U.S. patent application number 11/700822 was filed with the patent office on 2007-07-05 for crystals of benzimidazole compounds.
Invention is credited to Isao Aoki, Akira Fujishima, Keiji Kamiyama.
Application Number | 20070155796 11/700822 |
Document ID | / |
Family ID | 16187808 |
Filed Date | 2007-07-05 |
United States Patent
Application |
20070155796 |
Kind Code |
A1 |
Fujishima; Akira ; et
al. |
July 5, 2007 |
Crystals of benzimidazole compounds
Abstract
Crystals of
(S)-2[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1-
H-benzimidazole or salts thereof, useful as excellent antiulcer
drugs.
Inventors: |
Fujishima; Akira;
(Sanda-shi, JP) ; Aoki; Isao; (Kawanishi-shi,
JP) ; Kamiyama; Keiji; (Ibaraki-shi, JP) |
Correspondence
Address: |
WENDEROTH, LIND & PONACK, L.L.P.
2033 K STREET N. W.
SUITE 800
WASHINGTON
DC
20006-1021
US
|
Family ID: |
16187808 |
Appl. No.: |
11/700822 |
Filed: |
February 1, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11095547 |
Apr 1, 2005 |
7189744 |
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11700822 |
Feb 1, 2007 |
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10600640 |
Jun 23, 2003 |
6903122 |
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11095547 |
Apr 1, 2005 |
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10019254 |
Dec 28, 2001 |
6608092 |
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PCT/JP00/04279 |
Jun 29, 2000 |
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10600640 |
Jun 23, 2003 |
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Current U.S.
Class: |
514/338 |
Current CPC
Class: |
C07D 401/12 20130101;
A61K 31/4439 20130101; A61P 35/00 20180101; A61P 1/04 20180101 |
Class at
Publication: |
514/338 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 30, 1999 |
JP |
186403/1999 |
Claims
1-4. (canceled)
5. A method for treating or preventing reflux esophagitis in a
mammal in need thereof, which comprises administering to said
mammal an effective amount of a crystalline compound of
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole, its hydrate or a salt thereof.
6. The method of claim 5, wherein said crystalline compound is
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]sulfinyl]-
-1H-benzimidazole.
7. The method of claim 6, wherein said crystalline compound has a
powder X-ray diffraction pattern whose characteristic peaks appear
as the lattice spacing (d) of the powder X-ray diffraction at
11.68, 6.78, 5.85, 5.73, 4.43, 4.09, 3.94, 3.90, 3.69, 3.41, 3.11
angstrom.
8. The method of claim 5, wherein said crystalline compound is
(S)-2-[[[3
-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]sulfinyl]-1H-benzim-
idazole 1.5 hydrate which has a powder X-ray diffraction pattern
whose characteristic peaks appear as the lattice spacing (d) of the
powder X-ray diffraction at 13.22, 9.60, 8.87, 8.05, 6.61, 5.92,
5.65, 5.02, 4.50, 3.57, 3.00 angstrom.
9. A method for eradicating Helicobacter pylori in a mammal in need
thereof, which comprises administering to said mammal an effective
amount of a crystalline compound of
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]sulfinyl]-
-1H-benzimidazole, its hydrate or a salt thereof.
10. The method of claim 9, wherein said crystalline compound is
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]sulfinyl]-
-1H-benzimidazole.
11. The method of claim 10, wherein said crystalline compound has a
powder X-ray diffraction pattern whose characteristic peaks appear
as the lattice spacing (d) of the powder X-ray diffraction at
11.68, 6.78, 5.85, 5.73, 4.43, 4.09, 3.94, 3.90, 3.69, 3.41, 3.11
angstrom.
12. The method of claim 9, wherein said crystalline compound is
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]sulfinyl]-
-1H-benzimidazole 1.5 hydrate which has a powder X-ray diffraction
pattern whose characteristic peaks appear as the lattice spacing
(d) of the powder X-ray diffraction at 13.22, 9.60, 8.87, 8.05,
6.61, 5.92, 5.65, 5.02, 4.50, 3.57, 3.00 angstrom.
13. The method of claim 9, further comprising administering one to
three other active ingredients.
14. The method of claim 13, wherein said crystalline compound and
said other active ingredient are administered simultaneously or in
intervals.
15. The method of claim 13, wherein said other active ingredient is
selected from the group consisting of an anti-Helicobacter pylori
action substance, an imidazole compound, a bismuth salt, a
quinoline compound and combinations thereof.
16. The method of claim 15, wherein said anti-Helicobacter pylori
action substance is selected from the group consisting of
penicillins antibiotic, macrolide antibiotic and combinations
thereof.
Description
TECHNICAL FIELD
[0001] The present invention relates to crystals of a benzimidazole
compound that possesses an antiulcer action.
