MXPA02005326A

MXPA02005326A - Solid preparation.

Info

Publication number: MXPA02005326A
Application number: MXPA02005326A
Authority: MX
Inventors: Motokazu Iwata
Original assignee: Dainippon Pharmaceutical Co
Priority date: 1999-11-30
Filing date: 2000-11-24
Publication date: 2003-02-12
Also published as: NZ519086A; WO2001040182A2; WO2001040182A3; AU1550501A; JP2003515587A; PL356468A1; HUP0203865A3; EP1235801A2; HUP0203865A2; CN1433403A; NO20022541D0; SK7362002A3; IL149635A0; NO20022541L; CZ20021833A3; CA2391646A1

Abstract

The present invention provides a solid preparation comprising a crystal of [3 [(2R) [[(2R) (3 chlorophenyl) 2 hydroxyethyl]amino]propyl]mi nus;1H indol 7 yloxy]acetic acid (Compound A), especially a crystal of Compound A having a particle size of not larger than 100 mgr;m at the cumulative weight distribution value of 50 %, and not larger than 200 mgr;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

SOLID PREPARATION Technical field The present invention relates to a crystal of [3- [(2R) - [[(2R) - (3-chlorophenyl) -2-idroxyethyl] amino] -propyl] -lH-indol-7-yloxy] acetic acid ( hereinafter, occasionally referred to as Compound A), and to a pharmaceutical preparation containing as a drug substance the crystal of Compound A; especially, the present invention relates to a solid preparation in which the size (volume) of the preparation, the uniformity of contents of the drug substance and the stability of the drug substance are assured, and in addition the dissolution of the substance of drug preparation is fast.

BACKGROUND OF THE INVENTION Compound A exhibits a potent β3-adrenergic receptor stimulating activity with excellent adrenoreceptor selectivity, and is useful in the prophylaxis or treatment of diabetes mellitus and obesity (WO 96/16938). KEF : 139362 Compound A exhibits extremely potent pharmaceutical activities and when formulated in a pharmaceutical composition, that composition must be a low content preparation in which the content of the active compound per unit dose is low. However, along with the decrease in the content of Compound A in a preparation, the phenomenon has been discovered that the chemical stability of Compound A per se is extremely diminished. In addition, when the amount of excipients other than Compound A is increased to ensure that the size is suitable for use as a pharmaceutical preparation, the content of Compound A for each unit dose becomes non-uniform and it is difficult to provide a preparation having a uniform content of Compound A. Under the circumstances, it has been desired to develop a preparation of Compound A without the above-mentioned defects, from which Compound A can be dissolved. It is an object of the present invention to provide a preparation of Compound A in which the size (cubic capacity) of the preparation, the uniformity of content of Compound A and the stability of Compound A are assured, as well as from which Compound A can be rapidly dissolved.

Description of the invention The present invention includes the inventions of the following varied modalities. 1) A crystal of [3- [(2R) - [[(2R) - (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -lH-indol-7-yloxy] acetic acid (hereinafter referred to occasionally as "crystal of Compound A"); 2) A crystal of [3- [(2R) - [[(2R) - (3-chlorophenyl) -2-hydroxyethyl] to ino] propyl] -lH-indol-7-yloxy] acetic acid, which has peaks characteristic diffraction patterns at diffraction angles (2?) of approximately 5.9 °, approximately 17.9 °, approximately 20.5 ° and approximately 24.0 ° in the X-ray powder diffraction pattern (hereinafter, occasionally referred to as "Type I crystal"). Compound A "); 3) A crystal of Compound A having a particle size not greater than 100 μm at the cumulative weight distribution value of 50%, and a particle size not greater than 200 μm at the cumulative weight distribution value of 95 % (hereinafter, occasionally referred to as "drug substance"); 4) A granule consisting of the crystal of 3) (drug substance); 5) A granule consisting of a) a drug substance, ~ b) a filler, c) a disintegrant and d) a binder; 6) A solid preparation containing the granule of 4) above; 7) A tablet that is formulated by compressing the granule of the previous 4); 8) A tablet that is formulated by compressing the granule of the above 4) and external excipients; 9) A β3-adrenergic receptor agonist, which comprises the crystal of 3) above (drug substance); 10) An agent for the treatment of diabetes mellitus, which contains the crystal of 3) above (drug substance); and 11) An agent for the treatment of obesity, which contains the crystal of 3) above (drug substance). Throughout the present description and claims, the "crystal of Compound A" means a pure crystal of acid [3- [(2R) - [[(2R) - (3-chlorophenyl) -2- hydroxyethyl] amino] propyl] -lH-indol-7-yloxy] acetic acid, and, as described below, the crystal of Compound A can be grouped into crystal type I ("crystal type I of Compound A") and crystal type II ( "type II crystal of Compound A"), based on the diffraction peaks of the X-ray powder diffraction pattern thereof. The type I crystal, the type II crystal, or a mixture of these crystals, are obtained according to the process for their production. The "crystal of Compound A" includes all these crystals. The "drug substance" means the crystal of the Compound A above, which has a particle size no greater than 100 μm in the cumulative weight distribution value of 50%, and a particle size no greater than 200 μm in the cumulative weight distribution value of 95%. The particle size of the drug substance that is preferred is not greater than 50 μm in the cumulative weight distribution value of 50%, and not greater than 150 μm in the cumulative weight distribution value of 95%. The particle size of the drug substance that is most preferred is not greater than 30 μm in the cumulative weight distribution value of 50%, and not greater than 100 μm in the cumulative weight distribution value of 95%. The "drug substance" of the present invention includes all of these.

The "cumulative weight distribution value" means a value that is obtained by classifying the powders based on the particle size of the powders, and by adding the weights of each particle size from the end of the distribution, and expressing by percentages of the total weight of the powders. As a method for expressing the average particle size of the powders (particle aggregate) having a particle size distribution, the "particle size in the cumulative weight distribution value of 50%" is commonly used. In addition, throughout the present description and claims, the "particle size of the 95% cumulative weight distribution value" is used as an index to regulate the content of coarse particles that affect the dissolution pattern of the starting compound. of the preparation (see AJLfonso R. Gennard (Ed.): Particle Size Measurement and Classification, Remington's Pharmaceutical Sciences 17th edition, part 8, chapter 89, pp. 1588-1589; Swithenbank, J., Beer, JM, Taylot , DS, Abbot, D. and McCreath, GC: A laser diagnostics technique for the measurement of droplet and particle size distribution, AIAA Document No. 76-79 (1976) and Hayashi, S .: A laser small angle scattering instrument for the deter ination of size and concentration distribution in sprays (Hirleman, E.D. and other Eds.), Liquid particle size measurement techniques: 2nd. Volume, Philadelphia, ASTM, 1990).

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is the X-ray powder diffraction pattern of type I crystal of Compound A obtained in Preparation 1. Figure 2 is the X-ray powder diffraction pattern of type II crystal of Compound A obtained in Preparation 2.

Best way to carry out the invention The crystal of Compound A of the present invention can be prepared by the process illustrated in the following Reaction Scheme 1.

