Note: Descriptions are shown in the official language in which they were submitted.
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1
DESCRIPTION
SOLID PREPARATION
TECHNICAL FIELD
The present invention relates to a crystal of [3-[(2R)-[[(2R)-(3-
chlorophenyl)-2-hydroxyethyl)amino]propyl]-1 H-indol-7-yloxy]acetic
acid (hereinafter, occasionally referred to as Compound A), and a
pharmaceutical preparation containing as a drug substance the crystal
of Compound A, especially the present invention relates to a solid
preparation wherein the size (volume) of the preparation, the content
uniformity of the drug substance, and the stability of the drug substance
are secured, and further the dissolution of the drug substance from the
preparation is rapid.
BACKGROUND ART
Compound A exhibits a potent (33-adrenergic receptor-
stimulating activity with excellent adrenoceptor selectivity, and it is
useful in the prophylaxis or treatment of diabetes mellitus and obesity
(WO 96/ 16938).
Compound A exhibits extremely potent pharmaceutical activities,
and when it is formulated into a pharmaceutical composition, such
composition should be a low-content preparation wherein the content of
the active compound per dosage unit is low. However, in compliance
with the decrease of the content of Compound A in a preparation, there
has been discovered a phenomenon that the chemical stability of
Compound A per se is extremely lowered. In addition, when the
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amount of excipients other than Compound A is increased so that the
size being suitable to be used as a pharmaceutical preparation is
secured, the content of Compound A per each dosage unit becomes
uneven and it is difficult to give a preparation having 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 rapidly dissolve.
An object of the present invention is to provide a preparation of
Compound A wherein the size (cubic capacity) of the preparation, the
content uniformity of Compound A, and the stability of Compound A are
secured, as well as from which Compound A can rapidly dissolve out.
DISCLOSURE OF INVENTION
The present invention includes the inventions of the following
various embodiments.
(1) A crystal of [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]-
amino]propyl]-1H-indol-7-yloxy]acetic acid (hereinafter, occasionally
referred to as "crystal of Compound A");
(2) A crystal of [3-((2R)-([(2R)-(3-chlorophenyl)-2-hydroxyethyl]-
amino]propyl]-1H-indol-7-yloxy]acetic acid, which have characteristic
diffraction peaks at the diffraction angles (28) of about 5.9°, about
17.9°,
about 20.5° and about 24.0° in the powder X-ray diffraction
pattern
(hereinafter, occasionally referred to as "Compound A type-I crystal");
(3) A crystal of Compound A having a particle size of not larger than
100 um at the cumulative weight distribution value of 50 %, and a
particle size of not larger than 200 um at the cumulative weight
distribution value of 95 % (hereinafter, occasionally referred to as "drug
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3
substance");
(4) A granule consisting of the crystal of the above (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 the above (4);
(7) A tablet which is formulated by compressing the granule of the
above (4);
(8) A tablet which is formulated by compressing the granule of the
above (4) and external excipients;
(9) A (33-adrenergic receptor agonist, which comprises the crystal of
the above (3) (drug substance);
( 10) An agent for treatment of diabetes mellitus, which contains the
crystal of the above (3) (drug substance); and
( 11) An agent for treatment of obesity, which contains the crystal of
the above (3) (drug substance)
Throughout the present description and claims, the "crystal of
Compound A" means a pure crystal of 3-[(2R)-[[(2R)-(3-chlorophenyl)-2-
hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic acid, and as
described below, the crystal of Compound A can be grouped into type-1
crystal ("Compound A type-I crystal") and type-II crystal ("Compound A
type-II crystal"), based on the diffraction peaks of the powder X-ray
diffraction pattern thereof. The type-I crystal, the type-II crystal, or a
mixture of these crystals are obtained according to the process for
production thereof. The "crystal of compound A" includes all of these
crystals.
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The "drug substance" means the above crystal of Compound A,
having a particle size of not larger than 100 um at the cumulative weight
distribution value of 50 %, and a particle size of not larger than 200 um
at the cumulative weight distribution value of 95 %. Preferable particle
size of the drug substance is not larger than 50 >~m at the cumulative
weight distribution value of 50 %, and not larger than 150 um at the
cumulative weight distribution value of 95 %. More preferable particle
size is not larger than 30 um at the cumulative weight distribution value
of 50 % and not larger than 100 um at 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 which
is obtained by classifying the powders based on the particle size thereof,
and by adding up the weights of each particle size from the end of the
distribution, and is expressed by percentages to the total weight of the
powders. As a method for expressing the mean particle size of the
powders (aggregate of particles) having a distribution in the size of
particles, the "particle size at the cumulative weight distribution value of
50 %" is commonly used. In addition, throughout the present
description and claims, the "particle size of the cumulative weight
distribution value of 95 %" is used as an index for regulating the content
of coarse particles which affect the dissolution pattern of the compound
from the preparation (see Alfonso R. Gennard (Ed.): Particle Size
Measurement and Classification, Remington's Pharmaceutical Sciences
17th edition, Part 8 Chapter 89, pp 1588-1589, 1985; Swithenbank, J.,
Beer, J.M., Taylot, D.S., Abbot, D. and McCreath, G.C.: A laser
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diagnostics technique for the measurement of droplet and particle size
distribution. AIAA Paper no. 76-79 ( 1976); and Hayashi, S.: A laser small
angle scattering instrument for the determination of size and
concentration distribution in sprays, (Hirleman, E.D. and others Eds.),
5 Liquid particle Size Measurement Techniques: 2nd Volume,
Philadelphia, ASTM, 1990).
BRIEF DESCRIPTION OF DRAWINGS
Fig. 1 is the powder X-ray diffraction pattern of Compound A
type-I crystal obtained in Preparation 1.
Fig. 2 is the powder X-ray diffraction pattern of Compound A
a....... TT +.-.1 1.+..:... n.7 ' n..e..,.....,+;."., n
~y ~c-it i..i y'~ vcu v a t,cum.u iW i m.~rcu cmvm c,
BEST MODE FOR CARRYING OUT THE INVENTION
The crystal of Compound A of the present invention may be
prepared by the process as illustrated in the following Scheme 1.
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Step A O
1) Base ~ NHR~
I~ N~ I~ I
OR H 2) YOC NHR~ OR H H CH3
I H~~'~CH I I I I I
3
NHR~
Step B ~ , NHR Step C
I i N I H~CH3 I i NJ H~ .~ Hs
OR H OH H
IV V
Step D Step E ~ , NHZ
J
Y1CH2COX I / N I H~ CH3
XOCH2C0 H
VI VII
a (~ H
ii
Step F Step G ~ N ~ CI
I~ I ~ _ I~
_N. 3
CI ~ O HOOCH2C0 H H CH
I , IX
VIII
That is, the compound of the formula I (wherein R is a protecting
group for phenolic hydroxy group, or -CH2COX, X is a lower alkoxy group,
a benzyloxy group, a lower alkyl group, an amino group, a mono- or di-
lower alkylamino group, or a cyclic amino group) is reacted with the
compound of the formula II (wherein Rl is a protecting group for amino
group, and Y is a halogen atom) in the presence of a base to give the
compound of the formula III (wherein R and Rl are as defined above).
The compound III thus obtained is further reacted with a reducing agent
to give the compound of the formula IV (wherein Rll is a hydrogen atom
or a protecting group for amino group, and R is as defined above) . Then,
(i) when R of the formula IV is a protecting group for phenolic hydroxy
group (and if Rl' of the formula IV is a hydrogen atom, then the amino
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group of the compound IV is protected again), the protecting group for
phenolic hydroxy group is selectively removed, and the resulting
compound of the formula V (wherein Rl is as defined above) is reacted
with the compound of the formula VI (wherein Y1 is an alcoholic reactive
residue, and X is as defined above), and further the protecting group for
amino group is selectively removed to give the compound VII; or
(ii) when R of the formula IV is -CH2COX, and Rll is a protecting group
for amino group, the protecting group for amino group is selectively
removed to give the compound VII (wherein X is as defined above),
and the resulting compound VII is reacted with the compound of the
Ur111u1a VIII alld subsl.hiul.lltly thl. reJUltQlit 1J VubjWed tv
hydrogenolysis or hydrolysis under 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 di-lower alkylamino group" includes, for example,
methylamino, dimethylamino, ethylamino, methylethylamino,
diethylamino, propylamino, isopropylamino, and dipropylamino,
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preferably methylamino, dimethylamino, ethylamino, diethylamino, and
dipropylamino, and more 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 more preferably pyrrolidinyl and piperidinyl.
