U.S. patent application number 13/905090 was filed with the patent office on 2013-10-03 for pharmaceutical composition.
This patent application is currently assigned to TAKEDA PHARMACEUTICAL COMPANY LIMITED. The applicant listed for this patent is TAKEDA PHARMACEUTICAL COMPANY LIMITED. Invention is credited to Yasuhiro Hiraishi, Muneo Nonomura.
Application Number | 20130261156 13/905090 |
Document ID | / |
Family ID | 41327301 |
Filed Date | 2013-10-03 |
United States Patent
Application |
20130261156 |
Kind Code |
A1 |
Hiraishi; Yasuhiro ; et
al. |
October 3, 2013 |
PHARMACEUTICAL COMPOSITION
Abstract
The present invention provides a pharmaceutical composition or a
solid preparation containing a stabilized pharmaceutically active
ingredient and a stabilizing method thereof. According to the
present invention, a pharmaceutical composition can be stabilized
by containing a nonpeptidic pharmaceutically active ingredient
having a primary or secondary amino group, an excipient and an
acidic compound. In addition, a solid preparation containing a
pharmaceutically active ingredient, titanium oxide, a plasticizer
and a chain organic acid can enhance the stability of the
pharmaceutically active ingredient during light irradiation.
Inventors: |
Hiraishi; Yasuhiro;
(Osaka-Shi, JP) ; Nonomura; Muneo; (Osaka-Shi,
JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TAKEDA PHARMACEUTICAL COMPANY LIMITED |
Osaka-Shi |
|
JP |
|
|
Assignee: |
TAKEDA PHARMACEUTICAL COMPANY
LIMITED
Osaka-Shi
JP
|
Family ID: |
41327301 |
Appl. No.: |
13/905090 |
Filed: |
May 29, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13056593 |
Jan 28, 2011 |
|
|
|
PCT/JP2009/063708 |
Jul 27, 2009 |
|
|
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13905090 |
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Current U.S.
Class: |
514/333 ;
514/343 |
Current CPC
Class: |
A61P 1/00 20180101; A61K
9/2018 20130101; A61K 9/2853 20130101; A61K 31/4427 20130101; A61K
47/02 20130101; A61K 47/10 20130101; A61P 1/04 20180101; A61K 47/12
20130101; A61K 9/2866 20130101; A61K 9/2013 20130101 |
Class at
Publication: |
514/333 ;
514/343 |
International
Class: |
A61K 47/12 20060101
A61K047/12; A61K 47/10 20060101 A61K047/10; A61K 47/02 20060101
A61K047/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 28, 2008 |
JP |
2008-194219 |
Claims
1. A method of stabilizing a pharmaceutical composition comprising
a nonpeptidic pharmaceutically active ingredient having a primary
or secondary amino group and an excipient, comprising adding an
acidic compound to the pharmaceutical composition.
2. A solid preparation improved in the stability during light
irradiation, comprising a pharmaceutically active ingredient,
titanium oxide, a plasticizer and a chain organic acid.
3. The solid preparation of claim 2, wherein the plasticizer is
represented by the formula:
HOCH.sub.2(CH.sub.2OCH.sub.2).sub.nCH.sub.2OH (n=an integer of
2-870).
4. The solid preparation of claim 2, wherein the plasticizer is
polyethylene glycol (PEG).
5. The solid preparation of claim 2, wherein the chain organic acid
has pH 6.0 or below when dissolved or dispersed in water.
6. The solid preparation of claim 2, wherein the chain organic acid
has an acid dissociation constant (pKa) of a proton complex of 4.0
or below when dissolved or dispersed in water.
7. The solid preparation of claim 2, wherein the chain organic acid
is any one kind or more selected from the group consisting of
adipic acid, oleic acid, succinic acid, acetic acid, tartaric acid,
sorbic acid, fumaric acid, lactic acid, maleic acid, malonic acid,
citric acid and malic acid.
8. The solid preparation of claim 2, wherein the content (%) of the
chain organic acid is 0.01-50 wt %.
9. The solid preparation of claim 2, wherein the pharmaceutically
active ingredient is a compound represented by the formula:
##STR00019## wherein X and Y are the same or different and each is
a bond or a spacer having 1 to 20 atoms in the main chain, R.sup.4
is an optionally substituted hydrocarbon group or an optionally
substituted heterocyclic group, R.sup.2, R.sup.3 and R.sup.4 are
the same or different and each is a hydrogen atom, an optionally
substituted hydrocarbon group, an optionally substituted thienyl
group, an optionally substituted benzo[b]thienyl group, an
optionally substituted furyl group, an optionally substituted
pyridyl group, an optionally substituted pyrazolyl group, an
optionally substituted pyrimidinyl group, an acyl group, a halogen
atom, a cyano group or a nitro group, and R.sup.5 is a hydrogen
atom or an optionally substituted hydrocarbon group, or a salt
thereof.
10. The solid preparation of claim 2, wherein the pharmaceutically
active ingredient is
1-{5-(2-fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}--
N-methylmethanamine or a salt thereof,
1-[4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmet-
hanamine or a salt thereof,
N-methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-y-
l]methanamine or a salt thereof,
1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylme-
thanamine or a salt thereof,
N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]me-
thanamine or a salt thereof, or
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
-yl]-N-methylmethanamine or a salt thereof.
11. A method of stabilizing a solid preparation comprising a
pharmaceutically active ingredient, titanium oxide, and a
plasticizer during light irradiation, comprising adding a chain
organic acid to the solid preparation.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Divisional patent application of U.S.
Ser. No. 13/056,593, filed on Jan. 28, 2011 and published as US
2011-0124687 A1 on May 26, 2011. U.S. Ser. No. 13/056,593 is a
National Stage Application of PCT/JP2009/063708, filed on Jul. 27,
2009, which claims priority to Japanese Patent Application No.
2008-194219, filed on Jul. 28, 2008. The entire contents of the
above-mentioned applications are incorporated herein by
reference.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to a stabilized pharmaceutical
composition comprising a nonpeptidic pharmaceutically active
ingredient having a primary or secondary amino group, an excipient
and an acidic compound, and a stabilizing method thereof.
[0003] Furthermore, the present invention relates to a solid
preparation improved in the stability during light irradiation,
which comprises a pharmaceutically active ingredient, titanium
oxide, a plasticizer and a chain organic acid, and a stabilizing
method thereof.
BACKGROUND OF THE INVENTION
[0004] The "nonpeptidic pharmaceutically active ingredient having a
primary or secondary amino group" is widely used as a
pharmaceutically active ingredient for various diseases. For
example, patent document 1 describes a compound represented by the
following formula and a salt thereof as agents for the treatment or
prophylaxis of peptic ulcer, gastritis, erosive esophagitis and the
like.
##STR00001##
wherein r.sub.1 is a monocyclic nitrogen-containing heterocyclic
group optionally condensed with a benzene ring or a heterocycle,
the monocyclic nitrogen-containing heterocyclic group optionally
condensed with a benzene ring or a heterocycle optionally has
substituent(s), r.sub.2 is an optionally substituted C.sub.6-14
aryl group, an optionally substituted thienyl group or an
optionally substituted pyridyl group, r.sub.3 and r.sub.4 are each
a hydrogen atom, or one of r.sub.3 and r.sub.4 is a hydrogen atom,
and the other is an optionally substituted lower alkyl group, an
acyl group, a halogen atom, a cyano group or a nitro group, and
r.sub.5 is an alkyl group.
[0005] Patent document 2 describes a proton pump inhibitor (PPI)
comprising a compound represented by the following formula or a
salt thereof, or a prodrug thereof as an agent for the treatment or
prophylaxis of peptic ulcer, gastritis, erosive esophagitis and the
like.
##STR00002##
wherein Z and W are the same or different and each is a bond or a
spacer having 1 to 20 atoms in the main chain, r.sub.6 is an
optionally substituted hydrocarbon group or an optionally
substituted heterocyclic group, r.sub.7, r.sub.8 and r.sub.9 are
the same or different and each is a hydrogen atom, an optionally
substituted hydrocarbon group, an optionally substituted thienyl
group, an optionally substituted benzo[b]thienyl group, an
optionally substituted furyl group, an optionally substituted
pyridyl group, an optionally substituted pyrazolyl group, an
optionally substituted pyrimidinyl group, an acyl group, a halogen
atom, a cyano group or a nitro group, and r.sub.10 and r.sub.11 are
the same or different and each is a hydrogen atom or an optionally
substituted hydrocarbon group.
[0006] Patent document 3 describes
N-(1-octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanea-
mide (the following formula) or a pharmacologically acceptable salt
thereof as an active ingredient of a stabilized pharmaceutical
composition containing an indoline compound.
##STR00003##
[0007] Patent document 4 describes, as an improved preparation for
oral use of a compound, a pharmaceutical composition for oral
administration, which comprises at least a) ethyl
3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-met-
hyl-1H-benzoimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate
represented by the following formula or one of the pharmaceutically
acceptable salts thereof and b) one or more pharmaceutically
acceptable organic acids having water-solubility higher than 1
g/250 ml at 20.degree. C.
##STR00004##
[0008] On the other hand, regarding a stabilizer of a
pharmaceutically active ingredient in a pharmaceutical composition,
patent document 5 discloses an aqueous pharmaceutical solution
comprising an aqueous solution containing an organic acid salt of a
polymyxin antibiotic and carboxylic acid (organic acid, as a
stabilizer).
[0009] In addition, non-patent document 1 describes, for
stabilization of peptide (P66) in a nonaqueous solvent,
acidification of peptide by addition of HCl, TFA, H.sub.3PO.sub.4
and the like.
[0010] Beside the above, patent document 6 describes a
pharmaceutical composition comprising a proton pump antagonist
(acid pump antagonist, APA) and one or more basic excipients to
stabilize APA, and patent document 7 describes a sustained-release
pharmaceutical composition comprising reversible PPI, wherein APA
is stabilized with one or more basic excipients (carbonate,
magnesium salt etc.).
[0011] Patent document 8 discloses a stabilized pharmaceutical
preparation coated with a coating agent containing a) a light
shielding agent capable of generating free radical by UV light, and
b) a free radical scavenger. In addition, as the light shielding
agent capable of generating free radical by UV light, metal oxides
such as titanium oxide and the like are described, and as the free
radical scavenger, for example, organic acids such as benzoic acid
and the like are described.
[0012] In addition, non-patent document 2 describes the principles
of photocatalytic reaction of titanium oxide, and explains the
Honda Fujiyama effect that various substances adsorbed to a
photocatalytic surface are oxidized and reduced when titanium
oxide, which is one kind of the photocatalysts, is exposed to a
light having a wavelength of 380 nm or below.
CITATION LIST
Patent Literature
[0013] patent document 1: WO 2007/026916 [0014] patent document 2:
WO 2006/036024 [0015] patent document 3: JP-A-2005-263788 [0016]
patent document 4: JP-A-2007-056018 [0017] patent document 5:
JP-A-3-44333 (JP-B-2844351) [0018] patent document 6: WO
2004/089342 [0019] patent document 7: WO 2006/037766 [0020] patent
document 8: JP-A-11-147819
Non Patent Literature
[0020] [0021] non-patent document 1: International Journal of
Pharmaceutics (Volume 351, Issues 1-2, 3 Mar. 2008, Pages 1-7),
"Stabilization of a polypeptide in non-aqueous solvents" [0022]
non-patent document 2: titanium oxide (property and applied
technique): Manabu Kiyono, GIHODO SHUPPAN Co., Ltd.
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0023] An object of the present invention is to provide a
stabilized pharmaceutical composition for use of a nonpeptidic
pharmaceutically active ingredient having a primary or secondary
amino group as an active ingredient of a pharmaceutical composition
and a stabilizing method thereof.
[0024] A further object of the present invention is to provide a
solid preparation improved in the stability of a pharmaceutically
active ingredient during light irradiation, for use of a
pharmaceutically active ingredient as a solid active ingredient of
a pharmaceutical composition, and a stabilizing method thereof.
Means of Solving the Problems
[0025] The present inventors have conducted intensive studies of
stabilization of a pharmaceutical composition and found that the
stability of a pharmaceutical composition (pharmaceutically active
ingredient) can be further increased by adding an acidic compound
(e.g., particular organic acid) to a pharmaceutical composition
comprising a nonpeptidic pharmaceutically active ingredient having
a primary or secondary amino group, which resulted in the
completion of a first invention of the present invention. In
addition, they have conducted intensive studies of
photostabilization of a pharmaceutical composition and found that
the stability of a pharmaceutically active ingredient during light
irradiation can be improved by adding titanium oxide and a chain
organic acid to a solid preparation comprising the pharmaceutically
active ingredient, which resulted in the completion of a second
invention.
[0026] Accordingly, the first invention of the present invention
relates to
[1] a stabilized pharmaceutical composition comprising a
nonpeptidic pharmaceutically active ingredient having a primary or
secondary amino group, an excipient and an acidic compound, [2] the
pharmaceutical composition of the above-mentioned [1], wherein the
acidic compound is an organic acid or a salt thereof, [3] the
pharmaceutical composition of the above-mentioned [2], wherein the
nonpeptidic pharmaceutically active ingredient has a pKa value
higher than that of the organic acid or a salt thereof, [4] the
pharmaceutical composition of the above-mentioned [1], wherein the
nonpeptidic pharmaceutically active ingredient is an organic acid
salt, [5] the pharmaceutical composition of the above-mentioned
[1], wherein the excipient has pH 4.5 or above when dissolved or
dispersed in water, [6] the pharmaceutical composition of the
above-mentioned [1], wherein the excipient is any one kind or more
selected from the group consisting of mannitol, croscarmellose
sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose,
polyethylene glycol, polyvinylpyrrolidone, crystalline cellulose,
lactose, sucrose, starch, cornstarch, titanium oxide (TiO.sub.2)
and light anhydrous silicic acid, [7] the pharmaceutical
composition of the above-mentioned [1], wherein the nonpeptidic
pharmaceutically active ingredient is a salt with an unsaturated
carboxylic acid, [8] the pharmaceutical composition of the
above-mentioned [2], wherein the organic acid is any one kind or
more selected from the group consisting of adipic acid, ascorbic
acid, benzoic acid, oleic acid, succinic acid, acetic acid,
tartaric acid, sorbic acid, fumaric acid, lactic acid, maleic acid,
malonic acid, citric acid and malic acid, [9] the pharmaceutical
composition of the above-mentioned [1], wherein the nonpeptidic
pharmaceutically active ingredient is a compound represented by the
formula
##STR00005##
wherein R.sup.a is an organic residue, R.sup.b is a hydrogen atom
or a hydrocarbon group optionally having substituent(s), or a salt
thereof, [10] the pharmaceutical composition of the above-mentioned
[1], wherein the nonpeptidic pharmaceutically active ingredient is
a compound represented by the formula
##STR00006##
wherein X and Y are the same or different and each is a bond or a
spacer having 1 to 20 atoms in the main chain, R.sup.1 is an
optionally substituted hydrocarbon group or an optionally
substituted heterocyclic group, R.sup.2, R.sup.3 and R.sup.4 are
the same or different and each is a hydrogen atom, an optionally
substituted hydrocarbon group, an optionally substituted thienyl
group, an optionally substituted benzo[b]thienyl group, an
optionally substituted furyl group, an optionally substituted
pyridyl group, an optionally substituted pyrazolyl group, an
optionally substituted pyrimidinyl group, an acyl group, a halogen
atom, a cyano group or a nitro group, and R.sup.5 is a hydrogen
atom or an optionally substituted hydrocarbon group, or a salt
thereof, [11] the pharmaceutical composition of the above-mentioned
[1], wherein the nonpeptidic pharmaceutically active ingredient is
1-{5-(2-fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}--
N-methylmethanamine or a salt thereof,
1-[4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmet-
hanamine or a salt thereof,
N-methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-y-
l]methanamine or a salt thereof,
1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylme-
thanamine or a salt thereof,
N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]me-
thanamine or a salt thereof, or
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
-yl]-N-methylmethanamine or a salt thereof, [12] the pharmaceutical
composition of the above-mentioned [1], which is a solid
preparation, and [13] a method of stabilizing a pharmaceutical
composition comprising a nonpeptidic pharmaceutically active
ingredient having a primary or secondary amino group and an
excipient, comprising adding an acidic compound to the
pharmaceutical composition.
[0027] In addition, the second invention of the present invention
relates to
[14] a solid preparation improved in the stability during light
irradiation, comprising a pharmaceutically active ingredient,
titanium oxide, a plasticizer and a chain organic acid, [15] the
solid preparation of the above-mentioned [14], wherein the
plasticizer is represented by the formula
HOCH.sub.2(CH.sub.2OCH.sub.2).sub.nCH.sub.2OH
(n=an integer of 2-870), [16] the solid preparation of the
above-mentioned [14], wherein the plasticizer is polyethylene
glycol (PEG), [17] the solid preparation of the above-mentioned
[14], wherein the chain organic acid has pH 6.0 or below when
dissolved or dispersed in water, [18] the solid preparation of the
above-mentioned [14], wherein the chain organic acid has an acid
dissociation constant (pKa) of a proton complex of 4.0 or below
when dissolved or dispersed in water, [19] the solid preparation of
the above-mentioned [14], wherein the chain organic acid is any one
kind or more selected from the group consisting of adipic acid,
oleic acid, succinic acid, acetic acid, tartaric acid, sorbic acid,
fumaric acid, lactic acid, maleic acid, malonic acid, citric acid
and malic acid, [20] the solid preparation of the above-mentioned
[14], wherein the content (%) of the chain organic acid is 0.01-50
wt %, [21] the solid preparation of the above-mentioned [14],
wherein the pharmaceutically active ingredient is a compound
represented by the formula
##STR00007##
wherein X and Y are the same or different and each is a bond or a
spacer having 1 to 20 atoms in the main chain, R.sup.1 is an
optionally substituted hydrocarbon group or an optionally
substituted heterocyclic group, R.sup.2, R.sup.3 and R.sup.4 are
the same or different and each is a hydrogen atom, an optionally
substituted hydrocarbon group, an optionally substituted thienyl
group, an optionally substituted benzo[b]thienyl group, an
optionally substituted furyl group, an optionally substituted
pyridyl group, an optionally substituted pyrazolyl group, an
optionally substituted pyrimidinyl group, an acyl group, a halogen
atom, a cyano group or a nitro group, and R.sup.5 is a hydrogen
atom or an optionally substituted hydrocarbon group, or a salt
thereof, [22] the solid preparation of the above-mentioned [14],
wherein the pharmaceutically active ingredient is
1-{5-(2-fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}--
N-methylmethanamine or a salt thereof,
1-[4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmet-
hanamine or a salt thereof,
N-methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-y-
l]methanamine or a salt thereof,
1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylme-
thanamine or a salt thereof,
N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]me-
thanamine or a salt thereof, or
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
-yl]-N-methylmethanamine or a salt thereof, and [23] a method of
stabilizing a solid preparation comprising a pharmaceutically
active ingredient, titanium oxide and a plasticizer during light
irradiation, comprising adding a chain organic acid to the solid
preparation.
Effect of the Invention
[0028] According to the first invention of the present invention, a
stabilized pharmaceutical composition comprising a nonpeptidic
pharmaceutically active ingredient having a primary or secondary
amino group is provided. To be specific, since development of a
decomposed product of the pharmaceutically active ingredient
(nonpeptidic one having a primary or secondary amino group) in the
pharmaceutical composition is suppressed, a more stable
pharmaceutical composition is provided. According to the present
invention, moreover, since development of a decomposed product of
the pharmaceutically active ingredient is suppressed regardless of
being in a closed bottle/open bottle, a pharmaceutical composition
also superior in the preservation stability can be provided.
[0029] In addition, according to the second invention of the
present invention, a solid preparation improved in the stability of
a pharmaceutically active ingredient to light irradiation is
provided. To be specific, a solid preparation stable to light
irradiation can be provided by, when the pharmaceutically active
ingredient contained in the solid preparation is exposed to light,
shielding the light and suppressing an increase in a decomposed
product.
DETAILED DESCRIPTION OF THE INVENTION
[0030] Firstly, the first invention of the present invention is
explained in detail by referring to specific embodiments.
[0031] The pharmaceutical composition relating to the first
invention of the present invention is characterized by addition of
an acidic compound (third component) to a pharmaceutical
composition containing a nonpeptidic pharmaceutically active
ingredient having a primary or secondary amino group (first
component) and an excipient (second component). That is, the
composition contains at least a nonpeptidic pharmaceutically active
ingredient having a primary or secondary amino group, an excipient
and an acidic compound.
[1. Nonpeptidic Pharmaceutically Active Ingredient Having a Primary
or Secondary Amino Group (First Component)]
[0032] Examples of the first component, "nonpeptidic
pharmaceutically active ingredient having a primary or secondary
amino group", in the pharmaceutical composition of the present
invention include a compound represented by the following formula
or a salt thereof. The compound represented by the formula (A1) and
a salt thereof do not include a compound having an amide group and
a salt thereof.
##STR00008##
wherein R.sup.a is an organic residue, and R.sup.b is a hydrogen
atom or a hydrocarbon group optionally having substituent(s).
[0033] In the formula (A1), the "organic residue" for R.sup.a is a
monovalent group having 1 to 700 carbon atoms, and may contain,
besides a carbon atom, a hydrogen atom, a nitrogen atom, an oxygen
atom, a sulfur atom, a halogen atom (e.g., fluorine atom, chlorine
atom, bromine atom, iodine atom etc.) and the like. The "organic
residue" is a hydrocarbon group optionally having substituent(s).
Here, examples of the "hydrocarbon group optionally having
substituent(s)" include those similar to the "optionally
substituted hydrocarbon group" for the below-mentioned R.sup.40.
When the hydrocarbon group has two or more substituents, they may
form a ring.
[0034] Examples of the "hydrocarbon group optionally having
substituent(s)" for R.sup.b in the formula (A1) include those
similar to the "optionally substituted hydrocarbon group" for
R.sup.5 in a compound represented by the following (A2) to be
described in detail in the following.
[0035] In the nonpeptidic pharmaceutically active ingredient having
a primary or secondary amino group, which is represented by the
formula (A1), the more preferred are, for example, a compound
represented by the following formula (A1') and a salt thereof.
##STR00009##
wherein R.sup.C is an organic residue, and Y is a bond or a spacer
having 1 to 20 atoms in the main chain.
[0036] In the above-mentioned formula (A1'), the "organic residue"
for R.sup.c is as defined above.
[0037] In the above-mentioned formula (A1'), examples of the
"spacer having 1 to 20 atoms in the main chain" for Y include those
similar to Y in a compound represented by the following (A2).
[0038] Preferable examples of the above-mentioned nonpeptidic
pharmaceutically active ingredients having a primary or secondary
amino group include a compound disclosed in WO 2006/036024
represented by the following formula (A2) and a salt thereof.
##STR00010##
wherein X and Y are the same or different and each is a bond or a
spacer having 1 to 20 atoms in the main chain, R.sup.1 is an
optionally substituted hydrocarbon group or an optionally
substituted heterocyclic group, R.sup.2, R.sup.3 and R.sup.4 are
the same or different and each is a hydrogen atom, an optionally
substituted hydrocarbon group, an optionally substituted thienyl
group, an optionally substituted benzo[b]thienyl group, an
optionally substituted furyl group, an optionally substituted
pyridyl group, an optionally substituted pyrazolyl group, an
optionally substituted pyrimidinyl group, an acyl group, a halogen
atom, a cyano group or a nitro group, and R.sup.5 is a hydrogen
atom or an optionally substituted hydrocarbon group.
[0039] In the formula (A2), the "spacer having 1 to 20 atoms in the
main chain" for X or Y means a divalent group having 1 to 20
contiguous atoms in the main chain. Here, the "number of atoms in
the main chain" is counted such that the number of atoms in the
main chain becomes minimum.
[0040] As the "spacer having 1 to 20 atoms in the main chain", for
example, a divalent group that can be formed with 1 to 5
(preferably 1 to 3) contiguous groups selected from
--O--;
--S--;
--CO--;
--SO--;
--SO.sub.2--;
[0041] --NR.sup.40-- (wherein R.sup.40 is a hydrogen atom, an
optionally substituted hydrocarbon group, an optionally substituted
(e.g., halogenated) C.sub.1-6 alkyl-carbonyl, or an optionally
substituted (e.g., halogenated) C.sub.1-6 alkylsulfonyl); and a
divalent C.sub.1-6 aliphatic hydrocarbon group optionally having
substituent(s) and the like can be mentioned.
[0042] As the "hydrocarbon group" of the "optionally substituted
hydrocarbon group" for R.sup.40, for example, a chain or cyclic
hydrocarbon group (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
aralkyl etc.) can be mentioned. Of these, a chain or cyclic
hydrocarbon group having 1 to 16 carbon atoms and the like are
preferable.
[0043] As the "alkyl", for example, C.sub.2-6 alkyl (e.g., methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, hexyl etc.) and the like can be mentioned.
[0044] As the "alkenyl", for example, C.sub.2-6 alkenyl (e.g.,
vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl,
2-methyl-2-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl etc.)
and the like can be mentioned.
[0045] As the "alkynyl", for example, C.sub.2-6 alkynyl (e.g.,
ethynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl
etc.) and the like can be mentioned.
[0046] As the "cycloalkyl", for example, C.sub.3-7 cycloalkyl
(e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl etc.) and the like can be mentioned.
[0047] As the "aryl", for example, C.sub.6-14 aryl (e.g., phenyl,
1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl,
2-anthryl etc.) and the like can be mentioned.
[0048] As the "aralkyl", for example, C.sub.7-26 aralkyl (e.g.,
phenyl-C.sub.1-6 alkyl, naphthyl-C.sub.1-6 alkyl or
diphenyl-C.sub.1-4 alkyl etc. such as benzyl, phenethyl,
diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl,
2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl
and the like) and the like can be mentioned.
[0049] When the above-mentioned hydrocarbon group is an alkyl, an
alkenyl or an alkynyl, the hydrocarbon group is optionally
substituted by 1 to 3 substituents selected from (1) a halogen atom
(e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodine
atom etc.), (2) nitro, (3) cyano, (4) hydroxy, (5) C.sub.1-6 alkoxy
optionally having 1 to 3 halogen atoms (e.g., a fluorine atom, a
chlorine atom, a bromine atom, an iodine atom) (e.g., methoxy,
ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,
pentyloxy, hexyloxy, fluoromethoxy etc.), (6) C.sub.6-14 aryloxy
(e.g., phenyloxy, naphthyloxy etc.), (7) C.sub.7-16 aralkyloxy
(e.g., benzyloxy, phenethyloxy, diphenylmethyloxy,
1-naphthylmethyloxy, 2-naphthylmethyloxy, 2,2-diphenylethyloxy,
3-phenylpropyloxy, 4-phenylbutyloxy, 5-phenylpentyloxy etc.), (8)
mercapto, (9) C.sub.1-6 alkylthio optionally having 1 to 3 halogen
atoms (e.g., a fluorine atom, a chlorine atom, a bromine atom, an
iodine atom) (e.g., methylthio, difluoromethylthio,
trifluoromethylthio, ethylthio, propylthio, isopropylthio,
butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio etc.),
(10) C.sub.6-14 arylthio (e.g., phenylthio, naphthylthio etc.),
(11) C.sub.7-16 aralkylthio (e.g., benzylthio, phenethylthio,
diphenylmethylthio, 1-naphthylmethylthio, 2-naphthylmethylthio,
2,2-diphenylethylthio, 3-phenylpropylthio, 4-phenylbutylthio,
5-phenylpentylthio etc.), (12) amino, (13) mono-C.sub.1-6
alkylamino (e.g., methylamino, ethylamino etc.), (14)
mono-C.sub.6-14 arylamino (e.g., phenylamino, 1-naphthylamino,
2-naphthylamino etc.), (15) mono-C.sub.7-16 aralkylamino (e.g.,
benzylamino etc.), (16) di-C.sub.1-6 alkylamino (e.g.,
dimethylamino, diethylamino etc.), (17) di-C.sub.6-14 arylamino
(e.g., diphenylamino etc.), (18) di-C.sub.7-16 aralkylamino (e.g.,
dibenzylamino etc.), (19) formyl, (20) C.sub.1-6 alkyl-carbonyl
(e.g., acetyl, propionyl etc.), (21) C.sub.6-14 aryl-carbonyl
(e.g., benzoyl, 1-naphthoyl, 2-naphthoyl etc.), (22) carboxyl, (23)
C.sub.1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, tert-butoxycarbonyl etc.), (24) C.sub.6-14
aryloxy-carbonyl (e.g., phenoxycarbonyl etc.), (25) carbamoyl, (26)
thiocarbamoyl, (27) mono-C.sub.1-6 alkyl-carbamoyl (e.g.,
methylcarbamoyl, ethylcarbamoyl etc.), (28) di-C.sub.1-6
alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl,
ethylmethylcarbamoyl etc.), (29) C.sub.6-14 aryl-carbamoyl (e.g.,
phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.),
(30) C.sub.1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl
etc.), (31) C.sub.6-14 arylsulfonyl (e.g., phenylsulfonyl,
1-naphthylsulfonyl, 2-naphthylsulfonyl etc.), (32) C.sub.1-6
alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl etc.), (33)
C.sub.6-14 arylsulfinyl (e.g., phenylsulfinyl, 1-naphthylsulfinyl,
2-naphthylsulfinyl etc.), (34) formylamino, (35) C.sub.1-6
alkyl-carbonylamino (e.g., acetylamino etc.), (36) C.sub.6-14
aryl-carbonylamino (e.g., benzoylamino, naphthoylamino etc.), (37)
C.sub.1-6 alkoxy-carbonylamino (e.g., methoxycarbonylamino,
ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino
etc.), (38) C.sub.1-6 alkylsulfonylamino (e.g.,
methylsulfonylamino, ethylsulfonylamino etc.), (39) C.sub.6-14
arylsulfonylamino (e.g., phenylsulfonylamino,
2-naphthylsulfonylamino, 1-naphthylsulfonylamino etc.), (40)
C.sub.1-6 alkyl-carbonyloxy (e.g., acetoxy, propionyloxy etc.),
(41) C.sub.6-14 aryl-carbonyloxy (e.g., benzoyloxy,
naphthylcarbonyloxy etc.), (42) C.sub.1-6 alkoxy-carbonyloxy (e.g.,
methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,
butoxycarbonyloxy etc.), (43) mono-C.sub.1-6 alkyl-carbamoyloxy
(e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.), (44)
di-C.sub.1-6 alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,
diethylcarbamoyloxy etc.), (45) C.sub.6-14 aryl-carbamoyloxy (e.g.,
phenylcarbamoyloxy, naphthylcarbamoyloxy etc.), (46) a 5- to
7-membered saturated cyclic amino optionally containing, besides
one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero
atoms selected from a nitrogen atom, a sulfur atom and an oxygen
atom (e.g., pyrrolidin-1-yl, piperidino, piperazin-1-yl,
morpholino, thiomorpholino, hexahydroazepin-1-yl etc.), (47) a 5-
to 10-membered aromatic heterocyclic group containing, besides
carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a
nitrogen atom, a sulfur atom and an oxygen atom (e.g., 2-thienyl,
3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl,
4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl,
4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl,
2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,
2-benzo[b]furanyl, 3-benzo[b]furanyl etc.), (48) C.sub.1-3
alkylenedioxy (e.g., methylenedioxy, ethylenedioxy etc.), and (49)
C.sub.3-7 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl etc.) (hereinafter to be referred to as
substituent group A) and the like. The substituent may have 1 to 4
substituents at substitutable position. Examples of such
substituent include those similar to substituents in substituent
group A.
[0050] When the above-mentioned hydrocarbon group is a cycloalkyl,
an aryl or an aralkyl, the hydrocarbon group is optionally
substituted by 1 to 5 (preferably 1 to 3) substituents selected
from (1) a halogen atom (e.g., a fluorine atom, a chlorine atom, a
bromine atom, an iodine atom etc.), (2) nitro, (3) cyano, (4)
hydroxy, (5) C.sub.1-6 alkoxy optionally having 1 to 3 halogen
atoms (e.g., a fluorine atom, a chlorine atom, a bromine atom, an
iodine atom) (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, sec-butoxy, pentyloxy, hexyloxy, fluoromethoxy etc.),
(6) C.sub.6-14 aryloxy (e.g., phenyloxy, naphthyloxy etc.), (7)
C.sub.7-16 aralkyloxy (e.g., benzyloxy, phenethyloxy,
diphenylmethyloxy, 1-naphthylmethyloxy, 2-naphthylmethyloxy,
2,2-diphenylethyloxy, 3-phenylpropyloxy, 4-phenylbutyloxy,
5-phenylpentyloxy etc.), (8) mercapto, (9) C.sub.1-6 alkylthio
optionally having 1 to 3 halogen atoms (e.g., a fluorine atom, a
chlorine atom, a bromine atom, an iodine atom) (e.g., methylthio,
difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,
isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio,
hexylthio etc.), (10) C.sub.6-14 arylthio (e.g., phenylthio,
naphthylthio etc.), (11) C.sub.7-16 aralkylthio (e.g., benzylthio,
phenethylthio, diphenylmethylthio, 1-naphthylmethylthio,
2-naphthylmethylthio, 2,2-diphenylethylthio, 3-phenylpropylthio,
4-phenylbutylthio, 5-phenylpentylthio etc.), (12) amino, (13)
mono-C.sub.1-6 alkylamino (e.g., methylamino, ethylamino etc.),
(14) mono-C.sub.6-14 arylamino (e.g., phenylamino, 1-naphthylamino,
2-naphthylamino etc.), (15) mono-C.sub.7-16 aralkylamino (e.g.,
benzylamino etc.), (16) di-C.sub.1-6 alkylamino (e.g.,
dimethylamino, diethylamino etc.), (17) di-C.sub.6-14 arylamino
(e.g., diphenylamino etc.), (18) di-C.sub.7-16 aralkylamino (e.g.,
dibenzylamino etc.), (19) formyl, (20) C.sub.1-6 alkyl-carbonyl
(e.g., acetyl, propionyl etc.), (21) C.sub.6-14 aryl-carbonyl
(e.g., benzoyl, 1-naphthoyl, 2-naphthoyl etc.), (22) carboxyl, (23)
C.sub.1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, tert-butoxycarbonyl etc.), (24) C.sub.6-14
aryloxy-carbonyl (e.g., phenoxycarbonyl etc.), (25) carbamoyl, (26)
thiocarbamoyl, (27) mono-C.sub.1-6 alkyl-carbamoyl (e.g.,
methylcarbamoyl, ethylcarbamoyl etc.), (28) di-C.sub.1-6
alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl,
ethylmethylcarbamoyl etc.), (29) C.sub.6-14 aryl-carbamoyl (e.g.,
phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.),
(30) C.sub.1-6 alkylsulfonyl optionally having 1 to 3 halogen atoms
(e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodine
atom) (e.g., methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl
etc.), (31) C.sub.6-14 arylsulfonyl (e.g., phenylsulfonyl,
1-naphthylsulfonyl, 2-naphthylsulfonyl etc.), (32) C.sub.1-6
alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl etc.), (33)
C.sub.6-14 arylsulfinyl (e.g., phenylsulfinyl, 1-naphthylsulfinyl,
2-naphthylsulfinyl etc.), (34) formylamino, (35) C.sub.1-6
alkyl-carbonylamino (e.g., acetylamino etc.), (36) C.sub.6-14
aryl-carbonylamino (e.g., benzoylamino, naphthoylamino etc.), (37)
C.sub.1-6 alkoxy-carbonylamino (e.g., methoxycarbonylamino,
ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino
etc.), (38) C.sub.1-6 alkylsulfonylamino (e.g.,
methylsulfonylamino, ethylsulfonylamino etc.), (39) C.sub.6-14
arylsulfonylamino (e.g., phenylsulfonylamino,
2-naphthylsulfonylamino, 1-naphthylsulfonylamino etc.), (40)
C.sub.1-6 alkyl-carbonyloxy (e.g., acetoxy, propionyloxy etc.),
(41) C.sub.6-14 aryl-carbonyloxy (e.g., benzoyloxy,
naphthylcarbonyloxy etc.), (42) C.sub.1-6 alkoxy-carbonyloxy (e.g.,
methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,
butoxycarbonyloxy etc.), (43) mono-C.sub.1-6 alkyl-carbamoyloxy
(e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.), (44)
di-C.sub.1-6 alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,
diethylcarbamoyloxy etc.), (45) C.sub.6-14 aryl-carbamoyloxy (e.g.,
phenylcarbamoyloxy, naphthylcarbamoyloxy etc.), (46) a 5- to
7-membered saturated cyclic amino optionally containing, besides
one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero
atoms selected from a nitrogen atom, a sulfur atom and an oxygen
atom (e.g., pyrrolidin-1-yl, piperidino, piperazin-1-yl,
morpholino, thiomorpholino, hexahydroazepin-1-yl etc.), (47) a 5-
to 10-membered aromatic heterocyclic group containing, besides
carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a
nitrogen atom, a sulfur atom and an oxygen atom (e.g., 2-thienyl,
3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl,
4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl,
4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl,
2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,
2-benzo[b]furanyl, 3-benzo[b]furanyl etc.), (48) C.sub.1-3
alkylenedioxy (e.g., methylenedioxy, ethylenedioxy etc.), (49)
C.sub.3-7 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl etc.), (50) C.sub.1-6 alkyl group (e.g.,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl,
isohexyl etc.) optionally having 1 to 3 halogen atoms (e.g., a
fluorine atom, a chlorine atom, a bromine atom, an iodine atom) or
hydroxy groups, (51) a C.sub.2-6 alkenyl group (e.g., allyl,
isopropenyl, isobutenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl etc.)
optionally having 1 to 3 halogen atoms (e.g., a fluorine atom, a
chlorine atom, a bromine atom, an iodine atom), (52) a C.sub.2-6
alkynyl group (e.g., propargyl, 2-butynyl, 3-butynyl, 3-pentynyl,
3-hexynyl etc.), (53) mono-C.sub.3-7 cycloalkyl-carbamoyl (e.g.,
cyclopropylcarbamoyl, cyclobutylcarbamoyl etc.), and (54) a 5 to
10-membered heterocyclyl-carbonyl containing, besides carbon atom,
one or two kinds of 1 to 4 hetero atoms selected from a nitrogen
atom, a sulfur atom and an oxygen atom (e.g., 4-morpholinocarbonyl
etc.) (hereinafter to be referred to as substituent group B) and
the like.
[0051] In the present specification, the substituent of the
"optionally substituted hydrocarbon group" does not include an oxo
group.
[0052] As the "optionally halogenated C.sub.1-6 alkyl-carbonyl" for
R.sup.40, for example, C.sub.1-6 alkyl-carbonyl optionally having 1
to 5, preferably 1 to 3 halogen atoms (e.g., a fluorine atom, a
chlorine atom, a bromine atom, an iodine atom and the like) at
substitutable positions and the like can be mentioned. Specific
examples include, for example, acetyl, monochloroacetyl,
trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl,
hexanoyl and the like.
[0053] As the "optionally halogenated C.sub.1-6 alkylsulfonyl" for
R.sup.40, for example, C.sub.1-6 alkylsulfonyl optionally having 1
to 5, preferably 1 to 3 halogen atoms (e.g., a fluorine atom, a
chlorine atom, a bromine atom, an iodine atom and the like) at
substitutable positions and the like can be mentioned. Specific
examples include, for example, methylsulfonyl,
difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl,
propylsulfonyl, isopropylsulfonyl, butylsulfonyl,
4,4,4-trifluorobutylsulfonyl, sec-butylsulfonyl,
tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.
[0054] As the "divalent C.sub.1-6 aliphatic hydrocarbon group" of
the aforementioned "divalent C.sub.1-6 aliphatic hydrocarbon group
optionally having substituent(s)", an alkylene group, an alkenylene
group, an alkynylene group can be mentioned, for example,
(1) a C.sub.1-6 alkylene (e.g., --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--, --(CH.sub.2).sub.5--,
--(CH.sub.2).sub.6--, --CH(CH.sub.3)--, --C(CH.sub.3).sub.2--,
--(CH(CH.sub.3)).sub.2--, --(CH.sub.2).sub.2C(CH.sub.3).sub.2--,
--(CH.sub.2).sub.3C(CH.sub.3).sub.2-- and the like); (2) a
C.sub.2-6 alkenylene (e.g., --CH.dbd.CH--, --CH.sub.2--CH.dbd.CH--,
--CH.dbd.CH--CH.sub.2--, --CH.dbd.CH--CH.sub.2--CH.sub.2--,
--C(CH.sub.3).sub.2--CH.dbd.CH--,
--CH.sub.2--CH.dbd.CH--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.dbd.CH--, --CH.dbd.CH--CH.dbd.CH--,
--CH.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2-- and the like); (3) a
C.sub.2-6 alkynylene (e.g., --C.ident.C--, --CH.sub.2--C.ident.C--,
--CH.sub.2--C.ident.C--CH.sub.2--CH.sub.2-- and the like) and the
like can be mentioned.
[0055] As the "substituent" of the "divalent C.sub.1-6 aliphatic
hydrocarbon group optionally having substituent(s)", for example,
those similar to the substituents of the alkyl, alkenyl or alkynyl
exemplified as the aforementioned "optionally substituted
hydrocarbon group" for R.sup.40, can be mentioned, particularly,
halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine
atom, an iodine atom), hydroxy and the like are preferable. The
number of the substituents is, for example, 1 to 5, preferably 1 to
3.
[0056] As preferable examples of the "spacer having 1 to 20 atoms
in the main chain"
(1) an optionally substituted alkylene group: specifically, a
C.sub.1-20 alkylene (e.g., --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--, --CH(OH)--(CH.sub.2).sub.2--,
--(CH.sub.2).sub.4--, --(CH.sub.2).sub.5--, --(CH.sub.2).sub.6--,
--CHCH.sub.3--, --C(CH.sub.3).sub.2--, --CH(CF.sub.3)--,
--(CH(CH.sub.3)).sub.2--, --(CF.sub.2).sub.2--,
--(CH.sub.2).sub.2C(CH.sub.3).sub.2--,
--(CH.sub.2).sub.3C(CH.sub.3).sub.2--, --(CH.sub.2).sub.7--,
--(CH.sub.2).sub.8--, --(CH.sub.2).sub.9--, --(CH.sub.2).sub.10--,
--(CH.sub.2).sub.11--, --(CH.sub.2).sub.12--,
--(CH.sub.2).sub.13--, --(CH.sub.2).sub.14--,
--(CH.sub.2).sub.15--, --(CH.sub.2).sub.16--,
--(CH.sub.2).sub.17--, --(CH.sub.2).sub.18--,
--(CH.sub.2).sub.19--, --(CH.sub.2).sub.20-- and the like)
optionally having 1 to 3 substituents (preferably, halogen atom,
hydroxy and the like); (2) an optionally substituted alkenylene
group: specifically, a C.sub.2-20 alkenylene (e.g., --CH.dbd.CH--,
--CH.sub.2--CH.dbd.CH--, --CH.dbd.CH--CH.sub.2--,
--CH.dbd.CH--CH.sub.2--CH.sub.2--, --CH.sub.2--CF.dbd.CH--,
--C(CH.sub.3).sub.2--CH.dbd.CH--,
--CH.sub.2--CH.dbd.CH--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.dbd.CH--, --CH.dbd.CH--CH.dbd.CH--,
--CH.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2-- and the like)
optionally having 1 to 3 substituents (preferably, halogen atom,
hydroxy and the like); (3) an optionally substituted alkynylene
group: specifically, a C.sub.2-20 alkynylene (e.g., --C.ident.C--,
--CH.sub.2--C.ident.C--,
--CH.sub.2--C.ident.C--CH.sub.2--CH.sub.2-- and the like)
optionally having 1 to 3 substituents (preferably, halogen atom,
hydroxy and the like); (4)
--(CH.sub.2).sub.w1aO(CH.sub.2).sub.w2a--,
--(CH.sub.2).sub.w1aS(CH.sub.2).sub.w2a--,
--(CH.sub.2).sub.w1aCO(CH.sub.2).sub.w2a--,
--(CH.sub.2).sub.w1aSO(CH.sub.2).sub.w2a--,
--(CH.sub.2).sub.w1aSO.sub.2(CH.sub.2).sub.w2a--,
--(CH.sub.2).sub.w1aNR.sup.40(CH.sub.2).sub.w2a--; (5)
--(CH.sub.2).sub.w3aCO--,
--(CH.sub.2).sub.w3aCONR.sup.40(CH.sub.2).sub.w4a--,
--(CH.sub.2).sub.w3aNR.sup.40CO(CH.sub.2).sub.w4a--,
--(CH.sub.2).sub.w3aSO.sub.2NR.sup.40(CH.sub.2).sub.w4a--,
--(CH.sub.2).sub.w3aNR.sup.40SO.sub.2(CH.sub.2).sub.w4a--,
--(CH.sub.2).sub.w3aCOO(CH.sub.2).sub.w4a--; (6)
--(CH.sub.2).sub.w5aNR.sup.40CONR.sup.40b(CH.sub.2).sub.w6a--;
wherein R.sup.40 is as defined above; R.sup.40b is as defined as
R.sup.40; w1a and w2a are each an integer of 0 to 19, and w1a+w2a
is 0 to 19; w3a and w4a are each an integer of 0 to 18, and w3a+w4a
is 0 to 18; w5a and w6a are each an integer of 0 to 17, and w5a+w6a
is 0 to 17, and the like can be mentioned.
[0057] As the aforementioned "spacer having 1 to 20 atoms in the
main chain", the following "spacer having 1 to 8 atoms in the main
chain" is preferable.
(1) a C.sub.1-8 alkylene optionally having 1 to 3 substituents
(preferably, halogen atom, hydroxy and the like) (e.g.,
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--CH(OH)--(CH.sub.2).sub.2--, --(CH.sub.2).sub.4--,
--(CH.sub.2).sub.5--, --(CH.sub.2).sub.6--, --CHCH.sub.3--,
--C(CH.sub.3).sub.2--, --CH(CF.sub.3)--, --(CH(CH.sub.3)).sub.2--,
--(CF.sub.2).sub.2--, --(CH.sub.2).sub.2C(CH.sub.3).sub.2--,
--(CH.sub.2).sub.3C(CH.sub.3).sub.2-- and the like); (2) a
C.sub.2-8 alkenylene optionally having 1 to 3 substituents
(preferably, halogen atom, hydroxy and the like) (e.g.,
--CH.dbd.CH--, --CH.sub.2--CH.dbd.CH--, --CH.dbd.CH--CH.sub.2--,
--CH.dbd.CH--CH.sub.2--CH.sub.2--, --CH.sub.2--CF.dbd.CH--,
--C(CH.sub.3).sub.2--CH.dbd.CH--,
--CH.sub.2--CH.dbd.CH--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.dbd.CH--, --CH.dbd.CH--CH.dbd.CH--,
--CH.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2-- and the like); (3) a
C.sub.2-8 alkynylene (e.g., --C.ident.C--, --CH.sub.2--C.ident.C--,
--CH.sub.2--C.ident.C--CH.sub.2--CH.sub.2-- and the like)
optionally having 1 to 3 substituents (preferably, halogen atom,
hydroxy and the like); (4) --(CH.sub.2).sub.w1O(CH.sub.2).sub.w2--,
--(CH.sub.2).sub.w1S(CH.sub.2).sub.w2--,
--(CH.sub.2).sub.w1CO(CH.sub.2).sub.w2--,
--(CH.sub.2).sub.w1SO(CH.sub.2).sub.w2--,
--(CH.sub.2).sub.w1SO.sub.2(CH.sub.2).sub.w2--,
--(CH.sub.2).sub.w1NR.sup.40(CH.sub.2).sub.w2--; (5)
--(CH.sub.2).sub.w3CO--,
--(CH.sub.2).sub.w3CONR.sup.40(CH.sub.2).sub.w4--,
--(CH.sub.2).sub.w3NR.sup.40CO(CH.sub.2).sub.w4--,
--(CH.sub.2).sub.w3SO.sub.2NR.sup.40(CH.sub.2).sub.w4--,
--(CH.sub.2).sub.w3NR.sup.40SO.sub.2CH.sub.2).sub.w4--,
--(CH.sub.2).sub.w3COO(CH.sub.2).sub.w4--; (6)
--(CH.sub.2).sub.w5NR.sup.40CONR.sup.40b(CH.sub.2).sub.w6--;
wherein R.sup.40 is as defined above; R.sup.40b is as defined as
R.sup.40; w1 and w2 are each an integer of 0 to 5, and w1+w2 is 0
to 7; w3 and w4 are each an integer of 0 to 4, and w3+w4 is 0 to 6;
w5 and w6 are each an integer of 0 to 3, and w5+w6 is 0 to 5, and
the like can be mentioned.
