U.S. patent application number 14/418804 was filed with the patent office on 2015-07-30 for patch for anti-dermatophytosis.
This patent application is currently assigned to NICHIBAN COMPANY LIMITED. The applicant listed for this patent is MEIJI SEIKA PHARMA CO., LTD., NICHIBAN COMPANY LIMITED. Invention is credited to Noriko Kan, Koji Kawahara, Kyohei Matsuo, Shihoko Watanabe.
Application Number | 20150209301 14/418804 |
Document ID | / |
Family ID | 50027958 |
Filed Date | 2015-07-30 |
United States Patent
Application |
20150209301 |
Kind Code |
A1 |
Kawahara; Koji ; et
al. |
July 30, 2015 |
PATCH FOR ANTI-DERMATOPHYTOSIS
Abstract
A patch for nails or skin for prevention or treatment of
dermatophytosis, containing a layer including a pressure sensitive
adhesive layer and a compound represented by the formula:
##STR00001## wherein R.sup.1 represents hydrogen, C.sub.1-16 alkyl,
or trifluoromethyl; R.sup.2 represents hydrogen, C.sub.1-6 alkyl,
halogen, --COO(C.sub.1-6 alkyl), or (CH.sub.2).sub.1-3COOR; R.sup.3
represents hydrogen, C.sub.1-6 alkyl, amino, trifluoromethyl, or
OR; R.sup.4 represents hydroxyl; R.sup.5 represents hydrogen,
C.sub.1-6 alkyl, hydroxyl, or halogen; R.sup.6 represents hydrogen,
C.sub.1-6 alkyl, trifluoromethyl, halogen, amino,
--NR.sup.aR.sup.b, nitro, hydroxy-C.sub.1-6 alkyl,
--CONR.sup.aR.sup.b, --COO(C.sub.1-6 alkyl), --COOH,
--(CH.sub.2).sub.1-3COOR, or OR.sup.a (R.sup.a and R.sup.b each
represents hydrogen, C.sub.1-6 alkyl, or C.sub.1-6 acyl); R.sup.7
represents hydrogen, C.sub.1-6 alkyl, --OR, or halogen; R.sup.8
represents hydrogen, C.sub.1-6 alkyl, hydroxyl, amino, or nitro;
and R represents hydrogen or C.sub.1-6 alkyl; or a salt
thereof.
Inventors: |
Kawahara; Koji; (Tokyo,
JP) ; Kan; Noriko; (Tokyo, JP) ; Watanabe;
Shihoko; (Tokyo, JP) ; Matsuo; Kyohei; (Tokyo,
JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MEIJI SEIKA PHARMA CO., LTD.
NICHIBAN COMPANY LIMITED |
Chuo-ku, Tokyo
Bunkyo-ku, Tokyo |
|
JP
JP |
|
|
Assignee: |
NICHIBAN COMPANY LIMITED
Bunkyo-ku, Tokyo
JP
MEIJI SEIKA PHARMA CO., LTD.
Chuo-ku, Tokyo
JP
|
Family ID: |
50027958 |
Appl. No.: |
14/418804 |
Filed: |
July 30, 2013 |
PCT Filed: |
July 30, 2013 |
PCT NO: |
PCT/JP2013/070527 |
371 Date: |
January 30, 2015 |
Current U.S.
