CZ20021833A3 - Crystal of [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxy-ethyl]amino]propyl]-1H-indol-7-yloxy] acetic acid and granules containing thereof, solid preparation, tablet, irritable agent and agent for therapy - Google Patents

Abstract

The present invention provides a solid preparation comprising a crystal of [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic acid (Compound A), especially a crystal of Compound A having a particle size of not larger than 100 mu m at the cumulative weight distribution value of 50 %, and not larger than 200 mu m at the cumulative weight distribution value of 95 %, preferably a solid preparation having the excellent stability and the content uniformity of Compound A, which is prepared by preparing granules of the crystal of Compound A with fillers, disintegrants and binders, and then followed by mixing said granules with external excipients.

Description

[3 - [(2R) - [[(2R) - (3-Chlorophenyl) -2-hydroxyethyl] amino] propyl] -1H-indol-7-yloxy] acetic acid crystal containing granules, a tablet, an irritant and a treatment agent

TECHNICAL FIELD

The present invention relates to a crystal of [3 - [(2R) - [[(2R) - (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -1H-indol-7-yloxy] acetic acid (hereinafter referred to in this In particular, the present invention relates to a solid formulation in which the amount (volume) of the formulation, the uniform content of the active ingredient and the stability of the active ingredient are stabilized, and thus, further release of the active ingredient from the formulation is rapid.

BACKGROUND OF THE INVENTION

Compound A exhibits potent β ₃ -adrenaline receptor stimulating activity with excellent adrenoceptor selectivity and is useful for the prophylaxis or treatment of diabetes mellitus and obesity (WO 96/16938).

Compound A exhibits extremely potent pharmaceutical activities and is then used in the pharmaceutical composition. Such a composition should be a low-content composition in which the content of active compound per unit dose is low. However, depending on the decreasing content of Compound A in the formulation, it has been found that the chemical stability of Compound A as such decreases extremely. In addition, when the amount of other substances other than Compound A is increased such that the content suitable for use in the pharmaceutical composition is secured, the content of Compound A becomes uneven per unit dose and it is difficult to obtain a preparation, In these circumstances, it was desired to develop a composition of Compound A without the above-mentioned defects, and from which Compound A could be rapidly released.

It is an object of the present invention to provide a Compound A composition in which the size (volume capacity) of the composition, the content uniformity of Compound A and the stability of Compound A are assured as well as the ability of Compound A to dissolve rapidly from the composition.

i •

SUMMARY OF THE INVENTION

The present invention includes the inventions of the following various parts.

1) [3 - [(2R) - [[(2R) - (3-Chlorophenyl) -2-hydroxyethyl] amino] propyl] -1H-indol-7-yloxy] acetic acid crystal (hereinafter, occasionally referred to herein) as "crystal of compound A");

2) A crystal of [3 - [(2R) - [[(2R) - (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -1H-indol-7-yloxy] acetic acid having characteristic diffraction bands at diffraction angles (2 °) of about 5.9 °, about 17.9 °, about 20.5 °, and about 24.0 ° in the powder X-ray diffraction pattern (hereinafter, occasionally referred to as "Compound A Type 1 crystal");

3) A crystal of Compound A having a particle size of not more than 100 µm at a 50% cumulative weight distribution value and a particle size of not more than 200 µm at a 95% cumulative weight distribution value (hereinafter, occasionally referred to as "active ingredient, ,);

4) Granules comprising the aforementioned crystal (3) (active ingredient);

5) Granules comprising (a) the active ingredient, (b) a filler, (c) a disintegrant, and (d) a binder;

6) A solid preparation comprising the aforementioned granule (4);

7) A tablet which is formed by compressing said granule (4);

8) A tablet which is formed by compressing the aforementioned granule (4) with the other outer substances;

9) The β ₃ -adrenaline receptor irritant, which comprises the aforementioned crystal (3) (active ingredient);

10) An agent for the treatment of diabetes mellitus comprising the aforementioned crystal (3) (active ingredient); and

11) An agent for the treatment of obesity comprising the aforementioned crystal (3) (active ingredient).

Throughout the present specification and claims, "Compound A crystal" means pure [3 - [(2R) - [[(2R) - (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -1H-indole- 7-yloxy] acetic acid, and as described below, the crystal of compound A may be grouped into a type-I crystal ("type A-type I crystal") and a type-II crystal ("type-II crystal"). ) based on their diffraction bands of the X-ray diffraction profile. A type-I crystal, a type-II crystal, or a mixture of these crystals are obtained according to their production process. "Compound A crystal" includes all of these crystals.

"Active ingredient" means the above-mentioned crystal of compound A having a particle size of not more than 100 µm at a 50% cumulative mass distribution value and a particle size of not more than

200 µm at 95% cumulative weight distribution. The preferred particle size of the active ingredient is not greater than 50 µm at a 50% cumulative weight distribution value and not greater than 150 µm at a 95% cumulative weight distribution value. Most preferably, the particle size is not greater than 30 µm at a 50% cumulative weight distribution value and is not greater than 100 µm at a 95% cumulative weight distribution value. The "active ingredient" according to the present invention comprises all of the above substances.

"Cumulative mass distribution value" means a value that is obtained by classifying dusts based on the particle size present and adding masses to each particle size at the end of the distribution and expressed as a percentage of the total dust mass. Generally, the "particle size at 50% cumulative mass distribution value" is used as a method of expressing the particle size diameter of powders (particle aggregate) having a particle size distribution. In addition, throughout the present specification and claims, "particle size at 95% cumulative mass distribution value" is used as an index to control the coarse particle content that affects the soluble behavior of the compound in the composition (see Alfonso R. Gennard (Ed.): Particle Size Measurement and Classification, Remington's Pharmaceutical Sciences 17th edition, Part 8, Chapter 89, pp. 1588-1589, 1985; Swithenbank, J., Beer, JM, Taylor, DS, Abbot, D., and McCreath, GC: A Laser Diagnostics AIAA Paper No. 76-79 (1976) and Hayashi, S .: A Laser Smiles Angle Scattering Instrument for Sprays Determination of Size and Concentration, (Hirleman, ED and others Eds., Liquid Particle Size Measurement Techniques: 2nd Volume, Philadelphia, ASTM, 1990).

The crystal of Compound A of the present invention may be prepared according to the process as outlined in Scheme 1 below.

• ·

• · · · · · · · · · · · · ·

StepB

-►

Compounds of general formula I (wherein R is a protecting group or fenolhydroxy CH ₂ COX, X is a lower alkoxy group, benzyloxy group, lower alkyl, lower mono- and di-alkylamino group or a cyclic amino group) is reacted with a compound of formula II (wherein R ¹ is an amino protecting group and Y is a halogen atom) in the presence of a base to give a compound of formula III (wherein R ¹ and R ¹ are as defined above). The thus obtained compound III is further reacted with a reducing agent to give a compound of formula IV (wherein R is a hydrogen atom or an amino protecting group and R is as defined above). Then, (i) when R in formula IV is a phenolhydroxy protecting group (and if R ¹¹ of formula IV is a hydrogen atom, then the amino group of formula IV is again protected), the phenolhydroxy protecting group is selectively removed resulting in ··· ················ 1 · ·

the compound of formula V (wherein R ¹ is as defined above) is reacted with a compound of formula VI (wherein Y ¹ is an alcohol reactive moiety and X is as defined above) and further the amino protecting group is selectively removed to effect to form compound VII; or (ii) when R of formula IV is -CH ₂ COX, and R ¹¹ is an amino protecting group, the amino protecting group is selectively removed to give compound VII (where X is defined as above), and the resulting compound (VII) is reacted with a compound of formula (VIII) and subsequently the resulting compound is subjected to hydrogenolysis and hydrolysis under acidic or alkaline conditions to efficiently obtain a crystal of compound A.

The terms used in the crystal production process of Compound A of the present invention are explained below.

The terms "lower alkyl" and "lower alkyl" include straight chain or branched chain alkyl groups having from 1 to 6 carbon atoms, for example methoxy, ethoxy, propoxy and isopropoxy, more preferably methoxy, ethoxy and propoxy, and most preferably methoxy and ethoxy .

The term "mono- or di-lower alkylamino" includes, for example, methylamino, dimethylamino, ethylamino, methylethylmino, diethylamino, propylamino, isopropylamino and dipropylamino, more preferably methylamino, dimethylamino, ethylamino, diethylamino and dipropylamino, and most preferably dimethylamino and diethylamino.

The term "cyclic amino group" includes a 5- to 7-membered cyclic amino group, for example pyrrolidinyl, morpholinyl, piperidinyl and homopiperidinyl, more preferably pyrrolidinyl, morpholinyl and piperidinyl, most preferably pyrrolidinyl and piperidinyl.

The "phenolic hydroxy protecting group and the amino protecting group" may be conventional protecting groups that are used in the field of organic synthesis (e.g., TW Greene, PGM Muts, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc, Second Edition, 1991, pp. 143-170 and pp. 309-385) and include substituents that are readily removable by reduction or hydrolysis. The combination of a phenolic hydroxy protecting group and an amino protecting group should be selected such that one of the groups can be selectively removed.

The term "phenolic hydroxy protecting group" includes, for example, methyl, methoxymethyl, methoxyethoxymethyl, tetrahydropyranyl, phenacyl, allyl, isopropyl, tert-butyl, benzyl, diphenylmethyl, triphenylmethyl, acetyl, pivaloyl, benzoyl, methoxycarbonyl, 2,2,2trichlorethoxycarbonyl and benzyloxycarbonyl, more preferably methyl, tert-butyl, benzyl, diphenylmethyl, triphenylmethyl and allyl and most preferably methyl, benzyl, diphenylmethyl and triphenylmethyl.