That is, the compound of the formula I (wherein R is a protecting group for the phenolic hydroxy group, or -CH2COX, X is a lower alkoxy group, a benzyloxy group, a lower alkyl group, an amino group, a mono group - or dialkylamino lower, or a cyclic amino group) is reacted with the compound of formula II (wherein R1 is a protecting group for the amino group, and Y is a halogen atom) in the presence of a base to give the compound Formula III (where R and R1 are as defined above). The compound III obtained in this way is further reacted with a reducing agent to give the compound of the formula IV (wherein R11 is a hydrogen atom or a protecting group for the amine group, and R is as defined above). Then, i) when R of formula IV is a protecting group of the phenolic hydroxy group (and if R11 of formula IV is a hydrogen atom, then the amino group of compound IV is protected again), the protective group for the The phenolic hydroxy group is removed selectively, and the compound of the formula V (wherein R 1 is as defined above) is reacted with the compound of the formula VI (wherein Y 1 is a reactive alcohol residue, and X is as defined above), and in addition the protective group for the amino group is selectively removed to give compound VII; or ii) when R of formula IV is -CH2COX, and R11 is a protecting group for the amino group, the protecting group for the amino group is selectively removed to give compound VII (wherein X is as defined above), and the resulting compound VII is reacted with the compound of the formula VIII and subsequently the resulting compound is subjected to low hydrogenolysis or hydrolysis. acidic or alkaline conditions to effectively give the crystal of Compound A. The terms in the process for producing the crystal of Compound A of the present invention are explained below. The "lower alkyl group" and the "lower alkyl" include a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl and isobutyl, preferably methyl and ethyl, and more preferably methyl. The "lower alkoxy group" includes a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy and isopropoxy, preferably methoxy, ethoxy and propoxy, and more preferably methoxy and ethoxy . The "mono- or dialkylamino lower group" includes, for example, methylamino, dimethylamino, ethylamino, methylethylamino, diethylamino, propylamino, isopropylamino and dipropylamino, preferably methylamino, dimethylamino, ethylamino, diethylamino and dipropylamino, and most preferably dimethylamino and diethylamino. The "cyclic amino group" includes a 5- to 7-membered cyclic amino group, for example, pyrrolidinyl, morpholinyl, piperidinyl and homopiperidinyl, preferably pyrrolidinyl, morpholinyl and piperidinyl, and most preferably pyrrolidinyl and piperidinyl. The "protecting group for the phenolic hydroxy group and the protecting group for the amino group" may be conventional protecting groups that are used in the field of organic synthesis (eg, TW Greene, PGM Muts, Protective Groups in Organic Synthesis, John Wiley &Sons Inc., second edition, 1991, pp. 143-170 and pp. 309-385), and includes substituents that are easily removed by reduction or hydrolysis. A combination of a protecting group for the phenolic hydroxy group and a protecting group for the amino group must be selected so that one of them can be removed selectively. The "protecting group for the phenolic hydroxy 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 "protecting group for the amino group" includes, for example, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, vinyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, acetyl, trifluoroacetyl, benzoyl, phthalimido, p- toluenesulfonyl, benzenesulfonyl, methanesulfonyl and benzyl, preferably tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, acetyl and trifluoroacetyl, and most preferably tert-butoxycarbonyl, benzyloxycarbonyl and 9-fluorenylmethoxycarbonyl. The "reactive alcohol residue" includes, for example, a halogen atom, a lower alkylsulfonyloxy group (for example, methanesulfonyl, ethanesulfonyl), and an arylsulfonyloxy group (for example, benzenesulfonyloxy, p-toluenesulfonyloxy). The "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a chlorine atom. The process for producing the crystal of Compound A is explained in more detail below.

Step A: Preparation of the compound of the formula III The compound of the formula III can be prepared by reacting the compound of the formula I with the compound of the formula II in the presence of a base in a suitable solvent. The base includes, for example, sodium hydride, a metal alkoxide, a Grignard reagent, an alkyl lithium, sodium amide, a lithium diaqluyl, etc. In general, when an indole derivative is reacted with a nucleophilic reagent in the presence of a base, a mixture of a 1-substituted compound and a 3-substituted compound is obtained. Since a Grignard reagent is widely used to preferentially obtain the 3-substituted compound, a Grignard reagent is also preferred in the present step. The Grignard reagent includes methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium bromide, tert-butylmagnesium chloride, phenylmagnesium chloride, etc., and preferably methylmagnesium bromide and tert-butylmagnesium chloride. The Grignard reagent is typically used in an amount of about 1 to about 8 moles, preferably in an amount of about 2 to about 4 moles, to 1 mole of the compound of formula I. The reaction is usually carried out at a temperature of about -50 ° C to about 30 ° C, preferably at a temperature of -20. ° C at approximately 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 methylene chloride, and these solvents should be used in an anhydrous form. The compound of the formula II can be prepared by reacting an amino acid protected with an amino group with an inorganic halide compound (for example, phosphorus pentachloride, phosphorus trichloride, phosphorus tribromide, etc.) or a halide compound organic (for example, phosphoryl chloride, thionyl chloride, oxalyl chloride, phosgene, etc.) in a suitable solvent. The halide compound is used in an amount of about 1 to about 5 moles, preferably in an amount of about 1 to about 2.5 moles, to 1 mole of the starting compound. N, N, -dimethylformamide or hexamethylphosphorus triamide can be added to the reaction system. The reaction is usually carried out at a temperature from about 0 ° C to about 200 ° C, preferably at a temperature from 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 the compound of the formula IV The compound of the formula IV can be prepared by subjecting the compound of the formula III to reduction with a suitable reducing agent in a suitable solvent. The reducing agent can be, for example, lithium aluminum hydride, sodium bis (2-methoxyethoxy) -aluminum hydride, sodium borohydride, lithium borohydride, calcium borohydride, diborane, aluminum diisobutyl hydride, etc., and Preference is given to an alkali metal borohydride. The reduction of compound III, where R is -CH2COX should be carried out by the use of a reducing agent that does not reduce the group R.carbonyl The reducing agent is used in an amount of about 2 to about 6 moles, preferably in an amount of about 3 to about 4 moles, to 1 mole of the compound of formula III. The reaction temperature may vary depending on the types of the reducing agent that will be used, but is usually in the range of about -80 ° C to about 150 ° C, preferably in the range of about 25 ° C to about 150 ° C. The solvent is selected according to the types of reducing agent that will be used, and may be ethers (eg, diethyl ether, tetrahydrofuran, etc.), toluene, chloroform, methylene chloride, methanol, ethanol, isopropanol, acetonitrile, water , etc. In step B, when the compound of the formula IV is obtained wherein R is a protecting group for the phenolic hydroxy group and R11 is a hydrogen atom, the compound is used in the subsequent step C after the amino group of the same protect yourself again. The introduction of a protecting group for the amino group is carried out by a conventional method in the field of peptide synthesis (ie, Nobuo Izumiya et al., Fundamentals and Experiments of Peptide Synthesis, Maruzene, 1985, pp. 16-40 ). For example, the compound of Formula IV wherein R 11 is a hydrogen atom is reacted with di-tert-butyl bicarbonate in a suitable solvent at room temperature to give the compound of formula IV wherein R 11 is a tert-butoxycarbonyl group. Furthermore, in step B, when the compound of the formula IV is obtained wherein R is -CH2COX and R11 is a protecting group for the amino group, the compound can be used directly in the step E. In addition, in step B , when the compound of formula IV is obtained wherein R is -CH2COX and R11 is a hydrogen atom, the compound is identical to the compound of formula VII, and can be used directly in step F.

Step C: Preparation of the compound of the formula V The removal of a protecting group for the phenolic hydroxy group of the compound IV wherein R 11 is a protecting group for the amino group and R is a protecting group for the phenolic hydroxy group can be carried out by reduction or hydrolysis, which should be selected according to the types of the protective group that will be removed.

The reductive removal is carried out by hydrogenolysis or by the use of a metal powder such as zinc powder. The hydrogenolysis is carried out in the presence of a catalyst such as palladium on carbon, palladium hydroxide, platinum oxide, etc., under a hydrogen atmosphere. The reaction is usually carried out at a temperature of about 20 ° C to about 80 ° C, under atmospheric pressure or under pressure. The reduction by catalytic hydrogen transfer can be employed by using as a source of hydrogen ammonium formate, formic acid, cyclohexene, hydrazine, etc. The solvent may be alcohols (eg, 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 acid conditions or alkaline conditions. The reaction temperature may vary according to the types of the protecting group that will be removed, but it is usually in the range of about 0 ° C to about 150 ° C, preferably in the range of about 20 ° C to about 100 ° C. The solvent can be alcohols (for example, methanol, ethanol, etc.), acetonitrile, water, N, N- dimethylformamide, etc., and these solvents can 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, formic acid, acetic acid, methanesulfonic acid, etc.