BACKGROUND ART
[0002]
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfiny-
l]-1H-benzimidazole or a salt thereof, which possess an antiulcer
activity, has been described in JP 61-50978 A and the like.
DISCLOSURE OF THE INVENTION
[0003]
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfiny-
l]-1H-benzimidazole possesses a chiral sulfur within the molecule,
and two kinds of optical isomers thereof exist. As a result of
intensive investigations, the present inventors have succeeded in
the optical resolution and crystallization of the (S) isomer of
2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-b-
enzimidazole and have found for the first time that the crystals
are satisfactory enough for drugs, thereby having completed the
present invention on the basis of these findings.
[0004] In other words, the present invention relates to
(1) crystals of
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridinyl]methyl]sulfinyl]-1H-
-benzimidazole or a salt thereof,
(2) crystals of
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridinyl]methyl]sulfinyl]-1H-
-benzimidazole,
[0005] (3) the crystals as described in the above (2) which possess
a pattern of the powder X-ray diffraction whose characteristic
peaks appear at the lattice spacing (d) of the powder X-ray
diffraction of 11.68, 6.78, 5.85, 5.73, 4.43, 4.09, 3.94, 3.90,
3.69, 3.41, 3.11 angstrom (.ANG.),
(4) a pharmaceutical composition comprising the crystals as
described in the above (1) and the like.
[0006] As for the "salt" of
"(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-
-1H-benzimidazole or a salt thereof", a physiologically acceptable
salt is preferred, which is exemplified by a metal salt, a salt
with an organic base, a salt with a basic amino acid or the
like.
[0007] Examples of a metal salt include an alkaline metal salt such
as sodium salt, potassium salt, etc., an alkaline earth metal salt
such as calcium salt, magnesium salt, barium salt, etc., and the
like. A salt with an organic base is exemplified by a salt with
trimethylamine, triethylamine, pyridine, picoline, ethanolamine,
diethanolamine, triethanolamine, dicyclohexylamine,
N,N-dibenzylethylenediamine or the like. A salt with a basic amino
acid is exemplified by a salt with arginine, lysine or the
like.
[0008] Crystals of
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole or a salt thereof may be a hydrate or a
non-hydrate.
[0009] Said "hydrate" is exemplified by a 0.5 to 5.0 hydrate. Among
them, 0.5 hydrate, 1.0 hydrate, 1.5 hydrate, 2.0 hydrate, or 2.5
hydrate is preferable. Particularly preferred is 1.5 hydrate.
[0010] Crystals of
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole or a salt thereof can be obtained by subjecting
2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-b-
enzimidazole or a salt thereof to optical resolution or by
subjecting
2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzi-
midazole or a salt thereof to asymmetric oxidation to obtain the
(S)-isomer, followed by crystallization.
[0011] Examples of a method used for the optical resolution include
a per se known method such as a fractional recrystallization
method, a chiral column method, a diastereomer method and the like.
As asymmetric oxidation, a per se known method is used.
[0012] The "fractional recrystallization method" is exemplified by
a method, in which the racemate is treated with an optically active
compound [e.g., (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric
acid, (-)-tartaric acid, (+)-1-phenethylamine,
(-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.)
to form the salts, followed by separation by a fractional
recrystallization or the like, and, optionally, by subjecting the
resultant to a neutralization step to obtain the optical isomer in
the free form.
[0013] The "chiral column method" is exemplified by a method, in
which the racemate or a salt thereof is applied to a column for
separation of optical isomers (a chiral column). In the case of
liquid chromatography, for instance, there is exemplified a method,
in which the racemate is added to a chiral column such as
ENANTIO-OVM (manufactured by Toso Corporation), CHIRAL series
manufactured by Daicel Company or the like, which is eluted with
water, a buffer solution (e.g., a phosphate buffer solution), an
organic solvent (e.g., hexane, ethanol, methanol, isopropanol,
acetonitrile, trifluoroacetic acid, diethylamine, triethylamine,
etc.) or a mixed solvent thereof to separate the optical isomers.
In the case of gas chromatography, for instance, a separation
method using a chiral column such as CP-Chirasil-DeX CB
(manufactured by G-L Sciences Inc.) or the like is exemplified.
[0014] The "diastereomer method" is exemplified by a method, in
which the racemate is allowed to react with an optically active
reagent (preferably, to react with the optically active reagent at
position 1 of the benzimidazole group) to obtain a mixture of the
diastereomers, followed by treatment with a conventional separation
means (e.g., fractional recrystallization, chromatography method,
etc.) to obtain one of the diastereomers, which is then subjected
to a chemical reaction (e.g., acid hydrolysis reaction, basic
hydrolysis reaction, hydrogenolysis reaction, etc.) to cleave the
moiety of the optically active reagent, thereby obtaining the
objective optical isomer. Examples of said "optically active
reagent" include optically active organic acids such as MTPA
[.alpha.-methoxy-.alpha.-(trifluoromethyl)phenylacetic acid],
(-)-menthoxyacetic acid and the like; optically active alkoxymethyl
halides such as
(1R-endo)-2-(chloromethoxy)-1,3,3-trimethylbicyclo[2.2.1]heptane,
and the like.