The term "amino protecting group" includes, for example, methoxycarbonyl, ethoxycarbonyl,

2,2,2-trichloroethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, vinyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, acetyl, trifluoroacetyl, benzoyl, phthalimido, p-toluenesulfonyl, benzenesulfonyl, methanesulfonylcarbonyl, benzyl, more preferably tert-butoxycarbonyl, benzyl; and trifluoroacetyl, and most preferably tert-butoxycarbonyl, benzyloxycarbonyl and 9-fluorenylmethoxycarbonyl.

The term "alcoholic reactive moiety" includes, for example, a halogen atom, a lower alkylsulfonyloxy group (eg: methanesulfonyl, ethanesulfonyl) and an arylsulfonyloxy group (eg: benzenesulfonyloxy, p-toluenesulfonyloxy).

A "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and more preferably a chlorine atom.

The process for producing the crystal of Compound A is explained in more detail below.

Step A - Preparation of Compound (III):

A compound of formula III can be prepared by reacting a compound of formula I with a compound of formula II in the presence of a base in a suitable solvent.

For example, the base includes sodium hydroxide, metal alkoxide, Grignard reagent, lithium alkyl, sodium amide, lithium dialkylamide, etc. Generally speaking, when an indole derivative reacts with a nucleophilic reagent in the presence of a base, a mixture of the compound substituted at position 1 and the compound substituted at position 3. Since the Grignard reagent is widely used in order to preferentially obtain a compound substituted in the 3-position, the Grignard reagent is also preferred in this step.

The Grignard reagent includes methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium bromide, magnesium tert-butyl chloride, magnesium phenyl chloride, etc., more preferably methylmagnesium bromide and tert-butylmagnesium chloride. The Grignard reagent is generally used in an amount of from about 1 to about 8 moles, more preferably from about 2 to about 4 moles, per 1 mol of the compound of formula (I).

The reaction is usually carried out at a temperature of about -50 ° C to about 30 ° C, more preferably at a temperature of about -20 ° C to about 0 ° C. The reaction is preferably carried out under an atmosphere of an inert gas such as nitrogen or argon. In addition, an inorganic reagent such as zinc chloride, aluminum chloride, copper bromide, etc. may be added to the reaction system. The solvent may be aromatic hydrocarbons (eg: benzene, toluene, etc.), ethers (eg:

··· »*

Diethyl ether, tetrahydrofuran, etc.), chloroform and methyl chloride, and such solvents should be in anhydrous form.

The compound of formula II can be prepared by reacting the protected amino group α-amino acid with an inorganic halide compound (eg: pentachlorophosphide, trichlorophosphide, tribromphosphide, etc.) or an organic halide compound (eg: phosphoryl chloride, thionyl chloride, oxalyl chloride, phosgene, etc.) .) in a suitable solvent. The halide compound is used in an amount of from about 1 to about 5 moles, more preferably in an amount of from about 1 to 2.5 moles, per 1 mol of the starting compound. Ν, Ν-dimethylformamide or hexamethylphosphoric triamide can be added to the reaction system. The reaction is usually carried out at a temperature of about 0 ° C to about 200 ° C, at a temperature of about 25 ° C to about 130 ° C. The solvent may be aromatic hydrocarbons (eg: benzene, toluene, etc.) or halogenated hydrocarbons (eg: chloroform, methylene chloride, etc.).

Step B - Preparation of Compound (IV):

A compound of formula IV may be prepared by subjecting a compound of formula III to reduction with a suitable reducing agent in a suitable solvent. For example, the reducing agent may be lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, boron sodium hydride, boron lithium hydride, calcium boron hydride, diborane, diisobutyl aluminum hydride, etc., and more preferably boron and alkali metal hydrides. The reduction of a compound of formula III wherein R is -CH ₂ COX should be carried out using a reducing agent that does not reduce the carbonyl group R. The reducing agent is used in an amount of about 2 to about 6 moles, more preferably in an amount of about 3 to 4 moles, per 1 mol of the compound of formula III. The reaction temperature may vary depending on the kind of reducing agent used, but is usually in the range of about 25 ° C to about 150 ° C. The solvent is selected according to the type of reducing agent used, and may be ethers (e.g., diethyl ether, tetrahydrofuran, etc.), toluene, chloroform, methylene chloride, methanol, ethanol, isopropanol, acetonitrile, water, etc ..

In step B, when a compound of formula IV wherein R is a phenolic hydroxy protecting group and R ¹¹ is a hydrogen atom, said compound is used in the subsequent step C after its amino group is again protected.

Introduction of the amino protecting group is accomplished by a conventional method in the field of peptide synthesis (i.e., Nobuo Izumiya et al., Fundamentals and Experiments of Peptide Synthesis, Maruzene, 1985, pp. 16-40). For example, a compound of formula IV, wherein R ¹¹ is a hydrogen atom, is reacted with di-tert-butyl carbonate in a suitable solvent.

at room temperature to give a compound of formula IV wherein R ¹¹ is a tert-butoxycarbonyl group.

In addition, in step B, when a compound of formula IV wherein R is -CH ₂ COX and R ¹¹ is an amino protecting group, said compound can be used directly in step E.

Further, in step B, when a compound of formula IV, wherein R is -CH ₂ COX and R ¹¹ is a hydrogen atom, is obtained, the compound is identical to the compound of formula VII, and can be directly used in step F .

Step C - Preparation of Compound of General V:

Removal of the phenolic hydroxy protecting group of a compound of formula IV wherein R ¹¹ is an amino protecting group and R is a phenolic hydroxy protecting group may be accomplished by reduction or hydrolysis, which should be selected according to the type of protecting group to be removed. .

Reductive removal is accomplished by hydrogenolysis or by the use of a metal dust such as zinc dust.

Hydrogenolysis is carried out in the presence of a catalyst such as palladium on carbon, palladium hydroxide, platinum oxide, etc., in a hydrogen atmosphere. The reaction is usually carried out at a temperature of about 20 ° C to about 80 ° C, at atmospheric or other pressure. Catalytic hydrogen transfer reduction using ammonium formate, formic acid, cyclohexene, hydrazine, etc. may be used as the hydrogen source. The solvents may be alcohols (e.g., methanol, ethanol, etc.), ethyl acetate, acetic acid, water, etc. and these solvents may be used alone or in a mixture of two or more of these solvents.

The hydrolysis is carried out in a suitable solvent under acidic or alkaline conditions. The reaction temperature may vary depending on the type of protecting group to be removed, but is usually in the range of about 0 ° C to about 150 ° C, more preferably in the range of about 20 ° C to about 100 ° C. The solvent may be alcohols (e.g., methanol, ethanol, etc.), acetonitrile, water, N, N-dimethylformamide, etc., and these solvents may be used alone or in a mixture of two or more of these solvents. The base may be an alkali metal hydroxide (eg: sodium hydroxide, potassium hydroxide, etc.) and an organic base (eg: piperidine, piperazine, etc.) and the acid may be hydrochloric acid, hydrobromic acid, trifluoroacetic acid, sulfuric acid, acid formic, acetic acid, methanesulfonic acid, etc ..

Step D and Step E - Preparation of Compound VII:

• ftftft · ftftft ftftft ftftft ftftft ftft ftft ftft ftft ftft ftftft ftftft ftftft ftftft ·· ····

The compound of formula VII is prepared from the compound of formula V by steps D and E.

Step D: The compound of formula V and the compound of formula VI are subjected to an additional reaction in a suitable solvent. The reaction temperature may vary depending on the type of starting compounds to be used and is usually in the range of about 50 ° C to about 200 ° C. The solvent may be aromatic hydrocarbons (eg: benzene, toluene, etc.), ketones (eg: acetone, methylethylketone, etc.) ethers (eg: tetrahydrofuran, dioxane, etc.), alcohols (eg: ethanol, isopropanol , etc.), acetonitrile, Ν, Ν-dimethylformamide, 1,3-dimethyl-2-imidazolidine, etc., and these solvents may be used alone or in a mixture of two or more of these solvents.

The reaction may conveniently be carried out in the presence of a base. This may be, for example, an inorganic base such as an alkali metal carbonate (e.g.: sodium carbonate, potassium carbonate, etc.), an alkali metal bicarbonate (e.g.: sodium bicarbonate, potassium bicarbonate, etc.), an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.) or an organic base such as triethylamine, tributylamine, N-methylmorpholine, etc. When a compound of formula VI is used wherein Y ¹ is chlorine or bromine, the reaction may be carried out smoothly. adding an alkali metal iodide (e.g.: sodium iodide, potassium iodide, etc.) or halogenated tetraalkylammonium (e.g.: ammonium tetra-n-butyl chloride), etc.).

Using the present reaction, a compound of formula I wherein R is CH ₂ COX, and the like of formula VI, can be prepared from hydroxyindole.

Step E - The compound of formula VII can be prepared by selectively removing the amino protecting group from the compound prepared in Step D.

The amino protecting groups are removed by reduction or hydrolysis, which should be selected according to the type of protecting group to be removed.

Reductive removal is accomplished by hydrogenolysis or using a metal dust such as zinc dust.

The hydrogenolysis is carried out in the presence of a catalyst such as palladium or carbon, palladium hydroxide, platinum oxide, etc., in a hydrogen atmosphere. The reaction temperature is usually in the range of about 20 ° C to about 80 ° C, at atmospheric pressure or other pressure. In addition, a catalytic hydrogen transfer reduction may be used which uses ammonium formate, formic acid, cyclohexene, hydrazine, etc. as the hydrogen source. The solvents may be alcohols (e.g., methanol, ethanol, etc.), ethyl acetate, acetic acid, water , etc., and these solvents may be used alone or in a mixture of two or more of these solvents.