[0058] The "spacer having 1 to 20 atoms in the main chain" is
preferably the following (1) to (6).
(1) --SO.sub.2--; (2) --SO.sub.2--N(R.sup.7)-- wherein R.sup.7 is a
hydrogen atom or an optionally substituted hydrocarbon group, and
as the "optionally substituted hydrocarbon group" for R.sup.7,
those similar to the aforementioned "optionally substituted
hydrocarbon group" for R.sup.40 can be mentioned; (3)
--N(R.sup.8)--SO.sub.2-- wherein R.sup.8 is a hydrogen atom or an
optionally substituted hydrocarbon group, and as the "optionally
substituted hydrocarbon group" for R.sup.8, those similar to the
aforementioned "optionally substituted hydrocarbon group" for
R.sup.40 can be mentioned; (4) --N(R.sup.9)-- wherein R.sup.9 is a
hydrogen atom or an optionally substituted hydrocarbon group, and
as the "optionally substituted hydrocarbon group" for R.sup.9,
those similar to the aforementioned "optionally substituted
hydrocarbon group" for R.sup.40 can be mentioned; (5) --O--; (6) an
optionally substituted alkylene group, preferably a C.sub.1-8
alkylene optionally having 1 to 3 substituents (preferably, halogen
atom, hydroxy and the like) (e.g., --CH.sub.2--,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--CH(OH)--(CH.sub.2).sub.2--, --(CH.sub.2).sub.4--,
--(CH.sub.2).sub.5--, --(CH.sub.2).sub.6--, --CHCH.sub.3--,
--C(CH.sub.3).sub.2--, --CH(CF.sub.3)--, --(CH(CH.sub.3)).sub.2--,
--(CF.sub.2).sub.2--, --(CH.sub.2).sub.2C(CH.sub.3).sub.2--,
--(CH.sub.2).sub.3C(CH.sub.3).sub.2-- and the like).
[0059] In the formula (A2), X is preferably --SO.sub.2--,
--SO.sub.2--N(R.sup.7)-- (wherein R.sup.7 is as defined above),
--N(R.sup.8)--SO.sub.2-- (wherein R.sup.8 is as defined above),
--N(R.sup.9)-- (wherein R.sup.9 is as defined above) or --O--,
particularly preferably --SO.sub.2--.
[0060] Y is preferably a bond or a C.sub.1-8 alkylene (e.g.,
--CH.sub.2--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, --(CH.sub.2).sub.5--, --(CH.sub.2).sub.6--,
--CHCH.sub.3--, --C(CH.sub.3).sub.2--, --(CH(CH.sub.3)).sub.2--,
--(CH.sub.2).sub.2C(CH.sub.3).sub.2--,
--(CH.sub.2).sub.3C(CH.sub.3).sub.2-- and the like).
[0061] In the aforementioned formula (A2), R.sup.1 is an optionally
substituted hydrocarbon group or an optionally substituted
heterocyclic group.
[0062] As the "optionally substituted hydrocarbon group", those
similar to the aforementioned "optionally substituted hydrocarbon
group" for R.sup.40 can be mentioned.
[0063] As the "heterocyclic group" of the "optionally substituted
heterocyclic group", for example, a 3 to 8-membered heterocyclic
group (preferably 5- or 6-membered heterocyclic group) containing 1
to 4 hetero atoms selected from a nitrogen atom (optionally
oxidized), an oxygen atom, a sulfur atom (optionally mono- or
di-oxidized) and the like; or a group formed by condensing a 3 to
8-membered heterocyclic group (preferably 5- or 6-membered
heterocyclic group) containing 1 to 4 hetero atoms selected from a
nitrogen atom (optionally oxidized), an oxygen atom, a sulfur atom
(optionally mono- or di-oxidized) and the like, and a benzene ring
or a 3 to 8-membered heterocyclic group (preferably 5- or
6-membered heterocyclic group) containing 1 to 4 hetero atoms
selected from a nitrogen atom (optionally oxidized), an oxygen
atom, a sulfur atom (optionally mono- or di-oxidized) and the like,
preferably a group formed by condensing the 5- or 6-membered
heterocyclic group and a 5- or 6-membered ring containing 1 to 4
hetero atoms selected from a nitrogen atom (optionally oxidized),
an oxygen atom, a sulfur atom (optionally mono- or di-oxidized) and
the like, can be mentioned.
[0064] To be specific, aziridinyl (e.g., 1- or 2-aziridinyl),
azirinyl (e.g., 1- or 2-azirinyl), azetyl (e.g., 2-, 3- or
4-azetyl), azetidinyl (e.g., 1-, 2- or 3-azetidinyl),
perhydroazepinyl (e.g., 1-, 2-, 3- or 4-perhydroazepinyl),
perhydroazocinyl (e.g., 1-, 2-, 3-, 4- or 5-perhydroazocinyl),
pyrrolyl (e.g., 1-, 2- or 3-pyrrolyl), pyrazolyl (e.g., 1-, 3-, 4-
or 5-pyrazolyl), imidazolyl (e.g., 1-, 2-, 4- or 5-imidazolyl),
triazolyl (e.g., 1,2,3-triazol-1-, 4- or -5-yl, 1,2,4-triazol-1-,
3-, 4- or 5-yl), tetrazolyl (e.g., tetrazol-1-, 2- or 5-yl), furyl
(e.g., 2- or 3-furyl), thienyl (e.g., 2- or 3-thienyl), thienyl
wherein the sulfur atom is oxidized (e.g., 2- or
3-thienyl-1,1-dioxide), oxazolyl (e.g., 2-, 4- or 5-oxazolyl),
isoxazolyl (e.g., 3-, 4- or 5-isoxazolyl), oxadiazolyl (e.g.,
1,2,3-oxadiazol-4- or 5-yl, 1,2,4-oxadiazol-3- or 5-yl,
1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl), thiazolyl (e.g., 2-,
4- or 5-thiazolyl), isothiazolyl (e.g., 3-, 4- or 5-isothiazolyl),
thiadiazolyl (e.g., 1,2,3-thiadiazol-4- or 5-yl,
1,2,4-thiadiazol-3- or 5-yl, 1,2,5-thiadiazol-3-yl,
1,3,4-thiadiazol-2-yl), pyrrolidinyl (e.g., 1-, 2- or
3-pyrrolidinyl), pyridyl (e.g., 2-, 3- or 4-pyridyl), pyridyl
wherein the nitrogen atom is oxidized (e.g., 2-, 3- or
4-pyridyl-N-oxide), pyridazinyl (e.g., 3- or 4-pyridazinyl),
pyridazinyl wherein one or both of the nitrogen atom is oxidized
(e.g., 3-, 4-, 5- or 6-pyridazinyl-N-oxide), pyrimidinyl (e.g., 2-,
4- or 5-pyrimidinyl), pyrimidinyl wherein one or both of the
nitrogen atoms is(are) oxidized (e.g., 2-, 4-, 5- or
6-pyrimidinyl-N-oxide), pyrazinyl, piperidinyl (e.g., 1-, 2-, 3- or
4-piperidinyl), piperazinyl (e.g., 1- or 2-piperazinyl), indolyl
(e.g., 3H-indol-2-, 3-, 4-, 5-, 6- or 7-yl), pyranyl (e.g., 2-, 3-
or 4-pyranyl), thiopyranyl (e.g., 2-, 3- or 4-thiopyranyl),
thiopyranyl wherein the sulfur atom is oxidized (e.g., 2-, 3- or
4-thiopyranyl-1,1-dioxide), morpholinyl (e.g., 2-, 3- or
4-morpholinyl), thiomorpholinyl, quinolyl (e.g., 2-, 3-, 4-, 5-,
6-, 7- or 8-quinolyl), isoquinolyl, pyrido[2,3-d]pyrimidinyl (e.g.,
pyrido[2,3-d]pyrimidin-2-yl), naphthyridinyl such as 1,5-, 1,6-,
1,7-, 1,8-, 2,6- or 2,7-naphthyridinyl and the like (e.g.,
1,5-naphthyridin-2- or 3-yl), thieno[2,3-d]pyridyl (e.g.,
thieno[2,3-d]pyridin-3-yl), pyrazinoquinolyl (e.g.,
pyrazino[2,3-d]quinolin-2-yl), chromenyl (e.g., 2H-chromen-2- or
3-yl), 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl,
3-benzo[b]furanyl, 2,3-dihydro-1-benzofuranyl,
2,1,3-benzothiadiazolyl, 2,3-dihydro-1,4-benzodioxin-5- or -6-yl,
1,3-benzothiazol-6-yl, 1,1-dioxido-2,3-dihydro-1-benzothien-6-yl,
1-benzothienyl and the like can be used.
[0065] Examples of the "substituent" of the heterocyclic group
include those similar to the substituents selected from the
above-mentioned substituent group B. The number of the substituents
is, for example, 1 to 5, preferably 1 to 3.
[0066] R.sup.1 is preferably an optionally substituted alkyl group,
an optionally substituted aryl group, an optionally substituted
aralkyl group, an optionally substituted thienyl group or an
optionally substituted pyridyl group, more preferably an optionally
substituted alkyl group, an optionally substituted aryl group, an
optionally substituted aralkyl group or an optionally substituted
pyridyl group, particularly preferably an optionally substituted
aryl group or an optionally substituted pyridyl group.
[0067] To be specific, R.sup.1 is preferably [1] C.sub.1-6 alkyl
(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, hexyl etc.), [2] a C.sub.6-14 aryl
group (e.g., phenyl etc.) optionally substituted by 1 to 5
(preferably 1 to 3) substituents selected from (i) halogen (e.g.,
fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano,
(iv) C.sub.1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)
optionally substituted by 1 to 5 (preferably 1 to 3) halogens
(e.g., fluorine, chlorine, bromine, iodine), (v) C.sub.1-6 alkoxy
(e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1
to 5 (preferably 1 to 3) halogens (e.g., fluorine, chlorine,
bromine, iodine) and (vi) phenyl, or [3] an (unsubstituted) thienyl
group or [4] an (unsubstituted) pyridyl group,
particularly preferably a C.sub.6-14 aryl group (e.g., phenyl etc.)
optionally substituted by 1 to 5 (preferably 1 to 3) substituents
selected from halogen, hydroxy and C.sub.1-6 alkyl or an
(unsubstituted) pyridyl group.
[0068] In the aforementioned formula (A2), R.sup.2, R.sup.3 and
R.sup.4 are the same or different and each is a hydrogen atom or an
optionally substituted hydrocarbon group, an optionally substituted
thienyl group, an optionally substituted benzo[b]thienyl group, an
optionally substituted furyl group, an optionally substituted
pyridyl group, an optionally substituted pyrazolyl group, an
optionally substituted pyrimidinyl group, an acyl group, a halogen
atom, a cyano group or a nitro group, preferably, a hydrogen atom
or an optionally substituted hydrocarbon group, an optionally
substituted thienyl group, an optionally substituted
benzo[b]thienyl group, an optionally substituted furyl group, an
optionally substituted pyridyl group, an acyl group, a halogen
atom, a cyano group or a nitro group.
[0069] As the "optionally substituted hydrocarbon group" for
R.sup.2, R.sup.3 or R.sup.4, those similar to the aforementioned
"optionally substituted hydrocarbon group" for R.sup.40 can be
mentioned.
[0070] As the "thienyl group" of the "optionally substituted
thienyl group" for R.sup.2, R.sup.3 or R.sup.4, 2- or 3-thienyl can
be mentioned.
[0071] Examples of the "substituent" of the thienyl group include
those similar to the substituents selected from the above-mentioned
substituent group B. The number of the substituents is 1 to 3.
[0072] As the "benzo[b]thienyl group" of the "optionally
substituted benzo[b]thienyl group" for R.sup.2, R.sup.3 or R.sup.4,
2- or 3-benzo[b]thienyl can be mentioned.
[0073] Examples of the "substituent" of the benzo[b]thienyl group
include those similar to the substituents selected from the
above-mentioned substituent group B. The number of the substituents
is, for example, 1 to 5, preferably 1 to 3.
[0074] As the "furyl group" of the "optionally substituted furyl
group" for R.sup.2, R.sup.3 or R.sup.4, 2- or 3-furyl can be
mentioned.
[0075] Examples of the "substituent" of the furyl group include
those similar to the substituents selected from the above-mentioned
substituent group B. The number of the substituents is 1 to 3.
[0076] As the "pyridyl group" of the "optionally substituted
pyridyl group" for R.sup.2, R.sup.3 or R.sup.4, 2-, 3- or 4-pyridyl
can be mentioned.
[0077] Examples of the "substituent" of the pyridyl group include
those similar to the substituents selected from the above-mentioned
substituent group B. The number of the substituents is 1 to 3.
[0078] As the "pyrazolyl group" of the "optionally substituted
pyrazolyl group" for R.sup.2, R.sup.3 or R.sup.4, 3- or 4-pyrazolyl
can be mentioned.
[0079] Examples of the "substituent" of the pyrazolyl group include
those similar to the substituents selected from the above-mentioned
substituent group B. The number of the substituents is 1 to 3.
[0080] As the "pyrimidinyl group" of the "optionally substituted
pyrimidinyl group" for R.sup.2, R.sup.3 or R.sup.4, 2-, 4- or
5-pyrimidinyl can be mentioned.
[0081] Examples of the "substituent" of the pyrimidinyl group
include those similar to the substituents selected from the
above-mentioned substituent group B. The number of the substituents
is 1 to 3.
[0082] As the "acyl group" for R.sup.2, R.sup.3 or R.sup.4, an acyl
group having 1 to 20 carbon atoms, which is derived from an organic
carboxylic acid can be mentioned. For example, C.sub.1-7 alkanoyl
groups (e.g., formyl; C.sub.1-6 alkyl-carbonyl such as acetyl,
propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl and
the like; etc.), C.sub.6-14 aryl-carbonyl groups (e.g., benzoyl,
naphthalenecarbonyl etc.), C.sub.1-6 alkoxy-carbonyl groups (e.g.,
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,
sec-butoxycarbonyl, tert-butoxycarbonyl etc.), C.sub.6-14
aryloxy-carbonyl groups (e.g., phenoxycarbonyl group), C.sub.7-19
aralkyl-carbonyl groups (e.g., phenyl-C.sub.1-4 alkylcarbonyl such
as benzylcarbonyl, phenethylcarbonyl, phenylpropylcarbonyl and the
like, naphthyl-C.sub.1-4 alkylcarbonyl such as benzhydrylcarbonyl,
naphthylethylcarbonyl and the like, etc.), C.sub.7-19
aralkyloxy-carbonyl groups (e.g., phenyl-C.sub.1-4 alkyloxycarbonyl
such as benzyloxycarbonyl and the like, etc.), 5- or 6-membered
heterocyclyl-carbonyl group or condensed heterocyclyl-carbonyl
groups thereof (e.g., pyrrolylcarbonyl such as 2- or
3-pyrrolylcarbonyl and the like; pyrazolylcarbonyl such as 3-, 4-
or 5-pyrazolylcarbonyl and the like; imidazolylcarbonyl such as 2-,
4- or 5-imidazolylcarbonyl and the like; triazolylcarbonyl such as
1,2,3-triazol-4-ylcarbonyl, 1,2,4-triazol-3-ylcarbonyl and the
like; tetrazolylcarbonyl such as 1H- or 2H-tetrazol-5-ylcarbonyl
and the like; furylcarbonyl such as 2- or 3-furylcarbonyl and the
like; thienylcarbonyl such as 2- or 3-thienylcarbonyl and the like;
oxazolylcarbonyl such as 2-, 4- or 5-oxazolylcarbonyl and the like;
isoxazolylcarbonyl such as 3-, 4- or 5-isoxazolylcarbonyl and the
like; oxadiazolylcarbonyl such as 1,2,3-oxadiazol-4- or
5-ylcarbonyl, 1,2,4-oxadiazol-3- or 5-ylcarbonyl,
1,2,5-oxadiazol-3- or 4-ylcarbonyl, 1,3,4-oxadiazol-2-ylcarbonyl
and the like; thiazolylcarbonyl such as 2-, 4- or
5-thiazolylcarbonyl and the like; isothiazolylcarbonyl such as 3-,
4- or 5-isothiazolylcarbonyl and the like; thiadiazolylcarbonyl
such as 1,2,3-thiadiazol-4- or 5-ylcarbonyl, 1,2,4-thiadiazol-3- or
5-ylcarbonyl, 1,2,5-thiadiazol-3- or 4-ylcarbonyl,
1,3,4-thiadiazol-2-ylcarbonyl and the like; pyrrolidinylcarbonyl
such as 2- or 3-pyrrolidinylcarbonyl and the like; pyridylcarbonyl
such as 2-, 3- or 4-pyridylcarbonyl and the like; pyridylcarbonyl
wherein nitrogen atom is oxidized such as 2-, 3- or
4-pyridyl-N-oxidocarbonyl and the like; pyridazinylcarbonyl such as
3- or 4-pyridazinylcarbonyl and the like; pyridazinylcarbonyl
wherein one or both nitrogen atoms are oxidized, such as 3-, 4-, 5-
or 6-pyridazinyl-N-oxidocarbonyl and the like; pyrimidinylcarbonyl
such as 2-, 4- or 5-pyrimidinylcarbonyl and the like;
pyrimidinylcarbonyl wherein one or both nitrogen atoms are
oxidized, such as 2-, 4-, 5- or 6-pyrimidinyl-N-oxidocarbonyl and
the like; pyrazinylcarbonyl; piperidinylcarbonyl such as 2-, 3- or
4-piperidinylcarbonyl and the like; piperazinylcarbonyl;
indolylcarbonyl such as 3H-indol-2- or 3-ylcarbonyl and the like;
pyranylcarbonyl such as 2-, 3- or 4-pyranylcarbonyl and the like;
thiopyranylcarbonyl such as 2-, 3- or 4-thiopyranylcarbonyl and the
like; quinolylcarbonyl such as 3-, 4-, 5-, 6-, 7- or
8-quinolylcarbonyl and the like; isoquinolylcarbonyl;
pyrido[2,3-d]pyrimidinylcarbonyl (e.g.,
pyrido[2,3-d]pyrimidin-2-ylcarbonyl); naphthyridinylcarbonyl (e.g.,
1,5-naphthyridin-2- or 3-ylcarbonyl) such as 1,5-, 1,6-, 1,7-,
1,8-, 2,6- or 2,7-naphthyridinylcarbonyl and the like;
thieno[2,3-d]pyridylcarbonyl (e.g.,
thieno[2,3-d]pyridin-3-ylcarbonyl); pyrazinoquinolylcarbonyl (e.g.,
pyrazino[2,3-b]quinolin-2-ylcarbonyl); a 5- or 6-membered
heterocyclyl-carbonyl group (e.g., 5- or 6-membered
heterocyclyl-carbonyl group containing 1 to 4 hetero atoms such as
nitrogen atom (optionally oxidized), oxygen atom, sulfur atom
(optionally mono or dioxidized) and the like, such as
chromenylcarbonyl (e.g., 2H-chromen-2- or 3-ylcarbonyl etc.) and
the like), a 5- or 6-membered heterocyclyl-acetyl group (e.g., 5-
or 6-membered heterocyclyl-acetyl group containing 1 to 4 hetero
atoms such as nitrogen atom (optionally oxidized), oxygen atom,
sulfur atom (optionally mono or dioxidized) and the like, such as
2-pyrrolylacetyl, 3-imidazolylacetyl, 5-isoxazolylacetyl and the
like, and the like) can be used.
[0083] As regards the substituent of acyl group, for example, when
the above-mentioned acyl group is an alkanoyl group or
alkoxy-carbonyl group, the acyl group is optionally substituted by
1 to 3 selected from alkylthio groups (e.g., C.sub.1-4 alkylthio
such as methylthio, ethylthio, n-propylthio, isopropylthio and the
like, and the like), halogen (e.g., fluorine, chlorine, bromine,
iodine), alkoxy groups (e.g., C.sub.1-6 alkoxy such as methoxy,
ethoxy, n-propoxy, tert-butoxy, n-hexyloxy and the like, and the
like), a nitro group, alkoxy-carbonyl groups (e.g., C.sub.1-6
alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl,
n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,
isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the
like, and the like), alkylamino group (e.g., mono- or di-C.sub.1-6
alkylamino such as methylamino, ethylamino, n-propylamino,
n-butylamino, tert-butylamino, n-pentylamino, n-hexylamino,
dimethylamino, diethylamino, methylethylamino, di-(n-propyl)amino,
di-(n-butyl)amino and the like, and the like), alkoxyimino groups
(e.g., C.sub.1-6 alkoxyimino such as methoxyimino, ethoxyimino,
n-propoxyimino, tert-butoxyimino, n-hexyloxy-imino and the like,
and the like) and hydroxyimino.
[0084] When the above-mentioned acyl group is an aryl-carbonyl
group, an aryloxy-carbonyl group, an aralkyl-carbonyl group, an
aralkyloxycarbonyl group, a 5- or 6-membered heterocyclyl-carbonyl
group or a 5- or 6-membered heterocyclyl-acetyl group, the acyl
group is optionally substituted by 1 to 5 (preferably 1 to 3)
selected from alkyl groups (e.g., C.sub.1-6 alkyl such as methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl,
isohexyl and the like, C.sub.3-6 cycloalkyl such as cyclohexyl and
the like, and the like), alkenyl groups (e.g., C.sub.2-6 alkenyl
such as allyl, isopropenyl, isobutenyl, 1-methylallyl, 2-pentenyl,
2-hexenyl and the like, and the like), alkynyl groups (e.g.,
C.sub.2-6 alkynyl such as propargyl, 2-butynyl, 3-butynyl,
3-pentynyl, 3-hexynyl and the like, and the like), alkoxy groups
(e.g., C.sub.1-6 alkoxy such as methoxy, ethoxy, n-propoxy,
tert-butoxy, n-hexyloxy and the like, and the like), acyl groups
[e.g., C.sub.1-7 alkanoyl such as formyl, acetyl, propionyl,
butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl and the like;
C.sub.6-14 aryl-carbonyl such as benzoyl, naphthalenecarbonyl and
the like; C.sub.1-6 alkoxy-carbonyl such as methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,
butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,
tert-butoxycarbonyl and the like; C.sub.6-14 aryloxy-carbonyl such
as phenoxycarbonyl and the like; C.sub.7-19 aralkyl-carbonyl such
as phenyl-C.sub.1-4 alkyl-carbonyl (e.g., benzylcarbonyl,
phenethylcarbonyl, phenylpropylcarbonyl and the like) and the like;
C.sub.7-19 aralkyloxy-carbonyl such as phenyl-C.sub.1-4
alkyloxy-carbonyl (e.g., benzyloxycarbonyl and the like) and the
like, and the like], nitro, amino, hydroxy, cyano, sulfamoyl,
mercapto, halogen (e.g., fluorine, chlorine, bromine, iodine), and
alkylthio groups (C.sub.1-4 alkylthio such as methylthio,
ethylthio, n-propylthio, isobutylthio and the like, and the
like).
[0085] As the "halogen atom" for R.sup.2, R.sup.3 or R.sup.4,
fluorine atom, chlorine atom, bromine atom and iodine atom can be
mentioned.
[0086] R.sup.2 is preferably a hydrogen atom, an optionally
substituted hydrocarbon group, an optionally substituted thienyl
group, an optionally substituted benzo[b]thienyl group, an
optionally substituted furyl group, an optionally substituted
pyridyl group, an optionally substituted pyrazolyl group or an
optionally substituted pyrimidinyl group, more preferably a
hydrogen atom, an optionally substituted hydrocarbon group, an
optionally substituted thienyl group, an optionally substituted
benzo[b]thienyl group, an optionally substituted furyl group or an
optionally substituted pyridyl group, further more preferably a
hydrogen atom, an optionally substituted hydrocarbon group or an
optionally substituted pyridyl group, particularly preferably a
hydrogen atom, an optionally substituted aryl group or an
optionally substituted pyridyl group.
[0087] To be specific, R.sup.2 is preferably
[1] a hydrogen atom, [2] C.sub.6-14 aryl group (e.g., phenyl group)
optionally substituted by 1 to 5 (preferably 1 to 3) substituents
selected from (i) a halogen atom (e.g., a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom), (ii) cyano, (iii) amino
optionally substituted by 1 or 2 selected from C.sub.1-6 alkyl
(e.g., methyl, ethyl etc.) and acetyl, (iv) C.sub.1-6 alkyl (e.g.,
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5
(preferably 1 to 3) halogens (e.g., fluorine, chlorine, bromine,
iodine), (v) C.sub.1-6 alkoxy (e.g., methoxy, ethoxy, propoxy,
isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy
etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogens
(e.g., fluorine, chlorine, bromine, iodine), (vi) phenoxy, (vii)
C.sub.1-6 alkylthio (e.g., methylthio, ethylthio etc.) optionally
substituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,
chlorine, bromine, iodine), (viii) acetyl and (ix) aminocarbonyl,
or [3] thienyl group, benzo[b]thienyl group, furyl group, pyridyl
group, pyrazolyl group or pyrimidinyl group, each of which is
optionally substituted by 1 to 3 substituents selected from halogen
(e.g., fluorine, chlorine, bromine, iodine), C.sub.1-6 alkoxy
(e.g., methoxy, ethoxy etc.) and C.sub.1-6 alkyl (e.g., methyl,
ethyl, n-propyl, isobutyl etc.) (preferably 1 to 3 C.sub.1-6
alkoxy) [preferably thienyl group, benzo[b]thienyl group, furyl
group or pyridyl group, each of which is optionally substituted by
1 to 3 C.sub.1-6 alkoxy], particularly preferably [1] (i) a
hydrogen atom or (ii) a C.sub.6-14 aryl group (e.g., phenyl group)
optionally substituted by 1 to 5 (preferably 1 to 3) halogens atoms
(e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodine
atom) or [2] a pyridyl group optionally substituted by 1 to 3
halogen atoms (e.g., a fluorine atom, a chlorine atom, a bromine
atom, an iodine atom).
[0088] R.sup.3 and R.sup.4 are preferably the same or different and
each is a hydrogen atom or an optionally substituted hydrocarbon
group, an acyl group, a halogen atom, a cyano group or a nitro
group.
[0089] Of these, a hydrogen atom, a C.sub.1-6 alkyl group (e.g.,
methyl, ethyl, n-propyl, isobutyl etc.), a C.sub.6-14 aryl group
(e.g., phenyl etc.), a C.sub.1-6 alkyl-carbonyl group (e.g.,
acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl,
heptanoyl etc.), a halogen atom (e.g., a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom), a cyano group and a nitro
group are preferable, particularly, a hydrogen atom, a C.sub.1-6
alkyl group (e.g., methyl, ethyl, n-propyl, isobutyl etc.), a
C.sub.1-6 alkyl-carbonyl group (e.g., acetyl, propionyl, butyryl,
isobutyryl, pentanoyl, hexanoyl, heptanoyl etc.), a halogen atom
(e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodine
atom), a cyano group and a nitro group are preferable.
[0090] In the aforementioned formula (A2), R.sup.5 is a hydrogen
atom or an optionally substituted hydrocarbon group.
[0091] Examples of the "optionally substituted hydrocarbon group"
for R.sup.5 include those similar to the "optionally substituted
hydrocarbon group" for the aforementioned R.sup.40.
[0092] As R.sup.5, particularly, a C.sub.1-6 alkyl group (e.g.,
methyl, ethyl, n-propyl, isobutyl etc.) is preferable.
[0093] When the compound represented by the above-mentioned formula
(A2) has isomers such as optical isomer, stereoisomer, positional
isomer, rotational isomer and the like, and any isomers and
mixtures are encompassed in the compound (A2). For example, when
compound (A2) has an optical isomer, an optical isomer separated
from a racemate is also encompassed in the compound (A2). These
isomers can be obtained as independent products by a synthesis
means or a separation means (e.g., concentration, solvent
extraction, column chromatography, recrystallization and the like),
and the like known per se.
[0094] The compound (A2) may be a crystal, and both a single
crystal and crystal mixtures are encompassed in the compound (A2).
Crystals can be produced by crystallization according to
crystallization methods known per se.
[0095] The compound (A2) may be a solvate (e.g., hydrate etc.) or a
non-solvate, both of which are encompassed in the compound
(A2).
[0096] A compound labeled with an isotope (e.g., .sup.3H, .sup.14C,
.sup.35S, .sup.125I and the like) is also encompassed in the
compound (A2).
[0097] A compound represented by the above-mentioned formula (A2)
can be produced, for example, according to the method described in
WO 2006/036024.
[0098] In addition, preferable examples of the nonpeptidic
pharmaceutically active ingredient having a primary or secondary
amino group include the compound disclosed in WO 2007/026916, which
is represented by the following formula (A3), and a salt
thereof.
##STR00011##
wherein R.sup.1a is a nitrogen-containing monocyclic heterocyclic
group optionally condensed with a benzene ring or a heterocycle,
the nitrogen-containing monocyclic heterocyclic group optionally
condensed with a benzene ring or a heterocycle optionally has
substituent(s), R.sup.2a is an optionally substituted C.sub.6-14
aryl group, an optionally substituted thienyl group or an
optionally substituted pyridyl group, R.sup.3a and R.sup.4a are
each a hydrogen atom, or one of R.sup.3a and R.sup.4a is a hydrogen
atom, and the other is an optionally substituted lower alkyl group,
an acyl group, a halogen atom, a cyano group or a nitro group, and
R.sup.5a is an alkyl group.
[0099] In the formula (A3), as the "nitrogen-containing monocyclic
heterocyclic group optionally condensed with a benzene ring or a
heterocycle" for R.sup.1a,
(1) a nitrogen-containing monocyclic heterocyclic group, and (2) a
fused ring group represented by the formula:
##STR00012##
wherein ring A is a nitrogen-containing monocyclic heterocyclic
group, ring B is a benzene ring or a heterocycle, a and b are each
a bridgehead ring-constituting atom (e.g., a carbon atom, a
nitrogen atom and the like), and shows a single bond or a double
bond, provided that a bond to an --SO.sub.2-- group in the formula
(A3) is present in a ring A-constituting atom (ring atom) other
than the bridgehead ring-constituting atoms a and b, can be
mentioned.
[0100] As used herein, ring A needs only to contain, as a ring
A-constituting atom (ring atom), at least one (preferably 1 to 4,
more preferably 1 or 2) nitrogen atom, and one or both of the
bridgehead ring-constituting atoms a and b may be nitrogen
atoms.
[0101] The "nitrogen-containing monocyclic heterocyclic group
optionally condensed with a benzene ring or a heterocycle"
optionally has substituent(s), and the substituent(s) may be
present in any of ring A and ring B.
[0102] As the "nitrogen-containing monocyclic heterocyclic group"
of the "nitrogen-containing monocyclic heterocyclic group
optionally condensed with a benzene ring or a heterocycle" and the
above-mentioned ring A, for example, an aromatic
nitrogen-containing monocyclic heterocyclic group, a saturated or
unsaturated non-aromatic nitrogen-containing monocyclic
heterocyclic group (aliphatic nitrogen-containing monocyclic
heterocyclic group) and the like containing, as a ring-constituting
atom (ring atom), at least one (preferably 1 to 4, more preferably
1 or 2) nitrogen atom can be mentioned.
[0103] As the "aromatic nitrogen-containing monocyclic heterocyclic
group", for example, aromatic nitrogen-containing monocyclic
heterocyclic groups such as pyrrolyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, imidazolyl (1H-imidazol-1-yl,
1H-imidazol-4-yl etc.), pyrazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl (1,2,4-triazol-1-yl,
1,2,4-triazol-4-yl etc.), tetrazolyl, pyridyl (2-, 3- or 4-pyridyl
etc.), pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like,
and N-oxide forms thereof and the like can be mentioned. Of these,
a 5- or 6-membered aromatic nitrogen-containing monocyclic
heterocyclic group is preferable, and thiazolyl, imidazolyl,
pyrazolyl, pyridyl, pyrimidinyl and pyridazinyl are preferable, and
pyridyl is particularly preferable.
[0104] As the "saturated or unsaturated non-aromatic
nitrogen-containing monocyclic heterocyclic group", partially
reduced forms (e.g., imidazolinyl, tetrahydropyrimidinyl and the
like) of the above-mentioned "aromatic nitrogen-containing
monocyclic heterocyclic group" and, for example, azetidinyl,
pyrrolidinyl, piperidyl (2-, 3- or 4-piperidyl), morpholinyl,
thiomorpholinyl, piperazinyl (1-piperazinyl etc.), homopiperazinyl
and the like can be mentioned. Of these, a 5- or 6-membered
non-aromatic nitrogen-containing monocyclic heterocyclic group is
preferable.
[0105] As the "heterocycle" optionally condensed with a
nitrogen-containing monocyclic heterocyclic group, for example, an
aromatic heterocycle or non-aromatic heterocycle can be
mentioned.
[0106] As the "aromatic heterocycle", for example, 5- or 6-membered
aromatic heteromonocyclic rings such as a furan ring, a thiophene
ring, a pyrrole ring, an oxazole ring, an isoxazole ring, a
thiazole ring, an isothiazole ring, an imidazole ring, a pyrazole
ring, a 1,2,3-oxadiazole ring, a 1,2,4-oxadiazole ring, a
1,3,4-oxadiazole ring, a furazan ring, a 1,2,3-thiadiazole ring, a
1,2,4-thiadiazole ring, a 1,3,4-thiadiazole ring, a 1,2,3-triazole
ring, a 1,2,4-triazole ring, tetrazole ring, pyridine ring,
pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring and
the like and, for example, 8- to 12-membered aromatic fused
heterocycles such as a benzofuran ring, an isobenzofuran ring, a
benzo[b]thiophene ring, an indole ring, an isoindole ring, a
1H-indazole ring, a benzindazole ring, a benzoxazole ring, a
1,2-benzoisoxazole ring, a benzothiazole ring, a benzopyran ring, a
1,2-benzoisothiazole ring, a 1H-benzotriazole ring, a quinoline
ring, an isoquinoline ring, a cinnoline ring, a quinazoline ring, a
quinoxaline ring, a phthalazine ring, a naphthyridine ring, a
purine ring, a pteridine ring, a carbazole ring, an
.alpha.-carboline ring, a .beta.-carboline ring, a
.gamma.-carboline ring, an acridine ring, a phenoxathiine ring, a
phenothiazine ring, a phenazine ring, a phenoxathiine ring, a
thianthrene ring, a phenanthridine ring, a phenanthrone ring, an
indolizine ring, a pyrrolo[1,2-b]pyridazine ring, a
pyrazolo[1,5-a]pyridine ring, an imidazo[1,2-a]pyridine ring, an
imidazo[1,5-a]pyridine ring, an imidazo[1,2-b]pyridazine ring, an
imidazo[1,2-a]pyrimidine ring, a 1,2,4-triazolo[4,3-a]pyridine
ring, a 1,2,4-triazolo[4,3-b]pyridazine ring and the like
(preferably, a heterocycle wherein the aforementioned 5- or
6-membered aromatic heteromonocyclic ring is condensed with a
benzene ring or a heterocycle wherein the same or different two
heterocycles of the aforementioned 5- or 6-membered aromatic
heteromonocyclic ring are condensed, more preferably a heterocycle
wherein the aforementioned 5- or 6-membered aromatic monocyclic
heterocyclic group is condensed with a benzene ring, preferably
imidazopyrimidinyl etc.) and the like can be mentioned.
[0107] As the "non-aromatic heterocycle", for example, 3- to
8-membered saturated or unsaturated non-aromatic heterocycles such
as an oxirane ring, an azetidine ring, an oxetane ring, a thietane
ring, a pyrrolidine ring, a tetrahydrofuran ring, a thioran ring, a
piperidine ring, a tetrahydropyran ring, a morpholine ring, a
thiomorpholine ring, a piperazine ring, a
3-hexahydrocyclopenta[c]pyrrole ring, a homopiperidine ring, a
homopiperazine ring and the like, or non-aromatic heterocycles
wherein the double bonds of the aforementioned aromatic
heteromonocyclic ring or aromatic fused heterocycle are partly or
entirely saturated such as a dihydropyridine ring, a
dihydropyrimidine ring, a 1,2,3,4-tetrahydroquinoline ring, a
1,2,3,4-tetrahydroisoquinoline ring and the like, and the like can
be mentioned.
[0108] As preferable nitrogen-containing monocyclic heterocyclic
group condensed with a benzene ring or a heterocycle, for example,
nitrogen-containing aromatic fused heterocyclic groups such as 8-
to 16-membered (preferably 8- to 12-membered) nitrogen-containing
aromatic bicyclic fused heterocyclic groups such as 2- or
3-indolyl, 1- or 3-isoindolyl, 1H-indazol-3-yl, 2-benzimidazolyl,
2-benzoxazolyl, 3-benzoisoxazolyl, 2-benzothiazolyl,
3-benzoisothiazolyl, 2-, 3- or 4-quinolyl, 1-, 3- or 4-isoquinolyl,
3- or 4-cinnolinyl, 2- or 4-quinazolinyl, 2- or 3-quinoxalinyl, 1-
or 4-phthalazinyl, naphthyridinyl, purinyl, pteridinyl,
1,7-phenanthrolin-2-, 3- or 4-yl, 1-, 2- or 3-indolizinyl,
pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,
imidazo[1,2-a]pyridyl, imidazo[1,2-b]pyrazolyl,
imidazo[1,5-a]pyridyl, imidazo[4,5-c]pyridyl,
pyrazolo[1,5-a]pyrimidinyl, pyrazolo[1,5-c]pyrimidinyl,
pyrazolo[3,4-d]pyrimidinyl, imidazo[1,2-b]pyridazinyl,
imidazo[1,5-b]pyridazinyl, pyrazolo[3,4-b]pyridyl,
imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,
1,2,4-triazolo[4,3-b]pyridazinyl,
[1,2,4]triazolo[1,2-a]pyridazinyl,
[1,2,3]triazolo[1,5-a]pyrimidinyl,
[1,2,4]triazolo[1,5-c]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl,
[1,2,4]triazolo[4,3-a]pyridyl, pyrazolo[5,1-b]thiazolyl,
pyrrolo[2,1-f][1,2,4]triazinyl, pyrrolo[1,2-b]pyridazinyl,
pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridyl,
thieno[3,2-b]pyrimidinyl, thieno[2,3-b]pyridyl,
thieno[2,3-c]pyridyl, thieno[3,2-b]pyridyl, thieno[3,2-c]pyridyl,
pyrido[2,3-b]pyrazyl, pyrido[3,4-b]pyrazyl,
pyrido[2,3-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl,
pyrido[4,3-d]pyrimidinyl and the like, and the like, and the like
can be mentioned. As the nitrogen-containing aromatic fused
heterocycle, fused pyridine wherein a pyridine ring is condensed
with one or two (preferably one) of the aforementioned 5- or
6-membered nitrogen-containing aromatic monocyclic heterocycles or
one or two (preferably one) benzene rings (when condensed with a
benzene ring, the pyridine ring has a bond), fused pyrimidine
wherein a pyrimidine ring is condensed with one or two (preferably
one) of the aforementioned 5- or 6-membered nitrogen-containing
aromatic monocyclic heterocycles, or one or two (preferably one)
benzene rings (when condensed with a benzene ring, the pyrimidine
ring has a bond) and the like are preferable.
[0109] As the "non-aromatic nitrogen-containing heterocycle", for
example, 3- to 8-membered (preferably 5- or 6-membered)
nitrogen-containing saturated or unsaturated (preferably saturated)
non-aromatic heterocycle (aliphatic nitrogen-containing
heterocycle) such as azetidine, pyrrolidine, imidazolidine,
thiazolidine, oxazolidine, piperidine, morpholine, thiomorpholine,
piperazine and the like, or nitrogen-containing non-aromatic
heterocycle wherein the double bonds of the aforementioned
nitrogen-containing aromatic monocyclic heterocycle or
nitrogen-containing aromatic fused heterocycle are partly or
entirely saturated, such as 1,2,3,4-tetrahydroquinoline,
1,2,3,4-tetrahydroisoquinoline and the like, and the like can be
mentioned.
[0110] As the "nitrogen-containing monocyclic heterocyclic group
optionally condensed with a benzene ring or a heterocycle", a 5- or
6-membered aromatic nitrogen-containing monocyclic heterocyclic
group is preferable from among those mentioned above. Of them, a
6-membered aromatic nitrogen-containing heterocyclic group such as
pyridyl (e.g., 2-, 3- or 4-pyridyl etc.), pyrimidinyl (e.g., 2-, 4-
or 5-pyrimidinyl etc.), pyridazinyl (e.g., 3- or 4-pyridazinyl
etc.) and the like is preferable, and pyridyl is particularly
preferable.
[0111] As the substituent that the "nitrogen-containing monocyclic
heterocyclic group optionally condensed with a benzene ring or a
heterocycle" may have, the substituents of the above-mentioned
substituent group A and (50) a C.sub.1-6 alkyl group (e.g., methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl,
isohexyl etc.) optionally having 1 to 3 halogen atoms (e.g.,
fluorine, chlorine, bromine, iodine), (51) a C.sub.2-6 alkenyl
group (e.g., allyl, isopropenyl, isobutenyl, 1-methylallyl,
2-pentenyl, 2-hexenyl etc.) optionally having 1 to 3 halogen atoms
(e.g., fluorine, chlorine, bromine, iodine), (52) a C.sub.2-6
alkynyl group (e.g., propargyl, 2-butynyl, 3-butynyl, 3-pentynyl,
3-hexynyl etc.), (53) a C.sub.1-6 alkyl group substituted by 1 to 3
hydroxy (e.g., hydroxymethyl, hydroxyethyl etc.) and the like can
be mentioned.
[0112] The substituent may be present at a substitutable position,
and the number of the substituents is 1 to 5, preferably 1 to
3.
[0113] As the "C.sub.6-14 aryl group" of the "optionally
substituted C.sub.6-14 aryl group" for R.sup.2a, for example,
phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl,
4-biphenylyl, 2-anthryl and the like can be mentioned.
[0114] As the substituent that the "C.sub.6-14 aryl group"
optionally has, groups similar to the substituents that the
"nitrogen-containing monocyclic heterocyclic group optionally
condensed with a benzene ring or a heterocycle" for the
aforementioned R.sup.1a optionally has can be mentioned.
[0115] The number of the substituents is 1 to 5, preferably 1 to 3.
As the "thienyl group" of the "optionally substituted thienyl
group" for R.sup.2a, 2- or 3-thienyl can be mentioned.
[0116] As the substituent that the "thienyl group" optionally has,
groups similar to the substituents that the "nitrogen-containing
monocyclic heterocyclic group optionally condensed with a benzene
ring or a heterocycle" for the aforementioned R.sup.1a optionally
has can be mentioned.
[0117] The number of the substituents is 1 to 4, preferably 1 to
3.
[0118] As the "pyridyl group" of the "optionally substituted
pyridyl group" for R.sup.2a, 2-, 3- or 4-pyridyl, or bipyridyl
(e.g., 2,3'-bipyridin-5-yl) can be mentioned.
[0119] As the substituent that the "pyridyl group" optionally has,
groups similar to the substituents that the "nitrogen-containing
monocyclic heterocyclic group optionally condensed with a benzene
ring or a heterocycle" for the aforementioned R.sup.1a optionally
has can be mentioned.
[0120] The number of the substituents is 1 to 4, preferably 1 to
3.
[0121] As the "lower alkyl group" of the "optionally substituted
lower alkyl group" for R.sup.3a or R.sup.4a, for example, C.sub.1-4
alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl and the like, and the like can be
mentioned.
[0122] As the substituent that the "lower alkyl group" optionally
has, the substituents of the above-mentioned substituent group A
and the like can be mentioned.
[0123] The number of the substituents is 1 to 3.
[0124] Examples of the "acyl group" for R.sup.3a or R.sup.4a
include acyl groups similar to those exemplified as the "acyl
group" for R.sup.2, R.sup.3 or R.sup.4 of the above-mentioned
formula (A2).
[0125] As the "halogen atom" for R.sup.3a or R.sup.4a, a fluorine
atom, a chlorine atom, a bromine atom and an iodine atom can be
mentioned.
[0126] As the "alkyl group" for R.sup.5a, for example, C.sub.1-6
alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, hexyl etc.) and the like can be
mentioned.
[0127] As R.sup.1a, a "nitrogen-containing monocyclic heterocyclic
group optionally condensed with a benzene ring or a heterocycle"
(e.g., 5 or 6-membered aromatic nitrogen-containing monocyclic
heterocyclic groups such as thiazolyl, imidazolyl, pyrazolyl,
pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and the like, and the
like) optionally substituted by 1 to 3 substituents selected from
(i) halogen (e.g., fluorine, chlorine, bromine, iodine), (ii)
hydroxy, (iii) cyano, (iv) C.sub.1-6 alkyl (e.g., methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3)
halogen (e.g., fluorine, chlorine, bromine, iodine), (v) C.sub.1-6
alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally
substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine,
chlorine, bromine, iodine), (vi) amino group optionally substituted
by C.sub.1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.), (vii) oxo and
(viii) C.sub.1-6 alkoxy-carbonyl (e.g., methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl etc.) is
preferable.
[0128] As R.sup.1a, especially, a "nitrogen-containing monocyclic
heterocyclic group optionally condensed with a benzene ring or a
heterocycle" (e.g., a 5 or 6-membered aromatic nitrogen-containing
monocyclic heterocyclic group such as thiazolyl, imidazolyl,
pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and the
like, and the like), which is optionally substituted by 1 to 3
substituents selected from (i) halogen (e.g., fluorine, chlorine,
bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) C.sub.1-6 alkyl
(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted
by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine,
bromine, iodine), (v) C.sub.1-6 alkoxy (e.g., methoxy, ethoxy,
propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,
hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3)
halogen (e.g., fluorine, chlorine, bromine, iodine), (vi) an amino
group optionally substituted by C.sub.1-6 alkyl (e.g., methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, hexyl etc.) and (vii) oxo, is preferable.
