U.S. patent application number 10/355160 was filed with the patent office on 2003-08-21 for crystals of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidined- ione.
Invention is credited to Maruyama, Akira, Masuda, Katsuhiko, Oe, Takayuki, Ueno, Hiroaki.
Application Number | 20030158241 10/355160 |
Document ID | / |
Family ID | 18233859 |
Filed Date | 2003-08-21 |
United States Patent
Application |
20030158241 |
Kind Code |
A1 |
Oe, Takayuki ; et
al. |
August 21, 2003 |
Crystals of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidined-
ione
Abstract
The invention relates to type A crystal of
5-[{6-(2-fluorobenzyl)oxy-2-nap-
hthyl}methyl]-2,4-thiazolidinedione characterized to have
characteristic absorption peaks (2.theta.) at
11.5.degree..+-.0.3.degree., 14.5.degree..+-.0.2.degree.,
16.2.degree..+-.0.3.degree., 17.0.degree..+-.0.3.degree.,
17.7.degree..+-.0.20, 18.6.degree..+-.0.3.degree.,
19.1.degree..+-.0.2.degree., 21.3.degree..+-.0.4.degree.,
22.4.degree..+-.0.5.degree., 25.7.degree..+-.0.5.degree. and
28.3.degree..+-.0.5.degree. in a powder X-ray diffraction pattern,
and also to a method for preparation thereof, and a pharmaceutical
composition comprising the same. The crystal is excellent in
stability, and has advantages in handling, storage, and
pharmaceutical preparation. The invention also relates to type B, C
and D crystals of said compound.
Inventors: |
Oe, Takayuki; (Kanagawa,
JP) ; Ueno, Hiroaki; (Kanagawa, JP) ;
Maruyama, Akira; (Ibaraki, JP) ; Masuda,
Katsuhiko; (Ibaraki, JP) |
Correspondence
Address: |
WENDEROTH, LIND & PONACK, L.L.P.
2033 K STREET N. W.
SUITE 800
WASHINGTON
DC
20006-1021
US
|
Family ID: |
18233859 |
Appl. No.: |
10/355160 |
Filed: |
January 31, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10355160 |
Jan 31, 2003 |
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09856295 |
Aug 20, 2001 |
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6541493 |
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09856295 |
Aug 20, 2001 |
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PCT/JP99/06492 |
Nov 19, 1999 |
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Current U.S.
Class: |
514/369 ;
548/183 |
Current CPC
Class: |
A61P 35/02 20180101;
A61P 19/06 20180101; A61P 3/06 20180101; C07D 277/34 20130101; A61P
3/10 20180101; A61P 1/18 20180101 |
Class at
Publication: |
514/369 ;
548/183 |
International
Class: |
C07D 277/62; A61K
031/426 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 20, 1998 |
JP |
10/330546 |
Claims
1. Type A crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thia-
zolidinedione characterized to have characteristic absorption peaks
(2.theta.) at 11.5.degree..+-.0.3.degree. in a powder X-ray
diffraction pattern.
2. Type A crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thia-
zolidinedione characterized to have characteristic absorption peaks
(2.theta.) at 11.5.degree..+-.0.3.degree. and
25.7.degree..+-.0.5.degree. in a powder X-ray diffraction
pattern.
3. Type A crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thia-
zolidinedione characterized to have characteristic absorption peaks
(2 0) at 22.4.degree..+-.0.5.degree. and
25.7.degree..+-.0.5.degree. in a powder X-ray diffraction
pattern.
4. Type A crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thia-
zolidinedione characterized to have characteristic absorption peaks
(2 0) at 11.5.degree..+-.0.3.degree. and
22.4.degree..+-.0.5.degree. in a powder X-ray diffraction
pattern.
5. Type A crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thia-
zolidinedione characterized to have characteristic absorption peaks
(2.theta.) at 11.5.degree..+-.0.3.degree.,
17.0.degree..+-.0.3.degree., 17.7.degree..+-.0.2.degree.,
22.4.degree..+-.0.5.degree. and 25.7.degree..+-.0.5.degree. in a
powder X-ray diffraction pattern.
6. Type A crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thia-
zolidinedione characterized to have characteristic absorption peaks
(2.theta.) at 11.5.degree..+-.0.3.degree.,
14.5.degree..+-.0.2.degree., 16.2.degree..+-.0.3.degree.,
17.0.degree..+-.0.3.degree., 17.7.degree..+-.0.2.degree.,
18.6.degree..+-.0.3.degree., 19.1.degree..+-.0.2.degree.,
21.3.degree..+-.0.4.degree., 22.4.degree..+-.0.5.degree.,
25.7.degree..+-.0.5.degree. and 28.3.degree..+-.0.5.degree. in a
powder x-ray diffraction pattern.
7. A method for preparing the type A crystal of
5-[{6-(2-fluorobenzyl)oxy--
2-naphthyl}methyl]-2,4-thiazolidinedione according to claim 1,
which comprises the step of heating and stirring
5-[{6-(2-fluorobenzyl)oxy-2-na-
phthyl}methyl]-2,4-thiazolidinedione in an alcoholic solvent.
8. The method according to claim 7 wherein the alcoholic solvent is
an aliphatic alcohol.