• 4

The hydrolysis is carried out in a suitable solvent under acidic or alkaline conditions. The reaction temperature may vary depending on the type of protecting group to be removed, and is usually in the range of about 0 ° C to about 150 ° C, more preferably in the range of about 20 ° C to about 100 ° C. The solvent may be alcohols (e.g., methanol, ethanol, etc.), acetonitrile, water, Ν, dimethyl-dimethylformamide, etc., and these solvents may be used alone or in a mixture of two or more of these solvents. The base may be an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.) and the organic base may be a base such as piperidine, piperazine, etc. The acid may be hydrochloric acid, hydrobromic acid, trifluoroacetic acid, sulfuric acid, acid formic, acetic acid, methanesulfonic acid, etc ..

Step F and Step G - Preparation of Compound of General IX:

The compound of formula IX can be prepared from the compound of formula VII by steps F and G.

Step F: The compound of formula VII and the compound of formula VIII are reacted together in a suitable solvent or without a solvent.

The reaction temperature may vary depending on the kind of starting materials, and is usually in the range of about 20 ° C to about 150 ° C, more preferably in the range of about 25 ° C to about 100 ° C. The solvent may be aromatic hydrocarbons (e.g.: benzene, toluene, etc.), ketones (e.g.: acetone, methylethylketone, etc.), ethers (e.g.: tetrahydrofuran, dioxane, etc.), alcohols (e.g.: ethanol, isopropanol, etc.), acetonitrile, dimethylsulfoxide, Ν, Ν-dimethylformamide and 1,3-dimethyl-2-imidazolidine, and these solvents may be used alone or in a mixture of two or more of these solvents. Trimethylsilylacetamide or bistrimethylsilylacetamide may be added to the reaction system.

In the present reaction, an acid salt thereof may be added in place of the compound of formula VII, and the acid salt of the compound of formula VII may be a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, etc. or an organic acid salt such as oxalate, maleate, fumarate, etc. When the acid salt is used in the present reaction, the reaction is carried out in the presence of a base. The base includes, for example, inorganic bases such as alkali metal bicarbonates (eg: sodium bicarbonate, potassium bicarbonate, etc.) and alkali metal carbonates (eg: sodium carbonate, potassium carbonate, etc.) or organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, etc ..

00

00 00 0000 ·

0 0 0 0 ·· • 00 000 000 000 0 · 0000

Step G: A compound of Formula IX can be prepared by subsequently subjecting the compound obtained in Step F (except in the case of a compound wherein X is a lower alkyl group) to hydrogenolysis in a suitable solvent, or hydrolysis under acidic or alkaline conditions.

Hydrogenolysis is carried out in the presence of a catalyst such as palladium on carbon, palladium hydroxide, platinum oxide, etc., in a hydrogen atmosphere. The reaction is carried out at a temperature of about 20 ° C to about 80 ° C, at atmospheric or other pressure. Catalytic hydrogen transfer reduction using ammonium formate, formic acid, cyclohexene, hydrazine, etc. may be used as the hydrogen source. The solvents may be alcohols (e.g., methanol, ethanol, etc.), ethyl acetate, acetic acid, water, etc. and these solvents may be used alone or in a mixture of two or more of these solvents.

The hydrolysis is carried out in a suitable solvent under acidic or alkaline conditions. The reaction temperature may vary according to the nature of the starting materials, and is usually in the range of about 0 ° C to about 150 ° C, more preferably in the range of about 20 ° C to about 80 ° C. The solvent may be alcohols (e.g., methanol, ethanol, isopropanol, etc.), dioxane or water, a mixture of these solvents, and these solvents may be used alone or in a mixture of two or more of these solvents. The acid includes, for example, an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, etc., and an organic acid such as formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, etc. The bases include, for example, an alkali metal hydroxide (eg: sodium hydroxide, potassium hydroxide, etc.) and an alkali metal carbonate (eg: sodium carbonate, potassium carbonate, etc.).

The obtained crystal of compound A is a crystal of compound A of type-I, which exhibits characteristic diffraction bands at diffraction angles (20) of about 5.9 °, about 17.9 °, about 20.5 °, and about 24.0 ° in the X-ray distribution profile of dust spectrum.

A Type-I crystal is recrystallized from a solvent such as methanol to obtain a crystal exhibiting characteristic diffraction bands at diffraction angles (2 °) of about 5.9 °, about 17.9 °, about 20.8 ° and about 23.3 ° (crystal of Compound A type-II), but the crystal of Compound A type-I is much more industrially achievable than the crystal of Compound A type-II.

A crystal of Compound A having a particle size of not more than 100 µm at a 50% cumulative weight distribution value and a particle size of not more than 200 µm at a 95% cumulative weight distribution value, i.e.

4 fabric. Preferred particle sizes of the active ingredient are used at values not greater than 50 µm at a 50% cumulative weight distribution value and a particle size not greater than 150 µm at a 95% cumulative weight distribution value, most preferably a particle size not greater than 30 µm at a 50% value cumulative mass distribution and particle size not greater than 100 µm at 95% cumulative mass distribution. By using an active ingredient meeting the above-described requirements, a state from which the active ingredient dissolves readily can be achieved. In addition, since the active ingredient can optionally be obtained as an agglomerate, it is preferred that the active ingredient have a content of said agglomerate of less than 50% and a nearly uniform particle size distribution.

The particle sizes of the active ingredient (at 50% and 95% cumulative weight distribution values) are measured by a conventional method for measuring particle size of drugs, such as standard screening method, sedimentation method, light scattering method, image analysis, etc., but measurement should not be limited only these methods.

The present active ingredient meeting the above requirements can be obtained by selecting crystallization conditions in the synthesis process of compound A and / or selecting the comminution method after synthesis of compound A. For example, after synthesis of compound A, the active ingredient can be obtained by grinding it with a hammer mill, variable energy mill, rotary ball mill, vibratory ball mill, conical ball mill, roller mill, or nail mill, under conditions that are selected according to the mill to be used. The therapeutic agent can be obtained by controlling the particle size and agglutination rate of Compound A during its synthesis process, or by dissolving precipitated crystals during the synthesis process in an aqueous solvent such as water, an organic solvent, etc., and exposing the resulting solution to spray-drying or drying supercritical carbon dioxide gas, under selected conditions.

Granules containing the active ingredient are prepared to produce the desired pharmaceutical composition using the active ingredient so prepared.

The granules may contain, in addition to (a) the active ingredient, (b) a filler, (c) a disintegrant, and (d) a binder, a swallowing agent, a lubricant, etc.

Since other substances, other than the active ingredient, in the granules are in direct contact with the drug substance, it is preferred to use other substances which are compatible with the drug substance and by which the stability of the active ingredient is protected. Other substances in the granules, other than the active ingredient, including, for example, filler, disintegrant and binding agent, but if necessary a swallowing agent, lubricant, etc., may be used as other agents in the composition.

Other substances in the granules, other than the active ingredient, are usually present in an amount of 500 units or less, more preferably 300 units or less, most preferably 100 units or less, per 1 unit of active ingredient.

The filler includes, for example, lactose, corn starch, sucrose, trehalose, D-mannitol, erythritol, maltitol and ethyl cellulose. The disintegrant includes, for example, low-substituted hydroxypropylcellulose, calcium carmellose, and cross-linked carmellose sodium. The binder includes, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, vinylpyrrolidone poles, gelatin and carmellose sodium.

The swallowing agent and lubricant include, for example, magnesium stearate, hydrogenated vegetable oil (castor oil), light anhydrous silica and talc. When magnesium stearate is used, in an amount of from 1% to 5% by weight, more preferably in an amount of from 1% to 4% by weight, most preferably in an amount of from 1.5% to 3% by weight, depending on the total weight of the composition.

The granular preparation is preferably produced by first mixing the powder of the active ingredient and part or all of the filler and mixing them, followed by sieving or grinding, and then adding this mixture to the remaining substances and, if necessary, forming granules or controlling the size of the mixture, thereby the uniformity of content of the active ingredient is protected.

Mixing and sieving is performed manually using a 60 mesh 60 mesh screen, or using a sieving device having a suitable mixing capacity such as an oscillator. Mixing and comminution is performed using a comminution apparatus such as a hammer mill.

Granulation is carried out, for example, by wet-granulation using a moving bed granulator, a vibrating granulator or a high shear granulator.

The particle size of the granules thus prepared is usually not more than 350 μιη at 50% cumulative weight distribution value and not more than 1400 pm at 95% cumulative mass distribution value. More preferably, the particle size of the granules is not more than 300 µm at a 50% cumulative weight distribution value and not more than 1000 µm at a 95% cumulative weight distribution value. Most preferably, the particle size of the granules is not more than 250 µm at a 50% cumulative weight distribution value and not more than 800 µm at a 95% cumulative weight distribution value. By using granules having such a preferred particle size, the content uniformity of the active ingredient is more protected.

The particle sizes of the active ingredient (at 50% and 95% cumulative weight distribution values) are measured by a conventional method for measuring particle size of drugs, for example by the standard method of measuring the particle size of drugs. Sieving, sedimentation method, light scattering method, image analysis, etc., however, the measurement method should not be limited to these methods only.

The solid composition of the present invention comprises the granules so obtained. The solid composition may be, for example, tablets, capsules, granules, powder, suppositories, or external agents such as an adhesive tape.

The solid composition may contain only granules, but in a low-content composition containing 2 mg or less of active ingredient per dosage unit, it is preferred that the volume (weight) of the composition be increased by adding other substances to the granules in order to protect sufficient stability of the active ingredient as well as to protect a suitable size (usually from 4 to 10 mm in diameter, 25 to 300 mg).