Class: |
514/407 ;
514/406 |
Current CPC
Class: |
A61P 31/10 20180101;
A61K 9/7061 20130101; A61P 17/00 20180101; A61K 31/415
20130101 |
International
Class: |
A61K 9/70 20060101
A61K009/70; A61K 31/415 20060101 A61K031/415 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 30, 2012 |
JP |
PCT/JP2012/069285 |
Claims
1. A patch for a nail and/or skin for the prevention or treatment
of dermatophytosis which comprises a layer comprising a pressure
sensitive adhesive layer and a compound represented by the
following formula (I): ##STR00006## wherein R.sup.1 represents a
hydrogen atom, C.sub.1-6 alkyl, or trifluoromethyl, R.sup.2
represents a hydrogen atom, C.sub.1-6 alkyl, halogen,
--COO(C.sub.1-6 alkyl), or (CH.sub.2).sub.1-3COOR, wherein R
represents a hydrogen atom or C.sub.1-6 alkyl, R.sup.3 represents a
hydrogen atom, C.sub.1-6 alkyl, amino, trifluoromethyl, or OR,
wherein R represents a hydrogen atom or C.sub.1-6 alkyl, R.sup.4
represents a hydroxyl group, R.sup.5 represents a hydrogen atom,
C.sub.1-6 alkyl, a hydroxyl group, or halogen, R.sup.6 represents a
hydrogen atom, C.sub.1-6 alkyl, trifluoromethyl, halogen, amino,
--NR.sup.aR.sup.b, nitro, hydroxy-C.sub.1-6 alkyl,
--CONR.sup.aR.sup.b, --COO(C.sub.1-6 alkyl); --COOH,
--(CH.sub.2).sub.1-3COOR, or OR.sup.a, wherein R represents a
hydrogen atom or C.sub.1-6 alkyl, and R.sup.a and R.sup.b are the
same or different from each other, and each represents a hydrogen
atom, C.sub.1-6 alkyl, or C.sub.1-6 acyl, R.sup.7 represents a
hydrogen atom, C.sub.1-6 alkyl, --OR, wherein R represents a
hydrogen atom or C.sub.1-6 alkyl, or halogen, and R.sup.8
represents a hydrogen atom, C.sub.1-6 alkyl, a hydroxyl group,
amino, or nitro or a salt thereof.
2. The patch for a nail and/or skin according to claim 1, wherein
in the compound represented by the formula (I), R.sup.1 is a
hydrogen atom or C.sub.1-6 alkyl, R.sup.2 is a hydrogen atom,
C.sub.1-6 alkyl, halogen, or --(CH.sub.2).sub.1-3COOR, wherein R
represents a hydrogen atom or C.sub.1-6 alkyl, R.sup.3 is a
hydrogen atom, or C.sub.1-6 alkyl, R.sup.4 is a hydroxyl group,
R.sup.5 is a hydrogen atom, R.sup.6 is a hydrogen atom, C.sub.1-6
alkyl, trifluoromethyl, halogen, amino, --NR.sup.aR.sup.b, nitro,
hydroxy-C.sub.1-6 alkyl, --CONR.sup.aR.sup.b, --COOH, or OR.sup.a,
wherein R.sup.a and R.sup.b are the same or different from each
other, and each represent a hydrogen atom, C.sub.1-6 alkyl, or
C.sub.1-6 acyl, R.sup.7 is a hydrogen atom, and R.sup.8 is a
hydrogen atom, C.sub.1-6 alkyl, amino, or nitro; or a salt
thereof.
3. The patch for a nail and/or skin according to claim 1, wherein
in the compound represented by the formula (I), R.sup.1 is
C.sub.1-6 alkyl, R.sup.2 is a hydrogen atom, C.sub.1-6 alkyl, or
halogen, R.sup.3 is C.sub.1-6 alkyl, R.sup.4 is a hydroxyl group,
R.sup.5 is a hydrogen atom, R.sup.6 is a hydrogen atom, C.sub.1-6
alkyl, halogen, or OR.sup.a, wherein R.sup.a represents a hydrogen
atom, C.sub.1-6 alkyl, or C.sub.1-6 acyl, R.sup.7 is a hydrogen
atom, and R.sup.8 is a hydrogen atom; or a salt thereof.
4. The patch for a nail and/or skin according to claim 1, wherein
in the compound represented by the formula (I), R.sup.1 is
C.sub.1-6 alkyl, R.sup.2 is a hydrogen atom, R.sup.3 is C.sub.1-6
alkyl, R.sup.4 is a hydroxyl group, R.sup.5 is a hydrogen atom,
R.sup.6 is C.sub.1-6 alkyl, R.sup.7 is a hydrogen atom, and R.sup.8
is a hydrogen atom; or a salt thereof.