[0015]
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfiny-
l]-1H-benzimidazole or a salt thereof is produced according to the
method described in JP 61-50978 A, U.S. Pat. No. 4,628,098 or the
like, or a modified method thereof.
[0016] Examples of the method for crystallization include a per se
known method such as crystallization from a solution,
crystallization from a vapor, and crystallization from a melt.
[0017] Examples of the method for said "crystallization from a
solution" include a concentration method, a slow cooling method, a
reaction method (diffusion method or electrolysis method), a
hydrothermal formation method, a fluxing agent method and the like.
Examples of the solvent to be used include aromatic hydrocarbons
(e.g., benzene, toluene, xylene, etc.), halogenated hydrocarbons
(e.g., dichloromethane, chloroform, etc.), saturated hydrocarbons
(e.g., hexane, heptane, cyclohexane, etc.), ethers (e.g., diethyl
ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitrites
(e.g., acetonitrile, etc.), ketones (e.g., acetone, etc.),
sulfoxides (e.g., dimethyl sulfoxide, etc.), acid amides (e.g.,
N,N-dimethylformamide, etc.), esters (e.g., ethyl acetate, etc.),
alcohols (e.g., methanol, ethanol, isopropyl alcohol, etc.), water
and the like. These solvents are used alone or in combination of
two or more thereof in an adequate ratio (for example, 1:1 to
1:100).
[0018] Examples of the method for said "crystallization from a
vapor" include an evaporation method (a sealed tube method or an
air stream method), a vapor phase reaction method, a chemical
transportation method or the like.
[0019] Examples of the method for said "crystallization from a
melt" include a normal freezing method (pulling-up method,
temperature gradient method or Bridgman method), a zone melting
method (zone leveling method or float zone method), a special
growth method (VLS method or liquid-phase epitaxy method) and the
like.
[0020] As for an method for analyzing the thus-obtained crystals,
generally, crystal analysis by a X-ray diffraction method is
employed. Furthermore, a method for determining the orientation of
crystals is exemplified by a mechanical method, an optical method
or the like.
[0021] The thus-obtained crystals of
(S)-2-[[[3-methyl-4-(2,2,3-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole or a salt thereof (hereinafter, sometimes,
abbreviated as "the crystals of the present invention") possesses
an excellent antiulcer activity, an anti-gastric acid secreting
activity, a mucous membrane protecting activity, an
anti-Helicobacter pylori activity and the like, and is useful as
drugs owing to the low toxicity. Moreover, crystallization of the
S-form not only increases the stability but also facilitates the
handling of the compound, thereby making it possible to manufacture
solid pharmaceutical compositions in a reproducible manner. Also, a
shorter duration of the pharmacological activity is obtained in the
case of administration of the crystals of the present invention,
resulting in allowing a long-term administration.
[0022] The crystals of the present invention are useful for
therapeutics and prophylaxis of a peptic ulcer (e.g., gastric
ulcer, duodenal ulcer, stomal ulcer, Zollinger-Ellison's syndrome,
etc.), gastritis, reflux esophagitis, NUD (non-ulcer dyspepsia),
stomach cancer, gastric MALT lymphoma and the like, eradication of
Helicobacter pylori, suppression of bleeding of upper
gastrointestinal tract caused by peptic ulcer, acute stress ulcer
and hemorrhagic gastritis, suppression of bleeding of upper
gastrointestinal tract caused by invasive stress (stress caused by
major surgery requiring postoperative intensive care,
cerebrovascular disorder requiring intensive treatment, head
injury, multiple organ failure and extensive burn), therapeutics
and prophylaxis of ulcer caused by a nonsteroidal antiinflammatory
agent; therapeutics and prophylaxis of hyperacidity and ulcer
caused by postoperative stress; pre-anesthetic medication, and the
like, in mammals (e.g., human, monkey, sheep, cow, horse, dog, cat,
rabbit, rat, mouse, etc.).
[0023] The crystals of the present invention are low in the
toxicity and can be safely administered orally or parenterally (for
example, local, rectal and intravenous administrations, or the
like) as they are or as any of pharmaceutical compositions, which
are prepared by mixing with pharmacologically acceptable carriers
according to a per se known method, such as, for example, tablets
(including sugar-coated tablets and film-coated tablets), powders,
granular preparations, capsules (including soft capsules), oral
disintegrating tablets, solutions, injectable preparations,
suppositories, sustained release preparations, patches and the
like.