9. The method according to claim 7 or claim 8 wherein the alcoholic
solvent is an aliphatic alcohol having 1 to 4 carbon atoms.
10. The method according to any one of claims 7 to 9 wherein the
heating and stirring are carried out under atmospheric pressure or
under pressure at a temperature within the range of about
50.degree. C. to refluxing temperature.
11. A pharmaceutical composition comprising the type A crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione
according to any one of claims 1 to 6 and a pharmaceutically
acceptable carrier.
12. The pharmaceutical composition according to claim 11 which is
used for therapeutic treatment of diabetes and a complication
thereof, hyperlipidemia and a complication thereof, hyperuricemia,
leukemia, and pancreatitis.
13. Type B crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thi-
azolidinedione characterized to have characteristic diffraction
peaks (2.theta.) at 10.5.degree..+-.0.5.degree. in a powder X-ray
diffraction pattern.
14. Type B crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thi-
azolidinedione characterized to have characteristic diffraction
peaks (2.theta.) at 10.5.degree..+-.0.5.degree. and
20.9.degree..+-.0.5.degree. in a powder X-ray diffraction
pattern.
15. Type B crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thi-
azolidinedione characterized to have characteristic diffraction
peaks (2.theta.) at 20.9.degree..+-.0.5.degree. and
23.0.degree..+-.0.5.degree. in a powder X-ray diffraction
pattern.
16. Type B crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thi-
azolidinedione characterized to have characteristic diffraction
peaks (2.theta.) at 10.5.degree..+-.0.5.degree. and
23.0.degree..+-.0.5.degree. in a powder X-ray diffraction
pattern.
17. Type B crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thi-
azolidinedione characterized to have characteristic diffraction
peaks (2.theta.) at 10.5.degree..+-.0.5.degree.,
20.9.degree..+-.0.5.degree., 23.0.degree..+-.0.5.degree. and 29.2
.degree..+-.0.5.degree. in a powder X-ray diffraction pattern.
18. Type B crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thi-
azolidinedione characterized to have characteristic diffraction
peaks (2.theta.) at 10.5.degree..+-.0.5.degree.,
18.4.degree..+-.0.5.degree., 20.9.degree..+-.0.5.degree.,
23.0.degree..+-.0.5.degree., 26.7.degree..+-.0.5.degree. and
29.2.degree..+-.0.5.degree. in a powder X-ray diffraction
pattern.
19. Type C crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thi-
azolidinedione characterized to have characteristic diffraction
peaks (2.theta.) at 12.5.degree..+-.0.5.degree. in a powder X-ray
diffraction pattern.
20. Type C crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thi-
azolidinedione characterized to have characteristic diffraction
peaks (2.theta.) at 12.5.degree..+-.0.5.degree. and
14.5.degree..+-.0.5.degree. in a powder X-ray diffraction
pattern.
21. Type C crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thi-
azolidinedione characterized to have characteristic diffraction
peaks (2.theta.) at 14.5.degree..+-.0.5.degree. and
22.1.degree..+-.0.5.degree. in a powder X-ray diffraction
pattern.
22. Type C crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thi-
azolidinedione characterized to have characteristic diffraction
peaks (2.theta.) at 12.5.degree..+-.0.5.degree. and
22.1.degree..+-.0.5.degree. in a powder X-ray diffraction
pattern.
23. Type C crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thi-
azolidinedione characterized to have characteristic diffraction
peaks (2.theta.) at 12.5.degree..+-.0.5.degree.,
14.5.degree..+-.0.5.degree., 17.6.degree..+-.0.5.degree. and
22.1.degree..+-.0.5.degree. in a powder X-ray diffraction
pattern.
24. Type C crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thi-
azolidinedione characterized to have characteristic diffraction
peaks (2 0) at 12.5.degree..+-.0.5.degree.,
14.5.degree..+-.0.5.degree., 17.6.degree..+-.0.5.degree.,
18.8.degree..+-.0.5.degree., 22.1.degree..+-.0.5.degree.,
25.9.degree..+-.0.5.degree., 26.6.degree..+-.0.5.degree. and
28.3.degree..+-.0.5.degree. in a powder X-ray diffraction
pattern.
25. Type D crystal of
5-[{G-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thi-
azolidinedione characterized to have characteristic diffraction
peaks (2.theta.) at 17.4.degree..+-.0.2.degree. and
22.2.degree..+-.0.2.degree. in a powder X-ray diffraction
pattern.
26. Type D crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thi-
azolidinedione characterized to have characteristic diffraction
peaks (2 0) at 22.2.degree..+-.0.2.degree. and
25.3.degree..+-.0.2.degree. in a powder X-ray diffraction
pattern.
27. Type D crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thi-
azolidinedione characterized to have characteristic diffraction
peaks (2.theta.) at 17.4.degree..+-.0.2.degree. and
25.3.degree..+-.0.2.degree. in a powder X-ray diffraction
pattern.
28. Type D crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thi-
azolidinedione characterized to have characteristic diffraction
peaks (2.theta.) at 10.7.degree..+-.0.2.degree.,
17.4.degree..+-.0.2.degree., 22.2.degree..+-.0.2.degree. and
25.3.degree..+-.0.2.degree. in a powder X-ray diffraction
pattern.
