U.S. patent application number 16/985177 was filed with the patent office on 2021-04-22 for dihydrate of benzothiophene compound or of a salt thereof, and process for producing the same.
This patent application is currently assigned to OTSUKA PHARMACEUTICAL CO., LTD.. The applicant listed for this patent is OTSUKA PHARMACEUTICAL CO., LTD.. Invention is credited to Ryohei ETO, Yusuke HOSHIKA, Takuma IKEBUCHI, Nobuaki ITO, Shuuji KAWANO, Takuya MINOWA, Kei MORIYAMA, Takayuki NAKAMURA, Tetsuya SATO, Masahiro SOTA, Hidekazu TOYOFUKU, Tatsuya YAMAGUCHI, Hiroshi YAMASHITA.
Application Number | 20210115030 16/985177 |
Document ID | / |
Family ID | 1000005312726 |
Filed Date | 2021-04-22 |
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United States Patent
Application |
20210115030 |
Kind Code |
A1 |
YAMASHITA; Hiroshi ; et
al. |
April 22, 2021 |
DIHYDRATE OF BENZOTHIOPHENE COMPOUND OR OF A SALT THEREOF, AND
PROCESS FOR PRODUCING THE SAME
Abstract
An object of the present invention is to provide a compound that
can be used as a more superior therapeutic agent for central
nervous system diseases. The present invention provides a dihydrate
of
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
or of a salt thereof, and a process for producing the same
Inventors: |
YAMASHITA; Hiroshi; (Osaka,
JP) ; SATO; Tetsuya; (Osaka, JP) ; MINOWA;
Takuya; (Osaka, JP) ; HOSHIKA; Yusuke; (Osaka,
JP) ; TOYOFUKU; Hidekazu; (Osaka, JP) ;
YAMAGUCHI; Tatsuya; (Osaka, JP) ; SOTA; Masahiro;
(Osaka, JP) ; KAWANO; Shuuji; (Osaka, JP) ;
NAKAMURA; Takayuki; (Osaka, JP) ; ETO; Ryohei;
(Osaka, JP) ; IKEBUCHI; Takuma; (Osaka, JP)
; MORIYAMA; Kei; (Osaka, JP) ; ITO; Nobuaki;
(Osaka, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OTSUKA PHARMACEUTICAL CO., LTD. |
Tokyo |
|
JP |
|
|
Assignee: |
OTSUKA PHARMACEUTICAL CO.,
LTD.
Tokyo
JP
|
Family ID: |
1000005312726 |
Appl. No.: |
16/985177 |
Filed: |
August 4, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
16564972 |
Sep 9, 2019 |
|
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|
16985177 |
|
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|
|
15294644 |
Oct 14, 2016 |
10407415 |
|
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16564972 |
|
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14396224 |
Oct 22, 2014 |
9499525 |
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PCT/JP2013/062681 |
Apr 23, 2013 |
|
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15294644 |
|
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|
|
61636920 |
Apr 23, 2012 |
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61791378 |
Mar 15, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0019 20130101;
C07D 409/12 20130101 |
International
Class: |
C07D 409/12 20060101
C07D409/12; A61K 9/00 20060101 A61K009/00 |
Claims
1. A dihydrate of
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
or of a salt thereof.
2. A method for preventing and/or treating a central nervous system
disease comprising a dihydrate of
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
or of a salt thereof as an active ingredient.
3. The method according to claim 2 which is for preventing or
treating a central nervous system disease selected from the group
consisting of schizophrenia, treatment-resistant, refractory and
chronic schizophrenia, emotional disturbance, psychotic disorder,
mood disorder, bipolar disorder, mania, depression, endogenous
depression, major depression, melancholic and treatment-resistant
depression, dysthymic disorder, cyclothymic disorder, anxiety
disorder, somatoform disorder, factitious disorder, dissociative
disorder, sexual disorder, eating disorder, sleep disorder,
adjustment disorder, substance-related disorder, anhedonia,
delirium, cognitive impairment, cognitive impairment associated
with Alzheimer's disease, Parkinson's disease, and other
neurodegenerative diseases, BPSD caused by cognitive impairment,
cognitive impairment in schizophrenia, cognitive impairment caused
by treatment-resistant, refractory or chronic schizophrenia,
vomiting, motion sickness, obesity, migraine, pain, mental
retardation, autism, Tourette's syndrome, tic disorder, attention
deficit hyperactivity disorder, conduct disorder, and Down's
syndrome.
Description
[0001] This application is a continuation of application Ser. No.
16/564,972, filed Sep. 9, 2019, which is a continuation of
application Ser. No. 15/294,644, filed Oct. 14, 2016, now U.S. Pat.
No. 10,407,415, issued Sep. 10, 2019, which is a continuation of
application Ser. No. 14/396,224, filed Oct. 22, 2014, now U.S. Pat.
No. 9,499,525, issued Nov. 22, 2016, which is the National Stage of
PCT/JP2013/062681, filed Apr. 23, 2013, and claims the benefit of
U.S. Provisional Application No. 61/636,920, filed Apr. 23, 2012
and U.S. Provisional Application No. 61/791,378, filed Mar. 15,
2013, all of which are incorporated herein by reference.
TECHNICAL FIELD
[0002] The present invention relates to a dihydrate of a
benzothiophene compound or of a salt thereof, and a process for
producing the same.
BACKGROUND ART
[0003] A heterocyclic compound having a specific substituent or
substituents is known as an active ingredient that has serotonin
uptake inhibitory activity (or serotonin re-uptake inhibitory
activity) in addition to dopamine D.sub.2 receptor partial
agonistic activity (D.sub.2 receptor partial agonistic activity),
serotonin 5-HT.sub.2A receptor antagonistic activity (5-HT.sub.2A
receptor antagonistic activity), and adrenaline .alpha..sub.1
receptor antagonistic activity (.alpha..sub.1 receptor antagonistic
activity) (Patent Literature (PTL) 1). This active ingredient has a
wide therapeutic spectrum for central nervous system diseases
(particularly schizophrenia).
[0004] In the pharmaceutical field, the development of
pharmaceutical preparations that are suitable according to the
severity of disease in various patients in need of treatment,
patient predisposition, and other factors, has been desired.
Although the heterocyclic compound disclosed in the above PTL 1 is
known to have a wide therapeutic spectrum for neurological
diseases, the development of a more effective therapeutic agent is
currently desired.
CITATION LIST
Patent Literature
[0005] PTL 1: JP2006-316052A
SUMMARY OF INVENTION
Technical Problem
[0006] An object of the present invention is to provide a compound
that can be used as a more superior therapeutic agent for central
nervous system diseases.
Solution to Problem
[0007] The present inventors conducted extensive research to
develop a more superior therapeutic agent for central nervous
system diseases. As a result, the inventors found that among the
heterocyclic compounds disclosed in PTL 1, a specific
benzothiophene compound that is in the form of a dihydrate of the
benzothiophene compound or of a salt thereof (hereinafter also
referred to as the "dihydrate of the present invention") can be the
desired therapeutic agent. Further, the present inventors found
that when the dihydrate of the present invention is used as an
intramuscular injection for treating central nervous system
diseases, it functions as a highly effective pharmacologically
active substance.
[0008] The present invention has been accomplished based on this
finding. The present invention provides a novel dihydrate of the
benzothiophene compound represented by Formula (I) or of a salt
thereof, which is in the form of a hydrate, and further provides an
industrially advantageous process for producing the dihydrate.
[0009] The present invention provides a novel dihydrate, a process
for production thereof, and a benzothiophene compound comprising
the dihydrate shown in items 1 to 14. [0010] Item 1. A dihydrate of
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
or of a salt thereof. [0011] Item 2. The dihydrate according to
item 1 which has characteristic peaks at diffraction angles
(2.theta.) of 8.1.degree., 8.9.degree., 15.1.degree., 15.6.degree.,
and 24.4.degree. in an X-ray powder diffraction pattern measured by
copper radiation of .lamda.=1.5418.ANG. through a monochromator.