The other external substance can be, for example, in addition to other substances such as fillers, disintegrants, binders that can be used in the manufacture of granules, crystalline cellulose as filler.

In order to protect the uniformity of content of the active ingredient, the other external substances are present in an amount of from 0.01 to 100 weight units, preferably from 0.1 to 50 weight units, most preferably from 0.15 to 10 weight units, per 1 unit weight of granules.

When formulating the composition, the other external substances may be used for mixing with the granules containing the active ingredient only as a mixture of the external substances or after granulating the external substances or controlling their size to the same particle size as the active ingredient granules. Hydropropylcellulose, hydroxypropylmethylcellulose, pullulan, poly (pyrrolidone), gelatin, carmellose sodium may be used as the binding agent for granulating or controlling the size of the external substances. When the granules and the other other substances are mixed, a swallowing agent and / or a lubricant may be used.

The granules and the other other substances can be compressed together without mixing to obtain dry coated tablets or multilayer tablets. In this case, the external substances may be, for example, crystalline cellulose, and / or low substituted hydroxypropylcellulose and magnesium stearate and / or hydrogenated vegetable oil (castor oil). In addition, light anhydrous silicic acid and / or talc may be used. If necessary, hydropropylcellulose, hydroxypropylmethylcellulose or pullulan can be used as the binding agent.

When forming tablets from granules or from a mixture of granules and other substances, it is preferable to add magnesium stearate or hydrogenated vegetable oil (castor oil) in an amount of from 1% up to 9 99 * 9. • 9 »

9 · 9 9 9

9 β · 9 ··· * 9 9 · · 9% by weight of the granules or the mixture of granules and external substances to avoid sticking which can easily occur during the compression process, and then the mixture thus obtained is subjected to tablet compression in a suitable tabletting process devices to create the desired tablets.

In addition, to mask off-taste, increase tablet strength, improve ingestion and ease of use, the tablets thus obtained can be coated with a suitable polymeric ingredient to form film-coated tablets. The polymeric ingredient may be, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, methylcellulose, ethylcellulose, sodium carmellose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, dimethylaminoethyl methacrylate-methyl acrylate copolymer and copolymer. If necessary, for example, propylene glycol, glyceryl triacetate (triacetin), triethyl citrate, acetyl triethyl citrate, diethyl phthalate, diethyl sebacate, acetylated monoglyceride, vegetable oil (castor oil), or liquid paraffin, may be used as plasticizer for the polymeric ingredient in the coating agent. Further, to protect from light or improve resolution, a suitable coloring agent may be added to the coating agent. The coloring agent may be, for example, a water-soluble pigment such as Yellow No. 5, and the like. 4, Yellow 5, Blue 1, Blue 2, etc. and their clay stains, talc, titanium dioxide, metal oxides, calcium sulfate, calcium carbonate or riboflavin, carmine dye and ginger pigment may be added. In addition, a sweetening agent or flavoring may also be added to increase digestibility.

In addition, tablets can be converted to sugar coated tablets for the same purposes as mentioned above. The sugar coating agent may comprise, in addition to the main sucrose or sorbitol component, calcium carbonate, talc or titanium dioxide, and further comprise as a binding agent, for example, gelatin, acacia, polyvinyl alcohol, etc., or such cellulose derivatives such as pululan, hydroxypropylmethylcellulose, etc. and, if necessary, a water-soluble synthetic pigment such as Yellow No. 5, is used. 4, Yellow 5, Blue 1, Blue 2, etc. and their clay stains, talc, titanium dioxide, metal oxides, calcium sulfate, calcium carbonate or riboflavin, carmine dye and ginger pigment may be added. In addition, a sweetening agent or flavoring may also be added to increase digestibility.

The granules or the mixture of granules and the other other substances may be directly placed into the pure granular compositions, the granular compositions or the powder compositions, or into the capsule compositions by filling them in gelatin capsules. In this case •

The other ingredients are lactose, corn starch, sucrose, trehalose, D-mannitol, erythritol, maltitol and / or ethylcellulose, and magnesium stearate and / or hydrogenated vegetable oil (castor oil). Furthermore, light anhydrous silicic acid and / or talc may also be used. In the case of granular compositions, after granulation, hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, polyvinylpyrrolidone, gelatin or carmellose sodium may be added as fillers of the granular compositions.

Further, if necessary, in order to form dispensing enhancing tablets, the granules containing the active ingredient or tablets are coated with a drug dispensing control coating consisting of a polymeric agent or fats and oils to obtain reservoir type dispensing enhancing tablets. For example, the coating agent may be beeswax, kamauba wax, cetyl alcohol, cetyl stearyl alcohol, lipid fats and oils, resins (e.g. shellac), cellulose esters (e.g. ethylcellulose) and acrylic acid esters. If necessary, for example, propylene glycol, glycerol, polyethylene glycol, glyceryl triacetate (triacetin), triethyl citrate, acetyl triethyl citrate, diethyl phthalate, diethyl sebacate, acetylated monoglyceride, oil or vegetable oil may be added to the coating agent as plasticizer for the polymeric ingredient. In addition, the drug discharge controlling granules may be compressed to form tablets.

A matrix type of release promoting composition can be obtained by mixing the drug delivery control component such as the polymeric ingredients mentioned above or fats and oils together with other fillers in the granule and tablet manufacturing step. Further, if necessary, the granules thus controlled in the drug discharge can be compressed to form tablets.

The solid composition of the present invention thus obtained may be packaged, if necessary, in a blister pack, a heat-sealed pack, or vials of suitable materials, but the packs should not be limited to these types of packs. Further, if necessary, the solid composition of the present invention may be packaged together with a suitable drying agent such as silica gel.

Pharmaceutical experiment - the effect of the active ingredient of the present invention on human β-adrenaline receptors was studied.

Cell lines highly expressing human β _3- and β ₂ -adrenaline receptors were prepared according to the method described in WO 96/16938. A cell line highly expressing the human β, -adrenaline receptor was prepared according to the method described in WO 00/44721.

Experiment - stimulating human β ₃ ^ Γ6Μΐΐηονέ1ιο receptor activity • ·

A cell line highly expressing the human β ₃ -adrenaline receptor CHO / pKREX 10-36 was cultured for 2-3 days with MEM-Dulbecco medium supplemented with 10% germline bovine serum and 200 µg / ml G-418. Cells were exposed by incubation with sodium chloride buffered phosphate buffer containing 0.5 mM EDTA at 37 ° C for 10 minutes after the medium was removed. CHO / pKREX 10-36 cells were centrifuged and resuspended in Hank buffer (ICN Biomedicals) containing 1 mM L-ascorbic acid and 1 mM 3-isobutyl-1-methylxanthine at a concentration of approximately ^{5 x} 10 ⁵ cells / ml. This suspension (100

1) and test compound were mixed in the same buffer (500 μΐ) and incubated at 37 ° C for 30 minutes, followed by cooking for 5 minutes to complete the reaction. After centrifugation of the reaction mixture, the amount of cAMP in the supernatant was measured using the EIA System (Amersham).

Similarly, in the same manner was measured the amount of cAMP using CHO / pKEX21-8 cell line highly expressing human? ₂ receptor -adrenalinový or using CHO / pKREX23-30 for highly expressing cell line Human β, -adrenalinový receptor instead of the CHO / pKREX 10- 36 for a cell line highly expressing the human β ₃ -adrenaline receptor.

The amount of cAMP, after being added to the reaction mixture of 10 ^-5 M (-) - isoproterenol or not adding the substance at all, has been reported as 100% and 0%, respectively, and the relative maximal response of the active ingredient of the present invention (10 ⁶ to 10 µM) is expressed as true activity (PA). The EC ₅₀ value, which represents the concentration of test compound needed to achieve 50% cAMP accumulation, was calculated by the least squares regression analysis of the concentration response curve for each compound.

The results are shown in Table 1.

Table 1

tested compound stimulating activity of human β ₃ -, β ₂ - and β 1 -adrenaline receptors P ₃ -receptor P ₂ -receptor β! -receptor EC ₅₀ (nM) BYE. (%) EC ₅₀ (nM) BYE. (%) EC ₅₀ (nM) BYE. (%) AND' 0.27 110 21 45 3.5 83 jp ** 10 100 ALIGN! 4.2 100 ALIGN! 0.46 100 ALIGN!

Note: * means the active ingredient; ** means (-) - isoproterenol.

• ·

4 4 4

4 4 43 4

In this experiment, a compound having a low EC ₅₀ value and a high PA value is considered to have a stimulating activity of human β-adrenaline receptors. Thus, as is clear from Table 1, the active ingredient of the present invention is confirmed to have potent stimulatory activity of the human β ₃ -ββα-β-α-receptors, but the stimulating activities of the human β ₂ - and β-adrenaline receptors are relatively weak.

As shown in the above results, the active ingredient of the present invention can be considered as a stimulating agent of human β ₃ -adrenaline receptors with excellent adrenoceptor selectivity.

The active ingredient of the present invention is useful as a β ₃ adrenaline receptor stimulating agent in the prophylaxis or treatment of obesity, diabetes mellitus, hyperlipemia, irritable bowel syndrome, acute or chronic diarrhea, pollakiuria, enuresis, urinary count, etc.

In addition, the active ingredient of the present invention is also useful in ameliorating such symptoms as stomach pain, nausea, vomiting, epigastritis, symptoms associated with gastric ulcer, acute or chronic gastritis, biliary dyskiosis, cholecystitis, etc.