5. The patch for a nail and/or skin according to claim 1, wherein
the compound represented by formula (I) is
2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-methylphenol or a salt
thereof.
6. The patch for a nail and/or skin according to claim 1, wherein
the pressure sensitive adhesive layer comprises an acrylic-based
pressure sensitive adhesive.
7. The patch for a nail and/or skin according to claim 6, wherein
the acrylic-based pressure sensitive adhesive comprises a copolymer
of 2-ethylhexyl acrylate and N-vinylpyrrolidone.
8. The patch for a nail and/or skin according to claim 1, wherein
the compound represented by the formula (I) or a salt thereof is
contained in an amount of 5 to 30% by mass based on the total
amount of the pressure sensitive adhesive.
9. The patch for a nail and/or skin according claim 1, wherein the
compound represented by the formula (I) or a salt thereof is
contained in an amount of 5 to 20% by mass based on the total
amount of the pressure sensitive adhesive.
10. The patch for a nail and/or skin according to claim 1, wherein
the compound represented by the formula (I) or a salt thereof is
combined in an amount of 5 to 15% by mass based on the total amount
of the pressure sensitive adhesive.
11. The patch for a nail and/or skin according to claim 1, wherein
the dermatophytosis is caused by tinea unguium.
12. The patch for a nail and/or skin according to claim 8, wherein
the pressure sensitive adhesive is an acrylic-based pressure
sensitive adhesive.
13. The patch for a nail and/or skin according to claim 9, wherein
the pressure sensitive adhesive is an acrylic-based pressure
sensitive adhesive.
14. The patch for a nail and/or skin according to claim 10, wherein
the pressure sensitive adhesive is an acrylic-based pressure
sensitive adhesive.
Description
TECHNICAL FIELD
[0001] The present invention relates to a patch for prevention or
treatment of dermatophytosis comprising a novel
2-(1H-pyrazol-1-yl)phenol derivative or a pharmaceutically
acceptable salt thereof as an effective ingredient suitable for an
anti-dermatophytosis agent.
BACKGROUND ART
[0002] Mycosis is a disease caused by a fungus which infects to
human or animals. As representative mycoses in human, there have
been known candidiasis due to Candida, cryptococcosis due to
Cryptococcus, aspergillosis due to Aspergillus, zygomycosis due to
Zygomycetes, dermatophytosis (trichophytia) due to Trichophyton,
and the like (pathogenic fungi and mycosis (NANZANDO Co., Ltd.,
Revised 2nd Edition), pp. 42-45; Non-Patent Document 1).
[0003] Trichophyton which is one of pathogenic fungi of mycosis is
dermatophyte which could be pathogenic fungi of trichophytia, and
has the keratolytic ablity. According to this ability, it invades
into a skin, nail or hair to cause trichophytia (Pathogenic fungi
and mycosis (NANZANDO Co., Ltd., Revised 2nd Edition), pp. 184-187;
Non-Patent Document 2).
[0004] Tinea unguium is a disease of a nail caused by dermatophyte,
and a disease accompanied by symptoms of turbidity, thickening,
destruction, and deformation, etc. of the nail plate. At present,
it is said that there is one patient per ten Japaneses, and about
12 million patients in total. This is a disease frequently
appearing in aged person, and a further increase in a number of
patients will be concerned in the future. There is a report that a
diabetic patient easily contracts the disease so that the
possibility of causing serious complications is being pointed
out.
