SK7362002A3 - Solid pharmaceutical preparation - 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

Technical field

The present invention relates to a [3 - [(2R) - [[2R) - (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -1H-indol-7-yloxy] acetic acid crystal (hereinafter referred to occasionally as The present invention relates in particular to a solid composition in which the amount (volume) of the composition, the uniform content of the therapeutic substance and the stability of the therapeutic substance are stabilized and the further decomposition of the substance from the preparation 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).

Thus, a compound A exhibiting extremely potent pharmaceutical activities is contained 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, consistent with the decreasing content of Compound A in the formulation, it has been found that the chemical stability of Compound A per dose is extremely reduced. In addition, when the amount of other substances other than Compound A is increased so that a dimension considered suitable for use as a pharmaceutical composition is provided, the content of Compound A becomes uneven for each unit dose and it is difficult to obtain a composition having a uniform content of Compound A In these circumstances, it was desired to develop a Compound A formulation without the above defects, from which Compound A could dissolve rapidly.

It is an object of the present invention to provide a composition of Compound A in which the size (volume capacity) of the composition, the content unit 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.

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 referred to occasionally as " crystal of compound A ');

2) [3 - [(2R) - [[2R) - (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -1H-indol-7yloxy] acetic acid crystal having characteristic diffraction bands at diffraction angles (20) about 5.9 °, about 17.9 °, about 20.5 °, and about 24.0 ° in the X-ray powder diffraction pattern (hereinafter, occasionally referred to as "Compound A type-1 'crystal") ;

3) A Compound A crystal 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 referred to occasionally as "therapeutic agent") );

4) Granules comprising the above crystal (3) (drug substance);

5) Granules comprising (a) a drug substance, (b) a filler, (c) a disintegrant, and (d) a binder;

6) A solid composition comprising the above granules (4);

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

8) A tablet which is formed by compressing the above granule (4) and external substances;

9) The β ₃ -adrenaline receptor irritant, which comprises the above crystal (3) (drug substance);

10) An agent for treating diabetes mellitus comprising the above crystal (3) (therapeutic agent); and

11) An agent for treating obesity comprising the above crystal (3) (therapeutic agent).

Throughout the present specification and claims, "Compound A crystal" means pure [3 - [(2R) - [[2R) - (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -1H-indol-7- yloxy] acetic acid, and thus, as described below, the crystal of Compound A may be grouped into a type-1 crystal ("Compound A type-1 crystal") and a type-11 crystal ("Compound A type-11j crystal"). their diffraction strips of the X-ray diffraction pattern The type-1 crystal, the type-11 crystal, or a mixture of these crystals are obtained by a process for their production. "Compound A crystal" includes all these crystals.

A drug substance means the above Compound A crystal 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. The preferred particle size of the drug substance is not more than 50 µm at a 50% cumulative weight distribution value and not more 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 "therapeutic agent" of the present invention comprises all of the above.

"Cumulative mass distribution value" means the value obtained by classifying dusts based on the particle size present and adding weight to each particle size at the end of the distribution, expressed as a percentage of the total weight of the dusts. Generally, "particle size at 50% cumulative weight distribution" is used as a method of expressing the particle size diameter of dusts (particle aggregates) having a particle size distribution. In addition, throughout the present specification and claims, a "particle size at 95% cumulative weight distribution value" is used as an index to control the content of particles that affect the soluble behavior of a compound in a formulation (see Alfonzo R. Gennard (Ed.): Particle Size Measurement and Classification, Remington's Pharmacological Sciences 17th edition, Part 8, Chapter 89, pp. 15881589, 1985; Swithenbank, J., Beer, JM, Taylor, DS, Abbot, D., and McCreath, GC: A Laser Diagnostics Technique for the Measurement AIAA Páper No. 76-79 (1976) and Hayashi, S .; A small-angle laser scattering instrument for determining the size and concentration distribution in sprays, (Hirleman, ED and others Eds.) , Liquid Particle Size Measurement Techniques: Volume 2, Philadelphia, ASTM, 1990).

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

Step A

| Principle -------> ŽJYOG ^^ NHR H Z \ n OR I H CH}

A compound of formula I wherein R is a phenolhydroxy protecting group or -CH ₂ COX, X is a lower alkoxy, benzyloxy, lower alkyl, lower mono- and di-alkylamino or cyclic amino groups 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 form 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 ¹¹ 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 a compound of general formula of formula V, wherein R ¹ is as defined above, reacts with a compound of formula VI, wherein Y ¹ is an alcohol reactive residue and X is as defined above), and furthermore an amino protecting group is selectively removed to give compound VII; or (ii) when R 6 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, (wherein X is as defined 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 process for producing the crystal of Compound A of the present invention are explained below.

The terms "lower alkyl" and "lower alkyl" include a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, ethoxy, propoxy p 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, methylethylamino, diethylamino, propylamino, isopropylamino and dipropylamino, more preferably methylamino, dimethylamino, ethylamino, diethylamino and dipropylamino, and most preferably dimethylamino and diethylamino.

The term "cyclic amino" includes a 4- 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 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 p. 309385) 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,

2,2,2-trichloroethoxycarbonyl and benzyloxycarbonyl, 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, phthenesimido, p-sulfenesulfonyl, p-sulfenesulfonyl. methanesulfonyl and benzyl, more preferably tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, acetyl and trifluoroacetyl, and most preferably tert-butoxycarbonyl, benzyloxycarbonyl and 9-fluorenylmethoxycarbonyl.

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

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

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

Step A - Preparation of Formula III:

A compound of formula III may 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, alkyl lithium, sodium amide, lithium dialkylamide, etc. Generally speaking, when the indole derivative reacts in the presence of a nucleophilic reagent, a mixture of the compound substituted at position 1 and the compound substituted at position 3 is formed. Since the Grignard reagent is widely used to preferentially obtain the compound substituted at the 3-position, the Grignard reagent is also preferred in this step.

