U.S. patent application number 15/595039 was filed with the patent office on 2017-11-02 for novel form of pyrimidine compound having dibenzylamine structure.
This patent application is currently assigned to KOWA COMPANY, LTD.. The applicant listed for this patent is KOWA COMPANY, LTD.. Invention is credited to Taichi KUSAKABE, Kennosuke MATSUDA, Tadaaki OHGIYA, Kimiyuki SHIBUYA, Koichi YAMAZAKI.
Application Number | 20170313664 15/595039 |
Document ID | / |
Family ID | 51988925 |
Filed Date | 2017-11-02 |
United States Patent
Application |
20170313664 |
Kind Code |
A1 |
YAMAZAKI; Koichi ; et
al. |
November 2, 2017 |
NOVEL FORM OF PYRIMIDINE COMPOUND HAVING DIBENZYLAMINE
STRUCTURE
Abstract
It is an object of the present invention to provide a novel form
of
(S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methy-
lsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(e-
thyl)amino)methyl]cyclohexyl}acetic acid, which is useful for
preventing and/or treating diseases such as dyslipidemia.
(S)-trans-{4-[({2-[({1-[3,5-bis(Trifluoromethyl)phenyl]ethyl}{5-[2-(methy-
lsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(e-
thyl)amino)methyl]cyclohexyl}acetic acid hydrochloride.
Inventors: |
YAMAZAKI; Koichi; (Tokyo,
JP) ; MATSUDA; Kennosuke; (Tokyo, JP) ;
KUSAKABE; Taichi; (Chiba, JP) ; OHGIYA; Tadaaki;
(Saitama, JP) ; SHIBUYA; Kimiyuki; (Saitama,
JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
KOWA COMPANY, LTD. |
Aichi |
|
JP |
|
|
Assignee: |
KOWA COMPANY, LTD.
Aichi
JP
|
Family ID: |
51988925 |
Appl. No.: |
15/595039 |
Filed: |
May 15, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14784147 |
Oct 13, 2015 |
9682942 |
|
|
PCT/JP2014/064372 |
May 30, 2014 |
|
|
|
15595039 |
|
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|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07B 2200/13 20130101;
C07D 239/47 20130101; A61P 3/06 20180101 |
International
Class: |
C07D 239/47 20060101
C07D239/47 |
Foreign Application Data
Date |
Code |
Application Number |
May 31, 2013 |
JP |
2013-115189 |
Claims
1. A crystal of
(S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methy-
l-sulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(-
ethyl)amino)methyl]cyclohexyl}acetic acid hydrochloride.
2. The crystal according to claim 1, wherein the hydrochloride is a
monohydrochloride.
3. The crystal according to claim 1, which has excellent heat
stability.
4. A pharmaceutical composition comprising the crystal according to
claim 1 and a pharmaceutically acceptable carrier.
5. A method for producing a pharmaceutical composition, comprising
a step of mixing the crystal according to claim 1 with a
pharmaceutically acceptable carrier.
6. A pharmaceutical composition comprising the crystal according to
claim 2 and a pharmaceutically acceptable carrier.
7. A method for producing a pharmaceutical composition, comprising
a step of mixing the crystal according to claim 2 with a
pharmaceutically acceptable carrier.
8. A pharmaceutical composition comprising the crystal according to
claim 3 and a pharmaceutically acceptable carrier.
9. A method for producing a pharmaceutical composition, comprising
a step of mixing the crystal according to claim 3 with a
pharmaceutically acceptable carrier.
10. The crystal according to claim 2, which has excellent heat
stability.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation application of
pending U.S. application Ser. No. 14/784,147, filed on Oct. 13,
2015, which is a National Stage of International Patent Application
NO. PCT/JP2014/064372 filed on May 30, 2014, which claims priority
to Japanese Application No. 2013-115189 filed on May 31, 2013. The
disclosures of U.S. application Ser. No. 14/784,147 and
International Patent Application No. PCT/JP2014/064372 ate
incorporated by reference herein in their entireties.
TECHNICAL FIELD
[0002] The present invention relates to a novel form of
(S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methy-
lsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(e-
thyl)amino)methyl]cyclohexyl}acetic acid, which is a pyrimidine
compound having a dibenzylamine structure useful for preventing
and/or treating diseases such as dyslipidemia.
BACKGROUND ART
[0003] It has been known that
(S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methy-
lsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(e-
thyl)amino)methyl]cyclohexyl}acetic acid (hereinafter also referred
to as a "pyrimidine compound (1)" in the present description)
represented by the following formula (1):
##STR00001##
has an action to inhibit a cholesteryl ester transfer protein
(CETP), an action to reduce the amount of proprotein convertase
subtilisin/kexin 9 (PCSK9) protein and the like, and that this
compound is useful for preventing or treating diseases such as
dyslipidemia (Patent Literatures 1, 2, and 3).
[0004] With regard to the pyrimidine compound (1), it has been
disclosed so far that a racemate thereof was obtained in the form
of a light yellow oil in Example 45 of Patent Literature 1. In
addition, it has also been disclosed in Example 1 of Patent
Literature 2 and Production Example 2 of Patent Literature 3 that
the pyrimidine compound (1) was obtained in the form of a white
amorphous substance.
[0005] However, a crystal of the pyrimidine compound (1) has not
yet been reported so far.
[0006] In general, if a means for crystallizing a low-molecular
weight compound available as an active ingredient of pharmaceutical
product were established, the purity thereof could be improved by
recrystallization. Thus, a high-purity pharmaceutical product can
be provided. Moreover, when compared with forms having poor
crystallinity, such as an amorphous substance and an amorphous
solid, a crystal has excellent homogeneity and less likely to cause
unevenness in solubility and the like. Hence, it becomes possible
to provide a homogeneous pharmaceutical product from such a
crystal. Furthermore, since the crystal is generally a solid and is
easily handled, it is advantageous for production of a
pharmaceutical preparation.
[0007] Considering the aforementioned advantages, in general, it is
desired to develop a crystal form from a low-molecular-weight
compound available as an active ingredient of pharmaceutical
product. However, it is extremely unlikely to predict the formation
of a crystal from a compound, and thus, under the current
circumstances, the possibility of formation of a crystal,
conditions for crystal formation, etc. are totally unknown until
they are actually examined.