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

(Step D) The compound of the formula V and the compound of the formula VI are subjected to an addition reaction in a suitable solvent. The reaction temperature may vary according to the types of 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 (eg, benzene, toluene, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), ethers (eg. example, tetrahydrofuran, dioxane, etc.), alcohols (eg, ethanol, isopropanol, etc.), acetonitrile, N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, etc., and these solvents can be used alone or in a mixture of two or more of these solvents. The reaction can be carried out preferably in the presence of a base. The base may be, for example, an inorganic base such as an alkali metal carbonate. (eg, sodium carbonate, potassium carbonate, etc.), an alkali metal acid carbonate (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), an alkali metal hydroxide (eg, hydroxide) sodium, potassium hydroxide, etc.), or an organic base such as triethylamine, tributylamine, N-methylmorpholine, etc. When the compound of the formula VI is used wherein Y 1 is a chlorine atom or a bromine atom, the reaction may proceed smoothly by the addition of an alkali metal iodide (eg, sodium iodide, potassium iodide, etc.) .) or a halogenated tetraalkylammonium (for example, tetra-n-butylchloride ammonium, etc.). By using the present reaction, the compound I wherein R is -CH2C0X can be prepared from of hydroxyindole, and the compound of formula VI in a similar manner.

(Step E) The compound of the formula VII can be prepared by selectively removing the protecting group for the amino group of the compound prepared in step D. The protective group for the amino group is removed by reduction or hydrolysis, which should be selected in accordance with the types of the protective group that will be removed. The reductive removal is carried out by hydrogenolysis or by the use of a metal powder such as zinc powder. The hydrogenolysis is carried out in the presence of a catalyst such as palladium on carbon, palladium hydroxide, platinum oxide, etc., under a hydrogen atmosphere.

The reaction temperature is usually in the range from about 20 ° C to about 80 ° C, under atmospheric pressure or under pressure. In addition, reduction by catalytic hydrogen transfer can also be used using as a source of hydrogen ammonium formate, formic acid, cyclohexene, hydrazine, etc. The solvent can be alcohols (eg, methanol, ethanol, etc.), ethyl acetate, acetic acid, water, etc., and these solvents can be used alone or in a mixture of two or more of these solvents. The hydrolysis is carried out in a suitable solvent under acid conditions or alkaline conditions. The reaction temperature may vary according to the types of the protecting group that will be removed, and is usually in the range of about 0 ° C to about 150 ° C, preferably in the range of about 20 ° C to about 100 ° C. The solvent may be alcohols (eg, 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.) or an organic base such as piperidine, piperazine, etc. The acid can be hydrochloric acid, hydrobromic acid, trifluoroacetic acid, sulfuric acid, formic acid, acetic acid, oxalic acid, methanesulfonic acid, etc.

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

(Step F) The compound of the formula VII and the compound of the formula VTII are reacted in a suitable solvent or without a solvent. The reaction temperature may vary according to the types of the starting compounds, and is usually in the range of about 20 ° C to about 150 ° C, preferably in the range of about 25 ° C to about 100 ° C. The solvent may be aromatic hydrocarbons (eg, benzene, toluene, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), ethers (eg, tetrahydrofuran, dioxane, etc.), alcohols (eg, ethanol) , isopropanol, etc.), acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide and 1,3-dimethyl-2-imidazolidinone, and these solvents can be used alone or in a mixture of two or more of these solvents. In the system of In the reaction, trimethylsilylacetamide or bistrimethylsilylacetamide can be added. In the present reaction, instead of the compound of the formula VII, an acid addition salt thereof can be used, and the acid addition salt of the compound VII can be a salt with an inorganic acid such as hydrochloride, hydrobromide, etc. , or a salt with an organic acid such as oxalate, maleate, fumarate, etc. When an acid addition salt is used in the present reaction, the reaction is carried out in the presence of a base. The base includes, for example, an inorganic base such as an alkali metal carbonate. (eg, sodium carbonate, potassium carbonate, etc.) and an alkali metal carbonate (eg, sodium carbonate, potassium carbonate, etc.), or an organic base such as triethylamine, tributylamine, diisopropylethylamine, N -methylmorpholine, etc.