29. Type D crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thi-
azolidinedione characterized to have characteristic diffraction
peaks (2.theta.) at 10.7.degree..+-.0.2.degree.,
14.5.degree..+-.0.2.degree., 15.1.degree..+-.0.2.degree.,
15.8.degree..+-.0.2.degree., 17.4.degree..+-.0.2.degree.,
18.5.degree..+-.0.2.degree., 20.5.degree..+-.0.2.degree.,
22.2.degree..+-.0.2.degree., 25.3.degree..+-.0.2.degree.,
26.8.degree..+-.0.2.degree. and 27.8.degree..+-.0.2.degree. in a
powder X-ray diffraction pattern.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a stable and novel type A
crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione
(referred to as "MCC-555" in the specification), which is useful as
an active ingredient of therapeutic medicaments for diabetes and a
complication thereof, hyperlipidemia and a complication thereof and
the like.
BACKGROUND OF THE INVENTION
[0002] Diabetes is a complicated disease caused by hyperglycemia,
and the disease is brought by deficiency of insulin action which
reduces blood glucose. Diabetes can be classified into several
types based on their pathologic state. Among them, those regarded
as important are insulin dependent diabetes (type I diabetes) which
requires supplement of insulin because of its deficiency, and
non-insulin dependent diabetes (type II diabetes) where insulin
fails to effect due to abnormalities of receptors, saccharide
transporting carriers and the like, although sufficient amount of
insulin is secreted.
[0003] In recent years, agents improving insulin resistance have
been much interested which reduce blood glucose by improving
insulin resistance in peripheral tissues that is a cause of
non-insulin dependent diabetes.
[0004] Some of the inventors of the present invention achieved an
invention relating to
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-th-
iazolidinedione, an agent for improving insulin resistance that has
excellent hypoglycemic action and Ahypolipidemic action, and filed
patent applications directed to the invention (the Japanese Patent
Unexamined Publication (KOKAI) Nos. (Hei) 6-247945/1994 and (Hei)
10-139768/1998). The claims of the Japanese Patent Unexamined
Publication (KOKAI) (Hei) 6-247945/1994 are directed to novel
naphthalene derivatives including
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione
and salts thereof having hypoglycemic and hypolipidemic action, and
the claims of the Japanese Patent Unexamined Publication No. (Hei)
10-139768/1998 are directed to an industrial process of manufacture
thereof.
[0005] The present invention is based on the discovery that a novel
crystal form of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazoli-
dinedione is apparently superior to other crystal forms. The novel
crystal form is herein referred to as "type A crystal," whereas the
other crystal forms mentioned herein are referred to as "type B
crystal", "type C crystal," and "type D crystal" only for reasons
of convenience. The type A crystal has a novel crystal form, and
its excellent stability and a manufacturing process thereof have
not been known to date. According to the method disclosed in the
Japanese Patent Unexamined Publication (KOKAI) No. (Hei)
6-247945/1994, 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}met-
hyl]-2,4-thiazolidinedione is recrystallized in the presence of a
mixed solvent of ethyl acetate and hexane to obtain polymorphic
forms of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione.
As a product of the aforementioned method, the type D crystal or a
mixture mainly composed of the type D crystal may be obtained
depending on various factors such as heating temperature, an amount
or a mixing ratio of the solvents and the like, and accordingly,
the type A crystal cannot be obtained alone. According to the
method of the Japanese Patent Unexamined Publication (KOKAI) No.
(Hei) 10-139768/1998,
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione
is recrystallized in toluene as a solvent to obtain polymorphic
forms of the compound. This method may most frequently yield a
product comprising a mixture of the type A and type D crystals with
a fluctuating content ratio depending on various factors such as
heating temperature, a cooling rate, an amount of the solvent and
the like. However, these patent documents are silent about the
possibility of the polymorphism, and hence no information about the
type A, B, C and D crystals are disclosed therein.
DISCLOSURE OF THE INVENTION
[0006] The present invention provides a crystal of
5-[{6-(2-fluorobenzyl)o-
xy-2-naphthyl}methyl]-2,4-thiazolidinedione distinguishable from
the known crystals, which is novel and excellent in stability, and
has advantages in handling, storage, and manufacture of
pharmaceutical preparation.
[0007] The present invention thus provides Type A crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione
characterized to have characteristic absorption peaks (2.theta.) at
11.5.degree..+-.0.3.degree. in a powder X-ray diffraction
pattern.