The Grignard reagent includes methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium bromide, tert-butyl magnesium chloride, phenyl magnesium chloride, etc., more preferably methyl magnesium bromide and tert-butyl magnesium chloride. The Grignard reagent is usually used in an amount of from about 1 to about 8 moles, more preferably from 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 (e.g. benzene, toluene, etc.) ethers (e.g. diethyl ether, tetrahydrofuran, etc.), chloroform and methyl chloride, and these solvents should be in anhydrous form.

The compound of formula (II) can be prepared by reacting an amino-protected α-amino acid with an inorganic halide compound (e.g. pentachlorophosphide, trichlorophosphide, tribromophosphide, etc.) or an organic halide compound (e.g. 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 mole of the starting compound. Ν, Ν-dimethylformamide or hexamethyltriamidophosphorous may 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 (e.g. benzene, toluene, etc.) or halogenated hydrocarbons (e.g. chloroform, methylene chloride, etc.).

Step B - Preparation of Compound of Formula IV

The 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. The reducing agent may be, for example, 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 from about 2 to about 6 moles, more preferably from about 3 to about 4 moles per mole 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 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 is obtained, the subject compound is used in the next 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 provide 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, said compound is identical to the compound of formula VII and can be used directly in step F.

Step C - Preparation of Compound (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 using 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 pressure or other pressure. Catalytic hydrogen transfer reduction using ammonium formate, formic acid, cyclohexane, 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 (e.g., sodium hydroxide, potassium hydroxide, etc.) and an organic base (e.g., 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 of Formula VII

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 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 (e.g. benzene, toluene, etc.), ketones (e.g. acetone, methyl ethyl ketone, etc.) ethers (e.g. tetrahydrofuran, dioxane, etc.), alcohols (e.g. ethanol, isopropanol, etc.), acetonitrile, N, N-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. The base 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 a chlorine atom or a bromine atom, the reaction may be smoothly accomplished by the addition of an alkali metal iodide (e.g. sodium iodide, potassium iodide, etc.) or halogenated tetraalkylammonium (e.g. ammonium tetra-butyl chloride), etc.).

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

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 group is 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 by the use of 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 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 as 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 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, N, N-dimethylformamide, etc., and these solvents may be used alone or as a mixture of two or more of these solvents. The base may be hyd ^r of alkali metal (e.g. sodium, potassium, etc.) And the organic base may be one base, such as piperidine, piperazine, etc .. The acid may be hydrochloric acid, hydrobromic acid, trifluoroacetic acid , sulfuric acid, formic acid, acetic acid, methanesulfonic acid, etc.

Step F and Step G - Preparation of Compound of Formula 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 according to the nature of the 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, methyl ethyl ketone, 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 as a mixture of two or more of these solvents. Trimethylsilylacetamide or cis-trimethylsilylacetamide 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 an acid salt is used in the interleaved reaction, the reaction is carried out in the presence of a base such as alkali metal bicarbonates (e.g., sodium bicarbonate, potassium bicarbonate, etc.) and alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.). or organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, etc. >

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.

The 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 from about 20 ° C to about 80 ° C, at atmospheric pressure or other pressure. A catalytic hydrogen transfer reaction using ammonium formate, formic acid, cyclohexene, hydrazine, etc. can 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 as 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 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, water or a mixture of these solvents, and these solvents may be used alone or as 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 base includes, for example, an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.) and an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.).

The Compound A crystal thus obtained is a Type-1 crystal of Compound A, which exhibits characteristic diffraction bands at diffraction angles (2 °) of about 5.9 °, about 17.9 °, about 20.5 °, and about 24.0 ° in the diffraction profile. X-ray powder spectrum.

The crystal of Compound A type-1 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 ° (Compound A Type-II crystal), but the Type-1 Compound A crystal is much easier to prepare industrially than Compound A Type-I Crystal.

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. a therapeutic agent, is used in the preparation of a compound of the present invention. Preferred drug particle sizes are used at values not greater than 50 µm at 50% cumulative weight distribution and particle sizes not greater than 150 µm at 95% cumulative weight distribution, most preferred particle size not greater than 30 µm at 50% value cumulative mass distribution and particle size not greater than 100 µm at 95% cumulative mass distribution. By using a drug substance meeting the above-described requirements, a composition can be obtained from which the drug substance dissolves readily. In addition, since the therapeutic agent can optionally be obtained as an agglomerate, it is preferred that the therapeutic agent has a content of said agglomerate of less than 50% and an almost individual particle size distribution.

The particle size of the drug substance (at 50% and 95% cumulative weight distribution values) is measured by a conventional method for measuring particle size of the drug, for example by the standard screening method, sedimentation method, light scattering method, image analysis, etc. but be limited to these methods only.

The present therapeutic agent satisfying the above-described requirements can be obtained by selecting crystallization conditions in the synthesis process of Compound A and / or selecting a crushing method after the synthesis of Compound A. For example, after the synthesis of Compound A, the therapeutic agent can be obtained by crushing Compound A with a hammer mill, a rotary ball mill, a vibrating ball mill, a conical ball mill, a roller mill or a wedge mill, under conditions that are selected according to the mill to be used.

The drug substance may be obtained by controlling the particle size and agglutination rate of Compound A during their synthesis process, or by dissolving the precipitated crystals during the synthesis process in an aqueous solvent such as water, organic solvent, etc., and exposing the resulting solution to spray drying or supercritical carbon dioxide gas under selected conditions.

Granules containing the drug substance are prepared to prepare the desired pharmaceutical composition using the drug substance so prepared.

The granules may contain, in addition to (a) a therapeutic agent, (b) a filler, (c) a disintegrant, and (d) a binding agent, also an easier swallowing agent, a lubricant, etc.