[0012] Item 3. The dihydrate according to item 1 or 2 which has
characteristic peaks at 3509 cm.sup.-1, 2934 cm.sup.-1, 2812
cm.sup.-1, 1651 cm.sup.-1, 1626 cm.sup.-1, 1447 cm.sup.-1, 1223
cm.sup.-1, and 839 cm.sup.-1 in an infrared absorption spectrum as
measured by a potassium bromide tablet method. [0013] Item 4. The
dihydrate according to any one of items 1 to 3 which has
characteristic peaks at 1497 cm.sup.-1, 1376 cm.sup.-1, 1323
cm.sup.-1, 1311 cm.sup.-1, 1287 cm.sup.-1, 1223 cm.sup.-1, and 781
cm.sup.-1 in a Raman spectrum. [0014] Item 5. The dihydrate
according to any one of items 1 to 4 which contains water in an
amount of 6.5 to 8.8 wt. %. [0015] Item 6. The dihydrate according
to any one of items 1 to 5 which has peaks in a .sup.1H-NMR
spectrum at:
[0016] 1.64 ppm (tt, J=7.4 Hz, J=7.4 Hz, 2H),
[0017] 1.80 ppm (tt, J=7.0 Hz, J=7.0 Hz, 2H),
[0018] 2.44 ppm (t, J=7.5 Hz, 2H),
[0019] 2.62 ppm (br, 4H),
[0020] 3.06 ppm (br, 4H),
[0021] 3.32 ppm (s, 4H +H.sub.2O),
[0022] 4.06 ppm (t, J=6.5 Hz, 2H),
[0023] 6.29 ppm (d, J=9.5 Hz,1H),
[0024] 6.80 ppm (d, J=2.5 Hz, 1H),
[0025] 6.80 ppm (dd, J=2.5 Hz, J=9.0 Hz, 1H),
[0026] 6.88 ppm (d, J=7.5 Hz, 1H),
[0027] 7.27 ppm (dd, J=7.8 Hz, J=7.8 Hz, 1H),
[0028] 7.40 ppm (dd, J=0.5 Hz, J=5.5 Hz, 1H),
[0029] 7.55 ppm (d, J=9.0 Hz, 1H),
[0030] 7.61 ppm (d, J=8.0 Hz, 1H),
[0031] 7.69 ppm (d, J=5.5 Hz, 1H),
[0032] 7.80 ppm (d, J=9.5 Hz, 1H), and
[0033] 11.57 ppm (s, 1H). [0034] Item 7. A process for producing a
dihydrate of
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
or of a salt thereof, the process comprising: [0035] (1) mixing at
least one organic acid selected from the group consisting of acetic
acid and lactic acid, an ethanol-water mixed solution, and
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
to prepare an acid solution; [0036] (2) cooling the solution
obtained in step (1) to 5.degree. C. or less; and [0037] (3) mixing
the solution cooled in step (2) with an alkali to adjust the pH of
the solution to 7 or more. [0038] Item 8. A dihydrate of
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
or of a salt thereof obtained by the process according to item 7.
[0039] Item 9. A benzothiophene compound for use in treating and/or
preventing a central nervous system disease, the compound
comprising the dihydrate according to any one of items 1 to 6 and 8
and an anhydride of
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
or of a salt thereof, and the dihydrate being contained in an
amount of 60 wt. % or more in the compound. [0040] Item 10. A
method for preventing and/or treating a central nervous system
disease comprising the dihydrate according to any one of items 1 to
6 and 8 as an active ingredient. [0041] Item 11. The method
according to item 10 which is for preventing or treating a central
nervous system disease selected from the group consisting of
schizophrenia, treatment-resistant, refractory and chronic
schizophrenia, emotional disturbance, psychotic disorder, mood
disorder, bipolar disorder, mania, depression, endogenous
depression, major depression, melancholic and treatment-resistant
depression, dysthymic disorder, cyclothymic disorder, anxiety
disorder, somatoform disorder, factitious disorder, dissociative
disorder, sexual disorder, eating disorder, sleep disorder,
adjustment disorder, substance-related disorder, anhedonia,
delirium, cognitive impairment, cognitive impairment associated
with Alzheimer's disease, Parkinson's disease, and other
neurodegenerative diseases, BPSD caused by cognitive impairment,
cognitive impairment in schizophrenia, cognitive impairment caused
by treatment-resistant, refractory or chronic schizophrenia,
vomiting, motion sickness, obesity, migraine, pain, mental
retardation, autism, Tourette's syndrome, tic disorder, attention
deficit hyperactivity disorder, conduct disorder, and Down's
syndrome. [0042] Item 12. A dopamine D.sub.2 receptor partial
agonist and/or a 5-HT.sub.2A receptor antagonist and/or a serotonin
uptake inhibitor and/or a serotonin reuptake inhibitor and/or a
.alpha..sub.1 receptor antagonist comprising the dihydrate
according to any one of items 1 to 6 and 8 as an active ingredient.
[0043] Item 13. A pharmaceutical composition comprising the
dihydrate according to any one of items 1 to 6 and 8 and a
pharmaceutically acceptable carrier.
[0044] According to another embodiment of the present invention, a
hydrate of the benzothiophene compound described below is provided.
[0045] Item 14. A hydrate of
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
which has characteristic peaks at diffraction angles (2.theta.) of
7.7.degree., 9.4.degree., 11.8.degree., 18.9.degree., and
24.0.degree. in an X-ray powder diffraction pattern measured by
copper radiation of .lamda.=1.5418.ANG. through a
monochromator.
[0046] The dihydrate of the present invention and the process for
producing the dihydrate are described in detail below.
Process for Producing the Dihydrate of the Benzothiophene Compound
or of a Salt Thereof According to the Present Invention
[0047] The benzothiophene compound referred to in the dihydrate of
the benzothiophene compound or of a salt thereof according to the
present invention is
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
represented by Formula (I).
##STR00001##
[0048] The dihydrate of the benzothiophene compound represented by
Formula (I) or of a salt thereof according to the present invention
can be produced from an anhydride of the benzothiophene compound or
of a salt thereof.
[0049] The benzothiophene compound (in the form of an anhydride) of
Formula (I), from which the dihydrate of the present invention is
produced, is a known compound, and can be obtained by the
production method disclosed in Example 1 of JP2006-316052A or
according to Reference Examples 1 and 2 described below herein.
[0050] The dihydrate of the benzothiophene compound of Formula (I)
or of a salt thereof according to the present invention can be
produced by steps (1) to (3) described above.
[0051] In step (1), at least one organic acid selected from the
group consisting of acetic acid and lactic acid, an ethanol-water
mixed solution, and the benzothiophene compound of Formula (I) (in
the form of an anhydride) is mixed to prepare an acid solution.
[0052] Lactic acid that is used as an organic acid may be D-form,
L-form, or a mixture thereof.
[0053] The ethanol-water mixed solution used in step (1) is
preferably prepared so as to contain ethanol in an amount of about
95 volume % or less, more preferably about 70 volume % or less, and
even more preferably about 60 volume % or less. When the
ethanol-water mixed solution contains ethanol in an amount of 95
volume % or less, a dihydrate of the benzothiophene compound
represented by Formula (I) can be obtained. Although the lower
limit of the amount of ethanol in the solution is not particularly
limited, it is preferably about 20 volume %, and more preferably
about 30 volume %.
[0054] The concentration of the benzothiophene compound of Formula
(I) in the ethanol-water mixed solution is preferably about 0.1 to
30 wt. % (w/w %), more preferably about 0.5 to 20 wt. %, and even
more preferably about 1 to 10 wt. %. When the concentration of the
benzothiophene compound of Formula (I) is set to the aforementioned
range, the benzothiophene compound of Formula (I) can be fully
dissolved in the ethanol-water mixed solution, and a dihydrate with
a higher purity can be obtained by performing the subsequent steps
(steps (2) and (3)) described below.
[0055] The amount of the organic acid in the ethanol-water mixed
solution is not particularly limited insofar as the system can be
adjusted to an acidic condition. For example, the organic acid is
preferably contained in an amount of about 0.1 to 20 wt. %, more
preferably about 0.3 to 10 wt. %, and even more preferably about
0.5 to 5 wt. %.