(Step G) The compound of formula IX can be prepared by subsequently subjecting the compound obtained in the step F (except for the compound in which X is a lower alkyl group) to hydrogenolysis in a suitable solvent, or to 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., under a hydrogen atmosphere. The reaction is carried out at a temperature from about 20 ° C to about 80 ° C under atmospheric pressure or under pressure. The reduction by catalytic hydrogen transfer can be employed by using as a source of hydrogen ammonium formate, formic acid, cyclohexene, hydrazine, etc. The solvent may be alcohols (eg, 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 acid conditions or alkaline conditions. The reaction temperature may vary according to the types of the starting compounds, and is usually in the range from about 0 ° C to about 150 ° C, preferably in the range from about 20 ° C to about 80 ° C. The solvent may be alcohols (for example, methanol, ethanol, isopropanol, etc.), dioxane, water or a mixture 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 (eg, sodium hydroxide, potassium hydroxide, etc.) and an alkali metal carbonate (eg, sodium carbonate, potassium carbonate, etc.). The crystal of Compound A obtained in this manner is a type I crystal of Compound A which shows characteristic diffraction peaks at the diffraction angles (2?) Of approximately 5.9 °, approximately 17.9 °, approximately 20.5 ° and approximately 24.0 ° in the X-ray powder diffraction pattern. Type I crystal of Compound A is recrystallized from a solvent such as methanol to stop the crystal showing characteristic diffraction peaks at the diffraction angles (2?) of approximately 5.9 °, approximately 17.5 °, approximately 20.8 ° and approximately 23.3 ° (type II crystal of Compound A), but the type I crystal of Compound A is produced more easily industrially than the type II crystal of Compound A. In the preparation of the present invention, the crystal of Compound A which has a particle size not greater than 100 μm in the cumulative weight distribution value of 50%, and a particle size not greater than 200 μm in the cumulative weight distribution value of 95%, ie, the drug substance, is used. Preferably, those having a particle size not greater than 50 μm in the cumulative weight distribution value of 50%, and a particle size not greater than 150 μm in the cumulative weight distribution value of 95% are used. , most preferably those having a particle size not greater than 30 μm in the cumulative weight distribution value of 50%, and a particle size not greater than 100 μm in the cumulative weight distribution value of 95%. By using a drug substance that satisfies the above requirements, a preparation can be obtained from which the drug substance is rapidly dissolved. In addition, since a drug substance can be optionally obtained as an agglomerate, it is preferable that the drug substance has an agglomerate content of less than 50%, and an almost individual particle size distribution. The particle sizes of the drug substance (in the cumulative weight distribution values of 50% and 95% are measured by a conventional method for measurement of the particle size of medicines, for example, by a standard screening method, sedimentation method, light scattering method, image analysis, etc., but the measurement method should not be limited to these methods. The present drug substance satisfying the above requirements can be obtained by selecting the crystallization conditions in the synthesis process of Compound A and / or by selecting the spraying method after the synthesis of Compound A. For example, after synthesis of the Compound A, a drug substance can be obtained by spraying Compound-A with a hammer mill, a fluid energy mill, a planetary ball mill, a vibrating ball mill, a conical ball mill, a roller mill or a pin mill, under conditions that are selected according to the mill to be used. A drug substance can be obtained by controlling the particle size and rate of agglutination of Compound A during the process of synthesizing it, or by dissolving the crystals precipitated during the synthesis process in a suitable solvent such as water, an organic solvent, etc. ., and subjecting the resulting solution to spray drying or fluid drying supercritical gas of carbon dioxide, under the selected conditions. To prepare the desired pharmaceutical composition using the drug substance obtained in this manner, granules containing the drug substance are prepared. The granules may contain, in addition to a) a drug substance, b) a filler, c) a disintegrant and d) a binder, a glidant, a lubricant, etc. Since excipients other than the drug substance in the granules make direct contact with the drug substance, it is preferable to use excipients that are compatible with the drug substance and incorporate them in an appropriate ratio to the drug substance, thereby The stability of the drug substance is ensured. Excipients other than the drug substance in the granules include, for example, a filler, a disintegrant and a binder, but if necessary, a glidant, a lubricant, etc., can be used as an excipient. The excipients other than the drug substance in the granules are normally contained in an amount of 500 parts by weight or less, preferably in an amount of 300 parts by weight or less, most preferably in an amount of 100 parts by weight or less, to 1 part by weight of the drug substance. The filler includes, for example, lactose, corn starch, sucrose, trehalose, D-mannitol, erythritol, maltitol and ethylcellulose. The disintegrant includes, for example, lower substituted hydroxypropyl cellulose, carmellose calcium and croscarmellose sodium. The binder includes, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulana, polyvinylpyrrolidone, gelatin and carmellose sodium. The glidant and the lubricant include, for example, magnesium stearate, hydrogenated castor oil, light anhydrous silicic acid and talc. When magnesium stearate is used, it is used in an amount of 1% to 5% parts by weight, preferably in an amount of 1% to 4% parts by weight, most preferably in an amount of 1.5% to 3% parts by weight. weight, based on the total weight of the preparation. The preparation of the granules is preferably carried out by pre-preparing a mixing powder preparatory to the drug substance and part or all of the fillers by mixing them, followed by sieving or spraying, and then adding thereto the remaining excipients, and if necessary, followed by the granulation or regulation of the size of the mixture, whereby the uniformity of the content of the drug substance is ensured. Mixing and sieving are carried out manually using a 24 or 60 mesh screen, or using a screening apparatus having a suitable mixing capacity such as an oscillator. Mixing and spraying are carried out using a sprayer such as a hammer mill. The granulation is carried out, for example, by wet granulation using a fluid bed granulator, agitator granulator or high shear granulator. The particle size of the granules prepared in this way is usually not greater than 350 μm at the cumulative weight distribution value of 50% and not more than 1400 μm at the cumulative weight distribution value of 95%. Preferably, the particle size of the granules is not greater than 300 μm in the cumulative weight distribution value of 50% and not more than 1000 μm in the cumulative weight distribution value of 95%. Most preferably, the particle size of the granules is not greater than 250 μm in the weight distribution value cumulative of 50% and not greater than 800 μm in the cumulative weight distribution value of 95%. By using granules having this preferred particle size, the uniformity of the content of the drug substance is further ensured. The particle sizes of the drug substance (in the cumulative weight distribution values of 50% and 95%) are measured by a conventional method for measuring the particle size of drugs, for example, by a standard screening method, sedimentation method, light scattering method, image analysis, etc., but the method of Measurement should not be limited to these methods. The solid preparation of the present invention contains the granules obtained in this manner. The solid preparation can be, for example, tablets, capsules, granules, powders, suppositories or external preparations, such as adhesive tape. The solid preparation may contain only the granules, but in the low content preparation containing 2 mg or less of the drug substance per unit dose, it is preferable to increase the volume (weight) of the preparation by adding excipients external to the granules to ensure sufficient stability of the drug substance, as well as to ensure adequate size (usually 4 to 10 mm in diameter, 25 to 300 mg). The external excipient can be, for example, in addition to the excipients such as fillers, disintegrants, binders that can be used in the production of the granules, crystalline cellulose as a filler. To ensure uniformity of content of the drug substance, the external excipients are contained in an amount of 0.01 to 100 parts by weight, preferably in an amount of 0.10 to 50 parts by weight, most preferably in an amount of 0.15 to 10 parts by weight. by weight, to 1 part by weight of the granules. To formulate the preparation, the external excipients can be used to mix them with the drug substance containing the granules simply as a mixture of the external excipients, or after granulating the external excipients or of regulating the size thereof to the same particle size than the granules. For the granulation or size regulation of the external excipients, hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, can be used as binder, polyvinyl pyrrolidone, gelatin, carmellose sodium. When the granules and external excipients are mixed, a glidant and / or lubricant can be used. The granules and external excipients can be compressed together without mixing to give dry-coated tablets or multi-layer tablets. In this case, the external excipients may be, for example, crystalline cellulose and / or substituted lower hydroxypropylcellulose and magnesium stearate and / or hydrogenated castor oil. In addition, light anhydrous silicic acid and / or talc may be used. If necessary, hydroxypropylcellulose, hydroxypropylmethylcellulose or pullulan can be used as a binder. When the granules or a mixture of the granules and the external excipients are tabletted, it is preferable to add magnesium stearate or hydrogenated castor oil in an amount of 1% to 5% by weight to the granules or a mixture of the granules and the excipients external, in order to avoid the adhesion that could easily occur in the process of tabletting the composition, and then the mixture obtained in this way is subjected to compression tapping with a suitable tableting machine to give the desired tablets. In addition, to mask the bad flavors, to increase the resistance of the tablets, to improve a When they are taken and to increase ease of handling when used, the tablets obtained in this way can be coated with a suitable polymeric ingredient to give film-coated tablets. The polymeric ingredient may be, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, methylcellulose, ethylcellulose, carmellose sodium, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, dimethylaminoethyl methacrylate-methyl acrylate copolymer and ethyl acrylate-methacrylate copolymer. methyl. If necessary, as a plasticizer for the polymeric ingredient, for example, propylene glycol, glycerol, polyethylene glycol, glyceryl triacetate (triacetin), triethyl citrate, acetyltriethyl citrate, diethyl phthalate, diethyl sebacate, acetylated monoglyceride, castor oil or liquid paraffin can be added to a coating agent. In addition, to protect from light or to improve discrimination ability, a suitable coloring agent can be added to a coating agent. The coloring agent can be, for example, a water-soluble synthetic pigment such as Yellow No. 4, Yellow No. 5, Blue? O. 1, Blue? O. 2, etc., and you can add your aluminum lacquers, talc, titanium oxide, iron oxides, calcium sulfate, calcium carbonate or riboflavin, carmine, turmeric pigment. In addition, to increase palatability, a sweetening agent or a flavoring may also be added. In addition, tablets can be converted into sugar-coated tablets for the same purpose as the one mentioned above. The sugar coating agent can consist, in addition to the main component of sucrose or sorbitol, of calcium carbonate, talc or titanium oxide, and further contain as a binder, for example, gelatin, acacia, polyvinyl alcohol, etc., or a cellulose derivative such as pullulan, hydroxypropylmethylcellulose, etc., and if necessary, a synthetic water-soluble pigment such as Yellow No. 4, Yellow No. 5, Blue No. 1, Blue No. 2, etc., and you can add your aluminum lacquers, talc, titanium oxide, iron oxides, calcium sulfate, calcium carbonate or riboflavin, carmine, turmeric pigment. In addition, to increase palatability, a sweetening agent or a flavoring may also be added. Granules or a mixture of granules and external excipients can be formulated directly in 3? preparations of fine granules, preparations of granules or powder preparations, or in capsule preparations by filling them into gelatin capsules. In this case, the external excipients may be, for example, lactose, corn starch, sucrose, trehalose, D-mannitol, erythritol, maltitol and / or ethylcellulose, and magnesium stearate and / or hydrogenated castor oil. In addition, light anhydrous silicic acid and / or talc may be used. In the case of granule preparations, after granulating, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, pullulana, polyvinylpyrrolidone, gelatin or carmellose sodium can be added as a filler for granule preparations. If further necessary, for making prolonged-release tablets, the granules or tablets containing the drug substance are coated with a coating agent to control the release of a medicament consisting of a polymeric ingredient or fats and oils to give tablets of prolonged release type reservoir. The coating agent can be, for example, beeswax, carnauba wax, cetyl alcohol, cetylstearyl alcohol, fats and lipid oils, resins (for example, shellac), cellulose esters (for example, ethylcellulose) and acid esters. acrylic. If required, as a plasticizer for the polymeric ingredient, for example, propylene glycol, glycerol, polyethylene glycol, glyceryl triacetate (triacetin), triethyl citrate, acetyltriethyl citrate, diethyl phthalate, diethyl sebacate, acetylated monoglyceride, castor oil or liquid paraffin can added to a coating agent. In addition, the granules controlling the release of the drug can be compressed into tablets. A matrix-type prolonged-release preparation can be obtained by mixing a component to control the release of drugs such as polymeric ingredients such as those mentioned above, or fats and oils together with fillers in the step of producing granules and tablets. In addition, if necessary, the granules controlled in this way in the release of drugs can be compressed into tablets. The solid preparation of the present invention obtained in this way can be packaged, if necessary, in ampoule packing, heat seal packaging or bottles of suitable materials, but should not be limited to these packages. In addition, if necessary, the solid preparation of the present invention can 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-adrenergic receptors was studied. Cell lines that highly express the β3- and β2-adrenergic receptors were prepared according to the method described in WO 96/16938. The cell line that highly expresses the human ββ-adrenergic receptor was prepared according to the method described in WO 00/44721.