CITATION LIST
Patent Literature
[0008] [Patent Literature 1] WO 2008/129951
[0009] [Patent Literature 2] WO 2011/152508
[0010] [Patent Literature 3] WO 2012/046681
SUMMARY OF INVENTION
Technical Problem
[0011] It is an object of the present invention to provide a novel
form of the pyrimidine compound (1) useful for preventing and/or
treating diseases such as dyslipidemia.
Solution to Problem
[0012] In order to achieve the aforementioned object, the present
inventors have first conducted intensive studies regarding
crystallization of a free form of the pyrimidine compound (1).
However, it has been difficult to crystallize the pyrimidine
compound (1), which is in the state of a free form, and although
the inventors have studied it under various conditions, they could
not obtain a crystal.
[0013] Hence, the present inventors have converted the pyrimidine
compound (1) to various salts, and have then conducted more
intensive studies regarding crystallization of the salts. As a
result, the inventors have found that a sulfate, an arginine salt
and the like of the pyrimidine compound (1), and also a
hydrobromate which is one of hydrohalogenic acid salts could not be
crystallized, but that when the pyrimidine compound (1) was
converted to a hydrochloride which is also one of hydrohalogenic
acid salts, a crystal having excellent heat stability could be
specifically obtained, and using the obtained crystal, a stable
pharmaceutical composition could be provided, thereby completing
the present invention.
[0014] Specifically, the present invention relates to, for example,
the following inventions. [0015] [1] A hydrochloride of
(S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methy-
lsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(e-
thyl)amino)methyl]cyclohexyl}acetic acid. [0016] [2] The
hydrochloride according to [1], which is a monohydrochloride.
[0017] [3] A crystal of
(S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methy-
lsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(e-
thyl)amino)methyl]cyclohexyl}acetic acid hydrochloride. [0018] [4]
The crystal according to [3], which is a monohydrochloride. [0019]
[5] The crystal according to [3] or [4], wherein the powder X-ray
diffraction pattern obtained by irradiation with copper K.alpha. X
rays has a peak(s) at one or more diffraction angles (2.theta.)
selected from the group consisting of around 14.0.+-.0.2.degree.,
around 18.3.+-.0.2.degree., around 20.1.+-.0.2.degree., around
20.5.+-.0.2.degree., around 21.3.+-.0.2.degree., around
21.8.+-.0.2.degree., around 23.3.+-.0.2.degree., and around
24.0.+-.0.2.degree.. [0020] [6] The crystal according to [3] or
[4], wherein the powder X-ray diffraction pattern obtained by
irradiation with copper K.alpha. X rays has a peak at a diffraction
angle (2.theta.) around 20.5.+-.0.2.degree.. [0021] [7] The crystal
according to [3] or [4], wherein the powder X-ray diffraction
pattern obtained by irradiation with copper K.alpha. X rays has
peaks at diffraction angles (2.theta.) around 18.3.+-.0.2.degree.
and around 20.5.+-.0.2.degree.. [0022] [8] The crystal according to
[3] or [4], wherein the powder X-ray diffraction pattern obtained
by irradiation with copper K.alpha. X rays has peaks at diffraction
angles (2.theta.) around 14.0.+-.0.2.degree., around
18.3.+-.0.2.degree., around 20.1.+-.0.2.degree., around
20.5.+-.0.2.degree., around 21.3.+-.0.2.degree., around
21.8.+-.0.2.degree., around 23.3.+-.0.2.degree., and around
24.0.+-.0.2.degree.. [0023] [9] The crystal according to [3] or
[4], wherein the powder X-ray diffraction pattern obtained by
irradiation with copper K.alpha. X rays is substantially identical
to that shown in FIG. 1. [0024] [10] The crystal according to any
of [3] to [9], which has an endothermic peak around
162.+-.5.0.degree. C. in differential thermal analysis (DTA).
[0025] [11] The crystal according to any of [3] to [9], wherein the
results of thermal analysis measurements (differential thermal
analysis (DTA) and thermogravimetry (TG)) are substantially
identical to those shown in FIG. 2. [0026] [12] A pharmaceutical
composition comprising the compound according to any of [1] to [11]
above. [0027] [13] A pharmaceutical composition comprising the
compound according to any of [1] to [11] above and a
pharmaceutically acceptable carrier. [0028] [14] A method for
producing a pharmaceutical composition, comprising a step of mixing
the compound according to any of [1] to [11] above with a
pharmaceutically acceptable carrier. [0029] [15] Use of the
compound according to any of [1] to [11] above for production of a
pharmaceutical composition. [0030] [16] Use of the compound
according to any of [1] to [11] above as a raw material for
production of a pharmaceutical composition. [0031] [17] The
compound according to any of [1] to [11] above for use in
production of a pharmaceutical composition. [0032] [18] The
compound according to any of [1] to [11] above used as a raw
material for production of a pharmaceutical composition.
Advantageous Effects of Invention
[0033] The hydrochloride of the pyrimidine compound (1) according
to the present invention can be used as a raw material for
formation of a crystal of the pyrimidine compound (1), which is
difficult to be crystallized.
[0034] Moreover, the crystal of the pyrimidine compound (1)
hydrochloride has high heat stability and is useful for production
of a high-quality pharmaceutical product.
BRIEF DESCRIPTION OF DRAWINGS
[0035] FIG. 1 is a view showing a powder X-ray diffraction pattern
of the crystal of the pyrimidine compound (1) hydrochloride
obtained in 1-3 of Example 1.
[0036] FIG. 2 is a view showing the data of thermal analysis
measurements (TG-DTA measurements) of the crystal of the pyrimidine
compound (1) hydrochloride obtained in 1-3 of Example 1.
DESCRIPTION OF EMBODIMENTS
[0037]
(S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2--
(methylsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phe-
nyl}(ethyl)amino)methyl]cyclohexyl}acetic acid (pyrimidine compound
(1)) is represented by the above formula (1), and a free form of
this compound is disclosed, for example, in Patent Literature 2 and
Patent Literature 3. The descriptions of these literatures are
cited herein by reference in their entirety.
[0038] With regard to the hydrochloride of the pyrimidine compound
(1), the number of molecules of hydrogen chloride is not
particularly limited, and it may be any one of a monohydrochloride,
a dihydrochloride, a trihydrochloride and a tetrahydrochloride, or
it may also be a mixture thereof. A monohydrochloride is preferable
because the compound can be obtained in the form of a stable
acid-added salt.