Since the non-drug substance in the granules is in direct contact with the drug substance, it is preferable to use other substances which are compatible with the drug substance and which protect the stability of the drug substance. Other substances in the granules other than the therapeutic substance, including, for example, filler, disintegrant and binding agent, but if necessary a swallowing agent, lubricant, etc., may be used as additional substances in the composition.

The other substances in the granules, other than the drug substance, are usually contained in an amount of 500 units of weight or less, more preferably in an amount of 300 units of weight or less, most preferably in an amount of 100 units of weight or less.

The filler includes, for example, lactose, corn starch, sucrose, trehalose, Dmanitol, erythritol, maltitol and ethylcellulose. Disintegrant includes, for example, low-substituted hydroxypropylcellulose, calcium carmellose, and sodium cross-carmellose. The binder includes e.g. hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, polyvinylpyrrolidone, gelatin and carmellose sodium.

The swallowing agent and lubricant include, for example, magnesium stearate, hydrogenated vegetable oil (castor oil), anhydrous silicic acid, and talc.

When magnesium stearate is used, it is used in an amount of from 1% to 5% by weight, preferably from 1% to 4% by weight, most preferably from 1.5% to 3% by weight, depending on the total weight of the composition.

The granular preparation is preferably produced by preparing the first mixed powder of the drug substance and part or all of the filler and mixing them, followed by sieving or crushing and then adding these mixtures to the remaining other substances and, if necessary, forming granules or controlling the size of the mixture, thereby protecting the unity of the content of the therapeutic substance.

Mixing and sieving is performed manually using a 64-mesh sieve 24 or using a sieving device having a suitable mixing capacity such as an oscillator. The mixing and crushing is carried out using a crushing device such as a hammer mill.

Granulation is performed, for example, by hot 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 µm at a 50% cumulative weight distribution value and not more than 1400 µm at a 95% cumulative weight distribution value. More preferably, the particle size of the granules is not greater than 300 µm at a 50% cumulative weight distribution value and not greater than 1000 µm at a 95% cumulative weight distribution value. Most preferably, the particle size of the granules is not greater than 250 µm at a 50% cumulative weight distribution value and not greater than 800 µm at a 95% cumulative weight distribution value. By using granules having such a preferred particle size, the content of the drug substance is more protected.

Drug particle sizes (at 50% and 95% cumulative weight distribution values) are measured by a conventional drug particle size method, for example, a standard screening method, a sedimentation method, a light scattering method, image analysis, etc., but 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 can be, for example, tablets, capsules, granules, powder, lace, 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 therapeutic agent per dosage unit, it is preferred to increase the volume (weight) of the composition by adding other substances to the granules to protect sufficient stability. as well as to protect a suitable size (usually from 4 to 10 mm in diameter, 25 to 300 mg).

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

For reasons of protection by the content unit of the therapeutic substance, the other external substances are present in an amount of from 0.01 to 100 units of weight, preferably from 0.1 to 50 units of weight, most preferably from 0.15 to 10 units of weight, per 1 unit weight of granules.

When formulating the composition, the external other substances may be used for mixing with the granules containing the drug substance only as a mixture of the external substances or after granulating the external substances, or by controlling their size to the same particle size as the drug substance granules. Hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, polyvinylpyrrolidone, gelatin, carmellose sodium as a binding agent can be used to granulate or control the size of the external substances. When the granules and external substances are mixed, a swallowing agent and / or a lubricant may be used.

The granules and external substances may be compressed together without mixing to obtain a dry coated tablet or an Iti layered tablet. In this case, the external agents may be, for example, crystalline cellulose, and / or low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose or pullulan as a binding agent.

When tablets are formed from granules or from a mixture of granules and external other substances, it is preferred to add magnesium stearate or hydrogenated vegetable oil (castor oil) in an amount of 1% to 5% by weight of the granule or mixture of granules and external other substances. which can easily appear in the compression process and then the mixture thus obtained is subjected to tablet compression in a suitable tabletting machine to produce the desired tablets.

In addition, to mask off-taste, increase tablet strength, improve in-use feel and ease of use, the tablets thus obtained can be coated with a suitable polymeric ingredient to form filter-coated tablets. The polymeric ingredient may be, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, methylcellulose, ethylcellulose, sodium carmellose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, copolymer of dimethylaminoethyl methacrylate copolymer and ethyl ethyl methacrylate copolymer. If necessary, for example, propylene glycol, glyceryl triacetate (triacetin), triethyl citrate, acetyl triethyl citrate, diethyl phthalate, diethyl sebacate, acetyl monoglyceride, or vegetable oil may be used as plasticizer for the polymeric ingredient in the coating agent. Further, for reasons of protection from light or improved 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 aluminum mordants, talc, titanium dioxide, metal oxides, calcium sulfate, calcium carbonate or riboflavin, carmine dye, ginger pigment may be added. In addition, a sweetening agent or a flavoring may also be added to increase digestibility.

. In addition, tablets may be converted to sugar coated tablets for the same objectives as those set forth above. The sugar coating agent may include, 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 cellulose derivatives such as pullulan, hydroxypropylmethylcellulose, etc. and if a water-soluble synthetic pigment such as Yellow No. 5 is necessary. 4, Yellow 5, Blue 1, Blue 2, and their aluminum stains, talc, titanium dioxide, metal oxides, calcium sulfate, calcium carbonate or riboflavin, carmine dye, ginger pigment may also be added. In addition, a sweetening agent or a flavoring may also be added to increase digestibility.

Granules or a mixture of granules and external other substances can be directly placed in pure granular compositions, granular compositions or powder compositions, or in capsule compositions by filling them into gelatin capsules. In this case, the external substances may be lactose, corn starch, sucrose, trehalose, D-mannitol, erythritol, maltitol and / or ethyl cellulose and magnesium stearate and / or hydrogenated vegetable oil. Furthermore, light anhydrous silicic acid and / or talc can also be used. In the case of granular compositions, after the granules, hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, polyvinylpyrrolidone, gelatin or carmellose sodium may be added to fill the granular compositions.