[0056] The amount of the organic acid is not particularly limited,
insofar as the system can be adjusted to an acidic condition. For
example, the organic acid is preferably contained in an amount of
about 5 to 100 parts by weight, more preferably about 20 to 80
parts by weight, based on 100 parts by weight of the benzothiophene
compound of Formula (I).
[0057] The temperature at which the solution is prepared in step
(1) is not particularly limited insofar as the following conditions
are met: the benzothiophene compound of Formula (I) is dissolved in
a liquid containing the aforementioned organic acid and
ethanol-water mixed solution; ethanol, water, or the organic acid
does not vaporize; and the benzothiophene compound does not
decompose. Specifically, the temperature is preferably about 50 to
120.degree. C., and more preferably about 70 to 100.degree. C. A
reflux temperature (about 80.degree. C.) may be used.
[0058] In step (2), the solution obtained in step (1) is
cooled.
[0059] The cooling temperature is 5.degree. C. or less, preferably
about 0.degree. C. or less, and more preferably -2.degree. C. or
less. When the pH of the solution is adjusted with an alkali in a
subsequent step, heat is generated. Therefore, when the cooling
temperature is higher than 5.degree. C., the yield of the dihydrate
of the present invention tends to be insufficient. The lower limit
of the cooling temperature in step (2) is not particularly limited.
However, in view of the fact that the temperature must be raised in
the subsequent step and that water may be frozen, the lower limit
of the cooling temperature is preferably about -20.degree. C., and
more preferably about -10.degree. C.
[0060] In step (3), the solution cooled in step (2) is mixed with
an alkali to adjust the pH to 7 or more. Examples of the alkali
include sodium hydroxide, potassium hydroxide, and the like.
[0061] For mixing the solution cooled in step (2) with an alkali,
an aqueous alkali solution prepared in advance may be used. The
concentration of the aqueous alkali solution is, for example, about
0.1 to 25 wt. %, and more preferably about 0.5 to 10 wt. %.
[0062] To avoid a rapid temperature rise of the mixed solution in
the system by the addition of an alkali (aqueous solution) as
described above, the alkali (aqueous solution) is preferably
pre-cooled. The temperature of the alkali (aqueous solution) is
preferably about -5 to 15.degree. C., and more preferably about -2
to 5.degree. C.
[0063] The amount of alkali is not particularly limited insofar as
the solution in the system can be adjusted to a pH of 7 or more.
For example, an alkali is preferably added in an amount of about
0.3 to 10 parts by weight, and more preferably about 0.5 to 3 parts
by weight, per part by weight of the organic acid incorporated in
the solution in step (1).
[0064] In step (3), the solution is adjusted with an alkali to a pH
of 7 or more, more preferably about 7.5 or more, and still more
preferably about 8 or more. When the pH is less than 7, the yield
of the dihydrate of the present invention tends to be insufficient.
Although the upper limit of the pH is not particularly limited, it
is preferably, for example, a pH of about 12, and more preferably a
pH of about 10, to facilitate the washing of the precipitated
dihydrate of the present invention and the formation of a salt of
the benzothiophene compound under strongly alkaline conditions.
[0065] By performing steps (1) to (3), the dihydrate of the present
invention is precipitated.
[0066] The precipitated dihydrate of the present invention is
separated into solid and liquid phases by a known method and
purified by washing with water.
[0067] Preferably, the obtained dihydrate of the benzothiophene
compound of Formula (I) or of a salt thereof is heated to about
10.degree. C. or higher, and more preferably about 10 to about
50.degree. C.
Dihydrate of the Benzothiophene Compound of Formula (I) or of a
Salt Thereof
[0068] The physicochemical properties of the dihydrate of the
present invention obtained by the above production process are
shown below.
[0069] The crystalline form of the dihydrate of the present
invention obtained by the above production process may include a
hydrate of the benzothiophene compound or of a salt thereof
obtained by the above production process according to another
embodiment of the present invention.
X-ray Powder Diffraction
[0070] The dihydrate of the present invention is identified by an
X-ray powder diffraction pattern measured by copper radiation of
.lamda.=1.5418.ANG. through a monochromator. The dihydrate of the
present invention has peaks shown in FIG. 2 in the X-ray powder
diffraction pattern, and has characteristic peaks at the following
diffraction angles (2.theta.) in the X-ray powder diffraction
pattern. These peaks are different from the peaks of the known
benzothiophene compound of Formula (I) (in the form of an
anhydride).
[0071] Diffraction Angles (2.theta.)
[0072] 8.1.degree.
[0073] 8.9.degree.
[0074] 15.1.degree.
[0075] 15.6.degree.
[0076] 24.4.degree.
[0077] The dihydrate of the present invention has peaks at the
following diffraction angles (2.theta.) as shown in FIG. 2, in
addition to the aforementioned peaks.
[0078] Diffraction angles (2.theta.)
[0079] 11.6.degree., 12.2.degree., 14.0.degree., 16.3.degree.,
18.1.degree., 18.4.degree., 18.9.degree., 19.5.degree.,
20.5.degree., 21.5.degree., 22.6.degree., 23.3.degree.,
25.0.degree., 26.1.degree., 26.4.degree., 27.1.degree.,
28.1.degree., 28.5.degree., 28.9.degree., 29.8.degree.,
30.4.degree., 30.7.degree., 31.6.degree., 32.9.degree.,
33.9.degree., 34.4.degree., 35.2.degree., 36.0.degree.,
36.7.degree., 37.4.degree., 38.3.degree..
[0080] Although the above diffraction angles (2.theta.) may contain
an error of -0.2 to +0.2.degree. according to the measuring
apparatus, measurement conditions, etc., such a level of error is
within an acceptable range in the present invention.
Infrared Absorption Measurement
[0081] The dihydrate of the present invention is identified by an
infrared absorption spectrum measured by the potassium bromide
tablet method. In the infrared absorption spectrum, the dihydrate
of the present invention has a spectrum shown in FIG. 3, and has
peaks at the following wavenumbers (cm.sup.-1):
[0082] Wavenumbers
[0083] 3509 cm.sup.-1
[0084] 2934 cm.sup.-1
[0085] 2812 cm.sup.-1
[0086] 1651 cm.sup.-1
[0087] 1626 cm.sup.-1
[0088] 1447 cm.sup.-1
[0089] 1223 cm.sup.-1
[0090] 839 cm.sup.-1
[0091] The dihydrate of the present invention has peaks at the
wavenumbers shown in FIG. 3, in addition to the aforementioned
peaks.
[0092] Although the wavenumbers (cm.sup.-1) may contain an error of
-0.5 to +0.5% according to the measuring apparatus, measurement
conditions, etc., such a level of error is within an acceptable
range in the present invention.
[0093] The dihydrate of the present invention is identified by a
Raman spectrum. The dihydrate of the present invention has the
spectrum shown in FIG. 4 and has peaks in the vicinity of the
following wavenumbers (cm.sup.-1):
[0094] Wavenumbers
[0095] 1497 cm.sup.-1
[0096] 1376 cm.sup.-1
[0097] 1323 cm.sup.-1
[0098] 1311 cm.sup.-1
[0099] 1287 cm.sup.-1
[0100] 1223 cm.sup.-1
[0101] 781 cm.sup.-1
[0102] The dihydrate of the present invention has peaks in the
vicinity of the following wavenumbers as shown in FIG. 4, in
addition to the aforementioned peaks:
[0103] Wavenumbers
[0104] 1656 cm.sup.-1, 1613 cm.sup.-1, 1563 cm.sup.-1, 1512
cm.sup.-1, 1468 cm.sup.-1, 1446 cm.sup.-, 1241 cm.sup.-1, 1203
cm.sup.-1, 1145 cm.sup.-1, 1096 cm.sup.-1, 1070 cm.sup.-1, 971
cm.sup.-1, 822 cm.sup.-1
Water content
[0105] The dihydrate of the present invention contains water in an
amount of 6.5 to 8.8 wt. %, and more specifically 7.3 to 8.1 wt. %.