Experiment Human ß3-adrenergic receptor stimulating activity A CHO / pKREX10-36 cell line that highly expresses the human β3-adrenergic receptor was cultured for 2-3 days with MEM-Dulbecco's medium supplemented with 10% fetal bovine serum and 200 μg / ml of G-418. The cells were detached by incubation with pH regulated phosphate saline solution containing 0.5 mM EDTA at 37 ° C for 10 minutes after the medium was removed. CHO / pKREX10-36 cells were harvested by centrifugation, and suspended in Hank's pH buffer (ICN Biomedicals) containing 1 mM L-ascorbic acid and 1 mM 3-isobutyl-1-methyl-xanthine at the concentration of approximately 5 x 10 5 cells / ml. This suspension (100 μl) and a test compound were mixed in the same pH buffer (500 μl) and incubated at 37 ° C for 30 minutes, followed by boiling for 5 minutes to conclude the reaction. After centrifuging the reaction mixture, the amount of cAMP in the supernatant was measured using a cAMP EIA system (Amersham). Similarly, the amount of cAMP was measured in the same manner using CHO / pKREX21-8 to express highly human β2-adrenergic receptor, or by using CHO / pKREX23-30 to express highly human β-adrenergic receptor instead of of CHO / pKREX10-36 to express highly human ß3-adrenergic receptor. The amounts of cAMP when 10 ~ 5 M of (-) - isoproterenol was added to the reaction mixture or not by adding the same at all were designated as 100% and 0%, respectively, and the relative maximum response of the drug substance of the present preparation (10 ~ 6 to 10 -11 M) is expressed as intrinsic activity [IA]. the EC50 value which is a concentration of the test compound that is required to achieve 50% accumulation of cAMP was calculated by least squares regression analysis of a response curve to concentration of each compound. The results are shown in Table 1. Table 1 Note: * means drug substance; ** means (-) -isoprotenol. In this experiment, a compound that has a low EC50 value and a high I.A. it is considered to have a potent human ß-adrenergic receptor stimulating activity. Thus, as is clear from Table 1, the drug substance of the present preparation proves to have a potent human β3-adrenergic receptor stimulating activity, but the stimulating activity of human ß ^ - and ßi-adrenergic receptors thereof It is quite deficient.

As shown in the above results, the drug substance of the present invention can be expected as a human β3-adrenergic receptor stimulating agent with excellent adrenoreceptor selectivity. The drug substance of the present invention is useful as a β3-adrenergic receptor stimulating agent in the prophylaxis or treatment of obesity, diabetes mellitus, hyperlipaemia, irritable bowel syndrome, acute or chronic diarrhea, pollakiuria, enuresis, urinary calculi, etc. . In addition, the drug substance of the present invention is also useful in the improvement of symptoms such as stomach pain, nausea, vomiting, epigastric disease accompanied by peptic ulcer, acute or chronic gastritis, biliary dyskinesia, cholecystitis, etc. When the drug substance of the present invention is used as a β3-adrenergic receptor stimulating agent, it can be administered orally, parenterally or rectally, but preferably orally. The dose of the drug substance of the present invention may vary according to the route of administration, the conditions, age of the patients or types of objects (prophylaxis or treatment), etc., but it is usually on the scale of 0. 0002 mg / kg / day at 0.02 mg / kg / day, preferably on the scale from 0.001 mg / kg / day to 0.02 mg / kg / day.

Examples The present invention is illustrated in more detail by the following preparations, experiments and examples, but should not be considered limited thereto.

Preparation 1 Preparation of the crystal of Compound A The identification of the compounds was carried out by elemental analysis, mass spectrum analysis, infrared absorption spectrum (IR), proton nuclear magnetic resonance spectrum (1H-NMR) and by measurement of optical rotation. The optical purity was determined by high performance liquid chromatography. The following abbreviations can be used to simplify the description. F? Rioc: 9-fluorenylmethoxycarbonyl group Ala: alanine residue J: coupling constant s: singlet d: doublete dd: double double t: triplet quartet m: multiplet br: broad 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) oxalyl chloride (7 ml, 80 mmol) was added dropwise at room temperature under 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 subsequent reaction without further purification.

(Step 2) To a stirred and ice-cooled solution of commercially available 7-benzyloxyindole (11.2 g, 50 mmol) in methylene chloride (100 ml) was added a 3 M solution of methylmagnesium bromide diethyl ether (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 obtained in step 1 in methylene chloride (200 ml) under cooling with ice. The mixture was warmed to room temperature and further stirred for one hour. To the mixture was added 5% hydrochloric acid aqueous solution (100 ml) under cooling with ice, and everything was stirred for 15 minutes. The organic layer was separated, washed with water (100 ml) and dried over anhydrous 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 also used in the step subsequent 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) sodium borohydride was added in portions (5.67 g, 150 mmol) at room temperature, and the mixture was refluxed for 5 hours. The reaction mixture is cooled to room temperature, and methanol (100 ml) was added thereto. The reaction mixture was concentrated to dryness under reduced pressure. After the 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 anhydrous magnesium sulfate. The inorganic materials were removed, and to the resultant was added with stirring 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 to give the title compound (11.2 g, 61%) as white crystals, m.p. 206-208 ° C. [α] D 25 = -46.2 ° (c = 1.0, N, N-dimethylformamide); Spectrum of ^ -RMN (200 MHz, DMSO-d6, d 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, J = 5 Hz), 3.42 (1H,) , 5.26 (2H, s), 5.94 (4H, br), 6.75 (1H, d, J = 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).

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 oxalate. (R) -3- (2-aminopropyl) -7-benzyloxyindole (50 g, 135 mmol) obtained in 1) above, and the mixture was stirred. Then, di-tert-butyl bicarbonate (29.5 g) was added to the ice-cooled and stirred mixture., 135 mmol), and the mixture was stirred at room temperature for three hours. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride (150 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and n-hexane (150 ml) was added to the residue. The precipitated crystals were collected by filtration and dried to give the title compound (47.2 g, 92%) as white crystals, m.p. 94-95 ° C. [a] D25 = -21.0 ° (c = 1.0, methanol); Spectrum of 2 H-NMR (300 MHz, CHC13, d 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 = 7.5 Hz) , 6.97 (1H, d, J = 2.2 Hz), 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 [analysis conditions; Column [CHIRALPAK AD (diameter 4.6 mm x 250 mm: 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) -ter-butoxycarbonylamino] propyl] -lH-indol-7-yloxy] acetamide To an ice-cooled and stirred solution of (R) -7 benzyloxy-3- (2-tert-butoxycarbonylaminopropyl) indole (10 g, 26.3 mmol) obtained in 2) above in methanol (100 ml) was added 10% palladium on carbon (0.5 g), and the mixture was hydrogen under atmospheric pressure of hydrogen at room temperature for two 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 to the solution, and the mixture was added. it led to reflux for four hours. After cooling with ice the solvent was evaporated under reduced pressure. 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. The precipitated crystals were collected by filtration and dried to give the title compound (10.5 g, 100%) as white crystals, m.p. 142 ° C. [α] D 25 = -26.3 ° (c = 1.0, methanol); Spectrum of ^ H-NMR (300 MHz, CHC13, d 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, dd, 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 [analysis conditions; Column [CHIRALPAK AD (diameter 4.6 mm x 250 mm: 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.)].