The "protecting group for phenolic hydroxy group and protecting
group for amino group" may be conventional protecting groups being
used in the organic synthesis field (e.g., T. W. Greene, P. G. M. Muts,
Protective Groups in Organic Synthesis, John Wiley & Sons, Inc, Second
L~.ia:..... ~nno ins inn ,..r1 ., ~flC1 ZQ~1 nr,~i irm.liirloa ~~il~~titiiAnto
lillll,1V11, 1771, p. 1'TJ-1 I V a11~1 r!. VV7-VVV~, cuiu um.m.aw.v vu
vvuw.w.mV
being easily removed by reduction or hydrolysis. A combination of a
protecting group for phenolic hydroxy group and a protecting group for
amino group should be selected so that one of them can selectively be
removed.
The "protecting group for phenolic hydroxy group" includes, for
example, methyl, methoxymethyl, methoxyethoxymethyl, tetrahydro-
pyranyl, 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 more
preferably methyl, benzyl, diphenylmethyl, and triphenylmethyl.
The "protecting group for amino group" includes, for example,
methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, tert-
butoxycarbonyl, benzyloxycarbonyl, vinyloxycarbonyl, 9-fluorenyl-
methoxycarbonyl, formyl, acetyl, trifluoroacetyl, benzoyl, phthalimido,
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p-toluenesulfonyl, benzenesulfonyl, methanesulfonyl, and benzyl,
preferably tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenyl-
methoxycarbonyl, acetyl, and trifluoroacetyl, and more preferably tert-
butoxycarbonyl, benzyloxycarbonyl, and 9-fluorenylmethoxycarbonyl.
The "alcoholic reactive residue" includes, for example, a halogen
atom, a lower alkylsulfonyloxy group (e.g., methanesulfonyl, ethane-
sulfonyl), and an arylsulfonyloxy group (e.g., benzenesulfonyloxy, p-
toluenesulfonyloxy).
The "halogen atom" is fluorine atom, chlorine atom, bromine
atom, or iodine atom, and preferably chlorine atom.
The process for producing the crystal of Compound A is
explained in more detail below.
Step
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
dialkylamide, etc. In general, when an indole derivative is reacted with
a nucleophilic reagent in the presence of a base, there is obtained a
mixture of a 1-substituted compound and a 3-substituted compound.
Since a Grignard reagent is widely used in order to preferentially obtain
the 3-substituted compound, a Grignard reagent is also preferable in the
present step.
The Grignard reagent includes methylmagnesium chloride,
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methylmagnesium bromide, ethylmagnesium bromide, tert-butyl-
magnesium chloride, phenylmagnesium chloride, etc., and preferably
methylmagnesium bromide and tert-butylmagnesium chloride. The
Grignard reagent is usually used in an amount of about 1 to about 8
5 moles, preferably in an amount of about 2 to about 4 moles, to 1 mole of
the compound of the formula I.
The reaction is usually carried out at a temperature of from
about -50°C to about 30°C, preferably at a temperature of from -
20°C to
about 0°C. The reaction is preferably carried out under atmosphere of
10 an inert gas such as nitrogen or argon. Besides, an inorganic reagent
such as zinc chloride, aluminum chloride, copper bromide, etc. may be
added into the reaction system. The solvent may be aromatic
hydrocarbons (e.g., benzene, toluene, etc.), ethers (e.g., diethyl ether,
tetrahydrofuran, etc.), chloroform, and methylene chloride, and these
solvents should be used in an anhydrous form.
The compound of the formula II may be prepared by reacting an
amino group-protected a-amino acid with an inorganic halide compound
(e.g., phosphorus pentachloride, phosphorus trichloride, phosphorus
tribromide, 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 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
hexamethylphosphorous triamide may be added to the reaction system.
The reaction is usually carried out at a temperature of from about
0°C to
about 200°C, preferably at a temperature of from about 25°C to
about
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130°C. The solvent may be aromatic hydrocarbons (e.g., benzene,
toluene, etc.) or halogenated hydrocarbons (e.g., chloroform, methylene
chloride, etc.).
Step
Preparation of the compound of the formula IV:
The compound of the formula IV may be prepared by subjecting
the compound of the formula III to reduction with an appropriate
reducing agent in a suitable solvent. The reducing agent may be, for
example, lithium aluminum hydride, sodium bis(2-methoxyethoxy)-
aluminum hydride, sodium borohydride, lithium borohydride, calcium
borohydride, diborane, aluminum diisobutyl hydride, etc., and
preferably an alkali metal borohydride. The reduction of the compound
III wherein R is -CH2COX should be carried out by using a reducing
agent that does not reduce the carbonyl group of R. 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 the
formula III. The reaction temperature may vary depending on the kinds
of the reducing agent to be used, but it 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 kinds of the reducing
agent to be used, and may be ethers (e.g., diethyl ether, tetrahydrofuran,
etc.), toluene, chloroform, methylene chloride, methanol, ethanol,
isopropanol, acetonitrile, water, etc.
In Step B, when the compound of the formula IV wherein R is a
protecting group for phenolic hydroxy group and Rll is a hydrogen atom
is obtained, said compound is used in the subsequent Step C after the
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amino group thereof is protected again.
The introduction of a protecting group for amino group is carried
out by a conventional method in the peptide synthesis field (i.e., Nobuo
IZUMIYA et al., Fundamentals and Experiments of Peptide Synthesis,
Maruzene, 1985, p. 16-40). For example, the compound of the formula
IV wherein Rll is a hydrogen atom is reacted with di-tert-butyl
bicarbonate in an appropriate solvent at room temperature to give the
compound of the formula IV wherein Rll is a tert-butoxycarbonyl group.
In addition, in Step B, when the compound of the formula IV
wherein R is -CH2COX and Rll is a protecting group for amino group is
obtained, said compound can directly be used in Step E.
Further, in Step B, when the compound of the formula IV
wherein R is -CH2COX and Rll is a hydrogen atom is obtained, said
compound is identical to the compound of the formula VII, and can
directly be used in Step F.
Preparation of the compound of the formula V:
The removal of a protecting group for phenolic hydroxy group of
the compound IV wherein Rll is a protecting group for amino group and
R is a protecting group for phenolic hydroxy group may be carried out by
reduction or hydrolysis which should be selected according to the kinds
of the protecting group to be removed.
The reductive removal is carried out by hydrogenolysis or by
using a metal powder such as zinc powder.
The hydrogenolysis is carried out in the presence of a catalyst
such as palladium on caxbon, palladium hydroxide, platinum oxide, etc.,
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under hydrogen atmosphere. The reaction is usually carried out at a
temperature of from about 20°C to about 80°C, under atmospheric
pressure or under pressure. Catalytic hydrogen transfer reduction
using as a hydrogen source ammonium formate, formic acid, cyclo-
hexene, hydrazine, etc. may be employed. The solvent 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 an appropriate solvent under acid
conditions or alkaline conditions. The reaction temperature may vary
according to the kinds of the protecting group to 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 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, formic acid, acetic
acid, methanesulfonic acid; etc.
StP~ D a_n_d Ste~E.
Preparation of the compound of the formula VII:
The compound of the formula VII is prepared from the compound
of the formula V via Steps D and E.
(Step D):
The compound of the formula V and the compound of the
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formula VI are subjected to addition reaction in an appropriate solvent.
The reaction temperature may vary according to the kinds of the starting
compounds to be used, and it 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.), acetontirile, N,N-dimethylformamide, 1,3-dimethyl-2-
imidazolidinone, etc., and these solvents may be used alone or in a
mixture of two or more of these solvents.
The reaction may preferably 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 hydrogen carbonate (e.g., sodium hydrogen
carbonate, potassium hydrogen carbonate, etc.), an alkali metal
hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), or an
organic base such as triethylamine, tributylamine, N-methylmorpholine,
etc. When the compound of the formula VI wherein Y1 is a chlorine
atom or a bromine atom is used, the reaction can smoothly proceed by
addition of an alkali metal iodide (e.g., sodium iodide, potassium iodide,
etc.) or a halogenated tetraalkyl ammonium (e.g., ammonium tetra-n-
butyl chloride, etc.).