[0039] In the present invention, the hydrochloride of the
pyrimidine compound (1) is preferably
(S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methy-
lsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(e-
thyl)amino)methyl]cyclohexyl}acetic acid monohydrochloride
represented by the following formula (2):
##STR00002##
[0040] The specific crystal form of the crystal of the pyrimidine
compound (1) hydrochloride is not particularly limited. It may be
any one of different crystal forms, or it may also be a mixture
thereof. Further, it may also be a mixture of the crystal of the
pyrimidine compound (1) hydrochloride with the amorphous substance
of the pyrimidine compound (1) hydrochloride.
[0041] Whether or not the pyrimidine compound (1) hydrochloride is
a crystal can be confirmed by known methods that are used to
determine crystallinity, such as X-ray diffraction measurement
(specifically, powder X-ray diffraction measurement, etc.), thermal
analysis measurements (specifically, a differential thermal
analysis method (DTA), a differential scanning calorimetry (DSC),
etc.), confirmation of polarization (specifically, observation
under a polarization microscope, etc.), and a solid NMR
measurement. For example, a certain solid-state pyrimidine compound
(1) hydrochloride is subjected to a powder X-ray diffraction
measurement involving irradiation with copper K.alpha. X rays. When
a clear peak is observed, it can be confirmed that the pyrimidine
compound (1) hydrochloride is a crystal. It is to be noted that
such methods of determining crystallinity (a powder X-ray
diffraction measurement method, a thermal analysis method, etc.)
can be carried out with reference to the descriptions of Japanese
Pharmacopoeia, US Pharmacopeia, European Pharmacopoeia, etc.
[0042] Moreover, confirmation of the crystal may be carried out in
the coexistence of other components. For example, in the case of a
solid pharmaceutical composition (a tablet, a capsule, a granule, a
powder, etc.) comprising the hydrochloride of the pyrimidine
compound (1) and a pharmaceutically acceptable carrier, the solid
pharmaceutical composition is crushed as necessary, and is then
subjected to an X-ray diffraction measurement. When a peak derived
from the hydrochloride of the pyrimidine compound (1) is observed,
the hydrochloride of the pyrimidine compound (1) can be confirmed
to be a crystal.
[0043] In the present invention, the crystal of the pyrimidine
compound (1) hydrochloride is preferably a crystal, wherein the
powder X-ray diffraction pattern obtained by irradiation with
copper K.alpha. X rays has a peak(s) at one or more diffraction
angles (2.theta.) selected from the group consisting of, at least,
around 14.0.+-.0.2.degree., around 18.3.+-.0.2.degree., around
20.1.+-.0.2.degree., around 20.5.+-.0.2.degree., around
21.3.+-.0.2.degree., around 21.8.+-.0.2.degree., around
23.3.+-.0.2.degree., and around 24.0.+-.0.2.degree.; more
preferably a crystal, wherein the powder X-ray diffraction pattern
has a peak at least at a diffraction angle (2.theta.) around
20.5.+-.0.2.degree.; even more preferably a crystal, wherein the
powder X-ray diffraction pattern has peaks at least at diffraction
angles (2.theta.) around 18.3.+-.0.2.degree. and around
20.5.+-.0.2.degree.; further preferably a crystal, wherein the
powder X-ray diffraction pattern has peaks at least at diffraction
angles (2.theta.) around 14.0.+-.0.2.degree., around
18.3.+-.0.2.degree., around 20.1.+-.0.2.degree., around
20.5.+-.0.2.degree., around 21.3.+-.0.2.degree., around
21.8.+-.0.2.degree., around 23.3.+-.0.2.degree., and around
24.0.+-.0.2.degree.; and particularly preferably a crystal
substantially identical to that shown in FIG. 1.
[0044] Moreover, from another viewpoint, in the present invention,
the crystal of the pyrimidine compound (1) hydrochloride is
preferably a crystal having an endothermic peak around
approximately 162.+-.5.degree. C. in differential thermal analysis
(DTA), and is more preferably a crystal, the results of thermal
analysis measurements (differential thermal analysis (DTA) and
thermogravimetry (TG)) of which are substantially identical to
those shown in FIG. 2.
[0045] It is to be noted that the hydrochloride of the pyrimidine
compound (1) of the present invention and the crystal thereof may
be a solvate such as a hydrate, or a non-solvate such as an
anhydride. The hydrochloride of the pyrimidine compound (1) of the
present invention and the crystal thereof are preferably
anhydrides.
[0046] In the present invention, the hydrochloride of the
pyrimidine compound (1) and the crystal thereof can be produced,
for example, by the following steps, respectively: [0047] (Step 1)
a step of forming a hydrochloride from a free form of the
pyrimidine compound (1); and [0048] (Step 2) a step of forming a
crystal from the hydrochloride of the pyrimidine compound (1).
[0049] Hereinafter, individual steps will be described in detail,
separately. However, the methods for producing the hydrochloride of
the pyrimidine compound (1) of the present invention and the
crystal thereof are not limited to the method described below.
<Step 1: Formation of Hydrochloride from Free Form of Pyrimidine
Compound (1)>
[0050] The present step is a step of forming a hydrochloride by
allowing a pyrimidine compound (1) to coexist with hydrogen
chloride in the presence of a solvent. Specifically, the present
step is a step of dissolving a free form of the pyrimidine compound
(1) in a solvent and supplying hydrogen chloride to the solvent to
form a salt.
[0051] In the present step, the free form of the pyrimidine
compound (1) used as a starting material can be produced, for
example, according to the method described in Patent Literature
2.
[0052] The present step is carried out in the presence of a
solvent. The solvent used herein is not particularly limited, as
long as it is not involved in formation of a hydrochloride.
Examples of the solvent include: aromatic hydrocarbons such as
benzene, toluene, xylene, mesitylene, chlorobenzene,
1,2-dichlorobenzene, and nitrobenzene; ethers such as diethyl
ether, diisopropyl ether, tert-butyl methyl ether, and 1,4-dioxane;
acetic acid esters such as ethyl acetate, n-propyl acetate, and
isopropyl acetate; ketones such as acetone, 2-butanone, and
3-pentanone; aliphatic hydrocarbons such as n-pentane, n-hexane,
n-heptane, cyclohexane, n-octane, and n-decane; amides such as
N,N-dimethylformamide and N,N-dimethylacetamide; and sulfoxides
such as dimethyl sulfoxide. These solvents can be used singly or in
combination of two or more solvents. When two or more solvents are
used, the solvents may be mixed, and the pyrimidine compound (1)
may be then dissolved in the mixed solvent. Alternatively, the
pyrimidine compound (1) may be dissolved in a solvent, and the
remaining solvents may be then added to the obtained mixture.