[0129] As R.sup.1a, particularly, a 6-membered nitrogen-containing
aromatic heterocyclic group (e.g., pyridyl groups (e.g., 2-, 3- or
4-pyridyl etc.), pyrimidinyl groups (e.g., 2-, 4- or 5-pyrimidinyl
etc.), pyridazinyl groups (e.g., 3- or 4-pyridazinyl etc.) etc.)
optionally substituted by 1 to 3 substituents selected from (i)
halogen (e.g., fluorine, chlorine, bromine, iodine), (ii) hydroxy,
(iii) cyano, (iv) C.sub.1-6 alkyl (e.g., methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl
etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen
(e.g., fluorine, chlorine, bromine, iodine), (v) C.sub.1-6 alkoxy
(e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1
to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine,
bromine, iodine) and (vi) an amino group optionally substituted by
C.sub.1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) is preferable,
and a pyridyl group optionally substituted by 1 to 3 substituents
selected from (i) C.sub.1-6 alkyl (e.g., methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl
etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen
(e.g., fluorine, chlorine, bromine, iodine) and (ii) C.sub.1-6
alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally
substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine,
chlorine, bromine, iodine) is particularly preferable.
[0130] As R.sup.2a, [1] a C.sub.6-14 aryl group (e.g., phenyl
group) optionally substituted by 1 to 5 (preferably 1 to 3)
substituents selected from (i) a halogen atom (e.g., fluorine,
chlorine, bromine, iodine), (ii) cyano, (iii) C.sub.1-6 alkyl
(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted
by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine,
bromine, iodine), (iv) C.sub.1-6 alkoxy (e.g., methoxy, ethoxy,
propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,
hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3)
halogen (e.g., fluorine, chlorine, bromine, iodine), (v) acetyl,
(vi) C.sub.3-7 cycloalkyl (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl etc.), (vii) C.sub.1-6
alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.), (viii) a
C.sub.1-6 alkyl group substituted by 1 to 3 hydroxy (e.g.,
hydroxymethyl, hydroxyethyl etc.), (ix) C.sub.1-6 alkylthio (e.g.,
methylthio, ethylthio, propylthio, isopropylthio, butylthio,
isobutylthio, sec-butylthio, pentylthio, hexylthio etc.) optionally
substituted by 1 to 5 (preferably 1 to 3) halogen atoms (e.g.,
fluorine, chlorine, bromine, iodine) and (x) C.sub.1-6
alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl etc.),
[2] a thienyl group optionally substituted by 1 to 3 substituents
selected from (i) a halogen atom (e.g., fluorine, chlorine,
bromine, iodine), (ii) cyano, (iii) C.sub.1-6 alkyl (e.g., methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1
to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv)
C.sub.1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,
butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally
substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine,
chlorine, bromine, iodine) and (v) acetyl, or [3] a pyridyl group
optionally substituted by 1 to 4 substituents selected from (i) a
halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii)
cyano, (iii) lower (specifically C.sub.1-6) alkyl (e.g., methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1
to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv)
C.sub.1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,
butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally
substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine,
chlorine, bromine, iodine), (v) acyl (e.g., acetyl), (vi) nitro and
(vii) amino is preferable.
[0131] Of these, as R.sup.2a, [1] a C.sub.6-14 aryl group (e.g.,
phenyl group) optionally substituted by 1 to 5 (preferably 1 to 3)
substituents selected from (i) a halogen atom (e.g., fluorine,
chlorine, bromine, iodine), (ii) cyano, (iii) C.sub.1-6 alkyl
(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted
by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine,
bromine, iodine), (iv) C.sub.1-6 alkoxy (e.g., methoxy, ethoxy,
propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,
hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3)
halogen (e.g., fluorine, chlorine, bromine, iodine) and (v)
acetyl,
[2] a thienyl group optionally substituted by 1 to 3 substituents
selected from (i) a halogen atom (e.g., fluorine, chlorine,
bromine, iodine), (ii) cyano, (iii) C.sub.1-6 alkyl (e.g., methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1
to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv)
C.sub.1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,
butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally
substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine,
chlorine, bromine, iodine) and (v) acetyl, or [3] a pyridyl group
optionally substituted by 1 to 4 substituents selected from (i) a
halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii)
cyano, (iii) lower (specifically C.sub.1-6) alkyl (e.g., methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1
to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv)
C.sub.1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,
butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally
substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine,
chlorine, bromine, iodine), (v) acyl (e.g., acetyl), (vi) nitro and
(vii) amino is preferable.
[0132] Particularly, as R.sup.2a, [1] a phenyl group optionally
substituted by 1 to 5 (preferably 1 to 3) substituents selected
from (i) a halogen atom (e.g., fluorine, chlorine, bromine, iodine)
and (ii) C.sub.1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)
optionally substituted by 1 to 5 (preferably 1 to 3) halogen (e.g.,
fluorine, chlorine, bromine, iodine),
[2] a thienyl group optionally substituted by 1 to 3 substituents
selected from (i) a halogen atom (e.g., fluorine, chlorine,
bromine, iodine) and (ii) C.sub.1-6 alkyl (e.g., methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
hexyl tc.) optionally substituted by 1 to 5 (preferably 1 to 3)
halogen (e.g., fluorine, chlorine, bromine, iodine), or [3] a
pyridyl group optionally substituted by 1 to 4 substituents
selected from (i) a halogen atom (e.g., fluorine, chlorine,
bromine, iodine) and (ii) lower (specifically C.sub.1-6) alkyl
(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted
by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine,
bromine, iodine) is preferable.
[0133] Of those mentioned above, a preferable embodiment of
R.sup.2a include [1] a phenyl group optionally substituted by 1 to
5 substituents selected from (i) a halogen atom and (ii) C.sub.1-6
alkyl optionally substituted by 1 to 5 halogen atoms, [2] a pyridyl
group optionally substituted by 1 to 4 substituents selected from
lower (C.sub.1-6) alkyl, a halogen atom, alkoxy (C.sub.1-6 alkoxy),
cyano, acyl (e.g., acetyl), nitro and amino, and the like.
[0134] As R.sup.2a, a phenyl group, a 2-fluorophenyl group, a
2-methylphenyl group, a 2-fluoropyridin-3-yl group, a
3-fluoropyridin-4-yl group, a 2-chloropyridin-3-yl group, a
6-chloropyridin-3-yl group, a 4-methylpyridin-3-yl group, a
2-methylpyridin-3-yl group, a 3-methylpyridin-2-yl group, a
2-trifluoromethylpyridin-3-yl group and a
6'-chloro-2,3'-bipyridin-5-yl group are particularly
preferable.
[0135] Preferably R.sup.3a and R.sup.4a are each a hydrogen atom,
or one of R.sup.3a and R.sup.4a is a hydrogen atom and the other is
a C.sub.1-6 alkyl group (e.g., methyl, ethyl, n-propyl, isobutyl
etc.), a C.sub.1-6 alkyl-carbonyl group (e.g., acetyl, propionyl,
butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl etc.), a
halogen atom (e.g., fluorine, chlorine, bromine, iodine), a cyano
group or a nitro group. A compound wherein both R.sup.3 and R.sup.4
are hydrogen atoms is particularly preferable.
[0136] As the "alkyl" for R.sup.5a, methyl or ethyl is preferable,
and methyl is particularly preferable.
[0137] The above-mentioned preferable embodiments of the
substituents for R.sup.1a to R.sup.5a may be optionally combined to
achieve a preferable embodiment of compound (A3).
[0138] Of compounds (A3), a compound wherein R.sup.1a is a 5- or
6-membered aromatic nitrogen-containing monocyclic heterocyclic
group (e.g., thiazolyl, imidazolyl, pyrazolyl, pyridyl,
pyrimidinyl, pyridazinyl, pyrazinyl and the like) or an
imidazo[1,2-a]pyrimidinyl group, which are optionally substituted
by 1 to 3 substituents selected from (i) halogen (e.g., fluorine,
chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv)
C.sub.1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally
substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine,
chlorine, bromine, iodine), (v) C.sub.1-6 alkoxy (e.g., methoxy,
ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,
pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5
(preferably 1 to 3) halogen (e.g., fluorine, chlorine, bromine,
iodine), (vi) amino group optionally substituted by C.sub.1-6 alkyl
(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, hexyl etc.) and (vii) C.sub.1-6
alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, tert-butoxycarbonyl etc.); R.sup.2a is [1] a
C.sub.6-14 aryl group (e.g., phenyl group) optionally substituted
by 1 to 5 (preferably 1 to 3) substituents selected from (i) a
halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii)
cyano, (iii) C.sub.1-6 alkyl (e.g., methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl
etc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogen
(e.g., fluorine, chlorine, bromine, iodine), (iv) C.sub.1-6 alkoxy
(e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1
to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine,
bromine, iodine), (v) acetyl, (vi) C.sub.3-7 cycloalkyl (e.g.,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl
etc.), (vii) C.sub.1-6 alkylsulfonyl (e.g., methylsulfonyl,
ethylsulfonyl etc.), (viii) a C.sub.1-6 alkyl group substituted by
1 to 3 hydroxy (e.g., hydroxymethyl, hydroxyethyl etc.), (ix)
C.sub.1-6 alkylthio (e.g., methylthio, ethylthio, propylthio,
isopropylthio, butylthio, isobutylthio, sec-butylthio, pentylthio,
hexylthio etc.) optionally substituted by 1 to 5 (preferably 1 to
3) halogen atoms (e.g., fluorine, chlorine, bromine, iodine) and
(x) C.sub.1-6 alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl
etc.),
[2] a thienyl group optionally substituted by 1 to 3 substituents
selected from (i) a halogen atom (e.g., fluorine, chlorine,
bromine, iodine), (ii) cyano, (iii) C.sub.1-6 alkyl (e.g., methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1
to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv)
C.sub.1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,
butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally
substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine,
chlorine, bromine, iodine) and (v) acetyl, [3] a pyridyl group
optionally substituted by 1 to 4 substituents selected from (i) a
halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii)
cyano, (iii) lower (specifically C.sub.1-6) alkyl (e.g., methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1
to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), (iv)
C.sub.1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,
butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionally
substituted by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine,
chlorine, bromine, iodine), (v) acyl (e.g., acetyl), (vi) nitro and
(vii) amino, or [4] a bipyridyl group optionally substituted by 1
to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine);
R.sup.3a and R.sup.4a are each a hydrogen atom, or one of R.sup.3a
and R.sup.4a is a hydrogen atom and the other is a C.sub.1-6 alkyl
group (e.g., methyl, ethyl, n-propyl, isobutyl etc.), a C.sub.1-6
alkyl-carbonyl group (e.g., acetyl, propionyl, butyryl, isobutyryl,
pentanoyl, hexanoyl, heptanoyl etc.), a halogen atom (e.g.,
fluorine, chlorine, bromine, iodine), a cyano group or a nitro
group; R.sup.5a is methyl or ethyl is preferable, a compound
wherein, for example, R.sup.1a is a pyridyl group optionally
substituted by 1 to 3 substituents selected from (i) C.sub.1-6
alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted
by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine,
bromine, iodine) and (ii) C.sub.1-6 alkoxy (e.g., methoxy, ethoxy,
propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,
hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3)
halogen (e.g., fluorine, chlorine, bromine, iodine), R.sup.2a is
[1] a phenyl group optionally substituted by 1 to 5 (preferably 1
to 3) substituents selected from (i) a halogen atom (e.g.,
fluorine, chlorine, bromine, iodine) and (ii) C.sub.1-6 alkyl
(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted
by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine,
bromine, iodine), [2] a thienyl group optionally substituted by 1
to 3 substituents selected from (i) a halogen atom (e.g., fluorine,
chlorine, bromine, iodine) and (ii) C.sub.1-6 alkyl (e.g., methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1
to 3) halogen (e.g., fluorine, chlorine, bromine, iodine), or [3] a
pyridyl group optionally substituted by 1 to 4 substituents
selected from (i) a halogen atom (e.g., fluorine, chlorine,
bromine, iodine) and (ii) lower (specifically C.sub.1-6) alkyl
(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted
by 1 to 5 (preferably 1 to 3) halogen (e.g., fluorine, chlorine,
bromine, iodine), R.sup.3a and R.sup.4a are each a hydrogen atom,
and R.sup.5a is methyl is particularly preferable.
[0139] When the compound represented by the above-mentioned formula
(A3) has isomers such as optical isomer, stereoisomer, positional
isomer, rotational isomer and the like, any isomers and mixtures
are encompassed in the compound (A3). For example, when compound
(A3) has an optical isomer, an optical isomer separated from a
racemate is also encompassed in the compound (A3). These isomers
can be obtained as independent products by a synthesis means or a
separation means (e.g., concentration, solvent extraction, column
chromatography, recrystallization and the like), and the like known
per se.
[0140] The compound (A3) may be a crystal, and both a single
crystal and crystal mixtures are encompassed in the compound (A3).
Crystals can be produced by crystallization according to
crystallization methods known per se.
[0141] The compound (A3) may be a solvate (e.g., hydrate etc.) or a
non-solvate, both of which are encompassed in the compound
(A3).
[0142] A compound labeled with an isotope (e.g., .sup.3H, .sup.14C,
.sup.35S, .sup.125I and the like) is also encompassed in the
compound (A3).
[0143] The compound represented by the above-mentioned formula (A3)
can be produced, for example, according to the method described in
WO 2007/026916.
[0144] In addition, preferable examples of the nonpeptidic
pharmaceutically active ingredient having a primary or secondary
amino group also include the compound and a salt thereof disclosed
in WO 2008/108380, which is represented by the following formula
(A4).
##STR00013##
wherein R.sup.1b is an optionally substituted cyclic group,
R.sup.2b is a substituent, R.sup.3b is an optionally substituted
alkyl group, an acyl group, an optionally substituted hydroxy
group, an optionally substituted amino group, a halogen atom, a
cyano group or a nitro group, R.sup.4b and R.sup.5b are each a
hydrogen atom, an optionally substituted alkyl group, an acyl
group, an optionally substituted hydroxy group, an optionally
substituted amino group, a halogen atom, a cyano group or a nitro
group, R.sup.6b and R.sup.6b' are each a hydrogen atom or an alkyl
group, and n is an integer of 0-3.
[0145] Examples of the "optionally substituted cyclic group" for
R.sup.1b in the formula (A4) include an aryl group, an alicyclic
hydrocarbon group and a heterocyclic group, each of which is
optionally substituted.
[0146] Examples of the aryl group in the "optionally substituted
aryl group" for R.sup.ib include a C.sub.6-14 aryl group such as
phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl,
4-biphenylyl, 2-anthryl and the like.
[0147] Examples of the substituent of the aryl group include (1) a
halogen atom (e.g., fluorine atom, chlorine atom, bromine atom,
iodine atom etc.), (2) nitro, (3) cyano, (4) hydroxy, (5) C.sub.1-6
alkoxy optionally having 1 to 5 (preferably 1 to 3) halogen atoms
(e.g., fluorine, chlorine, bromine, iodine) (e.g., methoxy, ethoxy,
propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,
hexyloxy, fluoromethoxy etc.), (6) C.sub.6-14 aryloxy (e.g.,
phenyloxy, naphthyloxy etc.), (7) C.sub.7-16 aralkyloxy (e.g.,
benzyloxy, phenethyloxy, diphenylmethyloxy, 1-naphthylmethyloxy,
2-naphthylmethyloxy, 2,2-diphenylethyloxy, 3-phenylpropyloxy,
4-phenylbutyloxy, 5-phenylpentyloxy etc.), (8) mercapto, (9)
C.sub.1-6 alkylthio optionally having 1 to 5 (preferably 1 to 3)
halogen atoms (e.g., fluorine, chlorine, bromine, iodine) (e.g.,
methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,
propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,
pentylthio, hexylthio etc.), (10) C.sub.6-14 arylthio (e.g.,
phenylthio, naphthylthio etc.), (11) C.sub.7-16 aralkylthio (e.g.,
benzylthio, phenethylthio, diphenylmethylthio,
1-naphthylmethylthio, 2-naphthylmethylthio, 2,2-diphenylethylthio,
3-phenylpropylthio, 4-phenylbutylthio, 5-phenylpentylthio etc.),
(12) amino, (13) mono-C.sub.1-6 alkylamino (e.g., methylamino,
ethylamino etc.), (14) mono-C.sub.6-14 arylamino (e.g.,
phenylamino, 1-naphthylamino, 2-naphthylamino etc.), (15)
mono-C.sub.7-16 aralkylamino (e.g., benzylamino etc.), (16)
di-C.sub.1-6 alkylamino (e.g., dimethylamino, diethylamino etc.),
(17) di-C.sub.6-14 arylamino (e.g., diphenylamino etc.), (18)
di-C.sub.7-16 aralkylamino (e.g., dibenzylamino etc.), (19) formyl,
(20) C.sub.1-6 alkyl-carbonyl (e.g., acetyl, propionyl etc.), (21)
C.sub.6-14 aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl
etc.), (22) carboxyl, (23) C.sub.1-6 alkoxy-carbonyl (e.g.,
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
tert-butoxycarbonyl etc.), (24) C.sub.6-14 aryloxy-carbonyl (e.g.,
phenoxycarbonyl etc.), (25) carbamoyl, (26) thiocarbamoyl, (27)
mono-C.sub.1-6 alkyl-carbamoyl optionally substituted by hydroxyl
(e.g., methylcarbamoyl, ethylcarbamoyl, 2-hydroxyethylcarbamoyl
etc., preferably mono-C.sub.1-6 alkyl-carbamoyl), (28) di-C.sub.1-6
alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl,
ethylmethylcarbamoyl etc.), (29) C.sub.6-14 aryl-carbamoyl (e.g.,
phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.),
(30) C.sub.1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl
etc.), (31) C.sub.6-14 arylsulfonyl (e.g., phenylsulfonyl,
1-naphthylsulfonyl, 2-naphthylsulfonyl etc.), (32) C.sub.1-6
alkylsulfinyl (e.g. methylsulfinyl, ethylsulfinyl etc.), (33)
C.sub.6-14 arylsulfinyl (e.g., phenylsulfinyl, 1-naphthylsulfinyl,
2-naphthylsulfinyl etc.), (34) formylamino, (35) C.sub.1-6
alkyl-carbonylamino (e.g., acetylamino etc.), (36) C.sub.6-14
aryl-carbonylamino (e.g., benzoylamino, naphthoylamino etc.), (37)
C.sub.1-6 alkoxy-carbonylamino (e.g., methoxycarbonylamino,
ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino
etc.), (38) C.sub.1-6 alkylsulfonylamino (e.g.,
methylsulfonylamino, ethylsulfonylamino etc.), (39) C.sub.6-14
arylsulfonylamino (e.g., phenylsulfonylamino,
2-naphthylsulfonylamino, 1-naphthylsulfonylamino etc.), (40)
C.sub.1-6 alkyl-carbonyloxy (e.g., acetoxy, propionyloxy etc.),
(41) C.sub.6-14 aryl-carbonyloxy (e.g., benzoyloxy,
naphthylcarbonyloxy etc.), (42) C.sub.1-6 alkoxy-carbonyloxy (e.g.,
methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,
butoxycarbonyloxy etc.), (43) mono-C.sub.1-6 alkyl-carbamoyloxy
(e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.), (44)
di-C.sub.1-6 alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,
diethylcarbamoyloxy etc.), (45) C.sub.6-14 aryl-carbamoyloxy (e.g.,
phenylcarbamoyloxy, naphthylcarbamoyloxy etc.), (46) a 5- to
7-membered saturated cyclic amino optionally containing, besides
one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero
atoms selected from a nitrogen atom, a sulfur atom and an oxygen
atom (e.g., pyrrolidin-1-yl, piperidino, piperazin-1-yl,
morpholino, thiomorpholino, hexahydroazepin-1-yl etc.), (47) a 5-
to 10-membered aromatic heterocyclic group containing, besides
carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a
nitrogen atom, a sulfur atom and an oxygen atom (e.g., 2-thienyl,
3-thienyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl,
3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl,
3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl,
3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,
2-benzo[b]furanyl, 3-benzo[b]furanyl etc.), which is optionally
substituted by 1 to 3 C.sub.2-6 alkyl groups (e.g., methyl, ethyl,
n-propyl, isopropyl etc.), (48) C.sub.2-3 alkylenedioxy (e.g.,
methylenedioxy, ethylenedioxy etc.), (49) C.sub.3-7 cycloalkyl
(e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl etc.), (50) a C.sub.2-6 alkyl group optionally having 1
to 5 (preferably 1 to 3) halogen atoms (e.g., fluorine, chlorine,
bromine, iodine) or hydroxy (e.g., methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,
sec-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, hydroxymethyl
etc., preferably a C.sub.2-6 alkyl group optionally having 1 to 5
(preferably 1 to 3) halogen atoms), (51) a C.sub.2-6 alkenyl group
(e.g., allyl, isopropenyl, isobutenyl, 1-methylallyl, 2-pentenyl,
2-hexenyl etc.) optionally having 1 to 5 (preferably 1 to 3)
halogen atoms (e.g., fluorine, chlorine, bromine, iodine), (52) a
C.sub.2-6 alkynyl group (e.g., propargyl, 2-butynyl, 3-butynyl,
3-pentynyl, 3-hexynyl etc.), (53) a C.sub.6-24 aryl group (e.g.,
phenyl etc.) optionally having 1 to 5 (preferably 1 to 3) halogen
atoms (e.g., fluorine, chlorine, bromine, iodine), (54) C.sub.7-16
aralkyl (e.g., benzyl, phenethyl etc.) optionally having 1 to 5
(preferably 1 to 3) halogen atoms (e.g., fluorine, chlorine,
bromine, iodine), (55) oxo (hereinafter to be referred to as
substituent group C), and the like.
[0148] The substituent may be present at a substitutable position,
and the number of the substituents is 1 to 5, preferably 1 to
3.
[0149] Examples of the alicyclic hydrocarbon group in the
"optionally substituted alicyclic hydrocarbon group" for R.sup.1b
include a C.sub.3-14 cycloalkyl group such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, perhydronaphthyl,
perhydroanthranyl, bicyclo[2,2,1]heptyl and the like (preferably a
C.sub.3-7 cycloalkyl group), a C.sub.3-14 cycloalkenyl group such
as cyclopropenyl, cyclobuten-1- or 3-yl, cyclopenten-1-, 3- or
4-yl, cyclohexen-1- or 3-yl and the like (preferably a C.sub.3-7
cycloalkenyl group) and the like.
[0150] Examples of the substituent of the alicyclic hydrocarbon
group include those similar to the substituents selected from the
above-mentioned substituent group C. The substituent may be present
at a substitutable position, and the number of the substituents is
1 to 5, preferably 1 to 3.
[0151] Examples of the heterocyclic group in the "optionally
substituted heterocyclic group" for R.sup.1b include a 4- to
7-membered non-aromatic heterocyclic group (preferably, a 4- to
6-membered non-aromatic heterocyclic group) containing 1 to 3
hetero atom selected from nitrogen atom, oxygen atom, sulfur atom
and the like, such as oxiranyl, azetidinyl, oxetanyl, thietanyl,
pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl,
tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl,
homomorpholinyl, homopiperazinyl and the like, and a heteroaryl
group (preferably, a 5- or 6-membered aromatic heterocyclic group
or a fused ring group thereof) such as pyrrolyl (e.g., 1-, 2- or
3-pyrrolyl), pyrazolyl (e.g., 1-, 3-, 4- or 5-pyrazolyl),
imidazolyl (e.g., 1-, 2-, 4- or 5-imidazolyl), triazolyl (e.g.,
1,2,3-triazol-4-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-5-yl,
1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl,
1,2,4-triazol-5-yl), tetrazolyl (e.g., tetrazol-1-, 2- or 5-yl),
furyl (e.g., 2- or 3-furyl), thienyl (e.g., 2- or 3-thienyl),
oxazolyl (e.g., 2-, 4- or 5-oxazolyl), isoxazolyl (e.g., 3-, 4- or
5-isoxazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazol-4- or 5-yl,
1,2,4-oxadiazol-3- or 5-yl, 1,2,5-oxadiazol-3-yl,
1,3,4-oxadiazol-2-yl), thiazolyl (e.g., 2-, 4- or 5-thiazolyl),
isothiazolyl (e.g., 3-, 4- or 5-isothiazolyl), thiadiazolyl (e.g.,
1,2,3-thiadiazol-4- or 5-yl, 1,2,4-thiadiazol-3- or 5-yl,
1,2,5-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl), pyridyl (e.g., 1-,
2-, 3- or 4-pyridyl), pyridazinyl (e.g., 1-, 3- or 4-pyridazinyl),
pyrimidinyl (e.g., 1-, 2-, 4- or 5-pyrimidinyl), pyrazinyl (e.g.,
1- or 2-pyrazinyl), benzofuryl (e.g., 2- or 3-benzofuryl),
benzothienyl (e.g., 2- or 3-benzothienyl), isoindolyl (e.g., 1- or
3-isoindolyl), benzimidazolyl (e.g., 2-benzimidazolyl),
benzoxazolyl (e.g., 2-benzoxazolyl), benzisoxazolyl (e.g.,
3-benzisoxazolyl), benzothiazolyl (e.g., 2-benzothiazolyl),
benzisothiazolyl (e.g., 3-benzisothiazolyl), cinnolinyl (e.g., 3-
or 4-cinnolinyl), quinazolinyl (e.g., 2- or 4-quinazolinyl),
quinoxalinyl (e.g., 2- or 3-quinoxalinyl), phthalazinyl (e.g., 1-
or 4-phthalazinyl), pteridinyl, indolyl (e.g., 3H-indol-2-, 3-, 4-,
5-, 6- or 7-yl), quinolyl (e.g., 3-, 4-, 5-, 6-, 7- or 8-quinolyl),
isoquinolyl (e.g., 1-, 3- or 4-isoquinolyl),
pyrido[2,3-d]pyrimidinyl (e.g., pyrido[2,3-d]pyrimidin-2-yl),
naphthyridinyl such as 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or
2,7-naphthyridinyl and the like (e.g., 1,5-naphthyridin-2- or
3-yl), thieno[2,3-d]pyridyl (e.g., thieno[2,3-d]pyridin-3-yl),
pyrazinoquinolyl (e.g., pyrazino[2,3-d]quinolin-2-yl),
imidazo[1,2-a]pyridyl, imidazo[2,1-b]thiazolyl,
imidazo[1,2-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl,
imidazo[1,2-a]imidazolyl, imidazo[2,1-b](1.3.4)thiadiazolyl,
pyrazolo[1,5-a]pyrimidinyl, pyrazolo[5,1-b]thiazolyl or
pyrazolo[1,5-a]pyridyl and the like.
[0152] Examples of the substituent of the heterocyclic group
include those similar to the substituents selected from the
above-mentioned substituent group C. The substituent may be present
at a substitutable position, and the number of the substituents is
1 to 5, preferably 1 to 3.
[0153] R.sup.1b is preferably an "optionally substituted aryl group
or a heteroaryl group".
[0154] Examples of the "substituent" for R.sup.2b include an
electron withdrawing group and an electron donating group,
particularly preferably an electron withdrawing group.
[0155] Examples of the electron withdrawing group include a halogen
atom (e.g., fluorine, chlorine, bromine, iodine), a cyano group, an
acyl group, a halogenoalkyl group (e.g., a halogeno(C.sub.1-3)alkyl
group such as fluoromethyl, chloromethyl, bromomethyl, iodomethyl,
difluoromethyl, trifluoromethyl and the like etc.) and the
like.
[0156] Examples of the aforementioned "acyl group" include an acyl
group derived from an optionally substituted carboxylic acid, an
optionally substituted oxycarboxylic acid, an optionally
substituted sulfonic acid, an optionally substituted sulfinic acid
and the like, and the like, for example, a group represented by the
formula --S(O).sub.p--R.sup.7b wherein p is 1 or 2, and R.sup.7b is
a hydroxyl group, a hydrocarbon group optionally having
substituent(s) or a heterocyclic group optionally having
substituent(s), a group represented by the formula --COOR.sup.8b
wherein R.sup.8b is a hydrogen atom, a hydrocarbon group optionally
having substituent(s) or a heterocyclic group optionally having
substituent(s), a group represented by the formula
--CONR.sup.9bR.sup.10b wherein R.sup.9b and R.sup.10b are the same
or different and each is a hydrogen atom, a hydrocarbon group
optionally having substituent(s) or a heterocyclic group optionally
having substituent(s), a group represented by the formula
--SO.sub.2NH--R.sup.11b wherein R.sup.11b is a hydrogen atom, a
hydrocarbon group optionally having substituent(s) or a
heterocyclic group optionally having substituent(s), a group
represented by the formula --CO--R.sup.12b wherein R.sup.12b is a
hydrogen atom, a hydrocarbon group optionally having substituent(s)
or a heterocyclic group optionally having substituent(s), and the
like.
[0157] Examples of the "hydrocarbon group" of the "hydrocarbon
group optionally having substituent(s)" for R.sup.7b, R.sup.8b,
R.sup.9b, R.sup.10b, R.sup.11b or R.sup.12b include a chain or
cyclic hydrocarbon group (e.g., alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, aralkyl etc.). Of these, a chain or cyclic
hydrocarbon group having 1 to 16 carbon atoms and the like are
preferable.
[0158] Examples of the "alkyl" include C.sub.1-6 alkyl (e.g.,
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, hexyl etc.) and the like.
[0159] Examples of the "alkenyl" include C.sub.2-6 alkenyl (e.g.,
vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl,
2-methyl-2-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl etc.)
and the like.
[0160] Examples of the "alkynyl" include C.sub.2-6 alkynyl (e.g.,
ethynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl
etc.) and the like.
[0161] Examples of the "cycloalkyl" include C.sub.3-7 cycloalkyl
(e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl etc.) and the like.
[0162] Examples of the "aryl" include C.sub.6-14 aryl (e.g.,
phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl,
4-biphenylyl, 2-anthryl etc.) and the like.
[0163] Examples of the "aralkyl" include C.sub.7-16 aralkyl (e.g.,
phenyl-C.sub.1-6 alkyl, naphthyl-C.sub.1-6 alkyl or
diphenyl-C.sub.1-4 alkyl etc. such as benzyl, phenethyl,
diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl,
2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl
and the like) and the like.
[0164] When the above-mentioned "hydrocarbon group" of the
"hydrocarbon group optionally having substituent(s)" for R.sup.7b,
R.sup.8b, R.sup.9b, R.sup.10b, R.sup.11b or R.sup.12b is alkyl,
alkenyl or alkynyl, the group may be substituted by 1 to 3
substituents selected from (1) a halogen atom (e.g., fluorine atom,
chlorine atom, bromine atom, iodine atom etc.), (2) nitro, (3)
cyano, (4) hydroxy, (5) C.sub.1-6 alkoxy optionally having 1 to 3
halogen atoms (e.g., fluorine atom, chlorine atom, bromine atom,
iodine atom) (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, sec-butoxy, pentyloxy, hexyloxy, fluoromethoxy etc.),
(6) C.sub.6-14 aryloxy (e.g., phenyloxy, naphthyloxy etc.), (7)
C.sub.7-16 aralkyloxy (e.g., benzyloxy, phenethyloxy,
diphenylmethyloxy, 1-naphthylmethyloxy, 2-naphthylmethyloxy,
2,2-diphenylethyloxy, 3-phenylpropyloxy, 4-phenylbutyloxy,
5-phenylpentyloxy etc.), (8) mercapto, (9) C.sub.1-6 alkylthio
optionally having 1 to 3 halogen atoms (e.g., fluorine atom,
chlorine atom, bromine atom, iodine atom) (e.g., methylthio,
difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,
isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio,
hexylthio etc.), (10) C.sub.6-14 arylthio (e.g., phenylthio,
naphthylthio etc.), (11) C.sub.7-16 aralkylthio (e.g., benzylthio,
phenethylthio, diphenylmethylthio, 1-naphthylmethylthio,
2-naphthylmethylthio, 2,2-diphenylethylthio, 3-phenylpropylthio,
4-phenylbutylthio, 5-phenylpentylthio etc.) (12) amino, (13)
mono-C.sub.1-6 alkylamino (e.g., methylamino, ethylamino etc.),
(14) mono-C.sub.6-14 arylamino (e.g., phenylamino, 1-naphthylamino,
2-naphthylamino etc.), (15) mono-C.sub.7-16 aralkylamino (e.g.,
benzylamino etc.), (16) di-C.sub.1-6 alkylamino (e.g.,
dimethylamino, diethylamino etc.), (17) di-C.sub.6-14 arylamino
(e.g., diphenylamino etc.), (18) di-C.sub.7-16 aralkylamino (e.g.,
dibenzylamino etc.), (19) formyl, (20) C.sub.1-6 alkyl-carbonyl
(e.g., acetyl, propionyl etc.), (21) C.sub.6-14 aryl-carbonyl
(e.g., benzoyl, 1-naphthoyl, 2-naphthoyl etc.), (22) carboxyl, (23)
C.sub.1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, tert-butoxycarbonyl etc.), (24) C.sub.6-14
aryloxy-carbonyl (e.g., phenoxycarbonyl etc.), (25) carbamoyl, (26)
thiocarbamoyl, (27) mono-C.sub.1-6 alkyl-carbamoyl (e.g.,
methylcarbamoyl, ethylcarbamoyl etc.), (28) di-C.sub.1-6
alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl,
ethylmethylcarbamoyl etc.), (29) C.sub.6-14 aryl-carbamoyl (e.g.,
phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.),
(30) C.sub.1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl
etc.), (31) C.sub.6-14 arylsulfonyl (e.g., phenylsulfonyl,
1-naphthylsulfonyl, 2-naphthylsulfonyl etc.), (32) C.sub.1-6
alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl etc.), (33)
C.sub.6-14 arylsulfinyl (e.g., phenylsulfinyl, 1-naphthylsulfinyl,
2-naphthylsulfinyl etc.), (34) formylamino, (35) C.sub.1-6
alkyl-carbonylamino (e.g., acetylamino etc.), (36) C.sub.6-14
aryl-carbonylamino (e.g., benzoylamino, naphthoylamino etc.), (37)
C.sub.1-6 alkoxy-carbonylamino (e.g., methoxycarbonylamino,
ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino
etc.), (38) C.sub.1-6 alkylsulfonylamino (e.g.,
methylsulfonylamino, ethylsulfonylamino etc.), (39) C.sub.6-14
arylsulfonylamino (e.g., phenylsulfonylamino,
2-naphthylsulfonylamino, 1-naphthylsulfonylamino etc.), (40)
C.sub.1-6 alkyl-carbonyloxy (e.g., acetoxy, propionyloxy etc.),
(41) C.sub.6-14 aryl-carbonyloxy (e.g., benzoyloxy,
naphthylcarbonyloxy etc.), (42) C.sub.1-6 alkoxy-carbonyloxy (e.g.,
methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,
butoxycarbonyloxy etc.), (43) mono-C.sub.1-6 alkyl-carbamoyloxy
(e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.), (44)
di-C.sub.1-6 alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,
diethylcarbamoyloxy etc.), (45) C.sub.6-14 aryl-carbamoyloxy (e.g.,
phenylcarbamoyloxy, naphthylcarbamoyloxy etc.), (46) a 5- to
7-membered saturated cyclic amino optionally containing, besides
one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero
atoms selected from a nitrogen atom, a sulfur atom and an oxygen
atom (e.g., pyrrolidin-1-yl, piperidino, piperazin-1-yl,
morpholino, thiomorpholino, hexahydroazepin-1-yl etc.), (47) a 5-
to 10-membered aromatic heterocyclic group containing, besides
carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a
nitrogen atom, a sulfur atom and an oxygen atom (e.g., 2-thienyl,
3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl,
4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl,
4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl,
2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,
2-benzo[b]furanyl, 3-benzo[b]furanyl etc.), (48) C.sub.1-3
alkylenedioxy (e.g., methylenedioxy, ethylenedioxy etc.), (49)
C.sub.3-7 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl etc.) and the like.
[0165] In addition, when the "hydrocarbon group" of the
"hydrocarbon group optionally having substituent(s)" for R.sup.7b,
R.sup.8b, R.sup.9b, R.sup.10b, R.sup.11b or R.sup.12b is
cycloalkyl, aryl or aralkyl, the group may be substituted by 1 to 5
(preferably 1 to 3) substituents selected from (1) halogen atom
(e.g., fluorine atom, chlorine atom, bromine atom, iodine atom
etc.), (2) nitro, (3) cyano, (4) hydroxy, (5) C.sub.1-6 alkoxy
optionally having 1 to 3 halogen atoms (e.g., fluorine atom,
chlorine atom, bromine atom, iodine atom) (e.g., methoxy, ethoxy,
propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,
hexyloxy, fluoromethoxy etc.), (6) C.sub.6-14 aryloxy (e.g.,
phenyloxy, naphthyloxy etc.), (7) C.sub.7-16 aralkyloxy (e.g.,
benzyloxy, phenethyloxy, diphenylmethyloxy, 1-naphthylmethyloxy,
2-naphthylmethyloxy, 2,2-diphenylethyloxy, 3-phenylpropyloxy,
4-phenylbutyloxy, 5-phenylpentyloxy etc.), (8) mercapto, (9)
C.sub.1-6 alkylthio optionally having 1 to 3 halogen atoms (e.g.,
fluorine atom, chlorine atom, bromine atom, iodine atom) (e.g.,
methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,
propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,
pentylthio, hexylthio etc.), (10) C.sub.6-14 arylthio (e.g.,
phenylthio, naphthylthio etc.), (11) C.sub.7-16 aralkylthio (e.g.,
benzylthio, phenethylthio, diphenylmethylthio,
1-naphthylmethylthio, 2-naphthylmethylthio, 2,2-diphenylethylthio,
3-phenylpropylthio, 4-phenylbutylthio, 5-phenylpentylthio etc.),
(12) amino, (13) mono-C.sub.1-6 alkylamino (e.g., methylamino,
ethylamino etc.), (14) mono-C.sub.6-14 arylamino (e.g.,
phenylamino, 1-naphthylamino, 2-naphthylamino etc.), (15)
mono-C.sub.7-16 aralkylamino (e.g., benzylamino etc.), (16)
di-C.sub.1-6 alkylamino (e.g., dimethylamino, diethylamino etc.),
(17) di-C.sub.6-14 arylamino (e.g., diphenylamino etc.), (18)
di-C.sub.7-16 aralkylamino (e.g., dibenzylamino etc.), (19) formyl,
(20) C.sub.1-6 alkyl-carbonyl (e.g., acetyl, propionyl etc.), (21)
C.sub.6-14 aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl
etc.), (22) carboxyl, (23) C.sub.1-6 alkoxy-carbonyl (e.g.,
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
tert-butoxycarbonyl etc.), (24) C.sub.6-14 aryloxy-carbonyl (e.g.,
phenoxycarbonyl etc.), (25) carbamoyl, (26) thiocarbamoyl, (27)
mono-C.sub.1-6 alkyl-carbamoyl (e.g., methylcarbamoyl,
ethylcarbamoyl etc.), (28) di-C.sub.1-6 alkyl-carbamoyl (e.g.,
dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.),
(29) C.sub.6-14 aryl-carbamoyl (e.g., phenylcarbamoyl,
1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.), (30) C.sub.1-6
alkylsulfonyl optionally having 1 to 3 halogen atoms (e.g.,
fluorine atom, chlorine atom, bromine atom, iodine atom) (e.g.,
methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl etc.), (31)
C.sub.6-14 arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl,
2-naphthylsulfonyl etc.), (32) C.sub.1-6 alkylsulfinyl (e.g.,
methylsulfinyl, ethylsulfinyl etc.). (33) C.sub.6-14 arylsulfinyl
(e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl
etc.), (34) formylamino, (35) C.sub.1-6 alkyl-carbonylamino (e.g.,
acetylamino etc.), (36) C.sub.6-14 aryl-carbonylamino (e.g.,
benzoylamino, naphthoylamino etc.), (37) C.sub.1-6
alkoxy-carbonylamino (e.g., methoxycarbonylamino,
ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino
etc.), (38) C.sub.1-6 alkylsulfonylamino (e.g.,
methylsulfonylamino, ethylsulfonylamino etc.), (39) C.sub.6-14
arylsulfonylamino (e.g., phenylsulfonylamino,
2-naphthylsulfonylamino, 1-naphthylsulfonylamino etc.), (40)
C.sub.1-6 alkyl-carbonyloxy (e.g., acetoxy, propionyloxy etc.),
(41) C.sub.6-14 aryl-carbonyloxy (e.g., benzoyloxy,
naphthylcarbonyloxy etc.), (42) C.sub.1-6 alkoxy-carbonyloxy (e.g.,
methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,
butoxycarbonyloxy etc.), (43) mono-C.sub.1-6 alkyl-carbamoyloxy
(e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.), (44)
di-C.sub.1-6 alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,
diethylcarbamoyloxy etc.), (45) C.sub.6-14 aryl-carbamoyloxy (e.g.,
phenylcarbamoyloxy, naphthylcarbamoyloxy etc.), (46) a 5- to
7-membered saturated cyclic amino optionally containing, besides
one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 hetero
atoms selected from a nitrogen atom, a sulfur atom and an oxygen
atom (e.g., pyrrolidin-1-yl, piperidino, piperazin-1-yl,
morpholino, thiomorpholino, hexahydroazepin-1-yl etc.), (47) a 5-
to 10-membered aromatic heterocyclic group containing, besides
carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from a
nitrogen atom, a sulfur atom and an oxygen atom (e.g., 2-thienyl,
3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl,
4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl,
4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl,
2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,
2-benzo[b]furanyl, 3-benzo[b]furanyl etc.), (48) C.sub.1-3
alkylenedioxy (e.g., methylenedioxy, ethylenedioxy etc.), (49)
C.sub.3-7 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl etc.), (50) a C.sub.1-6 alkyl group (e.g.,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl,
isohexyl etc.) optionally having 1 to 3 halogen atoms (e.g.,
fluorine atom, chlorine atom, bromine atom, iodine atom) or hydroxy
group, (51) a C.sub.2-6 alkenyl group (e.g., allyl, isopropenyl,
isobutenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl etc.) optionally
having 1 to 3 halogen atoms (e.g., fluorine atom, chlorine atom,
bromine atom, iodine atom), (52) C.sub.2-6 alkynyl group (e.g.,
propargyl, 2-butynyl, 3-butynyl, 3-pentynyl, 3-hexynyl etc.), (53)
mono-C.sub.3-7 cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl,
cyclobutylcarbamoyl etc.), and (54) a 5- or 10-membered
heterocyclyl-carbonyl containing, besides carbon atom, 1 or 2 kinds
of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom
and an oxygen atom (e.g., 4-morpholinocarbonyl etc.) (hereinafter
to be referred to as substituent group D) and the like.
[0166] Examples of the "heterocyclic group" of the "heterocyclic
group optionally having substituent(s)" for R.sup.7b, R.sup.8b,
R.sup.9b, R.sup.10b, R.sup.11b or R.sup.12b include a 3- to
8-membered heterocyclic group (preferably a 5- or 6-membered
heterocyclic group) containing 1 to 4 hetero atoms selected from a
nitrogen atom (optionally oxidized), an oxygen atom, a sulfur atom
(optionally mono- or di-oxidized) and the like, or a group wherein
a 3- to 8-membered heterocyclic group (preferably a 5- or
6-membered heterocyclic group) containing 1 to 4 hetero atoms
selected from a nitrogen atom (optionally oxidized), an oxygen
atom, a sulfur atom (optionally mono- or di-oxidized) and the like
is condensed with a benzene ring or a 3- to 8-membered ring group
(preferably a 5- or 6-membered ring group) containing 1 to 4 hetero
atoms selected from a nitrogen atom (optionally oxidized), an
oxygen atom, a sulfur atom (optionally mono- or di-oxidized) and
the like, preferably a group wherein the 5- or 6-membered
heterocyclic group is condensed with a 5- or 6-membered ring
optionally containing 1 to 4 hetero atoms selected from a nitrogen
atom (optionally oxidized), an oxygen atom, a sulfur atom
(optionally mono- or di-oxidized) and the like.
[0167] Specific examples thereof include aziridinyl (e.g., 1- or
2-aziridinyl), azirinyl (e.g., 1- or 2-azirinyl), azetyl (e.g., 2-,
3- or 4-azetyl), azetidinyl (e.g., 1-, 2- or 3-azetidinyl),
perhydroazepinyl (e.g., 1-, 2-, 3- or 4-perhydroazepinyl),
perhydroazocinyl (e.g., 1-, 2-, 3-, 4- or 5-perhydroazocinyl),
pyrrolyl (e.g., 1-, 2- or 3-pyrrolyl), pyrazolyl (e.g., 1-, 3-, 4-
or 5-pyrazolyl), imidazolyl (e.g., 1-, 2-, 4- or 5-imidazolyl),
triazolyl (e.g., 1,2,3-triazol-1-, 4- or -5-yl, 1,2,4-triazol-1-,
3-, 4- or 5-yl), tetrazolyl (e.g., tetrazol-1-, 2- or 5-yl), furyl
(e.g., 2- or 3-furyl), thienyl (e.g., 2- or 3-thienyl), thienyl
wherein the sulfur atom is oxidized (e.g., 2- or
3-thienyl-1,1-dioxide), oxazolyl (e.g., 2-, 4- or 5-oxazolyl),
isoxazolyl (e.g., 3-, 4- or 5-isoxazolyl), oxadiazolyl (e.g.,
1,2,3-oxadiazol-4- or 5-yl, 1,2,4-oxadiazol-3- or 5-yl,
1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl), thiazolyl (e.g., 2-,
4- or 5-thiazolyl), isothiazolyl (e.g., 3-, 4- or 5-isothiazolyl),
thiadiazolyl (e.g., 1,2,3-thiadiazol-4- or 5-yl,
1,2,4-thiadiazol-3- or 5-yl, 1,2,5-thiadiazol-3-yl,
1,3,4-thiadiazol-2-yl), pyrrolidinyl (e.g., 1-, 2- or
3-pyrrolidinyl), pyridyl (e.g., 2-, 3- or 4-pyridyl), pyridyl
wherein the nitrogen atom is oxidized (e.g., 2-, 3- or
4-pyridyl-N-oxide), pyridazinyl (e.g., 3- or 4-pyridazinyl),
pyridazinyl wherein one or both of the nitrogen atoms are oxidized
(e.g., 3-, 4-, 5- or 6-pyridazinyl-N-oxide), pyrimidinyl (e.g., 2-,
4- or 5-pyrimidinyl), pyrimidinyl wherein one or both of the
nitrogen atoms are oxidized (e.g., 2-, 4-, 5- or
6-pyrimidinyl-N-oxide), pyrazinyl, piperidinyl (e.g., 1-, 2-, 3- or
4-piperidinyl), piperazinyl (e.g., 1- or 2-piperazinyl), indolyl
(e.g., 3H-indole-2-, 3-, 4-, 5-, 6- or 7-yl), pyranyl (e.g., 2-, 3-
or 4-pyranyl), thiopyranyl (e.g., 2-, 3- or 4-thiopyranyl),
thiopyranyl wherein the sulfur atom is oxidized (e.g., 2-, 3- or
4-thiopyranyl-1,1-dioxide), morpholinyl (e.g., 2-, 3- or
4-morpholinyl), thiomorpholinyl, quinolyl (e.g., 2-, 3-, 4-, 5-,
6-, 7- or 8-quinolyl), isoquinolyl, pyrido[2,3-d]pyrimidinyl (e.g.,
pyrido[2,3-d]pyrimidin-2-yl), naphthyridinyl such as 1,5-, 1,6-,
1,7-, 1,8-, 2,6- or 2,7-naphthyridinyl and the like (e.g.,
1,5-naphthyridin-2- or 3-yl), thieno[2,3-d]pyridyl (e.g.,
thieno[2,3-d]pyridin-3-yl), pyrazinoquinolyl (e.g.,
pyrazino[2,3-d]quinolin-2-yl), chromenyl (e.g., 2H-chromen-2- or
3-yl), 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl,
3-benzo[b]furanyl and the like.