The water content is measured by the Karl Fischer method.
.sup.1H-NMR Measurement
[0106] The dihydrate of the present invention is identified by
peaks measured by .sup.1H-NMR spectroscopy. The dihydrate of the
present invention has the .sup.1H-NMR spectrum shown in FIG. 1, and
has proton peaks in the .sup.1H-NMR spectrum measured in Example 1
below.
[0107] The hydrate of the benzothiophene compound of Formula (I)
according to another embodiment of the present invention is
obtained during the process of producing the dihydrate as described
above. The physicochemical properties of the hydrate are shown
below.
X-ray Powder Diffraction
[0108] The hydrate of the benzothiophene compound of Formula (I)
according to another embodiment of the present invention has peaks
shown in FIG. 10 in an X-ray powder diffraction pattern measured in
the same manner as above, and has characteristic peaks at the
following diffraction angles (2.theta.). These peaks are different
from the peaks of the known benzothiophene compound of Formula (I)
(in the form of an anhydride) in the X-ray powder diffraction
pattern.
[0109] Diffraction Angles (2.theta.)
[0110] 7.7.degree.
[0111] 9.4.degree.
[0112] 11.8.degree.
[0113] 18.9.degree.
[0114] 24.0.degree.
[0115] The hydrate of the benzothiophene compound of Formula (I)
according to another embodiment of the present invention has peaks
at the following diffraction angles (2.theta.) as shown in FIG. 10,
in addition to the aforementioned peaks.
[0116] Diffraction Angles (2.theta.)
[0117] 5.7.degree., 8.1.degree., 8.8.degree., 10.7.degree.,
12.6.degree., 13.6.degree., 13.9.degree., 15.0.degree.,
15.6.degree., 16.6.degree., 17.2.degree., 17.7.degree.,
19.8.degree., 20.4.degree., 21.2.degree., 21.6.degree.,
22.2.degree., 23.1.degree., 25.2.degree., 25.8.degree.,
26.7.degree., 27.2.degree., 27.9.degree., 28.7.degree.,
29.3.degree., 30.2.degree., 31.2.degree., 33.4.degree..
Benzothiophene Compound Containing the Dihydrate of the Present
Invention
[0118] The present invention further provides a benzothiophene
compound comprising a dihydrate of the benzothiophene compound of
Formula (I) or of a salt thereof and an anhydride of the
benzothiophene compound of Formula (I) or of a salt thereof. The
benzothiophene compound can be used as a therapeutic and/or
prophylactic agent for central nervous system diseases.
[0119] The dihydrate of the benzothiophene compound of Formula (I)
or of a salt thereof may consist only of the dihydrate of the
present invention or may be in the form of a mixture of the
dehydrate of the present invention with a hydrate of the
benzothiophene compound of Formula (I) according to another
embodiment of the present invention.
[0120] The benzothiophene compound preferably contains the
dihydrate in an amount of 60 wt. % or more, preferably 80 wt. % or
more, and more preferably 90 wt. % or more.
[0121] The dihydrate of the present invention may be further
pulverized to a desired mean particle diameter. Pulverization
methods that can be used include dry-milling processes and
wet-milling processes. Examples of mills usable in such milling
processes include jet mills, ball mills (e.g., Dyno-Mill), and
other low-energy mills (e.g., roller mills), and high-energy mills.
Examples of high-energy mills include Netzsch mills, DC mills,
planetary mills, and the like. The pulverized dihydrate of the
present invention preferably has a mean particle diameter of about
1 to 10 .mu.m, more preferably about 2 to 8 .mu.m, and even more
preferably about 2 to 6 .mu.m. The pulverized dihydrate is included
within the scope of the dihydrate of the present invention.
[0122] The term "mean particle diameter" as used herein refers to
the volume mean diameter as measured by a laser-light-scattering
(LLS) method. Particle size distribution is measured by an LLS
method, and mean particle diameter is calculated from the particle
size distribution.
[0123] The salt referred to in the dihydrate of the benzothiophene
compound of Formula (I) or of a salt thereof is not particularly
limited insofar as it is a pharmaceutically acceptable salt.
Examples of salts include alkali metal salts (e.g., sodium salts
and potassium salts), alkaline earth metal salts (e.g., calcium
salts and magnesium salts), and like metal salts; ammonium salts,
alkali metal carbonates (e.g., lithium carbonate, potassium
carbonate, sodium carbonate, and cesium carbonate), alkali metal
hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium
hydrogen carbonate, and potassium hydrogen carbonate), alkali metal
hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium
hydroxide, and cesium hydroxide), and like salts of inorganic
bases; tri(lower)alkylamines (e.g., trimethylamine, triethylamine,
and N-ethyldiisopropylamine), pyridine, quinoline, piperidine,
imidazole, picoline, dimethylaminopyridine, dimethylaniline,
N-(lower)alkyl-morpholines (e.g., N-methylmorpholine),
1,5-diazabicyclo[4.3.0]nonene-5 (DBN),
1,8-diazabicyclo[5.4.0]undecene-7 (DBU),
1,4-diazabicyclo[2.2.2]octane (DABCO), and like salts of organic
bases; and hydrochloride, hydrobromate, hydroiodide, sulfate,
nitrate, phosphate, and like salts of inorganic acids; formate,
acetate, propionate, oxalate, malonate, succinate, fumarate,
maleate, lactate, malate, citrate, tartrate, carbonate, picrate,
methanesulfonate, ethanesulfonate, p-toluenesulfonate, glutamate,
and like salts of organic acids. The term "(lower) alkyl" as used
herein refers to an "alkyl having 1 to 6 carbon atoms."
[0124] The dihydrate of the benzothiophene compound of Formula (I)
or of a salt thereof may be pharmaceutically acceptable co-crystals
or co-crystal salts. The term "co-crystal or co-crystal salt" as
used herein means a crystalline material comprised of two or more
unique solids at room temperature, each containing distinctive
physical characteristics (such as structure, melting point, and
heat of fusion). Co-crystals and co-crystal salts can be produced
according to known co-crystallization methods.
Pharmaceutical Preparation Containing the Dihydrate of the Present
Invention
[0125] The dihydrate of the present invention is usable as a
pharmaceutical preparation for treating central nervous system
diseases.
[0126] The pharmaceutical preparation is used in the form of an
ordinary pharmaceutical preparation, and is prepared using various
generally used diluents and excipients, such as fillers, extenders,
binders, moisturizing agents, disintegrators, surfactants,
lubricants, etc. The form of such a pharmaceutical preparation can
be selected according to the purpose of the therapy. Typical
examples include tablets, pills, powders, solutions, suspensions,
emulsions, granules, capsules, suppositories, injections
(solutions, suspensions, etc.) and the like.
[0127] To form tablets, any of various carriers conventionally
known in this field can be used. Examples thereof include lactose,
white sugar, sodium chloride, glucose, urea, starch, calcium
carbonate, kaolin, crystalline cellulose, silicic acid, and other
excipients; water, ethanol, propanol, simple syrup, glucose
solutions, starch solutions, gelatin solutions,
carboxymethylcellulose, shellac, methylcellulose, potassium
phosphate, polyvinylpyrrolidone and other binders; dry starch,
sodium alginate, agar powder, laminarin powder, sodium hydrogen
carbonate, calcium carbonate, fatty acid esters of polyoxyethylene
sorbitan, sodium lauryl sulfate, stearic acid monoglycerides,
starch, lactose, and other disintegrators; white sugar, stearin,
cacao butter, hydrogenated oils, and other disintegration
inhibitors; quaternary ammonium bases, sodium lauryl sulfate, and
other absorption promoters; glycerol, starch, and other
moisturizing agents; starch, lactose, kaolin, bentonite, colloidal
silicic acid, and other adsorbents; purified talc, stearates, boric
acid powder, polyethylene glycol, and other lubricants; etc.