[0053] As such a solvent, one or more selected from the group
consisting of diisopropyl ether, tert-butyl methyl ether,
1,4-dioxane, n-hexane, n-heptane, ethyl acetate and isopropyl
acetate are preferable; one or more selected from the group
consisting of diisopropyl ether, tert-butyl methyl ether,
1,4-dioxane and isopropyl acetate are more preferable; and
tert-butyl methyl ether or isopropyl acetate is particularly
preferable.
[0054] The amount of such a solvent is not particularly limited.
The solvent may be used in an amount 1 to 20 times (V/W), and
preferably 5 to 15 times (V/W), at a volume ratio with respect to
the weight of the free form of the pyrimidine compound (1).
[0055] The supply source of hydrogen chloride is not particularly
limited. Hydrogen chloride gas may be directly blown into the
solution. Otherwise, available concentrated hydrochloric acid, a 4
M HCl/ethyl acetate solution, a 4 M HCl/1,4-dioxane solution, etc.
can be used.
[0056] The amount of hydrogen chloride is not particularly limited,
and the hydrogen chloride is used in an amount of preferably 1 to 5
molar equivalents, and particularly preferably 1 to 4 molar
equivalents, with respect to the free form of the pyrimidine
compound (1).
[0057] The temperature applied upon formation of a salt is not
particularly limited. It is in the range of generally -50.degree.
C. to 150.degree. C., preferably -20.degree. C. to 80.degree. C.,
and more preferably -10.degree. C. to 40.degree. C. The time
required for formation of a salt is not particularly limited. It is
generally from 5 minutes to 48 hours, preferably from 30 minutes to
24 hours, and more preferably from 30 minutes to 3 hours.
[0058] The generated hydrochloride of the pyrimidine compound (1)
can be isolated. In this case, the salt precipitated as a solid may
be isolated by a method which is commonly applied in the present
technical field, such as filtration, and further, the isolated salt
may be dried, as necessary, by a method commonly applied in the
present technical field. The drying means is not particularly
limited, and examples of the drying means include heating and/or
drying under reduced pressure conditions. The drying temperature is
preferably 50.degree. C. or lower, and more preferably from
40.degree. C. to 50.degree. C. The drying time is preferably from 1
to 24 hours, and more preferably from 6 to 12 hours.
<Step 2: Formation of Crystal from Hydrochloride of Pyrimidine
Compound (1)>
[0059] The present step is a step of crystallizing, in the presence
of a solvent, the hydrochloride of the pyrimidine compound (1)
(e.g., an amorphous substance) obtained in Step 1. Specifically,
the present step is a step of adding the hydrochloride of the
pyrimidine compound (1) obtained in Step 1 to a solvent, then, as
necessary, dissolving the hydrochloride in the solvent by heating
or the like, and then crystallizing by cooling or the like.
[0060] The present step is carried out in the presence of a
solvent. Examples of the solvent include a mixed solution of
2-propanol and heptane, and a mixed solution of methyl ethyl ketone
and heptane. Of these, a mixed solution of 2-propanol and heptane
is preferable. The mixing ratio of solvents is not particularly
limited. Heptane may be used in an amount 0.1 to 2 times (V/V), and
preferably 0.2 to 1 time (V/V), at a volume ratio with respect to
the volume of 2-propanol or methyl ethyl ketone.
[0061] When the hydrochloride of the pyrimidine compound (1) is
dissolved in the solvents, after the solvents have previously been
mixed with each other, the hydrochloride of the pyrimidine compound
(1) may be dissolved in the mixed solvent. Otherwise, it is
preferable that the hydrochloride of the pyrimidine compound (1) is
dissolved in 2-propanol or methyl ethyl ketone, and that heptane is
then added to the obtained solution.
[0062] The amounts of the solvents are not particularly limited.
With regard to the total amount of the mixed solvent, the mixed
solvent may be used in an amount 1 to 20 times (V/W), and
preferably 5 to 10 times (V/W), at a volume ratio with respect to
the weight of the hydrochloride of the pyrimidine compound (1).
[0063] The temperature applied when the hydrochloride of the
pyrimidine compound (1) is dissolved in a solvent is not
particularly limited. It may be generally in the range of
40.degree. C. to 100.degree. C., and preferably of 50.degree. C. to
80.degree. C.
[0064] The temperature applied upon crystallization of the
hydrochloride of the pyrimidine compound (1) is not particularly
limited. Crystallization may be generally carried out in the range
of 5.degree. C. to 40.degree. C., and it is preferably 10.degree.
C. to 35.degree. C., more preferably 10.degree. C. to 30.degree.
C., and particularly preferably 15.degree. C. to 25.degree. C. When
the temperature applied when the hydrochloride of the pyrimidine
compound (1) is dissolved in a solvent is significantly different
from the temperature applied upon crystallization, the reaction
solution may be slowly cooled, as appropriate, over approximately 1
to 10 hours, depending on the temperature difference.
[0065] The time required for crystallization is not particularly
limited. It is generally 1 hour or more, preferably 6 to 24 hours,
and more preferably 8 to 16 hours.
[0066] The precipitated crystal of the pyrimidine compound (1)
hydrochloride may be isolated by a method which is commonly applied
in the present technical field, such as filtration, and further,
the isolated crystal may be dried, as necessary, by a method
commonly applied in the present technical field. The drying means
is not particularly limited, and examples of the drying means
include heating and/or drying under reduced pressure conditions.
The drying temperature is preferably 50.degree. C. or lower, and
more preferably from 40.degree. C. to 50.degree. C. The drying time
is preferably from 1 to 24 hours, and more preferably from 6 to 12
hours.
[0067] It is to be noted that Step 2 may also be carried out in the
presence of the crystal (seed crystal) of pyrimidine compound (1)
hydrochloride, which has been produced, separately. In this case,
isopropyl acetate may be used as a solvent, instead of the
aforementioned solvent. The amount of the seed crystal is not
particularly limited. The seed crystal may be used in an amount of
0.00001 to 0.05 parts by mass, and preferably 0.0001 to 0.01 parts
by mass, with respect to the hydrochloride of the pyrimidine
compound (1).
[0068] It is preferable to add the seed crystal after the
hydrochloride of the pyrimidine compound (1) has been dissolved in
a solvent.
[0069] Moreover, when the crystal of the pyrimidine compound (1)
hydrochloride of the present invention is produced, from the
viewpoint of simplification of the production processes, Step 1 and
Step 2 are continuously carried out without isolating the
hydrochloride of the pyrimidine compound (1), so that a crystal of
hydrochloride can be produced from the free form of the pyrimidine
compound (1) in the presence of a solvent. In this case, isopropyl
acetate is preferably used as a solvent.