With utilizing the present reaction, the compound I wherein R is
-CH2COX can be prepared from hydroxyindole and the compound of the
formula VI in a similar manner.
(Step E):
The compound of the formula VII may be prepared by selectively
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removing the protecting group for amino group of the compound
prepared in Step D.
The protecting group for the amino group is removed by
reduction or hydrolysis, which should be selected according to the kinds
5 of the protecting group to be removed.
The reductive removal is carried out by hydrogenolysis or by
using 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.
10 under hydrogen atmosphere. The reaction temperature is usually in
the range of about 20°C to about 80°C, under atmospheric
pressure or
under pressure. Besides, catalytic hydrogen transfer reduction using
as a hydrogen source ammonium formate, formic acid, cyclohexene,
hydrazine, etc. may also be employed. The solvent may be alcohols (e.g.,
15 methanol, ethanol, etc.), ethyl acetate, acetic acid, water, etc., and
these
solvents maybe used alone or in a mixture of two or more of these
solvents.
The hydrolysis is carried out under acidic conditions or alkaline
conditions in an appropriate solvent. The reaction temperature may
vary according to the kinds of the protecting group to be removed, and 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 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.), or an organic base such
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16
as piperidine, piperazine, etc. The acid may be hydrochloric acid,
hydrobromic acid, trifluoroacetic acid, sulfuric acid, formic acid, acetic
acid, oxalic acid, methanesulfonic acid, etc.
,~~ep F and Step G
Preparation of the compound of the formula IX:
The compound of the formula IX may be prepared from the
compound of the formula VII via Steps F and G.
(Step F):
The compound of the formula VII and the compound of the
formula VIII are reacted in an appropriate solvent or without a solvent.
The reaction temperature may vary according to the kinds of the
starting compounds, and it 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 (e.g., benzene, toluene, etc.),
ketones (e.g., acetone, methyl ethyl ketone, etc.), ethers (e.g., tetra-
hydrofuran, dioxane, etc.), alcohols (e.g., ethanol, isopropanol, etc.),
acetonitrile, dimethylsulfoxide, N,N-dimethylformamide, and 1,3-
dimethyl-2-imidazolidinone, and these solvents may be used alone or in
a mixture of two or more of these solvents. In the reaction system,
trimethylsilylacetamide or bistrimethylsilylacetamide may be added.
In the present reaction, instead of the compound of the formula
VII, an acid addition salt thereof may be used, and the acid addition salt
of the compound VII may 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.
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The base includes, for example, an inorganic base such as an alkali
metal hydrogen carbonate (e.g., sodium hydrogen carbonate, potassium
hydrogen carbonate, etc.) and an alkali metal carbonate (e.g., sodium
carbonate, potassium carbonate, etc.), or an organic base such as
triethylamine, tributylamine, diisopropylethylamine, N-methyl-
morpholine, etc.
(Step G):
The compound of the formula IX may be prepared by
subsequently subjecting the compound obtained in Step F (except for
the compound wherein X is a lower alkyl group) to hydrogenolysis in an
appropriate 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 hydrogen atmosphere. The reaction is carried out at a
temperature of from about 20°C to about 80°C under atmospheric
pressure or under pressure. Catalytic hydrogen transfer reduction
using as a hydrogen source ammonium formate, formic acid,
cyclohexene, hydrazine, etc. may also be employed. The solvent 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 solvent under acidic or alkaline
conditions. The reaction temperature may vary according to the kinds
of the starting compounds, and it is usually in the range of about 0°C
to
about 150°C, preferably in the range of about 20°C to about
80°C. The
solvent may be alcohols (e.g., methanol, ethanol, isopropanol, etc.),
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18
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, methane-
sulfonic 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 crystal of Compound A thus obtained is Compound A type-I
crystal showing characteristic diffraction peaks at the diffraction angles
(28) of about 5.9°, about 17.9°, about 20.5°, and about
24.0° in the
powder X ray diffraction pattern.
The Compound A type-I crystal is recrytallized from a solvent
such as methanol to give the crystal showing characteristic diffraction
peaks at the diffraction angles (28) of about 5.9°, about 17.5°,
about
20.8°, and about 23.3° (Compound A type-II crystal), but
Compound A
type-I crystal is more easily produced industrially than Compound A
type-II crystal.
In the preparation of the present invention, the crystal of
Compound A having a particle size of not larger than 100 ~m at the
cumulative weight distribution value of 50 %, and a particle size of not
larger than 200 ~m at the cumulative weight distribution value of 95 %,
i.e., drug substance, is used. Preferably, ones having a particle size of
not larger than 50 lZm at the cumulative weight distribution value of
50 %, and a particle size of not larger than 150 ~m at the cumulative
weight distribution value of 95 %, more preferably ones having a particle
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19
size of not larger than 30 um at the cumulative weight distribution value
of 50 %, and a particle size of not larger than 100 ~m at the cumulative
weight distribution value of 95 % are used. By using a drug substance
satisfying the above requirements, a preparation from which the drug
substance rapidly dissolve can be obtained. Besides, since a drug
substance may optionally be obtained as an agglomerate, it is preferable
that the drug substance has a content of said agglomerate of less than
50 %, and almost single particle size distribution.
The particle sizes of the drug substance (at the cumulative weight
distribution values of 50 % and 95 %) are measured by a conventional
method for measurement of particle size of medicaments, for example,
by a standard sieving method, sedimentation method, light scattering
method, image analysis, etc., but the method for measuring should not
be limited to these methods.
The present drug substance satisfying the above requirements
may be obtained by selecting the crystallization conditions in the
synthesis process of Compound A and/or by selecting the pulverizing
method after the synthesis of Compound A. For instance, after the
synthesis of Compound A, a drug substance can be obtained by
pulverizing Compound A by 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 which are selected according to the mill to
be used. A drug substance can be obtained by controlling the particle
size and the agglutination rate of Compound A during the synthesis
process thereof, or by dissolving the precipitated crystals during the
synthesis process in an appropriate solvent such as water, an organic
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solvent, etc., and subjecting the resulting solution to spray-drying or
drying in supercritical fluid of carbon dioxide gas, under the selected
conditions.
For preparing the desired pharmaceutical preparation using the
5 drug substance thus obtained, granules containing said drug substance
are prepared.
The granules can contain, in addition to (a) a drug substance, (b)
a filler, (c) a disintegrant, and (d) a binder, but further can contain a
glidant, a lubricant, etc.
10 Since the excipients other than the drug substance in the
granules directly contact the drug substance, it is preferable to use such
excipients compatible with the drug substance and to incorporate them
in a suitable ratio to the drug substance, by which the stability of the
drug substance is secured. The excipients other than the drug
15 substance in the granules include, for example, a filler, a disintegrant,
and a binder, but if necessary, a glidant, a lubricant, etc. may be used as
an excipient.
The excipients other than the drug substance in the granules are
usually contained in an amount of 500 parts by weight or less,
20 preferably in an amount of 300 parts by weight or less, more 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, maltitole, and ethyl cellulose. The
disintegrant includes, for example, low-substituted hydroxypropyl-
cellulose, carmellose calcium, and crosscarmellose sodium. The binder
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21
includes, for example, hydroxypropylcellulose, hydroxypropylmethyl-
cellulose, pullulan, polyvinyl pyrrolidone, 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
part by weight, preferably in an amount of 1 % to 4 % part by weight,
more preferably in an amount of 1.5 % to 3 % part by weight, based on
the total weight of the preparation.
The preparation of the granules is preferably carried out by
preparing previously a preparatory mixing powder of the drug substance
and a part or whole of fillers by mixing them, followed by sieving or
pulverizing, and then adding thereto the remaining excipients, and if
necessary, followed by granulating or regulating the size of the mixture,
by which the content uniformity of the drug substance is secured.
The mixing and sieving is carried out by hand using a sieve of 24
to 60 mesh, or by using a sieving apparatus having a suitable mixing
capacity such as an oscillator. The mixing and pulverizing is carried
out using a pulverizer such as a hammer mill.
The granulation is carried out, for example, by wet-granulation
using fluid bed granulator, agitation granulator, or high-shear
granulator.
The particle size of the granules thus prepared is usually not
larger than 350 um at the cumulative weight distribution value of 50 %,
and not larger than 1400 um at the cumulative weight distribution value
of 95 %. Preferably, the particle size of the granules is not larger than
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22
300 um at the cumulative weight distribution value 50 %, and not larger
than 1000 ~m at the cumulative weight distribution value of 95 %.