[0008] According to preferred embodiment of the present invention,
there are provided the type A crystal of said compound
characterized to have characteristic absorption peaks (2.theta.) at
11.5.degree..+-.0.3.degree. and 25.7.degree..+-.0.5.degree. in a
powder X-ray diffraction pattern; The type A crystal of said
compound characterized to have characteristic absorption peaks
(2.theta.) at 22.4.degree..+-.0.5.degree. and
25.7.degree..+-.0.5.degree. in a powder X-ray diffraction pattern;
The type A crystal of said compound characterized to have
characteristic absorption peaks (2.theta.) at
11.5.degree..+-.0.3.degree. and 22.4.degree..+-.0.5in a powder
X-ray diffraction pattern; The type A crystal of said, compound
characterized to have characteristic absorption peaks (2.theta.) at
11.5.degree..+-.0.3.degree., 17.0.degree..+-.0.3.degr- ee., 17.7
.degree..+-.0.2.degree., 22.4.degree..+-.0.5.degree. and
25.7.degree..+-.0.5.degree. in a powder X-ray diffraction pattern;
and the type A crystal of said compound characterized to have
characteristic absorption peaks (2.theta.) at
11.5.degree..+-.0.3.degree., 14.5.degree..+-.0.2.degree.,
16.2.degree..+-.0.3.degree., 17.0.degree..+-.0.3.degree.,
17.7.degree..+-.0.2.degree., 18.6.degree..+-.0.3.degree.,
19.1.degree..+-.0.2.degree., 21.3.degree..+-.0.4.degree.,
22.4.degree..+-.0.5.degree., 25.7.degree..+-.0.5.degree. and
28.3.degree..+-.0.5.degree. in a powder X-ray diffraction
pattern.
[0009] The present invention also provides a method for preparing
the aforementioned type A crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}met-
hyl]-2,4-thiazolidinedione, which comprises the step of heating and
stirring
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}-methyl]-2,4-thiazolidinedi-
one in an alcoholic solvent, and a pharmaceutical composition
comprising the aforementioned type A crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl-
}methyl]-2,4-thiazolidinedione and a pharmaceutically acceptable
carrier.
[0010] Furthermore, the present invention provides type B crystal
of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}
methyl]-2,4-thiazolidinedione characterized to have characteristic
diffraction peaks (2.theta.) at 10.5.degree..+-.0.5.degree.,
18.4.degree..+-.0.5.degree., 20.9.degree..+-.0.5.degree.,
23.0.degree..+-.0.5.degree., 26.7.degree..+-.0.5.degree. and
29.2.degree..+-.0.5.degree. in a powder X-ray diffraction
pattern;
[0011] type C crystal of said compound characterized to have
characteristic diffraction peaks (2.theta.) at
12.5.degree..+-.0.5.degree- ., 14.5.degree..+-.0.5.degree.,
17.6.degree..+-.0.5.degree., 18.8.degree..+-.0.5.degree.,
22.1.degree..+-.0.5.degree., 25.9.degree..+-.0.5.degree.,
26.6.degree..+-.0.5.degree. and 28.3.degree..+-.0.5.degree. in a
powder X-ray diffraction pattern; and
[0012] type D crystal of said compound characterized to have
characteristic diffraction peaks (2.theta.) at
10.7.degree..+-.0.2.degree- ., 14.5.degree..+-.0.2.degree.,
15.1.degree..+-.0.2.degree., 15.8.degree..+-.0.2.degree.,
17.4.degree..+-.0.2.degree., 18.5.degree..+-.0.2.degree., 20.5
.degree..+-.0.2.degree., 22.2.degree..+-.0.2.degree.,
25.3.degree..+-.0.2.degree., 26.8.degree..+-.0.2.degree. and
27.8.degree..+-.0.2.degree. in a powder X-ray diffraction
pattern.
BRIEF EXPLANATION OF THE INVENTION
[0013] FIG. 1 shows a powder X-ray diffraction pattern of the type
A crystal.
[0014] FIG. 2 shows a powder X-ray diffraction pattern of the type
B crystal.
[0015] FIG. 3 shows a powder X-ray diffraction pattern of the type
C crystal.
[0016] FIG. 4 shows a powder X-ray diffraction pattern of the type
D crystal.
[0017] FIG. 5 shows a powder X-ray diffraction pattern of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione
obtained by the method disclosed in Japanese Patent Unexamined
Publication (KOKAI) No. (Hei) 6-247945/1994.
[0018] FIG. 6 shows a powder X-ray diffraction pattern of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione
obtained by the method disclosed in Patent Unexamined Publication
(KOKAI) No. (Hei) 10-139768/1998.
[0019] FIG. 7 shows a differential scanning calorimetry pattern of
the type A crystal.
[0020] FIG. 8 shows a differential scanning calorimetry pattern of
the type B crystal.
[0021] FIG. 9 shows a differential scanning calorimetry pattern of
the type C crystal.
[0022] FIG. 10 shows a differential scanning calorimetry pattern of
the type D crystal.
[0023] FIG. 11 shows a differential scanning calorimetry pattern of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione
obtained by the method disclosed in Japanese Patent Unexamined
Publication (KOKAI) No. (Hei) 6-247945/1994.
[0024] FIG. 12 shows a differential scanning calorimetry pattern of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione
obtained by the method disclosed in Patent Unexamined Publication
(KOKAI) No. (Hei) 10-139768/1998.
BEST MODE FOR CARRYING OUT THE INVENTION
[0025] The novel type A crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}me-
thyl]-2,4-thiazolidinedione of the present invention, i.e.,
MCC-555, is a crystal of a compound represented by the following
chemical formula. 1
[0026] MCC-555 can be obtained by heating and stirring any one of
the crystal forms or a mixture thereof, preferably a mixture of
polymorphic forms containing the type A crystal, in an alcoholic
solvent.