Further, if it is desirable, for reasons of need, to form single release enhancing tablets, the granules containing the drug substance or tablets are coated with a drug dispensing control coating consisting of a polymeric agent or fats and oils to obtain reservoir-type discharge enhancing tablets. For example, the coating agent may be beeswax, carnauba wax, cetyl alcohol, cetyl stearyl alcohol, lipid fats and oils, resins (e.g. shellac), cellulose esters (e.g. ethylcellulose) and acrylic esters. If necessary, for example, propylene glycol, glycerol, polyethylene glycol, glyceryl triacetate (triacetin), triethylcitrate, acetyltriethylcitrate, diethyl phthalate, diethylseglinate, acetyl monoglycerin, acetyl monoglycerin, acetyl mono-oleate, acetyl mono-oleate, acetyl mono-oleate, acetyl mono-oleate, acetyl mono-oleate, acetyl mono-olefin; In addition, the drug dispensing controlling granule may be compressed to form tablets.

A matrix type of release enhancing agent can be obtained by mixing the drug release control component such as the polymeric ingredients as mentioned above, or fats and oils together with fillings in the granules and tablets 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 can 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 only. Further, if necessary, the solid composition of the present invention may be packaged together with a suitable desiccant such as silica gel.

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

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

Experiment - stimulating activity of human β ₃ - adrenaline receptor

The highly expressing human β ₃ -adrenaline receptor cell line CHO / pKREX10-36 was cultured for 2-3 days with MEM-Dulbecco medium supplemented with 10% germ-bovine serum and 200 µg / ml G-418. Cells were incubated with sodium chloride phosphate buffered saline containing 0.5 mM EDTA at 37 ° C for 10 minutes after the medium was removed. CHO / pKREX10-36 cells were centrifuged and resuspended in Hank buffer (INC 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 μΙ) and the test compound were mixed in the same buffer (500 μΙ) and incubated at 37 ° C for 30 minutes, followed by boiling for 5 minutes to complete the reaction. After centrifugation of the reaction mixture, the amount of cAMP in the suspernatant was measured using the EIA System (Amersham).

Similarly, the amount of cAMP was measured in the same manner using the CHO / pKEX21-8 the cell line highly expressing human? ₂ receptor and -adrenalínového using CHO / pKREX23-30 for highly expressing cell line of human β ₁ receptor instead of the CHO -adrenalínového / pKREX10-36 for a highly expressing human β ₃ -adrenaline receptor cell line.

The amount of cAMP after being added to the reaction mixture of 10 ' ⁵ M (-) isoproterenol or after not adding it at all was indicated as 100% and 0%, and the relative maximum response of the drug substance of the present invention (10' ⁶ to 10 ' ¹¹ M) 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 curve of the concentration response curve for each compound.

The results are shown in Table 1.

Table 1

Test compound Stimulating activity of human β ₃ -, β ₂ - and β-adrenaline receptors β ₃ - receptor β ₂ - receptor βι - receptor ΕΟδο (ηΜ) P.A.. (%) EC ₅₀ (nM) P.A.. (%) EC ₅₀ (nM) P.A.. (%) A * 0.27 110 21 45 3.5 83 IP ** 10 100 4.2 100 0.46 100

Note: * means a drug substance; ** means (-) - isoproterenol.

In this experiment, a compound having a low EC 50 value and a high PA value is considered to have a stimulating activity of the human β-adrenaline receptor. Also, as shown in Table 1, the therapeutic agent of the present invention is confirmed to have a potent stimulating activity of the human β ₃ adrenaline receptor, but the stimulating activities of the human β ₂ -? - adrenaline receptor of this substance are relatively weak.

As shown in the above results, the therapeutic agent of the invention may be regarded as a stimulating agent of human β ₃ adrenaline receptor with excellent adrenoceptor selectivity.

The medical material of the present invention is useful as an agent stimulating the β ₃ receptor in Γβη3ΐίηονέΐΊθ ^ profylakcii treating obesity, diabetes mellitus, hyperlipemia, irritable bowel syndrome, acute or chronic diarrhea, pollakiuria, enuresis, urinary calculus, etc ..

In addition, the therapeutic agent of the present invention is also useful in the treatment of symptoms such as stomach pain, nausea, vomiting, epigastritis associated with gastric ulcers, acute chronic gastritis, biliary dyskesis, cholecystitis, etc.

When the therapeutic agent of the present invention is used as an agent stimulating the β ₃ - ^ · Γβη3ΐίηονόΓ) ο receptor, it can be administered orally, parenterally or rectally, but the oral route is more appropriate. The dose of the therapeutic agent of the present invention may vary depending on the type of administration chosen, the conditions, the age of the patients or the type of use (prophylaxis or treatment), etc., but usually in the range of 0.0002 mg / kg / day to 0.02 mg / kg. preferably from 0.001 mg / kg / day to 0.02 mg / kg / day.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is the powder X-ray diffraction pattern of Compound A of the Type-1 crystal obtained in Preparation 1.

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

DETAILED DESCRIPTION OF THE INVENTION

The present invention is outlined in more detail in the following Preparations, Experiments and Examples, but should not be construed as limited to the foregoing.

Example 1

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

The following abbreviations may be used to simplify the description.

Fmoc: 9-Fluorenylmethoxycarboxylic acid

Ala: Alanine balance

J: Matching constant

S: Jedennásobok

D: Double

Dd: Double double

T: 3x q: 4x m: Multiple br: Wide part (1) Preparation of (R) -3- (2-aminopropyl) -7-benzyloxyindole 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 dropwise oxalyl chloride (7 mL, 80 mmol). ) at room temperature 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-C1, which was used in the next reaction without further purification.