[0024] The content of the crystals of the present invention in the
pharmaceutical compositions of the present invention is about 0.01
to 100% by weight based on the total weight of the composition.
Although the dose of any of said pharmaceutical compositions varies
depending on particular patient, route of administration, disease
and the like, in the case of oral administration to an adult (60
kg) as an antiulcer agent, for instance, the dose is about 0.5 to
1500 mg/day as the active ingredient, preferably about 5 to 150
mg/day. The daily dosage of the crystals of the present invention
may be administered at once or divided into 2 to 3 times per
day.
[0025] As for the pharmacologically acceptable carriers that may be
used for the manufacture of the pharmaceutical compositions of the
present invention, there are used a variety of conventional
pharmaceutically acceptable organic or inorganic carrier
substances, for example, excipients, lubricants, binding agents,
disintegrators, water-soluble high molecular substances and basic
inorganic salts for solid preparations; solvents, solubilizing
agents, suspending agents, isotonicity agents, buffering agents and
analgesics for liquid preparations, and the like. Also, as needed,
additives such as conventional preservatives, antioxidants,
coloring agents, sweeteners, acidifiers, foaming agents, flavors
and the like can be used.
[0026] Examples of said "excipients" include lactose, white soft
sugar, D-mannitol, starch, corn starch, crystalline cellulose,
light anhydrous silicic acid, titanium oxide and the like.
[0027] Examples of said "lubricants" include magnesium stearate, a
sucrose fatty acid ester, polyethylene glycol, talc, stearic acid
and the like.
[0028] Examples of said "binding agents" include hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, crystalline cellulose,
.alpha.-starch, polyvinyl pyrrolidone, gum arabic, gelatin,
Pullulan, low-substituted hydroxypropyl cellulose and the like.
[0029] Examples of said "disintegrators" include (1) crospovidon,
(2) a disintegrator that is designated as a super disintegrator
such as croscarmellose sodium (FMC-Asahi Kasei), carmellose calcium
(Gotoku Yakuhin) or the like, (3) carboxymethyl starch sodium
(e.g., manufactured by Matsutani Kagaku Kabushiki Kaisha), (4) a
low-substituted hydroxypropyl cellulose (e.g., manufactured by
Shin-Etsu Kagaku Kabushiki Kaisha), (5) corn starch, and the like.
Said "crospovidon" may be any of crosslinked polymers that have a
chemical name of 1-ethenyl-2-pyrrolidinone homopolymer, including
polyvinyl polypyrrolidone (PVPP) and so-called
1-vinyl-2-pyrrolidinone homopolymer, where specific examples
include Kollidon CL (manufactured by BASF AG), Polyplasdon XL
(manufactured by ISP Company), Polyplasdon XL-10 (manufactured by
ISP Company), Polyplasdon INF-10 (manufactured by ISP Company) and
the like.
[0030] Examples of said "water-soluble high molecular substances"
include an ethanol-soluble, water-soluble high molecular substance
[for example, a cellulose derivative such as hydroxypropyl
cellulose (hereinafter, may be described as HPC), polyvinyl
pyrrolidone and the like], an ethanol-insoluble, water-soluble high
molecular substance [for example, a cellulose derivative such as
hydroxypropylmethyl cellulose (hereinafter, may be described as
HPMC), methyl cellulose or carboxymethyl cellulose sodium, sodium
polyacrylate, polyvinyl alcohol, sodium alginate, guar gum and the
like] and the like.
[0031] Examples of said "basic inorganic salts" include a basic
inorganic salt of sodium, potassium, magnesium and/or calcium.
Preferably, it is a basic inorganic salt of magnesium and/or
calcium. More preferably, it is a basic inorganic salt of
magnesium. Examples of said basic inorganic salt of sodium include
sodium carbonate, sodium hydrogen carbonate, disodium hydrogen
phosphate and the like. Examples of said basic inorganic salt of
potassium include potassium carbonate, potassium hydrogen carbonate
and the like. Examples of said basic inorganic salt of magnesium
include magnesium carbonate heavy, magnesium carbonate, magnesium
oxide, magnesium hydroxide, magnesium metasilicate aluminate,
magnesium silicate, magnesium aluminate, synthetic hydrotalcite
(Mg.sub.6Al.sub.2(OH).sub.16.CO.sub.3.4 H.sub.2O] and alumina
magnesium hydroxide, preferably magnesium carbonate heavy,
magnesium carbonate, magnesium oxide, magnesium hydroxide and the
like. Examples of said basic inorganic salt of calcium include
precipitated calcium carbonate, calcium hydroxide and the like.