[0027] The alcoholic solvent is not particularly limited. Preferred
examples include aliphatic alcohols, more preferably aliphatic
alcohols having 1 to 4 carbon atoms. More specifically, examples
include ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol or
the like. According to the present invention, ethanol, in
particular, anhydrous ethanol can most preferably be used.
[0028] The reaction conditions are not particularly limited. The
crystal can be easily obtained with good reproducibility by heating
and stirring a mixture in a form of a suspension preferably under
atmospheric pressure or under pressure and at a temperature within
the range of from about 50.degree. C. to refluxing temperature,
preferably within the range of from 70 to 85.degree. C.
[0029] When any one of the crystal forms or a mixture thereof is
heated to a temperature within the optimum temperature range to
produce MCC-555, it is preferred that the alcoholic solvent is used
in an amount sufficient to achieve at least partial dissolution of
5-[{6-(2-fluorobenzyl)oxy-2-na-
phthyl}methyl]-2,4-thiazolidinedione. Generally, it is sufficient
to use about from 4 to 10 ml of an alcohol per 1 g of any one of
the crystal forms of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedio-
ne or a mixture thereof; however, a better result may sometimes be
obtained by using an increased or decreased amount of an
alcohol.
[0030] Heating time required for substantially complete formation
of MCC-555 according to the aforementioned method may vary from
several minutes to about 5 hours or more. An optimum heating time
required for an individual process may vary depending on several
factors such as temperature, an amount of solvent and the like.
When the above process is performed by heating and refluxing
ethanol under atmospheric pressure, or by heating at about
78.degree. C. under pressure, a time required for substantially
complete formation of the desired type A crystal is generally about
2 to 5 hours. Degree of the formation of MCC-555 can be observed by
collecting a sample, cooling the sample to room temperature,
isolating precipitates by filtration, and measuring the
precipitates by powder X-ray diffractometry. As will be described
below, each of the polymorphic forms of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thi-
azolidinedione provides respective characteristic absorption
bands.
[0031] When
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidined-
ione is heated and suspended in ethanol as a solvent, the type D
crystal herein defined or a mixture of the type A and type D
crystals may sometimes be obtained as a product, if a heating
temperature is below 78.degree. C., or if a heating time is
insufficient, even though the heating is performed at a temperature
within the above-mentioned range suitable for the formation of the
type A crystal.
[0032] The crystal forms of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2-
,4-thiazolidinedione and mixtures thereof can be prepared by the
methods described in the Japanese Patent Unexamined Publication
Nos. (Hei) 6-247945/1994 and (Hei) 10-139768/1998, or by similar
methods.
[0033] The type B crystal of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]--
2,4-thiazolidinedione can be obtained by recrystallization of any
one of the crystal forms or a mixture thereof from an organic
solvent, preferably from toluene, at a low temperature, preferably
at about 0.degree. C.
[0034] The type C crystal can be obtained by recrystallization of
one of the crystal forms or a mixture thereof from an organic
solvent, preferably 1-propanol or 1-butanol.
[0035] The type D crystal can be obtained by recrystallization of
one of the crystal forms or a mixture thereof from an organic
solvent, preferably a mixed solvent of ethyl acetate and
hexane.
[0036] The polymorphic form obtained by the method disclosed in the
Japanese Patent Unexamined Publication No. (Hei) 6-247945/1994 is
characterized by the data shown in FIG. 5 and FIG. 11, and the
polymorphic form obtained by the method disclosed in the Japanese
Patent Unexamined Publication No. (Hei) 10-139768/1998 is
characterized by the data shown in FIG. 6 and FIG. 12. By comparing
the data shown in these figures with the corresponding data of the
type A crystal of the present invention, it can readily be
understood that those known substances composed of a mixture are
different from the substance of the present invention. For example,
there are differences between the crystals obtained by the
conventional methods and the crystal of the present invention in
powder X-ray diffraction patterns. In addition, there are apparent
differences in differential scanning calorimetry patterns as shown
in FIGS. 7, 11 and 12, i.e., the type A crystal is characterized by
one sharp endothermic peak due to the fusion beginning at about
149.degree. C., whereas both of the crystals obtained by the
conventional methods show endothermic property due to the fusion at
a lower temperature than that observed in the type A crystal. By
comparing the data shown in these figures with the corresponding
data of the type B, C and D crystals of the present invention, it
can readily be understood that those known substances composed of a
mixture are different from the substances of the present
invention.
[0037] The powder X-ray diffraction data and the differential
scanning calorimetry data clearly demonstrate that the substance of
the present invention has distinguishable crystal form from the
known crystal forms of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione.
[0038] The compound of the present invention has excellent
hypoglycemic and hypolipidemic action, and can be used as a
medicament. The compound may be added with one or more ordinary
carriers and prepared as a pharmaceutical preparation suitable for
each route of administration. For example, the preparations for
oral administration may be manufactured in the form of tablets,
capsules, granules, powders, liquids and other. For the manufacture
of solid preparations for oral administration, conventional
excipients, binders, lubricants, colorants, disintegrating agents
and other can be used. The hypoglycemic and hypolipidemic agent;
can be used, for example, for the treatment of diabetes and a
complicaion thereof, hyperlipidemia and a complications thereof,
hyperuricemia, leukemia, and pancreatitis.