Step 2 - To an ice cold and stirred solution of commercially available 7benzyloxyindole (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-C1 methyl chloride (200 mL) obtained in step 1 on ice. The mixture was warmed to room temperature and further stirred for one hour. A 5% aqueous hydrochloric acid solution was added to the mixture on ice, and the whole was stirred for 15 minutes. The organic layer was separated, washed with water (100 mL) and dried over 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 was 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) at room temperature was added portionwise 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. Next, 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 the residue was treated with a solution of oxalic acid (4.50 g, 50 mmol) in ethyl acetate (45 mL) 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, mp 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 = 14 Hz), 3.42 (1H, m), 5.26 (2H, s), 5.94 (4H, br), 6.75 (1H, d, J = 8 Hz), 6.92 (1H, t, J = 8Hz), 7.11-7.22 (2H, m), 732-7.48 (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 above (1) and the mixture was stirred. Di-tert-butylbicarbonate (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, mp 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 (1H, m), 4.44 (1H, m), 5.18 (2H, s), 6.71 (1H, d, J = 7.5Hz), 6.97 (1H, d, J = 2.2Hz), 7.02 (1H, t, J = 7.9 Hz), 7.20 (1H, s), 7.24-7.51 (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 INDRUSTRIES, LTD)); mobile phase (n-hexane: isopropanol = 700: 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 an ice and stirred solution of (R) -7-benzyloxy-3- (2-tert-butoxycarbonylaminopropyl) indole (10g, 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, the insoluble materials were removed by filtration and the solvent was evaporated under reduced pressure. Chloroform (100 mL) and water (100 mL) were added to the residue, 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 (10.7 g, 100%) as white crystals, m.p. 142 ° C.

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

¹ H-NMR spectrum (300 MHz, CHCl ₃ , δ ppm): 1.10 (3H, d, J = 6.6 Hz), 1.17 (3H, t, J = 7.1 Hz) 1.22 (3H, t, J = 7.1 Hz), 1.43 (9H, s), 2.83 (1H, dd, J = 14.1 Hz, J = 7.0 Hz), 2.94 (1H δ d, J = 14.1 Hz, J = 5.1 Hz), 3.34 (2H, q, J = 7.1 Hz), 3.44 (2H, q, J = 7.1 Hz), 3.99 (1H, br), 4.45 (1H, br), 4.80 (2H, s), 6.67 (1H, d, J = 7.7 Hz), 6.99 (1H, t, J = 7.9 Hz), 7.10 (1H, s), 7.30 (1H, d, J = 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 INDRUSTRIES, 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] -1H-indol-7-yloxy] acetamide (12 g, 29.7 mmol) obtained in the above step (3) 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);

1 H-NMR spectrum (300 MHz, CHCl ₃ , δ ppm): 1.16 (3H, d, J = 6.6 Hz), 1.17 (3H, t, J = 7.1 Hz), 1.22 (3H, t, J = 7.1 Hz), 1.40-2.00 (2H, br), 2.64 (1H, dd, J = 14.1 Hz, J = 8.2 Hz), 2 .86 (1H; dd, J = 14.1 Hz, J = 5.0 Hz), 3.18 (1H, m), 3.35 (2H, q, J = 7.1 Hz), 3, 44 (2H, q, J = 7.1Hz), 4.80 (2H, s), 6.68 (1H, d, J = 7.5Hz), 6.99 (1H, t, J = 7) 9 Hz), 7.05 (1H, s), 7.28 (1H, d, J = 8.0Hz), 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: isoproponal: 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] -

H-indol-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 step (4) above 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 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 acenotril (21 mL) and (R) -3-chlorostyrene oxide (1.07 g, 6.9 mmol) were added again to the residue and the mixture was refluxed 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%), m.p. Mp 120-121 ° C.

[α] D ²⁵ = -69.1 ° (c = 1.0, methanol);

¹ H spectrum (300 MHz, CHCl ₃ , δ ppm): 1.11 (3H, d, J = 6.2 Hz), 1.16 (3H, t, J = 7.1)

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

Hz), 2.87 (1H, dd, J = 12.2 Hz, J = 3.7 Hz), 3.00 (1H, m), 3.34 (2H, q, J = 7.1 Hz) 3.43 (2H, q, J = 7.1Hz), 4.54 (1H, m), 4.78 (2H, s), 6.65 (1H, d, J = 7.3Hz) 6.98 (1H, t, J = 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-7yloxy] acetic acid (Compound A)

Ν, Ν-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. The 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, J = Hz), 2.61 (1H, m), 2.80-3.22 (4H, m), 4.54 (2H, s), 4.90 (1H, m), 6.48 (1H, d, J = 8Hz), 6.76 (1H, t, J = 8Hz), 6 98-7.02 (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 / min); temperature (30 ° C); detection wavelength (220 nm); retention time (27.4 min)]

The X-ray diffraction profile of the thus obtained crystals of Compound A was measured by an X-ray powder diffractometer (RINT1000-type; manufactured by RIGAKU CORPORATION) at 30 kV tube voltage and 20 mA tube current using a CuKa fiber in the diffraction angle range (20). The diffraction pattern of the crystals is shown in Figure 1. The diffraction angles in the X-ray powder diffraction profile of Compound A are about 5.9 °, about 17.9 °, about 18.8 °, about 20.5 °, about 23.3 °, 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 Compound A Type -II Crystals: To the Compound A Type-I crystals (100 mg) obtained in Preparation 1 was added methanol (35 mL) 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 pattern of the thus obtained crystals of Compound A Type-II 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 in the diffraction angle range. ). The diffraction profile of the crystals is shown in Figure 2. The diffraction angles in the powder X-ray diffraction profile 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 23.3 °. Diffraction angle values (2Θ) have standard accuracy.

Preparation 3 - Preparation of Therapeutic Substance (1) The crystals of Compound A type-1 obtained in Preparation 1 were reduced using a hammer mill (Sample Milk AP-S, manufactured by Hosokowa Micron Corporation, Japan) using a 0.7 mm open diameter sieve. .