[0032] Examples of said "solvents" include water for injection,
alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive
oil and the like.
[0033] Examples of said "solubilizing agents" include polyethylene
glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol,
trisamiomethane, cholesterol, triethanolamine, sodium carbonate,
sodium citrate and the like.
[0034] Examples of said "suspending agents" include a surface
active agent such as stearyltriethanolamine, sodium lauryl sulfate,
laurylaminopropionic acid, lecithin, benzalkonium chloride,
benzethonium chloride, glycerin monostearate or the like; a
hydrophilic, high molecular substance such as, for example,
polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl
cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl
cellulose, hydroxypropyl cellulose or the like, and the like.
[0035] Examples of said "isotonicity agents" include glucose,
D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
[0036] Examples of said "buffering agents" include a buffer
solution of a phosphate, an acetate, a carbonate, a citrate or the
like, and the like.
[0037] Examples of said "analgesics" include benzyl alcohol and the
like.
[0038] Examples of said "preservatives" include a paraoxybenzoic
acid ester, chlorobutanol, benzyl alcohol, phenethyl alcohol,
dehydroacetic acid, sorbic acid and the like.
[0039] Examples of said "antioxidants" include a sulfite salt,
ascorbic acid, .alpha.-tocopherol and the like.
[0040] Examples of said "coloring agents" include a food dye such
as food yellow No. 5, food red No. 2, food blue No. 2 or the like;
edible lake dye, iron oxide red and the like.
[0041] Examples of said "sweeteners" include saccharin sodium,
dipotassium glycyrrhizinate, aspartame, stevia, somatin and the
like.
[0042] Examples of said "acidifiers" include citric acid (anhydrous
citric acid), tartaric acid, malic acid and the like.
[0043] Examples of said "foaming agents" include sodium bicarbonate
and the like.
[0044] Examples of said "flavors", which may be either synthetic or
naturally occurring, include lemon, lime, orange, menthol,
strawberry and the like.
[0045] The oral preparations can be manufactured according to a per
se known method by adding to the crystals of the present invention,
for examples, a bulking agent, a disintegrator, a binding agent, a
lubricant and the like, and by subjecting the resulting mixture to
compression molding, as needed, followed by coating according to a
per se known method for the purpose of masking of the taste,
enteric coating or durability. In the case of the manufacture of an
enteric coated preparation, an intermediary phase may be provided
between the enteric coated phase and the drug-containing phase,
according to a per se known method, for the purpose of separating
both phases.
[0046] In the case where the crystals of the present invention are
used for the manufacture of an oral rapidly disintegrating tablet,
there is exemplified a method comprising coating a core containing
crystalline cellulose and lactose with the crystals of the present
invention and a basic inorganic salt, followed by further coating
with a coating layer containing a water-soluble high molecular
substance to obtain a composition, coating the thus-obtained
composition with an enteric coating layer containing polyethylene
glycol, coating with an enteric coating layer containing triethyl
citrate, coating with an enteric coating layer containing
polyethylene glycol, further coating with mannitol to obtain fine
granules, mixing the thus-obtained fine granules with an excipient
and molding, or the like. Examples of the above-described "enteric
coating layer" include one or more of an aqueous-type enteric high
molecular base such as cellulose acetate phthalate (CAP),
hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose
acetate succinate, a methacrylate copolymer [e.g., Eudragit L30D-55
(trade name; manufactured by Rohm Company), Kollicoat MAE30DP
(trade name; manufactured by BASF AG), Poliquid PA30 (trade name;
manufactured by Sanyo Kasei Company), etc.], carboxymethylethyl
cellulose, shellac or the like; a sustained-release base such as a
methacrylate copolymer [e.g., Eudragit NE30D (trade name), Eudragit
RL30D (trade name), Eudragit RS30D (trade name), etc.] or the like;
a water-soluble high molecular substance; plasticizers such as
triethyl citrate, polyethylene glycol, acetylated monoglyceride,
triacetin, castor oil, etc., and the like. Examples of the
above-described "additives" include a water-soluble sugar alcohol
(e.g., sorbitol, mannitol, maltitol, reducing saccharized starch,
xylitol, reducing palatinose, erythritol, etc.), crystalline
cellulose (e.g., Ceolus KG 801, Avicel PH 101, Avicel PH 102,
Avicel PH 301, Avicel PH 302, Avicel RC-591 (crystalline
cellulose/carmellose sodium), etc.), a low substitution degree
hydroxypropyl cellulose (e.g., LH-22, LH-32, LH-23, LH-33
(Shin-Etsu Kagaku Kabushiki Kaisha), a mixture thereof, etc.) or
the like, where there are further used a binding agent, an
acidifier, a foaming agent, a sweetener, a flavor, a lubricant, a
coloring agent, a stabilizer, an excipient, a disintegrator and the
like.