More preferably, the particle size of the granules is not larger than 250
um at the cumulative weight distribution value of 50 %, and not larger
than 800 um at the cumulative weight distribution value of 95 %. By
using granules having such a preferable particle size, the content
uniformity of the drug substance is more secured.
The particle sizes of the drug substance (at the cumulative weight
distribution values of 50 % and 95 %) are measured by a conventional
method for measurement of particle size of medicaments, for example,
by a standard sieving method, sedimentation method, light scattering
method, image analysis, etc., but the method for measuring should not
be limited to these methods.
The solid preparation of the present invention contains .the
granules thus obtained. The solid preparation may 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 dosage unit, it is preferable to increase the volume (weight) of the
preparation by adding external excipients into the granules in order to
secure the sufficient stability of the drug substance as well as to secure a
suitable size (usually 4 to 10 mm of diameter, 25 to 300 mg).
The external excipient may 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.
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In order to secure the content uniformity 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, more
preferably in an amount of 0.15 to 10 parts by weight, to 1 part by
weight of the granules.
In formulating the preparation, the external excipients may be
used for mixing with the drug substance containing granules merely as
a mixture of the external excipients, or after granulating the external
excipients or regulating in size thereof to the same particle size as those
of the granules. For granulation or regulation in size of the external
excipients, hydroxypropylcellulose, hydroxypropylmethylcellulose,
pullulan, polyvinylpyrrolidone, gelatin, carmellose sodium may be used
as a binder. When mixing the granules and the external excipients, a
glidant and/or lubricant may be used.
The granules and the external excipients may be compressed
together without mixing to give dry coated tablets or multilayer tablets.
In this case, the external excipients may be, for example, crystalline
cellulose and/or low substituted hydroxypropylcellulose and
magnesium stearate and/or hydrogenated castor oil. Moreover, light
anhydrous silicic acid and/or talc may be used. If necessary,
hydroxypropylcellulose, hydroxypropylmethylcellulose, or pullulan may
be used as a binder.
When tableting the granules or a mixture of the granules and the
external excipients, 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 external excipients, in
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24
order to prevent sticking which may easily occur in the compression
tableting procedure, and then the mixture thus obtained is subjected to
compression tableting with a suitable tableting machine to give the
desired tablets.
In addition, in order to mask bad tastes, to increase the strength
of tablets, to improve a feeling when taken, and to increase the easiness
when used, the tablets thus obtained may be coated with a suitable
polymeric ingredient to give film coated tablets. The polymeric
ingredient may be, for example, hydroxypropylmethylcellulose,
hydroxypropylcellulose, hydroxyethylcellulose, methylhydroxyethyl-
cellulose, methyl cellulose, ethyl cellulose, carmellose sodium,
polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, dimethyl-
aminoethyl metacrylate-methyl acrylate copolymer, and ethyl acrylate-
methyl metacrylate copolymer. If necessary, as a plasticizer for the
polymeric ingredient, for example, propyleneglycol, glycerol,
polyethyleneglycol, glyceryl triacetate (triacetin), triethyl citrate,
acetyltriethyl citrate, diethyl phthalate, diethyl sebacate, acetylated
monoglyceride, castor oil, or liquid paraffin may be added into a coating
agent. Further, in order to protect from light or to improve the
discriminability, a suitable coloring agent may be added into a coating
agent. The coloring agent may be, for example, a water-soluble
synthetic pigment such as Yellow No. 4, Yellow No. 5, Blue No. 1, Blue
No. 2, etc., and their aluminum lakes, talc, titanium oxide, iron oxides,
calcium sulfate, calcium carbonate, or riboflavin, carmine, turmeric
pigment may be added. Moreover, in order to increase palatability, a
sweetening agent or a flavor may be added as well.
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In addition, the tablets may be converted into sugar coated
tablets for the same purpose as mentioned above. The sugar coating
agent may consist of, in addition of the main component of sucrose or
sorbitol, calcium carbonate, talc or titanium oxide, and further contains
5 as a binder, for example, gelatin, acacia, polyvinyl alcohol, etc., or a
cellulose derivative such as pullulan, hydroxypropylmethylcellulose, etc.,
and if necessary, a water-soluble synthetic pigment such as Yellow No. 4,
Yellow No. 5, Blue No. 1, Blue No. 2, etc., and their aluminum lakes, talc,
titanium oxide, iron oxides, calcium sulfate, calcium carbonate, or
10 riboflavin, carmine, turmeric pigment may be added. Moreover, in
order to increase palatability, a sweetening agent or a flavor may be
added as well.
The granules or a mixture of the granules and the external
excipients may directly be formulated into fine granule preparations,
15 granule preparations or powder preparations, or into capsule
preparations by filing them in gelatin capsules. In this case, the
external excipients may be, for example, lactose, corn starch, sucrose,
trehalose, D-mannitol; erythritol, maltitole, and/or ethyl cellulose, and
magnesium stearate and/or hydrogenated castor oil. Further, light
20 anhydrous silicic acid and/or talc may be used as well. In the case of
granule preparations, after granulating, hydroxypropylcellulose,
hydroxypropylmethylcellulose, pullulan, polyvinylpyrrolidone, gelatin,
or carmelose sodium may be added as a filler for granule preparations.
If further necessary, in order to make the tablets sustained
25 release ones, the drug substance-containing granules or tablets are
coated with a coating gent for controlling the release of a medicament
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26
consisting of a polymeric ingredient or fats and oils to give reservior type
sustained release tablets. The coating agent may be, for example,
beeswax, carnauba wax, cetyl alcohol, cetylstearyl alcohol, lipid-fats and
oils, resins (e.g., shellac), cellulose esters (e.g., ethyl cellulose), and
acrylic acid esters. If necessary, as a plasticizer for the polymeric
ingredient, propylene glycol, glycerol, polyethylene glycol, glyceryl
triacetate (triacetin), triethyl citrate, acetyltriethyl citrate, diethyl
phthalate, diethyl sebacate, acetylated monoglyceride, castor oil, or
liquid paraffin may be added into a coating agent. In addition, the
granules controlling the release of the medicament may be compressed
to give tablets.
There may be obtained a matrix type sustained release
preparation by mixing a component for controlling the release of
medicament such as the polymeric ingredients as mentioned above or
fats and oils together with fillers in the step of producing granules and
tablets. Further, if necessary, the granules thus controlled in the
release of medicament can be compressed to give tablets.
The solid preparation of the present invention thus obtained may
be packed, if necessary, in blister pack, heat-seal pack, or bottles of
suitable materials, but should not be limited to these packages.
Further, if necessary, the solid preparation of the present invention may
be packed together with a suitable desiccant such as silica gel.
PHARMACEUTICAL EXPERIMENT
The effect on human (3-adrenergic receptors of the drug
substance of the present invention was studied.
The cell lines highly expressing human (33- and (32-adrenergic
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27
receptors were prepared according to the method disclosed in WO
96/ 16938. The cell line highly expressing human (31-adrenergic
receptor was prepared according to the method disclosed in WO
00/44721.
Experiment
Human (33-adrenergic receptor-stimulating activity:
Human (33-adrenergic receptor-highly expressing cell line
CHO/pKREXIO-36 was cultured for 2-3 days with MEM-Dulbecco's
medium supplemented with 10% fetal bovine serum and 200 ~g/ml G-
418. The cells were peeled off by incubation with phosphate-buffered
saline containing 0.5 mM EDTA at 37°C for 10 minutes after the medium
was removed. The CHO/pKREXIO-36 cells were collected by
centrifugation, and suspended in Hanks' buffer (ICN Biomedicals)
containing 1 mM L-ascorbic acid and 1 mM 3-isobutyl-1-methyl-
xanthine at the concentration of about 5 x 105 cells/ml. This
suspension ( 100 ~l) and a test compound were mixed in the same buffer
(500 u1) and incubated at 37°C for 30 minutes, followed by boiling for
5
minutes to terminate the reaction. After centrifugation of the reaction
mixture, the amount of cAMP in the supernatant was measured by using
cAMP EIA System (Amersham).
