prevention or treatment of glaucoma or ocular hypertension 14 - The use of an indole derivative represented by the general formula (wherein R represents an ethyl group or a 2,2,2-tr? fluoroetyl group, Y represents a hydroxy group or a pivaloyloxy group, and the carbon atom marked with (R) represents a carbon atom in the configuration (R)), or a pharmaceutically acceptable salt thereof, as an agent for the prevention or treatment of glaucoma or ocular hypertension 15 - The use according to claim 14 of an indole derivative represented by the general formula (wherein R represents an ethyl group or a 2,2,2-tr? fluoroetyl group, and the carbon atom marked with (R) represents a carbon atom in the (R) -configuration), or a pharmaceutically salt acceptable to it, as an agent for prevention or Treatment of Glaucoma or Ocular Hypertension 16 - A process for the manufacture of a pharmaceutical composition for the prevention or treatment of glaucoma or ocular hypertension, characterized by the use, as an essential constituent of said pharmaceutical composition, of an indole derivative represented by the General Formula (wherein R represents an ethyl group or a 2,2,2-tr? fluoroetyl group, Y represents a hydroxy group or a pivaloyloxy group, and the carbon atom marked with (R) represents a carbon atom in the configuration (R)), or a pharmaceutically salt thereof 17 - A process for the manufacture of a pharmaceutical composition for the prevention or treatment of glaucoma or ocular hypertension according to claim 16, characterized by use, as an essential constituent of said pharmaceutical composition, of an indole derivative represented by the general formula (wherein R represents an ethyl group or a 2,2,2-trifluoroethyl group, and the carbon atom marked with (R) represents a carbon atom in the (R) -configuration or a pharmaceutically acceptable salt thereof.