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

(3) The particle size at 50% and 95% of the cumulative weight distribution of each of the reduced granules thus obtained was measured using a laser particle size diffraction analyzer (HELOS & RODOS (Trade Mark), manufactured by SYMPATEC GmbH, Germany) and calculated from the cumulative size distribution. particles 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 (1) Particle size of the drug substance - as prescribed in Table 2, was added to the mixed powder of drug substance or non-reduced crystals of Compound A, lactose, low-substituted hydroxypropylcellulose, water and mixing started to form granules (shaping granulation) and sized in order to obtain granules. The granules so obtained were mixed with crystalline cellulose, light anhydrous silicic acid and magnesium stearate and compressed to form tablets containing 1 mg of the active substance or unabsorbed crystals of compound A. The therapeutic substance used was that which was reduced using a hammer mill (Sample Milli). AP-S, manufactured by Hosokawa Micron Corporation, Japan using a 0.7 mm or 1 mm open diameter screen, or reduced using a Variable Energy Mill (Single Truck Jet Mill 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 carried out according to the Thirteenth Edition of the Pharmacopoeia of Japan (paddle method, 50 rpm). / min, water 37 ° C, 900 ml) and the relationship between the particle size of the drug substance and its decomposition from tablets was evaluated The degradation rate was measured for 15 minutes. The results are shown in Table 3.

Table 2

Components weight (mg) Ganuly the drug substance or crystal of Compound A 1 lactose 70 low-substituted hydroxypropylcellulose 10 hydroxypropyl 2.5 external other substances crystalline cellulose 1.5 magnesium stearate 1 light anhydrous silicic acid 0.5 Pretty 100

Table 3

Method of grinding Particle size (pm) at 50% cumulative weight distribution Particle size (pm) at 95% cumulative weight distribution Solubility after 15 min. (%) Exp. 1-1 mill with variable energy 1.7 3.8 100 Exp. 1-2 hammer mill (open window diameter 0.7 mm) 9.4 43 97 Exp. 1-3 hammer mill (open window diameter 0.7 mm) 17 42 100 Exp. 1-4 hammer mill (open window diameter 0.7 mm) 21 75 99 Exp. 1-5 hammer mill (open window diameter 0.7 mm) 12.5 45 100 Exp. 1-6 hammer mill (open window diameter 0.7 mm) 45 144 96 Comparative Exp. 1-1 not lessening 85 366 60

Tablets prepared using a drug substance have a particle size at 50% cumulative weight distribution value not greater than 100 μίτι and a particle size at 95% cumulative weight distribution value not greater than 200 μΓη 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 drug substance and other substances than the drug substance

A drug substance powder blend (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 lower substituted hydroxypropylcellulose were treated with an aqueous solution of hydroxypropylcellulose and a granulator and a granulator dryer were used. As shown in Table 4, 3 kinds of granules were prepared where the content of other components other than the drug substance was different in the granules -

82.5 units of mass (experiment 2-1), 417 units of mass (experiment 2-2) 834 units of mass (comparison experiment 2-1) per unit mass of drug substance. A fixed amount of crystalline cellulose, light anhydrous silicic acid and magnesium stearate were added to each granule and 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 their growth was recalculated to the original amount. The results are presented in Table 5.

Table 4

Components Exp. 2-1 Exp. 2-2 comparative Exp. 2-1 granules The active substance 1 0.2 0.1 Lactose Lower substituted 70 70.8 70.9 hydroxypropyl 10 10 10 Other substances hydroxypropyl 2.5 2.5 2.5 Crystalline cellulose 15 15 15 stearate 1 1 1 Magnesium Light anhydrous silicic acid 0.5 0.5 0.5 Total (mg) 100 100 100 Units of weight in granules of added substances other than 82.5 417 834 therapeutic substance per unit weight of the drug substance

Table 5

Exp. 2-1 Exp.2-2 Comparative Exp. 2-1 Increase (%) of degradation 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 the Experimental 2-1, which contains more than 500 units of weight of added components in granules as therapeutic agent per unit of therapeutic agent weight, it has been shown that the chemical stability of the drug substances in the experiment tablets 2-1 and 2-2 is higher.

Example 4

The ratio of the composition in the granules to the weight of the drug substance and other substances than the drug substance

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

Table 6

Components Weight (mg) Granules of added substances lactose Lower substituted hydroxypropylcellulose Hydroxypropylcellulose 71 10 2.5 Pretty 83.5

To a mixture of the drug substance powder (used above in Experiment 1-4), lactose and lower substituted hydroxypropylcellulose was added a solution of hydroxypropylcellulose in purified water to form granules (kneading granulation), which were dried and resized to match the granule parameters. Four types of granules were produced whose content of substances other than the therapeutic substance 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 4-2), to 1 unit weight of drug substance. Additive granules obtained according to the prescription given in Table 6, crystalline cellulose, light anhydrous silicic acid and magnesium stearate were added to the 4 second granules and the mixture was compressed into tablets each containing 0.1 mg of drug substance and 1.87 units of weight additives per unit weight of granules (experiment 31), tablets containing 0.2 mg of drug substance and 2.59 units weight of additives per unit weight of additives per unit weight of granules (Comparative Experiment 3-1) and tablets containing 0 , 2 mg of drug substance and 0.02 units of weight of additives per unit weight of granules (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 decomposition products was measured by high pressure liquid chromatography, the growth of the products was recalculated to the original amount. The results are reviewed in Table 8.