Similarly, the amount of cAMP was measured in the same
manner by using CHO/pKREX21-8 for highly expressing human (32-
adrenergic receptor, or by using CHO/pKREX23-30 for highly
expressing human (31-adrenergic receptor instead of the
CHO/pKREXIO-36 for highly expressing human (33-adrenergic receptor.
The amounts of CAMP when adding 10-5 M of (-)-isoproterenol to
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the reaction mixture or not adding thereof at all were designated as
100 % and 0 %, respectively, and the relative maximal response of the
drug substance of the present preparation (10-6 to 10-'1 M) is expressed
as intrinsic activity [LA.]. ECso value which is a concentration of the
test compound to be required to achieve 50 % of cAMP accumulation
was calculated by least squares regression analysis of a concentration-
response curve of each compound.
The results are shown in Table 1.
Table 1
Human (33-,
~i2- and
X31-adrenergic
receptor-stimulating
activity
Test
(33-receptor (32-receptor [3,-receptor
Com
p.
ECso (nM) LA. EC5o (nM) LA. ECso (nM) LA.
(%) (%) (%)
A* 0.27 110 21 45 3.5 83
IP** 10 100 4.2 100 0.46 100
Note: * means drug substance; ** means (-)-isoproterenol.
In this experiment, a compound having a low ECso value and a
high I.A. value is considered to have a potent human (3-adrenergic
receptor-stimulating activity. Thus, as is clear from Table l, the drug
substance of the present preparation is proven to have a potent
stimulating activity of human [33-adrenergic receptor, but the
stimulating activity of human (32- and (31-adrenergic receptors thereof is
quite weak.
As is shown in the above results, the drug substance of the
present invention can be expected as a human (33-adrenergic receptor-
stimulating agent with excellent adrenoceptor selectivity.
The drug substance of the present invention is useful as a (33-
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29
adrenergic receptor-stimulating agent in the prophylaxis or treatment of
obesity, diabetes mellitus, hyperlipemia, irritable bowel syndrome, acute
or chronic diarrhea, pollakisuria, enuresis, urinary calculus, etc.
Besides, the drug substance of the present invention is also useful in the
improvement of the symptoms such as stomach ache, nausea, vomiting,
epigastrium sickness, accompanying with peptic ulcer, acute or chronic
gastritis, biliary dyskinesia, cholecystitis, etc.
When the drug substance of the present invention is used as a
(33-adrenergic receptor-stimulating agent, it may be administered orally,
parenterally, or rectally, but preferably by oral route. The dose of the
drug substance of the present invention may vary according to the
administration route, the conditions, ages of the patients, or kinds of
objects (prophylaxis or treatment), etc., but it is usually in the range of
0.0002 mg/kg/day to 0.02 mg/kg/day, preferably in the range of 0.001
mg/kg/day to 0.02 mg/kg/day.
Example s
The present invention is illustrated in more detail by the
following Preparations, Experiments, and Examples, but should not be
construed to be limited thereto.
Pr~aration 1
Preparation of crystal of Compound A:
The identification of the compounds was carried out by
Elementary analysis, Mass spectrum analysis, Infrared (IR) absorption
spectrum, Proton nuclear magnetic resonance (1H-NMR) spectrum, and
by measurement of optical rotation. The optical purity was determined
by high performance liquid chromatography.
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The following abbreviations may be used in order to simplify the
disclosure.
Fmoc: 9-Fluorenylmethoxycarbonyl group
Ala: Alanine residue
5 J: Coupling constant
s: Singlet
d: Doublet
dd: Double doublet
t: Triplet
10 q: Quartet
m: Multiplet
br: Broad
(1) Preparation of (R)-3-(2-aminopropyl)-7-benzyloxyindole oxalate:
(Step 1)
15 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
under stirring, and the mixture was further stirred for one hour. The
reaction mixture was concentrated to dryness under reduced pressure
20 to give a solid containing Fmoc-D-Ala-Cl, which was used in the
subsequent reaction without further purification.
(Step 2)
To an ice cooled and stirred solution of commercially available
7-benzyloxyindole ( 11.2 g, 50 mmol) in methylene chloride ( 100 ml) was
25 added a 3 M diethyl ether solution of methylmagnesium bromide (50 ml,
150 mmol) under argon atmosphere. The mixture was warmed to room
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31
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 ice-cooling. The mixture was
warmed to room temperature and further stirred for one hour. To the
mixture was added 5 % aqueous hydrochloric acid solution ( 100 ml)
under ice-cooling, and the whole 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
further used in the subsequent Step without further purification.
(Step 3)
To a stirred mixture of the oil obtained in Step 2 in a mixture of
acetonitrile ( 100 ml) and 2-propanol ( 15.03 ml) was added portionwise
sodium borohydride (5.67 g, 150 mmol) at room temperature, and the
mixture was refluxed for 5 hours. The reaction mixture was cooled to
room temperature, and thereto was added dropwise methanol ( 100 ml).
The reaction mixture was concentrated to dryness under reduced
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 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.
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32
[a]D25 = -46.2° (c = 1.0, N,N-dimethylformamide);
1H-NMR spectrum (200 MHz, DMSO-d6, b ppm): 1.14 (3H, d,
J=7Hz), 2.80 (1H, dd, J=l4Hz, J=8Hz), 3.03 (1H, dd, J=l4Hz, J=5Hz),
3.42 (1H, m), 5.26 (2H, s), 5.94 (4H, br), 6.75 (1H, d, J=8Hz), 6.92 (1H, t,
J=8Hz), 7.11-7.22 (2H, m), 7.32-7.48 (3H, m), 7.51-7.62 (2H, m), 11.11
(1H, s).
(2) Preparation of (R)-3-(2-tert-butoxycarbonylaminopropyl)-7-
benzyloxyindole:
To a mixture of potassium carbonate (28 g), water (500 ml) and
ethyl acetate (250 ml) was added (R)-3-(2-aminopropyl)-7-benzyloxy-
indole oxalate (50 g, 135 mmol) obtained in the above (1), and the
mixture was stirred. Then, to the ice cooled and stirred mixture was
added di-tert-butyl bicarbonate (29.5 g, 135 mmol), and the mixture was
stirred at room temperature for 3 hours. The organic layer was
separated, washed with a saturated aqueous sodium chloride solution
(150 ml), and dried over anhydrous magnesium sulfate. The solvent
was evaporated under reduced pressure, and to the residue was added
n-hexane ( 150 ml) . 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);
1H-NMR spectrum (300 MHz, CHC13, 8 ppm): 1.11 (3H, d,
J=6.6Hz), 1.43 (9H, s), 2.83 (1H, dd, J=14.5Hz, J=6.7Hz), 2.94 (1H, dd,
J=14.5Hz, 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).
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33
Optical purity: 98.5 % ee [conditions for analysis; 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); Wave length for
Detection (254 nm); Retention time (8.8 min.)]
(3) Preparation of N,N-diethyl-[3-[[(2R)-tert-butoxycarbonylamino]-
propyl]-1 H-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
the above (2) in methanol ( 100 ml) was added 10 % palladium on carbon
(0.5 g), and the mixture was hydrogenated under atmospheric pressure
of 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 to the solution were added potassium
carbonate (4.54 g), N,N-diethylchloroacetamide (4.72 g, 31.6 mmol) and
potassium iodide (0.55 g), 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. To the residue
were 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 to the residue was added diisopropyl ether (30 ml). The
precipitated crystals were collected by filtration and dried to give the title
compound ( 10.7 g, 100 %) as white crystals, m.p. 142°C.
[a]D25 = -26.3° (c = 1.0, methanol);
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34
1H-NMR spectrum (300 MHz, CDC13, s 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
( 1 H, dd, J = 14.1 Hz, J = 7.0 Hz), 2.94 ( 1 H, 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 [conditions for analysis; 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); Wave length for
Detection (254 nm); Retention time (6.6 min.)]
(4) Preparation of N,N-diethyl-[3-[(2R)-aminopropy]-1H-indol-7-
yloxy]acetamide:
To a solution of N,N-diethyl-[3-[((2R)-tert-butoxycarbonyl-
amino]propy]-1H-indol-7-yloxy]acetamide (12 g, 29.7 mmol) obtained in
the above (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 with ice, and the precipitated crystals were collected by filtration
and washed with acetonitrile. To the resulting crystals were 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 to the residue was added
diisopropyl ether (30 ml) . 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.