[0168] Examples of the "substituent" of the heterocyclic group
include those similar to the substituents selected from the
above-mentioned substituent group D. The number of the substituents
is 1 to 5, preferably 1 to 3.
[0169] Of the above-mentioned group, the electron withdrawing group
is preferably a halogen atom, a cyano group, an acyl group or a
trifluoromethyl group.
[0170] Examples of the electron donating group include a C.sub.1-6
alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.), a C.sub.1-6
alkylthio group (e.g., methylthio, ethylthio, propylthio,
isopropylthio, butylthio, pentylthio, hexylthio etc.), a C.sub.1-6
alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy,
pentyloxy, hexyloxy etc.), a group represented by the
--NR.sup.13bR.sup.14b wherein R.sup.13b and R.sup.14b are the same
or different and each is a hydrogen atom or an alkyl group, and the
like. Examples of the alkyl group for R.sup.13b or R.sup.14b
include a C.sub.1-6 alkyl group such as methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl
and the like, particularly preferably a C.sub.1-3 alkyl group.
[0171] Of the above-mentioned group, the electron donating group is
preferably a C.sub.1-3 alkyl, a C.sub.1-3 alkylthio, or a group
represented by the formula --NR.sup.13bR.sup.14b wherein each
symbol is as defined above.
[0172] Of the aforementioned group, the "substituent" for R.sup.2b
is preferably, for example, an electron withdrawing group or
electron donating group having not more than 7 atoms and
comparatively low molecular weight shown above.
[0173] In the formula (A4), R.sup.3b is an optionally substituted
alkyl group, an acyl group, an optionally substituted hydroxy
group, an optionally substituted amino group, a halogen atom, a
cyano group or a nitro group. R.sup.3b is preferably an alkyl group
optionally substituted by halogen, an acyl group, a halogen atom, a
cyano group or a nitro group.
[0174] R.sup.4b and R.sup.5b are the same or different and each is
a hydrogen atom, an optionally substituted alkyl group, an acyl
group, an optionally substituted hydroxy group, an optionally
substituted amino group, a halogen atom, a cyano group or a nitro
group. Preferably, R.sup.4b and R.sup.5b are the same or different
and each is a hydrogen atom, an alkyl group optionally substituted
by halogen, an acyl group, a halogen atom, a cyano group or a nitro
group.
[0175] Examples of the "alkyl group" in the "optionally substituted
alkyl group" for R.sup.3b, R.sup.4b or R.sup.5b include a C.sub.1-6
alkyl group such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.
Examples of the "substituent" of the alkyl include those similar to
the substituents that the above-mentioned "hydrocarbon group" for
R.sup.7b, R.sup.8b, R.sup.9b, R.sup.10b, R.sup.11b or R.sup.12b may
have when it is alkyl, alkenyl or alkynyl. The number of the
substituents is 1 to 5, preferably 1 to 3.
[0176] Preferable examples of the substituent of the alkyl group
for R.sup.3b, R.sup.4b or R.sup.5b include halogen (e.g., a
fluorine atom, a chlorine atom, a bromine atom, an iodine atom).
The number of the halogen atom as a substituent is 1 to 5,
preferably 1 to 3.
[0177] Examples of the "acyl group" for R.sup.3b, R.sup.4b or
R.sup.5b include acyl groups having 1 to 20 carbon atoms, which is
derived from organic carboxylic acids, for example, C.sub.1-7
alkanoyl groups (e.g., formyl; C.sub.1-6 alkyl-carbonyl such as
acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl,
heptanoyl and the like; etc.), C.sub.6-14 aryl-carbonyl groups
(e.g., benzoyl, naphthalenecarbonyl etc.), C.sub.1-6
alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl etc.),
C.sub.6-14 aryloxy-carbonyl groups (e.g., phenoxycarbonyl group),
C.sub.7-19 aralkyl-carbonyl groups (e.g., phenyl-C.sub.1-4
alkylcarbonyl such as benzylcarbonyl, phenethylcarbonyl,
phenylpropylcarbonyl and the like, naphthyl-C.sub.1-4 alkylcarbonyl
such as benzhydrylcarbonyl, naphthylethylcarbonyl and the like,
etc.), C.sub.7-19 aralkyloxy-carbonyl groups (e.g.,
phenyl-C.sub.1-4 alkyloxycarbonyl such as benzyloxycarbonyl and the
like, etc.), 5- or 6-membered heterocyclyl-carbonyl groups or
condensed heterocyclyl-carbonyl groups thereof (e.g.,
pyrrolylcarbonyl such as 2- or 3-pyrrolylcarbonyl and the like;
pyrazolylcarbonyl such as 3-, 4- or 5-pyrazolylcarbonyl and the
like; imidazolylcarbonyl such as 2-, 4- or 5-imidazolylcarbonyl and
the like; triazolylcarbonyl such as 1,2,3-triazol-4-ylcarbonyl,
1,2,4-triazol-3-ylcarbonyl and the like; tetrazolylcarbonyl such as
1H- or 2H-tetrazol-5-ylcarbonyl and the like; furylcarbonyl such as
2- or 3-furylcarbonyl and the like; thienylcarbonyl such as 2- or
3-thienylcarbonyl and the like; oxazolylcarbonyl such as 2-, 4- or
5-oxazolylcarbonyl and the like; isoxazolylcarbonyl such as 3-, 4-
or 5-isoxazolylcarbonyl and the like; oxadiazolylcarbonyl such as
1,2,3-oxadiazol-4- or 5-ylcarbonyl, 1,2,4-oxadiazol-3- or
5-ylcarbonyl, 1,2,5-oxadiazol-3- or 4-ylcarbonyl,
1,3,4-oxadiazol-2-ylcarbonyl and the like; thiazolylcarbonyl such
as 2-, 4- or 5-thiazolylcarbonyl and the like; isothiazolylcarbonyl
such as 3-, 4- or 5-isothiazolylcarbonyl and the like;
thiadiazolylcarbonyl such as 1,2,3-thiadiazol-4- or 5-ylcarbonyl,
1,2,4-thiadiazol-3- or 5-ylcarbonyl, 1,2,5-thiadiazol-3- or
4-ylcarbonyl, 1,3,4-thiadiazol-2-ylcarbonyl and the like;
pyrrolidinylcarbonyl such as 2- or 3-pyrrolidinylcarbonyl and the
like; pyridylcarbonyl such as 2-, 3- or 4-pyridylcarbonyl and the
like; pyridylcarbonyl wherein the nitrogen atom is oxidized, such
as 2-, 3- or 4-pyridyl-N-oxidocarbonyl and the like;
pyridazinylcarbonyl such as 3- or 4-pyridazinylcarbonyl and the
like; pyridazinyl wherein one or both of the nitrogen atoms are
oxidized, such as 3-, 4-, 5- or 6-pyridazinyl-N-oxidocarbonyl and
the like; pyrimidinylcarbonyl such as 2-, 4- or
5-pyrimidinylcarbonyl and the like; pyrimidinylcarbonyl wherein one
or both of the nitrogen atoms are oxidized, such as 2-, 4-, 5- or
6-pyrimidinyl-N-oxidocarbonyl and the like; pyrazinylcarbonyl;
piperidinylcarbonyl such as 2-, 3- or 4-piperidinylcarbonyl and the
like; piperazinylcarbonyl; indolylcarbonyl such as 3H-indol-2- or
3-ylcarbonyl and the like; pyranylcarbonyl such as 2-, 3- or
4-pyranylcarbonyl and the like; thiopyranylcarbonyl such as 2-, 3-
or 4-thiopyranylcarbonyl and the like; quinolylcarbonyl such as 3-,
4-, 5-, 6-, 7- or 8-quinolylcarbonyl and the like;
isoquinolylcarbonyl; pyrido[2,3-d]pyrimidinylcarbonyl (e.g.,
pyrido[2,3-d]pyrimidin-2-ylcarbonyl); naphthyridinylcarbonyl (e.g.,
1,5-naphthyridin-2- or 3-ylcarbonyl) such as 1,5-, 1,6-, 1,7-,
1,8-, 2,6- or 2,7-naphthyridinylcarbonyl and the like;
thieno[2,3-d]pyridylcarbonyl (e.g.,
thieno[2,3-d]pyridin-3-ylcarbonyl); pyrazinoquinolylcarbonyl (e.g.,
pyrazino[2,3-b]quinolin-2-ylcarbonyl); 5- or 6-membered
heterocyclyl-carbonyl groups (e.g., 5- or 6-membered
heterocyclylcarbonyl group containing 1 to 4 hetero atoms such as a
nitrogen atom (optionally oxidized), an oxygen atom, a sulfur atom
(optionally mono- or di-oxidized) and the like, such as
chromenylcarbonyl (e.g., 2H-chromen-2- or 3-ylcarbonyl etc.) and
the like), 5- or 6-membered heterocyclyl-acetyl groups (e.g., 5- or
6-membered heterocyclyl-acetyl groups containing 1 to 4 hetero
atoms such as a nitrogen atom (optionally oxidized), an oxygen
atom, a sulfur atom (optionally mono- or di-oxidized) and the like
such as 2-pyrrolylacetyl, 3-imidazolylacetyl, 5-isoxazolylacetyl
and the like), and the like can be used.
[0178] As regards the substituent of acyl group, for example, when
the above-mentioned acyl group is an alkanoyl group or an
alkoxy-carbonyl group, it is optionally substituted by 1 to 3
alkylthio groups (e.g., C.sub.1-4 alkylthio such as methylthio,
ethylthio, n-propylthio, isopropylthio and the like, and the like),
halogen (e.g., fluorine, chlorine, bromine, iodine), an alkoxy
group (e.g., C.sub.1-6 alkoxy such as methoxy, ethoxy, n-propoxy,
tert-butoxy, n-hexyloxy and the like, and the like), a nitro group,
an alkoxy-carbonyl group (e.g., C.sub.1-6 alkoxy-carbonyl such as
methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,
isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl,
sec-butoxycarbonyl, tert-butoxycarbonyl and the like, and the
like), an alkylamino group (e.g., mono- or di-C.sub.1-6 alkylamino
such as methylamino, ethylamino, n-propylamino, n-butylamino,
tert-butylamino, n-pentylamino, n-hexylamino, dimethylamino,
diethylamino, methylethylamino, di-(n-propyl)amino,
di-(n-butyl)amino and the like, and the like), an alkoxyimino group
(e.g., C.sub.1-6 alkoxyimino such as methoxyimino, ethoxyimino,
n-propoxyimino, tert-butoxyimino, n-hexyloxy-imino and the like,
and the like) or hydroxyimino.
[0179] When the above-mentioned acyl group is an aryl-carbonyl
group, an aryloxy-carbonyl group, an aralkyl-carbonyl group, an
aralkyloxycarbonyl group, a 5- or 6-membered heterocyclyl-carbonyl
group or a 5- or 6-membered heterocyclyl-acetyl group, it is
optionally substituted by 1 to 5 (preferably 1 to 3) alkyl group
(e.g., C.sub.1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl,
isopentyl, neopentyl, n-hexyl, isohexyl and the like, C.sub.3-6
cycloalkyl such as cyclohexyl and the like, and the like), an
alkenyl group (e.g., C.sub.2-6 alkenyl such as allyl, isopropenyl,
isobutenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl and the like, and
the like), an alkynyl group (e.g., C.sub.2-6 alkynyl such as
propargyl, 2-butynyl, 3-butynyl, 3-pentynyl, 3-hexynyl and the
like, and the like), an alkoxy group (e.g., C.sub.1-6 alkoxy such
as methoxy, ethoxy, n-propoxy, tert-butoxy, n-hexyloxy and the
like, and the like), an acyl group [e.g., C.sub.1-7 alkanoyl such
as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl,
hexanoyl, heptanoyl and the like; C.sub.6-14 aryl-carbonyl such as
benzoyl, naphthalenecarbonyl and the like; C.sub.1-6
alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the
like; C.sub.6-14 aryloxy-carbonyl such as phenoxycarbonyl and the
like; C.sub.7-19 aralkyl-carbonyl such as phenyl-C.sub.1-4
alkyl-carbonyl (e.g., benzylcarbonyl, phenethylcarbonyl,
phenylpropylcarbonyl and the like) and the like; C.sub.7-19
aralkyloxy-carbonyl such as phenyl-C.sub.1-4 alkyloxy-carbonyl
(e.g., benzyloxycarbonyl and the like) and the like, and the like],
nitro, amino, hydroxy, cyano, sulfamoyl, mercapto, halogen (e.g.,
fluorine, chlorine, bromine, iodine) or an alkylthio group
(C.sub.1-4 alkylthio such as methylthio, ethylthio, n-propylthio,
isobutylthio and the like, and the like).
[0180] Examples of the "optionally substituted hydroxy group" for
R.sup.3b, R.sup.4b or R.sup.5b include a group represented by
--OR.sup.16b wherein R.sup.16b is a hydrogen atom, an optionally
substituted hydrocarbon group, an optionally substituted
heterocyclic group or an acyl group.
[0181] Examples of the "optionally substituted hydrocarbon group"
for R.sup.16b include those similar to the "optionally substituted
hydrocarbon group" for the above-mentioned R.sup.7b, R.sup.8b,
R.sup.9b, R.sup.10b, R.sup.11b or R.sup.12b.
[0182] Examples of the "optionally substituted heterocyclic group"
for R.sup.16b include those similar to the "optionally substituted
heterocyclic group" for the above-mentioned R.sup.7b, R.sup.8b,
R.sup.9b, R.sup.10b, R.sup.11b or R.sup.12b.
[0183] Examples of the "acyl group" for R.sup.16b include those
similar to the "acyl group" exemplified as the above-mentioned
"substituent" for R.sup.2b.
[0184] Examples of the "optionally substituted amino group" for
R.sup.3b, R.sup.4b or R.sup.5b include a group represented by
--NR.sup.17bR.sup.18b wherein R.sup.17b and R.sup.18b are the same
or different and each is a hydrogen atom, an optionally substituted
hydrocarbon group, an optionally substituted heterocyclic group or
an acyl group.
[0185] Examples of the "optionally substituted hydrocarbon group"
for R.sup.17b or R.sup.18b include those similar to the "optionally
substituted hydrocarbon group" for the above-mentioned R.sup.7b,
R.sup.8b, R.sup.9b, R.sup.10b, R.sup.11b or R.sup.12b.
[0186] Examples of the "optionally substituted heterocyclic group"
for R.sup.17b or R.sup.18b include those similar to the "optionally
substituted heterocyclic group" for the above-mentioned R.sup.7b,
R.sup.8b, R.sup.9b, R.sup.10b, R.sup.11b or R.sup.12b.
[0187] Examples of the "optionally substituted acyl group" for
R.sup.17b or R.sup.18b include those similar to the "acyl group"
exemplified as the above-mentioned "substituent" for R.sup.2b.
[0188] Examples of the "halogen atom" for R.sup.3b, R.sup.4b or
R.sup.5b include fluorine, chlorine, bromine and iodine.
[0189] In the formula (A4), R.sup.3b is optionally substituted at
any substitutable position of the pyridine ring. The number (i.e.,
n) of substituent R.sup.3b is 0 to 3. When n is 2 or 3, each of
R.sup.3b is the same or different.
[0190] Preferably, n is 0.
[0191] Preferably, R.sup.4b and R.sup.5b are the same or different
and each is a hydrogen atom or a halogen atom.
[0192] Examples of the "alkyl group" for R.sup.6b or R.sup.6b'
include a C.sub.1-6 alkyl group such as methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl
and the like, preferably a C.sub.1-3 alkyl group, particularly
preferably methyl.
[0193] Preferable embodiment of the partial structure of the
formula (A4):
##STR00014##
wherein R.sup.6b is an alkyl group.
[0194] When the compound represented by the above-mentioned formula
(A4) has isomers such as optical isomer, stereoisomer, positional
isomer, rotational isomer and the like, any isomers and mixtures
are encompassed in the compound (A4). For example, when compound
(A4) has an optical isomer, an optical isomer separated from a
racemate is also encompassed in the compound (A4). These isomers
can be obtained as independent products by a synthesis means or a
separation means (e.g., concentration, solvent extraction, column
chromatography, recrystallization and the like), and the like known
per se.
[0195] The compound (A4) may be a crystal, and both a single
crystal and crystal mixtures are encompassed in the compound (A4).
Crystals can be produced by crystallization according to
crystallization methods known per se.
[0196] The compound (A4) may be a solvate (e.g., hydrate etc.) or a
non-solvate, both of which are encompassed in the compound
(A4).
[0197] A compound labeled with an isotope (e.g., .sup.3H,
.sup.14.sub.C, .sup.35S, .sup.125I and the like) is also
encompassed in the compound (A4).
[0198] The compound represented by the above-mentioned formula (A4)
can be produced, for example, according to the method described in
WO 2008/108380.
[0199] In the pharmaceutical composition of the present invention,
preferable examples of the nonpeptidic pharmaceutically active
ingredient having a primary or secondary amino group include the
following compounds. [0200]
N-methyl-1-{1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanam-
ine or a salt thereof, [0201]
1-{1-[(4-fluorophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanam-
ine or a salt thereof, [0202]
1-[1-(methylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-N-methylmethanamine
or a salt thereof, [0203]
1-{1-[(4-methoxyphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmethana-
mine or a salt thereof, [0204]
1-{1-[(4-fluorophenyl)sulfonyl]-2-methyl-5-phenyl-1H-pyrrol-3-yl}-N-methy-
lmethanamine or a salt thereof, [0205]
1-{5-(4-fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-3-yl}-N-meth-
ylmethanamine or a salt thereof, [0206]
N-methyl-1-{5-(3-methylphenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-3-y-
l}methanamine or a salt thereof, [0207]
N-methyl-1-{5-(3-fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-3-y-
l}methanamine or a salt thereof, [0208]
N-methyl-1-{1-[(2-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanam-
ine or a salt thereof, [0209]
N-methyl-1-(5-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrol-3--
yl)methanamine or a salt thereof, [0210]
1-{1-[(4-fluoro-2-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methy-
lmethanamine or a salt thereof, [0211]
N,N-dimethyl-1-(5-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrro-
l-3-yl)methanamine or a salt thereof, [0212]
1-[5-(4-fluorophenyl)-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanam-
ine or a salt thereof, [0213]
N-methyl-1-[5-(2-methylphenyl)-1-(4-methylphenylsulfonyl)-1H-pyrrol-3-yl]-
methanamine or a salt thereof, [0214]
1-{5-(4-fluorophenyl)-1-[(4-fluorophenyl)sulfonyl]-1H-pyrrol-3-yl}-N-meth-
ylmethanamine or a salt thereof, [0215]
1-(5-(4-fluorophenyl)-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrol-3-
-yl)-N-methylmethanamine or a salt thereof, [0216]
1-[1-[(4-fluorophenyl)sulfonyl]-5-(4-methoxyphenyl)-1H-pyrrol-3-yl]-N-met-
hylmethanamine or a salt thereof, [0217]
1-{1-[(4-fluorophenyl)sulfonyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrol-3-
-yl}-N-methylmethanamine or a salt thereof, [0218]
N-methyl-1-{1-(4-methylphenyl)sulfonyl}-5-[2-(trifluoromethyl)phenyl]-1H--
pyrrol-3-yl}methanamine or a salt thereof, [0219]
N-methyl-1-[2-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanami-
ne or a salt thereof, [0220]
1-{5-(2,4-difluorophenyl)-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl}-N-
-methylmethanamine or a salt thereof, [0221]
1-[1-[(4-methoxyphenyl)sulfonyl]-5-(4-phenoxyphenyl)-1H-pyrrol-3-yl]-N-me-
thylmethanamine or a salt thereof, [0222]
1-[1-[(4-methoxyphenyl)sulfonyl]-5-(2-naphthyl)-1H-pyrrol-3-yl]-N-methylm-
ethanamine or a salt thereof, [0223]
3-{1-[(4-methoxyphenyl)sulfonyl]-4-[(methylamino)methyl]-1H-pyrrol-2-yl}a-
niline or a salt thereof, [0224]
1-{1-[(4-methoxyphenyl)sulfonyl]-5-pyridin-3-yl-1H-pyrrol-3-yl}-N-methylm-
ethanamine or a salt thereof, [0225]
1-{1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanamine
or a salt thereof, [0226]
N-methyl-1-{4-methyl-1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl-
}methanamine or a salt thereof, [0227]
3-{4-[(methylamino)methyl]-1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-2-yl}be-
nzonitrile or a salt thereof, [0228]
4-{4-[(methylamino)methyl]-1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-2-yl}be-
nzonitrile or a salt thereof, [0229]
N-methyl-1-[1-(phenylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methanamine
or a salt thereof, [0230]
N-methyl-1-[5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanamine
or a salt thereof, [0231]
1-{1-[(4-fluorophenyl)sulfonyl]-5-(3-thienyl)-1H-pyrrol-3-yl}-N-methylmet-
hanamine or a salt thereof, [0232]
1-{1-[(3-chlorophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanam-
ine or a salt thereof, [0233]
1-[1-[(3-chlorophenyl)sulfonyl]-5-(3-thienyl)-1H-pyrrol-3-yl]-N-methylmet-
hanamine or a salt thereof, [0234]
1-[1-[(3-chlorophenyl)sulfonyl]-5-(4-fluorophenyl)-1H-pyrrol-3-yl]-N-meth-
ylmethanamine or a salt thereof, [0235]
1-{1-[(4-chlorophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanam-
ine or a salt thereof, [0236]
1-{1-[(3,4-difluorophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmeth-
anamine or a salt thereof, [0237]
1-[1-(2,3-dihydro-1-benzofuran-5-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-N-m-
ethylmethanamine or a salt thereof, [0238]
1-[1-(butylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-N-methylmethanamine
or a salt thereof, [0239]
1-{1-[(4-isopropoxyphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmeth-
anamine or a salt thereof, [0240]
1-{1-[(3-methoxyphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmethana-
mine or a salt thereof, [0241]
3-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzonitrile
or a salt thereof, [0242]
N-methyl-1-[5-phenyl-1-(3-thienylsulfonyl)-1H-pyrrol-3-yl]methanamine
or a salt thereof, [0243]
1-[5-(3-furyl)-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl]-N-methylmeth-
anamine or a salt thereof, [0244]
1-{1-[(2,5-dichloro-3-thienyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methyl-
methanamine or a salt thereof, [0245]
1-(2-chloro-5-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrol-3--
yl)-N-methylmethanamine or a salt thereof, [0246]
1-{1-[(3-chlorophenyl)sulfonyl]-2-methyl-5-phenyl-1H-pyrrol-3-yl}-N-methy-
lmethanamine or a salt thereof, [0247]
N-methyl-1-(5-phenyl-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}-1H-pyrrol-3-
-yl)methanamine or a salt thereof, [0248]
N-methyl-1-[5-phenyl-1-(2-thienylsulfonyl)-1H-pyrrol-3-yl]methanamine
or a salt thereof, [0249]
N-methyl-1-[2-methyl-1-(phenylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]meth-
anamine or a salt thereof, [0250]
1-[5-(4-fluorophenyl)-2-methyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methy-
lmethanamine or a salt thereof, [0251]
N-ethyl-1-[5-(4-fluorophenyl)-2-methyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-
methylamine or a salt thereof, [0252]
1-[2,4-dimethyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmetha-
namine or a salt thereof, [0253]
N-methyl-1-[5-phenyl-1-(phenylsulfonyl)-4-propyl-1H-pyrrol-3-yl]methanami-
ne or a salt thereof, [0254]
1-[4,5-diphenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine
or a salt thereof, [0255]
1-[2-chloro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanami-
ne or a salt thereof, [0256]
1-[2-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanami-
ne or a salt thereof, [0257]
1-[2-chloro-4-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methyl-
methanamine or a salt thereof, [0258]
1-[4-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanami-
ne or a salt thereof, [0259]
N-methyl-1-{2-methyl-1-[(3-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl-
}methanamine or a salt thereof, [0260]
N-methyl-1-[1-(2-methylpyrimidin-5-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]me-
thanamine or a salt thereof, [0261]
N-methyl-1-{4-methyl-[1-(3-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl-
}methanamine or a salt thereof, [0262]
1-{[1-(4-fluorophenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrol-3-yl}-N-methy-
lmethanamine or a salt thereof, [0263]
N-methyl-1-[2-methyl-1-(pyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]met-
hanamine or a salt thereof, [0264]
1-[4-chloro-2-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methyl-
methanamine or a salt thereof, [0265]
1-[5-butyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine
or a salt thereof, [0266]
1-[5-cyclohexyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine
or a salt thereof, [0267]
1-[5-cyclopropyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine
or a salt thereof, [0268]
N-methyl-1-(1-{[3-(methylsulfonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrol-3-y-
l)methanamine or a salt thereof, [0269]
1-(1-{[3-(ethylsulfonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrol-3-yl)-N-methy-
lmethanamine or a salt thereof, [0270]
1-[1-(2,3-dihydro-1,4-benzodioxyn-6-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]--
N-methylmethanamine or a salt thereof, [0271]
2-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzonitrile
or a salt thereof, [0272]
4-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzonitrile
or a salt thereof, [0273] methyl
2-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzoate
or a salt thereof, [0274] methyl
2-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzoate
or a salt thereof, [0275] methyl
3-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzoate
or a salt thereof, [0276] methyl
3-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzoate
or a salt thereof, [0277]
2-chloro-4-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)ben-
zonitrile or a salt thereof, [0278]
[1-(1,3-benzothiazol-6-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-N-methylmetha-
namine or a salt thereof, [0279]
1-{1-[(1,1-dioxide-2,3-dihydro-1-benzothien-6-yl)sulfonyl]-5-phenyl-1H-py-
rrol-3-yl}-N-methylmethanamine or a salt thereof, [0280]
1-[1-(1-benzothien-2-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-N-methylmethana-
mine or a salt thereof, [0281]
N-methyl-1-(1-{[4-(methylsulfonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrol-3-y-
l)methanamine or a salt thereof, [0282]
1-[3-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)phenyl]et-
hanone or a salt thereof, [0283]
N-methyl-1-{1-[(3-nitrophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanami-
ne or a salt thereof, [0284]
N-methyl-1-[5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanamine
or a salt thereof, [0285]
1-{1-[(6-methoxypyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylm-
ethanamine or a salt thereof, [0286]
N-methyl-1-[1-(4-methylaminopyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl-
]methanamine or a salt thereof, [0287]
N-methyl-1-[1-(2-methylaminopyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl-
]methanamine or a salt thereof, [0288]
N-methyl-1-[1-(2-methylaminopyrimidin-5-ylsulfonyl)-5-phenyl-1H-pyrrol-3--
yl]methanamine or a salt thereof, [0289]
1-[5-(2-fluorophenyl)-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrol-3--
yl]-N-methylmethanamine or a salt thereof, [0290]
1-[1-{[3-(ethylsulfonyl)phenyl]sulfonyl}-5-(2-fluorophenyl)-1H-pyrrol-3-y-
l]-N-methylmethanamine or a salt thereof, [0291]
2-{[2-(2-fluorophenyl)-4-[(methylamino)methyl]-1H-pyrrol-1-yl]sulfonyl}be-
nzonitrile or a salt thereof, [0292]
4-{[2-(2-fluorophenyl)-4-[(methylamino)methyl]-1H-pyrrol-1-yl]sulfonyl}be-
nzonitrile or a salt thereof, [0293]
1-{5-(2-fluorophenyl)-1-[(2-fluorophenyl)sulfonyl]-1H-pyrrol-3-yl}-N-meth-
ylmethanamine or a salt thereof, [0294]
1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylme-
thanamine or a salt thereof, [0295]
N-methyl-1-(1-{[3-(methylsulfonyl)phenyl]sulfonyl}-5-[2-(trifluoromethyl)-
phenyl]-1H-pyrrol-3-yl)methanamine or a salt thereof, [0296]
N-methyl-1-{1-(pyridin-3-ylsulfonyl)-5-[2-(trifluoromethyl)phenyl]-1H-pyr-
rol-3-yl}methanamine or a salt thereof, [0297]
N-methyl-1-[5-(2-methylphenyl)-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H--
pyrrol-3-yl]methanamine or a salt thereof, [0298]
N-methyl-1-[1-(phenylsulfonyl)-5-(pyridin-2-yl)-1H-pyrrol-3-yl]methanamin-
e or a salt thereof, [0299]
1-{1-[(3,4-difluorophenyl)sulfonyl]-5-(pyridin-2-yl)-1H-pyrrol-3-yl}-N-me-
thylmethanamine or a salt thereof, [0300]
1-[1-(2,3-dihydro-1,4-benzodioxyn-5-ylsulfonyl)-4-methyl-5-phenyl-1H-pyrr-
ol-3-yl]-N-methylmethanamine or a salt thereof, [0301]
1-{1-[(2,5-dimethoxyphenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrol-3-yl}-N--
methylmethanamine or a salt thereof, [0302]
1-[1-(2,3-dihydro-1,4-benzodioxyn-6-ylsulfonyl)-4-methyl-5-phenyl-1H-pyrr-
ol-3-yl]-N-methylmethanamine or a salt thereof, [0303]
1-(1-{[3-(methylsulfonyl)phenyl]sulfonyl}-4-methyl-5-phenyl-1H-pyrrol-3-y-
l)-N-methylmethanamine or a salt thereof, [0304]
N-methyl-1-{4-methyl-5-phenyl-1-(3-thienylsulfonyl)-1H-pyrrol-3-yl}methan-
amine or a salt thereof, [0305]
N-methyl-1-[4-methyl-1-(pyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]met-
hanamine or a salt thereof, [0306]
N-methyl-1-[4-methyl-1-(pyridin-2-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]met-
hanamine or a salt thereof, [0307]
1-{1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrro-
l-3-yl}-N-methylmethanamine or a salt thereof, [0308]
1-{1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-methyl-5-phenyl--
1H-pyrrol-3-yl}-N-methylmethanamine or a salt thereof, [0309]
1-{1-[(1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrol-
-3-yl}-N-methylmethanamine or a salt thereof, [0310]
1-{1-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrro-
l-3-yl}-N-methylmethanamine or a salt thereof, [0311]
[5-(2-fluorophenyl)-4-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-m-
ethylmethanamine or a salt thereof, [0312]
N-methyl-[2-methyl-1-(phenylsulfonyl)-5-(3-pyridyl)-1H-pyrrol-3-yl]methan-
amine or a salt thereof, [0313]
N-methyl-[2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-pyr-
rol-3-yl]methanamine or a salt thereof, [0314]
N-methyl-1-[4-methyl-1-(phenylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]meth-
anamine or a salt thereof, [0315]
1-[5-phenyl-1-({4-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-1H-pyrrol-3-
-yl]-N-methylmethanamine or a salt thereof, [0316]
1-[5-phenyl-1-({3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-1H-pyrrol-3-
-yl]-N-methylmethanamine or a salt thereof, [0317]
1-[5-(2-fluorophenyl)-1-({3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-1-
H-pyrrol-3-yl]-N-methylmethanamine or a salt thereof, [0318]
N-methyl-1-[4-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanami-
ne or a salt thereof, [0319]
1-{1-[(3-chlorophenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrol-3-yl}-N-methy-
lmethanamine or a salt thereof, [0320]
5-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)pyrimidin-2--
amine or a salt thereof, [0321]
1-[(imidazo[1,2-a]pyrimidin-6-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-N-meth-
ylmethanamine or a salt thereof, [0322]
N-methyl-1-[1-(pyridazin-3-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]methanamin-
e or a salt thereof, [0323]
N,N-dimethyl-1-[5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanamine
or
a salt thereof, [0324]
N,N-dimethyl-1-[5-phenyl-1-(3-thienylsulfonyl)-1H-pyrrol-3-yl]methanamine
or a salt thereof, [0325]
N,N-dimethyl-1-{5-phenyl-1-(3-pyridinesulfonyl)-1H-pyrrol-3-yl}methanamin-
e or a salt thereof, [0326]
1-[4-ethyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamin-
e or a salt thereof, [0327]
1-[4-isopropyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethan-
amine or a salt thereof, [0328]
2-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzoic
acid or a salt thereof, [0329]
3-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzoic
acid or a salt thereof, [0330]
3-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzamide
or a salt thereof, [0331]
N-cyclopropyl-3-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfony-
l)benzamide or a salt thereof, [0332]
N-methyl-3-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)ben-
zamide or a salt thereof, [0333]
N,N-dimethyl-3-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl-
)benzamide or a salt thereof, [0334]
N-methyl-1-(1-{[3-(morpholin-4-ylcarbonyl)phenyl]sulfonyl}-5-phenyl-1H-py-
rrol-3-yl)methanamine or a salt thereof,
[0335]
2-[3-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl]sulfonyl)ph-
enyl}propan-2-ol or a salt thereof, [0336]
2-fluoro-4-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)ben-
zonitrile or a salt thereof, [0337]
N-methyl-1-(5-phenyl-1-{[3-(1H-tetrazol-5-yl)phenyl]sulfonyl}-1H-pyrrol-3-
-yl)methanamine or a salt thereof, [0338]
2-({4-[(methylamino)methyl]-2-(pyridin-3-yl)-1H-pyrrol-1-yl}sulfonyl)benz-
onitrile or a salt thereof, [0339]
N-methyl-1-(1-{[3-(methylsulfonyl)phenyl]sulfonyl}-5-(3-thienyl)-1H-pyrro-
l-3-yl)methanamine or a salt thereof, [0340]
N-methyl-1-(1-{[3-(methylsulfonyl)phenyl]sulfonyl}-5-(pyridin-3-yl)-1H-py-
rrol-3-yl)methanamine or a salt thereof, [0341]
1-[1-(2-chloropyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-N-methylmeth-
anamine or a salt thereof, [0342]
N-methyl-1-[1-(5-methyl-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]metha-
namine or a salt thereof, [0343]
5-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)pyridin-2-ol
or a salt thereof, [0344]
5-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)pyridine-2-c-
arbonitrile or a salt thereof [0345]
N-methyl-1-{1-[(6-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}me-
thanamine or a salt thereof, [0346]
N-methyl-1-[1-(pyridin-3-ylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methana-
mine or a salt thereof, [0347]
1-[5-(4-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylme-
thanamine or a salt thereof, [0348]
N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]me-
thanamine or a salt thereof, [0349]
1-[5-(4-fluoro-2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-
-methylmethanamine or a salt thereof, [0350]
N-methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-y-
l]methanamine or a salt thereof, [0351]
3-[4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-2-yl]benzon-
itrile or a salt thereof, [0352]
1-[5-(2-chlorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylme-
thanamine or a salt thereof, [0353]
1-[5-(2,4-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-meth-
ylmethanamine or a salt thereof, [0354]
1-[5-(2,5-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-meth-
ylmethanamine or a salt thereof, [0355]
1-[5-(4-chloro-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-
-methylmethanamine or a salt thereof, [0356]
1-[5-(3-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylme-
thanamine or a salt thereof, [0357]
N-methyl-1-[1-(phenylsulfonyl)-5-(pyrimidin-5-yl)-1H-pyrrol-3-yl]methanam-
ine or a salt thereof, [0358]
N-methyl-1-[1-(phenylsulfonyl)-5-(pyridin-3-yl)-1H-pyrrol-3-yl]methanamin-
e or a salt thereof, [0359]
{1-[5-(2-fluorophenyl)-2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]--
N-methylmethanamine or a salt thereof, [0360]
2,2,2-trifluoro-N-({1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-
methyl)ethaneamine or a salt thereof, [0361]
N-methyl-1-{1-[6-(methylamino)pyridin-3-ylsulfonyl]-5-phenyl-1H-pyrrol-3--
yl}methanamine or a salt thereof, [0362]
N-methyl-1-{1-[2-(methylamino)pyridin-3-ylsulfonyl]-5-phenyl-1H-pyrrol-3--
yl}methanamine or a salt thereof, [0363]
N-methyl-1-{1-[2-(methylamino)pyrimidin-3-ylsulfonyl]-5-phenyl-1H-pyrrol--
3-yl}methanamine or a salt thereof, [0364]
N-methyl-1-[2-methyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]met-
hanamine or a salt thereof, [0365]
N-methyl-1-[1-(2-methylpyrimidin-5-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-m-
ethanamine or a salt thereof, [0366]
N-methyl-1-[4-methyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]met-
hanamine or a salt thereof, [0367]
N-methyl-1-[4-methyl-5-phenyl-1-(pyridin-2-ylsulfonyl)-1H-pyrrol-3-yl]met-
hanamine or a salt thereof, [0368]
N-methyl-1-[5-phenyl-1-(pyridazin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanamin-
e or a salt thereof, [0369]
N-methyl-1-(5-phenyl-1-{[5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-1H-pyr-
rol-3-yl)methanamine or a salt thereof, [0370]
N-methyl-1-{1-[(2-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}me-
thanamine or a salt thereof, [0371]
1-[5-(2,6-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-meth-
ylmethanamine or a salt thereof, [0372]
1-[5-(4-cyclohexylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-meth-
ylmethanamine or a salt thereof, [0373]
1-[4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmet-
hanamine or a salt thereof, [0374]
1-[4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmet-
hanamine or a salt thereof, [0375]
1-[4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmet-
hanamine or a salt thereof, [0376]
1-{5-(2-fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}--
N-methylmethanamine or a salt thereof, [0377]
1-[5-(2-fluorophenyl)-1-(pyridin-2-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylme-
thanamine or a salt thereof, [0378]
1-{5-(2-fluorophenyl)-1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-1H-pyrrol-3--
yl}-N-methylmethanamine or a salt thereof, [0379]
N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]me-
thanamine or a salt thereof, [0380]
1-[4-chloro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-
-methylmethanamine or a salt thereof, [0381]
1-[4-fluoro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-
-methylmethanamine or a salt thereof, [0382]
1-[4-fluoro-5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-
-methylmethanamine or a salt thereof, [0383]
1-[2-chloro-5-(2,6-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-y-
l]-N-methylmethanamine or a salt thereof, [0384]
1-[2-chloro-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-
-methylmethanamine or a salt thereof, [0385]
1-{1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmet-
hanamine or a salt thereof, [0386]
5-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)nicotinonitr-
ile or a salt thereof, [0387] methyl
5-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)nicotinate
or a salt thereof, [0388]
N-methyl-1-{1-[(5-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}me-
thanamine or a salt thereof, [0389]
1-[5-(2,4-dimethylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-meth-
ylmethanamine or a salt thereof, [0390]
N-methyl-1-{5-[4-(methylsulfonyl)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrr-
ol-3-yl}methanamine or a salt thereof, [0391]
(2-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-2-yl}pheny-
l)methanol or a salt thereof, [0392]
N-methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-y-
l]methanamine or a salt thereof, [0393]
N-methyl-1-(5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methanamine
or a salt thereof, [0394]
1-[5-mesityl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine
or a salt thereof, [0395]
N-methyl-1-{5-[2-(methylthio)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
-yl}methanamine or a salt thereof, [0396]
N-methyl-1-{5-[2-(methylsulfonyl)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrr-
ol-3-yl}methanamine or a salt thereof, [0397]
2-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-2-yl}benzon-
itrile or a salt thereof, [0398]
1-[5-(2,6-dimethylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-meth-
ylmethanamine or a salt thereof, [0399]
N-methyl-1-{5-[2-(methylsulfinyl)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrr-
ol-3-yl}methanamine or a salt thereof, [0400]
2-(2-fluorophenyl)-4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-py-
rrole-3-carbonitrile or a salt thereof, [0401]
5-(2-fluorophenyl)-3-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-py-
rrole-2-carbonitrile or a salt thereof, [0402]
4-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-2-yl}benzon-
itrile or a salt thereof, [0403]
4-fluoro-3-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-2--
yl}benzonitrile or a salt thereof, [0404]
1-[5-(2-fluoro-5-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]--
N-methylmethanamine or a salt thereof, [0405]
1-(2-fluoro-3-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-
-2-yl}phenyl)ethanone or a salt thereof, [0406]
1-[5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-me-
thylmethanamine or a salt thereof, [0407]
1-[5-(3-fluoropyridin-4-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-me-
thylmethanamine or a salt thereof, [0408]
1-[5-(2-chloropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-me-
thylmethanamine or a salt thereof, [0409]
1-[5-(6-chloropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-me-
thylmethanamine or a salt thereof, [0410]
1-[5-(6'-chloro-2,3'-bipyridin-5-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
-yl]-N-methylmethanamine or a salt thereof, [0411]
1-{5-(2-fluoropyridin-3-yl)-1-[(6-methoxypyridin-3-yl)sulfonyl]-1H-pyrrol-
-3-yl}-N-methylmethanamine or a salt thereof, [0412]
(2-fluoro-3-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-2-
-yl}phenyl)methanol or a salt thereof, [0413]
1-(2-fluoro-3-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-
-2-yl}phenyl)ethanol or a salt thereof, [0414]
1-[5-(2-fluoro-3-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]--
N-methylmethanamine or a salt thereof, [0415]
1-[5-(2-fluoro-6-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]--
N-methylmethanamine or a salt thereof, [0416]
1-{5-[4-(difluoromethoxy)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl}-
-N-methylmethanamine or a salt thereof, [0417]
N-methyl-1-[5-(4-methylpyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
-yl]methanamine or a salt thereof, [0418]
N-methyl-1-[5-(2-methylpyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
-yl]methanamine or a salt thereof, [0419]
1-{5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol--
3-yl}-N-methylmethanamine or a salt thereof, [0420]
1-[4-chloro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
-yl]-N-methylmethanamine or a salt thereof, [0421]
N-methyl-1-[1-(pyridin-3-ylsulfonyl)-5-(2-thienyl)-1H-pyrrol-3-yl]methana-
mine or a salt thereof, [0422]
N-methyl-1-[5-(3-methylpyridin-2-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
-yl]methanamine or a salt thereof, [0423]
2-fluoro-3-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-2--
yl}benzonitrile or a salt thereof, [0424]
4-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-2-yl}thioph-
ene-3-carbonitrile or a salt thereof, [0425]
1-[5-(2-fluoropyridin-3-yl)-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylme-
thanamine or a salt thereof, [0426]
1-{1-[(2-fluorophenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}--
N-methylmethanamine or a salt thereof, [0427]
1-[5-(2-fluoropyridin-3-yl)-1-(2-furylsulfonyl)-1H-pyrrol-3-yl]-N-methylm-
ethanamine or a salt thereof, [0428]
1-(5-(2-fluoropyridin-3-yl)-1-[[3-(methylsulfonyl)phenyl]sulfonyl]-1H-pyr-
rol-3-yl)-N-methylmethanamine or a salt thereof, [0429]
1-[5-(2-fluoropyridin-3-yl)-1-(2-thienylsulfonyl)-1H-pyrrol-3-yl]-N-methy-
lmethanamine or a salt thereof, [0430]
1-[1-(1,3-benzodioxol-5-ylsulfonyl)-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3--
yl]-N-methylmethanamine or a salt thereof, [0431]
1-(4-chloro-5-(2-fluoropyridin-3-yl)-1-[[3-(methylsulfonyl)phenyl]sulfony-
l]-1H-pyrrol-3-yl)-N-methylmethanamine or a salt thereof, [0432]
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
-yl]-N-methylmethanamine or a salt thereof, [0433]
1-{5-(2-chloropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol--
3-yl}-N-methylmethanamine or a salt thereof, [0434]
3-{1-[(3-fluorophenyl)sulfonyl]-4-[(methylamino)methyl]-1H-pyrrol-2-yl}py-
ridine-2-carbonitrile or a salt thereof, [0435]
1-{5-(2-fluoropyridin-3-yl)-1-[(3-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl}-
-N-methylmethanamine or a salt thereof, [0436]
1-{1-[(3-fluorophenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}--
N-methylmethanamine or a salt thereof, [0437]
1-[5-(2-fluoro-6-methylpyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
-yl]-N-methylmethanamine or a salt thereof, [0438]
3-{4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-2-yl}pyridi-
ne-2-carbonitrile or a salt thereof, [0439]
1-[5-(2-chloropyridin-3-yl)-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylme-
thanamine or a salt thereof, [0440]
3-{4-[(methylamino)methyl]-1-(phenylsulfonyl)-1H-pyrrol-2-yl}pyridine-2-c-
arbonitrile or a salt thereof, [0441]
1-[5-(2-fluoropyridin-3-yl)-1-(3-thienylsulfonyl)-1H-pyrrol-3-yl]-N-methy-
lmethanamine or a salt thereof, [0442]
3-({2-(2-fluoropyridin-3-yl)-4-[(methylamino)methyl]-1H-pyrrol-1-yl}sulfo-
nyl)benzonitrile or a salt thereof, [0443]
1-[3-({2-(2-fluoropyridin-3-yl)-4-[(methylamino)methyl]-1H-pyrrol-1-yl]su-
lfonyl)phenyl}ethanone or a salt thereof, [0444]
1-{1-[(4-fluorophenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}--
N-methylmethanamine or a salt thereof, [0445]
1-{1-[(2,3-difluorophenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3--
yl}-N-methylmethanamine or a salt thereof, [0446]
1-{1-[(3,4-difluorophenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3--
yl}-N-methylmethanamine or a salt thereof, [0447]
1-{1-[(3-fluoro-4-methylphenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrr-
ol-3-yl}-N-methylmethanamine or a salt thereof, [0448]
1-{1-[(2,5-difluorophenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3--
yl}-N-methylmethanamine or a salt thereof, [0449]
1-[5-(2-fluoropyridin-3-yl)-4-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
-yl]-N-methylmethanamine or a salt thereof, [0450]
1-[5-(2-fluoropyridin-3-yl)-4-methyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-
-methylmethanamine or a salt thereof, [0451]
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
-yl]-N-methylmethanamine or a salt thereof, [0452]
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
-yl]-N-methylmethanamine or a salt thereof, [0453]
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-
-methylmethanamine or a salt thereof, [0454]
1-{4-fluoro-1-(phenylsulfonyl)-5-[2-(trifluoromethyl)pyridin-3-yl]-1H-pyr-
rol-3-yl}-N-methylmethanamine or a salt thereof, [0455]
1-{4-fluoro-1-(pyridin-3-ylsulfonyl)-5-[2-(trifluoromethyl)pyridin-3-yl]--
1H-pyrrol-3-yl}-N-methylmethanamine or a salt thereof, [0456]
1-[5-(2-chloropyridin-3-yl)-4-fluoro-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-
-methylmethanamine or a salt thereof, [0457]
3-[3-fluoro-4-[(methylamino)methyl]-1-(phenylsulfonyl)-1H-pyrrol-2-yl]pyr-
idine-2-carbonitrile or a salt thereof, [0458]
1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-methoxyphenyl)sulfonyl]-1H-pyr-
rol-3-yl}-N-methylmethanamine or a salt thereof, [0459]
1-{4-fluoro-1-[(3-fluorophenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrr-
ol-3-yl}-N-methylmethanamine or a salt thereof, [0460]
1-{5-(2-chloropyridin-3-yl)-4-fluoro-1-[(3-methoxyphenyl)sulfonyl]-1H-pyr-
rol-3-yl}-N-methylmethanamine or a salt thereof, [0461]
1-[5-(2-chloropyridin-3-yl)-4-fluoro-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
-yl]-N-methylmethanamine or a salt thereof, [0462]
1-{5-(2-chloropyridin-3-yl)-4-fluoro-1-[(3-fluorophenyl)sulfonyl]-1H-pyrr-
ol-3-yl}-N-methylmethanamine or a salt thereof, [0463]
3-({2-(2-chloropyridin-3-yl)-3-fluoro-4-[(methylamino)methyl]-1H-pyrrol-1-
-yl}sulfonyl)benzonitrile or a salt thereof, [0464]
3-{3-fluoro-1-[(3-methoxyphenyl)sulfonyl]-4-[(methylamino)methyl]-1H-pyrr-
ol-2-yl}pyridine-2-carbonitrile or a salt thereof,
[0465]
3-{3-fluoro-1-[(3-fluorophenyl)sulfonyl]-4-[(methylamino)methyl]-1-
H-pyrrol-2-yl}pyridine-2-carbonitrile or a salt thereof, [0466]
3-{1-[(3-cyanophenyl)sulfonyl]-3-fluoro-4-[(methylamino)methyl]-1H-pyrrol-
-2-yl}pyridine-2-carbonitrile or a salt thereof, [0467]
3-[3-fluoro-4-[(methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-2--
yl]pyridine-2-carbonitrile or a salt thereof, [0468]
3-({3-fluoro-2-(2-fluoropyridin-3-yl)-4-[(methylamino)methyl]-1H-pyrrol-1-
-yl}sulfonyl)benzonitrile or a salt thereof, [0469]
1-(4-fluoro-5-(2-fluoropyridin-3-yl)-1-{[3-(methylsulfonyl)phenyl]sulfony-
l}-1H-pyrrol-3-yl)-N-methylmethanamine or a salt thereof, [0470]
3-({3-fluoro-2-(2-fluoropyridin-3-yl)-4-[(methylamino)methyl]-1H-pyrrol-1-
-yl}sulfonyl)-N-(2-hydroxyethyl)benzamide or a salt thereof, [0471]
[3-({3-fluoro-2-(2-fluoropyridin-3-yl)-4-[(methylamino)methyl]-1H-pyrrol--
1-yl]sulfonyl)phenyl}methanol or a salt thereof, [0472]
3-({3-fluoro-2-(2-fluoropyridin-3-yl)-4-[(methylamino)methyl]-1H-pyrrol-1-
-yl}sulfonyl)benzyl acetate or a salt thereof, [0473]
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(3-furylsulfonyl)-1H-pyrrol-3-yl]--
N-methylmethanamine or a salt thereof, [0474]
1-[5-(2-fluoropyridin-3-yl)-1-(3-furylsulfonyl)-1H-pyrrol-3-yl]-N-methylm-
ethanamine or a salt thereof, [0475]
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-({3-[(methylsulfonyl)methyl]phenyl-
}sulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine or a salt thereof,
[0476]
1-(4-fluoro-5-(2-fluoropyridin-3-yl)-1-{[3-(5-methyl-1,3,4-oxadiazol-2-yl-
)phenyl]sulfonyl}-1H-pyrrol-3-yl)-N-methylmethanamine or a salt
thereof, [0477]
3-({2-(2-chloropyridin-3-yl)-4-[(methylamino)methyl]-1H-pyrrol-1-y-
l}sulfonyl)benzonitrile or a salt thereof, [0478]
1-[1-(cyclohexylsulfonyl)-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-y-
l]-N-methylmethanamine or a salt thereof, [0479]
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(piperidin-1-ylsulfonyl)-1H-pyrrol-
-3-yl]-N-methylmethanamine or a salt thereof, [0480]
1-{1-[(2,6-difluorophenyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H--
pyrrol-3-yl}-N-methylmethanamine or a salt thereof, [0481]
1-{4-chloro-5-(2-fluoropyridin-3-yl)-1-[(1-methyl-1H-pyrazol-4-yl)sulfony-
l]-1H-pyrrol-3-yl}-N-methylmethanamine or a salt thereof, [0482]
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(2-thienylsulfonyl)-1H-pyrrol-3-yl-
]-N-methylmethanamine or a salt thereof, [0483]
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(2-furylsulfonyl)-1H-pyrrol-3-yl]--
N-methylmethanamine or a salt thereof, [0484]
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(3-thienylsulfonyl)-1H-pyrrol-3-yl-
]-N-methylmethanamine or a salt thereof, [0485]
1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(1-methyl-1H-pyrazol-4-yl)sulfony-
l]-1H-pyrrol-3-yl}-N-methylmethanamine or a salt thereof, [0486]
Methyl
5-({3-fluoro-2-(2-fluoropyridin-3-yl)-4-[(methylamino)methyl]-1H-pyrrol-1-
-yl}sulfonyl)-2-furoate or a salt thereof, [0487]
[5-({3-fluoro-2-(2-fluoropyridin-3-yl)-4-[(methylamino)methyl]-1H-pyrrol--
1-yl}sulfonyl)-2-furyl]methanol or a salt thereof, [0488]
[5-({3-fluoro-2-(2-fluoropyridin-3-yl)-4-[(methylamino)methyl]-1H-pyrrol--
1-yl}sulfonyl)-2-furyl]methyl acetate or a salt thereof, [0489]
1-[4-fluoro-1-{[5-(fluoromethyl)-2-furyl]sulfonyl}-5-(2-fluoropyridin-3-y-
l)-1H-pyrrol-3-yl]-N-methylmethanamine or a salt thereof, [0490]
5-({3-fluoro-2-(2-fluoropyridin-3-yl)-4-[(methylamino)methyl]-1H-pyrrol-1-
-yl}sulfonyl)-2-furamide or a salt thereof, [0491]
5-({3-fluoro-2-(2-fluoropyridin-3-yl)-4-[(methylamino)methyl]-1H-pyrrol-1-
-yl}sulfonyl)-2-furonitrile or a salt thereof, [0492]
1-[1-{[5-(difluoromethyl)-2-furyl]sulfonyl}-4-fluoro-5-(2-fluoropyridin-3-
-yl)-1H-pyrrol-3-yl]-N-methylmethanamine or a salt thereof, [0493]
1-[5-({3-fluoro-2-(2-fluoropyridin-3-yl)-4-[(methylamino)methyl]-1H-pyrro-
l-1-yl}sulfonyl)-2-furyl]ethanol or a salt thereof, [0494]
1-[5-({3-fluoro-2-(2-fluoropyridin-3-yl)-4-[(methylamino)methyl]-1H-pyrro-
l-1-yl}sulfonyl)-2-furyl]ethanone or a salt thereof, [0495]
1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methylfuran-3-yl)sulfonyl]-1H--
pyrrol-3-yl}-N-methylmethanamine or a salt thereof, [0496]
1-[1-[(5-chloro-2-thienyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H--
pyrrol-3-yl]-N-methylmethanamine or a salt thereof, [0497]
1-[1-[(5-bromo-2-thienyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-p-
yrrol-3-yl]-N-methylmethanamine or a salt thereof, [0498]
1-[1-[(4-bromo-3-thienyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-p-
yrrol-3-yl]-N-methylmethanamine or a salt thereof, [0499]
4-({3-fluoro-2-(2-fluoropyridin-3-yl)-4-[(methylamino)methyl]-1H-pyrrol-1-
-yl}sulfonyl)thiophene-3-carbonitrile or a salt thereof, [0500]
Methyl
3-({3-fluoro-2-(2-fluoropyridin-3-yl)-4-[(methylamino)methyl]-1H-pyrrol-1-
-yl}sulfonyl)thiophene-2-carboxylate or a salt thereof, [0501]
1-{5-(2-fluoropyridin-3-yl)-1-[(5-isoxazol-5-yl-2-thienyl)sulfonyl]-1H-py-
rrol-3-yl}-N-methylmethanamine or a salt thereof, [0502]
1-{1-[(1-ethyl-1H-pyrazol-4-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl-
)-1H-pyrrol-3-yl}-N-methylmethanamine or a salt thereof, [0503]
1-{1-[(1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-
-3-yl)-1H-pyrrol-3-yl}-N-methylmethanamine or a salt thereof,
[0504]
1-[1-{[1-(difluoromethyl)-1H-pyrazol-4-yl]sulfonyl}-4-fluoro-5-(2-fluorop-
yridin-3-yl)-1H-pyrrol-3-yl]-N-methylmethanamine or a salt thereof,
[0505]
1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(1-methyl-1H-imidazol-2-yl)sulfon-
yl]-1H-pyrrol-3-yl}-N-methylmethanamine or a salt thereof, [0506]
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(1,3-thiazol-2-ylsulfonyl)-1H-pyrr-
ol-3-yl]-N-methylmethanamine or a salt thereof, [0507]
1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methoxypyridin-3-yl)sulfonyl]--
1H-pyrrol-3-yl}-N-methylmethanamine or a salt thereof, [0508]
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(pyridin-2-ylsulfonyl)-1H-pyrrol-3-
-yl]-N-methylmethanamine or a salt thereof, [0509]
1-[1-[(2-chloropyridin-3-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1-
H-pyrrol-3-yl]-N-methylmethanamine or a salt thereof, [0510]
2-({3-fluoro-2-(2-fluoropyridin-3-yl)-4-[(methylamino)methyl]-1H-pyrrol-1-
-yl}sulfonyl)benzonitrile or a salt thereof, [0511]
4-({3-fluoro-2-(2-fluoropyridin-3-yl)-4-[(methylamino)methyl]-1H-pyrrol-1-
-yl}sulfonyl)phenol or a salt thereof, [0512]
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(morpholin-4-ylsulfonyl)-1H-pyrrol-
-3-yl]-N-methylmethanamine or a salt thereof, [0513]
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(pyrrolidin-1-ylsulfonyl)-1H-pyrro-
l-3-yl]-N-methylmethanamine or a salt thereof, [0514]
1-[5-(2-fluoropyridin-3-yl)-1-(1,3-thiazol-2-ylsulfonyl)-1H-pyrrol-3-yl]--
N-methylmethanamine or a salt thereof, [0515]
3-{1-(2-furylsulfonyl)-4-[(methylamino)methyl]-1H-pyrrol-2-yl}pyridine-2--
carbonitrile or a salt thereof, [0516]
3-{1-(3-furylsulfonyl)-4-[(methylamino)methyl]-1H-pyrrol-2-yl}pyridine-2--
carbonitrile or a salt thereof, [0517]
3-[4-[(methylamino)methyl]-1-(2-thienylsulfonyl)-1H-pyrrol-2-yl]pyridine--
2-carbonitrile or a salt thereof, [0518]
3-[4-[(methylamino)methyl]-1-(3-thienylsulfonyl)-1H-pyrrol-2-yl]pyridine--
2-carbonitrile or a salt thereof, [0519]
3-{1-[(2,6-difluorophenyl)sulfonyl]-4-[(methylamino)methyl]-1H-pyrrol-2-y-
l}pyridine-2-carbonitrile or a salt thereof, [0520]
3-{1-[(2,4-difluorophenyl)sulfonyl]-4-[(methylamino)methyl]-1H-pyrrol-2-y-
l}pyridine-2-carbonitrile or a salt thereof, [0521]
3-{4-[(methylamino)methyl]-1-[(2-methylphenyl)sulfonyl]-1H-pyrrol-2-yl}py-
ridine-2-carbonitrile or a salt thereof, [0522]
3-{1-[(2-chlorophenyl)sulfonyl]-4-[(methylamino)methyl]-1H-pyrrol-2-yl}py-
ridine-2-carbonitrile or a salt thereof, [0523]
3-{1-[(2-fluorophenyl)sulfonyl]-4-[(methylamino)methyl]-1H-pyrrol-2-yl}py-
ridine-2-carbonitrile or a salt thereof, [0524]
3-{1-[(2-cyanophenyl)sulfonyl]-4-[(methylamino)methyl]-1H-pyrrol-2-yl}pyr-
idine-2-carbonitrile or a salt thereof, [0525]
3-{1-[(6-methoxypyridin-3-yl)sulfonyl]-4-[(methylamino)methyl]-1H-pyrrol--
2-yl}pyridine-2-carbonitrile or a salt thereof, [0526]
1-methyl-3-{4-[(methylamino)methyl]-1-(phenylsulfonyl)-1H-pyrrol-2-yl}pyr-
idin-2(1H)-one or a salt thereof, [0527]
3-{4-[(dimethylamino)methyl]-1-(phenylsulfonyl)-1H-pyrrol-2-yl}-1-methylp-
yridin-2(1H)-one or a salt thereof, [0528]
3-[4-[(methylamino)methyl]-1-(phenylsulfonyl)-1H-pyrrol-2-yl]pyridin-2(1H-
)-one or a salt thereof, [0529]
1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-fluoropyridin-2-yl)sulfonyl]-1-
H-pyrrol-3-yl}-N-methylmethanamine or a salt thereof, [0530]
1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methoxypyridin-2-yl)sulfonyl]--
1H-pyrrol-3-yl}-N-methylmethanamine or a salt thereof, [0531]
1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-2-yl)sulfonyl]-1-
H-pyrrol-3-yl}-N-methylmethanamine or a salt thereof.