When the active ingredient of the present invention is used as a β ₃ adrenaline receptor stimulating agent, it may be administered orally, parentally, or rectally, but more preferably by the oral route. The dose of the active ingredient of the present invention may vary depending on the kind of administration chosen, the conditions, the age of the patients, or the kind of use (prophylaxis or treatment), etc., but is usually in the range of 0.0002 mg / kg / day to 0.02 mg. / kg / day, more preferably in the range of 0.001 mg / kg / day to 0.02 mg / kg / day.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the X-ray powder diffraction pattern of the Type-I compound crystal obtained in Preparation 1.

Figure 2 is a powder X-ray diffraction pattern of the crystal of Compound A type-II obtained in Preparation 2.

000 ··

0 0 0 «0 0 0 0 • 0 0

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EXAMPLES OF EMBODIMENTS OF THE INVENTION

The present invention is illustrated in more detail in the following Preparations, Experiments and Examples, but should not be construed as limited to the statements set forth herein.

Example 1

Preparation 1 - Crystal Preparation of Compound A: Compound identification was performed by elemental analysis, mass spectrum analysis, infrared (IR) absorption spectroscopy, proton nuclear magnetic resonance (1H-NMR) spectra and optical rotation measurement. Optical purity was determined by high pressure liquid chromatography.

The following abbreviations can be used to simplify the description.

Fmoc: 9-Fluorenylmethoxycarbonyl

Ala: Alanine residue

J: Pairing constant s: 1-fold d: 2-fold dd: 2-fold t: 3-fold q: 4-fold m: 3-fold br: Wide part (1) Preparation of (R) -3- (2-aminopropyl) -7-benzyloxyindol oxalate:

Step 1 - To a suspension of Fmoc-D-Ala-OH (23.35 g, 75 mmol), methylene chloride (240 mL) and N, N -dimethylformamide (0.39 mL) was added oxalyl chloride (7 mL, 80 mmol) dropwise at at room temperature and with stirring and the mixture was further stirred for one hour. The reaction mixture was concentrated to dryness under reduced pressure to give a solid containing Fmoc-D-Ala-Cl, which was used in the next reaction without further purification.

Step 2 - To an ice-cold and stirred solution of commercially available 7-benzyloxyindole (11.2 g, 50 mmol) in methylene chloride (100 mL) was added a 3 M diethyl ether solution of methylmagnesium bromide (50 mL, 150 mmol) under an argon atmosphere. The mixture was warmed to room temperature and further stirred for one hour. To the reaction mixture was added dropwise a solution of Fmoc-D-Ala-Cl methyl chloride (200 mL) obtained in Step 1 on ice. The mixture was warmed to room temperature and further stirred for one hour. To the mixture was added ice to ice

• · · φ · «· φ · φ · φ a a

A 5% aqueous hydrochloric acid solution and the whole mixture was stirred for 15 minutes. The organic layer was separated, washed with water (100 mL) and dried over dry magnesium sulfate. The solvent was evaporated under reduced pressure to give an oil (40.05 g) containing (R) -7-benzyloxy-3 - [[2- (9-fluorenylmethoxycarbonyl) amino] propionyl] indole, which is further used in the next reaction without further purification.

Step 3 - To a stirred mixture of the oil obtained in Step 2 in a mixture of acetonitrile (100 mL) and 2-propanol (15.03 mL) was added portionwise at room temperature sodium borohydride (5.67 g, 150 mmol) and the mixture was refluxed for five hours. The reaction mixture was cooled to room temperature and methanol (100 mL) was added dropwise. Further, the reaction mixture was dried under pressure. After addition of ethyl acetate (250 mL) and water (100 mL) to the residue, the mixture was stirred. The organic layer was separated, washed with water (100 mL) and dried over dry magnesium sulfate. The inorganic portion was separated and a solution of oxalic acid (4.50 g, 50 mmol) in ethyl acetate (45 mL) was added to the residue at room temperature. The precipitated crystals were collected by filtration, washed with ethyl acetate and dried. The title compound (11.2 g, 61%) was obtained as white crystals, m.p. 206-208 ° C.

[α] D ²⁵ = -46.2 ° (c = 1.0, N, N-dimethylformamide);

1 H-NMR spectrum (200 MHz, DMSO-d ₆ , δ ppm): 1.14 (3H, d, J = 7 Hz), 2.80 (1H, dd, J = 14 Hz, J = 8 Hz) 3.03 (1H, dd, J = 14Hz, J = 5Hz), 3.42 (1H, m), 5.26 (2H, s), 5.94 (4H, br), 6.75 ( 1 H, d,> 8 Hz), 6.92 (1H, t, J = 8 Hz), 7.11-7.22 (2H, m), 7.32-7.48 (3H, m), 7 51-7.62 (2H, m), 11.11 (1H, s).

(2) Preparation of (R) -3- (2-tert-butoxycarbonylaminopropyl) -7-benzyloxyindole:

To a mixture of potassium carbonate (28 g), water (500 mL) and ethyl acetate (250 mL) was added (R) -3- (2-aminopropyl) -7-benzyloxyindole oxalate (50 g, 135 mmol) obtained previously (1) and the mixture was stirred. Di-tert-butyl bicarbonate (29.5 g, 135 mmol) was then added to the ice-cold and stirred mixture, and the mixture was stirred at room temperature for 3 hours. The organic layer was separated, washed with saturated aqueous sodium chloride solution (150 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated under pressure and n-hexane (150 mL) was added to the residue. The precipitated crystals were collected by filtration and dried. The title compound (47.2 g, 92%) was obtained as white crystals, m.p. 94-95 ° C.

[α] D ²⁵ = -21.0 ° (c = 1.0, N, N-methanol);

1 H-NMR spectrum (300 MHz, CHCl ₃ , δ ppm): 1.11 (3H, d, J = 6.6 Hz), 1.43 (9H, s), 2.83 (1H, dd, J) = 14.5 Hz, J = 6.7 Hz), 2.94 (1H, dd, J = 14.5 Hz, J = 5.1 Hz), 4.00 (IH, m), 4.44 ( IH, m), 5.18 ftft (2H, s), 6.71 (1H, d, J = 7.5 Hz), 6.97 (1H, d, J = 2.2 Hz) 7.02 (1H, t,> 7.9 Hz), 7.20 (1H, s), 7.247.51 (5H, m), 8.30 (1H, s).

Optical purity: 98.5% ee [conditions for analysis; column (CHIRALPAK AD (4.6 mm x 250 mm diameter: manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.)); mobile phase (n-hexane: isopropanol = 70:30); flow rate (0.8 mL / min); temperature (25 ° C); detection wavelength (254 nm); retention time (8.8 min)] (3) Preparation of N, N-diethyl- [3 - [(2R) -tert-butoxycarbonylamino] propyl] -1H-indol-7-yloxy] acetamide:

To the ice-cold and stirred solution of (R) -7-benzyloxy-3- (2-tert-butoxycarbonylaminopropyl) indole (10 g, 26.3 mmol) obtained in step (2) above in methanol (100 mL) was added 10 % palladium on carbon (0.5 g) and the mixture was hydrogenated at atmospheric pressure with hydrogen at room temperature for 2 hours. After the theoretical amount of hydrogen gas was consumed, the catalyst was removed and the solvent was evaporated under reduced pressure. The residue was dissolved in acetone (60 mL) and potassium carbonate (4.54 g), N, N-diethylchloroacetamide (4.72 g, 31.6 mmol) and potassium iodide (0.55 g) were added and the mixture was refluxed for 4 hours. After ice cooling, insoluble materials were removed by filtration and the solvent was evaporated under reduced pressure. To the residue was added chloroform (100 mL) and water (100 mL), and the mixture was stirred. The chloroform layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and diisopropyl ether (30 mL) was added to the residue. Precipitated crystals were collected by filtration and dried to give the final compound (10.7 g, 100%) as white crystals, m.p. 142 [deg.] C.

[α] D ²⁵ = -26.3 ° (c = 1.0, methanol);

1 H-NMR spectrum (300 MHz, CHCl ₃ , δ ppm): 1.10 (3H, d,> 6.6 Hz), 1.17 (3H, t,> 7.1 Hz),

1.22 (3H, t,> 7.1 Hz), 1.43 (9H, s), 2.83 (1H, dd,> 14.1 Hz,> 7.0 Hz), 2.94 (1H) , dd, > 14.1 Hz, > 5.1 Hz), 3.34 (2H, q, > 7.1 Hz), 3.44 (2H, q, > 7.1 Hz), 3.99 ( 1 H, br), 4.45 (1 H, br), 4.80 (2H, s), 6.67 (1 H, d,> 7.7 Hz), 6.99 (1 H, t,> 7.9 Hz), 7.10 (1H, s), 7.30 (1H, d,> 7.9 Hz), 9.41 (1H, s).

Optical purity:> 99% ee [conditions for analysis; column (CHIRALPAK AD (4.6 mm x 250 mm diameter: manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.)); mobile phase (n-hexane: isopropanol = 50:50); flow rate (0.8 mL / min); temperature (25 ° C); detection wavelength (254 nm); retention time (6.6 min)] (4) Preparation of N, N-diethyl- [3 - [(2R) -aminopropyl] -1H-indol-7-yloxy] acetamide:

To a solution of N, N-diethyl- [3 - [(2R) -tert-butoxycarbonylamino] propyl] -1H-indol-7-yloxy] acetamide (12 g, 29.7 mmol) obtained in step (3) above in acetonitrile (120 mL) was added oxalic acid (10.71 g, 119 mmol) and the mixture was refluxed for 2 hours. The mixture was cooled on ice and the precipitated crystals were collected by filtration and washed with acetonitrile. To the resulting crystals was added 10% potassium carbonate solution (50 mL) and chloroform (120 mL), and the mixture was stirred. The chloroform layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and diisopropyl ether (30 mL) was added to the residue. The precipitated crystals were collected by filtration and dried to give the final compound (6.84 g, 75%) as white crystals, m.p. 133 ° C.