[0039] Examples of the excipients include, for example, lactose,
starch, talc, magnesium stearate, crystal cellulose,
methylcellulose, carboxymethylcellulose, glycerin, sodium alginate,
gum Arabic and the like. Examples of the binders include, for
example, polyvinyl alcohol, polyvinyl ether, ethylcellulose, gum
Arabic, shellac, saccharose and the like. Examples of the
lubricants include, for example, magnesium stearate, talc and the
like. In addition, commonly used known colorants, disintegrating
agents and the like can be suitably used. Tablets may be coated in
a well-known manner.
[0040] The liquid preparations may be in the form of aqueous or oil
suspensions, solutions, syrups, elixirs or other, and such
preparations may be manufactured by a conventional method. When an
injection is prepared, the compound of the present invention may be
added with a pH modifier, a buffering agent, a stabilizer, an
isotonicity, a local anesthetic agent and other, and prepared as
subcutaneous, intramuscular, or intravenous injections in a
conventional manner. As a base material for the manufacture of
suppositories, for example, oil and fat bases such as cacao butter,
polyethylene glycol, Witepsol (registered trademark of Dynamite
Nobel) and other can be used.
[0041] Doses of the pharmaceutical preparation produced as
described above may vary depending on symptoms, body weight and age
of a patient, route of administration and the like, and the same
dose may not be always applied. However, in general, the compound
of the present invention may preferably be administered in an
amount within the range of about 0.01 to 2000 mg per day for an
adult, and generally, the dose may preferably be administered once
a day or two to four times a day as divided portions.
[0042] The type A crystal of the present invention has higher
stability compared to the other crystal forms, and is a unique
crystal which is kept as the stable form under various conditions
in usual handling, storage, manufacturing process of preparations
and the like. Accordingly, the medicaments for therapeutic
treatment of diabetes and a complication thereof, hyperlipidemia
and a complication thereof and the like can be supplied steadily
and in large quantity by using the type A crystal of the present
invention. Furthermore, the present invention provides the other
new crystal forms, the type B, C and D.
EXAMPLES
[0043] The present invention will be further explained in detail by
referring to examples. However, the scope of the present invention
is not limited to these examples.
Reference Example 1
[0044] Preparation of a mixture of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}me-
thyl]-2,4-thiazolidinedione Polymorphic Forms
[0045] 50.0 g of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazoli-
dinedione (roughly purified product, prepared by the method
described in the Japanese Patent Unexamined Publication No. (Hei)
6-247945/1994), was add to 375 ml of toluene and heated with
stirring at refluxing temperature. After the solid was completely
dissolved, the solution was cooled to 20.degree. C. with stirring.
The reaction mixture was filtered, and the filter cake was washed
with toluene and dried under reduced pressure to obtain 48.8 g of a
mixture of polymorphic forms comprising the type A and type D
crystals of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}me-
thyl]-2,4-thiazolidinedione (98% of theoretical yield). Melting
point: 149-151.degree. C.
[0046] Elemental analysis (as C.sub.21H.sub.16FNO.sub.3S):
[0047] Calculated (%): C, 66.13; H, 4.23; N, 3.67 Found: C, 66.06;
H, 4.08; N, 3.68
Example 1
[0048] Preparation of MCC-555 (1)
[0049] The mixture of polymorphic forms of the type A and type D
crystals obtained in Reference Example 1 (400 mg) was suspended in
ethanol (4.0 ml), heated under reflux for one hour with stirring,
and then cooled to room temperature with stirring. The reaction
mixture was filtered, and the filter cake was washed with ethanol
and dried under reduced pressure to obtain 361 mg of MCC-555 as
white crystals (90% of theoretical yield). Melting point:
150-152.degree. C.
Example 2
[0050] Preparation of MCC-555 (2)
[0051] The mixture of polymorphic forms of the type A and type D
crystals obtained in Reference Example 1 (15.0 g) was added to
ethanol (68 ml) and suspended with heating under pressure in an
autoclave at 78.degree. C. for 3 hours. Then, the mixture was
cooled to room temperature and further stirred for 1 hour. The
reaction mixture was filtered, and the filter cake was washed with
ethanol and dried under reduced pressure to obtain 14.6 g of
MCC-555 as white crystals (97% of theoretical yield). Melting
point: 150-152.degree. C.
Example 3
[0052] Preparation of Type B Crystal
[0053] The mixture of polymorphic forms of the type A and type D
crystals obtained in Reference Example 1 (1.62 g) was added to
toluene (250 ml) and heated to about 65.degree. C. with stirring.
After the crystals were completely dissolved, the solution was
slowly cooled to about 0.degree. C. with stirring. The reaction
mixture was filtered, and the filter cake was dried under reduced
pressure at room temperature to obtain 0.94 g of type B crystals as
white crystals (58% of theoretical yield). Melting point:
148-150.degree. C.
Example 4
[0054] Preparation of Type C Crystal
[0055] The mixture of polymorphic forms of the type A and type D
crystals obtained in Reference Example 1 (300 mg) was added to
1-propanol (2.0 ml) and heated at refluxing temperature with
stirring. After the crystals were completely dissolved, the
solution was slowly cooled to room temperature with stirring. The
reaction mixture was filtered, and the filter cake was washed with
1-propanol, and dried under reduced pressure to obtain 281 mg of
type C crystals as white crystals (94% of theoretical yield).