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[a]D25 = -46.3° (c = 1.0, methanol);
1H-NMR spectrum (300 MHz, CDCl3, S 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 ( 1 H, dd, J = 14.1 Hz, J = 8.2 Hz), 2.86( 1 H, dd, J = 14.1 Hz, J = 5.0
5 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 [conditions for analysis; Column
(CHIRALPAK AD (diameter 4.6 mm x 250 mm: manufactured by DAICEL
10 CHEMICAL INDUSTRIES, LTD.)); Mobile phase (n-hexane : isopropanol
diethylamine = 85 : 15 : 0.8); Flow rate ( 1.0 ml/min); Temperature
(25°C); Wave length for Detection (254 nm); Retention time ( 19.9
min.)]
(5) Preparation of N,N-diethyl-[3-[(2R)-[[(2R)-(3-chlorophenyl)-2-
hydroxyethyl]amino]propyl]-1 H-indol-7-yloxy]acetamide:
15 To a solution of N,N-diethyl-[3-[(2R)-aminopropy]-1H-indol-7-
yloxy]acetamide (21 g, 69.2 mmol) obtained in the above (4) in
acetonitrile (42 ml) was added (R)-3-chlorostylene oxide ( 11.77 g, 76.1
mmol), and the mixture was refluxed for 5 hours. The mixture was
cooled with ice, and thereto was added diisopropyl ether ( 168 ml). The
20 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 unreacted starting materials was concentrated to
dryness under reduced pressure, and to the residue were added again
acetonitrile (21 ml) and (R)-3-chlorostyrene oxide ( 1.07 g, 6.9 mmol), and
25 the mixture was refluxed for 6 hours. The mixture was cooled with ice,
and thereto was added diisopropyl ether (63 ml) . The precipitated
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36
crystals were collected by filtration and dried to give the title compound
(2.86 g, 9 %), m.p. 120-121°C.
[a]D25 = -69.1° (c = 1.0, methanol);
1H-NMR spectrum (300 MHz, CDC13, S 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 ( 1 H, m), 4.78 (2H, s), 6.65 ( 1 H, d, J = 7.3 Hz), 6.98 ( 1 H, t, J =
7.9 Hz),
6.99 ( 1 H, s), 7.12-7.30 (4H, m), 7.34 ( 1 H, s), 9.60 ( 1 H, s) .
(6) Preparation of [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethylj-
aminoJpropyl)-1H-indol-7-yloxy)acetic acid (Compound A):
N,N-Diethyl-[3-[(2R)-[((2R)-(3-chlorophenyl)-2-hydroxyethyl]-
amino]propyl]-1H-indol-7-yloxy)acetamide (4 g, 8.7 mmol) obtained in
the above (5) 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 3 hours and 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.
[a]D25 _ -24.4° (c = 1.0, 1 N aqueous sodium hydroxide solution);
'H-NMR spectrum (200 MHz, DMSO-d6, 8 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, m), 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 [conditions for analysis; Column
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(CHIRAL-AGP (diameter 4.0 mm x 100 mm: manufactured by SHINWA
KAKO CO., LTD.)); Mobile phase (aqueous (20 mM Na2HP04 + 2 mM
ammonium tetrabutyl hydrogen sulfite) solution (pH 7.0) : isopropanol =
98: 2); Flow rate (0.7 ml/min); Temperature (30°C); Wave length for
Detection (220 nm); Retention time (27.4 min.)]
The X-ray diffraction pattern of the crystals of Compound A thus
obtained was measured with an X-ray powder diffractometer
(RINT1000-type; manufactured by RIGAKU CORPORATION) at a tube
voltage of 30 kV, and a tube electric current of 20 mA using CuKa wire in
terms of diffraction angle (28). The diffraction pattern thereof is shown
in Fig. 1. The diffraction angles in the X-ray powder diffraction pattern
of the crystals of Compound A are about 5.9°, about 17.9°, about
18.8°,
about 20.5°, about 23.3°, about 24.0°, and about
24.9°, and there are
characteristic peaks at about 5.9°, about 17.9°, about
20.5°, and about
24.0°. The values of the diffraction angle (28) have the 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 with warming in a water bath at 100°C. The precipitated
crystals were collected by filtration, and dried to give Compound A
Type-II crystals.
The X-ray diffraction pattern of Compound A Type-II crystals
thus obtained was measured with an X-ray powder diffractometer (RINT
ULTIMA Type; manufactured by RIGAKU CORPORATION) at a tube
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voltage of 40 kV, and a tube electric current of 30 mA using CuKa wire in
terms of diffraction angle (28). The diffraction pattern thereof is shown
in Fig. 2. The diffraction angles in the X-ray powder diffraction pattern
of Compound A Type-II crystals are about 5.9°, about 17.5°,
about 19.4°,
about 20.8°, about 23.3°, about 24.0°, and about
24.9°, and there are
characteristic peaks at about 5.9°, about 17.5°, about
20.8°, and about
23.3°. The values of the diffraction angle (28) have the standard
accuracy.
per pa_ration 3
Preparation of drug substance:
( 1 ) The Compound A Type-I crystals obtained in Preparation 1 were
micronized using a hammer mill (Sample Mill AP-S, manufactured by
Hosokawa Micron Corporation, Japan) using a screen with opening
diameter of 0.7 mm.
(2) Separately, the Compound A Type-I crystals obtained in
Preparation 1 were micronized using a fluid energy mill (Single Truck Jet
Mill FS-4, manufactured by SEISHIN ENTERPRISE CO., LTD., Japan)
with compression air pressure of 7 kgf/cm2.
(3) The particle sizes at the cumulative weight distribution value of
50 % and 95 % of each micronized granules thus obtained were
measured using a laser diffraction particle size distribution analyzer
(HELOS 8v RODOS (trademark), manufactured by SYMPATEC GmbH,
Germany), and calculated from cumulative particle size distribution on
volume basis by dry air dispersion method (dispersion air pressure: 1
atm). The particle size of the crystals obtained in (1) at the cumulative
weight distribution value of 50 % is not larger than 21 Vim, and that at
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the cumulative weight distribution value of 95 % was not larger than 75
um. The particle size of the crystals obtained in (2) at the cumulative
weight distribution value of 50 % is not larger than 1.7 Vim, and that at
the cumulative weight distribution value of 95 % was not larger than 3.8
um. By either method for micronization, there can be obtained the
crystals of Compound A having a particle size at the cumulative weight
distribution value of 50 % of not larger than 100 um, and a particle size
at the cumulative weight distribution value of 95 % of not larger than
200 um.
ExQeriment 1
Particle size of the drug substance:
According to the prescription in Table 2, to a mixed powder of a
drug substance or unmicronized crystals of Compound A, lactose, low
substituted hydroxypropylcellulose and hydroxypropylcellulose was
added water with stirring to give the granules (kneading granulation),
which are dried, and regulated in size to give the granules. The
granules thus obtained were mixed with crystalline cellulose, light
anhydrous silicic acid and magnesium stearate, and compressed to give
the tablets containing 1 mg of the drug substance or the unmicronized
crystals of Compound A each. As a drug substance, ones micronized
using a hammer mill (Sample Mill AP-S manufactured by Hosokawa
Micron Corporation, Japan) using a screen with opening diameter of 0.7
mm or 1.0 mm, or ones micronized using a fluid energy mill (Single
Truck Jet Mill 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 were used. The dissolution test of the
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tablets thus obtained was carried out according to the Thirteenth
Edition of the Pharmacopoeia of Japan (Paddle method, 50 rpm, water
37°C, 900 ml), and the relation between the particle size of the drug
substance and the dissolution thereof was evaluated by measuring the
5 dissolution rate at 15 minutes. The results are shown in Table 3.