[α] D ²⁵ = -46.3 ° (c = 1.0, methanol);

Ή-NMR spectrum (300 MHz, CHCl ₃ , δ ppm): 1.16 (3H, d, 3 = 6.6 Hz), 1.17 (3H, t,> 7.1 Hz),

1.22 (3H, t,> 7.1 Hz), 1.40 to 2.00 (2H, br), 2.64 (1H, dd,> 14.1 Hz,> 8.2 Hz), 2 .86 (1H, dd, > 14.1 Hz, > 5.0 Hz), 3.18 (1H, m), 3.35 (2H, q, > 7.1 Hz), 3.44 (2H, q,> 7.1 Hz), 4.80 (2H, s), 6.68 (1H, d,> 7.5 Hz), 6.99 (1H, t,> 7.9 Hz), 7, Δ (1H, s), 7.28 (1H, d, J = 8.0 Hz), 9.42 (1H, s). Optical purity:> 99% ee [conditions for analysis; column (CHIRALPAK AD (4.6 mm x 250 mm diameter: manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.)); mobile phase (n-hexane: isopropanol: diethylamine = 85: 15: 0.8); flow rate (1.0 mL / min); temperature (25 ° C); detection wavelength (254 nm); retention time (19.9 min)] (5) Preparation of N, N-diethyl- [3 - [(2R) - [[(2R) - (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -1H-indole -7-yloxy] acetamide:

To a solution of N, N-diethyl- [3 - [(2R) - [[(2R) - (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -1H-indol-7-yloxy] acetamide (21 g, 69, 2 mmol) obtained in the above step (4) in acetonitrile (42 mL) was added (R) -3-chlorostyrene oxide (11.77 g, 76.1 mmol) and the mixture was refluxed for 5 hours. The mixture was cooled on ice and diisopropyl ether (168 mL) was added. The precipitated crystals were collected by filtration and dried to give the final compound (16.99 g, 54%) as white crystals. On the other hand, the filtrate containing unreacted starting material was concentrated to dryness under reduced pressure and acetonitrile (21 mL) and (R) -3-chlorostyrene oxide (1.07 g, 6.9 mmol) were added to the residue and the mixture was refluxed for for 6 hours. . The mixture was cooled on ice and diisopropyl ether (63 mL) was added. The precipitated crystals were collected by filtration and dried to give the final compound (2.86 g, 9%), mp 120-121 ° C. [α] D ²⁵ = -69.1 ° (c = 1.0, methanol);

Ή-NMR spectrum (300 MHz, CHCl ₃ , δ ppm): 1.11 (3H, d, 3 = 6.2 Hz), 1.16 (3H, t,> 7.1 Hz),

1.22 (3H, t,> 7.1 Hz), 2.66 (1H, dd,> 12.2 Hz, J = 9.2 Hz), 2.81 (2H, d,> 6.6 Hz) ), 2.87 (1H, dd,

J = 12.2 Hz, > 3.7 Hz), 3.00 (1H, m), 3.34 (2H, q, > 7.1 Hz), 3.43 (2H, q, > 7.1) Hz), 4.54 (1H, m), 4.78 (2H, s), 6.65 (1H, d,> 7.3 Hz), 6.98 (1H, t,> 7.9 Hz) 6.99 (1H, s), 7.12 to 7.30 (4H, m), 7.34 (1H, s), 9.60 (1H, s).

(6) Preparation of [3 - [(2R) - [[(2R) - (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -1H-indol-7-yloxy] acetic acid (Compound A):

N, N-diethyl- [3 - [(2R) - [[(2R) - (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -1H-indol-7-yloxy] acetamide (4 g, 8 7 mmol) obtained in the above step (5) was added to a solution of potassium hydroxide (1.96 g, 34.9 mmol) in 50% aqueous ethanol (32 mL) and the mixture was refluxed for 3 hours and then cooled to room temperature. The mixture was dissolved in acetic acid (2.3 g, 38.4 mmol) and stirred at room temperature overnight. Precipitated crystals were collected by filtration and dried to give the final compound (3.1 g, 88%) as white crystals, m.p. Mp 230-231 ° C.

[α] D ²⁵ = -24.4 ° (c = 1.0, 1 M aqueous sodium hydroxide);

¹ H-NMR spectrum (200 MHz, DMSO-d ₆ , δ ppm): 0.93 (3H, d,> 7 Hz), 2.61 (1H, m), 2.80-

3.22 (4H, m), 4.54 (2H, s), 4.90 (1H, m), 6.48 (1H, d,> 8 Hz), 6.76 (1H, t,> 8 Hz), 6.89-7.02 (2H, m), 7.28-7.40 (3H, m), 7.46 (1H, s), 11.01 (1H, s).

Optical purity:> 99% ee [conditions for analysis; column (CHIRALPAK AD (4.0 mm x 100 mm diameter: manufactured by SHINWA ΚΑΚΟ CO., LTD.)); mobile phase (aqueous (20 mM Na ₂ HPO ₄ + 2 mM tetrabutylammonium bisulfite) solution (pH 7.0): isopropanol = 98: 2); flow rate (0.7 mL / min); temperature (30 ° C); detection wavelength (220 nm); retention time (27.4 min)]

The X-ray diffraction profile of the thus obtained Compound A crystals was measured by an X-ray powder diffractometer (RINT100O-type; manufactured by RIGAKU CORPORATION) at 30 kV tube voltage and at 20 mA tube current using CuKa fiber within a diffraction angle (2 °). The diffraction profile of the crystals is shown in Figure 1. The diffraction angles in the X-ray powder diffraction profile of Compound A crystals are about 5.9 °, about 17.9 °, about 18.8 °, about 20.5 °, about 23.3 °, about 24.0 ° and about 24.9 ° and there are characteristic diffraction bands at about 5.9 °, about 17.9 °, about 20.5 °, and about 24.0 °. Diffraction angle values (20) have standard accuracy.

Preparation 2 - Preparation of Type A-II Crystals: To the Type A-I crystals (100 mg) obtained in Preparation 1, methanol (35 mL) was added and the mixture was dissolved by heating in a water bath at 100 ° C. The precipitated crystals were collected by filtration and dried to give crystals of Compound A Type-II.

The X-ray diffraction profile of the thus obtained Compound A Type-II crystals was measured by an X-ray powder diffractometer (RINT ULTIMA type; manufactured by RIGAKU CORPORATION) at 40 kV tube voltage and 30 mA tube current using CuKa fiber within the diffraction angle range. 2Θ). The diffraction pattern of the crystallites is shown in Figure 2. The diffraction angles in the powder X-ray diffraction pattern of Compound A Type-II crystals are about 5.9 °, about 17.5 °, about 19.4 °, about 20.8 °, about 23.3 About 24.0 ° and about 24.9 ° and there are characteristic diffraction bands at about 5.9 °, about 17.5 °, about 20.8 °, and about 23.3 °. Diffraction angle values (2Θ) have standard accuracy.

Preparation 3 - preparation of the active ingredient:

(2) The crystals of Compound A type-I obtained in Preparation 1 were reduced using a hammer mill (Sample Mil AP-S, manufactured by Hosokawa Micron Corporation, Japan) and using a 0.7 mm open diameter sieve.

(3) Separately, the crystals of Compound A type-I obtained in Preparation 1 were reduced using a variable energy mill (Single Truck Jet Milk FS-4, manufactured by SEISHIN ENTERPRISE CO., LTD, Japan) with a compressed air pressure of 7 kg / cm. ² .

(4) The particle sizes at 50% and 95% of the cumulative weight distribution of each of the reduced granules so obtained were measured using a laser particle size diffraction analyzer (HELOS & RODOS (Trade Mark), manufactured by SYMPATEC Gmbh, Germany) and calculated from cumulative particle size distribution on a volumetric basis by the dry air dispersion method (dispersed air pressure: 1 atm) The particle size of the crystals obtained in (1) at a 50% cumulative weight distribution value is not greater than 21 µm and at a 95% cumulative weight distribution value is not greater than 75 µm. The particle size of the crystals obtained in (2) at a 50% cumulative weight distribution value is not greater than 1.7 µm and at a 95% cumulative weight distribution value is not greater than 3.8 µm. By any reduction method, crystals of Compound A having a particle size of not more than 100 µm at a 50% cumulative weight distribution value and a particle size of not more than 200 µm at a 95% cumulative weight distribution value can be obtained.

Example 2

Particle size of the active ingredient - as prescribed in Table 2, added to the mixed powder of the active ingredient or non-reduced crystals of Compound A, lactose, low-substituted hydroxypropylcellulose, water and mixing began to form granules (molding granulations) that are dried and regulated size to obtain granules. Thus obtained

The granules were blended with crystalline cellulose, light anhydrous silica and magnesium stearate, and compressed to form tablets containing 1 mg of active ingredient or non-reduced crystals of Compound A. The active ingredient was one that was reduced using a hammer mill ( Sample AP1-S, manufactured by Hosokawa Micron Corporation, Japan) using a 0.7 mm or 1 mm open diameter sieve or reduced using a variable energy mill (Single Truck Jet Miles FS-4, manufactured by SEISHIN ENTERPRISE CO.). , LTD, Japan) with a compressed air pressure of 7 kg / cm ² having different particle sizes as shown in Table 3. The degradation test of the tablets thus obtained was performed according to the Thirteenth Edition of the Pharmacopoeia of Japan (paddle method, 50). rpm, water 37 ° C, 900 ml) and the relationship between the particle size of the active ingredient and its decomposition from the tablets was evaluated by speed within 15 minutes. The results are shown in Table 3.