[0070] Furthermore, it is also possible to carry out Step 2, while
omitting the time required for formation of a salt in Step 1. That
is to say, it is also possible that the free form of the pyrimidine
compound (1) is dissolved in a solvent, that hydrogen chloride is
then supplied to the obtained solution, and that the mixed solution
is subjected to heating or the like, and then to cooling or the
like, so as to carry out crystallization.
[0071] Other operations, etc. performed in individual steps are the
same as those described above.
[0072] The pyrimidine compound (1) has an action to inhibit CETP,
an action to reduce the amount of a PCSK9 protein, etc.
Accordingly, the hydrochloride of the pyrimidine compound (1) of
the present invention and the crystal thereof can be used as
components of medicinal drugs useful for preventing and/or treating
diseases such as dyslipidemia, hyper-LDL cholesterolemia and
hypo-HDL-cholesterolemia.
[0073] As is apparent from Test Example 2 as described later, the
crystal of the pyrimidine compound (1) hydrochloride of the present
invention has excellent heat stability and can be particularly
preferably used as a stable component of pharmaceutical
composition.
[0074] Moreover, since the crystal of the pyrimidine compound (1)
hydrochloride of the present invention has excellent heat
stability, it also has high stability when it is preserved as a raw
material. Thus, the crystal of the pyrimidine compound (1)
hydrochloride of the present invention can be preferably used as a
raw material for the production of a pharmaceutical composition.
When the crystal of the pyrimidine compound (1) hydrochloride is
used as such a raw material, it is not necessarily required that a
crystalline form is maintained in the produced pharmaceutical
composition.
[0075] When a medicinal drug comprising the hydrochloride of the
pyrimidine compound (1) of the present invention or a crystal
thereof is produced, the hydrochloride of the pyrimidine compound
(1) or the crystal may be used singly. However, the medicinal drug
may be preferably produced in the form of a pharmaceutical
composition for oral administration or parenteral administration.
Specific examples of the dosage form of the pharmaceutical
composition for oral administration include a tablet, a capsule, a
granule, a powder, a liquid and a solution for oral administration,
a syrup, and a jelly for oral administration. On the other hand,
specific examples of the dosage form of the pharmaceutical
composition for parenteral administration include an injection, an
inhalation, an ophthalmic preparation, an ear preparation, a nasal
preparation, a suppository, a solid dosage form for cutaneous
application, a liquid and a solution for cutaneous application, a
spray, an ointment, a cream, a gel, and a patch.
[0076] These pharmaceutical compositions can be produced by adding
a pharmaceutically acceptable carrier (additive). Examples of such
an additive include an excipient, a binder, an extender, a
disintegrator, a surfactant, a lubricant, a dispersing agent, a
buffer agent, a preservative, a corrigent, a flavor, a coating
agent, and a diluent, but the examples are not limited thereto.
[0077] The applied dose of the pyrimidine compound (1) is different
depending on the body weight, age, sex and symptoms of a patient,
etc. In general, in the case of an adult patient, approximately
0.01 to 1,000 mg of the pyrimidine compound (1) in terms of the
free form thereof can be administered to the patient in one to four
divided doses per day. Preferably, approximately 0.1 to 100 mg of
the pyrimidine compound (1) in terms of the free form thereof can
be administered to the patient in one to four divided doses per
day.
EXAMPLES
[0078] Hereinafter, the present invention will be more specifically
described in the following examples, test examples, and the like.
However, these examples are not intended to limit the scope of the
present invention. In the following examples, test examples and the
like, the free form of
(S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methy-
lsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(e-
thyl)amino)methyl]cyclohexyl}acetic acid (the free form of a
pyrimidine compound (1)) can be produced by the method described in
Patent Literature 2.
[0079] It is to be noted that abbreviations used in the
below-mentioned examples have the following meanings.
[0080] s: singlet
[0081] d: doublet
[0082] t: triplet
[0083] q: quartet
[0084] m: multiplet
[0085] br: broad
[0086] J: coupling constant
[0087] Hz: Hertz
[0088] DMSO-d.sub.6: deuterated dimethyl sulfoxide
[0089] .sup.1H-NMR: proton nuclear magnetic resonance
Test Example 1
Studies Regarding Crystallization Conditions
[0090] Conditions for crystallization of various types of samples
(the free form of the pyrimidine compound (1), and the salts
thereof (a hydrochloride, a hydrobromate, a sulfate, a
D-(-)-arginine salt, and a cinchonidine salt)), were studied
according to the following method.
[0091] The hydrochloride of the pyrimidine compound (1) was
obtained by the method described in Step 1 in 1-1 of Example 1.
Other salts were obtained by mixing, at an equimolar ratio, the
free form of the pyrimidine compound (1) dissolved in methanol with
an acid or a base dissolved in water, then stirring the mixture,
and then distilling away the solvents.
[0092] Various types of samples were each dissolved in Solvent 1
which was in an amount 4 to 100 times (V/W) of each sample. Solvent
2 was added to the obtained solution until the solution has begun
to become clouded, and predetermined operations were then
performed. Thereafter, the state of the solution was observed by
visual inspection, and the presence or absence of formation of a
crystal was evaluated.
[0093] The results regarding the free form of the pyrimidine
compound (1) are shown in Table 1, the results regarding the
hydrochloride are shown in Table 2, the results regarding the
hydrobromate are shown in Table 3, the results regarding the
sulfate are shown in Table 4, the results regarding the
D-(-)-arginine salt are shown in Table 5, and the results regarding
the cinchonidine salt are shown in Table 6.