Table 2
Weight
Components
(mg)
Drug substance or
1
Unmicronized crystal of Compound
A
Granules Lactose 70
Low substituted hydroxypropylcellulose10
Hydroxypropylcellulose 2.5
Crystalline cellulose 15
External
1
Magnesium stearate
excipients
Light anhydrous silicic acid 0.5
Total 100
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Table 3
Particle Particle
size size
(11m) of (um) of 95 Dissolution
50 % %
Method for cumulative cumulative rate after
15
micronization weight weight
min. ( /)
distributiondistribution
value value
Exp. 1-1 Fluid energy 1.7 3.8 100
mill
Hammer mill
(screen
Exp. 1-2 opening 9.4 43 97
diamter:
0.7mm)
Hammer mill
(screen
Exp. 1-3 opening 17 42 100
diamter:
0.7mm)
Hammer mill
(screen
Exp. 1-4 opening 21 75 99
diamter:
0.7mm)
Hammer mill
(screen
Exp. 1-5 opening 12.5 45 100
diamter:
0.7mm)
Hammer mill
(screen
Exp. 1-6 opening 45 144 96
diamter:
l.Omm)
Comp. Unmicronized 85 366 60
Exp. 1-1
The tablets prepared using the drug substance having a particle
size at the cumulative weight distribution value of 50 % of not larger
than 100 um and a particle size at the cumulative weight distribution
value of 95 % of not larger than 200 ~m showed a distribution rate of
almost 100 % at 15 minutes, which is good dissolution ability.
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Experiment 2
Composition ratio in the granules by weight of the drug substance and
the excipients other than the drug substance:
To a mixed powder of the drug substance (ones used in the above
Experiment 1-3 for Experiment 2-1 and Comparative Experiment 2-1,
and one used in the above Experiment 1-2 for Experiment 2-2), lactose,
and low substituted hydroxypropylcellulose was sprayed an aqueous
solution of hydroxypropylcelluose using a fluid bed granulator and drier,
and granulated and dried to give the granules. As shown in Table 4,
there were prepared three kinds of granules, wherein the content of the
excipients other than the drug substance in the granules was different
such as 82.5 parts by weight (Experiment 2-1), 417 parts by weight
(Experiment 2-2), and 834 parts by weight (Comparative Experiment 2-
1) to 1 part by weight of the drug substance. To each granule were
added a fixed amount of crystalline cellulose, light anhydrous silicic acid
and magnesium stearate, and the mixture was compressed to give
tablets. These tablets were stored under conditions of 40°C-75 % RH
(relative humidity) for 4 months, and the content of all of the
decomposition products derived from the drug substance was measured,
and the increase thereof was calculated from the initial amount. The
results are shown in Table 5.
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Table 4
Component Exp.2-1 Exp.2-2 Comp.
Exp. 2-1
Drug substance1 0.2 0.1
Lactose 70 70.8 70.9
Low substituted
Granules hydroxypropyl-10 10 10
cellulose
Hydroxypropyl-2.5 2.5 2.5
cellulose
Crystalline 15 15 15
cellulose
External Magnesium 1 1 1
excipients stearate
Light anhydrous0.5 0.5 0.5
silicic acid
Total (mg) 100 lOG 100
Parts in the
granules
by weight
of
excipients g2.5 417 834
other than
drug
substance
of 1 part
by weight
of
drug substance
Table 5
Comparative
Exp.2-1 Exp.2-2 Ex . 2-1
Increase (%) of amount 0.20 ~ 0.69 ~ 1.45
of all of ~
the decomposition products
In the tablets of Experiment 2-1 and 2-2, the amount of all of the
decomposition products axe produced less, as compared with the tablets
of Comparative Experiment 2-1, which contains more than 500 parts in
the granules by weight of the excipients other than the drug substance
to 1 part by weight of the drug substance, by which it is proven that the
chemical stability of the drug substance per se in the tablets of
Experiments 2-1 and 2-2 is high.
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ExQeriment 3
Composition ratio in the granules by weight of the drug substance and
the excipients other than the drug substance:
According to the prescription of Table 6, to a mixed powder of
lactose and low substituted hydroxypropylcellulose was added a
solution of hydroxypropylcellulose in purified water to give granules
(kneading granulation), which were dried and regulated in size to give
the granules of the external excipients.
Table 6
Components Weight (mg)
Lactose 71
Granules of Low substituted
external ~excipients
hydroxypropylcellulose 10
Hydroxypropylcellulose 2.5
Total 83.5
To a mixed powder of the drug substance (one used in the above
Experiment 1-4), lactose and low substituted hydroxypropylcellulose
was added a solution of hydroxypropylcellulose in purified water to give
granules (kneading granulation), which were dried and regulated in size
to give the granules. Form this granules, there were obtained 4 kinds of
the granules wherein the content of the excipients other than 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. To 4 kinds of the granules
were added the granules of the external excipients obtained according to
the prescription of the above Table 6, crystalline cellulose, light
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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 part by weight of the external excipients to 1 part by
weight of the granules (Experiment 3-1), tablets containing 0.2 mg of the
5 drug substance each as well as 2.59 parts by weight of the external
excipients to 1 part by weight of the granules (Experiment 3-2), tablets
containing 0.1 mg of the drug substance each as well 0.20 part by weight
of the external excipients to 1 part by weight of the granules
(Comparative Experiment 3-1), and tablets containing 0.2 mg of the drug
10 substance each as well 0.20 part 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 of the decomposition
products derived from the drug substance was measured by high
15 performance liquid chromatography, and the increase thereof was
calculated from the initial amount. The results are shown in Table 8.
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Table 7
Component Exp.3-1 Exp.3-2 Comp. Comp.
Exp.3-1 Exp.3-2
Drug substance0.1 0.2 0.1 0.2
Lactose 35.4 70.8 85.1 212.8
Low substituted
Granules hydroxypropyl-5 10 12 30
cellulose
Hydroxypropyl-1.25 2.5 3 7.5
cellulose
Granules of
external 58.45 167 - -
excipients
Crystalline 18 45 18 45
External cellulose
excipients
Magnesium 1.2 3 1.2 3
stearate
Light anhydrousp.6 1.5 0,6 1.5
silicic acid
Total (mg) 120 300 120 300
Parts in
the granules
by weight
of
excipients 416.5 416.5 1001 1251.5
other than
drug
substance
to 1 part
by weight
of
drug substance
Parts by
weight external
excipients 1.87 2.59 0.20 0.20
to 1 part
by weight
of
granules
Table 8
Exp.3-1 Exp.3.2 Cmp. Comp.
Exp.3-1 Exp.3-2
Increase (%) of amount
of all
of the decomposition 0.75 % 0.83 % 1.31 ~0 1.76
products
In the tablets of Experiments 3-1 and 3-2, the amount of all of
the decomposition products are produced less, as compared with the
tablets of Comparative Experiments 3-1 and 3-2, by which it is proven
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that the chemical stability of the drug substance per se in the tablets of
Experiments 3-1 and 3-2 is high.
Experiment 4
Premixing during the preparation of granules:
According to the prescription of Table 9, there were obtained
tablets containing 0.05 mg of the drug substance (one used in the above
Experiment 1-5) per each. When preparing the granules, the drug
substance was previously mixed and micronized with lactose using a
mixer sieve (a stainless sieve of 50 mesh = Experiment 3-1) or using a
granulator (a hammer mill = Experiment 3-2), and thereto were added
low substituted hydroxypropylcellulose and hydroxypropylcellulose.
Water was added with stirring to the mixture to give granules (kneading
granulation), and dried and regulated in size to give the granules. To
the granules thus obtained were added and mixed crystalline cellulose,
light anhydrous silicic acid and magnesium stearate, and the mixture
was compressed to give the tablets. The content uniformity of the
tablets thus obtained was tested according Content Uniformity Test in
the Thirteenth Edition of the Pharmacopoeia of Japan (whereby the
result of below 15 % is considered adequate). The results are shown in
Table 10.
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Table 9
Weight
Com onents
P (mg)
Drug substance 0.05
Lactose 17.7
Granules
Low substituted hydroxypropylcellulose2.5
Hydroxypropylcellulose 0.625
Crystalline cellulose 3.75
External
Magnesium stearate 0.25
excipients
Light anhydrous silicic acid 0.125
Total 2 5
Table 10
Exp . 4-1 Exp . 4-2
Method for premixingStainless sieve Hammer mill
Content uniformity 10.0 4.0
(%)
In Content Uniformity Test in the Thirteenth Edition of the
Pharmacopoeia of Japan, the result of below 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
According to the prescription of Table 11, there were obtained the
tablets containing 1 mg of the drug substance (one used in Experiment
1-3 as mentioned above) each. When preparing the granules, the drug
substance was previously mixed and sieved with lactose using a
hammer mill, and thereto were added low substituted hydroxypropyl-
cellulose and hydroxypropylcellulose. Water was added to the mixture
with stirring to give the granules (kneaded granulation), which ware
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dried and regulated in size to give granules having a particle size of not
larger than 250 um at the cumulative weight distribution value of 50 %,
and a particle size of not larger than 600 um at 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 thus obtained had a suitable size and the content uniformity and
the stability of the drug substance were reserved, and the dissolution of
the drug substance from the tablets was rapid.