Table 2

Components weight (mg) the active ingredient, or a non-reduced crystal of Compound A 1 granule lactose 70 low-substituted hydroxypropylcellulose 10 hydroxypropylcellulose 2.5 crystalline cellulose 15 Dec external other substances magnesium stearate 1 Light anhydrous silicic acid 0.5 total 100 ALIGN!

Table 3

Method of grinding Particle size (μ m) at 50% value distribution cumulative weight Particle size (μ m) at 95% value distribution cumulative weight Solubility after 15 min. (%) Exp. 1-1 Mill with changeable energy 1.7 3.8 100 ALIGN!

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0 * * ♦

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Exp. 1-2 Hammer mill (open diameter) windows 0.7 mm) 9.4 43 97 Exp. 1-3 Hammer mill (open diameter) windows 0.7 mm) 17 42 100 ALIGN! Exp. 1-4 Hammer mill (open diameter) windows 0.7 mm) 21 75 99 Exp. 1-5 Hammer mill (open diameter) windows 0.7 mm) 12.5 45 100 ALIGN! Exp. 1-6 Hammer mill (open diameter) windows 0.7 mm) 45 144 96 Comparative Exp. 1-1 Not reduced 85 366 60

Tablets prepared using the active ingredient have a particle size at 50% cumulative weight distribution value not greater than 100 μηι and a particle size at 95% cumulative mass distribution value not greater than 200 µm shows a distribution number of nearly 100% in 15 minutes, which is a good soluble property .

Example 3

The ratio of the composition in the granules relative to the weight of the active ingredient and other substances than the active ingredient

A mixture of the active ingredient powder (used in Experiment 1-3 for Experiment 2-1 and Comparative Experiment 2-1, also in Experiment 1-2 above for Experiment 2-2), lactose and hydroxypropyl cellulose substituted below were sprayed with an aqueous solution of hydroxypropyl cellulose and a granulator and a granulator dryer were used. As shown in Table 4, 3 kinds of granules were prepared wherein the content of other components other than the active ingredient was different in the granules 82.5 units of mass (experiment 2-1), 417 units of mass (experiment 2-2) and 834 Units of Weight (Comparative Experiment 2-1) per 1 unit of active ingredient. A fixed amount of crystalline cellulose, light anhydrous silicic acid and magnesium stearate were added to each granule, and the mixture was compressed into tablets. These tablets were stored under conditions of 40 ° C - 75% RH (relative humidity) for 4 months and the content of all degradation products was measured and increased to the original amount. The results are presented in Table 5.

• * • «· «· • · · * 0 • · · ♦ • · and • 0 * ·· «· · • ·

Table 4

Components Exp. 2-1 Exp. 2-2 Comparative Exp. 2-1 Granule Therapeutic substance 1 0.2 0.1 Lactose 70 70.8 70.9 Substituted below hydroxypropylcellulose 10 10 10 Hydroxypropylcellulose 2.5 2.5 2.5 Other substances Crystalline cellulose 15 Dec 15 Dec 15 Dec Magnesium stearate 1 1 1 Light waterless silicic acid 0.5 0.5 0.5 Total (mg) 100 ALIGN! 100 ALIGN! 100 ALIGN! Units of weight in granules additives other than the active ingredient per unit weight of active ingredient 82.5 417 834

Table 5

Exp. 2-1 Exp. 2-2 Comparative Exp. 2-1 Increase (%) of quantity decomposition products 0.2 0.69 1.45

In the tablets in Experiment 2-1 and 2-2, the content of degradation products is less compared to the tablets in Comparative Experiment 2-1, which contains more than 500 units of weight of additional components in granules than the active ingredient per unit of active ingredient, ♦ ♦ -Β ·

ΒΒ ΒΒ thus demonstrating that the chemical stability of the active substances in tablets of experiments 2-1 and 2-2 is higher.

Example 4

The ratio of the composition in the granules to the weight of the active ingredient and other substances than the active ingredient:

As described in Table 6, a solution of hydroxypropylcellulose in purified water was added to the mixture of lactose powder and hydroxy substituted propyl cellulose to form granules (kneaded granulations), which were dried and resized to match the granules of the additives.

Table 6

Components Weight (mg) Lactose 71 Granules of additives Substituted below hydroxypropylcellulose 10 Hydroxypropylcellulose 2.5 Total 83.5

A mixture of the hydroxypropylcellulose in purified water was added to a mixture of the active ingredient powder (used above in Experiment 1-4), lactose, and the substituted hydroxypropylcellulose to form granules (kneaded granulations), which were dried and resized to match the granule parameters. Four types of granules were produced whose content of non-active ingredients varied, namely 416.5 weight units (experiment 4-1, experiment 4-2), 1001 weight units (comparative experiment 4-1), 1251.5 weight units (Comparative Experiment 42), to 1 unit of active ingredient weight. Additive granules obtained in accordance with the above formula in Table 6, crystalline cellulose, light anhydrous silicic acid and magnesium stearate were added to 4 granules and the mixture was compressed into tablets, each containing 0.1 mg of active ingredient and 1.87 units. weight of additives per unit weight of granules (experiment 3-1), tablets containing 0.2 mg of active ingredient and 2.59 units of weight of additives per unit weight of granules (experiment 3-2), tablets containing 0.1 mg of active ingredient ingredients and 0.20 units of additive weight per unit granule weight (Comparative Experiment 3-1) and tablets containing 0.2 mg of active ingredient and 0.20 units of additive weight per unit granule weight (Comparative Experiment 3-2) . These tablets were stored under conditions of 40 ° C - 75% RH (relative humidity) for 1 month and the content of all degradation products was measured by high pressure liquid chromatography, the increase of the products was recalculated to the original amount. The results are presented in Table 8.

Table 7

Components Exp. 3-1 Exp. 3-2 Comparative Exp. 3-1 Comparative Exp. 3-2 Therapeutic substance 0.1 0.2 0.1 0.2 Lactose 35.4 70.8 85.1 212.8 Granule Substituted below hydroxypropylcellulose 5 10 12 30 Hydroxypropylcellulose 1,25 2.5 3 7.5 Granules accessory 58.45 167 - - substances External Crystalline cellulose 18 45 18 45 other substances Magnesium stearate 1,2 3 1,2 3 Light waterless silicic acid 0.6 1.5 0.6 1.5 Total (mg) 120 300 120 300 Units of weight in granules additives other than active component per 1 weight unit 416.5 416.5 1001 1251.5 active ingredient Units of weight of additives others on 1 granules unit weight 1.87 2.59 0.20 0.20

*

8 8 • · 8 8

Table 8

Exp. 3-1 Exp. 3-2 Comparative Exp. 3-1 Comparative Exp. 3-2 Increase (%) of quantity decomposition products 0.75% 0.83% 1,31% 1,76%

In tablets in Experiments 3-1 and 3-2, the amount of all degradation products produced was lower compared to the tablets in Comparative Experiments 3-1 and 3-2, thus demonstrating that the chemical stability of the active ingredient in tablets of Experiments 3-1 and 3-2 is higher.

Example 5

Pre-mixed during granule preparation:

According to the prescription in Table 9, tablets each containing 0.05 mg of the active ingredient (used in Experiment 1-5) were obtained. To prepare the granules, the active ingredient was first mixed and ground with lactose in a mixing screen (50 mesh stainless steel screen = experiment 3-1) or a granulator was used (hammer mill = experiment 3-2) and the lower substituted hydroxypropyl cellulose and hydroxypropyl cellulose were added. . Water was added with stirring to the mixture and the resulting granules (kneaded granulation) were dried and formed to the appropriate size. Crystalline cellulose, light anhydrous silicic acid and magnesium stearate were mixed with the granules so obtained and compressed into tablets. The uniform content of the obtained tablets was tested according to the Content Uniformity Test in the Thirteenth Edition of the Pharmacopoeia of Japan (where a result below 15% is appropriate). The results are shown in Table 10.

Table 9

Components Weight (mg) Therapeutic substance 0.05 Granule Lactose Substituted below 17.7 hydroxypropylcellulose 2.5 Hydroxypropylcellulose 0.625 Granules of additives 3.75

External other substances Crystalline cellulose Magnesium stearate 0.25 0.125 Total 25

Table 10

Exp. 4-1 Exp. 4-2 Pre-mixing method Non-corroding sieves Hammer mill Uniform content (%) 10.0 4.0

In the Content Uniformity Test in the Thirteenth Edition of the Pharmacopoeia of Japan, a result below 15% is appropriate. If the results of the tablet uniformity test in Experiments 4-1 and 4-2 are below 15%, uniformity of drug content is ensured in these tablets.

Example 6

According to the prescription in Table 11, tablets containing 1 mg of the active ingredient in each of them (obtained in Experiment 1-3 as mentioned above) were obtained. To prepare the granules, the active ingredient was premixed and sieved with lactose using a hammer mill, and then low substituted hydroxypropylcellulose and hydroxypropylcellulose were added. The water was mixed into the mixture to form granules (kneaded granulation), which were dried and formed to a size of not more than 250 µm at 50% cumulative weight distribution and not more than 600 µm at 95% cumulative weight distribution. Crystalline cellulose, light anhydrous silicic acid and magnesium stearate were mixed with the granules so obtained and compressed into tablets. The tablets thus obtained were of adequate size and uniform content and the stability of the active ingredient was guaranteed, and the solubility of the active ingredient was very rapid.

Table 11

Components Weight (mg) Therapeutic substance 1 Granule Lactose Substituted below 70 hydroxypropylcellulose 10 Hydroxypropylcellulose 2.5

• ··· * • 4 · • · ♦ · ♦

♦ · ♦ ··· ««

4 · · ·

0

0 • 0 •

♦ * 0 0 0 0 0 ·

External other substances Crystalline cellulose Magnesium stearate Light anhydrous acid siliceous 15 Dec 1 0.5 Total 100 ALIGN!