TABLE-US-00001 TABLE 1 Studies regarding crystallization of free
form of pyrimidine compound (1) Observation Solvent 1 Solvent 2
Operations results 2-Propanol Water Hermetically sealed and Oil
left to stand at room temperature for 72 hours Acetone Water
Hermetically sealed and Separated left to stand at room into two
temperature for 72 hours layers Dichloromethane Heptane Left to
stand at room Oil temperature for 72 hours Ethanol Heptane Left to
stand at room Oil temperature for 72 hours 2-Propanol Heptane Left
to stand at room Oil temperature for 72 hours Ethyl acetate Heptane
Left to stand at room Oil temperature for 72 hours Methyl ethyl
Heptane Left to stand at room Oil ketone temperature for 72 hours
Toluene Heptane Left to stand at room Oil temperature for 72
hours
TABLE-US-00002 TABLE 2 Studies regarding crystallization of
hydrochloride of pyrimidine compound (1) Observation Solvent 1
Solvent 2 Operations results Ethanol Toluene Hermetically sealed
and Homogeneous left to stand at room solution temperature for 96
hours Ethanol Water Hermetically sealed and Separated left to stand
at room into two temperature for 96 hours layers 2-Propanol Heptane
Hermetically sealed and Crystal left to stand at room precipitated
temperature for 96 hours Methyl ethyl Heptane Hermetically sealed
and Crystal ketone left to stand at room precipitated temperature
for 96 hours Dichloromethane Heptane Hermetically sealed and Oil
left to stand at room temperature for 96 hours Tetrahydrofuran
Toluene Left to stand at room Oil temperature for 96 hours
1,4-Dioxane tert-Butyl Left to stand at room Oil methyl ether
temperature for 72 hours Dichloromethane tert-Butyl Left to stand
at room Oil methyl ether temperature for 72 hours
TABLE-US-00003 TABLE 3 Studies regarding crystallization of
hydrobromate of pyrimidine compound (1) Observation Solvent 1
Solvent 2 Operations results 2-Propanol Toluene Left to stand at
room Oil temperature for 96 hours Ethyl acetate Toluene Left to
stand at room Oil temperature for 96 hours 2-Propanol Heptane Left
to stand at room Oil temperature for 72 hours 1,4-Dioxane Heptane
Left to stand at room Oil temperature for 72 hours Methyl ethyl
Heptane Left to stand at room Oil ketone temperature for 72 hours
Dichloromethane tert-Butyl Left to stand at room Oil methyl
temperature for 72 hours ether 1,4-Dioxane tert-Butyl Left to stand
at room Oil methyl temperature for 72 hours ether Acetone
tert-Butyl Left to stand at room Oil methyl temperature for 72
hours ether
TABLE-US-00004 TABLE 4 Studies regarding crystallization of sulfate
of pyrimidine compound (1) Observation Solvent 1 Solvent 2
Operations results 2-Propanol Toluene Left to stand at room Oil
temperature for 96 hours Tetrahydrofuran Toluene Left to stand at
room Oil temperature for 96 hours 2-Propanol Heptane Left to stand
at room Oil temperature for 96 hours Methyl ethyl Heptane Left to
stand at room Oil ketone temperature for 72 hours Ethyl acetate
Heptane Left to stand at room Oil temperature for 72 hours
1,4-Dioxane Heptane Left to stand at room Oil temperature for 72
hours 2-Propanol tert-Butyl Left to stand at room Oil methyl
temperature for 72 hours ether Acetonitrile tert-Butyl Left to
stand at room Oil methyl temperature for 72 hours ether
TABLE-US-00005 TABLE 5 Studies regarding crystallization of
D-(-)-arginine salt of pyrimidine compound (1) Observation Solvent
1 Solvent 2 Operations results Methanol Water Left to stand at room
Gelatinous temperature for 2 days substance Ethanol Toluene Left to
stand at room Homogeneous temperature for 2 days solution Ethanol
Heptane Left to stand at room Homogeneous temperature for 2 days
solution Acetonitrile tert-Butyl Left to stand at room Oil methyl
ether temperature for 2 days Ethyl acetate Toluene Left to stand at
room Oil temperature for 2 days Ethyl acetate Heptane Left to stand
at room Oil temperature for 2 days Tetrahydrofuran Water Left to
stand at room Oil temperature for 2 days Tetrahydrofuran Heptane
Left to stand at room Oil temperature for 2 days
TABLE-US-00006 TABLE 6 Studies regarding crystallization of
cinchonidine salt of pyrimidine compound (1) Observation Solvent 1
Solvent 2 Operations results Methanol -- Left to stand at room
Homogeneous temperature for 2 days solution Ethanol -- Left to
stand at room Homogeneous temperature for 2 days solution
2-Propanol -- Left to stand at room Homogeneous temperature for 2
days solution Tetrahydrofuran -- Left to stand at room Homogeneous
temperature for 2 days solution Chloroform -- Left to stand at room
Homogeneous temperature for 2 days solution Ethyl acetate -- Left
to stand at room Homogeneous temperature for 2 days solution
Acetone -- Left to stand at room Homogeneous temperature for 2 days
solution tert-Butyl -- Left to stand at room Homogeneous methyl
ether temperature for 2 days solution
[0094] From the above study results, it became clear that a crystal
is specifically precipitated from the pyrimidine compound (1), when
the pyrimidine compound (1) is converted to a hydrochloride.
Example 1
Production of crystal of
(S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methy-
lsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(e-
thyl)amino)methyl]cyclohexyl}acetic acid hydrochloride
1-1: Production of Crystal of Pyrimidine Compound (1)
Hydrochloride, Part 1
[0095] Step 1
[0096] 1.1 kg (1.35 mol) of a free form of
(S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methy-
lsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(e-
thyl)amino)methyl]cyclohexyl}acetic acid was dissolved in
tert-butyl methyl ether (15.3 kg) under an argon atmosphere, and
the obtained solution was then cooled to 0.degree. C. Subsequently,
503.9 g of a 16.7% hydrogen chloride/1,4-dioxane solution (hydrogen
chloride: 2.31 mol) was added dropwise to the obtained solution at
a temperature of 0.degree. C. to 10.degree. C., and the obtained
mixture was then stirred at the same temperature as described above
for 1 hour. Thereafter, the precipitated solid was collected by
filtration, and was then washed with cooled tert-butyl methyl ether
(1.85 kg). The resultant was dried under reduced pressure at a
temperature of 40.degree. C. to 50.degree. C. for 12 hours, so as
to afford 1.14 kg of an amorphous substance of the
(S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methy-
lsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(e-
thyl)amino)methyl]cyclohexyl}acetic acid hydrochloride (yield:
100%).
[0097] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.72-0.92 (7H,
m), 1.30 (1H, m), 1.50 (3H, d, J=6.6 Hz), 1.62-1.70 (5H, m), 2.02
(2H, d, J=6.8 Hz), 2.71 (1H, m), 2.75 (1H, brs), 2.90 (3H, brs),
3.07 (3H, s), 3.62 (2H, t, J=5.5 Hz), 4.40 (2H, t, J=5.7 Hz), 4.67
(1H, d, J=17.6 Hz), 4.80 (1H, d, J=17.8 Hz), 6.24 (1H, q, J=6.8
Hz), 7.10 (1H, s), 7.33 (1H, brs), 7.47 (1H, d, J=8.3 Hz), 7.84
(2H, s), 7.94 (1H, s), 8.35 (2H, s).