Further, such tablets may be coated with typical coating materials
as required, to prepare, for example, sugar-coated tablets,
gelatin-coated tablets, enteric-coated tablets, film-coated
tablets, double- or multi-layered tablets, etc.
[0128] To form pills, any of various carriers conventionally known
in this field can be used. Examples thereof include glucose,
lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin,
talc, and other excipients; powdered acacia, powdered tragacanth,
gelatin, ethanol, and other binders; laminarin, agar, and other
disintegrators; etc.
[0129] To form suppositories, any of various carriers
conventionally known in this field can be used. Examples thereof
include polyethylene glycol, cacao butter, higher alcohols, esters
of higher alcohols, gelatin, semi synthetic glycerides, etc.
[0130] Capsules can be prepared by mixing the active ingredient
with an above-mentioned carrier and enclosing the result in a hard
gelatin capsule, soft capsule, or the like.
[0131] To form injectable preparations, a solution, emulsion or
suspension is sterilized and preferably made isotonic to blood. Any
of the diluents widely used for such forms in this field can be
employed to form the injectable preparation. Examples of such
diluents include water, ethanol, macrogol, propylene glycol,
ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol,
fatty acid esters of polyoxyethylene sorbitan, etc.
[0132] In this case, the pharmaceutical preparation may contain
sodium chloride, glucose or glycerol in an amount sufficient to
prepare an isotonic solution, and may contain conventional
solubilizers, buffers, analgesic agents, etc. Further, if
necessary, the pharmaceutical preparation may contain coloring
agents, preservatives, fragrances, flavors, sweetening agents,
etc., and/or other medicines.
[0133] The amount of the dihydrate of the present invention
contained in the pharmaceutical preparation is not limited, and can
be suitably selected from a wide range. The amount is generally
about 1 to 70% by weight, and preferably about 1 to 30% by weight
of the pharmaceutical preparation.
[0134] The route of administration of the pharmaceutical
preparation of the present invention is not particularly limited,
and the preparation is administered by a route suitable to the form
of the preparation, the patient's age, sex and other conditions,
and the status of the disease. For example, tablets, pills,
solutions, suspensions, emulsions, granules and capsules are
administered orally. Injectable preparations are intravenously
administered singly or mixed with typical injection transfusions,
such as glucose solutions, amino acid solutions or the like, or
singly administered intramuscularly, intracutaneously,
subcutaneously or intraperitoneally, as required. Suppositories are
administered intrarectally.
[0135] The dosage of the pharmaceutical preparation of the present
invention is suitably selected according to the method of use, the
patient's age, sex and other conditions, and the severity of the
disease. The amount of active ingredient is usually about 0.1 to 10
mg/kg body weight/day. Further, it is desirable that the
pharmaceutical preparation in each unit of the administration form
contain the active ingredient in an amount of about 1 to 200
mg.
[0136] Specific examples of the central nervous system diseases
treated by the pharmaceutical preparation containing the dihydrate
of the present invention include schizophrenia, such as
treatment-resistant, refractory and chronic schizophrenia,
emotional disturbance, psychotic disorder, mood disorder, bipolar
disorder (e.g., bipolar I disorder and bipolar II disorder), mania,
depression, endogenous depression, major depression, melancholic
and treatment-resistant depression, dysthymic disorder, cyclothymic
disorder, anxiety disorder (e.g., panic attack, panic disorder,
agoraphobia, social phobia, obsessive-compulsive disorder, post
traumatic stress disorder, generalized anxiety disorder, and acute
stress disorder), somatoform disorder (e.g., hysteria, somatization
disorder, conversion disorder, pain disorder, and hypochondria),
factitious disorder, dissociative disorder, sexual disorder (e.g.,
sexual dysfunction, libido disorder, sexual arousal disorder, and
erectile dysfunction), eating disorder (e.g., anorexia nervosa and
bulimia nervosa), sleep disorder, adjustment disorder,
substance-related disorder (e.g., alcohol abuse, alcohol
intoxication and drug addiction, amphetamine addiction, and
narcotism), anhedonia (e.g., iatrogenic anhedonia, anhedonia of a
psychic or mental cause, anhedonia associated with depression,
anhedonia associated with schizophrenia), delirium, cognitive
impairment, cognitive impairment associated with Alzheimer's
disease, Parkinson's disease, and other neurodegenerative diseases,
BPSD (Behavioral and Psychological Symptoms of Dementia) caused by
cognitive impairment, cognitive impairment in schizophrenia,
cognitive impairment caused by treatment-resistant, refractory or
chronic schizophrenia, vomiting, motion sickness, obesity,
migraine, pain, mental retardation, autistic disorder (autism),
Tourette's syndrome, tic disorder, attention deficit hyperactivity
disorder, conduct disorder, Down's syndrome, etc.; and various
other central nervous system diseases. The pharmaceutical
preparation containing the dihydrate of the benzothiophene compound
is extremely effective for the amelioration of these central
nervous system diseases.
Advantageous Effects of Invention
[0137] The present invention provides a novel dihydrate of the
benzothiophene compound represented by Formula (I) or of a salt
thereof. The present invention also enables the production of a
desired dihydrate in an industrially advantageous manner by
employing a specific manufacturing method for the benzothiophene
compound represented by Formula (I) or a salt thereof.
[0138] Furthermore, the present invention is advantageous in that
when the dihydrate is used as a drug, its pharmacological effect
can be remarkably retained after administration to a patient.
[0139] When the dihydrate of the present invention is used as the
active ingredient of an intramuscular injectable preparation,
stimulation after intramuscular injection is low and thus
effective.
BRIEF DESCRIPTION OF DRAWINGS
[0140] FIG. 1 shows the .sup.1H-NMR spectrum of the dihydrate of
the benzothiophene compound represented by Formula (I) prepared in
Example 1.
[0141] FIG. 2 shows the X-ray powder diffraction pattern of the
dihydrate of the benzothiophene compound represented by Formula (I)
prepared in Example 1.
[0142] FIG. 3 shows the infrared absorption spectrum of the
dihydrate of the benzothiophene compound represented by Formula (I)
prepared in Example 1.
[0143] FIG. 4 shows the Raman spectrum of the dihydrate of the
benzothiophene compound represented by Formula (I) prepared in
Example 1.
[0144] FIG. 5 shows the .sup.1H-NMR spectrum of the benzothiophene
compound represented by Formula (I) prepared in Example 2.
[0145] FIG. 6 shows the X-ray powder diffraction pattern of the
dihydrate of the benzothiophene compound represented by Formula (I)
prepared in Example 2.
[0146] FIG. 7 shows the infrared absorption spectrum of the
dihydrate of the benzothiophene compound represented by Formula (I)
prepared in Example 2.
[0147] FIG. 8 shows the Raman spectrum of the dihydrate of the
benzothiophene compound represented by Formula (I) prepared in
Example 2.
[0148] FIG. 9 shows the Raman spectrum of the dihydrate of the
benzothiophene compound represented by Formula (I) prepared in
Example 3.
[0149] FIG. 10 shows the X-ray powder diffraction pattern of the
dihydrate of the benzothiophene compound represented by Formula (I)
prepared in Reference Example 3.
[0150] FIG. 11 shows the .sup.1H-NMR spectrum of the anhydride of
the benzothiophene compound represented by Formula (I) prepared in
Comparative Example 1.
[0151] FIG. 12 shows the X-ray powder diffraction pattern of the
anhydride of the benzothiophene compound prepared in Comparative
Example 1.
[0152] FIG. 13 shows the infrared absorption spectrum of the
anhydride of the benzothiophene compound prepared in Comparative
Example 1.
[0153] FIG. 14 is a graph showing the mean blood concentration-time
profile of Compound (I) after being injected into the thigh muscle
of a dog.
DESCRIPTION OF EMBODIMENTS
EXAMPLES
[0154] The present invention is described in further detail with
reference to Examples and Test Examples. However, the scope of the
invention is not limited to these Examples.