Preparation of N, N-diethyl- [3- [(2R) -aminopropyl] -lH-indol-7-yloxy] acetamide To a solution of N, N-diethyl- [3- [[(2R) -ter-butoxycarbonylamino] ] propyl] -lH-indol-7-yloxy] acetamide (12 g, 29.7 mmoles) obtained in 3) above in acetonitrile (120 ml) was added oxalic acid (10.71 g, 119 mmol), and the mixture was at reflux for two hours. The mixture was cooled with ice, and the precipitated crystals were collected by filtration and washed with acetonitrile. To the resulting crystals was added 10% aqueous 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 title compound (6.84 g, 75%) as white crystals, m.p. 133 ° C. [α] D25 = -46.3 ° (c = 1.0, methanol); 1 H-NMR spectrum (300 MHz, CDClJ d 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 = 7.1 Hz), 4.80 (2H, s), 6.68 (1H, d, J = 7.5 Hz), 6.99 (1H, t, J = 7.9 Hz), 7.05 (1H, s), 7.28 (1H, d, J = 8.0 Hz), 9.42 (1H, s). Optical purity: > 99% ee [analysis conditions; Column [CHIRALPAK AD (diameter 4.6 mm x 250 mm: 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-chloro-phenyl) -2-hydroxyethyl] amino] propyl] -lH-indol-7-yloxy] -acetamide To a solution of N, N-diethyl- [3- [(2R) -aminopropyl] -lH-indol-7-yloxy] acetamide (21 g, 69.2 mmol) obtained in the 4) above in acetonitrile (42 ml) was added rust (R) -3-chlorostylene (11.77 g, 76.1 mmol) and the mixture was refluxed for five hours. The mixture was cooled with ice, and diisopropyl ether (168 ml) was added thereto. The precipitated crystals were collected by filtration and dried to give the title compound (16.99 g, 54%) as white crystals. On the other hand, the filtrate containing the starting materials did not The reaction was concentrated to dryness under reduced pressure, and acetonitrile (21 ml) and (R) -3-chlorostyrene oxide (1.07 g, 6.9 mol) were again added to the residue and the mixture was refluxed for six hours. hours. The mixture was cooled with ice and thereto was added diisopropyl ether (63 ml). The precipitated crystals were collected by filtration and dried to give the title compound (2.86 g, 9%), m.p. 120-121 ° C. [α] D 25 = -69.1 ° (c = 1.0, methanol); Spectrum of 1 H-R N (300 MHz, CDC13, d 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 = 7.1 Hz), 4.54 (1H, m), 4.78 (2H, s), 6.65 (1H, d, J = 7.3 Hz), 6.98 (1H, t, J = 7.9 Hz), 6.99 (1H, s), 7.12-7.30 (4H, m), 7.34 (1H, s), 9.60 (1H, s). 6) Preparation of acid [3- [(2R) - [[(2R) - (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -lH-indol-7-yloxy] acetic acid (Compound A) N, N -diethyl- [3- [(2R) - [[(2R) - (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -lH-indol-7-yloxy] acetamide (4 g, 8. 7 mmoles) obtained in 5) above was added to a solution of potassium hydroxide (1.96 g, 34.9 mmol) in 50% aqueous ethanol solution (32 ml), and the mixture was refluxed for three hours and the mixture was refluxed for three hours. 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 title compound (3.1 g, 88%) as white crystals, m.p. 230-231 ° C. [α] D 25 -24.4 ° (c = 1.0, aqueous solution of sodium hydroxide IN); Spectrum of ^? - NMR (200 MHz, DMSO-d6, d ppm): 0.93 (3H, d, J = 7 Hz), 2.61 (1H, m), 2.80 - 3.22 (4H, m), 4.54 (2H, s), 4.90 (1H,), 6.48 (1H, d, J = 8 Hz), 6.76 (1H, t, J = 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 [analysis conditions; Column [CHIRAL-AGP (diameter .0 mm x 100 mm: manufactured by SHINWA KAKO CO., LTD.)); Mobile phase (aqueous solution (20 mM Na2HP04 + 2 mM ammonium tetrabutyl acid sulfate) (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 pattern of the crystals of Compound A thus obtained was measured as an X-ray powder diffractometer (RINT1000 type, manufactured by RIGAKU CORPORATION) at a tube voltage of 30 kV and an electric tube current. of 20 mA using CuKa wire in terms of diffraction angle (2?). The diffraction pattern thereof is shown in Figure 1. The diffraction angles in the X-ray powder diffraction pattern of the crystals of Compound A measure approximately 5.9 °, approximately 17.9 °, approximately 18.8 °, approximately 20.5 ° , approximately 23.3 °, approximately 24.0 ° and approximately 24.9 ° and there are characteristic peaks at approximately 5.9 °, approximately 17.9 °, approximately 20.5 ° and approximately 24.0 °. The diffraction angle values (2?) Have the standard precision.

Preparation 2 Preparation of type II crystals of Compound A To the type I crystals of Compound ^ A (100 mg) obtained in Preparation 1 were added methanol (35 ml) and the mixture was dissolved with heating in a water bath to a 100 ° C. The precipitated crystals were collected by filtration and dried to give type II crystals of Compound A. The X-ray diffraction pattern of type II crystals of Compound A was measured with an X-ray powder diffractometer (RINT type ULTIMA; by RIGAKU CORPORATION) at a tube voltage of 40 kV and a tube current of 30 mA using CuKa wire in terms of diffraction angle (2?). The diffraction pattern thereof is shown in Figure 2. The diffraction angles in the powder diffraction pattern of X-rays of type II crystals of Compound A measure approximately 5.9 °, approximately 17.5 °, approximately 19.4 °, approximately 20.8 °, approximately 23.3 °, approximately 24.0 ° and approximately 24.9 °, and there are characteristic peaks at approximately 5.9 °, approximately 17.5 °, approximately 20.8 ° and approximately 23.3 °. The diffraction angle values (2?) Have the standard precision.

Preparation 3 Preparation of the drug substance 1) Type I crystals of Compound A obtained in Preparation 1 were micronized using a hammer mill (Sample Mili AP-S, manufactured by Hosokawa Micron Corporation, Japan) using a sieve with an aperture diameter of 0.7 mm. 2) Separately, Type I crystals of Compound A obtained in Preparation 1 were micronized using a fluid energy mill (Single Truck Jet Mili FS-4, manufactured by SEISHIN ENTERPRISE CO., LTD., Japan) with pressure from compression air of 7 kgf / cm2. 3) The particle sizes in the cumulative weight distribution value of 50% and 95% of each micronized granule obtained in this manner were measured using a laser diffraction particle size distribution analyzer (HELOS &RODOS (registered trademark ), manufactured by SYMPATEC GMBH, Germany) and calculated from the cumulative particle size distribution based on volume by the dry air dispersion method (dispersion air pressure: 1 atm). The particle size of the crystals obtained in 1) in the value of The cumulative weight distribution of 50% is not greater than 21 μm, and that in the 95% cumulative weight distribution value was not greater than 75 μm. The particle size of the crystals obtained in 2) in the cumulative weight distribution value of 50% is not greater than 1.7 um, and that in the cumulative weight distribution value of 95% was not greater than 3.8 μm. By any micronization method, crystals of Compound A having a particle size in the cumulative weight distribution value of 50% no greater than 100 μm, and a particle size in the cumulative weight distribution value can be obtained 95% no greater than 200 μm.