Table 7

Components Exp. 3-1 Exp. 3-2 Comparative Exp. 3-1 Comparative Exp. 3-2 granules The active substance 0.1 0.2 0.1 0.2 Lactose Lower substituted 35.4 70.8 85.1 212.8 hydroxypropyl 5 10 12 30 hydroxypropyl 1.25 2.5 3 7.5 external granules 58.45 167 - - other substances Additives Crystalline 18 45 18 45 Cellulose Magnesium stearate Light anhydrous 1.2 3 1.2 3 silicic acid 0.6 1.5 0.6 1.5 Total (mg) 120 300 120 300 units weight in granules of additives other than the therapeutic agent per unit of therapeutic weight 416.5 416.5 1001 1,251.5 substances units weight other additives per unit weight of granules 1.87 2.59 0.20 0.20

Table 8

Exp. 3-1 Exp. 3-2 comparative Exp. 3-1 comparative Exp. 3-2 Increase (%) of degradation products 0.75% 0.83% 1.31% 1,76%

In the tablets in Experiments 3-1 and 3-2, the amount of all degradation products produced is lower compared to the tablets in the relative Experiments 3-1 and 3-2, thus demonstrating that the chemical stability of the drug substance in the tablets of Experiment 3-1 and 3-2 is higher.

Example 5

Pre-mixing during the preparation of the granules

As prescribed in Table 9, tablets each containing 0.05 mg of the drug substance (used in Experiment 1-5) were obtained. To prepare the granules, the drug substance was first mixed and ground with lactose in a mixing screen (stainless steel sieve with 50 mesh = experiment 3-1) or a granulator (hammer mill = experiment 3-2) was used and lower substituted hydroxypropyl cellulose and hydroxypropyl cellulose were added. . Water was added by stirring the mixture and the resulting granules (kneading granulation) were dried and formed to the appropriate size. Crystalline cellulose, light anhydrous silicic acid and magnesium stearate were added to 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 equivalent). The results are shown in Table 10.

Table 9

Components Weight (mg) granules The active substance 0.05 lactose 17.7 Lower substituted hydroxypropylcellulose 2.5 hydroxypropyl 0,625 External others Additive granules 3.75 substances Crystalline cellulose 0.25 Magnesium stearate 0,125 Pretty 25

Table 10

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

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

Example 6

As prescribed in Table 11, tablets containing 1 mg of the drug substance in each of them were obtained (used in Experiment 1-3 as above). To prepare the granules, the drug substance was premixed and screened with lactose using a hammer mill, and then the lower substituted hydroproyl cellulose and hydroxypropyl cellulose were added. Water was mixed into the mixture to form granules (kneaded granulation), which were dried and shaped to a size of not more than 250 µm at 50% cumulative weight distribution value and not more than 600 µm at 95% cumulative weight distribution value. Crystalline cellulose, light anhydrous silicic acid and magnesium stearate were added to the granules so obtained and compressed into tablets. The tablets thus obtained were of adequate size and uniform content and the stability of the drug substance was guaranteed, the solubility of the drug substance was very rapid.

Table 11

Components Weight (mg) granules The active substance 1 lactose 70 Lower substituted hydroxypropyl 10 hydroxypropyl 2.5 External other substances Crystalline cellulose 15 Magnesium stearate 1 Light anhydrous acid silicic 0.5 cekom 100

Example 7

As prescribed in Table 12, tablets containing 0.1 mg of the drug substance in each of them were obtained (used in Experiment 1-5 as above). To prepare the granules, the drug substance was premixed and screened with lactose using a hammer mill, and then a lower substituted hydroxypropylcellulose was added. Water was mixed into the mixture to form granules (kneaded granulation), which were dried and shaped to a size of not more than 250 µm at 50% cumulative weight distribution value and not more than 600 µm at 95% cumulative weight distribution value. Crystalline cellulose, light anhydrous silicic acid and magnesium stearate were added to the granules so obtained and compressed into tablets. The tablets thus obtained were of adequate size and uniform content and the stability of the drug substance was guaranteed, the solubility of the drug substance was very rapid.

Table 12

Components Weight (mg) granules The active substance 1 lactose Lower substituted 35.3 hydroxypropyl 5 hydroxypropyl 1.25 External other substances Crystalline cellulose 7.5 Magnesium stearate Light anhydrous acid 0.5 silicic 0.25 Pretty 50

Example 8

According to the prescription in Table 13, tablets containing 0.05 drug substance in each of them were obtained (used in Experiment 1-5 as above). To prepare the granules, the drug substance was premixed and screened with lactose using a hammer mill, and then lower substituted hydroxypropylcellulose and hydroxypropylcellulose were added. Water was mixed into the mixture to form granules (kneading granulation), which were dried and shaped to a size of not more than 250 µm at 50% cumulative weight distribution. Crystalline cellulose, light anhydrous silicic acid and magnesium stearate were added to the granules so obtained and compressed into tablets. The tablets thus obtained were of adequate size and uniform content and the stability of the drug substance was guaranteed, the solubility of the drug substance was very rapid.

Table 13

Components Weight (mg) granules The active substance 0.5 lactose Lower substituted 17.7 hydroxypropyl 2.5 hydroxypropyl 0,625 External other substances Crystalline cellulose 3.75 Magnesium stearate Light anhydrous acid 0.25 silicic 0,125 Pretty 25

Example 9

As prescribed in Table 14, tablets containing 0.2 mg of the drug substance in each of them were obtained (used in Experiment 1.3 as above). The mixture of drug substance powder, low substituted hydroxypropylcellulose and hydroxypropylcellulose was mixed with water to form granules (kneaded granulation), which were dried and formed to a size of not more than 350 µm at a 50% cumulative weight distribution value and not more than 1000 µm at 95% cumulative mass distribution. Crystalline cellulose, light anhydrous silicic acid and magnesium stearate were admixed 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 drug substance was guaranteed, the solubility of the drug substance was very rapid.