[0532] In addition, the compounds shown in the following Tables 1-1
to 1-4 and salts thereof are also preferable as a pharmaceutically
active ingredient having a primary or secondary amino group in the
pharmaceutical composition of the present invention.
TABLE-US-00001 TABLE 1-1 ##STR00015## LC/MS HPLC m/e Ar R.sup.q
purity (%) (M.sup.+ + 1) 3-pyridyl methoxy 97 358 3-thienyl methoxy
96 363 p-tolyl methoxy 96 371 4-cyanophenyl methoxy 100 382
3,5-dimethylphenyl methoxy 96 385 4-methoxyphenyl methoxy 97 387
4-chlorophenyl methoxy 91 391 4-acetylphenyl methoxy 98 399
3-acetylphenyl methoxy 97 399 4-aminocarbonylphenyl methoxy 98 400
4-(N,N-dimethylamino)phenyl methoxy 98 400 4-(methylthio)phenyl
methoxy 81 403 benzo[b]thiophen-2-yl methoxy 99 413
3-(acetylamino)phenyl methoxy 93 414 2,4-dimethoxyphenyl methoxy 97
417 3-(trifluoromethyl)phenyl methoxy 94 425
4-(trifluoromethoxy)phenyl methoxy 87 441 2-isopropoxyphenyl
methoxy 99 415 3-(6-methoxy)pyridyl methoxy 93 388 3-cyanophenyl
methoxy 98 382 3-furyl methyl 98 331
TABLE-US-00002 TABLE 1-2 ##STR00016## LC/MS HPLC m/e Ar R.sup.q
purity (%) (M.sup.+ + 1) 3-pyridyl methyl 100 342 3-thienyl methyl
99 347 p-tolyl methyl 96 355 4-cyanophenyl methyl 98 366
3,5-dimethylphenyl methyl 93 369 4-methoxyphenyl methyl 99 371
4-chlorophenyl methyl 93 375 4-acetylphenyl methyl 98 383
3-acetylphenyl methyl 98 383 4-aminocarbonylphenyl methyl 98 384
4-(N,N-dimethylamino)phenyl methyl 99 384 4-(methylthio)phenyl
methyl 96 387 benzo[b]thiophen-2-yl methyl 99 397
3-(acetylamino)phenyl methyl 89 398 2,4-dimethoxyphenyl methyl 99
401 3-(trifluoromethyl)phenyl methyl 81 409
4-(trifluoromethoxy)phenyl methyl 89 425 2-isopropoxyphenyl methyl
92 399 3-(hydroxymethyl)phenyl methyl 91 371 3-(6-methoxy)pyridyl
methyl 99 372 3-cyanophenyl methyl 98 366
TABLE-US-00003 TABLE 1-3 ##STR00017## LC/MS HPLC m/e R.sup.r purity
(%) (M.sup.+ + 1) 4-biphenyl 100 403 m-toluyl 100 341
2,4-dichlorophenyl 100 395 2-methoxy-4-methylphenyl 100 371
2-chlorophenyl 100 361 4-carboxyphenyl 99 371 3,5-dimethylphenyl
100 355 3,5-dichlorophenyl 93 395 4-tert-butylphenyl 99 383
n-propyl 99 293 ethyl 100 279 3,4-dimethoxyphenyl 95 387
3-chlorophenyl 100 361 4-cyanophenyl 98 352 3-cyanophenyl 98 352
2-cyanophenyl 99 352 2,1,3-benzothiadiazol-4-yl 96 385
3,4-dichlorophenyl 99 395 3-thienyl 96 333 phenyl 100 327
TABLE-US-00004 TABLE 1-4 ##STR00018## LC/MS HPLC m/e R.sup.r purity
(%) (M.sup.+ + 1) 1-naphthyl 97 377 p-styryl 99 353 4-ethylphenyl
100 355 2,5-dichlorophenyl 99 395 isopropyl 100 293
2-(1-naphthyl)ethyl 99 405 2-naphthyl 99 377 2,4,6-trimethylphenyl
100 369 4-bromophenyl 99 405
[0533] Of these, preferred are the following compounds. [0534]
N-methyl-1-[1-(phenylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methanamine
or a salt thereof, [0535]
N-methyl-1-[5-phenyl-1-(3-thienylsulfonyl)-1H-pyrrol-3-yl]methanamine
or a salt thereof, [0536]
N-methyl-1-(1-{[3-(methylsulfonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrol-3-y-
l)methanamine or a salt thereof, [0537]
1-[1-(1-benzothien-2-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-N-methylmethana-
mine or a salt thereof, [0538]
1-[5-(2-fluorophenyl)-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrol-3--
yl]-N-methylmethanamine or a salt thereof, [0539]
1-{5-(2-fluorophenyl)-1-[(2-fluorophenyl)sulfonyl]-1H-pyrrol-3-yl}-N-meth-
ylmethanamine or a salt thereof, [0540]
N-methyl-3-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)ben-
zamide or a salt thereof, [0541]
1-{5-(2-fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}--
N-methylmethanamine or a salt thereof, [0542]
1-[4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmet-
hanamine or a salt thereof, [0543]
N-methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-y-
l]methanamine or a salt thereof, [0544]
1-[5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-me-
thylmethanamine or a salt thereof, [0545]
1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylme-
thanamine or a salt thereof, [0546]
N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]me-
thanamine or a salt thereof, [0547]
1-[5-(2-Fluoropyridin-3-yl)-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylme-
thanamine or a salt thereof, [0548]
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
-yl]-N-methylmethanamine or a salt thereof, [0549]
1-[5-(2-chloropyridin-3-yl)-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylme-
thanamine or a salt thereof, [0550]
3-{4-[(methylamino)methyl]-1-(phenylsulfonyl)-1H-pyrrol-2-yl}pyridine-2-c-
arbonitrile or a salt thereof, or [0551]
1-{1-[(4-fluorophenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}--
N-methylmethanamine or a salt thereof [0552]
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(3-furylsulfonyl)-1H-pyrrol-3-yl]--
N-methylmethanamine or a salt thereof, [0553]
1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methylfuran-3-yl)sulfonyl]-1H--
pyrrol-3-yl}-N-methylmethanamine or a salt thereof, [0554]
1-[1-{[1-(difluoromethyl)-1H-pyrazol-4-yl]sulfonyl]-4-fluoro-5-(2-fluorop-
yridin-3-yl)-1H-pyrrol-3-yl}-N-methylmethanamine or a salt thereof,
[0555]
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(pyridin-2-ylsulfonyl)-1H-pyrrol-3-
-yl]-N-methylmethanamine or a salt thereof.
[0556] Most preferred as a pharmaceutically active ingredient
having a primary or secondary amino group in the pharmaceutical
composition of the present invention are [0557]
1-{5-(2-fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}--
N-methylmethanamine or a salt thereof, [0558]
1-[4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmet-
hanamine or a salt thereof, [0559]
N-methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-y-
l]methanamine or a salt thereof, [0560]
1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylme-
thanamine or a salt thereof, [0561]
N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]me-
thanamine or a salt thereof, and [0562]
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
-yl]-N-methylmethanamine or a salt thereof, and more preferred are
[0563]
1-{5-(2-fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}--
N-methylmethanamine or a salt thereof, [0564]
1-[4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmet-
hanamine or a salt thereof, [0565]
N-methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-y-
l]methanamine or a salt thereof, [0566]
1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylme-
thanamine or a salt thereof, and [0567]
N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]me-
thanamine or a salt thereof.
[0568] Examples of the salt of the above-mentioned "nonpeptidic
pharmaceutically active ingredient having a primary or secondary
amino group" include metal salt, ammonium salt, salt with organic
base, salt with inorganic acid, salt with organic acid, salt with
basic or acidic amino acid and the like.
[0569] Preferable examples of the metal salt include alkali metal
salts such as sodium salt, potassium salt and the like; alkaline
earth metal salts such as calcium salt, magnesium salt, barium salt
and the like; aluminum salt and the like. Preferable examples of
the salt with an organic base include salts with trimethylamine,
triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine,
diethanolamine, triethanolamine, cyclohexylamine,
dicyclohexylamine, N,N'-dibenzylethylenediamine and the like.
Preferable examples of the salt with an inorganic acid include
salts with hydrochloric acid, hydrobromic acid, nitric acid,
sulfuric acid, phosphoric acid and the like. Preferable examples of
the salt with an organic acid include salts with adipic acid,
ascorbic acid, benzoic acid, oleic acid, succinic acid, acetic
acid, tartaric acid, sorbic acid, fumaric acid, lactic acid, maleic
acid, malonic acid, citric anhydride, maleic anhydride, phthalic
acid, phthalic anhydride, malic acid, formic acid, trifluoroacetic
acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid and the like. Preferable examples of the
salt with a basic amino acid include salts with arginine, lysine,
ornithine and the like, and preferable examples of the salt with an
acidic amino acid include salts with aspartic acid, glutamic acid
and the like.
[0570] Of these, a salt with an organic acid is preferable for the
pharmaceutical composition of the present invention. Examples of
the salt with an organic acid for such nonpeptidic pharmaceutically
active ingredient having a primary or secondary amino group include
salts with adipic acid, ascorbic acid, benzoic acid, oleic acid,
succinic acid, acetic acid, tartaric acid, sorbic acid, fumaric
acid, lactic acid, maleic acid, malonic acid, citric anhydride,
maleic anhydride, phthalic anhydride, malic acid and the like. In
addition, of the organic acid salts, a salt with an unsaturated
carboxylic acid is particularly preferably used. Examples of the
salt with such unsaturated carboxylic acid include salts with
fumaric acid, sorbic acid, maleic acid, oleic acid, succinic acid,
tartaric acid and the like. Of these, the salts with fumaric acid,
succinic acid and tartaric acid are preferable.
[0571] In the whole pharmaceutical composition of the present
invention (a pharmaceutical composition containing at least a
nonpeptidic pharmaceutically active ingredient having a primary or
secondary amino group, an excipient and an acidic compound), the
content (%) of the "pharmaceutically active ingredient having a
primary or secondary amino group or a salt thereof" is preferably
0.1-80%, further preferably 0.1-60%, particularly preferably
0.1-50% (in the present specification, "%" means weight percent
unless otherwise specified).
[2. Excipient (Second Component)]
[0572] As the "excipient", which is the second component of the
pharmaceutical composition of the present invention, preferred is
an excipient having pH 4.5 or above when dissolved or dispersed in
water.
[0573] Examples of such excipient include mannitol, croscarmellose
sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose,
polyethylene glycol, polyvinylpyrrolidone, crystalline cellulose,
lactose, sucrose, starch, cornstarch, titanium oxide (TiO.sub.2),
light anhydrous silicic acid and the like. These excipients may be
used alone or two or more kinds thereof may be used in combination.
Of these, as the excipient, mannitol, hydroxypropylcellulose and
crystalline cellulose are preferable.
[0574] The content (%) of the excipient in the whole pharmaceutical
composition of the present invention is preferably 20-99.8%,
further preferably 40-99.8%, particularly preferably 50-99.8%.
[0575] In the pharmaceutical composition of the present invention,
the mixing ratio of the "excipient" to the "nonpeptidic
pharmaceutically active ingredient having a primary or secondary
amino group or a salt thereof" (to be abbreviated as
"pharmaceutically active ingredient") is preferably
pharmaceutically active ingredient:excipient=1:0.25-1:998, further
preferably 1:0.67-1:998, particularly preferably 1:1-1:998. The
above-mentioned mixing ratio is a weight ratio.
[3. Acidic Compound (Third Component)]
[0576] Here, the term acidic compound has a general meaning.
Specifically, for example, the term can be defined based on the
value of pKa (logarithm of reciprocal of acid dissociation
constant) of the compound. The "acidic compound" means a compound
having a partial structure having pKa of not more than 6.5
(preferably not more than 5.5). The acidic compound to be used in
the present invention may be either a solid or a liquid at ambient
temperature (15-25.degree. C.). The above-mentioned "partial
structure having pKa" refers to a partial structure that releases
H.sup.+.
[0577] The above-mentioned "nonpeptidic pharmaceutically active
ingredient having a primary or secondary amino group (first
component)" has a "primary or secondary amino group having high
nucleophilicity". Thus, when a trace amount of a basic component is
contained in the excipient, the basic component acts as a basic
catalyst and highly possibly causes problems of Michael addition
of, for example, fumaric acid and the like to an .alpha. or
.beta.-unsaturated carbonyl compound (nucleophilic addition
reaction of a carbon at the end of a conjugated system in
conjugation with an electron-withdrawing substituent) and the
like.
[0578] Examples of the above-mentioned basic compound which is
contained in the excipient and having a possibility of acting as a
basic catalyst include a basic salt, oxide and hydroxide, such as
metal carbonates such as alkali metal hydrogen carbonates (e.g.,
sodium hydrogen carbonate etc.), alkali metal carbonates (e.g.,
sodium carbonate, potassium carbonate etc.), alkaline earth metal
carbonates (e.g., calcium carbonate, magnesium carbonate etc.) and
the like; di-salt hydrogen phosphate such as di-alkali metal salt
hydrogen phosphates (e.g., disodium hydrogen phosphate, dipotassium
hydrogen phosphate, etc.) and the like; silicates such as calcium
silicate, magnesium silicate and the like; metal oxides such as
magnesium oxide and the like; metal hydroxides such as sodium
hydroxide, calcium hydroxide, magnesium hydroxide, aluminum
hydroxide and the like; citrates such as sodium citrate and the
like; tartrates such as sodium dl- and l-tartrates and the like;
pantothenates such as calcium pantothenate etc, and the like.
[0579] Therefore, a stabilizer is added to the pharmaceutical
composition of the present invention. The stabilizer stabilizes the
pharmaceutical composition by preventing a reaction of an amino
group in the nonpeptidic pharmaceutically active ingredient having
a primary or secondary amino group with an .alpha..quadrature. or
.beta.-unsaturated carbonyl compound. As the stabilizer, any
substance can be used as long as it is an acidic compound which can
protonate, by releasing H.sup.+, the amino group of the nonpeptidic
pharmaceutically active ingredient having a primary or secondary
amino group, preferably an organic acid or a salt thereof
(particularly organic acid).
[0580] Specifically, the pharmaceutical composition of the present
invention characteristically contains an acidic compound (third
component) as the stabilizer in addition to a pharmaceutical
composition containing a nonpeptidic pharmaceutically active
ingredient having a primary or secondary amino group (first
component) and an excipient (second component).
[0581] As the "acidic compound" to be used in the present
invention, an inorganic acid such as hydrochloric acid, hydrobromic
acid, nitric acid, sulfuric acid, phosphoric acid and the like, or
an organic acid similar to the organic acid exemplified in the
explanation of the above-mentioned "salt with an organic acid of a
nonpeptidic pharmaceutically active ingredient having a primary or
secondary amino group" can be used. Particularly preferable
examples thereof include edible organic acids such as adipic acid,
ascorbic acid, benzoic acid, oleic acid, succinic acid, acetic
acid, tartaric acid, sorbic acid, fumaric acid, lactic acid, maleic
acid, malonic acid, citric anhydride, maleic anhydride, phthalic
anhydride, malic acid and the like. In addition, an organic acid
such as formic acid, trifluoroacetic acid, phthalic acid, oxalic
acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic
acid and the like can also be used for the object of stabilization
of the pharmaceutical composition.
[0582] The organic acid may be a salt. Examples of the salt with an
organic acid include sodium ascorbate, sodium fumarate, and those
similar to the salts exemplified in the above-mentioned "salt with
an organic acid of a nonpeptidic pharmaceutically active ingredient
having a primary or secondary amino group". Of these, those similar
to the salts exemplified in the above-mentioned "salt with an
organic acid of a nonpeptidic pharmaceutically active ingredient
having a primary or secondary amino group" are preferable. In
addition, the salt with an organic acid similar to the
above-mentioned respective organic acids are preferable.
[0583] These organic acids and salts thereof may be used alone or
two or more kinds thereof may be used simultaneously. In addition,
the organic acid to be used for the above-mentioned "salt with an
organic acid of a nonpeptidic pharmaceutically active ingredient
having a primary or secondary amino group" and an organic acid to
be used as a stabilizer may be the same or different.
[0584] As the organic acid to be used for the above-mentioned "salt
with an organic acid of a nonpeptidic pharmaceutically active
ingredient having a primary or secondary amino group", preferred
are fumaric acid, malonic acid, citric anhydride, maleic anhydride,
succinic acid and tartaric acid, more preferred are fumaric acid,
citric anhydride, succinic acid, tartaric acid, and still more
preferred are fumaric acid, succinic acid and tartaric acid.
[0585] The pH of an excipient or acidic compound is measured under
the following conditions. To be specific, the pH of an aqueous
solution or dispersion obtained by dissolving or dispersing an
excipient in water at 1% w/v is measured at 25.degree. C. with a
commercially available pH meter.
[0586] In the pharmaceutical composition of the present invention,
the pKa value of the "nonpeptidic pharmaceutically active
ingredient having a primary or secondary amino group" is preferably
higher for stabilization of the pharmaceutical composition than
that of the "organic acid or a salt thereof" to be added.
[0587] Particularly, the difference between the pKa value of the
"nonpeptidic pharmaceutically active ingredient having a primary or
secondary amino group" and that of the "organic acid" is preferably
not less than 4, further preferably not less than 5, particularly
preferably not less than 6.
[0588] For example, when the pharmaceutically active ingredient is
represented by the formula (A2), an "organic acid" is preferably
used as an acidic compound. Examples of the "organic acid" include
edible organic acids such as adipic acid, ascorbic acid, benzoic
acid, oleic acid, succinic acid, acetic acid, tartaric acid, sorbic
acid, fumaric acid, lactic acid, maleic acid, malonic acid, citric
acid, malic acid and the like. In addition, organic acids such as
formic acid, trifluoroacetic acid, phthalic acid, oxalic acid,
methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid
and the like can also be used for stabilizing the pharmaceutical
composition. Of these, fumaric acid is particularly preferable.
[0589] The content (%) of the acidic compound in the whole
pharmaceutical composition of the present invention is preferably
0.1-20% (more preferably 0.1-19%), further preferably 1-10%,
particularly preferably 2-10%. In another embodiment, it is
0.01-50%, preferably 0.05-19%, more preferably 0.1-10%.
[0590] In the pharmaceutical composition of the present invention,
the mixing ratio of the "acidic compound" to the "nonpeptidic
pharmaceutically active ingredient having a primary or secondary
amino group" (to be abbreviated as a "pharmaceutically active
ingredient") is preferably pharmaceutically active
ingredient:acidic compound=1:0.00125-1:200, further preferably
1:0.0167-1:200, particularly preferably 1:0.04-1:100.
[0591] In the pharmaceutical composition of the present invention,
the mixing ratio of the "acidic compound" to the "excipient" is
preferably excipient:acidic compound=1:0.0001-1:1, further
preferably 1:0.01-1:0.5, particularly preferably 1:0.02-1:0.2.
[0592] When producing the pharmaceutical composition of the present
invention, the "acidic compound" may be added as a powder in a
granulation step or a mixing step. In addition, an acidic compound
can be sprayed by dissolving or dispersing in a binder solution in
the granulation step or in a film coating solution in a film
coating step.
[0593] The above-mentioned "binder solution" is prepared by
dissolving a binder in an aqueous solution. Examples of the
"binder" include hydroxypropylcellulose,
hydroxypropylmethylcellulose, crystalline cellulose, starch,
polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan,
low-substituted hydroxypropylcellulose and the like.
[0594] The above-mentioned "film coating solution" is prepared, for
example, by dissolving or suspending a film coating polymer in a
solvent. The film coating solution may further contain a colorant
(preferably, diiron trioxide and yellow ferric oxide), a light
shielding agent (preferably, titanium oxide) and the like. Examples
of the "film coating polymer" include hydroxypropylmethylcellulose,
ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose acetate succinate, acrylic resin
(methacrylic acid-acrylic acid copolymer, aminoalkylmethacrylate
copolymer etc.), shellac, polyvinyl acetate phthalate, gum arabic,
cellulose acetate phthalate, hydroxypropylmethylcellulose
phthalate, carboxymethylethyl cellulose and the like. Examples of
the "solvent" include water, alcohols (e.g., ethanol, isopropyl
alcohol, n-propyl alcohol, methanol, etc.), acetone, ethyl acetate,
dichloromethane, chloroform, hexane, toluene, heptane and the like.
The amount of the "film coating polymer" to be used can be
determined according to the kind of the solid preparation. For
example, when the solid preparation is a tablet, the amount is
about 0.5-10 wt % of the tablet. The spray temperature is generally
25-80.degree. C., the spray time is generally 5 min-24 hr, and the
drying conditions are generally at 30-80.degree. C. for about 1
min-24 hr. The film coating layer of the present invention can be
generally formed at ratio of 1-10 parts by weight, preferably 2-6
parts by weight, per 100 parts by weight of the solid preparation
(preferably tablet, more preferably ellipse or round tablet) of the
present invention.
[0595] To use the pharmaceutical composition of the present
invention as a more stable pharmaceutical composition, the content
of the decomposed product of the pharmaceutically active ingredient
in the whole pharmaceutical composition does not desirably exceed,
according to the ICH guideline, a lower of 1.0% and a total daily
ingestion amount of 5 .mu.g when the pharmaceutically active
ingredient to be administered per day is <1 mg, a lower of 0.5%
and a total daily ingestion amount of 20 .mu.g when the
pharmaceutically active ingredient to be administered per day is 1
mg-10 mg, a lower of 0.2% and a total daily ingestion amount of 2
mg when the pharmaceutically active ingredient to be administered
per day is >10 mg-2 g, 0.10% when the pharmaceutically active
ingredient to be administered per day is >2 g, a lower of 1.0%
and a total daily ingestion amount of 50 .mu.g when the
pharmaceutically active ingredient to be administered per day is
<10 mg, a lower of 0.5% and a total daily ingestion amount of
200 .mu.g when the pharmaceutically active ingredient to be
administered per day is 10 mg-100 mg, a lower of 0.2% and a total
daily ingestion amount of 3 mg when the pharmaceutically active
ingredient to be administered per day is >100 mg-2 g, and 0.15%
when the pharmaceutically active ingredient to be administered per
day is >2 g.
[0596] The preservation environment of a pharmaceutical product
after being placed in the market by a manufacturer is difficult to
control. To maintain the quality of a pharmaceutical product,
therefore, the content of the decomposed product is preferably as
small as possible under any temperature and humidity conditions
(60.degree. C., 40.degree. C., 75% RH, 30.degree. C., 65% RH etc.)
and in any packaging form (open bottle, closed bottle etc.).
[0597] The pharmaceutical composition of the present invention
shows a small content of a decomposed product under any conditions
(60.degree. C., 40.degree. C., 75% RH, 30.degree. C., 65% RH etc.)
whether in an open bottle or a closed bottle.
[0598] Therefore, the pharmaceutical composition of the present
invention can retain preservation stability and can maintain high
quality under any conditions.
[0599] The pharmaceutical composition of the present invention has
low toxicity, and can be safely administered orally or parenterally
(e.g., topical, rectal, intravenous administration etc.) as it is
or in the form of a pharmaceutical composition containing a
pharmacologically acceptable carrier according to a method known
per se, for example, preparations such as tablet (core tablet,
sugar-coated tablet, film-coated tablet etc.), powder, granule,
capsule (including soft capsule), orally disintegrating tablet,
liquid, injection, suppository, sustained-release preparation,
plaster and the like. The pharmaceutical composition of the present
invention is preferably administered as an oral preparation such as
tablet, granule, capsule and the like. Of these, a solid
preparation such as tablet, capsule and the like is preferable, a
sugar-coated tablet, a film-coated tablet and the like are
especially preferable, and a film-coated tablet is particularly
preferable.
[0600] Examples of the pharmacologically acceptable carrier that
can be used for the production of the pharmaceutical composition of
the present invention include various organic or inorganic carrier
substances conventionally used as preparation materials. For
example, filler, lubricant, binder, disintegrant, water-soluble
polymer and basic inorganic salt for solid preparations; solvent,
solubilizing agent, suspending agent, isotonicity agent, buffering
agent and soothing agent for liquid preparation and the like can be
mentioned. Where necessary, general additives such as preservative,
antioxidant, colorant, sweetening agent, foaming agent, flavor and
the like can also be used.
[0601] Examples of the "lubricant" include magnesium stearate,
sucrose fatty acid ester, polyethylene glycol, talc, stearic acid
and the like.
[0602] Examples of the "binder" include hydroxypropylcellulose,
hydroxypropylmethylcellulose, crystalline cellulose, starch,
polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan,
low-substituted hydroxypropylcellulose and the like.
[0603] Examples of the "disintegrant" include (1) crospovidone, (2)
disintegrants referred to as super disintegrants such as
croscarmellose sodium (FMC-Asahi Kasei), carmellose calcium (Gotoku
Yakuhin) and the like, (3) sodium carboxymethyl starch (e.g.,
manufactured by Matsutani Chemical Industry Co., Ltd.), (4)
low-substituted hydroxypropylcellulose (e.g., manufactured by
Shin-Etsu Chemical Co., Ltd.), (5) cornstarch and the like. The
"crospovidone" may be any crosslinked polymer having a chemical
name of 1-ethenyl-2-pyrrolidinone homopolymer including
polyvinylpolypyrrolidone (PVPP) and 1-vinyl-2-pyrrolidinone
homopolymer. Specific examples thereof include Kollidon CL
(manufactured by BASF), Polyplasdone XL (manufactured by ISP),
Polyplasdone XL-10 (manufactured by ISP), Polyplasdone INF-10
(manufactured by ISP) and the like.
[0604] Examples of the "water-soluble polymer" include
ethanol-soluble water-soluble polymer [e.g., cellulose derivatives
such as hydroxypropylcellulose (hereinafter to be sometimes
indicated as HPC) and the like, polyvinylpyrrolidone and the like],
ethanol-insoluble water-soluble polymer [e.g., cellulose derivative
such as hydroxypropylmethylcellulose (hereinafter to be sometimes
indicated as HPMC), methylcellulose, carboxymethylcellulose sodium
and the like, sodium polyacrylate, polyvinyl alcohol, sodium
alginate, guar gum and the like] and the like.
[0605] Examples of the "basic inorganic salt" include basic
inorganic salts of sodium, potassium, magnesium and/or calcium.
Preferred are basic inorganic salts of magnesium and/or calcium.
More preferred is a basic inorganic salt of magnesium. Examples of
the basic inorganic salt of sodium include sodium carbonate, sodium
hydrogen carbonate, disodium hydrogen phosphate and the like.
Examples of the basic inorganic salt of potassium include potassium
carbonate, potassium hydrogen carbonate and the like. Examples of
the basic inorganic salt of magnesium include heavy magnesium
carbonate, magnesium carbonate, magnesium oxide, magnesium
hydroxide, magnesium aluminometasilicate, magnesium silicate,
magnesium aluminate, synthetic hydrotalcite
[Mg.sub.6Al.sub.2(OH).sub.16CO.sub.3.4H.sub.2O] and alumina
magnesium hydroxide, preferably, heavy magnesium carbonate,
magnesium carbonate, magnesium oxide, magnesium hydroxide and the
like. Examples of the basic inorganic salt of calcium include
precipitated calcium carbonate, calcium hydroxide and the like.
[0606] Examples of the "solvent" include water for injection,
alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive
oil and the like.
[0607] Examples of the "solubilizing agent" include polyethylene
glycol, propylene glycol, benzyl benzoate, ethanol,
trisaminomethane, cholesterol, triethanolamine, sodium carbonate,
sodium citrate and the like.
[0608] Examples of the "suspending agent" include surfactants such
as stearyltriethanolamine, sodium lauryl sulfate, lauryl
aminopropionic acid, lecithin, benzalkonium chloride, benzethonium
chloride, glycerol monostearate and the like; hydrophilic polymers
such as polyvinyl alcohol, polyvinylpyrrolidone, sodium
carboxymethylcellulose, methylcellulose, hydroxymethylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose and the like, and the
like.
[0609] Examples of the "isotonicity agent" include glucose,
D-sorbitol, sodium chloride, glycerol, D-mannitol and the like.
[0610] Examples of the "buffering agent" include buffers such as
phosphate, acetate, carbonate, citrate and the like, and the
like.
[0611] Examples of the "soothing agent" include benzyl alcohol and
the like.
[0612] Examples of the "preservative" include paraoxybenzoates,
chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic
acid, sorbic acid and the like.
[0613] Examples of the "antioxidant" include sulfite, ascorbic
acid, .alpha.-tocopherol and the like.
[0614] Examples of the "colorant" include food colors such as Food
Color Yellow No. 5, Food Color Red No. 2, Food Color Blue No. 2 and
the like; food lake colors, ferric oxide red, yellow ferric oxide
and the like.
[0615] Examples of the "sweetening agent" include saccharin sodium,
dipotassium glycyrrhizinate, aspartame, stevia, thaumatin and the
like.
[0616] Examples of the "foaming agent" include sodium bicarbonate
and the like.
[0617] As the "flavor", any of synthetic substance and
naturally-occurring substance may be used. Examples thereof include
flavors such as lemon, lime, orange, menthol, strawberry and the
like.
[0618] The pharmaceutical composition of the present invention does
not have to contain a souring agent.
[0619] The pharmaceutical composition of the present invention can
be formulated into a preparation for oral administration
(film-coated tablet) by, for example, adding a pharmacologically
acceptable carrier such as binder, disintegrant, lubricant and the
like as necessary to a granulated powder containing the
above-mentioned first to third components, tableting the obtained
mixture by a method known per se (preparation of core tablet
(core)) and, where necessary, coating the tablet by a method known
per se for masking of taste, enteric coating or sustained release.
When the pharmaceutical composition of the present invention is,
for example, formulated into an orally disintegrating tablet, the
above-mentioned composition containing the first to third
components can be produced by a method known per se. Moreover, such
tablet can be produced by a method including coating a core
containing crystalline cellulose and lactose with the
pharmaceutical composition of the present invention, forming an
enteric coating layer by a method known per se to give fine
granules, mixing the obtained fine granules and an additive and
molding the mixture.
[0620] A film-coated tablet is more preferable.
[0621] In addition, a core material containing an acidic compound
and a layer containing a pharmaceutically active ingredient do not
need to be separated by a separating layer.
[0622] Examples of the above-mentioned "enteric coating layer"
include a layer comprised of a mixture of one or more kinds from
aqueous enteric polymer base such as cellulose acetate phthalate
(CAP), hydroxypropylmethylcellulose phthalate,
hydroxymethylcellulose acetate succinate, methacrylic acid
copolymer [for example, Eudragit L30D-55 (trade name; manufactured
by Roehm), Kollicoat MAE30DP (trade name; manufactured by BASF),
Polyquid PA30 (trade name; manufactured by
[0623] Sanyo chemical industries, Ltd.) etc.],
carboxymethylethylcellulose, shellac and the like;
sustained-release base such as methacrylic acid copolymer [for
example, Eudragit NE30D (trade name), Eudragit RL30D (trade name),
Eudragit RS30D (trade name) etc.] and the like; water-soluble
polymer; plasticizer such as triethyl citrate, polyethylene glycol,
acetylated monoglyceride, triacetine, castor oil etc. and the
like.
[0624] Examples of the above-mentioned "additive" include
water-soluble sugar alcohol (e.g., sorbitol, mannitol and maltitol,
reduced starch saccharides, xylitol, reduced paratinose, 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.), low-substituted
hydroxypropylcellulose (e.g., LH-22, LH-32, LH-23, LH-33 (Shin-Etsu
Chemical Co., Ltd.) and a mixture thereof etc.) and the like.
Furthermore, binder, foaming agent, sweetening agent, flavor,
lubricant, colorant, stabilizer, excipient, disintegrant and the
like can also be used.
[0625] The pharmaceutical composition of the present invention is
superior in the preservation stability. Particularly, when the
pharmaceutical composition of the present invention contains a
compound represented by the above-mentioned formula (A2) or (A3) as
a pharmaceutically active ingredient, such pharmaceutical
composition is useful for the treatment or prophylaxis of peptic
ulcer (e.g., gastric ulcer, ulcer due to postoperative stress,
duodenal ulcer, anastomotic ulcer, ulcer caused by non-steroidal
anti-inflammatory agent etc.); Zollinger-Ellison syndrome;
gastritis; erosive esophagitis; reflux esophagitis such as erosive
reflux esophagitis and the like; symptomatic gastroesophageal
reflux disease (Symptomatic GERD) such as nonerosive esophageal
reflux, esophageal reflux unaccompanied by esophagitis and the
like; functional dyspepsia; Barrett esophagus; gastric cancer
(including gastric cancer associated with promoted production of
interleukin-1.beta. due to gene polymorphism of interleukin-1);
stomach MALT lymphoma; hyperacidity; upper gastrointestinal
hemorrhage caused by peptic ulcer, acute stress ulcer, hemorrhagic
gastritis, invasive stress (e.g., stress caused by major surgery
requiring post-operative intensive management, or cerebrovascular
disorder, head trauma, multiple organ failure or extensive burn
requiring intensive treatment) and the like; airway disorders;
asthma; and the like in mammals (e.g., human, monkey, sheep,
bovine, horse, dog, cat, rabbit, rat, mouse etc.), pre-anesthetic
administration, eradication or assistant to eradication of
Helicobacter pylori and the like.
[0626] While the dose of the pharmaceutical composition of the
present invention varies depending on the subject of
administration, administration route, disease and the like, for
oral administration to an adult (60 kg) as, for example, an
antiulcerogenic drug, it is preferably administered in an amount of
about 0.5-about 1500 mg/day, preferably about 5-about 150 mg/day,
as a pharmaceutically active ingredient. The pharmaceutical
composition of the present invention may be administered once a day
or in 2-3 portions a day.