Experiment 1 Particle size of the drug substance According to the prescription of Table 2, to a mixed powder of a drug substance or non-micronized crystals of Compound A, lactose, substituted hydroxypropylcellulose and hydroxypropylcellulose was added water with stirring to give the granules (granulation by kneading), which are dried and regulated in size to give the granules. The granules obtained in this way are mixed with crystalline cellulose, anhydrous silicic acid and magnesium stearate, and compressed to give the tablets containing 1 mg of the drug substance or the micronized crystals of Compound A each. As a drug substance, the micronized ones were used using a hammer mill (Sample Mili AP-S manufactured by Hosokawa Micron Corporation, Japan) using a screen with an aperture diameter of 0.7 mm or 1.0 mm, or micronized using a mill of fluid energy (Single Truck Jet Mili FS-4, manufactured by SEISHIN ENTERPRISE CO., LTD., Japan) with compression air pressure of 7 kgf / cm2, having various particle sizes as listed in Table 3. The dissolution test of the tablets obtained in this way was carried out in accordance with the thirteenth edition of the Japan Pharmacopoeia (paddle method, 50 rpm, water at 37 ° C, 900 ml), and the ratio between the particle size of the drug substance and the dissolution of They were evaluated by measuring the dissolution rate at 15 minutes. The results are shown in Table 3.

Table 2 Table 3 Tablets prepared using the drug substance having a particle size in the value of 50% cumulative weight distribution of not more than 100 μm and a particle size in the 95% cumulative weight distribution value of no more than 200 μm showed a distribution speed of almost 100% at 15 minutes, which It is a good dissolving capacity.

Experiment 2 Composition ratio in the granules by weight of the drug substance and the excipients that are not the drug substance To a mixed powder of the drug substance (those used in experiment 1-3 above for experiment 2-1 and comparative experiment 2-1, and that used in experiment 1-2 above for experiment 2-2) , lactose and substituted lower hydroxypropylcellulose were sprayed with an aqueous solution of hydroxypropylcellulose using a fluidized bed granulator and a dryer, and granulated and dried to give the granules. As shown in Table 4, three types of granules were prepared, wherein the content of the excipients that are not the drug substance in the granules was different such as 82.5 parts by weight (experiment 2-1), 417 parts ( comparative experiment 2-1) a 1 part by weight of the drug substance. 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 four months, and the content of all the decomposition products derived from the drug substance was measured, and the increase thereof was calculated from of the initial amount. The results are shown in Table 5.

Table 4 Table 5 In the tablets of experiment 2-1 and 2-2, the amount of all the decomposition products are produced less, compared to the tablets of comparative experiment 2-1, which confers more than 500 parts on the granules by weight of the excipients that are not the drug substance to 1 part by weight of the drug substance, whereby the chemical stability of the drug substance per se in the tablets of experiments 2-1 and 2-2 is shown to be high .

Experiment 3 Composition ratio in the granules by weight of the drug substance and the excipients that are not the drug substance In accordance with the prescription of Table 6, a solution of hydroxypropylcellulose was added to a mixed powder of lactose and substituted hydroxypropylcellulose underneath. in purified water to give granules (granulation by kneading), which are dried and regulated in size to give the granules of the external excipients. Table 6 To a mixed powder of the drug substance (that used in experiment 1-4 above), lactose and substituted lower hydroxypropylcellulose was added a solution of hydroxypropylcellulose in purified water to give granules (granulation by kneading), which were dried and dried. they were adjusted in size to give the granules. From these granules, four types of granules were obtained in which the content of the excipients that were not the drug substance in the granules was different such as 416.5 parts by weight (experiment 4-1, experiment 4-2), 1001 parts by weight (comparative experiment 4-1), 1251.5 parts by weight (comparative experiment 4-2) to 1 part by weight of the drug substance. Four types of granules are they added the granules of the external excipients obtained according to the prescription of Table 6 above, crystalline cellulose, light anhydrous silicic acid and magnesium stearate, and the mixture was compressed to give tablets containing 0.1 mg of the drug substance each , as well as 1.87 parts by weight of the external excipients to 1 part by weight of the granules (experiment 3-19), tablets containing 0.2 mg of the drug substance each, as well as 2.59 parts by weight of the excipients external to 1 part by weight of the granules (experiment 3-2), tablets containing 0.1 mg of the drug substance each, as well as 0.20 parts by weight of the excipients external to 1 part by weight of the granules (comparative experiment 3-1) and tablets containing 0.2 mg of the drug substance each, as well as 0.20 parts by weight of the external excipients to 1 part by weight of the granules (comparative experiment 3 -2) . These tablets were stored under conditions of 40 ° C-75% RH (relative humidity) for one month, and the content of all the decomposition products derived from the drug substance was measured by high performance liquid chromatography, and the increase of them was calculated from the initial amount. The results are shown in Table 8.

Table 7 Table 8 In the tablets of experiments 3-1 and 3-2, the amount of all the decomposition products is produced less, compared to the tablets of comparative experiments 3-1 and 3-2, whereby it is proved that the Chemical stability of the drug substance per se in the tablets of experiments 3-1 and 3-2 is high.

Experiment 4 Premixed during the preparation of the granules In accordance with the prescription of Table 9, tablets containing 0.05 mg of the drug substance (the one used in experiment 1-5 above) were obtained for each. When the granules were prepared, the drug substance was previously mixed and micronized with lactose using a mixer screen (a 50 mesh stainless sieve = Experiment 3-1) or using a granulator (a hammer = Experiment 3-2), and substituted lower hydroxypropylcellulose and hydroxypropylcellulose were added thereto. Water was added with stirring to the mixture to give granules (granulation by kneading) and dried and regulated in size to give the granules. To the granules thus obtained, crystalline cellulose, light anhydrous silicic acid and magnesium stearate were added and mixed, and the mixture was compressed to give the tablets. The uniformity of content of the tablets obtained in this way was tested according to the Uniformity Test of Content in the thirteenth edition of the Japan Pharmacopoeia (with which the result of less than 15% is considered adequate). The results are shown in Table 10.

Table 9 Table 10 In the Content Uniformity Test in the thirteenth edition of the Japan Pharmacopoeia, the result of less than 15% is considered adequate. Since the results of the uniformity test of the tablets of experiments 4-1 and 4-2 were both below 15%, the uniformity of the content of the drug substance was reserved in these tablets - Example 1 In accordance with the prescription of Table 11, tablets were obtained containing 1 mg of the drug substance (the one used in experiment 1-3 mentioned above) each. When the granules were prepared, the drug substance was previously mixed and sieved with lactose using a hammer mill, and added thereto. lower substituted hydroxypropylcellulose and hydroxypropylcellulose. Water with stirring was added to the mixture to give the granules (kneading granulation), which were dried and adjusted in size to give the granules having a particle size of not more than 250 μm in the cumulative weight distribution value 50%, and a particle size of not more than 600 μm in the cumulative weight distribution value of 95%. The granules thus obtained were mixed with crystalline cellulose, light anhydrous silicic acid and magnesium stearate, and the mixture was compressed to give the tablets. The tablets obtained in this way were of adequate size and the uniformity of content and stability of the drug substance were reserved, and the dissolution of the drug substance from the tablets was rapid.

Table 11 Example 2 In accordance with the prescription of Table 12, tablets were obtained containing 0.1 mg of the drug substance (the one used in experiment 1-5 mentioned above) each. When the granules were prepared, the drug substance was mixed above and sieved with lactose using a hammer mill, and substituted hydroxypropylcellulose and hydroxypropylcellulose were added thereto. Water was added with stirring to the mixture to give the granules (granulation by kneading), which were dried and adjusted in size to give the granules which had a particle size of not more than 250 μm in the cumulative weight distribution value of 50%, and a particle size of not more than 600 μm in the cumulative weight distribution value of 95%. The granules thus obtained were mixed with crystalline cellulose, light anhydrous silicic acid and magnesium stearate, and the mixture was compressed to give the tablets. The tablets obtained in this way were of adequate size and the uniformity of content and stability of the drug substance were reserved, and the dissolution of the drug substance from the tablets was rapid.