[0047] The crystals of the present invention may be used together
with 1 to 3 kinds of other active components.
[0048] Examples of said "other active components" include an
anti-Helicobacter pylori substance, an imidazole compound, a
bismuth salt, a quinolone compound and the like. Among these, an
anti-Helicobacter pylori substance, an imidazole compound and the
like are preferable. Examples of said "anti-Helicobacter pylori
substance" include a penicillin antibiotic (e.g., amoxicillin,
benzyl penicillin, piperacillin, mecillinam, etc.), a cephem
antibiotic (e.g., cefixime, cefaclor, etc.), a macrolide antibiotic
(e.g., erythromycin, clarithromycin, etc.), a tetracycline
antibiotic (e.g., tetracycline, minocycline, streptomycin, etc.),
an aminoglycoside antibiotic (e.g., gentamycin, amikacin, etc.),
imipenem and the like. A penicillin antibiotic, a macrolide
antibiotic and the like are especially preferable. Examples of said
"imidazole compound" include metronidazole, miconazole and the
like. Examples of said "bismuth salt" include bismuth acetate,
bismuth citrate and the like. Examples of said "quinolone compound"
include ofloxacin, ciproxacin and the like.
[0049] Said "other active components" and the crystals of the
present invention may be mixed and formulated into a single
pharmaceutical composition (e.g., a tablet, a powder, a granule
preparation, a capsule (including a soft capsule), a liquid and
solution, an injection, a suppository, a sustained release
preparation, etc.) according to a per se known method, or may be
formulated separately and administered to the same subject at the
same time or at a certain interval.
[0050] The following Reference Examples and Examples further
illustrate the present invention in more detail, but they are not
intended to limit the present invention.
[0051] In the following Reference Examples and Examples, room
temperature means a temperature of about 15 to 30.degree. C.
[0052] The melting points were measured by the use of a Micro
Melting Point Apparatus (manufactured by Yanagimoto Seisakusho),
and uncorrected values are shown.
[0053] The .sup.1H-NMR spectra were measured by the use of a Varian
Gemini-2000 using CDCl.sub.3 as a solvent, and the chemical shifts
.delta. (ppm) from tetramethylsilane used as the internal standard
are shown.
[0054] The IR spectra were measured with a SHIMAZU FTIR-8200.
[0055] The UV spectra were measured with a HITACHI U-3200
Spectrophotometer.
[0056] The optical rotations [.alpha..sub.D] were measured at 20
C..degree. by the use of a DIP-370 Digital polarimeter
(manufactured by Nihon Bunko (JASCO)).
[0057] The measurement of optical purity was conducted by HPLC
using a chiral column (column: CHIRALCEL OD 4.6 mm .phi..times.250
mm, temperature: about 20 C..degree., mobile phase:
hexane/2-propanol=80/20 or hexane/2-propanol=85/15, flow rate: 1.0
mL/minute, detection wavelength: 285 nm).
[0058] The crystal data of X-ray diffraction analysis for
determining the absolute structure of the sulfoxide were measured
by the use of a 4-circle diffractometer (RIGAKU AFC5R) using the
Cu-K.alpha. radiation. An initial phase was determined by the
direct method, and the structure was refined with a SHELXL-93. The
powder X-ray diffraction was measured by the use of an X-ray Powder
Diffractometer Rigaku RINT 2500 (ultra X18) No. PX-3.
[0059] The other symbols in the present specification indicate the
following meanings.
[0060] S: singlet
[0061] d: doublet
[0062] t: triplet
[0063] q: qualtet
[0064] m: multiplet
[0065] bs: broad singlet
[0066] J: coupling constant
REFERENCE EXAMPLE 1
[0067] Preparative separation of
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole (S(-)-lansoprazole)
[0068]
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfiny-
l]-1H-benzimidazole (lansoprazole) (racemate) (3.98 g) dissolved in
the mobile phase described below (330 mL) and acetonitrile (37 mL)
was fractionated by HPLC (column: CHIRALCEL OD 20 mm.phi..times.250
mm, temperature: 30.degree. C., mobile phase:
hexane/2-propanol/ethanol=255/35/10, flow rate: 16 mL/minute,
detection wavelength: 285 nm, one shot: 20 to 25 mg). The fractions
of the optical isomer having a longer retention time were collected
and were concentrated, all lots were combined and were dissolved in
ethanol, the resulting solution was filtered through a 0.45 .mu.m
filter and the filtrate that was mixed with hexane was evaporated
to dryness again to obtain S(-)-lansoprazole (1.58 g, an optical
purity of 92.6% ee) as an amorphous material.