Example 7

As prescribed in Table 12, tablets containing 0.1 mg of the active ingredient in each of them (obtained in Experiment 1-5 as mentioned above) were obtained. To prepare the granules, the active ingredient was premixed and sieved through a hammer mill and then substituted hydroxypropyl cellulose and hydroxypropyl cellulose were substituted. The water was mixed into the mixture to form granules (kneaded granulation), which were dried and formed to a size of not more than 250 µm at 50% cumulative weight distribution and not more than 600 µm at 95% cumulative weight distribution. Crystalline cellulose, light anhydrous silicic acid and magnesium stearate were mixed with the granules so obtained and compressed into tablets. The tablets thus obtained had an appropriate size and uniform content and the stability of the active ingredient was guaranteed, the solubility of the active ingredient being very rapid.

Table 12

Components Weight (mg) Therapeutic substance 1 Granule Lactose Substituted below 35.3 hydroxypropylcellulose 5 Hydroxypropylcellulose 1,25 Crystalline cellulose 7.5 External other substances Magnesium stearate Light anhydrous acid 0.5 siliceous 0.25 Total 50

0 ** · ·

0 0 0 ♦ ♦

0 ·

0 • · • 0 0 ·

0000

Example 8

As prescribed in Table 13, tablets containing 0.05 mg of the active ingredient in each of them were obtained (used in Experiment 1-5, as mentioned above). To prepare the granules, the active ingredient was premixed and sieved with lactose using a hammer mill and then the lower substituted hydroxypropylcellulose and hydroxypropylcellulose were added. The water was mixed into the mixture to form granules (kneaded granulation), which were dried and formed to a size of not more than 250 µm at 50% cumulative weight distribution and not more than 600 µm at 95% cumulative weight distribution. Crystalline cellulose, light anhydrous silicic acid and magnesium stearate were mixed with the granules so obtained and compressed into tablets. The tablets thus obtained had an appropriate size and uniform content and the stability of the active ingredient was guaranteed, the solubility of the active ingredient being very rapid.

Table 13

Components Weight (mg) Therapeutic substance 0.05 Granule Lactose Substituted below 17.7 hydroxypropylcellulose 2.5 Hydroxypropylcellulose 0.625 Crystalline cellulose 3.75 External other substances Magnesium stearate Light anhydrous acid 0.25 siliceous 0.125 Total 25

Example 9

As prescribed in Table 14, tablets containing 0.2 mg of the active ingredient in each of them were obtained (used in Experiment 1-3 as mentioned above). Water was mixed into the powder mixture of the active ingredient, low substituted hydroxypropylcellulose and hydroxypropylcellulose to form granules (kneaded granulation), which were dried and formed to a size of not more than 350 pm at 50% cumulative weight distribution and not more than 1000 pm at 95% cumulative mass distribution. Crystalline cellulose, light anhydrous silicic acid and magnesium stearate were mixed with the granules so obtained and compressed into tablets.

The tablets thus obtained were of adequate size and uniform content and the stability of the active ingredient was guaranteed, and the solubility of the active ingredient was very rapid.

· * ♦ · ► · ·

I ♦ »·· ·· ♦ ·

Table 14

Components Weight (mg) Therapeutic substance 0.2 Granule Lactose Substituted below 70.8 hydroxypropylcellulose 10 Hydroxypropylcellulose 2.5 Crystalline cellulose 15 Dec External other substances Magnesium stearate Light anhydrous acid 1 siliceous 0.5 Total 100 ALIGN!

Example 10

According to the prescription in Table 15, a mixture of the active ingredient powder (used in Experiment 1-4 as mentioned above), lactose and low substituted hydroxypropylcellulose was sprayed with a solution of hydroxypropylcellulose in purified water to form granules (conveyor granulation) which were dried and dried. size adjusted to match granule parameters. Crystalline cellulose and light anhydrous silica were mixed with the granules so obtained and compressed into tablets each containing 0.5 mg of active ingredient. The tablets thus obtained were of adequate size and uniform content and the stability of the active ingredient was guaranteed, and the solubility of the active ingredient was very rapid.

Table 15

Components Weight (mg) Therapeutic substance 0.5 Granule Lactose Substituted below 84.7 hydroxypropylcellulose 12 Hydroxypropylcellulose 3

9 ·

* 99 99 99

External other substances Crystalline cellulose Magnesium stearate Light anhydrous acid siliceous 18 1,2 0.6 Total 120

Example 11

According to the prescription in Table 16, a mixture of the active ingredient powder (used in Experiment 1-4 as mentioned above), lactose and low substituted hydroxypropylcellulose was sprayed with a solution of hydroxypropylcellulose in purified water to form granules (conveyor granulation) which were dried and treated their size to match the granule parameters. The granules so obtained were admixed with additive granules, crystalline cellulose and light anhydrous silica and compressed into tablets each containing 0.5 mg of active ingredient. The tablets thus obtained were of adequate size and uniform content and the stability of the active ingredient was guaranteed, and the solubility of the active ingredient was very rapid.

Table 16

Components Weight (mg) Therapeutic substance 0.5 Granule Lactose Substituted below 169.39 hydroxypropylcellulose 24 Hydroxypropylcellulose 6 Crystalline cellulose 36 External other substances Magnesium stearate Light anhydrous acid 2.4 siliceous 1,2 Total 240

Example 12

As prescribed in Table 17, a mixture of lactose powder and low substituted hydroxypropylcellulose was sprayed with a solution of hydroxypropylcellulose in purified water and thereby.

• ··· · · · · Granules (conveyor granulation) have been formed which have been dried and resized to match the parameters for the additive granules.

Table 17

Components Weight (mg) Lactose 71 Granules of additives Substituted below hydroxypropylcellulose 10 Hydroxypropylcellulose 2.5 Total 83.5

As prescribed in Table 18, a mixture of the active ingredient powder (used in Experiment 1-4 as mentioned above), lactose and low substituted hydroxypropylcellulose was sprayed with a solution of hydroxypropylcellulose in purified water to form granules (conveyor granulation), which were dried and treated their size to match the granule parameters. The granules so obtained were admixed with the granules of the additives obtained as prescribed in Table 17, crystalline cellulose and light anhydrous silica, and the mixture was compressed into tablets each containing 0.1 mg of active ingredient. The tablets thus obtained were of adequate size and uniform content and the stability of the active ingredient was guaranteed, and the solubility of the active ingredient was very rapid.

Table 18

Components Weight (mg) Therapeutic substance 0.1 Granule Lactose 35.4 Substituted below hydroxypropylcellulose 5 Hydroxypropylcellulose 1,25 Granules of additives 58.45 External other substances Crystalline cellulose 2.4 Magnesium stearate 1,2 Light anhydrous acid siliceous 0.6

B «'« 4

Total 120

Example 13

As prescribed in Table 19, a mixture of the active ingredient powder (used in Experiment 1-4 as mentioned above), lactose and low substituted hydroxypropylcellulose was sprayed with a solution of hydroxypropylcellulose in purified water to form granules (conveyor granulation) which were dried and dried. size adjusted to match granule parameters. The granules so obtained were admixed with additive granules, crystalline cellulose and light anhydrous silica and compressed into tablets each containing 0.2 mg of active ingredient. The tablets thus obtained had an appropriate size and uniform content and the stability of the active ingredient was guaranteed, the solubility of the active ingredient being very rapid.

Table 19

Components Weight (mg) Therapeutic substance 0.2 Granule Lactose Substituted below 70.8 hydroxypropylcellulose 10 Hydroxypropylcellulose 2.5 Granules of additives 167 External other substances Crystalline cellulose 45 Magnesium stearate Light anhydrous acid 3 siliceous 1.5 Total 300

INDUSTRIAL APPLICABILITY

Crystals of Compound A in the present application having a particle size of not more than 100 μιη at a 50% cumulative weight distribution value and not more than 200 µm at a 95% cumulative weight distribution value (active ingredients from the present application) are used as starting material for the preparation . The active ingredient in the present application exhibits a strong stimulating effect.

activity for β ₃ adrenaline receptors and excellent adrenoceptor selectivity and therefore is used in the prophylaxis or treatment of obesity and diabetes. The preparation using the active ingredient of the present invention is an excellent preparation, characterized in that the size (volume) of the composition, the content uniformity of the active ingredient and the stability of the active ingredient are protected, and also that the release of the active ingredient is therefore very fast.

Claims (10)

A crystal of [3 - [(2R) - [[(2R) - (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -1H-indol-7-yloxy] acetic acid. 2. The [3 - [(2R) - [[(2R) - (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -1H-indol-7-yloxy] acetic acid crystal exhibits characteristic diffraction bands at diffraction angles ( 2Θ) about 5.9 °, about 17.9 °, about 20.5 °, and about 24.0 ° in the X-ray powder diffraction pattern. The crystal of claim 1 having a particle size of not more than 100 µm at a 50% cumulative weight distribution value and not more than 200 µm at a 95% cumulative weight distribution value. A granule comprising the crystal of claim 3. A granule according to claim 4, characterized in that (a) it comprises a crystal according to claim 3, (b) a filling, (c) a disintegrant and (d) a binder. Granules according to claim 5, characterized in that the total weight of the filler, disintegrant and binder is less than 500 weight units per 1 weight unit of crystal according to claim 3. 7. A solid composition comprising the granules of claim 4. A solid composition according to claim 7, characterized in that it comprises external substances. The solid composition of claim 7, wherein the crystal content of claim 3 is less than 2 mg per dosage unit. 10. The solid composition of claim 7 in the form of tablets.