[0627] The pharmaceutical composition of the present invention may
be used in combination with other active ingredient as long as the
activity of the nonpeptidic pharmaceutically active ingredient
having a primary or secondary amino group is not impaired.
[0628] Examples of the "other active ingredient" include anti-AM
Helicobacter pylori active substance, imidazole compound, bismuth
salt, quinolone compound and the like.
[0629] Examples of the "anti-Helicobacter pylori active substance"
include penicillin antibiotic (e.g., amoxicillin, benzyl
penicillin, piperacillin, mecillinam, ampicillin, temocillin,
bacampicillin, aspoxicillin, sultamicillin, lenampicillin, etc.),
cephem antibiotic (e.g., cefixime, cefaclor, etc.), macrolide
antibiotic (e.g., erythromycin, clarithromycin, roxithromycin,
rokitamycin, flurithromycin, telithromycin, etc.), tetracycline
antibiotic (e.g., tetracycline, minocycline, streptomycin etc.),
aminoglycoside antibiotic (e.g., gentamicin, amikacin etc.),
imipenem and the like. Of these, penicillin antibiotic, macrolide
antibiotic and the like are preferable.
[0630] Examples of the "imidazole compound" include metronidazole,
miconazole and the like.
[0631] Examples of the "bismuth salt" include bismuth acetate,
bismuth citrate, bithmuth subsalicylate and the like.
[0632] Examples of the "quinolone compound" include ofloxacin,
ciploxacin and the like.
[0633] Particularly, for Helicobacter pylori eradication, in the
pharmaceutical composition of the present invention wherein the
pharmaceutically active ingredient is a compound represented by the
above-mentioned (A2), (A3) or (A4), a penicillin antibiotic (e.g.,
amoxicillin etc.) and an erythromycin antibiotic (e.g.,
clarithromycin etc.) are preferably used. For Helicobacter pylori
eradication, while the pharmaceutical composition of the present
invention has an anti-H. pylori action (bacteriostatic or
eradication action) by itself, it can enhance an antibacterial
action of other antibiotics by regulating its pH in the stomach and
the like, thus acting as an aid for the eradication effect based on
the action of the antibiotic to be used in combination.
[0634] In addition, the pharmaceutical composition of the present
invention may be used in combination with a gastric motility
enhancer, a drug acting on the lower esophageal sphincter (e.g.,
transient lower esophageal sphincter relaxation inhibitor, etc.),
C1C-2 channel opener (intestinal juice secretion accelerating
agent), histamine H2 receptor antagonist, antacid, sedative,
stomachic or non-steroidal anti-inflammatory drug (NSAID).
[0635] Examples of the "gastric motility enhancer" include
domperidone, metoclopramide, mosapride, itopride, tegaserod and the
like.
[0636] Examples of the "drug acting on the lower esophageal
sphincter" include GABA-B receptor agonists such as baclofen, an
optically active form thereof and the like, and the like.
[0637] Examples of the "C1C-2 channel opener (intestinal juice
secretion accelerating agent)" include lubiprostone and the
like.
[0638] Examples of the "histamine H2 receptor antagonist" include
cimetidine, ranitidine, famotidine, roxatidine, nizatidine,
lafutidine and the like.
[0639] Examples of the "antacid" include sodium hydrogen carbonate,
aluminum hydroxide and the like.
[0640] Examples of the "sedative" include diazepam,
chlordiazepoxide and the like.
[0641] Examples of the "stomachic" include Gentiana lutea, swertia
japonica, diastase and the like.
[0642] Examples of the "non-steroidal anti-inflammatory drug"
include aspirin, indomethacin, ibuprofen, mefenamic acid,
diclofenac, etodolac, piroxicam, celecoxib and the like.
[0643] The pharmaceutical composition of the present invention may
also be used in combination with the following medicaments.
[0644] (i) proton pump inhibitor, e.g., omeprazole, esomeprazole,
pantoprazole, rabeprazole, tenatoprazole, ilaprazole and
lansoprazole;
[0645] (ii) oral antacid-combination agent, e.g., Maalox
(registered trade mark), Aludrox (registered trade mark) and
Gaviscon (registered trade mark);
[0646] (iii) mucous membrane protector, e.g., polaprezinc, ecabet
sodium, rebamipide, teprenone, cetraxate, sucralfate,
chlorophylline-copper and plaunotol;
[0647] (iv) anti-gastrin agent, e.g., anti-gastrin vaccine,
itriglumide and Z-360;
[0648] (v) 5-HT.sub.3 antagonist, e.g., dolasetron, palonosetron,
alosetron, azasetron, ramosetron, mitrazapine, granisetron,
tropisetron, E-3620, ondansetron and indisetron;
[0649] (vi) 5-HT.sub.4 agonist, e.g., tegaserod, mosapride,
cinitapride and oxitriptane;
[0650] (vii) laxative, e.g., Trifyba (registered trade mark),
Fybogel (registered trade mark), Konsyl (registered trade mark),
Isogel (registered trade mark), Regulan (registered trade mark),
Celevac (registered trade mark) and Normacol (registered trade
mark);
[0651] (viii) GABA.sub.B agonist, e.g., baclofen and AZD-3355;
[0652] (ix) GABA.sub.B antagonist, e.g., GAS-360 and SGS-742;
[0653] (x) calcium channel blocker, e.g., aranidipine, lacidipine,
falodipine, azelnidipine, clinidipine, lomerizine, diltiazem,
gallopamil, efonidipine, nisoldipine, amlodipine, lercanidipine,
bevantolol, nicardipine, isradipine, benidipine, verapamil,
nitrendipine, barnidipine, propafenone, manidipine, bepridil,
nifedipine, nilvadipine, nimodipine and fasudil;
[0654] (xi) dopamine antagonist, e.g., metoclopramide, domperidone
and levosulpiride;
[0655] (xii) tachykinin (NK) antagonist, particularly, NK-3, NK-2
and NK-1 antagonist, e.g., nepadutant, saredutant, talnetant,
(.alpha.R,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-m-
ethyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-d-
ione (TAK-637),
5-[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluoroph-
enyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one
(MK-869), lanepitant, dapitant and
3-[[2-methoxy-5-(trifluoromethoxy)phenyl]methylamino]-2-phenyl-piperidine
(2S,3S);
[0656] (xiii) nitric oxide synthase inhibitor, e.g., GW-274150,
tilarginine, P54, guanidioethyldisulfide and nitroflurbiprofen;
[0657] (xiv) vanilloid receptor 1 antagonist, e.g., AMG-517 and
GW-705498;
[0658] (xv) ghrelin agonist, e.g., capromorelin and TZP-101;
[0659] (xvi) AchE release stimulant, e.g., Z-338 and KW-5092;
[0660] (xvii) therapeutic agent for insomnia (etizolam, zopiclone,
triazolam, zolpidem, ramelteon, indiplon etc.),
[0661] (xviii) potassium ion competitive acid secretion blocker
(P-CAB),
[0662] (xix) melatonin agonist,
[0663] (xx) melatonin, and the like.
[0664] The above-mentioned medicaments (i)-(xx) may be used in
combination by adding to the pharmaceutical composition of the
present invention. Alternatively, the above-mentioned medicaments
(i)-(xx) and the pharmaceutical composition of the present
invention may be separately produced and simultaneously
administered or administered in a staggered manner to the same
subject.
[0665] Next, the second invention of the present invention is
explained in detail by referring to a specific embodiment.
[0666] The solid preparation of the second invention of the present
invention contains a pharmaceutically active ingredient, titanium
oxide, a plasticizer and a chain organic acid, and is
characteristically a solid preparation improved in the stability
during light irradiation.
[0667] When a pharmaceutically active ingredient unstable to light
irradiation is formulated into a preparation, titanium oxide
(TiO.sub.2) is generally used together with a film coating agent
(also referred to as a coating agent) for shielding to ensure
light-stability of the preparation. However, TiO.sub.2 shows a
shielding function due to its high refractive index, but also shows
a strong oxidation action caused by hole generation during light
irradiation. The cause is presumed to be that 1) titanium oxide in
a coating agent develops a free radical due to UV light, 2) the
drug and alcohols in the coating agent such as polyethylene glycol
and the like are decomposed due to free radical, 3) a decomposed
product of alcohols (e.g., polyethylene glycol and the like), for
example, aldehydes such as formaldehyde, acetoaldehyde and the
like, an acid such as formic acid and the like, and peroxide in the
coating agent further cause decomposition of the drug. To improve
the light-stability of the preparation, therefore, it is necessary
to suppress the decomposed product due to its strong oxidation
action while utilizing the light shielding effect of TiO.sub.2.
Conventionally, as a means to suppress an increase in the
decomposed product, a method including forming an intermediate
layer between a film coating and a core tablet and a method
including removing PEG (plasticizer) from a film coating component
have generally been employed. However, these methods may decrease
the productivity during film coating, which may influence the final
appearance of a film-coated tablet.
[0668] The present inventors have found an effect of suppressing a
decomposed product during light irradiation by adding a chain
organic acid to the solid preparation (either core or film),
without decreasing the productivity during film coating. The solid
preparation of the present invention improved in the light
stability is explained in the following.
[Pharmaceutically Active Ingredient (Component I)]
[0669] The form of the pharmaceutically active ingredient to be
used in the present invention may be any of solid, powder, crystal,
oil, solution and the like, and its efficacy is not particularly
limited. For example, one or more kinds of components selected from
nutritional supplement, antipyretic analgesic antiphlogistic drug,
psychotropic drug, antianxiety drug, antidepressant, hypnosedative,
anticonvulsant drug, central nervous system neural active agent,
brain metabolism improving agent, brain circulation improving
agent, antiepilepsy agent, sympathetic nerve stimulant, digestive
medicine, antacid, anti-ulcer agent, antitussive expectorant,
antiemetic, respiratory stimulant, bronchodilator, antiallergic
agent, dental and oral drug, antihistamine agent, cardiotonic
agent, antiarrhythmic agent, diuretic, antihypertensive agent,
vasoconstrictor, coronary vasodilator, peripheral vasodilator,
lipid-lowering agent, cholagogue, antibiotic, chemotherapeutic
agent, diabetes agent, osteoporosis agent, anti-rheumatic drug,
skeleton muscle relaxants, hormone agent, narcotic alkaloid, sulfa
drug, gout a therapeutic drug for, anticoagulant, anti-malignant
tumor agent, therapeutic drug for Alzheimer's disease, potassium
ion competitive acid secretion inhibitor and the like can be
used.
[0670] Examples of the nutritional supplement include vitamins such
as vitamin A, vitamin D, vitamin E (d-.alpha.-tocopherol acetate
and the like), vitamin B1 (dibenzoylthiamine, fursultiamine
hydrochloride and the like), vitamin B2 (riboflavin butyrate and
the like), vitamin B6 (pyridoxine hydrochloride and the like),
vitamin C (ascorbic acid, sodium L-ascorbate and the like), vitamin
B12 (hydroxocobalamin acetate, cyanocobalamin and the like),
mineral such as calcium, magnesium, iron and the like, protein,
amino acid, oligosaccharide, crude drug and the like.
[0671] Examples of the antipyretic analgesic antiphlogistic drug
include aspirin, acetaminophen, ethenzamide, ibuprofen,
diphenhydramine hydrochloride, dl-chlorpheniramine maleate,
dihydrocodeine phosphate, noscapine, methylephedrine hydrochloride,
phenylpropanolamine hydrochloride, caffeine, anhydrous caffeine,
serrapeptase, lysozyme chloride, tolfenamic acid, mefenamic acid,
diclofenac sodium, flufenamic acid, salicylamide, aminopyrine,
ketoprofen, indomethacin, bucolome, pentazocine and the like.
[0672] Examples of the psychotropic drug include chlorpromazine,
reserpine and the like.
[0673] Examples of the antianxiety drug include alprazolam,
chlordiazepoxide, diazepam and the like.
[0674] Examples of the antidepressant include imipramine,
maprotiline hydrochloride, amphetamine and the like.
[0675] Examples of the hypnosedatives include estazolam,
nitrazepam, diazepam, perlapine, phenobarbital sodium and the
like.
[0676] Examples of the anticonvulsant include scopolamine
hydrobromide, diphenhydramine hydrochloride, papaverine
hydrochloride, meclizine hydrochloride, dimenhydrinate and the
like.
[0677] Examples of the central nervous system neural active agent
include citicoline and the like.
[0678] Examples of the brain metabolism improving agent include
meclofenoxate hydrochloride and the like.
[0679] Examples of the brain circulation improving agent include
vinpocetine and the like.
[0680] Examples of the antiepilepsy agent include phenyloin,
carbamazepine and the like.
[0681] Examples of the sympathetic nerve stimulant include
isoproterenol hydrochloride and the like.
[0682] Examples of the digestive medicine include stomachics and
digestives such as diastase, saccharated pepsin, scopolia extract,
cellulose AP3, lipase AP, cassia oil and the like, antiflatulent
such as berberine chloride, resistant lactobacilli, bifidobacteria
and the like, and the like.
[0683] Examples of the antacid include magnesium carbonate, sodium
hydrogen carbonate, magnesium alumino metasilicate, synthetic
hydrotalcite, precipitated calcium carbonate, magnesium oxide and
the like.
[0684] Examples of the anti-ulcer agent include lansoprazole,
omeprazole, rabeprazole, pantoprazole, ilaprazole, tenatoprazole,
famotidine, cimetidine, ranitidine hydrochloride and the like.
[0685] Examples of the antitussive expectorant include cloperastine
hydrochloride, dextromethorphan hydrobromide, theophylline,
potassium guaiacolsulfonate, guaifenesin, codeine phosphate and the
like.
[0686] Examples of the antiemetic include difenidol hydrochloride,
metoclopramide and the like.
[0687] Examples of the respiratory stimulant include levallorphan
tartrate and the like.
[0688] Examples of the bronchodilator include theophylline,
salbutamol sulfate and the like.
[0689] Examples of the antiallergic agent include amlexanox,
seratrodust and the like.
[0690] Examples of the dental and oral drug include
oxytetracycline, triamcinolone acetonide, chlorhexidine
hydrochloride, lidocain and the like.
[0691] Examples of the antihistamine agent include diphenhydramine
hydrochloride, promethazine, isothipendyl hydrochloride,
dl-chlorpheniramine maleate and the like.
[0692] Examples of the cardiotonic agent include caffeine, digoxin
and the like.
[0693] Examples of the antiarrhythmic agent include procaineamide
hydrochloride, propranolol hydrochloride, pindolol and the
like.
[0694] Examples of the diuretic include thiazide such as
isosorbide, furosemide, HCTZ and the like, and the like.
[0695] Examples of the antihypertensive agent include delapril
hydrochloride, captopril, hexamethonium bromide, hydralazine
hydrochloride, labetalol hydrochloride, manidipine hydrochloride,
candesartancilexetil, methyldopa, losartan, valsartan, eprosartan,
irbesartan, tasosartan, telmisartan and the like.
[0696] Examples of the vasoconstrictor include phenylephrine
hydrochloride and the like.
[0697] Examples of the coronary vasodilator include carbochromene
hydrochloride, molsidomine, verapamil hydrochloride and the
like.
[0698] Examples of the peripheral vasodilator include cinnarizinee
and the like.
[0699] Examples of the lipid-lowering agent include cerivastatin
sodium, simvastatin, pravastatin sodium and the like.
[0700] Examples of the cholagogue include dehydrocholic acid,
trepibutone and the like.
[0701] Examples of the antibiotic include cephem antibiotics such
as cefalexin, cefaclor, amoxicillin, pivmecillinam hydrochloride,
cefotiam hexetil hydrochloride, cefadroxil, cefixime, cefditoren
pivoxil, cefteram pivoxil, cefpodoxime proxetil, cefotiam
hydrochloride, cefozopran hydrochloride, cefmenoxime hydrochloride,
cefsulodin sodium and the like, synthetic antibacterial agents such
as ampicillin, ciclacillin, sulbenicillin sodium, naldixic acid,
enoxacin and the like, monobactum antibiotics such as carumonam
sodium and the like, penem and carbapenem antibiotics and the
like.
[0702] Examples of the chemotherapeutic agent include sufamethizol,
sufamethizol hydrochloride, thiazosulfone and the like.
[0703] Examples of the diabetes agent include tolbutamide,
pioglitazone hydrochloride, voglibose, glibenclamide, troglitazone,
rosiglitazone maleate, acarbose, miglitol, emiglitate and the
like.
[0704] Examples of the osteoporosis agent include ipriflavone and
the like.
[0705] Examples of the skeleton muscle relaxant include
methocarbamol and the like.
[0706] Examples of the anti-rheumatic drug include methotrexate,
bucillamine and the like.
[0707] Examples of the hormone agent include liothyronine sodium,
dexamethasone sodium phosphate, prednisolone, oxendolone,
leuprorelin acetate and the like.
[0708] Examples of the narcotic alkaloid include opium, morphine
hydrochloride, ipecac, oxycodon hydrochloride, opium alkaloid
hydrochloride, cocaine hydrochloride and the like.
[0709] Examples of the sulfa drug include sulfamin, sulfisomidine,
sufamethizol and the like.
[0710] Examples of the therapeutic drug for gout include
allopurinol, colchicine and the like.
[0711] Examples of the anticoagulant include dicoumarol and the
like.
[0712] Examples of the anti-malignant tumor agent include
5-fluorouracil, uracil, mitomycin and the like.
[0713] Examples of the therapeutic drug for Alzheimer's disease
include idebenone, vinpocetine and the like.
[0714] Examples of the potassium ion competitive acid secretion
blocker (P-CAB) include a compound represented by the
above-mentioned formula (A1), the formula (A2), the formula (A3) or
the formula (A4) and the like.
[0715] Of the aforementioned pharmaceutically active ingredients, a
pharmaceutically active ingredient that can particularly enjoy the
effect of the invention is a pharmaceutically active ingredient
unstable to light irradiation. For example, the present invention
is particularly effective for a pharmaceutically active ingredient
represented by the above-mentioned formula (A1), the formula (A2),
the formula (A3) or the formula (A4), which belongs to the
"pharmaceutically active ingredient unstable to light irradiation".
That is, the present invention has a remarkable effect for
improving the stability of a pharmaceutically active ingredient
represented by the above-mentioned formula (A1), the formula (A2),
the formula (A3) or the formula (A4) to light irradiation.
[Titanium Oxide (Component II)]
[0716] In the present invention, titanium oxide has a superior
shielding effect against light. The particle size of titanium oxide
to be used in the present invention is generally about 0.01-about
1.5 .mu.m, preferably about 0.1-about 0.7 .mu.m. When titanium
oxide is added to a coating agent for film-coated tablets and the
like, the content of titanium oxide is such an amount capable of
achieving the object of shielding of the pharmaceutical
preparation, which is preferably about 5-about 30 wt %, more
preferably about 5-about 20 wt %, of the coating agent.
[Plasticizer (Component III)]
[0717] Examples of the "plasticizer" to be used in the present
invention include plasticizers generally used in a pharmaceutical
preparation. Specifically, for example, esters such as triethyl
citrate, medium-chain triglyceride, diethyl phthalate, dibutyl
phthalate, triacetine (triacetyl glycerol), butyl phthalyl butyl
glycolate, glyceryl caprylate and the like; alcohols such as
glycerol, propylene glycol, polyethylene glycol and the like, and
the like. As the plasticizer, a compound of the chemical formula
[HOCH.sub.2(CH.sub.2OCH.sub.2).sub.nCH.sub.2OH (n=integer of
2-870)] is preferable, and polyethylene glycol (PEG) is
particularly preferable. Examples of PEG actually used as the
plasticizer include macrogol (manufactured by Sanyo chemical
industries, Ltd.). While the average molecular weight of PEG is not
particularly limited, it is preferably not less than 200, more
preferably 200-20000, since a smaller average molecular weight
increases hygroscopicity. When PEG is added to a coating agent for
a film-coated tablet and the like, the content of PEG is preferably
about 5-about 30 wt %, especially about 10-25 wt %, more preferably
about 10-about 20 wt %, of the coating agent.
[Chain Organic Acid (Component IV)]
[0718] In the solid preparation of the present invention, titanium
oxide is used for shielding. However, it is known that since
titanium oxide has a strong oxidation action as mentioned above,
when a coating agent containing a light shielding agent such as
titanium oxide and the like and a plasticizer such as polyethylene
glycol and the like is applied to a drug-containing tablet during
formulation of a preparation of a drug unstable to light, the
obtained film-coated tablet becomes inferior to the tablet before a
coating treatment in the stability to light. The present invention
effectively suppresses, without decreasing the productivity during
film coating, generation of a decomposed product during light
irradiation by adding an organic acid, particularly a chain organic
acid, together with titanium oxide to, for example, a solid
preparation such as a film coating agent and the like. Examples of
the chain organic acid include adipic acid, oleic acid, succinic
acid, acetic acid, tartaric acid, sorbic acid, fumaric acid, lactic
acid, maleic acid, malonic acid, citric acid, malic acid and the
like. These organic acids may be used alone, or two or more kinds
thereof may be used simultaneously. The chain organic acid
preferably has pH 6.0 or below when dissolved or dispersed in
water. The chain organic acid is preferably fumaric acid, citric
acid, succinic acid or tartaric acid, more preferably fumaric acid,
succinic acid or tartaric acid.
[0719] The pH of a chain organic acid is measured under the
following conditions. To be specific, the pH of an aqueous solution
or dispersion obtained by dissolving or dispersing a measurement
target in water at 1% w/v is measured at 25.degree. C. with a
commercially available pH meter.
[0720] The content (%) of the chain organic acid in the whole
pharmaceutical composition of the present invention is preferably
0.1-20% (more preferably 0.1-19%), further preferably 1-10%,
particularly preferably 2-10%. In another embodiment, it is
0.01-50%, preferably 0.05-19%, more preferably 0.1-10%.
[0721] When producing the pharmaceutical composition of the present
invention, the "chain organic acid" may be added as a powder in a
granulation step or a mixing step. In addition, a chain organic
acid can be sprayed by dissolving or dispersing in a binder
solution in the granulation step or in a film coating solution in a
film coating step.
[0722] The solid preparation containing the pharmaceutically active
ingredient of the present invention has low toxicity, and can be
safely administered orally or parenterally (e.g., topical, rectal,
intravenous administration etc.) as it is or in the form of a
pharmaceutical composition containing a pharmacologically
acceptable carrier according to a method known per se, for example,
as preparations such as tablet (core tablet, sugar-coated tablet,
film-coated tablet etc.), powder, granule, capsule (including soft
capsule), orally disintegrating tablet, suppository,
sustained-release preparation and the like. The pharmaceutical
composition of the present invention is preferably administered as
an oral preparation such as tablet, granule, capsule and the like.
Of these, tablet and capsule are preferable, and a sugar-coated
tablet and a film-coated tablet are especially preferable.
[0723] As the pharmacologically acceptable carrier that can be used
for the production of the pharmaceutical composition of the present
invention, those similar to the examples recited for the first
invention can be mentioned.
[0724] The pharmaceutical composition of the present invention does
not have to contain a souring agent.
[0725] Now, as one embodiment of the present invention, an example
wherein a solid preparation containing a pharmaceutically active
ingredient, titanium oxide, a plasticizer and a chain organic acid,
as explained above, is applied to a film-coated tablet is explained
in the following. The film-coated tablet is obtained by coating a
core tablet (core) containing a pharmaceutically active ingredient
with a film coating layer comprising the following film coating
polymer. Generally, a pharmaceutically active ingredient is
contained in a core, but titanium oxide, a chain organic acid and a
plasticizer may be contained in either or both of a core or(and) a
film coating layer. Particularly, titanium oxide and a plasticizer
are preferably contained in a film coating layer. In addition, a
core material containing a chain organic acid and a layer
containing an active ingredient do not need to be separated by a
separating layer.
[0726] A film coating solution is sprayed on a solid preparation
(preferably tablet, more preferably ellipse or round tablet), and
dried as necessary. The "film coating solution" is prepared by, for
example, dissolving or suspending a film coating polymer in a
solvent. The film coating solution may further contain, for
example, a colorant (preferably, diiron trioxide and yellow ferric
oxide), a light shielding agent (preferably, titanium oxide) and
the like. Examples of the "film coating polymer" include
hydroxypropylmethylcellulose, ethylcellulose,
hydroxymethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose acetate succinate, acrylic resin
(methacrylic acid-acrylic acid copolymer, aminoalkylmethacrylate
copolymer etc.), shellac, polyvinyl acetatephthalate, gum arabic,
cellulose acetate phthalate, hydroxypropylmethylcellulose
phthalate, carboxymethylethylcellulose and the like. Examples of
the "solvent" include water, alcohols (e.g., ethanol, isopropyl
alcohol, n-propyl alcohol, methanol and the like), acetone, ethyl
acetate, dichloromethane, chloroform, hexane, toluene, heptane and
the like. The amount of the "film coating polymer" to be used can
be selected according to the kind of the solid preparation and,
when the solid preparation is a tablet, it is, for example, about
0.5-10 wt % of a tablet. The spraying temperature is generally
25-80.degree. C., the spraying time is generally 5 min-24 hr, and
the drying conditions are generally 30-80.degree. C. for about 1
min-24 hr. The film coating layer of the present invention can be
formed at a ratio of generally 1-10 parts by weight, preferably 2-6
parts by weight, per 100 parts by weight of the solid preparation
(preferably tablet, more preferably ellipse or round tablet) of the
present invention.
[0727] The pharmaceutical composition of the present invention can
be formulated into a preparation for oral administration
(film-coated tablet) by, for example, adding, where necessary, an
excipient to the above-mentioned component I and component IV to
give a granulated powder, adding, where necessary, a binder, a
disintegrant, a lubricant and the like thereto, tableting the
obtained mixture by a method known per se and, where necessary,
coating the tablet by a method known per se for masking of taste,
enteric coating or sustained release.
[0728] The core tablet of the pharmaceutical composition of the
present invention can be obtained by adding an excipient and the
above-mentioned component IV (chain organic acid) to the
above-mentioned component I (pharmaceutically active ingredient),
adding, where necessary, a binder, sieving the obtained granulated
powder, adding, where necessary, a disintegrant and, where
necessary, a lubricant, mixing the mixture, and punching the
obtained mixed powder. The obtained core tablet can be formulated
into a film-coated tablet of the pharmaceutical composition of the
present invention by coating the core tablet by a method known per
se.
[0729] A binder can be added by spraying an aqueous solution
thereof and the like.
[0730] The coating by a method known per se includes, for example,
separately preparing a coating solution using a disperser or a
propeller stirring machine, and the like, and spraying and coating
the solution on tablets charged in a film coating machine.
[0731] Examples of the above-mentioned "excipient", "binder",
"disintegrant" and "lubricant" respectively include those similar
to the examples recited for the above-mentioned first
invention.
[0732] The pharmaceutical composition of the present invention is
superior in the stability during light irradiation. The
pharmaceutical composition of the present invention can be used in
the same manner as described in the above-mentioned first
invention.
[0733] The pharmaceutical composition of the present invention may
have the characteristics of both the first invention and the second
invention.
EXAMPLES
[0734] The present invention is explained in more detail in the
following by referring to Comparative Examples, Examples and
Experimental Examples, which are not to be construed as limitative.
In the formulations described as Examples, Pharmacopoeia compatible
products and Japanese Pharmaceutical Excipients compatible products
were used as the components other than the active ingredient
(additives). In the following Examples and Comparative Examples,
the Japanese Pharmacopoeia 15th Edition or Japanese Pharmaceutical
Excipients 2003 compatible products were used as the preparation
additives (e.g., lactose, D-mannitol, hydroxypropylcellulose,
crospovidone, magnesium stearate, crystalline cellulose).
[0735] Unless otherwise specified, % in the following means wt
%.
[0736] Firstly, the results of the stability evaluation of the
pharmaceutical composition of the first invention of the present
invention, containing a nonpeptidic pharmaceutically active
ingredient having a primary or secondary amino group, an excipient
and an acidic compound are explained by Examples 1-44 and
Comparative Examples 1-6.
Comparative Example 1
Sample 1
[0737] A plain tablet (core tablet) containing
1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylme-
thanamine fumarate (hereinafter to be referred to as compound A)
was produced as follows at the composition ratio shown in Table
2-1.
[0738] That is, compound A (24.491 g), mannitol (4350.0 g) and
crystalline cellulose (540.0 g) were placed in a fluidized bed
dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and
the mixture was preheated and mixed. The mixture was granulated
while spraying an aqueous solution (2700.0 g) of
hydroxypropylcellulose (162.0 g) to give a granulated powder. The
obtained granulated powder (4568.0 g) was passed through a
powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to
give a sized powder. The sized powder (4230.0 g), croscarmellose
sodium (225.0 g) and magnesium stearate (45.007 g) were placed in a
tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai
Kosakusho), and mixed to give a mixed powder. The mixed powder was
tableted by a rotary tableting machine (COLLECT 12HUK, manufactured
by Kikusui Seisakusho, Ltd.) using a 9 mm.phi. punch to give plain
tablets (core tablets, 300 mg per tablet).
TABLE-US-00005 TABLE 2-1 Composition of plain tablet (core tablet)
containing compound A (sample 1) composition amount (mg) 1)
compound A* 1.336 2) mannitol 241.664 3) crystalline cellulose 30
4) hydroxypropylcellulose 9 5) croscarmellose sodium 15 6)
magnesium stearate 3 total 300.0 *Where necessary, the content was
amended using mannitol as an adjustment component.
Comparative Example 2
Sample 2
[0739] The plain tablet (core tablet) (sample 1, 3300.0 g) obtained
in Comparative Example 1 was placed in a film coating machine
(DRC-500, manufactured by POWREX CORPORATION), and film-coated
tablets (about 312 mg per tablet) were obtained while spraying a
film coating solution (1372.0 g) having the composition ratio shown
in Table 2-2. The obtained film-coated tablet was placed in a glass
bottle, tightly sealed and preserved at 60.degree. C. for 2 weeks,
and at 40.degree. C., 75% RH for 2 or 6 months. The film-coated
tablet was placed in a glass bottle, and preserved in an open
bottle at 40.degree. C., 75% RH for 6 months.
TABLE-US-00006 TABLE 2-2 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 10.8 2) titanium
oxide 1 3) diiron trioxide 0.2 4) purified water 108 total
120.0
Example 1
Sample 3
[0740] A plain tablet (core tablet) containing compound A was
produced as follows at the composition ratios shown in Table 3.
That is, compound A (4.01 g), mannitol (722.6 g) and crystalline
cellulose (90.6 g) were placed in a fluidized bed dryer granulator
(LAB-1, manufactured by POWREX CORPORATION), and the mixture was
preheated and mixed. The mixture was granulated while spraying an
aqueous solution (452.4 g) of hydroxypropylcellulose (27.0 g) and
fumaric acid (2.4 g) to give a granulated powder. The obtained
granulated powder was passed through a 16M (1000 .mu.m) sieve to
give a sized powder. To the sized powder (564.3 g) were added
croscarmellose sodium (30.00 g) and magnesium stearate (6.000 g)
and the mixture was mixed in a bag to give a mixed powder. The
mixed powder was tableted by a rotary tableting machine (COLLECT
19K, manufactured by Kikusui Seisakusho, Ltd.) using a 9 mm.phi.
punch to give plain tablets (core tablets, 300 mg per tablet). A
part of the obtained plain tablet (core tablet) was used for
preservation measurement. That is, the plain tablet (core tablet)
was placed in a glass bottle, tightly sealed and preserved at
60.degree. C. for 2 weeks.
TABLE-US-00007 TABLE 3 Composition of plain tablet (core tablet)
containing compound A (sample 3) composition amount (mg) 1)
compound A 1.336 2) mannitol 240.864 3) crystalline cellulose 30 4)
hydroxypropylcellulose 9 5) fumaric acid 0.8 6) croscarmellose
sodium 15 7) magnesium stearate 3 total 300.0
Example 2
Sample 4
[0741] A plain tablet (core tablet) containing compound A was
produced as follows at the composition ratios shown in Table 4.
[0742] That is, compound A (4.01 g), mannitol (635.2 g),
crystalline cellulose (90.0 g) and fumaric acid (90.1 g) were
placed in a fluidized bed dryer granulator (LAB-1, manufactured by
POWREX CORPORATION), and the mixture was preheated and mixed. The
mixture was granulated while spraying an aqueous solution (450.0 g)
of hydroxypropylcellulose (27.0 g) to give a granulated powder. The
obtained granulated powder was passed through a 16M (1000 .mu.m)
sieve to give a sized powder. To the sized powder (564.2 g) were
added croscarmellose sodium (30.00 g) and magnesium stearate (6.000
g) and the mixture was mixed in a bag to give a mixed powder. The
mixed powder was tableted by a rotary tableting machine (COLLECT
19K, manufactured by Kikusui Seisakusho, Ltd.) using a 9 mm.phi.
punch to give plain tablets (core tablets, 300 mg per tablet). A
part of the obtained plain tablet (core tablet) was used for
preservation measurement. That is, the plain tablet (core tablet)
was placed in a glass bottle, tightly sealed and preserved at
60.degree. C. for 2 weeks.
TABLE-US-00008 TABLE 4 Composition of plain tablet (core tablet)
containing compound A (sample 4) composition amount (mg) 1)
compound A 1.336 2) mannitol 211.664 3) crystalline cellulose 30 4)
hydroxypropylcellulose 9 5) fumaric acid 30 6) croscarmellose
sodium 15 7) magnesium stearate 3 total 300.0
Example 3
Sample 5
[0743] A plain tablet (core tablet) containing compound A was
produced as follows at the composition ratios shown in Table 5.
[0744] That is, compound A (4.01 g), mannitol (635.0 g),
crystalline cellulose (90.0 g) and fumaric acid (87.7 g) were
placed in a fluidized bed dryer granulator (LAB-1, manufactured by
POWREX CORPORATION), and the mixture was preheated and mixed. The
mixture was granulated while spraying an aqueous solution (452.4 g)
of hydroxypropylcellulose (27.0 g) and fumaric acid (2.4 g) to give
a granulated powder. The obtained granulated powder was passed
through a 16M (1000 .mu.m) sieve to give a sized powder. To the
sized powder (564.1 g) were added croscarmellose sodium (30.20 g)
and magnesium stearate (6.000 g) and the mixture was mixed in a bag
to give a mixed powder. The mixed powder was tableted by a rotary
tableting machine (COLLECT 19K, manufactured by Kikusui Seisakusho,
Ltd.) using a 9 mm.phi. punch to give plain tablets (core tablets,
300 mg per tablet). The plain tablet (core tablet) was placed in a
glass bottle, tightly sealed and preserved at 60.degree. C. for 2
weeks.
TABLE-US-00009 TABLE 5 Composition of plain tablet (core tablet)
containing compound A (sample 5) composition amount (mg) 1)
compound A 1.336 2) mannitol 211.664 3) crystalline cellulose 30 4)
hydroxypropylcellulose 9 5) fumaric acid 30 6) croscarmellose
sodium 15 7) magnesium stearate 3 total 300.0
Example 4
Sample 6
[0745] A plain tablet (core tablet) containing compound A was
produced as follows at the composition ratios shown in Table 6.
[0746] That is, compound A (2.6719 g), mannitol (481.8 g),
crystalline cellulose (60.0 g) and fumaric acid (1.61 g) were
placed in a fluidized bed dryer granulator (LAB-1, manufactured by
POWREX CORPORATION), and the mixture was preheated and mixed. The
mixture was granulated while spraying an aqueous solution (300.0 g)
of hydroxypropylcellulose (18.0 g) to give a granulated powder. The
obtained granulated powder was passed through a 16M (1000 .mu.m)
sieve to give a sized powder. To the sized powder (507.8 g) were
added croscarmellose sodium (27.00 g) and magnesium stearate
(5.4000 g) and the mixture was mixed in a bag to give a mixed
powder. The mixed powder was tableted by a rotary tableting machine
(COLLECT 19K, manufactured by Kikusui Seisakusho, Ltd.) using a 9
mm.phi. punch to give plain tablets (core tablets, 300 mg per
tablet).
TABLE-US-00010 TABLE 6 Composition of plain tablet (core tablet)
containing compound A (sample 6) composition amount (mg) 1)
compound A 1.336 2) mannitol 240.864 3) crystalline cellulose 30 4)
hydroxypropylcellulose 9 5) fumaric acid 0.8 6) croscarmellose
sodium 15 7) magnesium stearate 3 total 300.0
Example 5
Sample 7
[0747] A plain tablet (core tablet) containing compound A was
produced as follows at the composition ratios shown in Table 7.
[0748] That is, compound A (2.6724 g), mannitol (480.3 g),
crystalline cellulose (60.0 g) and fumaric acid (3.01 g) were
placed in a fluidized bed dryer granulator (LAB-1, manufactured by
POWREX CORPORATION), and the mixture was preheated and mixed. The
mixture was granulated while spraying an aqueous solution (300.0 g)
of hydroxypropylcellulose (18.0 g) to give a granulated powder. The
obtained granulated powder was passed through a 16M (1000 .mu.m)
sieve to give a sized powder. To the sized powder (507.9 g) were
added croscarmellose sodium (27.00 g) and magnesium stearate
(5.4000 g) and the mixture was mixed in a bag to give a mixed
powder. The mixed powder was tableted by a rotary tableting machine
(COLLECT 19K, manufactured by Kikusui Seisakusho, Ltd.) using a 9
mm.phi. punch to give plain tablets (core tablets, 300 mg per
tablet).
TABLE-US-00011 TABLE 7 Composition of plain tablet (core tablet)
containing compound A (sample 7) composition amount (mg) 1)
compound A 1.336 2) mannitol 240.164 3) crystalline cellulose 30 4)
hydroxypropylcellulose 9 5) fumaric acid 1.5 6) croscarmellose
sodium 15 7) magnesium stearate 3 total 300.0
Example 6
Sample 8
[0749] A plain tablet (core tablet) containing compound A was
produced as follows at the composition ratios shown in Table 8.
[0750] That is, compound A (2.6721 g), mannitol (477.3 g),
crystalline cellulose (60.0 g) and fumaric acid (6.01 g) were
placed in a fluidized bed dryer granulator (LAB-1, manufactured by
POWREX CORPORATION), and the mixture was preheated and mixed. The
mixture was granulated while spraying an aqueous solution (300.0 g)
of hydroxypropylcellulose (18.0 g) to give a granulated powder. The
obtained granulated powder was passed through a 16M (1000 .mu.m)
sieve to give a sized powder. To the sized powder (507.7 g) were
added croscarmellose sodium (27.00 g) and magnesium stearate
(5.4000 g) and the mixture was mixed in a bag to give a mixed
powder. The mixed powder was tableted by a rotary tableting machine
(COLLECT 19K, manufactured by Kikusui Seisakusho, Ltd.) using a 9
mm.phi. punch to give plain tablets (core tablets, 300 mg per
tablet).
TABLE-US-00012 TABLE 8 Composition of plain tablet (core tablet)
containing compound A (sample 8) composition amount (mg) 1)
compound A 1.336 2) mannitol 238.664 3) crystalline cellulose 30 4)
hydroxypropylcellulose 9 5) fumaric acid 3 6) croscarmellose sodium
15 7) magnesium stearate 3 total 300.0
Example 7
Sample 9
[0751] A plain tablet (core tablet) containing compound A was
produced as follows at the composition ratios shown in Table 9.
[0752] That is, compound A (2.6715 g), mannitol (469.3 g),
crystalline cellulose (60.0 g) and fumaric acid (14.00 g) were
placed in a fluidized bed dryer granulator (LAB-1, manufactured by
POWREX CORPORATION), and the mixture was preheated and mixed. The
mixture was granulated while spraying an aqueous solution (300.0 g)
of hydroxypropylcellulose (18.0 g) to give a granulated powder. The
obtained granulated powder was passed through a 16M (1000 .mu.m)
sieve to give a sized powder. To the sized powder (507.5 g) were
added croscarmellose sodium (27.00 g) and magnesium stearate
(5.4000 g) and the mixture was mixed in a bag to give a mixed
powder. The mixed powder was tableted by a rotary tableting machine
(COLLECT 19K, manufactured by Kikusui Seisakusho, Ltd.) using a 9
mm.phi. punch to give plain tablets (core tablets, 300 mg per
tablet).
TABLE-US-00013 TABLE 9 Composition of plain tablet (core tablet)
containing compound A (sample 9) composition amount (mg) 1)
compound A 1.336 2) mannitol 234.664 3) crystalline cellulose 30 4)
hydroxypropylcellulose 9 5) fumaric acid 7 6) croscarmellose sodium
15 7) magnesium stearate 3 total 300.0
Example 8
Sample 10
[0753] A plain tablet (core tablet) containing compound A was
produced as follows at the composition ratios shown in Table
10.
[0754] That is, compound A (20.04 g), mannitol (451.0 g),
crystalline cellulose (60.0 g) and fumaric acid (15.0 g) were
placed in a fluidized bed dryer granulator (LAB-1, manufactured by
POWREX CORPORATION), and the mixture was preheated and mixed. The
mixture was granulated while spraying an aqueous solution (300.0 g)
of hydroxypropylcellulose (18.0 g) to give a granulated powder. The
obtained granulated powder was passed through a 16M (1000 .mu.m)
sieve to give a sized powder. To the sized powder (526.4 g) were
added croscarmellose sodium (28.00 g) and magnesium stearate (5.60
g) and the mixture was mixed in a bag to give a mixed powder. The
mixed powder was tableted by a rotary tableting machine (COLLECT
19K, manufactured by Kikusui Seisakusho, Ltd.) using a 8 mm.phi.
punch to give plain tablets (core tablets, 200 mg per tablet).
TABLE-US-00014 TABLE 10 Composition of plain tablet (core tablet)
containing compound A (sample 10) composition amount (mg) 1)
compound A 6.68 2) mannitol 150.32 3) crystalline cellulose 20 4)
hydroxypropylcellulose 6 5) fumaric acid 5 6) croscarmellose sodium
10 7) magnesium stearate 2 total 200.0
Example 9
Sample 11
[0755] A plain tablet (core tablet) containing compound A was
produced as follows at the composition ratios shown in Table
11.
[0756] That is, compound A (80.16 g), mannitol (390.9 g),
crystalline cellulose (60.0 g) and fumaric acid (15.0 g) were
placed in a fluidized bed dryer granulator (LAB-1, manufactured by
POWREX CORPORATION), and the mixture was preheated and mixed. The
mixture was granulated while spraying an aqueous solution (300.0 g)
of hydroxypropylcellulose (18.0 g) to give a granulated powder. The
obtained granulated powder was passed through a 16M (1000 .mu.m)
sieve to give a sized powder. To the sized powder (526.4 g) were
added croscarmellose sodium (28.00 g) and magnesium stearate (5.60
g) and the mixture was mixed in a bag to give a mixed powder. The
mixed powder was tableted by a rotary tableting machine (COLLECT
19K, manufactured by Kikusui Seisakusho, Ltd.) using a 8 mm.phi.
punch to give plain tablets (core tablets, 200 mg per tablet).
TABLE-US-00015 TABLE 11 Composition of plain tablet (core tablet)
containing compound A (sample 11) composition amount (mg) 1)
compound A 26.72 2) mannitol 130.28 3) crystalline cellulose 20 4)
hydroxypropylcellulose 6 5) fumaric acid 5 6) croscarmellose sodium
10 7) magnesium stearate 2 total 200.0
Example 10
Sample 12
[0757] A plain tablet (core tablet) containing compound A was
produced as follows at the composition ratios shown in Table
12.
[0758] That is, compound A (160.32 g), mannitol (310.7 g),
crystalline cellulose (60.6 g) and fumaric acid (15.0 g) were
placed in a fluidized bed dryer granulator (LAB-1, manufactured by
POWREX CORPORATION), and the mixture was preheated and mixed. The
mixture was granulated while spraying an aqueous solution (300.0 g)
of hydroxypropylcellulose (18.0 g) to give a granulated powder. The
obtained granulated powder was passed through a 16M (1000 .mu.m)
sieve to give a sized powder. To the sized powder (526.4 g) were
added croscarmellose sodium (28.00 g) and magnesium stearate (5.60
g) and the mixture was mixed in a bag to give a mixed powder. The
mixed powder was tableted by a rotary tableting machine (COLLECT
19K, manufactured by Kikusui Seisakusho, Ltd.) using a 8 mm.phi.
punch to give plain tablets (core tablets, 200 mg per tablet).
TABLE-US-00016 TABLE 12 Composition of plain tablet (core tablet)
containing compound A (sample 12) composition amount (mg) 1)
compound A 53.44 2) mannitol 103.56 3) crystalline cellulose 20 4)
hydroxypropylcellulose 6 5) fumaric acid 5 6) croscarmellose sodium
10 7) magnesium stearate 2 total 200.0
Example 11
Sample 13
[0759] A plain tablet (core tablet) containing compound A was
produced as follows at the composition ratios shown in Table
13.
[0760] That is, compound A (160.32 g), mannitol (265.7 g),
crystalline cellulose (60.0 g) and fumaric acid (60.0 g) were
placed in a fluidized bed dryer granulator (LAB-1, manufactured by
POWREX CORPORATION), and the mixture was preheated and mixed. The
mixture was granulated while spraying an aqueous solution (300.0 g)
of hydroxypropylcellulose (18.0 g) to give a granulated powder. The
obtained granulated powder was passed through a 16M (1000 .mu.m)
sieve to give a sized powder. To the sized powder (526.4 g) were
added croscarmellose sodium (28.00 g) and magnesium stearate (5.60
g) and the mixture was mixed in a bag to give a mixed powder. The
mixed powder was tableted by a rotary tableting machine (COLLECT
19K, manufactured by Kikusui Seisakusho, Ltd.) using a 8 mm.phi.
punch to give plain tablets (core tablets, 200 mg per tablet).
TABLE-US-00017 TABLE 13 Composition of plain tablet (core tablet)
containing compound A (sample 13) composition amount (mg) 1)
compound A 53.44 2) mannitol 88.56 3) crystalline cellulose 20 4)
hydroxypropylcellulose 6 5) fumaric acid 20 6) croscarmellose
sodium 10 7) magnesium stearate 2 total 200.0
Example 12
Sample 14
[0761] A plain tablet (core tablet) containing compound A was
produced as follows at the composition ratios shown in Table
14.
[0762] That is, compound A (80.890 g), mannitol (4065.0 g),
crystalline cellulose (528.0 g) and fumaric acid (132.0 g) were
placed in a fluidized bed dryer granulator (FD-5S, manufactured by
POWREX CORPORATION), and the mixture was preheated and mixed. The
mixture was granulated while spraying an aqueous solution (2640.0
g) of hydroxypropylcellulose (158.4 g) to give a granulated powder.
The obtained granulated powder (4550.0 g) was passed through a
powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to
give a sized powder. The sized powder (4239.0 g), croscarmellose
sodium (225.5 g) and magnesium stearate (45.10 g) were placed in a
tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai
Kosakusho), and mixed therein to give a mixed powder. The mixed
powder was tableted by a rotary tableting machine (COLLECT 12HUK,
manufactured by Kikusui Seisakusho, Ltd.) using a 8 mm.phi. punch
to give plain tablets (core tablets, 220 mg per tablet).