[0069] The thus-obtained amorphous material was fractionated again
in the same way as described above to obtain S(-)-lansoprazole
(0.94 g, an optical purity of 99.0% ee) as an amorphous
substance.
[0070] [.alpha..sub.D]=-175.4.degree. (c=1.003%, CHCl.sub.3)
REFERENCE EXAMPLE 2
[0071] Preparative separation of
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole (S(-)-lansoprazole)
[0072] Lansoprazole (racemate) (34.2 g) dissolved in 2-propanol
(1710 mL) and hexane (1140 mL) containing triethylamine (0.2%) was
fractionated by HPLC (column: CHIRALCEL OD 50 mm.phi..times.500 mm,
temperature: room temperature, mobile phase:
hexane/2-propanol=85/15, flow rate: 60 mL/minute, detection
wavelength: 285 nm, one shot: about 300 mg). The fractions of the
optical isomer having a longer retention time were collected and
were concentrated, all lots were combined and were dissolved in
ethanol (250 mL) and the resulting solution, into which
triethylamine (3 mL) was added, was then filtered through a 0.45
.mu.m filter. The filtrate was concentrated, was mixed with hexane
and was evaporated again to dryness to obtain S(-)-lansoprazole
(9.15 g, an optical purity of 93.3% ee) as an amorphous
substance.
REFERENCE EXAMPLE 3
[0073] Preparative separation of
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole (S(-)-lansoprazole)
[0074] Lansoprazole (racemate) (4.1 g) dissolved in the mobile
phase described below (100 mL) and ethanol (100 mL) was
fractionated by HPLC (column: CHIRALCEL OD 50 mm.phi..times.500 mm,
temperature; 30.degree. C., mobile phase: hexane/2-propanol=85/15,
flow rate: 60 mL/minute, detection wavelength: 285 nm, one shot:
260 to 300 mg). The fractions of the optical isomer having a longer
retention time were collected and were concentrated, all lots were
combined and were dissolved in ethanol, the resulting solution was
filtered through a 0.45 .mu.m filter and the filtrate that was
mixed with hexane was evaporated to dryness again to obtain
S(-)-lansoprazole (1.6 g) as an amorphous material.
[0075] The thus-obtained amorphous material was fractionated again
in the same way as described above to obtain S(-)-lansoprazole
(1.43 g, an optical purity of 97.4% ee) as an amorphous
substance.
EXAMPLE 1
[0076] Crystals of
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole (S(-)-lansoprazole)
[0077] The amorphous S(-)-lansoprazole (400 mg) obtained in
Reference Example 3 was dissolved in ethanol (20 mL), and the
resulting solution was decolorized by treatment with an activated
charcoal to obtain a yellow amorphous material (320 mg). The
thus-obtained amorphous material (40 mg) was dissolved in
isopropanol (0.3 mL) and was mixed with n-hexane (1 mL). The
mixture was kept in a refrigerator for one week, and the
thus-obtained single crystals were subjected to the X-ray structure
analysis to reveal that the absolute configuration of the sulfoxide
is the S configuration according to a judgment method by the use of
the Flack parameters. TABLE-US-00001 TABLE 1 Crystal data and
parameters for structure refinement Molecular formula
C.sub.16H.sub.14N.sub.3O.sub.2F.sub.3S Molecular weight 369.36
Color and shape of the crystal colorless, plate Size 0.40 .times.
0.20 .times. 0.20 (mm) Crystal system monoclinic Cell parameters a
= 8.545 (1) (.ANG.) b = 23.3495 (2) (.ANG.) c = 8.723 (1) (.ANG.)
.beta. = 103.88 (1) (.degree.) V = 1689.8 (4) (.ANG..sup.3) Space
group P2.sub.1 Z 4 Density (calculated) 1.452 (g/cm.sup.3) The
number of effective reflections/ 11.22 the number of parameters R
(I .gtoreq. 2.sigma. (I)) 0.037 Flack parameters 0.02 (2)
EXAMPLE 2
[0078] Crystals of
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole (S(-)-lansoprazole)
[0079] To the amorphous
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole (9.04 g) obtained in Reference Example 2, which
was dissolved in acetone (25 mL), was added water (15 mL) with
slight heating. The resulting mixture was allowed to stand at room
temperature overnight, was then mixed with water (10 mL) and was
sonicated. The solid material was collected by filtration, washed
with water (35 mL, 25 mL) and then washed with diisopropyl ether
(10 mL). The resulting material was dried under reduced pressure to
obtain a solid material (8.51 g). A solution of the thus-obtained
solid material (8.41 g) in acetone (30 mL) was filtered, and
diisopropyl ether (50 mL) was then added to the filtrate. Small
crystals were added therein and the resulting mixture was allowed
to stand at room temperature overnight. The precipitated crystals
were collected by filtration and were washed three times with
diisopropyl ether (10 mL). The resulting crystals were dried under
reduced pressure to obtain crystals (6.39 g). The thus-obtained
crystals (6.39 g) were dissolved in acetone (35 mL) and water (30
mL) with heating, and the resulting solution was allowed to stand
at room temperature for 1 hour. The precipitated crystals were
collected by filtration, were washed with acetone-water (1:4) (15
mL) and were dried under reduced pressure to obtain crystals (3.54
g). The thus-obtained crystals (3.54 g) were dissolved in acetone
(4 mL) with heating and thereto was added diisopropyl ether (14
mL). The resulting mixture was allowed to stand at room temperature
for 30 minutes and was then sonicated. The precipitated crystals
were collected by filtration, were washed twice with diisopropyl
ether and were dried under reduced pressure to obtain the crystals
of S(-)-lansoprazole (3.33 g, optical purity 99.4% ee).