Melting point: 144-146.degree. C.
Example 5
[0056] Preparation of Type D Crystal
[0057] 7.0 g of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolid-
inedione (semi-purified product) was add to a mixed solvent of 100
ml of ethyl acetate and 80 ml of hexane, and then heated with
stirring at refluxing temperature. After the solid material was
completely dissolved, the solution was cooled to room temperature
with stirring. The reaction mixture was filtered, and the filter
cake was washed with hexane and dried under reduced pressure to
obtain 5.4 g of type D crystals as white crystals (77% of
theoretical yield). Melting point,: 145-147.degree. C.
[0058] Elemental analysis (as C.sub.21H.sub.16FNO.sub.3S):
[0059] Calculated (%): C, 66.13; H, 4.23; N, 3.67 Found: C, 66.35;
H, 4.20; N, 3.63
Example 6
[0060] Preparation of Single Crystal of Type A
[0061] The type A crystal obtained in Example 1 or Example 2 (2.6
g) was added with toluene (50.5 g), and the mixture was heated at
100.degree. C. with gentle stirring. The mixture was then cooled to
90.degree. C. at cooling rate of 2.degree. C./min, and the solvent
was gently evaporated under reduced pressure at 300 mmHg. After the
evaporation to dryness, the residue was cooled to 30.degree. C. at,
cooling rate of 2.degree. C./min and then allowed to stand for
cooling at room temperature to obtain a transparent and colorless
single crystal of 0.21 mm.times.0.066 mm.times.0.027 mm. The
intensity of the resulting single crystal was measured by X-ray
two-dimensional diffractmeter SMART 1000 using MoK.alpha. (50 kV,
40 mA) at -170.degree. C., and then the structure was characterized
according to the direct method by conducting the high precision
structure analysis based on the full-matrix method of least
squares.
[0062] Crystallographic Data
[0063] Lattice Constant
1 a 15.843(2).ANG. b 18.380(3).ANG. c 6.0002(9).ANG. .alpha.
91.576(3).degree. .beta. 95.776(1).degree. .gamma.
84.764(4).degree.
[0064] Volume: 1730.9(4) .ANG..sup.3
[0065] Space Group: P1
[0066] Z: 4
[0067] Dx: 1.464 g/cm.sup.3
[0068] On the basis of the crystal structure, the powder pattern
was simulated to confirm that the resulting single crystal was the
type A crystal.
Example 7
[0069] Preparation of Single Crystal of Type B
[0070] The powder of the type A crystal obtained in Example 1 or
Example 2 was add to a mixed solvent of 500 .mu.l of toluene, 200
.mu.l of ethanol and 100 .mu.l of methanol and the mixture was left
stand at room temperature for about three months to obtain a
transparent and colorless single crystal of 0.3 mm.times.0.3
mm.times.0.05 mm. The intensity of the resulting single crystal was
measured by X-ray four-axes diffractmeter ENRAF-Nonius CAD4
(ENRAF-Nonius) using CuK.alpha. (40 kV, 80 mA), and then the
structure was characterized according to the direct method by
conducting the high precision structure analysis based on the
full-matrix method of least squares.
[0071] Crystallographic Data
[0072] Lattice Constant
2 a 11.158(3).ANG. b 6.586(1).ANG. c 49.243(5).ANG. .beta.
93.85(1).degree.
[0073] Volume: 3610.5(12) .ANG..sup.3
[0074] Space Group: P21/n
[0075] Z: 8
[0076] Dx: 1.403 g/cm.sup.3
[0077] On the basis of the crystal structure, the powder pattern
was simulated to confirm that the resulting single crystal was the
type B crystal.
Example 8
[0078] Preparation of Single Crystal of Type D
[0079] The powder of the type A crystal obtained in Example 1 or
Example 2 was add to a mixed solvent of 300 .mu.l of methanol, 100
.mu.l of ethanol and 400 .mu.l of acetonitrile and the mixture was
left stand at room temperature for about five days to obtain a
transparent and colorless single crystal of 0.3 mm.times.0.05
mm.times.0.02 mm. The intensity of the resulting single crystal was
measured by X-ray four-axes diffractmeter ENRAF-Nonius CAD4
(ENRAF-Nonius) using CuK.alpha. (40 kV, 80 mA), and then the
structure was characterized according to the direct method by
conducting the high precision structure analysis based on the
full-matrix method of least squares.
[0080] Crystallographic Data
[0081] Lattice Constant
3 a 18.458(2).ANG. b 5.9879(3).ANG. c 17.819(2).ANG. .beta.
115.94(1).degree.
[0082] Volume: 1771.0 (3) .ANG..sup.3
[0083] Space Group: P21/n
[0084] Z: 4
[0085] Dx: 1.427g/cm.sup.3
[0086] On the basis of the crystal structure, the powder pattern
was simulated to confirm that the resultant single crystal was that
of the type D crystal.
Test Example 1
[0087] Characteristics of Various Crystal Forms
[0088] (1) Powder X-ray Diffraction Analysis
[0089] Powder X-ray diffraction patterns of the four polymorphic
forms of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione,
i.e., the types A, B, C, and D, were determined by an X-ray
diffractometer PW-1700 or PW-1710 (Philips).