TABLE-US-00018 TABLE 14 Composition of plain tablet (core tablet)
containing compound A (sample 14) composition amount (mg) 1)
compound A* 3.34 2) mannitol 169.36 3) crystalline cellulose 22 4)
hydroxypropylcellulose 6.6 5) fumaric acid 5.5 6) croscarmellose
sodium 11 7) magnesium stearate 2.2 total 220.0 *Where necessary,
the content was amended using mannitol as an adjustment
component.
Example 13
Sample 15
[0763] A plain tablet (core tablet) containing compound A was
produced as follows at the composition ratios shown in Table
15.
[0764] That is, compound A (161.8 g), mannitol (3984.0 g),
crystalline cellulose (528.0 g) and fumaric acid (132.0 g) were
placed in a fluidized bed dryer granulator (FD-5S, manufactured by
POWREX CORPORATION), and the mixture was preheated and mixed. The
mixture was granulated while spraying an aqueous solution (2640.0
g) of hydroxypropylcellulose (158.4 g) to give a granulated powder.
The obtained granulated powder (4550.0 g) was passed through a
powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to
give a sized powder. The sized powder (4239.0 g), croscarmellose
sodium (225.5 g) and magnesium stearate (45.1 g) were placed in a
tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai
Kosakusho), and mixed therein to give a mixed powder. The mixed
powder was tableted by a rotary tableting machine (COLLECT 12HUK,
manufactured by Kikusui Seisakusho, Ltd.) using a 8 mm.phi. punch
to give plain tablets (core tablets, 220 mg per tablet).
TABLE-US-00019 TABLE 15 Composition of plain tablet (core tablet)
containing compound A (sample 15) composition amount (mg) 1)
compound A* 6.68 2) mannitol 166.02 3) crystalline cellulose 22 4)
hydroxypropylcellulose 6.6 5) fumaric acid 5.5 6) croscarmellose
sodium 11 7) magnesium stearate 2.2 total 220.0 *Where necessary,
the content was amended using mannitol as an adjustment
component.
Example 14
Sample 16
[0765] A plain tablet (core tablet) containing compound A was
produced as follows at the composition ratios shown in Table
16.
[0766] That is, compound A (323.5 g), mannitol (3824.0 g),
crystalline cellulose (528.0 g) and fumaric acid (132.0 g) were
placed in a fluidized bed dryer granulator (FD-5S, manufactured by
POWREX CORPORATION), and the mixture was preheated and mixed. The
mixture was granulated while spraying an aqueous solution (2640.0
g) of hydroxypropylcellulose (158.4 g) to give a granulated powder.
The obtained granulated powder (4550.0 g) was passed through a
powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to
give a sized powder. The sized powder (4239.0 g), croscarmellose
sodium (225.5 g) and magnesium stearate (45.1 g) were placed in a
tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai
Kosakusho), and mixed therein to give a mixed powder. The mixed
powder was tableted by a rotary tableting machine (COLLECT 12HUK,
manufactured by Kikusui Seisakusho, Ltd.) using a 8 mm.phi. punch
to give plain tablets (core tablets, 220 mg per tablet).
TABLE-US-00020 TABLE 16 Composition of plain tablet (core tablet)
containing compound A (sample 16) composition amount (mg) 1)
compound A* 13.36 2) mannitol 159.34 3) crystalline cellulose 22 4)
hydroxypropylcellulose 6.6 5) fumaric acid 5.5 6) croscarmellose
sodium 11 7) magnesium stearate 2.2 total 220.0 *Where necessary,
the content was amended using mannitol as an adjustment
component.
Example 15
Sample 17
[0767] A plain tablet (core tablet) containing compound A was
produced as follows at the composition ratios shown in Table 17.
That is, compound A (647.1 g), mannitol (3504.0 g), crystalline
cellulose (528.0 g) and fumaric acid (132.0 g) were placed in a
fluidized bed dryer granulator (FD-5S, manufactured by POWREX
CORPORATION), and the mixture was preheated and mixed. The mixture
was granulated while spraying an aqueous solution (2640.0 g) of
hydroxypropylcellulose (158.4 g) to give a granulated powder. The
obtained granulated powder (4550.0 g) was passed through a
powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to
give a sized powder. The sized powder (4239.0 g), croscarmellose
sodium (225.5 g) and magnesium stearate (45.1 g) were placed in a
tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai
Kosakusho), and mixed therein to give a mixed powder. The mixed
powder was tableted by a rotary tableting machine (COLLECT 12HUK,
manufactured by Kikusui Seisakusho, Ltd.) using a 8 mm.phi. punch
to give plain tablets (core tablets, 220 mg per tablet).
TABLE-US-00021 TABLE 17 Composition of plain tablet (core tablet)
containing compound A (sample 17) composition amount (mg) 1)
compound A* 26.72 2) mannitol 145.98 3) crystalline cellulose 22 4)
hydroxypropylcellulose 6.6 5) fumaric acid 5.5 6) croscarmellose
sodium 11 7) magnesium stearate 2.2 total 220.0 *Where necessary,
the content was amended using mannitol as an adjustment
component.
Example 16
Sample 18
[0768] The plain tablet (core tablet) (sample 3, 299.95 g) obtained
in Example 1 was placed in a film coating machine (HCT-MINI type,
manufactured by Freund Corporation), and film-coated tablets (about
312 mg per tablet) were obtained while spraying a film coating
solution (136.9 g) having the composition ratio shown in Table 18.
The obtained film-coated tablet was placed in a glass bottle,
tightly sealed and preserved at 60.degree. C. for 2 weeks, and at
40.degree. C., 75% RH for 2 or 6 months. The film-coated tablet was
placed in a glass bottle, and preserved in an open bottle at
40.degree. C., 75% RH for 2 or 6 months.
TABLE-US-00022 TABLE 18 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 10.8 2) titanium
oxide 1 3) diiron trioxide 0.2 4) purified water 108 total
120.0
Example 17
Sample 19
[0769] The plain tablet (core tablet) (sample 4, 250.0 g) obtained
in Example 2 was placed in a film coating machine (HCT-MINI type,
manufactured by Freund Corporation), and film-coated tablets (about
312 mg per tablet) were obtained while spraying a film coating
solution (103.1 g) having the composition ratio shown in Table 19.
The obtained film-coated tablet was placed in a glass bottle,
tightly sealed and preserved at 60.degree. C. for 2 weeks, and at
40.degree. C., 75% RH for 2 or 6 months. The film-coated tablet was
placed in a glass bottle, and preserved in an open bottle at
40.degree. C., 75% RH for 2 or 6 months.
TABLE-US-00023 TABLE 19 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 10.8 2) titanium
oxide 1 3) diiron trioxide 0.2 4) purified water 108 total
120.0
Example 18
Sample 20
[0770] The plain tablets (core tablets) obtained in Example 3
(sample 5, 300.0 g) were placed in a film coating machine (HCT-MINI
type, manufactured by Freund Corporation), and film-coated tablets
(about 312 mg per tablet) were obtained while spraying a film
coating solution (126.6 g) having the composition ratio shown in
Table 20. The obtained film-coated tablet was placed in a glass
bottle, tightly sealed and preserved at 60.degree. C. for 2 weeks,
and at 40.degree. C., 75% RH for 2 or 6 months. The film-coated
tablet was placed in a glass bottle, and preserved in an open
bottle at 40.degree. C., 75% RH for 2 or 6 months.
TABLE-US-00024 TABLE 20 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 10.8 2) titanium
oxide 1 3) diiron trioxide 0.2 4) purified water 108 total
120.0
Example 19
Sample 21
[0771] The plain tablets (core tablets) obtained in Example 4
(sample 6, 300.0 g) were placed in a film coating machine (HCT-MINI
type, manufactured by Freund Corporation), and film-coated tablets
(about 312 mg per tablet) were obtained while spraying a film
coating solution (145.0 g) having the composition ratio shown in
Table 21. The obtained film-coated tablet was placed in a glass
bottle, tightly sealed and preserved at 60.degree. C. for 2 weeks,
and at 40.degree. C., 75% RH for 2 or 6 months. The film-coated
tablet was placed in a glass bottle, and preserved in an open
bottle at 40.degree. C., 75% RH for 2 or 6 months.
TABLE-US-00025 TABLE 21 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 10.8 2) titanium
oxide 1 3) diiron trioxide 0.2 4) purified water 108 total
120.0
Example 20
Sample 22
[0772] The plain tablets (core tablets) obtained in Example 5
(sample 7, 300.1 g) were placed in a film coating machine (HCT-MINI
type, manufactured by Freund Corporation), and film-coated tablets
(about 312 mg per tablet) were obtained while spraying a film
coating solution (143.5 g) having the composition ratio shown in
Table 22. The obtained film-coated tablet was placed in a glass
bottle, tightly sealed and preserved at 60.degree. C. for 2 weeks,
and at 40.degree. C., 75% RH for 2 or 6 months. The film-coated
tablet was placed in a glass bottle, and preserved in an open
bottle at 40.degree. C., 75% RH for 2 or 6 months.
TABLE-US-00026 TABLE 22 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 10.8 2) titanium
oxide 1 3) diiron trioxide 0.2 4) purified water 108 total
120.0
Example 21
Sample 23
[0773] The plain tablets (core tablets) obtained in Example 6
(sample 8, 300.1 g) were placed in a film coating machine (HCT-MINI
type, manufactured by Freund Corporation), and film-coated tablets
(about 312 mg per tablet) were obtained while spraying a film
coating solution (158.3 g) having the composition ratio shown in
Table 23. The obtained film-coated tablet was placed in a glass
bottle, tightly sealed and preserved at 60.degree. C. for 2 weeks,
and at 40.degree. C., 75% RH for 2 or 6 months. The film-coated
tablet was placed in a glass bottle, and preserved in an open
bottle at 40.degree. C., 75% RH for 2 or 6 months.
TABLE-US-00027 TABLE 23 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 10.8 2) titanium
oxide 1 3) diiron trioxide 0.2 4) purified water 108 total
120.0
Example 22
Sample 24
[0774] The plain tablets (core tablets) obtained in Example 7
(sample 9, 300.0 g) were placed in a film coating machine (HCT-MINI
type, manufactured by Freund Corporation), and film-coated tablets
(about 312 mg per tablet) were obtained while spraying a film
coating solution (138.1 g) having the composition ratio shown in
Table 24. The obtained film-coated tablet was placed in a glass
bottle, tightly sealed and preserved at 60.degree. C. for 2 weeks,
and at 40.degree. C., 75% RH for 2 or 6 months. The film-coated
tablet was placed in a glass bottle, and preserved in an open
bottle at 40.degree. C., 75% RH for 2 or 6 months.
TABLE-US-00028 TABLE 24 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 10.8 2) titanium
oxide 1 3) diiron trioxide 0.2 4) purified water 108 total
120.0
Example 23
Sample 25
[0775] The plain tablets (core tablets) obtained in Example 8
(sample 10, 350.1 g) were placed in a film coating machine
(HCT-MINI type, manufactured by Freund Corporation), and
film-coated tablets (about 209 mg per tablet) were obtained while
spraying a film coating solution (192.0 g) having the composition
ratio shown in Table 25. The obtained film-coated tablet was placed
in a glass bottle, tightly sealed and preserved at 60.degree. C.
for 2 weeks, and at 40.degree. C., 75% RH for 2 months. The
film-coated tablet was placed in a glass bottle, and preserved in
an open bottle at 40.degree. C., 75% RH for 2 months.
TABLE-US-00029 TABLE 25 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 6.732 2) macrogol
6000 1.350 3) titanium oxide 0.9 4) diiron trioxide 0.018 5)
purified water 90 total 99.0
Example 24
Sample 26
[0776] The plain tablets (core tablets) obtained in Example 9
(sample 11, 350.0 g) were placed in a film coating machine
(HCT-MINI type, manufactured by Freund Corporation), and
film-coated tablets (about 209 mg per tablet) were obtained while
spraying a film coating solution (182.3 g) having the composition
ratio shown in Table 26. The obtained film-coated tablet was placed
in a glass bottle, tightly sealed and preserved at 60.degree. C.
for 2 weeks, and at 40.degree. C., 75% RH for 2 months. The
film-coated tablet was placed in a glass bottle, and preserved in
an open bottle at 40.degree. C., 75% RH for 2 months.
TABLE-US-00030 TABLE 26 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 6.732 2) macrogol
6000 1.350 3) titanium oxide 0.9 4) diiron trioxide 0.018 5)
purified water 90 total 99.0
Example 25
Sample 27
[0777] The plain tablets (core tablets) obtained in Example 10
(sample 12, 350.1 g) were placed in a film coating machine
(HCT-MINI type, manufactured by Freund Corporation), and
film-coated tablets (about 209 mg per tablet) were obtained while
spraying a film coating solution (189.0 g) having the composition
ratio shown in Table 27. The obtained film-coated tablet was placed
in a glass bottle, tightly sealed and preserved at 60.degree. C.
for 2 weeks, and at 40.degree. C., 75% RH for 2 months. The
film-coated tablet was placed in a glass bottle, and preserved in
an open bottle at 40.degree. C., 75% RH for 2 months.
TABLE-US-00031 TABLE 27 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 6.732 2) macrogol
6000 1.350 3) titanium oxide 0.9 4) diiron trioxide 0.018 5)
purified water 90 total 99.0
Example 26
Sample 28
[0778] The plain tablets (core tablets) obtained in Example 11
(sample 13, 240.1 g) were placed in a film coating machine
(HCT-MINI type, manufactured by Freund Corporation), and
film-coated tablets (about 209 mg per tablet) were obtained while
spraying a film coating solution (126.3 g) having the composition
ratio shown in Table 28. The obtained film-coated tablet was placed
in a glass bottle, tightly sealed and preserved at 60.degree. C.
for 2 weeks, and at 40.degree. C., 75% RH for 2 months. The
film-coated tablet was placed in a glass bottle, and preserved in
an open bottle at 40.degree. C., 75% RH for 2 months.
TABLE-US-00032 TABLE 28 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 6.732 2) macrogol
6000 1.350 3) titanium oxide 0.9 4) diiron trioxide 0.018 5)
purified water 90 total 99.0
Example 27
Sample 29
[0779] The plain tablets (core tablets) obtained in Example 12
(sample 14, 3300.0 g) were placed in a film coating machine
(DRC-500, manufactured by POWREX CORPORATION), and film-coated
tablets (about 229 mg per tablet) were obtained while spraying a
film coating solution (1480.9 g) having the composition ratio shown
in Table 29. The film-coated tablet was placed in a glass bottle,
and preserved in an open bottle at 40.degree. C., 75% RH for 2
months.
TABLE-US-00033 TABLE 29 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 6.6 2) macrogol
6000 1.5 3) titanium oxide 0.75 4) yellow ferric oxide 0.075 5)
diiron trioxide 0.075 6) purified water 81 total 90.0
Example 28
Sample 30
[0780] The plain tablets (core tablets) obtained in Example 13
(sample 15, 3300.0 g) were placed in a film coating machine
(DRC-500, manufactured by POWREX CORPORATION), and film-coated
tablets (about 229 mg per tablet) were obtained while spraying a
film coating solution (1501.0 g) having the composition ratio shown
in Table 30. The film-coated tablet was placed in a glass bottle,
and preserved in a closed bottle or an open bottle at 40.degree.
C., 75% RH for 2 months.
TABLE-US-00034 TABLE 30 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 6.6 2) macrogol
6000 1.5 3) titanium oxide 0.75 4) yellow ferric oxide 0.075 5)
diiron trioxide 0.075 6) purified water 81 total 90.0
Example 29
Sample 31
[0781] The plain tablets (core tablets) obtained in Example 14
(sample 16, 3300.0 g) were placed in a film coating machine
(DRC-500, manufactured by POWREX CORPORATION), and film-coated
tablets (about 229 mg per tablet) were obtained while spraying a
film coating solution (1514.0 g) having the composition ratio shown
in Table 31. The film-coated tablet was placed in a glass bottle,
and preserved in a closed bottle or an open bottle at 40.degree.
C., 75% RH for 2 months.
TABLE-US-00035 TABLE 31 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 6.6 2) macrogol
6000 1.5 3) titanium oxide 0.75 4) yellow ferric oxide 0.075 5)
diiron trioxide 0.075 6) purified water 81 total 90.0
Example 30
Sample 32
[0782] The plain tablets (core tablets) obtained in Example 15
(sample 17, 3300.0 g) were placed in a film coating machine
(DRC-500, manufactured by POWREX CORPORATION), and film-coated
tablets (about 229 mg per tablet) were obtained while spraying a
film coating solution (1374.0 g) having the composition ratio shown
in Table 32. The film-coated tablet was placed in a glass bottle,
and preserved in a closed bottle or an open bottle at 40.degree.
C., 75% RH for 2 months.
TABLE-US-00036 TABLE 32 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 6.6 2) macrogol
6000 1.5 3) titanium oxide 0.75 4) yellow ferric oxide 0.075 5)
diiron trioxide 0.075 6) purified water 81 total 90.0
Comparative Example 3
Sample 33
[0783] A plain tablet (core tablet) containing
N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]me-
thanamine fumarate (hereinafter to be referred to as compound B)
was produced as follows at the composition ratio shown in Table
33.
[0784] That is, compound B (2.680 g), mannitol (483.320 g) and
crystalline cellulose (60.0 g) were placed in a fluidized bed dryer
granulator (LAB-1, manufactured by POWREX CORPORATION), and the
mixture was preheated and mixed. The mixture was granulated while
spraying an aqueous solution (300.0 g) of hydroxypropylcellulose
(18.0 g) to give a granulated powder. The obtained granulated
powder was passed through a 16M (1000 .mu.m) sieve to give a sized
powder. Croscarmellose sodium (27.00 g) and magnesium stearate
(5.400 g) were added to the sized powder (507.6 g) and mixed to
give a mixed powder. The mixed powder was tableted by a rotary
tableting machine (COLLECT 19K, manufactured by Kikusui Seisakusho,
Ltd.) using a 9 mm.phi. punch to give plain tablets (core tablets,
300 mg per tablet).
TABLE-US-00037 TABLE 33 Composition of plain tablet (core tablet)
containing compound B composition amount (mg) 1) compound B 1.340
2) mannitol 241.66 3) crystalline cellulose 30 4)
hydroxypropylcellulose 9 5) croscarmellose sodium 15 6) magnesium
stearate 3 total 300.0
Comparative Example 4
Sample 34
[0785] The plain tablets (core tablets) obtained in Comparative
Example 3 (sample 33, 200.0 g) were placed in a film coating
machine (DRC-200, manufactured by POWREX CORPORATION), and
film-coated tablets (about 312 mg per tablet) were obtained while
spraying a film coating solution (96.8 g) having the composition
ratio shown in Table 34. The obtained film-coated tablet was placed
in a glass bottle, tightly sealed and preserved at 40.degree. C.,
75% RH for 2 months. The film-coated tablet was placed in a glass
bottle, and preserved in an open bottle at 40.degree. C., 75% RH
for 2 months.
TABLE-US-00038 TABLE 34 composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 8.8 2)
polyethylene glycol 2 3) titanium oxide 1 4) diiron trioxide 0.2 5)
purified water 108 total 120.0
Example 31
Sample 35
[0786] A plain tablet (core tablet) containing compound B was
produced as follows at the composition ratio shown in Table 35.
[0787] That is, compound B (24.54 g), mannitol (4223.0 g),
crystalline cellulose (540.0 g) and fumaric acid (126.0 g) were
placed in a fluidized bed dryer granulator (FD-5S, manufactured by
POWREX CORPORATION), and the mixture was preheated and mixed. The
mixture was granulated while spraying an aqueous solution (2700.0
g) of hydroxypropylcellulose (162.0 g) to give a granulated powder.
The obtained granulated powder (4568.0 g) was passed through a
powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to
give a sized powder. The sized powder (4230.0 g), croscarmellose
sodium (225.0 g) and magnesium stearate (45.00 g) were placed in a
tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai
Kosakusho), and mixed to give a mixed powder. The mixed powder was
tableted by a rotary tableting machine (COLLECT 12HUK, manufactured
by Kikusui Seisakusho, Ltd.) using a 9 mm.phi. punch to give plain
tablets (core tablets, 300 mg per tablet).
TABLE-US-00039 TABLE 35 Composition of plain tablet (core tablet)
containing compound B composition amount (mg) 1) compound B 1.340
2) mannitol 234.66 3) crystalline cellulose 30 4)
hydroxypropylcellulose 9 5) fumaric acid 7 6) croscarmellose sodium
15 7) magnesium stearate 3 total 300.0
Example 32
Sample 36
[0788] The plain tablets (core tablets) obtained in Example 31
(sample 35, 3300.0 g) were placed in a film coating machine
(DRC-500, manufactured by POWREX CORPORATION), and film-coated
tablets (about 312 mg per tablet) were obtained while spraying a
film coating solution (1432.0 g) having the composition ratio shown
in Table 34. The obtained film-coated tablet was placed in a glass
bottle, tightly sealed and preserved at 40.degree. C., 75% RH for 2
months. The film-coated tablet was placed in a glass bottle, and
preserved in an open bottle at 40.degree. C., 75% RH for 2
months.
Example 33
Sample 37
[0789] A plain tablet (core tablet) containing compound B was
produced as follows at the composition ratio shown in Table 36.
That is, compound B (5.360 g), mannitol (479.2 g) and crystalline
cellulose (60.00 g) were placed in a fluidized bed dryer granulator
(LAB-1, manufactured by POWREX CORPORATION), and the mixture was
preheated and mixed. The mixture was granulated while spraying an
aqueous solution (301.4 g) of hydroxypropylcellulose (18.0 g) and
fumaric acid (0.60 g) to give a granulated powder. The obtained
granulated powder was passed through a 16M (1000 .mu.m) sieve to
give a sized powder. Croscarmellose sodium (24.75 g) and magnesium
stearate (4.950 g) were added to the sized powder (465.3 g), and
mixed to give a mixed powder. The mixed powder was tableted by a
rotary tableting machine (COLLECT 19K, manufactured by Kikusui
Seisakusho, Ltd.) using a 7 mm.phi. punch to give plain tablets
(core tablets, 150 mg per tablet).
TABLE-US-00040 TABLE 36 Composition of plain tablet (core tablet)
containing compound B composition amount (mg) 1) compound B 1.340
2) mannitol 119.81 3) crystalline cellulose 15 4)
hydroxypropylcellulose 4.5 5) fumaric acid 0.35 6) croscarmellose
sodium 7.5 7) magnesium stearate 1.5 total 150.0
Example 34
Sample 38
[0790] The plain tablets (core tablets) obtained in Example 33
(sample 37, 180.3 g) were placed in a film coating machine
(DRC-200, manufactured by POWREX CORPORATION), and film-coated
tablets (core tablet, 156.1 mg per tablet) while spraying a film
coating solution (75.0 g) having the composition ratio shown in
Table 37. The obtained film-coated tablet was placed in a glass
bottle, tightly sealed and preserved at 40.degree. C., 75% RH for 2
months. The film-coated tablet was placed in a glass bottle, and
preserved in an open bottle at 40.degree. C., 75% RH for 2
months.
TABLE-US-00041 TABLE 37 composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 4.47 2) macrogol
6000 1.02 3) titanium oxide 0.508 4) yellow ferric oxide 0.051 5)
diiron trioxide 0.051 6) purified water 54.9 total 61.0
Example 35
Sample 39
[0791] A plain tablet (core tablet) containing compound B was
produced as follows at the composition ratio shown in Table 38.
[0792] That is, compound B (24.54 g), mannitol (4223.0 g),
crystalline cellulose (540.0 g) and fumaric acid (126.0 g) were
placed in a fluidized bed dryer granulator (FD-5S, manufactured by
POWREX CORPORATION), and the mixture was preheated and mixed. The
mixture was granulated while spraying an aqueous solution (2700.0
g) of hydroxypropylcellulose (162.0 g) to give a granulated powder.
The obtained granulated powder (4568.0 g) was passed through a
powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to
give a sized powder. The sized powder (4230.0 g), croscarmellose
sodium (225.0 g) and magnesium stearate (45.00 g) were placed in a
tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai
Kosakusho), and mixed to give a mixed powder. The mixed powder was
tableted by a rotary tableting machine (COLLECT 12HUK, manufactured
by Kikusui Seisakusho, Ltd.) using a 7 mm.phi. punch to give plain
tablets (core tablets, 150 mg per tablet).
TABLE-US-00042 TABLE 38 Composition of plain tablet (core tablet)
containing compound B composition amount (mg) 1) compound B 0.67 2)
mannitol 117.33 3) crystalline cellulose 15 4)
hydroxypropylcellulose 4.5 5) fumaric acid 3.5 6) croscarmellose
sodium 7.5 7) magnesium stearate 1.5 total 150.0
Example 36
Sample 40
[0793] The plain tablets (core tablets) obtained in Example 35
(sample 39, 3300.0 g) were placed in a film coating machine
(DRC-500, manufactured by POWREX CORPORATION), and film-coated
tablets (about 156 mg per tablet) were obtained while spraying a
film coating solution (1470.0 g) having the composition ratio shown
in Table 34. The obtained film-coated tablet was placed in a glass
bottle, tightly sealed and preserved at 40.degree. C., 75% RH for 2
months. The film-coated tablet was placed in a glass bottle, and
preserved in an open bottle at 40.degree. C., 75% RH for 2
months.
Example 37
Sample 41
[0794] A plain tablet (core tablet) containing compound B was
produced as follows at the composition ratio shown in Table 39.
That is, compound B (245.4 g), mannitol (4003.0 g), crystalline
cellulose (540.0 g) and fumaric acid (126.0 g) were placed in a
fluidized bed dryer granulator (FD-5S, manufactured by POWREX
CORPORATION), and the mixture was preheated and mixed. The mixture
was granulated while spraying an aqueous solution (2700.0 g) of
hydroxypropylcellulose (162.0 g) to give a granulated powder. The
obtained granulated powder (4568.0 g) was passed through a
powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to
give a sized powder. The sized powder (4230.0 g), croscarmellose
sodium (225.0 g) and magnesium stearate (45.00 g) were placed in a
tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai
Kosakusho), and mixed to give a mixed powder. The mixed powder was
tableted by a rotary tableting machine (COLLECT 12HUK, manufactured
by Kikusui Seisakusho, Ltd.) using a 9 mm.phi. punch to give plain
tablets (core tablets, 300 mg per tablet).
TABLE-US-00043 TABLE 39 Composition of plain tablet (core tablet)
containing compound B composition amount (mg) 1) compound B 13.4 2)
mannitol 222.6 3) crystalline cellulose 30 4)
hydroxypropylcellulose 9 5) fumaric acid 7 6) croscarmellose sodium
15 7) magnesium stearate 3 total 300.0
Example 38
Sample 42
[0795] The plain tablets (core tablets) obtained in Example 37
(sample 41, 3300.0 g) were placed in a film coating machine
(DRC-500, manufactured by POWREX CORPORATION), and film-coated
tablets (about 312 mg per tablet) were obtained while spraying a
film coating solution (1425.0 g) having the composition ratio shown
in Table 34. The obtained film-coated tablet was placed in a glass
bottle, tightly sealed and preserved at 40.degree. C., 75% RH for 2
months. The film-coated tablet was placed in a glass bottle, and
preserved in an open bottle at 40.degree. C., 75% RH for 2
months.
Example 39
Sample 43
[0796] A plain tablet (core tablet) containing compound B was
produced as follows at the composition ratio shown in Table 40.
That is, compound B (981.5 g), mannitol (3267.0 g), crystalline
cellulose (540.0 g) and fumaric acid (126.0 g) were placed in a
fluidized bed dryer granulator (FD-5S, manufactured by POWREX
CORPORATION), and the mixture was preheated and mixed. The mixture
was granulated while spraying an aqueous solution (2700.0 g) of
hydroxypropylcellulose (162.0 g) to give a granulated powder. The
obtained granulated powder (4568.0 g) was passed through a
powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to
give a sized powder. The sized powder (4230.0 g), croscarmellose
sodium (225.0 g) and magnesium stearate (45.00 g) were placed in a
tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai
Kosakusho), and mixed to give a mixed powder. The mixed powder was
tableted by a rotary tableting machine (COLLECT 12HUK, manufactured
by Kikusui Seisakusho, Ltd.) using a 9 mm.phi. punch to give plain
tablets (core tablets, 300 mg per tablet).
TABLE-US-00044 TABLE 40 Composition of plain tablet (core tablet)
containing compound B composition amount (mg) 1) compound B 53.6 2)
mannitol 182.4 3) crystalline cellulose 30 4)
hydroxypropylcellulose 9 5) fumaric acid 7 6) croscarmellose sodium
15 7) magnesium stearate 3 total 300.0
Example 40
Sample 44
[0797] The plain tablets (core tablets) obtained in Example 39
(sample 43, 3300.0 g) were placed in a film coating machine
(DRC-500, manufactured by POWREX CORPORATION), and film-coated
tablets (about 312 mg per tablet) were obtained while spraying a
film coating solution (1417.2 g) having the composition ratio shown
in Table 34. The obtained film-coated tablet was placed in a glass
bottle, tightly sealed and preserved at 40.degree. C., 75% RH for 2
months. The film-coated tablet was placed in a glass bottle, and
preserved in an open bottle at 40.degree. C., 75% RH for 2
months.
Comparative Example 5
Sample 45
[0798] A plain tablet (core tablet) containing
1-[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
-yl]-N-methylmethanamine fumarate (hereinafter to be referred to as
compound C) was produced as follows at the composition ratio shown
in Table 41.
[0799] That is, compound C (2.318 g), mannitol (483.7 g) and
crystalline cellulose (60.0 g) were placed in a fluidized-bed dryer
(LAB-1, manufactured by POWREX CORPORATION), and the mixture was
preheated and mixed. The mixture was granulated while spraying an
aqueous solution (300.0 g) of hydroxypropylcellulose (18.0 g) to
give a granulated powder. The obtained granulated powder was passed
through a 16M (1000 .mu.m) sieve to give a sized powder.
Croscarmellose sodium (27.0 g) and magnesium stearate (5.40 g) were
added to the sized powder (507.6 g), and mixed in a bag to give a
mixed powder. The mixed powder was tableted by a rotary tableting
machine (COLLECT 19K, manufactured by Kikusui Seisakusho, Ltd.)
using a 9 mm.phi. punch to give plain tablets (core tablets, 300 mg
per tablet).
TABLE-US-00045 TABLE 41 Composition of plain tablet (core tablet)
containing compound C composition amount (mg) 1) compound C 1.159
2) mannitol 238.841 3) crystalline cellulose 30 4)
hydroxypropylcellulose 9 5) croscarmellose sodium 15 6) magnesium
stearate 3 total 300.0
Comparative Example 6
Sample 46
[0800] The plain tablets (core tablets) obtained in Comparative
Example 5 (sample 45, 200.0 g) were placed in a film coating
machine (Hicoater mini, manufactured by Freund Corporation), and
film-coated tablets (about 312 mg per tablet) were obtained while
spraying a film coating solution (136.3 g) having the composition
ratio shown in Table 42. The obtained film-coated tablet was placed
in a glass bottle, tightly sealed and preserved at 40.degree. C.,
75% RH for 1 month. The film-coated tablet was placed in a glass
bottle, and preserved in an open bottle at 40.degree. C., 75% RH
for 1 month.
TABLE-US-00046 TABLE 42 composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 8.8 2)
polyethylene glycol 2 3) titanium oxide 1 4) diiron trioxide 0.2 5)
purified water 108 total 120.0
Example 41
Sample 47
[0801] A plain tablet (core tablet) containing compound C was
produced as follows at the composition ratio shown in Table 43.
That is, compound C (2.318 g), mannitol (482.082 g) and crystalline
cellulose (60 g) were placed in a fluidized bed dryer granulator
(LAB-1, manufactured by POWREX CORPORATION), preheated and mixed. A
granulated powder was obtained while spraying an aqueous solution
(300.0 g) of tartaric acid (1.60 g) and hydroxypropylcellulose
(18.0 g). The obtained granulated powder was passed through a 16M
(1000 .mu.m) sieve to give a sized powder. Croscarmellose sodium
(24.08 g) and magnesium stearate (4.81 g) were added to the sized
powder (451.2 g), and mixed in a bag to give a mixed powder. The
mixed powder was tableted by a rotary tableting machine (COLLECT
19K, manufactured by Kikusui Seisakusho, Ltd.) using a 9 mm.phi.
punch to give plain tablets (core tablets, 300 mg per tablet).
TABLE-US-00047 TABLE 43 Composition of plain tablet (core tablet)
containing compound C composition amount (mg) 1) compound C 1.159
2) mannitol 241.041 3) crystalline cellulose 30 4)
hydroxypropylcellulose 9 5) tartaric acid 0.8 6) croscarmellose
sodium 15 7) magnesium stearate 3 total 300.0
Example 42
Sample 48
[0802] The plain tablets (core tablets) obtained in Example 41
(sample 47, 200.23 g) were placed in a film coating machine
(Hicoater mini, manufactured by Freund Corporation), and
film-coated tablets (about 312 mg per tablet) were obtained while
spraying a film coating solution (101.7 g) having the composition
ratio shown in Table 42. The obtained film-coated tablet was placed
in a glass bottle, tightly sealed and preserved at 40.degree. C.,
75% RH for 1 month.
Example 43
Sample 49
[0803] A plain tablet (core tablet) containing compound C was
produced as follows at the composition ratio shown in Table 44.
[0804] That is, compound C (6.954 g), mannitol (477.4 g) and
crystalline cellulose (60 g) were placed in a fluidized bed dryer
granulator (LAB-1, manufactured by POWREX CORPORATION), preheated
and mixed. A granulated powder was obtained while spraying an
aqueous solution (300.0 g) of tartaric acid (1.60 g) and
hydroxypropylcellulose (18.0 g). The obtained granulated powder was
passed through a 16M (1000 .mu.m) sieve to give a sized powder. The
sized powder (376.0 g), croscarmellose sodium (20.00 g) and
magnesium stearate (4.00 g) were added, and mixed to give a mixed
powder. The mixed powder was tableted by a rotary tableting machine
(COLLECT 19K, manufactured by Kikusui Seisakusho, Ltd.) using a 6
mm.phi. punch to give plain tablets (core tablets, 100 mg per
tablet).
TABLE-US-00048 TABLE 44 Composition of plain tablet (core tablet)
containing compound C composition amount (mg) 1) compound C 1.159
2) mannitol 79.5743 3) crystalline cellulose 30 4)
hydroxypropylcellulose 3 5) tartaric acid 0.2667 6) croscarmellose
sodium 5 7) magnesium stearate 1 total 100.0
Example 44
Sample 5
[0805] The plain tablets (core tablets) obtained in Example 43
(sample 49, 280.03 g) were placed in a film coating machine
(Hicoater mini, manufactured by Freund Corporation), and
film-coated tablets (about 104 mg per tablet) were obtained while
spraying a film coating solution (115.4 g) having the composition
ratio shown in Table 42. The obtained film-coated tablet was placed
in a glass bottle, tightly sealed and preserved at 40.degree. C.,
75% RH for 1 month. The film-coated tablet was placed in a glass
bottle, and preserved in an open bottle at 40.degree. C., 75% RH
for 1 month.
Experimental Example 1
Decomposed Product Measurement Method
[0806] The film-coated tablets of Comparative Example 2 and
Examples 16-30 and the core tablets of Examples 1-3 were examined
for production of decomposed product U-6 of compound A (relative
retention time: about 0.70) and other decomposed products before
preservation (initial) and after preservation.
[0807] The decomposed product was measured by extracting the
tablets with 0.05 mol/L phosphoric acid/MeCN mixture (19:1) or
water/MeCN mixture (19:1) by HPLC. The HPLC test conditions are as
follows.
[0808] detector: ultraviolet absorption spectrophotometer
(measurement wavelength: 230 nm)
[0809] column: CAPCELL PAK C18 MGII, 3 .mu.m, 4.6 mm i.d..times.150
mm (manufactured by Shiseido Co., Ltd.)
[0810] column temperature: fixed temperature around 25.degree.
C.
[0811] mobile phase A: 0.05 mol/L sodium phosphate buffer (pH
6.0)/acetonitrile mixture (95:5)
[0812] mobile phase B: 0.05 mol/L sodium phosphate buffer (pH
6.0)/acetonitrile mixture (40:60)
[0813] mobile phase delivery: density gradient was controlled by
changing mixing ratio of mobile phase A and mobile phase B as
follows.
TABLE-US-00049 TABLE 45 time (min) after mobile phase A mobile
phase B injection (%) (%) 0 100 0 10 80 20 60 70 30 110 0 100 110.1
100 0 120 100 0 measurement range of peak area: 110 min
Experiment Results 1
[0814] The decomposed products before preservation and after
preservation at 60.degree. C. for 2 weeks were measured, and the
results of total decomposed product and U-6 that remarkably
increased in the absence of organic acid are shown in Table 46.
TABLE-US-00050 TABLE 46 decomposed product after preservation at
60.degree. C. for 2 weeks core tablet organic before preservation
after preservation or film- compound A acid total decomposed total
decomposed coated concentra- concentra- decomposed product U-6
decomposed product U-6 sample tablet tion (%) tion (%) preservation
state product (%) (%) product (%) (%) sample 2 film-coated 0.4 0
closed glass bottle 0.68 0.31 2.00 1.48 (comparison tablet control)
sample 3 core tablet 0.4 0.3 closed glass bottle 0.92 0.27 1.20
0.55 sample 4 core tablet 0.4 10 closed glass bottle 0.90 0.26 1.12
0.48 sample 5 core tablet 0.4 10 closed glass bottle 0.91 0.27 1.16
0.48 sample 18 film-coated 0.4 0.3 closed glass bottle 0.88 0.26
1.15 0.54 tablet sample 19 film-coated 0.4 10 closed glass bottle
0.89 0.26 1.11 0.49 tablet sample 20 film-coated 0.4 10 closed
glass bottle 0.88 0.26 1.12 0.48 tablet sample 21 film-coated 0.4
0.3 closed glass bottle 0.91 0.28 1.90 1.28 tablet sample 22
film-coated 0.4 0.5 closed glass bottle 0.95 0.28 1.65 1.04 tablet
sample 23 film-coated 0.4 1.0 closed glass bottle 0.86 0.26 1.41
0.85 tablet sample 24 film-coated 0.4 2.3 closed glass bottle 0.86
0.26 1.07 0.30 tablet sample 25 film-coated 3.3 2.5 closed glass
bottle 0.76 0.25 0.80 0.30 tablet sample 26 film-coated 13.4 2.5
closed glass bottle 0.74 0.25 0.77 0.27 tablet sample 27
film-coated 26.7 2.5 closed glass bottle 0.60 0.20 0.61 0.20 tablet
sample 28 film-coated 26.7 10 closed glass bottle 0.61 0.20 0.61
0.20 tablet
Experiment Results 2
[0815] The decomposed products before preservation and after
preservation at 40.degree. C., 75% RH for 2 months were measured,
and the results of total decomposed product and U-6 that remarkably
increased in the absence of organic acid are shown in Table 47.
TABLE-US-00051 TABLE 47 decomposed product after preservation at
40.degree. C., 75% RH for 2 months organic before preservation
after preservation core tablet compound A acid total decomposed
total decomposed or film-coated concentra- concentra- decomposed
product U-6 decomposed product U-6 sample tablet tion (%) tion (%)
preservation state product (%) (%) product (%) (%) sample 2
film-coated 0.4 0 closed glass bottle 0.68 0.31 1.91 1.38
(comparison tablet control) sample 18 film-coated 0.4 0.3 closed
glass bottle 0.88 0.26 1.11 0.47 tablet open glass bottle 0.88 0.26
0.99 0.39 sample 19 film-coated 0.4 10.0 closed glass bottle 0.89
0.26 1.03 0.44 tablet open glass bottle 0.89 0.26 1.38 0.37 sample
20 film-coated 0.4 10.0 closed glass bottle 0.88 0.26 1.08 0.47
tablet open glass bottle 0.88 0.26 1.09 0.37 sample 21 film-coated
0.4 0.3 closed glass bottle 0.91 0.28 1.90 1.08 tablet open glass
bottle 0.91 0.28 1.17 0.52 sample 22 film-coated 0.4 0.5 closed
glass bottle 0.95 0.28 1.47 0.87 tablet open glass bottle 0.95 0.28
1.00 0.46 sample 23 film-coated 0.4 1.0 closed glass bottle 0.86
0.26 1.45 0.74 tablet open glass bottle 0.86 0.26 0.97 0.40 sample
24 film-coated 0.4 2.3 closed glass bottle 0.86 0.26 1.01 0.43
tablet open glass bottle 0.86 0.26 1.08 0.35 sample 25 film-coated
3.3 2.5 closed glass bottle 0.76 0.25 0.95 0.32 tablet open glass
bottle 0.76 0.25 0.81 0.30 sample 26 film-coated 13.4 2.5 closed
glass bottle 0.74 0.25 0.84 0.30 tablet open glass bottle 0.74 0.25
0.80 0.28 sample 27 film-coated 26.7 2.5 closed glass bottle 0.60
0.20 0.78 0.30 tablet open glass bottle 0.60 0.20 0.74 0.28 sample
28 film-coated 26.7 2.5 closed glass bottle 0.61 0.20 0.87 0.29
tablet open glass bottle 0.61 0.20 1.23 0.39 sample 29 film-coated
1.5 2.5 closed glass bottle 0.74 0.31 0.98 0.45 tablet open glass
bottle 0.74 0.31 0.75 0.35 sample 30 film-coated 3.0 2.5 closed
glass bottle 0.71 0.29 0.81 0.34 tablet open glass bottle 0.71 0.29
0.70 0.30 sample 31 film-coated 6.1 2.5 closed glass bottle 0.79
0.29 0.83 0.32 tablet open glass bottle 0.79 0.29 0.75 0.29 sample
32 film-coated 12.1 2.5 closed glass bottle 0.68 0.27 0.72 0.29
tablet open glass bottle 0.68 0.27 0.74 0.27
Experiment Results 3
[0816] The decomposed products before preservation and after
preservation at 40.degree. C., 75% RH for 6 months were measured,
and the results of total decomposed product and U-6 that remarkably
increased in the absence of organic acid are shown in Table 48.
TABLE-US-00052 TABLE 48 decomposed product after preservation at
40.degree. C., 75% RH for 6 months organic before preservation
after preservation core tablet compound A acid total decomposed
total decomposed or film-coated concentra- concentra- decomposed
product U-6 decomposed product U-6 sample tablet tion (%) tion (%)
preservation state product (%) (%) product (%) (%) sample 2
film-coated 0.4 0 closed glass bottle 0.68 0.31 2.80 2.07
(comparison tablet open glass bottle 0.68 0.31 3.19 2.1 control)
sample 18 film-coated 0.4 0.3 closed glass bottle 0.88 0.26 1.45
0.65 tablet open glass bottle 0.88 0.26 1.18 0.50 sample 19
film-coated 0.4 10.0 closed glass bottle 0.89 0.26 1.03 0.54 tablet
open glass bottle 0.89 0.26 1.49 0.46 sample 20 film-coated 0.4
10.0 closed glass bottle 0.88 0.26 1.21 0.58 tablet open glass
bottle 0.88 0.26 1.77 0.48 sampel 21 film-coated 0.4 0.3 closed
glass bottle 0.91 0.28 2.66 1.77 tablet open glass bottle 0.91 0.28
1.59 0.87 sample 22 film-coated 0.4 0.5 closed glass bottle 0.95
0.28 2.32 1.45 tablet open glass bottle 0.95 0.28 1.50 0.66 sample
23 film-coated 0.4 1.0 closed glass bottle 0.86 0.26 1.92 1.12
tablet open glass bottle 0.86 0.26 1.16 0.58 sample 24 film-coated
0.4 2.3 closed glass bottle 0.86 0.26 1.29 0.65 tablet open glass
bottle 0.86 0.26 1.15 0.49
[0817] By the addition of an organic acid, an increase in the
decomposed product U-6 was suppressed irrespective of the
preservation conditions and preservation state. Particularly, an
increase in the decomposed product U-6, which strikingly increases
in the absence of an organic acid, was remarkably suppressed.
[0818] U-6 was remarkably suppressed when fumaric acid was added
during granulation by any of solution/dispersion addition including
dissolving or dispersing fumaric acid in water and spraying the
solution or dispersion, powder addition including addition of
organic acid as a powder, and a combination of solution/dispersion
addition and powder addition.
[0819] An increase in the decomposed product was suppressed as the
concentration of the organic acid in the tablet became higher. When
the organic acid concentration was 1% or above, an increase in U-6
was strikingly suppressed. When it was 2% or above, the suppressive
effect was still more remarkable.
[0820] By the addition of an organic acid, a remarkable decomposed
product suppressive effect was observed in both a plain tablet
(core tablet) and a film-coated tablet, and the plain tablet (core
tablet) and the film-coated tablet showed no difference in the
amount of increase.
[0821] By the addition of an organic acid, a decomposed product
suppressive effect was observed irrespective of the concentration
of compound A.
Experimental Example 2
Measurement Method of Decomposed Product
[0822] The film-coated tablets of Comparative Example 4 were
examined for the production of compound B decomposed product U-1
(relative retention time: about 0.75) and other decomposed
products, before preservation (initial) and after preservation
(sample 34). The decomposed product was measured by extracting the
tablets with water/MeCN mixture (1:3) by HPLC. The HPLC test
conditions are as follows.
[0823] detector: ultraviolet absorption spectrophotometer
(measurement wavelength: 230 nm)
[0824] column: CAPCELL PAK C18 MGII, 3 .mu.m, 4.6 mm i.d..times.100
mm (manufactured by Shiseido Co., Ltd.)
[0825] column temperature: fixed temperature around 40.degree.
C.
[0826] mobile phase A: 0.05 mol/L sodium phosphate buffer (pH
7.0)/acetonitrile mixture (9:1)
[0827] mobile phase B: 0.05 mol/L sodium phosphate buffer (pH
7.0)/acetonitrile mixture (2:3)
[0828] mobile phase delivery: density gradient was controlled by
changing mixing ratio of mobile phase A and mobile phase B as
follows.
TABLE-US-00053 TABLE 49 time (min) after injection mobile phase A
(%) mobile phase B (%) 0 100 0 100 0 100 100.1 100 0 110 100 0
measurement range of peak area: 100 min
Experimental Example 3
Measurement Method of Decomposed Product
[0829] The film-coated tablets of Examples 32, 34, 36, 38 and 40
were examined for the production of compound B decomposed product
U-1 (relative retention time: about 0.75) and other decomposed
products, before preservation (initial) and after preservation. The
decomposed product was measured by extracting the tablets with
water/MeCN mixture (1:3) by HPLC. The HPLC test conditions are as
follows.
[0830] detector: ultraviolet absorption spectrophotometer
(measurement wavelength: 230 nm)
[0831] column: CAPCELL PAK C18 MGII, 3 .mu.m, 4.6 mm i.d..times.100
mm (manufactured by Shiseido Co., Ltd.)
[0832] column temperature: fixed temperature around 40.degree.
C.
[0833] mobile phase A: 0.03 mol/L sodium phosphate buffer (pH
7.0)/acetonitrile mixture (9:1)
[0834] mobile phase B: 0.03 mol/L sodium phosphate buffer (pH
7.0)/acetonitrile mixture (2:3)
[0835] mobile phase delivery: density gradient was controlled by
changing mixing ratio of mobile phase A and mobile phase B in the
same manner as in Table 49.