[0080] mp: 146.0-147.0 C..degree. (decomposed)
[0081] Elemental Analysis
[0082] Calcd.: C, 52.03; H, 3.82; N, 11.38; S, 8.68; F, 15.43; O,
8.66.
[0083] Found: C, 51.96; H, 4.06; N, 11.20; S, 8.88; F, 15.40.
[0084] .sup.1H-NMR: 2.24 (3H, s), 4.39 (2H, q, J=7.8 Hz), 4.72 (1H,
d, J=13.9 Hz), 4.87 (1H, d, J=13.9 Hz), 6.68 (1H, d, J=5.8 Hz),
7.27-7.37 (2H, m), 7.48 (1H, m), 7.79 (1H, m), 8.36 (1H, d, J=5.8
Hz).
[0085] IR (v cm.sup.-1): 3083, 3036, 2967, 1584, 1478, 1441, 1306,
1267, 1163.
[0086] UV.sub.max (CHCl.sub.3): 283.9 nm
[0087] [.alpha.].sub.D=-179.1.degree. (c=0.995%, CHCl.sub.3)
TABLE-US-00002 TABLE 2 Data of powder X-ray diffraction
Half-valence Relative 2.theta. (.degree.) breadth d Value (.ANG.)
intensity(%) 7.560 0.141 11.6841 92 13.040 0.141 6.7836 65 15.140
0.165 5.8471 49 15.440 0.141 5.7342 100 20.020 0.165 4.4315 32
21.700 0.141 4.0920 99 22.540 0.141 3.9414 30 22.780 0.165 3.9004
24 24.080 0.141 3.6927 46 26.120 0.188 3.4088 39 28.680 0.282
3.1100 28
EXAMPLE 3
[0088] Crystals of
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole (S(-)-lansoprazole) 1.5 hydrate
[0089] To the amorphous
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole (100 mg) obtained in Reference Example 2, which
was dissolved in acetone (2 mL), was added water (2 mL). An
insoluble material was removed by filtration and acetone was then
allowed to be gradually evaporated from the filtrate. Small
crystals were added therein and the resulting mixture was allowed
to stand at room temperature overnight. The precipitated crystals
were collected by filtration, were washed twice with diisopropyl
ether (1 mL) and were dried under reduced pressure to obtain the
crystals of
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole (S(-)-lansoprazole) 1.5 hydrate (62 mg).
[0090] mp: 80.0-84.0.degree. C.
[0091] Elemental Analysis
[0092] Calcd.: C, 48.48; H, 4.32; N, 10.60; S, 8.09; F, 14.38; O,
14.13.
[0093] Found: C, 48.48; H, 4.28; N, 10.67. TABLE-US-00003 TABLE 3
Data of powder X-ray diffraction Half-valence Relative 2.theta.
(.degree.) breadth d Value (.ANG.) intensity(%) 6.680 0.141 13.2212
16 9.200 0.141 9.6046 30 9.960 0.165 8.8734 59 10.980 0.165 8.0513
49 13.380 0.165 6.6120 36 14.960 0.141 5.9170 42 15.680 0.165
5.6469 100 17.660 0.212 5.0180 73 19.720 0.212 4.4982 42 24.900
0.141 3.5729 26 29.780 0.235 2.9976 17
INDUSTRIAL APPLICABILITY
[0094] The crystals of the present invention possess an excellent
antiulcer action, an anti-gastric acid secreting action, a mucous
membrane protecting action, an anti-Helicobacter pylori action and
the like, and is useful as drugs owing to the low toxicity.
Moreover, crystallization of the S-form not only increases the
stability but also facilitates the handling of the compound,
thereby making it possible to manufacture the solid pharmaceutical
compositions in a reproducible manner. Also, a shorter duration of
the effect is obtained in the case of the administration of the
crystals of the present invention, resulting in allowing a
long-term administration.
* * * * *