Table 12 Example 3 In accordance with the prescription of Table 13, tablets containing 0.05 mg of the drug substance (the one used in experiment 1-5 mentioned above) each were obtained. When the granules were prepared, the drug substance was mixed above and sieved with lactose using a hammer mill, and substituted hydroxypropylcellulose and hydroxypropylcellulose were added thereto. Water with stirring was added to the mixture to give the granules (kneading granulation), which were dried and adjusted in size to give the granules having a particle size of not more than 250 μm in the cumulative weight distribution value 50%, and a particle size of not more than 600 μm in the cumulative weight distribution value of 95%. The granules thus obtained were mixed with crystalline cellulose, light anhydrous silicic acid and magnesium stearate, and the mixture was compressed to give the tablets. The tablets obtained in this way were of adequate size and the uniformity of content and stability of the drug substance were reserved, and the dissolution of the drug substance from the tablets was rapid.

Table 13 Example 4 In accordance with the prescription of Table 14, tablets containing 0.2 mg of the drug substance (the one used in experiment 1-3 mentioned above) each were obtained. To a mixed powder of the drug substance, substituted lower hydroxypropylcellulose and hydroxypropylcellulose was added water with stirring to give the granules (granulation by kneading), which were dried and regulated in size to give the granules having a particle size of not more than 350 μm in the cumulative weight distribution value of 50%, and a size of particle of not more than 1000 μm in the cumulative weight distribution value of 95%. The granules thus obtained were mixed with crystalline cellulose, light anhydrous silicic acid and magnesium stearate, and the mixture was compressed to give the tablets. The tablets obtained in this way were of adequate size and the uniformity of content and stability of the drug substance were reserved, and the dissolution of the drug substance from the tablets was rapid.

Table 14 Example 5 According to the prescription of Table 15, a mixed powder of the drug substance (the one used in experiment 1-4 mentioned above), lactose and substituted lower hydroxypropylcellulose was sprayed with a solution of hydroxypropylcellulose in purified water to give the granules (fluidized bed granulation), which were dried and regulated in size to give the granules. The granules thus obtained were mixed with crystalline cellulose and light anhydrous silicic acid, and the mixture was compressed to give the tablets containing 0.5 mg of the drug substance each. The tablets obtained in this way were of adequate size and the uniformity of content and stability of the drug substance were reserved, and the dissolution of the drug substance from the tablets was rapid.

Table 15 Example 6 According to the prescription of Table 16, a mixed powder of the drug substance (the one used in experiment 1-4 mentioned above), lactose and substituted lower hydroxypropylcellulose was sprinkled with a solution of hydroxypropylcellulose in purified water to give the granules (fluidized bed granulation), which were dried and regulated in size to give the granules. The granules thus obtained were mixed with granules of the external excipients, crystalline cellulose and light anhydrous silicic acid, and the mixture was compressed to give the tablets containing 0.5 mg of the drug substance each. The tablets obtained in this way were of adequate size and the uniformity of content and stability of the drug substance were reserved, and the dissolution of the drug substance from the tablets was rapid.

Table 16 Example 7 In accordance with the prescription of Table 17, a mixed hydroxypropylcellulose solution in purified water was added to a mixed powder of lactose and substituted lower hydroxypropylcellulose to give the granules (granulation in fluidized bed), which were dried and regulated in size to give the granules of the external excipients.

Table 17 According to the prescription of Table 18, a mixed powder of the drug substance (the one used in experiment 1-4 mentioned above), lactose and substituted lower hydroxypropyl cellulose was sprinkled with a solution of hydroxypropylcellulose in purified water to give the granules (fluidized bed granulation), which were dried and regulated in size to give the granules. The granules thus obtained were mixed with granules of the external excipients obtained according to the prescription of Table 17, crystalline cellulose and light anhydrous silicic acid, and the mixture was compressed to give the tablets that they contained 0.1 mg of the drug substance each. The tablets obtained in this way were of adequate size and the uniformity of content and stability of the drug substance were reserved, and the dissolution of the drug substance from the tablets was rapid.

Table 18 Example 8 According to the prescription of Table 19, to a mixed powder of the drug substance (the one used in experiment 1-4 mentioned above), lactose and substituted hydroxypropylcellulose was sprayed with a solution of hydroxypropylcellulose in purified water to give the granules (fluidized bed granulation), which were dried and adjusted in size to give the granules. The granules thus obtained were mixed with. the granules of the external excipients, crystalline cellulose and light anhydrous silicic acid, and the mixture was compressed to give the tablets containing 0.2 mg of the drug substance each. The tablets obtained in this way were of adequate size and the uniformity of content and stability of the drug substance were reserved, and the dissolution of the drug substance from the tablets was rapid.

Table 19 Industrial Applicability The crystals of Compound A of the present invention having a particle size not greater than 100 μm in the cumulative weight distribution value of 50%, and a particle size not greater than 200 μm in the distribution value of 95% cumulative weight (the drug substance of the present invention) are useful as a preparation starting material. The drug substance of the present invention exhibits a potent β3-adrenergic receptor stimulating activity with excellent adrenoreceptor selectivity, and therefore, is useful in the prophylaxis or treatment of obesity or diabetes mellitus. The preparation containing the drug substance of the present invention is an excellent preparation which is further characterized in that the size (volume) of the preparation, the uniformity of the content of the drug substance and the stability of the drug substance are ensured, and because the dissolution of the drug substance therefrom is rapid. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims

READ NDICATIONS Having described the invention as above, the content of the following claims is claimed as property:

1. A crystal of [3- [(2R) - [[(2R) - (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -lH-indol-7-yloxy] acetic acid crystal.

2. A crystal of [3- [(2R) - [[(2R) - (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -lH-indol-7-yloxy] acetic acid, characterized in that it shows characteristic diffraction peaks to the diffraction angles (2?) of approximately 5.9 °, approximately 17.9 °, approximately 20.5 ° and approximately 24.0 ° in the powder diffraction pattern of X-rays.

3. The crystal according to claim 1, characterized in that the particle size thereof is not greater than 100 μm in the cumulative weight distribution value of 50%, and not greater than 200 μm in the cumulative weight distribution value of the 95%

4. A granule characterized by glass consists of the crystal according to claim 3.

5. The granule according to claim 4, characterized in that it consists of a) the crystal according to claim 3, b) a filler, c) a disintegrant and d) a binder.

6. The granule according to claim 5, characterized in that the total weight of the filler, the disintegrant and the binder is less than 500 parts by weight to 1 part by weight of the glass according to claim 3.

7. A solid preparation, characterized in that it comprises the granule according to the claim.

8. The solid preparation according to claim 7, characterized in that it contains external excipients.

9. The solid preparation according to claim 7, characterized in that the content of the The crystal according to claim 3 is less than 2 mg per dose unit.

10. The solid preparation according to claim 1, characterized in that it is in the form of a tablet.

11. A tablet characterized in that it is prepared by compression tabletting of the granule according to claim 4.

12. The tablet according to claim 11, characterized in that the content of the crystal according to claim 3 is not more than 2 mg per dose unit.

13. A tablet characterized in that it is prepared by adding external excipients to the granule according to claim 4, followed by the compression tapping of the mixture.

14. The tablet according to claim 13, characterized in that the content of the crystal of according to claim 3 is no more than 2 mg per unit dose.

15. An ß3-adrenergic receptor agonist, characterized in that it comprises the crystals according to claim 3.

16. An agent for the treatment of diabetes mellitus, characterized in that it comprises the crystal according to claim 3.

17. An agent for the treatment of obesity, characterized in that it comprises the crystal according to claim 3.