Step 2
[0098] The amorphous substance (676 mg) of the
(S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methy-
lsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(e-
thyl)amino)methyl]cyclohexyl}acetic acid hydrochloride obtained in
Step 1 was dissolved in 2-propanol (1.35 mL) by heating it at a
temperature of 50.degree. C. to 55.degree. C. Thereafter, heptane
(676 .mu.L) was added to the obtained solution at 50.degree. C.,
and the obtained mixture was hermetically sealed and was left to
stand at a temperature of 5.degree. C. to 15.degree. C. for 14
hours. Thereafter, the precipitated solid was collected by
filtration, and was then dried under reduced pressure at 40.degree.
C. to afford 576 mg of a crystal of the
(S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methy-
lsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(e-
thyl)amino)methyl]cyclohexyl}acetic acid hydrochloride (yield:
85%).
1-2: Production of Crystal of Pyrimidine Compound (1)
Hydrochloride, Part 2
[0099] 1.14 kg (1.35 mol) of the amorphous substance of the
(S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methy-
lsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(e-
thyl)amino)methyl]cyclohexyl}acetic acid hydrochloride obtained by
the method described in Step 1 of 1-1 above was suspended in
isopropyl acetate (9.98 kg), followed by heating it to a
temperature of 65.degree. C. to 75.degree. C., so that the
amorphous substance was dissolved therein. Thereafter, 11 g of the
crystal of the
(S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methy-
lsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(e-
thyl)amino)methyl]cyclohexyl}acetic acid hydrochloride obtained by
the method described in Step 2 of 1-1 above was added as a seed
crystal to the obtained solution and the obtained mixture was then
stirred for 3 hours at the same temperature as described above.
Thereafter, the reaction mixture was cooled to a temperature of
45.degree. C. to 55.degree. C. over 2 hours, and was then cooled to
a temperature of 15.degree. C. to 25.degree. C. over 3 hours, and
the resultant was further stirred for 16 hours at the same
temperature as described above. After that, the precipitated
crystal was collected by filtration, and was then washed with
isopropyl acetate (1,720 g). Thereafter, the resulting crystal was
dried under reduced pressure at a temperature of 35.degree. C. to
45.degree. C. for 12 hours to afford 1.02 kg of a crystal of the
(S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methy-
lsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(e-
thyl)amino)methyl]cyclohexyl}acetic acid hydrochloride (yield:
85%).
[0100] As a result of the elemental analysis, it became clear that
the obtained hydrochloride was a monohydrochloride, as described
below.
Elemental analysis results:
[0101] Calculated (as a monohydrochloride): C: 50.91%, H: 4.98%, N:
6.60%, and Cl: 4.17%
[0102] Found: C: 50.79%, H: 4.70%, N: 6.40%, and Cl: 3.94%
[0103] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.72-0.92 (7H,
m), 1.29 (1H, m), 1.49 (3H, d, J=6.8 Hz), 1.62-1.70 (5H, m), 2.02
(2H, d, J=6.6 Hz), 2.71 (1H, m), 2.80-2.90 (3H, m), 3.07 (3H, s),
3.62 (2H, t, J=5.5 Hz), 4.40 (2H, t, J=5.7 Hz), 4.65 (1H, d, J=16.4
Hz), 4.78 (1H, d, J=17.1 Hz), 6.23 (1H, q, J=6.8 Hz), 7.09 (1H, s),
7.29 (1H, d, J=8.0 Hz), 7.45 (1H, d, J=7.8 Hz), 7.83 (2H, s), 7.94
(1H, s), 8.35 (2H, s).
1-3: Production of Crystal of Pyrimidine Compound (1)
Hydrochloride, Part 3
[0104] 16.1 kg (19.8 mol) of a free form of the
(S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methy-
lsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(e-
thyl)amino)methyl]cyclohexyl}acetic acid was dissolved in isopropyl
acetate (124 kg) under an argon atmosphere. The obtained solution
was heated to a temperature of 40.degree. C. to 50.degree. C.
Subsequently, 15.0 kg of a 6.3% hydrogen chloride/isopropyl acetate
solution (hydrogen chloride: 25.98 mol) was added dropwise to the
obtained solution, and the obtained mixture was then heated to a
temperature of 65.degree. C. to 75.degree. C. 25 g of the crystal
of the
(S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methy-
lsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(e-
thyl)amino)methyl]cyclohexyl}acetic acid hydrochloride obtained by
the method described in Step 2 of 1-1 above was added as a seed
crystal to the obtained solution, and 7.0 kg of a 6.3% hydrogen
chloride/isopropyl acetate solution (hydrogen chloride: 12.08 mol)
was further added dropwise to the mixed solution, and the obtained
mixture was then stirred for 7 hours at the same temperature as
described above. Thereafter, the reaction solution was cooled to a
temperature of 45.degree. C. to 55.degree. C. over 3 hours, and was
then cooled to a temperature of 15.degree. C. to 25.degree. C. over
4 hours, and the resultant was further stirred at the same
temperature as described above for 16 hours. Thereafter, the
precipitated crystal was collected by filtration, and was then
washed with isopropyl acetate (32.4 kg). The resultant was dried
under reduced pressure at a temperature of 40.degree. C. to
50.degree. C. for 12 hours to afford 15.35 kg of a crystal of the
(S)-trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methy-
lsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(e-
thyl)amino)methyl]cyclohexyl}acetic acid hydrochloride (yield:
91%).
[0105] As a result of the elemental analysis, it became clear that
the obtained hydrochloride was a monohydrochloride.
Elemental analysis results:
[0106] Calculated (as a monohydrochloride): C: 50.91%, H: 4.98%, N:
6.60%, and Cl: 4.17%
[0107] Found: C: 50.82%, H: 4.98%, N: 6.56%, and Cl: 4.15%
[0108] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.72-0.92 (7H,
m), 1.29 (1H, m), 1.49 (3H, d, J=6.8 Hz), 1.62-1.70 (5H, m), 2.02
(2H, d, J=6.6 Hz), 2.71 (1H, m), 2.80-2.90 (3H, m), 3.07 (3H, s),
3.62 (2H, t, J=5.5 Hz), 4.40 (2H, t, J=5.7 Hz), 4.65 (1H, d, J=16.4
Hz), 4.78 (1H, d, J=17.1 Hz), 6.23 (1H, q, J=6.8 Hz), 7.09 (1H, s),
7.29 (1H, d, J=8.0 Hz), 7.45 (1H, d, J=7.8 Hz), 7.83 (2H, s), 7.94
(1H, s), 8.35 (2H, s).