Reference Example 1
Synthesis of 7-(4-chlorobutoxy)-1H-quinolin-2-one
[0155] Methanol (149 L), 7-hydroxy-1H-quinolin-2-one (14.87 kg),
and potassium hydroxide (6.21 kg) were mixed and stirred. After
dissolution, 1-bromo-4-chlorobutane (47.46 kg) was further added
thereto and the resulting mixture was stirred under reflux for
seven hours. Thereafter, the mixture was stirred at 10.degree. C.
for one hour. The precipitated crystal was centrifuged and washed
with methanol (15 L). The wet crystal was collected and placed in a
tank. Water (149 L) was added thereto, followed by stirring at room
temperature. After centrifugation, the resulting solid was washed
with water (30 L). The wet crystal was collected and placed in a
tank. After adding methanol (74 L), the mixture was stirred under
reflux for one hour, cooled to 10.degree. C., and then stirred. The
precipitated crystal was centrifuged and washed with methanol (15
L). The separated crystal was dried at 60.degree. C. to obtain
7-(4-chlorobutoxy)-1H-quinolin-2-one (15.07 kg).
Reference Example 2
Synthesis of
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
[0156] Water (20 L), potassium carbonate (1.84 kg),
1-benzo[b]thiophen-4-yl-piperazine hydrochloride (3.12 kg), and
ethanol (8 L) were mixed and stirred at 50.degree. C.
7-(4-Chlorobutoxy)-1H-quinolin-2-one (2.80 kg) obtained in
Reference Example 1 was added to the mixture and stirred under
reflux for nine hours. After concentrating the solvent (8 L) under
ordinary pressure, the mixture was stirred at 90.degree. C. for one
hour and then cooled to 9.degree. C. The precipitated crystal was
centrifuged and then sequentially washed with water (8 L) and
ethanol (6 L). The separated crystal was dried at 60.degree. C. to
obtain a crude product. The crude product (4.82 kg) and ethanol (96
L) were mixed in a reaction vessel, and acetic acid (4.8 L) was
introduced into the reaction vessel. The mixture was stirred under
reflux for one hour to dissolve the crude product. After
introducing hydrochloric acid (1.29 kg), the mixture was cooled to
10.degree. C. The mixture was heated again, refluxed for one hour,
and cooled to 7.degree. C. The precipitated crystal was centrifuged
and washed with ethanol (4.8 L). The separated crystal was dried at
60.degree. C. to obtain
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
hydrochloride (5.09 kg). The resulting
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
hydrochloride (5.00 kg), ethanol (45 L), and water (30 L) were
mixed in a reaction vessel. The mixture was stirred under reflux to
dissolve the
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
hydrochloride. Activated carbon (500 g) and water (5 L) were added
thereto, and an activated carbon treatment was conducted under
reflux for 30 minutes. After performing hot filtration, a solution
containing sodium hydroxide (511 g) dissolved in water (1.5 L) was
flowed into the reaction vessel while stirring the filtrate under
reflux. After stirring under reflux for 30 minutes, water (10 L)
was introduced thereto and the mixture was cooled to approximately
40.degree. C. The precipitated crystal was centrifuged and washed
with water (125 L). The separated crystal was dried at 80.degree.
C. to obtain
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
(3.76 kg).
Example 1
[0157] Preparation of
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
dihydrate
[0158] The
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinoli-
n-2-one (3.2 kg) obtained in Reference Example 2, ethanol (64 L),
water (74 L), and acetic acid (1.77 kg) were mixed in a reaction
vessel to prepare an acidic liquid mixture. The mixture was stirred
under reflux to dissolve the
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
(reflux temperature: 84.degree. C.). After cooling to -5.degree.
C., the solution obtained above was introduced, over a period of 30
minutes, into a solution containing 25% sodium hydroxide (5.9 kg)
and water (54 L) that was cooled to 0.degree. C., to prepare a
liquid mixture with pH10. After being stirred at 5.degree. C. or
below for one hour, the mixture was heated to 20 to 30.degree. C.
and further stirred for seven hours. The precipitated crystal was
filtered and washing with water (320 L) was performed until alkali
in the solid component disappeared (i.e., until the pH value of the
filtrate became 7). The solid component was then air-dried until
its weight became constant to obtain a white solid
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
dihydrate (unground, 3.21 kg).
[0159] FIG. 1 shows the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) of
the dihydrate prepared by the aforesaid method. As shown in FIG. 1,
in the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS), peaks were
observed at 1.64 ppm (tt, J=7.4 Hz, J=7.4 Hz, 2H), 1.80 ppm (tt,
J=7.0 Hz, J=7.0 Hz, 2H), 2.44 ppm (t, J=7.5 Hz, 2H), 2.62 ppm (br,
4H), 3.06 ppm (br, 4H), 3.32 ppm (s, 4H+H.sub.2O), 4.06 ppm (t,
J=6.5 Hz, 2H), 6.29 ppm (d, J=9.5 Hz, 1H), 6.80 ppm (d, J=2.5 Hz,
1H), 6.80 ppm (dd, J=2.5 Hz, J=9.0 Hz, 1H), 6.88 ppm (d, J=7.5 Hz,
1H), 7.27 ppm (dd, J=7.8 Hz, J=7.8 Hz, 1H), 7.40 ppm (dd, J=0.5 Hz,
J=5.5 Hz, 1H), 7.55 ppm (d, J=9.0 Hz, 1H), 7.61 ppm (d, J=8.0 Hz,
1H), 7.69 ppm (d, J=5.5 Hz, 1H), 7.80 ppm (d, J=9.5 Hz, 1H), and
11.57 ppm (s, 1H).
[0160] The X-ray powder diffraction spectrum of the dihydrate
prepared by the aforesaid method was measured using an X-ray
diffractometer (D8 ADVANCE, available from Bruker AXS). FIG. 2
shows the X-ray powder diffraction spectrum. As shown in FIG. 2, in
the X-ray powder diffraction spectrum, diffraction peaks were
observed at 2.theta.=8.1.degree., 8.9.degree., 15.1.degree.,
15.6.degree., and 24.4.degree.. Other than those mentioned above,
the diffraction peaks were also observed at 2.theta.=11.6.degree.,
12.2.degree., 14.0.degree., 16.3.degree., 18.1.degree.,
18.4.degree., 18.9.degree., 19.5.degree., 20.5.degree.,
21.5.degree., 22.6.degree., 23.3.degree., 25.0.degree.,
26.1.degree., 26.4.degree., 27.1.degree., 28.1.degree.,
28.5.degree., 28.9.degree., 29.8.degree., 30.4.degree.,
30.7.degree., 31.6.degree., 32.9.degree., 33.9.degree.,
34.4.degree., 35.2.degree., 36.0.degree., 36.7.degree.,
37.4.degree., and 38.3.degree..
[0161] The IR (KBr) spectrum of the dihydrate prepared by the
aforesaid method was measured. FIG. 3 shows the IR (KBr) spectrum.
As shown in FIG. 3, in the IR (KBr) spectrum, absorption bands were
observed in the vicinity of wavenumbers 3509 cm.sup.-1, 2934
cm.sup.-1, 2812 cm.sup.-1, 1651 cm.sup.-1, 1626 cm.sup.-1, 1447
cm.sup.-1, 1223 cm.sup.-1 and 839 cm.sup.-1.
[0162] The Raman spectrum of the dihydrate prepared by the
aforesaid method was measured. FIG. 4 shows the Raman spectrum. As
shown in FIG. 4, in the Raman spectrum, absorption bands were
observed in the vicinity of wavenumbers 1497 cm.sup.-1, 1376
cm.sup.-1, 1323 cm.sup.-1, 1311 cm.sup.-1, 1287 cm.sup.-1, 1223
cm.sup.-1, and 781 cm.sup.-1.
[0163] Other than those mentioned above, absorption was also
observed in the vicinity of wavenumbers 1656 cm.sup.-1, 1613
cm.sup.-1, 1563 cm.sup.-1, 1512 cm.sup.-1, 1468 cm.sup.-1, 1446
cm.sup.-1, 1241 cm.sup.-1, 1203 cm.sup.-1, 1145 cm.sup.-1, 1096
cm.sup.-1, 1070 cm.sup.-1, 971 cm.sup.-1, and 822 cm.sup.-1.