Table 11
Weight
Components
(mg)
Drug substance 1
Lactose 70
Granules
Low substituted hydroxypropylcellulose10
Hydroxypropylcellulose 2.5
Crystalline cellulose 15
External
Magnesium stearate 1
excipients
Light anhydrous silicic acid 0.5
Total 100
Example 2
According to the prescription of Table 12, there were obtained
tablets containing 0.1 mg of the drug substance (one used in Experiment
1-5 as mentioned above) each. When preparing the granules, the drug
substance was previously mixed and sieved with lactose using a
hammer mill, and thereto were added low substituted hydroxypropyl-
cellulose and hydroxypropylcellulose. Water was added to the mixture
with stirring to give the granules (kneaded granulation), and dried and
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regulated in size to give the granules having a particle size of not larger
than 250 um at the cumulative weight distribution value of 50 %, and a
particle size of not larger than 600 um at the cumulative weight
distribution value of 95 %. The granules thus obtained were mixed
5 with crystalline cellulose, light anhydrous silicic acid and magnesium
stearate, and the mixture was compressed to give the tablets. The
tablets thus obtained had a suitable size and the content uniformity and
the stability of the drug substance were reserved, and the dissolution of
the drug substance from the tablets was rapid.
10 Table 12
Weight
Com onents
P (mg)
Drug substance
Lactose 35.3
Granules
Low substituted hydroxypropylcellulose5
Hydroxypropylcellulose 1.25
Crystalline cellulose 7.5
External
Magnesium stearate 0.5
excipients
Light anhydrous silicic acid 0.25
Total 50
Example 3
According to the prescription of Table 13, there were obtained
tablets containing 0.05 mg of the drug substance (one used in
Experiment 1-5 as mentioned above) each. When preparing the
15 granules, the drug substance was previously mixed and sieved with
lactose using a hammer mill, and thereto were added low substituted
hydroxypropylcellulose and hydroxypropylcellulose. Water was added
to the mixture with stirring to give the granules (kneaded granulation),
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and dried and regulated in size to give the granules having a particle size
of not larger than 250 ~m at the cumulative weight distribution value of
50 %, and a particle size of not larger than 600 um at 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 thus obtained had a suitable size and the content uniformity
and the stability of the drug substance were reserved, and the
dissolution of the drug substance from the tablets was rapid.
Table 13
Weight
Components
(mg)
Drug substance 0.05
Lactose 17.7
Granules
Low substituted hydroxypropylcellulose2.5
Hydroxypropylcellulose 0.625
Crystalline cellulose 3.75
External
Magnesium stearate 0.25
excipients
Light anhydrous silicic acid 0.125
Total 25
Example 4
According to the prescription of Table 14, there were obtained
tablets containing 0.2 mg of the drug substance (one used in Experiment
1-3 as mentioned above) each. To a mixed powder of the drug
substance, low substituted hydroxypropylcellulose and hydroxypropyl-
cellulose was added water with stirring to give the granules (kneaded
granulation), which were dried and regulated in size to give the granules
having a particle size of not larger than 350 um at the cumulative weight
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distribution value of 50 %, and a particle size of not larger than 1000 um
at 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 thus obtained had a suitable size and the
content uniformity and the stability of the drug substance were reserved,
and the dissolution of the drug substance from the tablets was rapid.
Table 14
Weight
Components
(mg)
Drug substance 0.2
Lactose
Granules
Low substituted hydroxypropylcellulose10
Hydroxypropylcellulose 2.5
Crystalline cellulose 15
External
Magnesium stearate 1
excipients
Light anhydrous silicic acid 0.5
Total 100
Example 5
According to the prescription of Table 15, to a mixed powder of
the drug substance (one used in Experiment 1-4 as mentioned above),
lactose, and low substituted hydroxypropylcellulose was sprayed a
solution of hydroxypropylcellulose in purified water to give the granules
(fluid 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 thus obtained had a suitable size and the content
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uniformity and the stability of the drug substance were reserved, and
the dissolution of the drug substance from the tablets was rapid.
Table 15
Weight
Components (mgt
Drug substance 0.5
Lactose
Granules
Low substituted hydroxypropylcellulose12
Hydroxypropylcellulose 3
Crystalline cellulose
External
Magnesium stearate 1.2
excipients
Light anhydrous silicic acid 0.6
Total 120
Example 6
According to the prescription of Table 16, to a mixed powder of
the drug substance (one used in Experiment 1-4 as mentioned above),
lactose, low substituted hydroxypropylcellulose was sprayed a solution
of hydroxypropylcellulose in purified water to give the granules (fluid 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 thus obtained had a suitable size and
the content uniformity and the stability of the drug substance were
reserved, and the dissolution of the drug substance from the tablets was
rapid.
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Table 16
Weight
Components
~mg)
Drug substance 0.5
Lactose 169.39
Granules
Low substituted hydroxypropylcellulose24
Hydroxypropylcellulose
Crystalline cellulose 36
External
Magnesium stearate 2.4
excipients
Light anhydrous silicic acid 1.2
Total 240
Example 7
According to the prescription of Table 17, to a mixed powder of
lactose and low substituted hydroxypropyleellulose was sprayed a
solution of hydroxypropylcellulose in purified water to give the granules
(fluid bed granulation), which were dried and regulated in size to give the
granules of the external excipients.
Table 17
Weight
Components (mg)
Granules Lactose 71
of
External Low substituted hydroxypropylcellulose 10
excipients
Hydroxypropylcellulose 2.5
Total 83. 5
According to the prescription of Table 18, to a mixed powder of
the drug substance (one used in Experiment 1-4 as mentioned above),
lactose, and low substituted hydroxypropylcellulose was sprayed a
solution of hydroxypropylcellulose in purified water to give the granules
(fluid bed granulation), which were dried and regulated in size to give the
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granules. The granules thus obtained were mixed with the 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 containing 0.1 mg of the
5 drug substance each. The tablets thus obtained had a suitable size and
the content uniformity and the stability of the drug substance were
reserved, and the dissolution of the drug substance from the tablets was
rapid.
Table 18
~ Weight
Components (mg)
Drug substance 0.1
Lactose 35.4
Granules
Low substituted hydroxypropylcellulose5
Hydroxypropylcellulose 1.25
Granules of external excipients 58.45
External Crystalline cellulose 18
excipients Magnesium stearate 1.2
Light anhydrous silicic acid 0.6
Total 120
10 Example 8
According to the prescription of Table 19, to a mixed powder of
the drug substance (one used in Experiment 1-4 as mentioned above),
lactose, and low substituted hydroxypropylcellulose was sprayed a
solution of hydroxypropylcellulose in purified water to give the granules
15 (fluid bed granulation), which were dried and regulated 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
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56
acid, and the mixture was compressed to give the tablets containing 0.2
mg of the drug substance each. The tablets thus obtained had a
suitable size and the content uniformity and the stability of the drug
substance were reserved, and the dissolution of the drug substance from
the tablets was rapid.
Table 19
Weight
Components
(mg)
Drug substance 0.2
Lactose 70.8
Granules
Low substituted hydroxypropylcellulose10
Hydroxypropylcellulose 2.5
Granules of external excipients 167
External Crystalline cellulose 45
excipients Magnesium stearate 3
Light anhydrous silicic acid 1.5
Total 300
INDUSTRIAL APPLICABILITY
The crystals of Compound A of the present invention having a
particle size of not larger than 100 um at the cumulative weight
distribution value of 50 % and a particle size of not larger than 200 um
at the cumulative weight distribution value of 95 % (the drug substance
of the present invention) are useful as a starting material for preparation.
The drug substance of the present invention exhibits a potent ~i3-
adrenergic receptor-stimulating activity with excellent adrenoceptor
selectivity, and hence, it is useful in the prophylaxis or treatment of
obesity or diabetic mellitus. The preparation containing the drug
substance of the present invention is an excellent preparation being
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57
characteristic in that the size (volume) of the preparation, the content
uniformity of the drug substance, and the stability of the drug substance
are secured, and that the dissolution of the drug substance therefrom is
rapid.