1-4: Evaluation of Physical Properties of Crystal of Pyrimidine
Compound (1)
[0109] The crystal obtained in 1-3 above was subjected to a powder
X-ray diffraction measurement and a thermal analysis measurement,
as described below.
<Powder X-ray Diffraction Measurement>
[0110] The crystal obtained in 1-3 above was subjected to a powder
X-ray diffraction measurement. The crushed crystal sample was
mounted on a sample holder portion of a silicon reflection-free
sample plate for X-ray diffraction, and the powder X-ray
diffraction measurement was then carried out under the following
conditions.
[0111] Powder X-ray diffraction measurement apparatus:
RINT-UltimaIV-Protectus (manufactured by Rigaku Corporation)
[0112] Type of X-ray: copper K.alpha. X rays (.lamda.=1.54
.ANG.)
[0113] Scanning field of diffraction angle 2.theta.: 3.00.degree.
to 40.00.degree.
[0114] Sampling width: 0.02.degree.
[0115] Scanning rate: 2.00.degree./min
[0116] The obtained diffraction pattern is shown in FIG. 1. In FIG.
1, the longitudinal axis indicates diffraction intensity (count/sec
(cps)), and the horizontal axis indicates diffraction angle
2.theta. (.degree.).
[0117] With regard to major peaks having a relative intensity of 30
or more, the diffraction angle 2.theta., full width at half
maximum, d value, intensity, and relative intensity of the peaks
are shown in Table 7.
[0118] From FIG. 1 and Table 7, it became clear that major peaks
are found at diffraction angles (2.theta.) around
14.0.+-.0.2.degree., around 18.3.+-.0.2.degree., around
20.1.+-.0.2.degree., around 20.5.+-.0.2.degree., around
21.3.+-.0.2.degree., around 21.8.+-.0.2.degree., around
23.3.+-.0.2.degree., and around 24.0.+-.0.2.degree..
[0119] Moreover, it also became clear that peaks with strong
intensity are found at diffraction angles (2.theta.) around
18.3.+-.0.2.degree. and around 20.5.+-.0.2.degree., and in
particular, around 20.5.+-.0.2.degree..
TABLE-US-00007 TABLE 7 Full width Peak at half Relative No.
2.theta. maximum d value Intensity intensity 1 14.000 0.235 6.3205
1232 31 2 18.260 0.235 4.8545 2486 62 3 20.100 0.235 4.4140 1279 32
4 20.500 0.235 4.3288 4040 100 5 21.340 0.235 4.1603 1194 30 6
21.780 0.235 4.0772 1386 35 7 23.320 0.235 3.8113 1415 36 8 23.960
0.212 3.7109 1421 36
<Thermal Analysis Measurement>
[0120] The crystal obtained in Example 1-3 was subjected to a
thermal analysis measurement. Approximately 5 mg of a sample was
precisely weighed in an aluminum pan for thermal analysis, and
Al.sub.2O.sub.3 was used as a reference substance. The thermal
analysis was carried out under a nitrogen atmosphere (150 mL/min)
at a temperature increase rate of 10.degree. C./min by a
differential thermal analysis method (DTA) and a thermogravimetry
method (TG), using a thermal analysis apparatus Thermo Plus 2
System (manufactured by Rigaku Corporation).
[0121] The results of the thermal analysis measurement are shown in
FIG. 2. In FIG. 2, the longitudinal axis indicates the thermal
electromotive force (.mu.V) of thermocouple with respect to a DTA
curve, and also indicates mass change (mg) with respect to a TG
curve. The horizontal axis indicates temperature (.degree. C.).
[0122] As shown in FIG. 2, the crystal of the pyrimidine compound
(1) hydrochloride had an endothermic peak around 162.+-.5.degree.
C. (which is specifically 161.6.degree. C.) in the differential
thermal analysis (DTA). From the aforementioned thermal analysis
measurement results, it was considered that the crystal of the
pyrimidine compound (1) hydrochloride has a melting point around
approximately 162.+-.5.degree. C.
Test Example 2
Heat Stability Test
[0123] A test compound was placed in a glass bottle, and it was
then preserved for a predetermined period of time under temperature
conditions of 80.degree. C., 100.degree. C., or 120.degree. C.
Thereafter, the remaining percentage (%) of the pyrimidine compound
(1) in the test compound was measured.
[0124] The remaining percentage was obtained by measuring the rate
of the pyrimidine compound (1) contained in the test compound
according to high performance liquid chromatography and expressing
the measured value as a peak area percentage. In the measurement
according to high performance liquid chromatography, an ODS column
was used as a column, and a mixture of two solvents, namely, a 0.1%
TFA aqueous solution and a 0.1% TFA acetonitrile solution, was used
as a solvent. The detection wavelength was set at 242 nm.
[0125] From the obtained area percentage of the pyrimidine compound
(1), the remaining percentage was calculated according to the
following calculation formula.
[Expression 1]
[0126] Remaining percentage (%)=Area percentage of pyrimidine
compound (1) after preservation/area percentage of pyrimidine
compound (1) before preservation.times.100
[0127] As test compounds, the crystal obtained in Example 1-3 (a
crystal of the pyrimidine compound (1) hydrochloride) and a free
form of the pyrimidine compound (1) were used.
[0128] The results are shown in Table 8.
TABLE-US-00008 TABLE 8 Remaining percentage (%) After After After
preservation preservation preservation at 80.degree. C. for at
100.degree. C. for at 120.degree. C. for 72 hours 24 hours 16 hours
Crystal of pyrimidine 100.0 100.0 99.5 compound (1) hydrochloride
Free form of pyrimidine 99.5 89.3 71.5 compound (1)
[0129] From the test results shown in Table 8, it became clear that
the crystal of the pyrimidine compound (1) hydrochloride has
excellent heat stability.
[Industrial Applicability]
[0130] According to the present invention, the pyrimidine compound
(1) useful for preventing and/or treating diseases such as
dyslipidemia can be provided in a form, which is highly pure and
homogeneous, and is suitable for production of pharmaceutical
products with high quality, and thus, it can be utilized, for
example, in the industry of pharmaceutical products.
* * * * *