[0164] The water content of the dihydrate prepared by the aforesaid
method was measured using a moisture meter (CA-100, available from
Mitsubishi Chemical Analytech Co., Ltd.) by the Karl Fischer
method. As a result, the dihydrate had a water content of 7.79% by
weight.
Example 2
Preparation of Finely Ground Dihydrate
[0165] Dihydrate crystal (2.73 kg) obtained in Example 1 was ground
using a jet mill. Here, the air pressure was set at 5 kgf/cm.sup.2,
and the rotational speed of the feeder was set at 20 rpm. As a
result, finely ground
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-
-one dihydrate (2.61 kg, 95.6%) was obtained.
[0166] The dihydrate (finely ground product) thus obtained had a
mean particle diameter of 5.5 .mu.m. The mean particle diameter was
measured using a Microtrack HRA, manufactured by Nikkiso Co.,
Ltd.
[0167] FIG. 5 shows the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) of
the dihydrate prepared by the above method. As shown in FIG. 5, in
the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS), peaks were observed
at 1.64 ppm (tt, J=7.3 Hz, J=7.3 Hz, 2H), 1.80 ppm (tt, J=6.9 Hz,
J=6.9 Hz, 2H), 2.44 ppm (t, J=7.3 Hz, 2H), 2.62 ppm (br, 4H), 3.06
ppm (br, 4H), 3.32 ppm (s, 4H+H.sub.2O), 4.06 ppm (t, J=6.5 Hz,
2H), 6.29 ppm (d, J=9.5 Hz, 1H), 6.80 ppm (d, J=2.5 Hz, 1H), 6.80
ppm (dd, J=2.3 Hz, J=9.3 Hz, 1H), 6.88 ppm (d, J=7.5 Hz, 1H), 7.27
ppm (dd, J=8.0 Hz, J=8.0 Hz, 1H), 7.40 ppm (d, J=5.5 Hz, 1H), 7.55
ppm (d, J=9.5 Hz, 1H), 7.61 ppm (d, J=8.0 Hz, 1H), 7.69 ppm (d,
J=5.5 Hz, 1H), 7.80 ppm (d, J=9.5 Hz, 1H), and 11.57 ppm (s,
1H).
[0168] The X-ray powder diffraction spectrum of the dihydrate
prepared by the aforesaid method was measured in the same manner as
in Example 1. FIG. 6 shows the X-ray powder diffraction spectrum.
As shown in FIG. 6, in the X-ray powder diffraction spectrum,
diffraction peaks were observed at 2.theta.=8.2.degree.,
8.9.degree., 15.2.degree., 15.7.degree. and 24.4.degree..
[0169] Other than those mentioned above, the diffraction peaks were
also observed at 2.theta.=6.8.degree., 12.2.degree., 14.0.degree.,
14.5.degree., 17.4.degree., 18.1.degree., 18.5.degree.,
19.0.degree., 19.2.degree., 19.6.degree., 20.3.degree.,
20.6.degree., 21.5.degree., 22.7.degree., 23.4.degree.,
25.0.degree., 26.1.degree., 27.1.degree., 28.6.degree.,
29.0.degree., 30.4.degree., 34.0.degree., 34.5.degree.,
35.3.degree., and 36.7.degree..
[0170] The IR (KBr) spectrum of the dihydrate prepared by the
aforesaid method was measured in the same manner as in Example 1.
FIG. 7 shows the IR (KBr) spectrum. As shown in FIG. 7, in the IR
(KBr) spectrum, absorption bands were observed in the vicinity of
wavenumbers 3507 cm.sup.-1, 2936 cm.sup.-1, 2812 cm.sup.-1, 1651
cm.sup.-1, 1626 cm.sup.-1, 1447 cm.sup.-1, 1223 cm.sup.-1 and 839
cm.sup.-1.
[0171] The Raman spectrum of the dihydrate prepared by the
aforesaid method was measured. FIG. 8 shows the Raman spectrum. As
shown in FIG. 8, in the Raman spectrum, absorption bands were
observed in the vicinity of wavenumbers 1496 cm.sup.-1, 1376
cm.sup.-1, 1323 cm.sup.-1, 1311 cm.sup.-1, 1286 cm.sup.-1, 1223
cm.sup.-1, and 781cm.sup.31 1.
[0172] Other than those mentioned above, absorption was also
observed in the vicinity of wavenumbers 1656 cm.sup.-1, 1614
cm.sup.-1, 1563 cm.sup.-1, 1512 cm.sup.-1, 1467 cm.sup.-1, 1446
cm.sup.-1, 1241 cm.sup.-1, 1203 cm.sup.-1, 1145 cm.sup.-1, 1095
cm.sup.-1, 1069 cm.sup.-1, 971 cm.sup.-1, and 822 cm.sup.-1.
[0173] The water content of the dihydrate prepared by the aforesaid
method was measured using a moisture meter (CA-100, available from
Mitsubishi Chemical Analytech Co., Ltd.) by the Karl Fischer
method. As a result, the dihydrate had a water content of 6.74% by
weight.
Example 3
Preparation of
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
dihydrate
[0174]
7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2--
one (5.0 kg), ethanol (100 L), water (115 L), and DL-lactic acid
(2.29 kg) were mixed to prepare an acidic liquid mixture. The
liquid mixture was stirred under reflux to dissolve the
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
(reflux temperature: 82.degree. C.). After cooling to -5.degree.
C., the solution obtained above was introduced, over a period of
about 15 minutes, into a solution containing sodium hydroxide (1.48
kg) and water (135 L) that was cooled to 1.degree. C., to prepare a
liquid mixture with pH11. After being stirred at approximately 2 to
5.degree. C. for three hours, the mixture was heated to 45.degree.
C. and further stirred at 45 to 50.degree. C. for two hours. The
precipitated crystal was filtered and washing with water (200 L)
was performed until alkali in the solid component disappeared
(i.e., until the pH value of the filtrate became 7). The solid
component was further washed with a liquid mixture of ethanol (15
L) and water (20 L). The solid component was then dried at room
temperature until its weight became constant to obtain a white
solid
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
dihydrate (unground, 5.11 kg).
[0175] The dihydrate thus obtained was the same as that obtained in
Example 1.
[0176] The Raman spectrum of the dihydrate prepared by the
aforesaid method was measured. FIG. 9 shows the Raman spectrum. As
shown in FIG. 9, in the Raman spectrum, absorption bands were
observed in the vicinity of wavenumbers 1497 cm.sup.-1, 1376
cm.sup.-1, 1323 cm.sup.-1, 1311 cm.sup.-1, 1287 cm.sup.-1, 1223
cm.sup.-1, and 782 cm.sup.-1.
[0177] Other than those mentioned above, absorption was also
observed in the vicinity of wavenumbers 1656 cm.sup.-1, 1614
cm.sup.-1, 1563 cm.sup.-1, 1512 cm.sup.-1, 1468 cm.sup.-1, 1446
cm.sup.-1, 1241 cm.sup.-1, 1203 cm.sup.-1, 1145 cm.sup.-1, 1126
cm.sup.-1, 1096 cm.sup.-1, 1070 cm.sup.-1, 972 cm.sup.-1, and 822
cm.sup.-1.
Reference Example 3
[0178]
7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2--
one anhydride (7 g), ethanol (140 mL), water (161 mL), and lactic
acid (2.7 mL) were mixed in a reaction vessel. The mixture was
heated to reflux while being stirred to dissolve the
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
anhydride. After being cooled to approximately -10.degree. C., the
solution obtained above was introduced, while being stirred, into a
solution containing sodium hydroxide (2.1 g) and water (189 mL)
that was cooled to approximately 0.degree. C. After being stirred
at a temperature of approximately 0.degree. C. for 3 hours,
solid-liquid separation was performed.
[0179] The X-ray powder diffraction spectrum of the hydrate
prepared by the aforesaid method was measured in the same manner as
in Example 1. FIG. 10 shows the X-ray powder diffraction spectrum.