Experiment Results 4
[0836] The decomposed products before preservation and after
preservation in closed bottle or open bottle at 40.degree. C., 75%
RH for 2 months were measured, and the results of total decomposed
product and U-1 that remarkably increased in the absence of organic
acid are shown in Table 50.
TABLE-US-00054 TABLE 50 decomposed product after preservation at
40.degree. C., 75% RH for 2 months organic before preservation
after preservation core tablet compound B acid total decomposed
total decomposed or film-coated concentra- concentra- decomposed
product U-1 decomposed product U-1 sample tablet tion (%) tion (%)
preservation state product (%) (%) product (%) (%) sample 34
film-coated 0.4 0 closed glass bottle 2.45 0.86 5.06 3.14
(comparison tablet open glass bottle control) sample 36 film-coated
0.4 2.3 closed glass bottle 2.25 0.79 4.56 2.01 tablet open glass
bottle 2.36 0.87 3.14 1.36 sample 38 film-coated 0.9 0.2 closed
glass bottle 1.86 0.71 2.75 1.22 tablet open glass bottle 1.86 0.71
2.37 1.10 sample 40 film-coated 0.4 2.3 closed glass bottle 2.33
0.81 5.18 2.11 tablet open glass bottle 2.33 0.81 3.34 1.27 sample
42 film-coated 4.5 2.3 closed glass bottle 2.23 0.78 2.60 0.92
tablet open glass bottle 2.23 0.78 2.18 0.81 sample 44 film-coated
17.9 2.3 closed glass bottle 2.25 0.80 2.40 0.90 tablet open glass
bottle 2.25 0.80 2.21 0.79
[0837] By the addition of an organic acid, irrespective of the
preservation conditions and preservation state, an increase in the
decomposed product U-1 was suppressed. Particularly, an increase in
the decomposed product U-1, which strikingly increases in the
absence of an organic acid, was remarkably suppressed.
[0838] U-1 was remarkably suppressed when fumaric acid was added
during granulation by any of solution/dispersion addition including
dissolving or dispersing fumaric acid in water and spraying the
solution or dispersion, powder addition including addition of
organic acid as a powder, and a combination of solution/dispersion
addition and powder addition.
[0839] By the addition of an organic acid, a decomposed product
suppressive effect was observed irrespective of the concentration
of compound B.
Experimental Example 4
Measurement Method of Decomposed Product
[0840] The film-coated tablets of Comparative Example 6 and
Examples 42 and 44 were examined for production of compound C
decomposed product, before preservation (initial) and after
preservation. The decomposed product U-2 (relative retention time:
about 0.6), decomposed product U-3 (relative retention time: about
0.8) and other decomposed products were measured by extracting the
tablets with 0.02 mol/L phosphate buffer (pH 7.0)/acetonitrile
mixture (2:1) by HPLC. The HPLC test conditions are as follows.
[0841] detector: ultraviolet absorption spectrophotometer
(measurement wavelength: 230 nm)
[0842] column: Zorbax Eclipse XDB-C18, 5 .mu.m, 4.6 mm
i.d..times.150 mm (manufactured by Agilent)
[0843] column temperature: fixed temperature around 25.degree.
C.
[0844] mobile phase A: 0.02 mol/L phosphate buffer (pH
7.0)/acetonitrile mixture (19:1)
[0845] mobile phase B: acetonitrile/0.02 mol/L phosphate buffer (pH
7.0) mixture (3:2)
[0846] mobile phase delivery: density gradient was controlled by
changing mixing ratio of mobile phase A and mobile phase B as
follows.
TABLE-US-00055 TABLE 51 time (min) after injection mobile phase A
(%) mobile phase B (%) 0 100 0 5 100 0 80 0 100 81 100 0 90 100 0
measurement range of peak area: 80 min
Experiment Results 5
[0847] The decomposed products were measured before preservation
and after preservation in a closed glass bottle at 40.degree. C.,
75% RH for 1 month, and the total decomposed product and the
amounts of U-2 and U-3 that remarkably increased in the absence of
organic acid are shown in Table 52.
TABLE-US-00056 TABLE 52 decomposed product after preservation at
40.degree. C., 75% RH for 1 month before preservation after
preservation compound organic acid total decomposed decomposed
total decomposed decomposed concentra- concentra- preservation
decomposed product U-2 product U-3 decomposed product U-2 product
U-3 sample tion (%) tion (%) state product (%) (%) (%) product (%)
(%) (%) sample 46 0.4 0 closed glass bottle 3.23 0.54 1.55 12.47
2.99 7.50 (comparison open glass bottle 3.23 0.54 1.55 7.68 2.38
3.76 control) sample 48 0.4 0.3 closed glass bottle 0.87 0.10 0.10
2.39 0.31 0.98 sample 50 1.2 0.3 closed glass bottle 1.13 0.11 0.13
3.89 0.38 1.62 open glass bottle 1.13 0.11 0.13 4.32 0.63 2.29
[0848] By the addition of an organic acid, an increase in the
decomposed products U-2 and U-3 was suppressed irrespective of the
preservation conditions and preservation state. Particularly, an
increase in the decomposed products U-2 and U-3 that remarkably
increase in the absence of organic acid was markedly
suppressed.
[0849] By the addition of an organic acid, a decomposed product
suppressive effect was observed irrespective of the concentration
of compound C.
[0850] The solid preparation of the present invention containing a
pharmaceutically active ingredient, titanium oxide, a plasticizer
and a chain organic acid, which is the second invention of the
present invention, was evaluated for the stability during light
irradiation. The results are now explained by Examples 45-71 and
Comparative Examples 7-9.
Example 45
Sample 51
[0851] A plain tablet (core tablet) containing
1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylme-
thanamine fumarate (hereinafter to be referred to as compound A)
was produced as follows at the composition ratio shown in Table
53.
[0852] That is, compound A (24.340 g), mannitol (4350.2 g) and
crystalline cellulose (540.1 g) were placed in a fluidized bed
dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and
the mixture was preheated and mixed. The mixture was granulated
while spraying an aqueous solution (2700.0 g) of
hydroxypropylcellulose (162.1 g) to give a granulated powder. The
obtained granulated powder (4568.1 g) was passed through a
powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to
give a sized powder (Batch 1).
[0853] Compound A (24.341 g), mannitol (4350.0 g) and crystalline
cellulose (540.0 g) were placed in a fluidized bed dryer granulator
(FD-5S, manufactured by POWREX CORPORATION), and the mixture was
preheated and mixed. The mixture was granulated while spraying an
aqueous solution (2700.0 g) of hydroxypropylcellulose (162.0 g) to
give a granulated powder. The obtained granulated powder (4568.1 g)
was passed through a powermill (P-3, manufactured by Showa Kagaku
Kikai Kosakusho) to give a sized powder (Batch 2).
[0854] The sized powders (Batch 1 and Batch 2, 8460.0 g),
croscarmellose sodium (450.0 g) and magnesium stearate (90.007 g)
were placed in a tumbler mixer (TM-60S, manufactured by Showa
Kagaku Kikai Kosakusho), and mixed to give a mixed powder. The
mixed powder was tableted by a rotary tableting machine (AQUARIUS
08242L2JI, manufactured by Kikusui Seisakusho, Ltd.) using a 9
mm.phi. punch to give plain tablets (core tablets, 300 mg per
tablet).
TABLE-US-00057 TABLE 53 composition of plain tablet (core tablet)
containing compound A (sample 51) composition amount (mg) 1)
compound A* 1.336 2) mannitol 241.664 3) crystalline cellulose 30
4) hydroxypropylcellulose 9 5) croscarmellose sodium 15 6)
magnesium stearate 3 total 300.0 *Where necessary, the content was
amended using mannitol as an adjustment component.
Example 46
Sample 52
[0855] The plain tablets (core tablets) obtained in Example 45
(sample 51, 30.0 g) were placed in a film coating machine (DRC-200,
manufactured by POWREX CORPORATION), and film-coated tablets (about
312 mg per tablet) were obtained while spraying a film coating
solution (65.9 g) having the composition ratio shown in Table 54.
The obtained film-coated tablets were arranged on a plastic petri
dish (45 sample cup, manufactured by Shinwa Kagaku), and exposed to
xenon light (1200000 Lux/hr) by a xenon fade meter (SX75,
manufactured by Suga Test Instruments).
TABLE-US-00058 TABLE 54 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 8.8 2) macrogol
6000 2 3) titanium oxide 1 4) diiron trioxide 0.2 5) purified water
108 total 120.0
Example 47
Sample 53
[0856] The plain tablets (core tablets) obtained in Example 45
(sample 51, 30.0 g) were placed in a film coating machine (DRC-200,
manufactured by POWREX CORPORATION), and film-coated tablets (about
312 mg per tablet) were obtained while spraying a film coating
solution (66.2 g) having the composition ratio shown in Table 55.
The obtained film-coated tablets were arranged on a plastic petri
dish (45 sample cup, manufactured by Shinwa Kagaku), and samples
shielded with aluminum foil and non-shielded samples were exposed
to xenon light (1200000 Lux/hr).
TABLE-US-00059 TABLE 55 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 8.595 2) macrogol
6000 1.953 3) titanium oxide 0.977 4) diiron trioxide 0.195 5)
fumaric acid 0.28 6) purified water 108 total 120.0
Example 48
Sample 54
[0857] The plain tablets (core tablets) obtained in Example 45
(sample 51, 30.0 g) were placed in a film coating machine (DRC-200,
manufactured by POWREX CORPORATION), and film-coated tablets (about
312 mg per tablet) were obtained while spraying a film coating
solution (75.1 g) having the composition ratio shown in Table 56.
The obtained film-coated tablets were arranged on a plastic petri
dish (45 sample cup, manufactured by Shinwa Kagaku), and exposed to
xenon light (1200000 Lux/hr) by a xenon fade meter (SX75,
manufactured by Suga Test Instruments).
TABLE-US-00060 TABLE 56 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 8.389 2) macrogol
6000 1.907 3) titanium oxide 0.953 4) diiron trioxide 0.191 5)
fumaric acid 0.56 6) purified water 108 total 120.0
Example 49
Sample 55
[0858] A plain tablet (core tablet) containing compound A was
produced as follows at the composition ratio shown in Table 57.
[0859] That is, compound A (2.4074 g), mannitol (432.3 g),
crystalline cellulose (54.0 g) and fumaric acid (2.70 g) were
placed in a fluidized bed dryer granulator (LAB-1, manufactured by
POWREX CORPORATION), and the mixture was preheated and mixed. The
mixture was granulated while spraying an aqueous solution (270.0 g)
of hydroxypropylcellulose (16.2 g) to give a granulated powder. The
obtained granulated powder was passed through a 16M (1000 .mu.m)
sieve to give a sized powder. Croscarmellose sodium (22.50 g) and
magnesium stearate (4.5011 g) were added to the sized powder (423.0
g), and mixed to give a mixed powder. The mixed powder was tableted
by a rotary tableting machine (COLLECT 19K, manufactured by Kikusui
Seisakusho, Ltd.) using a 9 mm.phi. punch to give plain tablets
(core tablets, 300 mg per tablet).
TABLE-US-00061 TABLE 57 composition of plain tablet (core tablet)
containing compound A (sample 55) composition amount (mg) 1)
compound A* 1.336 2) mannitol 240.164 3) crystalline cellulose 30
4) hydroxypropylcellulose 9 5) fumaric acid 1.5 6) croscarmellose
sodium 15 7) magnesium stearate 3 total 300.0 *Where necessary, the
content was amended using mannitol as an adjustment component.
Example 50
Sample 56
[0860] A plain tablet (core tablet) containing compound A was
produced as follows at the composition ratio shown in Table 58.
[0861] That is, compound A (2.4080 g), mannitol (429.6 g),
crystalline cellulose (54.0 g) and fumaric acid (5.40 g) were
placed in a fluidized bed dryer granulator (LAB-1, manufactured by
POWREX CORPORATION), and the mixture was preheated and mixed. The
mixture was granulated while spraying an aqueous solution (270.0 g)
of hydroxypropylcellulose (16.2 g) to give a granulated powder. The
obtained granulated powder was passed through a 16M (1000 .mu.m)
sieve to give a sized powder. Croscarmellose sodium (22.50 g) and
magnesium stearate (4.5012 g) were added to the sized powder (423.0
g), and mixed to give a mixed powder. The mixed powder was tableted
by a rotary tableting machine (COLLECT 19K, manufactured by Kikusui
Seisakusho, Ltd.) using a 9 mm.phi. punch to give plain tablets
(core tablets, 300 mg per tablet).
TABLE-US-00062 TABLE 58 composition of plain tablet (core tablet)
containing compound A (sample 56) composition amount (mg) 1)
compound A* 1.336 2) mannitol 238.664 3) crystalline cellulose 30
4) hydroxypropylcellulose 9 5) fumaric acid 3 6) croscarmellose
sodium 15 7) magnesium stearate 3 total 300.0 *Where necessary, the
content was amended using mannitol as an adjustment component.
Example 51
Sample 57
[0862] A plain tablet (core tablet) containing compound A was
produced as follows at the composition ratio shown in Table 59.
[0863] That is, compound A (2.4095 g), mannitol (422.4 g),
crystalline cellulose (54.0 g) and fumaric acid (12.60 g) were
placed in a fluidized bed dryer granulator (LAB-1, manufactured by
POWREX CORPORATION), and the mixture was preheated and mixed. The
mixture was granulated while spraying an aqueous solution (270.0 g)
of hydroxypropylcellulose (16.2 g) to give a granulated powder. The
obtained granulated powder was passed through a 16M (1000 .mu.m)
sieve to give a sized powder. Croscarmellose sodium (22.50 g) and
magnesium stearate (4.5017 g) were added to the sized powder (423.0
g), and mixed to give a mixed powder. The mixed powder was tableted
by a rotary tableting machine (COLLECT 19K, manufactured by Kikusui
Seisakusho, Ltd.) using a 9 mm.phi. punch to give plain tablets
(core tablets, 300 mg per tablet).
TABLE-US-00063 TABLE 59 composition of plain tablet (core tablet)
containing compound A (sample 57) composition amount (mg) 1)
compound A* 1.336 2) mannitol 234.664 3) crystalline cellulose 30
4) hydroxypropylcellulose 9 5) fumaric acid 7 6) croscarmellose
sodium 15 7) magnesium stearate 3 total 300.0 *Where necessary, the
content was amended using mannitol as an adjustment component.
Example 52
Sample 58
[0864] The plain tablets (core tablets) obtained in Example 49
(sample 55, 100.0 g) were placed in a film coating machine
(DRC-200, manufactured by POWREX CORPORATION), and film-coated
tablets (about 312 mg per tablet) were obtained while spraying a
film coating solution (49.2 g) having the composition ratio shown
in Table 60. The obtained film-coated tablets were arranged on a
plastic petri dish (45 sample cup, manufactured by Shinwa Kagaku),
and exposed to xenon light (1200000 Lux/hr) by a xenon fade meter
(SX75, manufactured by Suga Test Instruments).
TABLE-US-00064 TABLE 60 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 8.8 2) macrogol
6000 2 3) titanium oxide 1 4) diiron trioxide 0.2 5) purified water
108 total 120.0
Example 53
Sample 59
[0865] The plain tablets (core tablets) obtained in Example 50
(sample 56, 100.0 g) were placed in a film coating machine
(DRC-200, manufactured by POWREX CORPORATION), and film-coated
tablets (about 312 mg per tablet) were obtained while spraying a
film coating solution (61.4 g) having the composition ratio shown
in Table 61. The obtained film-coated tablets were arranged on a
plastic petri dish (45 sample cup, manufactured by Shinwa Kagaku),
and exposed to xenon light (1200000 Lux/hr) by a xenon fade meter
(SX75, manufactured by Suga Test Instruments).
TABLE-US-00065 TABLE 61 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 8.8 2) macrogol
6000 2 3) titanium oxide 1 4) diiron trioxide 0.2 5) purified water
108 total 120.0
Example 54
Sample 60
[0866] The plain tablets (core tablets) obtained in Example 51
(sample 57, 100.0 g) were placed in a film coating machine
(DRC-200, manufactured by POWREX CORPORATION), and film-coated
tablets (about 312 mg per tablet) were obtained while spraying a
film coating solution (59.5 g) having the composition ratio shown
in Table 62. The obtained film-coated tablets were arranged on a
plastic petri dish (45 sample cup, manufactured by Shinwa Kagaku),
and exposed to xenon light (1200000 Lux/hr) by a xenon fade meter
(SX75, manufactured by Suga Test Instruments).
TABLE-US-00066 TABLE 62 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 8.8 2) macrogol
6000 2 3) titanium oxide 1 4) diiron trioxide 0.2 5) purified water
108 total 120.0
Comparative Example 7
Sample 61
[0867] A plain tablet (core tablet) containing compound A was
produced as follows at the composition ratio shown in Table 63.
[0868] That is, compound A (24.491 g), mannitol (4350.0 g) and
crystalline cellulose (540.0 g) were placed in a fluidized bed
dryer granulator (FD-5S, manufactured by POWREX CORPORATION), and
the mixture was preheated and mixed. The mixture was granulated
while spraying an aqueous solution (2700.0 g) of
hydroxypropylcellulose (162.0 g) to give a granulated powder. The
obtained granulated powder (4568.0 g) was passed through a
powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to
give a sized powder. The sized powder (4230.0 g), croscarmellose
sodium (225.0 g) and magnesium stearate (45.007 g) were placed in a
tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai
Kosakusho), and mixed to give a mixed powder. The mixed powder was
tableted by a rotary tableting machine (COLLECT 12HUK, manufactured
by Kikusui Seisakusho, Ltd.) using a 9 mm.phi. punch to give plain
tablets (core tablets, 300 mg per tablet).
TABLE-US-00067 TABLE 63 composition of plain tablet (core tablet)
containing compound A (sample 61) composition amount (mg) 1)
compound A* 1.336 2) mannitol 241.664 3) crystalline cellulose 30
4) hydroxypropylcellulose 9 5) croscarmellose sodium 15 6)
magnesium stearate 3 total 300.0 *Where necessary, the content was
amended using mannitol as an adjustment component.
Comparative Example 8
Sample 62
[0869] The plain tablets (core tablets) obtained in Comparative
Example 7 (sample 61, 3300.0 g) were placed in a film coating
machine (DRC-500, manufactured by POWREX CORPORATION), and
film-coated tablets (about 312 mg per tablet) were obtained while
spraying a film coating solution (1372.0 g) having the composition
ratio shown in Table 64. The obtained film-coated tablets were
arranged on a plastic petri dish (45 sample cup, manufactured by
Shinwa Kagaku), and exposed to xenon light (1200000 Lux/hr) by a
xenon fade meter (SX75, manufactured by Suga Test Instruments).
TABLE-US-00068 TABLE 64 Composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 10.8 2) titanium
oxide 1 3) diiron trioxide 0.2 4) purified water 108 total
120.0
Example 55
Sample 63
[0870] A plain tablet (core tablet) containing compound A is
produced as follows at the composition ratio shown in Table 65.
[0871] That is, compound A (641.28 g), mannitol (3503.52 g),
fumaric acid (132.0 g) and crystalline cellulose (528.0 g) are
placed in a fluidized bed dryer granulator (FD-5S, manufactured by
POWREX CORPORATION), and the mixture is preheated and mixed. The
mixture is granulated while spraying an aqueous solution (2640.0 g)
of hydroxypropylcellulose (158.4 g) to give a granulated powder.
The obtained granulated powder (4653.0 g) is passed through a
powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to
give a sized powder. The sized powder (4342.8 g), croscarmellose
sodium (231.0 g) and magnesium stearate (46.2 g) are placed in a
tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai
Kosakusho), and mixed to give a mixed powder. The mixed powder is
tableted by a rotary tableting machine (COLLECT 12HUK, manufactured
by Kikusui Seisakusho, Ltd.) using a 6.5 mm.phi. punch to give
plain tablets (core tablets, 110 mg per tablet). The obtained plain
tablets (core tablets, 3300.0 g) are placed in a film coating
machine (DRC-500, manufactured by POWREX CORPORATION), and
film-coated tablets (about 114.4 mg per tablet) are obtained while
spraying a film coating solution (1380.0 g) having the composition
ratio shown in Table 66.
TABLE-US-00069 TABLE 65 composition of plain tablet (core tablet)
containing compound A composition amount (mg) 1) compound A 13.36
2) mannitol 72.99 3) crystalline cellulose 11 4)
hydroxypropylcellulose 3.3 5) fumaric acid 2.75 6) croscarmellose
sodium 5.5 7) magnesium stearate 1.1 total 110.0
TABLE-US-00070 TABLE 66 composition of aqueous film coating
solution composition amount (mg) 1) hypromellose 6.6 2) macrogol
6000 1.5 3) titanium oxide 0.75 4) yellow ferric oxide 0.075 5)
diiron trioxide 0.075 6) purified water 81 total 90.0
Example 56
Sample 64
[0872] A plain tablet (core tablet) containing compound A is
produced as follows at the composition ratio shown in Table 67.
[0873] That is, compound A (641.28 g), mannitol (3503.52 g),
fumaric acid (132.0 g) and crystalline cellulose (528.0 g) are
placed in a fluidized bed dryer granulator (FD-5S, manufactured by
POWREX CORPORATION), and the mixture is preheated and mixed. The
mixture is granulated while spraying an aqueous solution (2640.0 g)
of hydroxypropylcellulose (158.4 g) to give a granulated powder.
The obtained granulated powder (4653.0 g) is passed through a
powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to
give a sized powder. The sized powder (4342.8 g), croscarmellose
sodium (231.0 g) and magnesium stearate (46.2 g) are placed in a
tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai
Kosakusho), and mixed to give a mixed powder. The mixed powder is
tableted by a rotary tableting machine (COLLECT 12HUK, manufactured
by Kikusui Seisakusho, Ltd.) using a 7 mm.phi. punch to give plain
tablets (core tablets, 165 mg per tablet). The obtained plain
tablets (core tablets, 3300.0 g) are placed in a film coating
machine (DRC-500, manufactured by POWREX CORPORATION), and
film-coated tablets (about 171.6 mg per tablet) are obtained while
spraying a film coating solution (1380.0 g) having the composition
ratio shown in Table 66.
TABLE-US-00071 TABLE 67 composition of plain tablet (core tablet)
containing compound A composition amount (mg) 1) compound A 20.04
2) mannitol 109.485 3) crystalline cellulose 16.5 4)
hydroxypropylcellulose 4.95 5) fumaric acid 4.125 6) croscarmellose
sodium 8.25 7) magnesium stearate 1.65 total 165.0
Example 57
Sample 65
[0874] A plain tablet (core tablet) containing compound A is
produced as follows at the composition ratio shown in Table 68.
[0875] That is, compound A (641.28 g), mannitol (3503.52 g),
fumaric acid (132.0 g) and crystalline cellulose (528.0 g) are
placed in a fluidized bed dryer granulator (FD-5S, manufactured by
POWREX CORPORATION), and the mixture is preheated and mixed. The
mixture is granulated while spraying an aqueous solution (2640.0 g)
of hydroxypropylcellulose (158.4 g) to give a granulated powder.
The obtained granulated powder (4653.0 g) is passed through a
powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to
give a sized powder. The sized powder (4342.8 g), croscarmellose
sodium (231.0 g) and magnesium stearate (46.2 g) are placed in a
tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai
Kosakusho), and mixed to give a mixed powder. The mixed powder is
tableted by a rotary tableting machine (COLLECT 12HUK, manufactured
by Kikusui Seisakusho, Ltd.) using a 9.5 mm.phi. punch to give
plain tablets (core tablets, 330 mg per tablet). The obtained plain
tablets (core tablets, 3300.0 g) is placed in a film coating
machine (DRC-500, manufactured by POWREX CORPORATION), and
film-coated tablets (about 343.2 mg per tablet) is obtained while
spraying a film coating solution (1380.0 g) having the composition
ratio shown in Table 66.
TABLE-US-00072 TABLE 68 composition of plain tablet (core tablet)
containing compound A composition amount (mg) 1) compound A 40.08
2) mannitol 218.97 3) crystalline cellulose 33 4)
hydroxypropylcellulose 9.9 5) fumaric acid 8.25 6) croscarmellose
sodium 16.5 7) magnesium stearate 3.3 total 330.0
Example 58
Sample 66
[0876] A plain tablet (core tablet) containing compound A is
produced as follows at the composition ratio shown in Table 69.
[0877] That is, compound A (641.28 g), mannitol (3503.52 g),
fumaric acid (132.0 g) and crystalline cellulose (528.0 g) are
placed in a fluidized bed dryer granulator (FD-5S, manufactured by
POWREX CORPORATION), and the mixture is preheated and mixed. The
mixture is granulated while spraying an aqueous solution (2640.0 g)
of hydroxypropylcellulose (158.4 g) to give a granulated powder.
The obtained granulated powder (4653.0 g) is passed through a
powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to
give a sized powder. The sized powder (4342.8 g), croscarmellose
sodium (231.0 g) and magnesium stearate (46.2 g) are placed in a
tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai
Kosakusho), and mixed to give a mixed powder. The mixed powder is
tableted by a rotary tableting machine (COLLECT 12HUK, manufactured
by Kikusui Seisakusho, Ltd.) using a 14.times.8 mm.phi. punch to
give plain tablets (core tablets, 440 mg per tablet). The obtained
plain tablets (core tablets, 3300.0 g) are placed in a film coating
machine (DRC-500, manufactured by POWREX CORPORATION), and
film-coated tablets (about 457.6 mg per tablet) are obtained while
spraying a film coating solution (1380.0 g) having the composition
ratio shown in Table 66.
TABLE-US-00073 TABLE 69 composition of plain tablet (core tablet)
containing compound A composition amount (mg) 1) compound A 53.44
2) mannitol 291.96 3) crystalline cellulose 44 4)
hydroxypropylcellulose 13.2 5) fumaric acid 11 6) croscarmellose
sodium 22 7) magnesium stearate 4.4 total 440
Example 59
Sample 67
[0878] A plain tablet (core tablet) containing compound A is
produced as follows at the composition ratio shown in Table 70.
[0879] That is, compound A (881.76 g), mannitol (3263.04 g),
fumaric acid (132.0 g) and crystalline cellulose (528.0 g) are
placed in a fluidized bed dryer granulator (FD-5S, manufactured by
POWREX CORPORATION), and the mixture is preheated and mixed. The
mixture is granulated while spraying an aqueous solution (2640.0 g)
of hydroxypropylcellulose (158.4 g) to give a granulated powder.
The obtained granulated powder (4653.0 g) is passed through a
powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to
give a sized powder. The sized powder (4342.8 g), croscarmellose
sodium (231.0 g) and magnesium stearate (46.2 g) are placed in a
tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai
Kosakusho), and mixed to give a mixed powder. The mixed powder is
tableted by a rotary tableting machine (COLLECT 12HUK, manufactured
by Kikusui Seisakusho, Ltd.) using a 6.5 mm.phi. punch to give
plain tablets (core tablets, 120 mg per tablet). The obtained plain
tablets (core tablets, 3300.0 g) are placed in a film coating
machine (DRC-500, manufactured by POWREX CORPORATION), and
film-coated tablets (about 124.8 mg per tablet) are obtained while
spraying a film coating solution (1380 g) having the composition
ratio shown in Table 66.
TABLE-US-00074 TABLE 70 composition of plain tablet (core tablet)
containing compound A composition amount (mg) 1) compound A 20.04
2) mannitol 74.16 3) crystalline cellulose 12 4)
hydroxypropylcellulose 3.6 5) fumaric acid 3 6) croscarmellose
sodium 6 7) magnesium stearate 1.2 total 120
Example 60
Sample 68
[0880] A plain tablet (core tablet) containing compound A is
produced as follows at the composition ratio shown in Table 71.
That is, compound A (881.76 g), mannitol (3263.04 g), fumaric acid
(132.0 g) and crystalline cellulose (528.0 g) are placed in a
fluidized bed dryer granulator (FD-5S, manufactured by POWREX
CORPORATION), and the mixture is preheated and mixed. The mixture
is granulated while spraying an aqueous solution (2640.0 g) of
hydroxypropylcellulose (158.4 g) to give a granulated powder. The
obtained granulated powder (4653.0 g) is passed through a powermill
(P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized
powder. The sized powder (4342.8 g), croscarmellose sodium (231.0
g) and magnesium stearate (46.2 g) are placed in a tumbler mixer
(TM-15S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed
to give a mixed powder. The mixed powder is tableted by a rotary
tableting machine (COLLECT 12HUK, manufactured by Kikusui
Seisakusho, Ltd.) using a 7 mm.phi. punch to give plain tablets
(core tablets, 160 mg per tablet). The obtained plain tablets (core
tablets, 3300.0 g) are placed in a film coating machine (DRC-500,
manufactured by POWREX CORPORATION), and film-coated tablets (about
166.4 mg per tablet) are obtained while spraying a film coating
solution (1380 g) having the composition ratio shown in Table
66.
TABLE-US-00075 TABLE 71 composition of plain tablet (core tablet)
containing compound A composition amount (mg) 1) compound A 26.72
2) mannitol 98.88 3) crystalline cellulose 16 4)
hydroxypropylcellulose 4.8 5) fumaric acid 4 6) croscarmellose
sodium 8 7) magnesium stearate 1.6 total 160
Example 61
Sample 69
[0881] A plain tablet (core tablet) containing compound A is
produced as follows at the composition ratio shown in Table 72.
[0882] That is, compound A (881.76 g), mannitol (3263.04 g),
fumaric acid (132.0 g) and crystalline cellulose (528.0 g) are
placed in a fluidized bed dryer granulator (FD-5S, manufactured by
POWREX CORPORATION), and the mixture is preheated and mixed. The
mixture is granulated while spraying an aqueous solution (2640.0 g)
of hydroxypropylcellulose (158.4 g) to give a granulated powder.
The obtained granulated powder (4653.0 g) is passed through a
powermill (P-3, manufactured by Showa Kagaku Kikai Kosakusho) to
give a sized powder. The sized powder (4342.8 g), croscarmellose
sodium (231.0 g) and magnesium stearate (46.2 g) are placed in a
tumbler mixer (TM-15S, manufactured by Showa Kagaku Kikai
Kosakusho), and mixed to give a mixed powder. The mixed powder is
tableted by a rotary tableting machine (COLLECT 12HUK, manufactured
by Kikusui Seisakusho, Ltd.) using a 8 mm.phi. punch to give plain
tablets (core tablets, 240 mg per tablet). The obtained plain
tablets (core tablets, 3300.0 g) are placed in a film coating
machine (DRC-500, manufactured by POWREX CORPORATION), and
film-coated tablets (about 249.6 mg per tablet) are obtained while
spraying a film coating solution (1380 g) having the composition
ratio shown in Table 66.
TABLE-US-00076 TABLE 72 composition of plain tablet (core tablet)
containing compound A composition amount (mg) 1) compound A 40.08
2) mannitol 148.32 3) crystalline cellulose 24 4)
hydroxypropylcellulose 7.2 5) fumaric acid 6 6) croscarmellose
sodium 12 7) magnesium stearate 2.4 total 240
Example 62
Sample 70
[0883] A plain tablet (core tablet) containing compound A is
produced as follows at the composition ratio shown in Table 73.
That is, compound A (881.76 g), mannitol (3263.04 g), fumaric acid
(132.0 g) and crystalline cellulose (528.0 g) are placed in a
fluidized bed dryer granulator (FD-5S, manufactured by POWREX
CORPORATION), and the mixture is preheated and mixed. The mixture
is granulated while spraying an aqueous solution (2640.0 g) of
hydroxypropylcellulose (158.4 g) to give a granulated powder. The
obtained granulated powder (4653.0 g) is passed through a powermill
(P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized
powder. The sized powder (4342.8 g), croscarmellose sodium (231.0
g) and magnesium stearate (46.2 g) are placed in a tumbler mixer
(TM-15S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed
to give a mixed powder. The mixed powder is tableted by a rotary
tableting machine (COLLECT 12HUK, manufactured by Kikusui
Seisakusho, Ltd.) using a 9.5 mm.phi. punch to give plain tablets
(core tablets, 320 mg per tablet). The obtained plain tablets (core
tablets, 3300.0 g) are placed in a film coating machine (DRC-500,
manufactured by POWREX CORPORATION), and film-coated tablets (about
332.8 mg per tablet) are obtained while spraying a film coating
solution (1380 g) having the composition ratio shown in Table
66.
TABLE-US-00077 TABLE 73 composition of plain tablet (core tablet)
containing compound A composition amount (mg) 1) compound A 53.44
2) mannitol 197.76 3) crystalline cellulose 32 4)
hydroxypropylcellulose 9.6 5) fumaric acid 8 6) croscarmellose
sodium 16 7) magnesium stearate 3.2 total 320
Example 63
Sample 71
[0884] A plain tablet (core tablet) containing compound A is
produced as follows at the composition ratio shown in Table 74.
That is, compound A (961.92 g), mannitol (3182.88 g), fumaric acid
(132.0 g) and crystalline cellulose (528.0 g) are placed in a
fluidized bed dryer granulator (FD-5S, manufactured by POWREX
CORPORATION), and the mixture is preheated and mixed. The mixture
is granulated while spraying an aqueous solution (2640.0 g) of
hydroxypropylcellulose (158.4 g) to give a granulated powder. The
obtained granulated powder (4653.0 g) is passed through a powermill
(P-3, manufactured by Showa Kagaku Kikai Kosakusho) to give a sized
powder. The sized powder (4342.8 g), croscarmellose sodium (231.0
g) and magnesium stearate (46.2 g) are placed in a tumbler mixer
(TM-15S, manufactured by Showa Kagaku Kikai Kosakusho), and mixed
to give a mixed powder. The mixed powder is tableted by a rotary
tableting machine (COLLECT 12HUK, manufactured by Kikusui
Seisakusho, Ltd.) using a 8 mm.phi. punch to give plain tablets
(core tablets, 220 mg per tablet). The obtained plain tablets (core
tablets, 3300.0 g) are placed in a film coating machine (DRC-500,
manufactured by POWREX CORPORATION), and film-coated tablets (about
228.8 mg per tablet) are obtained while spraying a film coating
solution (1380 g) having the composition ratio shown in Table
66.
TABLE-US-00078 TABLE 74 composition of plain tablet (core tablet)
containing compound A composition amount (mg) 1) compound A 40.08
2) mannitol 132.62 3) crystalline cellulose 22 4)
hydroxypropylcellulose 6.6 5) fumaric acid 5.5 6) croscarmellose
sodium 11 7) magnesium stearate 2.2 total 220
Example 64
Sample 72
[0885] The plain tablets (core tablets) obtained in Example 12
(sample 14, 3300.0 g) were placed in a film coating machine
(DRC-500, manufactured by POWREX CORPORATION), and film-coated
tablets (about 229 mg per tablet) were obtained while spraying a
film coating solution (1480.9 g) having the composition ratio shown
in Table 29. The obtained film-coated tablets were exposed to xenon
light (1200000 Lux/hr) by a fade meter (SX75, manufactured by Suga
Test Instruments).
Example 65
Sample 73
[0886] The plain tablets (core tablets) obtained in Example 13
(sample 15, 3300.0 g) were placed in a film coating machine
(DRC-500, manufactured by POWREX CORPORATION), and film-coated
tablets (about 229 mg per tablet) were obtained while spraying a
film coating solution (1501.0 g) having the composition ratio shown
in Table 30. The obtained film-coated tablets were exposed to xenon
light (1200000 Lux/hr) by a fade meter (SX75, manufactured by Suga
Test Instruments).
Example 66
Sample 74
[0887] The plain tablets (core tablets) obtained in Example 14
(sample 16, 3300.0 g) were placed in a film coating machine
(DRC-500, manufactured by POWREX CORPORATION), and film-coated
tablets (about 229 mg per tablet) were obtained while spraying a
film coating solution (1514.0 g) having the composition ratio shown
in Table 31. The obtained film-coated tablets were exposed to xenon
light (1200000 Lux/hr) by a fade meter (SX75, manufactured by Suga
Test Instruments).
Example 67
Sample 75
[0888] The plain tablets (core tablets) obtained in Example 15
(sample 17, 3300.0 g) were placed in a film coating machine
(DRC-500, manufactured by POWREX CORPORATION), and film-coated
tablets (about 229 mg per tablet) were obtained while spraying a
film coating solution (1374.0 g) having the composition ratio shown
in Table 32. The obtained film-coated tablets were exposed to xenon
light (1200000 Lux/hr) by a fade meter (SX75, manufactured by Suga
Test Instruments).
Comparative Example 9
Sample 76
[0889] The plain tablets (core tablets) obtained in Comparative
Example 3 (sample 33, 200.0 g) were placed in a film coating
machine (DRC-200, manufactured by POWREX CORPORATION), and
film-coated tablets (about 312 mg per tablet) were obtained while
spraying a film coating solution (96.8 g) having the composition
ratio shown in Table 34. The obtained film-coated tablets were
exposed to xenon light (1200000 Lux/hr) by a fade meter (SX75,
manufactured by Suga Test Instruments).
Example 68
Sample 77
[0890] The plain tablets (core tablets) obtained in Example 31
(sample 35, 3300.0 g) were placed in a film coating machine
(DRC-500, manufactured by POWREX CORPORATION), and film-coated
tablets (about 312 mg per tablet) were obtained while spraying a
film coating solution (1432.0 g) having the composition ratio shown
in Table 34. The obtained film-coated tablets were exposed to xenon
light (1200000 Lux/hr) by a fade meter (SX75, manufactured by Suga
Test Instruments).
Example 69
Sample 78
[0891] The plain tablets (core tablets) obtained in Example 35
(sample 39, 3300.0 g) were placed in a film coating machine
(DRC-500, manufactured by POWREX CORPORATION), and film-coated
tablets (about 156 mg per tablet) were obtained while spraying a
film coating solution (1470.0 g) having the composition ratio shown
in Table 37. The obtained film-coated tablets were exposed to xenon
light (1200000 Lux/hr) by a fade meter (SX75, manufactured by Suga
Test Instruments).
Example 70
Sample 79
[0892] The plain tablets (core tablets) obtained in Example 37
(sample 41, 3300.0 g) were placed in a film coating machine
(DRC-500, manufactured by POWREX CORPORATION), and film-coated
tablets (about 312 mg per tablet) were obtained while spraying a
film coating solution (1425.0 g) having the composition ratio shown
in Table 37. The obtained film-coated tablets were exposed to xenon
light (1200000 Lux/hr) by a fade meter (SX75, manufactured by Suga
Test Instruments).
Example 71
Sample 80
[0893] The plain tablets (core tablets) obtained in Example 39
(sample 43, 3300.0 g) were placed in a film coating machine
(DRC-500, manufactured by POWREX CORPORATION), and film-coated
tablets (about 312 mg per tablet) were obtained while spraying a
film coating solution (1417.2 g) having the composition ratio shown
in Table 37. The obtained film-coated tablets were exposed to xenon
light (1200000 Lux/hr) by a fade meter (SX75, manufactured by Suga
Test Instruments).
Experimental Example 5
Measurement Method of Decomposed Product
[0894] The film-coated tablets of Examples 46-48, Examples 52-54,
Examples 64-67 and Comparative Example 8 were examined for the
production of compound A decomposed product, before xenon light
irradiation and after xenon light irradiation. The decomposed
product U-6 was measured by extracting the tablets with 0.05 mol/L
phosphoric acid/MeCN mixture (19:1) or water/MeCN mixture (19:1) by
HPLC. The HPLC test conditions are as follows.
[0895] detector: ultraviolet absorption spectrophotometer
(measurement wavelength: 230 nm)
[0896] column: CAPCELL PAK C18 MGII, 3 .mu.m, 4.6 mm i.d..times.150
mm (manufactured by Shiseido Co., Ltd.)
[0897] column temperature: fixed temperature around 25.degree.
C.
[0898] mobile phase A: 0.05 mol/L sodium phosphate buffer (pH
6.0)/acetonitrile mixture (95:5)
[0899] mobile phase B: 0.05 mol/L sodium phosphate buffer (pH
6.0)/acetonitrile mixture (40:60)
[0900] mobile phase delivery: density gradient was controlled by
changing mixing ratio of mobile phase A and mobile phase B as
follows.
TABLE-US-00079 TABLE 75 time (min) after mobile mobile phase
injection phase A (%) B (%) 0 100 0 10 80 20 60 70 30 110 0 100
110.1 100 0 120 100 0 measurement range of peak area: 110 min
Experiment Results 6
[0901] The compound A decomposed product U-6 (relative retention
time: about 0.7) and other decomposed products were measured before
xenon light irradiation and after xenon light irradiation, and the
results of the total decomposed products are shown in Table 76.
TABLE-US-00080 TABLE 76 organic acid compound concentration (%)
total decomposed product (%) PEG addition concentra- core tablet
film before xenon after xenon sample to film part tion (%) part
part light irradiation light irradiation sample 52 added 0.4 0 0
0.70 1.59 sample 53 added 0.4 0 2.3 0.71 1.05 sample 54 added 0.4 0
4.7 0.85 0.84 sample 58 added 0.4 0.5 0 0.84 1.15 sample 59 added
0.4 1.0 0 0.85 1.03 sample 60 added 0.4 2.3 0 0.83 0.92 sample 72
added 1.5 2.5 0 0.74 0.76 sample 73 added 3.0 2.5 0 0.71 0.73
sample 74 added 6.1 2.5 0 0.79 0.74 sample 75 added 12.1 2.5 0 0.68
0.70 sample 62 not added 0.4 0 0 1.00 1.12 Comparative Example *
organic acid concentration (%) of core tablet part = (organic acid
mass contained in core tablet part/core tablet mass) .times. 100 *
organic acid concentration (%) of film part = (organic acid mass
contained in film part/film mass) .times. 100 * compound
concentration (%) = (added compound weight/core tablet weight)
.times. 100
[0902] Even when PEG was added to film coating component,
production of a decomposed product after light irradiation was
suppressed by the addition of an organic acid.
[0903] Even when organic acid was added to the core tablet part or
the film part, a decomposed product suppressive effect was
observed. When added to the core tablet part, a remarkable
suppression was observed with 2.3% or above. When added to the film
part, a remarkable suppression was observed with 4.7% or above.
[0904] Even when PEG was added to a film coating component,
stabilization was achieved to a level equal to or higher than the
absence of PEG by the addition of an organic acid.
[0905] Since the production of a decomposed product can be
suppressed by the addition of an organic acid, suppression of
change in the appearance after light irradiation is sufficiently
predicted. Hence, a high quality pharmaceutical composition
superior in light-stability can be provided.
Experimental Example 6
Measurement Method of Decomposed Product
[0906] The film-coated tablet (sample 76) obtained in Comparative
Example 9 was examined for the production of compound B total
decomposed product before xenon light irradiation and after xenon
light irradiation. The decomposed product was measured by
extracting the tablet with water/MeCN mixture (1:3) by HPLC. The
HPLC test conditions are as follows.
[0907] detector: ultraviolet absorption spectrophotometer
(measurement wavelength: 230 nm) column: CAPCELL PAK C18 MGII, 3
.mu.m, 4.6 mm i.d..times.100 mm (manufactured by Shiseido Co.,
Ltd.)
[0908] column temperature: fixed temperature around 40.degree.
C.
[0909] mobile phase A: 0.05 mol/L sodium phosphate buffer (pH
7.0)/acetonitrile mixture (9:1)
[0910] mobile phase B: 0.05 mol/L sodium phosphate buffer (pH
7.0)/acetonitrile mixture (2:3)
[0911] mobile phase delivery: density gradient was controlled by
changing mixing ratio of mobile phase A and mobile phase B as
follows.
TABLE-US-00081 TABLE 77 time (min) after injection mobile phase A
(%) mobile phase B (%) 0 100 0 100 0 100 100.1 100 0 110 100 0
measurement range of peak area: 100 min
Experimental Example 7
Measurement Method of Decomposed Product
[0912] The film-coated tablets obtained Examples 68-71 (samples 77,
78, 79 and 80) were examined for the production of compound B total
decomposed product before xenon light irradiation and after xenon
light irradiation. The decomposed products were measured by
extracting the tablets with water/MeCN mixture (1:3) by HPLC. The
HPLC test conditions are as follows.
[0913] detector: ultraviolet absorption spectrophotometer
(measurement wavelength: 230 nm) column: CAPCELL PAK C18 MGII, 3
.mu.m, 4.6 mm i.d..times.100 mm (manufactured by Shiseido Co.,
Ltd.)
[0914] column temperature: fixed temperature around 40.degree.
C.
[0915] mobile phase A: 0.03 mol/L sodium phosphate buffer (pH
7.0)/acetonitrile mixture (9:1)
[0916] mobile phase B: 0.03 mol/L sodium phosphate buffer (pH
7.0)/acetonitrile mixture (2:3)
[0917] mobile phase delivery: density gradient was controlled by
changing mixing ratio of mobile phase A and mobile phase B as
follows.
TABLE-US-00082 TABLE 78 time (min) after injection mobile phase A
(%) mobile phase B (%) 0 100 0 100 0 100 100.1 100 0 110 100 0
measurement range of peak area: 100 min
Experiment Results 7
[0918] The decomposed products of film-coated tablets were measured
before xenon light irradiation and after xenon light irradiation,
and the results of the total decomposed products are shown in Table
79.
TABLE-US-00083 TABLE 79 decomposed products after xenon light
irradiation organic acid core tablet compound concentration (%)
before preservation after preservation or film- concentra- core
tablet total decomposed total decomposed sample coated tablet tion
(%) part film part product (%) product (%) sample 76 film-coated
0.4 0 0 2.45 2.87 (comparison tablet control) sample 77 film-coated
0.4 2.3 0 2.36 2.65 tablet sample 78 film-coated 0.4 2.3 0 2.33
2.55 tablet sample 79 film-coated 4.5 2.3 0 2.23 2.24 tablet sample
80 film-coated 17.9 2.3 0 2.25 2.29 tablet
[0919] Since the production of a decomposed product can be
suppressed by the addition of an organic acid, suppression of
change in the appearance after light irradiation is sufficiently
predicted. Hence, a high quality pharmaceutical composition
superior in light-stability can be provided.
INDUSTRIAL APPLICABILITY
[0920] According to the first invention of the present invention, a
stabilized pharmaceutical composition comprising a nonpeptidic
pharmaceutically active ingredient having a primary or secondary
amino group is provided. To be specific, since development of a
decomposed product of the pharmaceutically active ingredient
(nonpeptidic one having a primary or secondary amino group) in the
pharmaceutical composition is suppressed, a more stable
pharmaceutical composition is provided. According to the present
invention, moreover, since development of a decomposed product of
the pharmaceutically active ingredient is suppressed regardless of
being in a closed bottle/open bottle, a pharmaceutical composition
also superior in the preservation stability can be provided. In
addition, according to the second invention of the present
invention, a solid preparation improved in the stability of a
pharmaceutically active ingredient to light irradiation is
provided. To be specific, a solid preparation stable to light
irradiation can be provided by, when the pharmaceutically active
ingredient contained in the solid preparation is exposed to light,
shielding the light and suppressing an increase in a decomposed
product.
[0921] This application is based on a patent application No.
2008-194219 filed in Japan, the contents of which are incorporated
in full herein by this reference.
* * * * *