Table 14

Components Weight (mg) granules The active substance 0.2 lactose Lower substituted 70.8 hydroxypropyl 10 hydroxypropyl 2.5 External other substances Crystalline cellulose 15 Magnesium stearate Light anhydrous acid 1 silicic 0.5 Pretty '100

Example 10

As prescribed in Table 15, a mixture of the drug substance powder (used in Experiment 1-4 as above), lactose and low substituted hydroxypropyl cellulose were sprayed with a solution of hydroxypropyl cellulose in purified water to form granules (conveyor granulation) which were dried and resized to fit the granule parameters. Crystalline cellulose and light anhydrous silicic acid were added to the granules so obtained and compressed into tablets each containing 0.5 mg of the drug substance. The tablets thus obtained were of adequate size and uniform content and the stability of the drug substance was guaranteed, the solubility of the drug substance was very rapid.

Table 15

Components Weight (mg) granules The active substance 0.5 lactose Lower substituted 84.7 hydroxypropyl 12 hydroxypropyl 3 External other substances Crystalline cellulose 18 Magnesium stearate Light anhydrous acid 1.2 silicic 0.6 Pretty 120

Example 11

According to the prescription in Table 16, a mixture of the drug substance powder (used in Experiment 1-4 as above), lactose and low substituted hydroxypropyl cellulose were sprayed with a solution of hydroxypropyl cellulose in purified water to form granules (conveyor granulation) which were dried and resized to fit the granule parameters. The granules thus obtained were admixed with additive granules, crystalline cellulose and light anhydrous silica, and the mixture was compressed into tablets each containing 0.5 mg of the drug substance. The tablets thus obtained had an appropriate size and uniform content and the stability of the drug substance was guaranteed, the solubility of the drug substance was very fast

Table 16

Components Weight (mg) granules The active substance 0.5 lactose Lower substituted 169.39 hydroxypropyl 24 hydroxypropyl 6 External other substances Crystalline cellulose 36 Magnesium stearate Light anhydrous acid 2.4 silicic 1.2 Pretty 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 to form granules (conveyor granulation), which were dried and resized to match the parameters for the additive granules.

Table 17

Components Weight (mg) Additive granules lactose Lower substituted hydroxypropylcellulose 71 10 2.5 Pretty 83.5

As prescribed in Table 18, a mixture of the drug substance powder (used in Experiment 1-4 as above), lactose and low substituted hydroxypropyl cellulose was sprayed with a solution of hydroxypropyl cellulose in purified water to form granules (conveyor granulation) which were dried and resized to fit the granule parameters. The granules so obtained were admixed with the granules of the additive obtained as prescribed in Table 17, crystalline cellulose and light anhydrous silicic acid, and the mixture was compressed into tablets each containing 0.1 mg of the drug substance. The tablets thus obtained were of adequate size and uniform content and the stability of the drug substance was guaranteed, the solubility of the drug substance was very rapid.

Table 18

Components Weight (mg) granules The active substance 0.1 lactose 35.4 Lower substituted 5 hydroxypropylcellulose 12.5 External other substances Additive granules 58.45 Crystalline cellulose 2.4 Magnesium stearate Light anhydrous acid 1.2 silicic 0.6 Pretty 120

Example 13

As prescribed in Table 19, a mixture of the drug substance powder (used in Experiment 1-4 as above), lactose and low substituted hydroxypropyl cellulose were sprayed with a solution of hydroxypropyl cellulose in purified water to form granules (conveyor granulation) which were dried and resized to fit the granule parameters. The granules so obtained were admixed with additive granules, crystalline cellulose and light anhydrous silicic acid and compressed into tablets each containing 0.2 mg of the drug substance. The tablets thus obtained were of adequate size and uniform content and the stability of the drug substance was guaranteed, the solubility of the drug substance was very rapid.

Table 19

Components Weight (mg) granules The active substance 0.2 lactose Lower substituted 70.8 hydroxypropyl 10 hydroxypropyl 2.5 External other substances Additive granules 167 Crystalline cellulose 45 Magnesium stearate Light anhydrous acid 3 silicic 1.5 Pretty 300

Industrial usability

Crystals of Compound A in the present application having a particle size of not more than 100 µm at a 50% cumulative weight value and not more than 200 µm at a 95% cumulative weight distribution value (drug substance of the present application) are used as starting material for preparation. The active substance in the present application shows a strong stimulating activity for β ₃ adrenaline receptors and excellent adrenaline selectivity and is therefore used in the prophylaxis or treatment of obesity and diabetes. The formulation using the drug substance of the present invention is an excellent formulation, characterized in that the size (volume) of the formulation, the content unit of the drug substance and the stability of the drug substance are protected in that the release of the drug substance is therefore rapid.

Claims (17)

PATENT CLAIMS A crystal of [3 - [(2R) - [[2R) - (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -1H-indol-7yloxy] acetic acid. [3 - [(2R) - [[2R) - (3-Chlorophenyl) -2-hydroxyethyl] amino] propyl] -1H-indol-7-yloxy] acetic acid crystal characterized by 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 ^ 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 filler, (c) a desitergrant and (d) a binder. A granule according to claim 5, characterized in that the total weight of the filler, disintegrant and binder is less than 500 units of weight to 1 unit of weight of the crystal of claim 3. A solid composition comprising the granules of claim 4. 8. A solid composition comprising external other substances. The solid composition of claim 7, wherein the crystal content of claim 3 is less than 2 mg per dosage unit. A solid composition according to claim 7, characterized in that it is in the form of tablets. A tablet which is prepared by compressing a granule according to claim 4. Tablet according to claim 11, characterized in that the crystal content according to claim 3 is not more than 2 mg per dosage unit. A tablet, characterized in that it is prepared by adding external substances to the granule according to claim 4, followed by compression of the tablet mixture. Tablet according to claim 13, characterized in that the crystal content according to claim 3 is not more than 2 mg per dosage unit. The β ₃ -adrenaline receptor irritant comprising the crystals of claim 3. 16. An agent for the treatment of diabetes mellitus comprising the crystals of claim 3. An agent for the treatment of obesity, characterized in that it comprises the crystals of claim 3.