[0090] The powder X-ray diffraction patterns of the polymorphic
forms are shown in FIGS. 1 to 4. Characteristic peaks of the
crystal forms are summarized in Table 1.
4TABLE 1 Crystal form Characteristic peak (2.theta.) A Sharp peaks
at 11.4.degree., 16.9.degree., 17.6.degree., 22.3.degree. and
25.5.degree. B Sharp peaks at 10.2.degree., 21.0.degree.,
22.7.degree. and 29.0.degree. C Sharp peaks at 12.2.degree.,
14.3.degree., 17.5.degree. and 22.0.degree. D Sharp peaks at
10.6.degree., 17.4.degree., 22.1.degree. and 25.2.degree.
[0091] As clearly seen from these powder X-ray diffraction
patterns,
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione
exist as the four polymorphic forms which provide different
diffraction patterns.
[0092] The powder X-ray analyses of the four distinguishable
crystals, i.e., the type A to D crystals, were repeated several
times. As a result, slight experimental deviation of 2.theta.
values of the characteristic peaks was observed in every
determinations, mainly attributable to differences in the preferred
orientation of test samples. Accordingly, in the appended claims
and the specification, the characteristic peaks are defined as
values indicating the median of the dispersed 2.theta. values of
the characteristic peaks together with the range of dispersion. It
should thus be noted that medians of the characteristic peaks
defined in the claims and the specification are not necessarily
identical to the values of characteristic peaks shown in Table
1.
[0093] (2) Differential Scanning Calorimetry Analysis (DSC)
[0094] A sample (1-3 mg) was placed on a differential scanning
calorimetry meter DSC-7 (Perkin-Elmer), or TAS-200 (RIGAKU
CORPORATION), and measurement was performed by heating at a rate of
20.degree. C./minute.
[0095] The results obtained are shown in FIGS. 7 to 10 and Table
2.
5TABLE 2 Crystal form Characteristic A Sharp endothermic band with
a peak at 152.degree. C. B Sharp endothermic band with a peak at
128.degree. C. C Sharp endothermic band with a peak at 146.degree.
C. D Sharp endothermic band with a peak at 147.degree. C.
[0096] Each crystal form gave apparently distinguishable
endothermic peak, and the differences of the polymorphic forms were
also verified by this analysis.
[0097] (3) Microscopic Observation
[0098] Crystal shapes of the type A to D crystals were examined
under an optical microscope. As a result, it was found that the
type A and type D crystals were needles, and type A crystal was
relatively larger. It was also found that the type B and type C
crystals were composed of massive crystals in variety of sizes.
Differences in shape were also clearly recognized among the crystal
forms.
Test Example 2
[0099] Stability of the Plural Crystal Forms
[0100] (1) Change of a Crystal Form by Fusion-Solidification
[0101] A sample (1 to 3 mg) of each of the type A-D crystals was
placed on a differential scanning calorimetry meter TAS-200 (RIGAKU
CORPORATION), and fused by heating at a rate of 10.degree.
C./minute up to a temperature where the crystals were completely
fused. Then, the sample was immediately cooled to allow
re-solidification. The resulting crystal forms are shown in Table
3.
6 TABLE 3 Crystal form before the test Crystal form after the test
A A B A C A D A
[0102] Each of the different crystal forms, i.e., types A to D,
gave type A crystals after the fusion in these experiments. The
results demonstrate that the type A crystal has higher thermal
stability compared to the other crystals.
[0103] (2) Stability to Physical Impact
[0104] A sample (1 g) of each of the type A-D crystals was placed
in an agate mortar, and ground for 1 minute, and powder X-ray
diffraction pattern of the ground sample was determined. The
pattern was compared with that of the crystal form before the
grinding to examine a change of the crystal form. The results are
shown in Table 4.
7TABLE 4 Crystal form Change after grinding A No change B Partially
changed C No change D Partially changed
[0105] Partial changes due to impact by the grinding were observed
in the crystals of types B and D. Whereas, the crystals of types A
and C gave no change, which revealed their stability to physical
impact.
[0106] (3) Thermal Stability
[0107] A sample (about 50 mg) of each of the crystals of types A, C
and D was placed in a transparent glass bottle, and heated under
atmosphere in an oven at 70.degree. C. for 24 hours. After cooling,
powder X-ray diffraction pattern was measured to examine a change
of the crystal form. As a result, partial change of the crystal
form was observed in the type C crystals, whereas the type A and D
crystals gave no change in the crystal forms and were found to have
excellent thermal stability.
[0108] (4) Stability in a Solvent
[0109] The type A crystals were heated with stirring in a state of
suspension in a variety of solvents including water, methylene
chloride, hexane, ethyl acetate-hexane and ethanol, and then
examined the absence or presence of a change of the crystal form
after the treatment. As a result, no change was observed in the
type A crystals before and after the treatment.
INDUSTRIAL APPLICABILITY
[0110] The results of the above studies on the plural crystal forms
of
5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione
demonstrate that the type A crystals has apparently higher
stability compared to the other crystals. The type A crystal is the
only crystal form which is stable under the various conditions in
usual handling, storage and manufacturing process of preparations.
Furthermore, the crystal can be easily prepared with good
reproducibility according to the method described herein.
* * * * *