In the X-ray powder diffraction spectrum, diffraction peaks were
observed at 2.theta.=7.7.degree., 9.4.degree., 11.8.degree.,
18.9.degree., and 24.0.degree.. Other than those mentioned above,
diffraction peaks were also observed at 2.theta.=5.7.degree.,
8.1.degree., 8.8.degree., 10.7.degree., 12.6.degree., 13.6.degree.,
13.9.degree., 15.0.degree., 15.6.degree., 16.6.degree.,
17.2.degree., 17.7.degree., 19.8.degree., 20.4.degree.,
21.2.degree., 21.6.degree., 22.2.degree., 23.1.degree.,
25.2.degree., 25.8.degree., 26.7.degree., 27.2.degree.,
27.9.degree., 28.7.degree., 29.3.degree., 30.2.degree.,
31.2.degree., and 33.4.degree..
Comparative Example 1
Preparation of
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
anhydride
[0180] The
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinoli-
n-2-one (700 g) prepared in Reference Example 2, ethanol (14 L),
and acetic acid (1.4 L) were mixed in a reaction vessel. The
mixture was heated to the reflux temperature (76.degree. C.) to
dissolve
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one.
Concentrated hydrochloric acid (158 mL) was further added thereto
and then cooled to 10.degree. C. while being stirred. Thereafter,
the mixture was heated again, stirred under reflux for one hour,
and then cooled to 8.degree. C. The precipitated solid was filtered
by suction and washed with ethanol (0.7 L). The solid component was
then dried at 60.degree. C. until its weight became constant to
obtain a white solid
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
hydrochloride (814 g).
7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
hydrochloride (800 g), ethanol (7.2 L), and water (4.8 L) were
mixed in a reaction vessel, and the mixture was heated to the
reflux temperature (80.degree. C.) while being stirred. After
performing hot filtration, the mixture was heated again to
78.degree. C., and the crystal precipitated in the filtrate was
dissolved. A solution containing sodium hydroxide (81.6 g)
dissolved in water (240 mL) was flowed into the above-obtained
solution and the mixture was stirred under reflux for 30 minutes.
Water (2.4 L) was added to the mixture, followed by cooling to
40.degree. C. while being stirred. The precipitated solid was
filtered and washed with water (16 L). The solid was dried at
80.degree. C. to obtain a white solid
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2--
one anhydride (637 g).
[0181] The .sup.1H-NMR spectrum of the anhydride obtained above was
measured in the same manner as in Example 1. FIG. 11 shows the
.sup.1H-NMR spectrum (DMSO-d.sub.6, TMS). As shown in FIG. 11, in
the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS), peaks were observed
at 1.63 ppm (tt, J=7.3 Hz, J=7.1 Hz, 2H), 1.80 ppm (tt, J=7.3 Hz,
J=6.3 Hz, 2H), 2.44 ppm (t, J=7.1 Hz, 2H), 2.61 ppm (m, 4H), 3.05
ppm (m, 4H), 4.05 ppm (t, J=6.3 Hz, 2H), 6.29 ppm (d, J=9.5 Hz,
1H), 6.80 ppm (d, J=2.5 Hz, 1H), 6.80 (dd, J=9.4 Hz, J=2.5 Hz, 1H),
6.88 ppm (dd, J=7.8 Hz, 0.8 Hz, 1H), 7.27 ppm (dd, J=7.8 Hz, J=7.8
Hz, 1H), 7.39 ppm (dd, J=5.6 Hz, 0.8 Hz, 1H), 7.55 ppm (d, J=9.4
Hz, 1H), 7.61 ppm (d, J=7.8 Hz, 1H), 7.69 ppm (d, J=5.6 Hz, 1H),
7.80 ppm (d, J=9.5 Hz, 1H), and 11.60 (s, 1H).
[0182] The X-ray powder diffraction spectrum of the anhydride
obtained above was measured in the same manner as in Example 1.
FIG. 12 shows the X-ray powder diffraction spectrum. As shown in
FIG. 12, in the X-ray powder diffraction spectrum, diffraction
peaks were observed at 2.theta.=14.4.degree., 19.1.degree.,
20.2.degree., 21.3.degree., and 23.2.degree..
[0183] The IR (KBr) spectrum of the anhydride obtained above was
measured in the same manner as in Example 2. FIG. 13 shows the IR
(KBr) spectrum. As shown in FIG. 13, the
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one
had absorption bands in the IR (KBr) spectrum in the vicinity of
wavenumbers 2941 cm.sup.-1, 2818 cm.sup.-1, 1655 cm.sup.-1, 1624
cm.sup.-1, 1449 cm.sup.-1, 1221 cm.sup.-1, and 833 cm.sup.-1.
[0184] The water content of the anhydride prepared by the aforesaid
method was measured in the same manner as in Example 2. The result
revealed that the anhydride that was obtained had a water content
of 0.04% by weight.
Test Example 1
Measurement of Drug Residue in Muscle
[0185] The dihydrate of the present invention (150 mg) was
dispersed to the suspension medium (1 mL) described below, and
pulverized using 5 mm zirconia beads (1.2 g, pulverization time: 30
min) while being stirred with a stirrer. The suspension medium used
for pulverization was a solution containing 0.832% (w/v) sodium
carboxymethylcellulose (CMC-Na), 4.16% (w/v) mannitol, and 0.074%
(w/v) sodium dihydrogenphosphatemonohydrate. The pH thereof was
adjusted to 7.0 by adding an appropriate amount of sodium
hydroxide. The concentration of each preparation was adjusted to
100 mg/mL using this medium.
[0186] The dihydrate (finely ground product) thus obtained had a
mean particle diameter of 3.5 .mu.m. An anhydride was subjected to
pulverization in the same manner to obtain an anhydride (finely
ground product) having a mean particle diameter of 3.5 .mu.m. The
mean particle diameter was measured using a laser diffraction
particle size analyzer (SAUD-3000) or SALD-3100, manufactured by
Shimadzu Corporation).
[0187] Injectable preparations each containing the dihydrate of the
present invention (finely ground product, mean particle diameter:
3.5 .mu.m) or an anhydride (finely ground product, mean particle
diameter: 3.5 .mu.m) were obtained by the procedure described
above. Table 1 shows the formulations thereof.
[0188] Each injectable preparation thus obtained was
intramuscularly injected into a rat in a dosage of 25 mg/kg. Each
injectable preparation was injected into three rats. 56 days after
the injection, the rats were dissected, and the number of rats
exhibiting drug residue in muscle was counted. Table 2 shows the
results.
TABLE-US-00001 TABLE 1 Formulations Active ingredient 100 mg Sodium
8.32 mg carboxymethylcellulose Mannitol 41.6 mg Sodium 0.74 mg
dihydrogenphosphate monohydrate Sodium hydroxide Q.S. (adjusted to
pH7) Distilled water Q.S. Total 1 mL
TABLE-US-00002 TABLE 2 The number having residue in muscle (Number
having Active ingredient residue/Total) Dihydrate 3/3 Anhydride
0/3
Test Example 2
Pharmacokinetics Test Using a Dog
[0189] Injectable preparations containing the dihydrate of the
present invention as an active ingredient were formulated as shown
in Table 3. Each of the injectable preparations was injected into
the thigh muscle of a dog in such a dosage that 10 mg/kg of active
ingredient calculated as the anhydride of the present invention was
contained. FIG. 14 is a graph showing the mean blood
concentration-time profile after the injection. As is clear from
FIG. 14, the sustained release property can be stably maintained
for more than 30 days from the injection. Stimulation at the
injection site was observed 7 days after the injection and the
results showed that the stimulation was low.
TABLE-US-00003 TABLE 3 Test Example 2 Component Amount (mg)
Dihydrate of the present invention 108 Sorbitol 50 Sodium
carboxymethylcellulose 10 Sodium dihydrogenphosphate dihydrate 0.78
Benzyl benzoate 1 Polysorbate 80 2 Sodium hydroxide Q.S. (pH 7.0)
Injection water Q.S. Total 1 mL
* * * * *