[0005] As a treatment method of onychomycosis in Japan nowadays,
only an oral medicine of an antifungal agent (itraconazole and
terbinafine, etc.) has been approved. However, the antifungal agent
for oral administration has been pointed out that it has drug
interaction, liver damage, and side effect(s) due to long term
administration. In addition, an aged person, diabetic patient,
etc., having a high morbidity of tinea unguium often takes multiple
types of drugs, so that oral administration of the anti-fungal
agent for the treatment of tinea unguium is difficult in many cases
(Br. J. of Dermatol., vol. 139 (4), p. 665, 1998; Non-Patent
Document 3).
[0006] As for an anti-dermatophytosis drug for external use, to
exert the medical effect of the anti-dermatophytosis drug for
external use, it is required to deliver the drug to an epidermal
horny layer and a nail which are infected portions, with a high
level of a drug concentration in addition to have the drug itself
having a potent antifungal activity against dermatophytes. However,
the antifungal drug for external use to be used for usual skin
mycosis cannot reach to the horny or inside of the nail, or to a
nail matrix with a sufficient concentration, whereby a sufficient
effect cannot be obtained.
[0007] In abroad, a nail lacquer for external use of amorolfine or
ciclopirox has been approved and used. However, their
permeabilities into the nail are very low, so that it cannot be
expected to deliver to nail matrix cells by further permeation.
[0008] Therefore, a patch for external use of dermatophytosis such
as tinea unguium, etc., is required to have not only a potent
antifungal activity against dermatophytes, but also high
permeability to a nail, but such a patch for external use has not
yet been found out.
[0009] On the other hand, as a compound having a
2-(1H-pyrazol-1-yl)phenol backbone,
2-(3,5-dimethyl-1H-pyrazol-1-yl)phenol which has methyl groups at
the 3-position and 5-position of the pyrazole ring has been known
(Annual Report of Takeda Research Center (1963) 22, p. 27;
Non-Patent Document 4). These compounds are directed to prevent
growth of Mycobacterium tuberculosis in human. However, in
Non-Patent Document 4, there is no disclosure of the
2-(1H-pyrazol-1-yl)phenol compound other than
2-(3,5-dimethyl-1H-pyrazol-1-yl)phenol.
[0010] As the compound having a 2-(1H-pyrazol-1-yl)phenol backbone
other than 2-(3,5-dimethyl-1H-pyrazol-1-yl)phenol,
2-(1H-pyrazol-1-yl)phenol,
2-(3,5-dimethyl-1H-pyrazol-1-yl)-1,4-benzenediol and
2-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)-1,4-benzenediol have been
known. These have been utilized for various kinds of chemical
reactions, a starting material as a compound for
electroluminescence devices (JP Patent No. 4284169: Patent Document
1), a photostabilizer (Spanish Patent Laid-Open No. 20158648A:
Patent Document 2), etc. Also, in WO 2003/005999 (Patent Document
3), 2-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)-5-methylphenol is
disclosed.
[0011] However, in these prior art literatures, there is neither
suggestion nor disclosure about its antifungal activity against
dermatophytes of the compound having a 2-(1H-pyrazol-1-yl)phenol
backbone.
PRIOR ART LITERATURES
Patent Documents
[0012] [Patent Document 1] JP Patent No. 4284169 [0013] [Patent
Document 2] Spanish Patent Laid-Open No. 20158648A [0014] [Patent
Document 3] WO 2003/005999A
Non-Patent Documents
[0014] [0015] [Non-Patent Document 1] Pathogenic fungi and mycosis
(NANZANDO Co., Ltd., Revised 2nd Edition), pp. 42-45 [0016]
[Non-Patent Document 2] Pathogenic fungi and mycosis (NANZANDO Co.,
Ltd., Revised 2nd Edition), pp. 184-187 [0017] [Non-Patent Document
3] Br. J. of Dermatol., vol. 139 (4), p. 665, 1998 [0018]
[Non-Patent Document 4] Annual Report of Takeda Research Center
(1963) 22, p. 27
DISCLOSURE OF THE INVENTION
Problems to be Solved by the Invention
[0019] As mentioned above, a patch for external use of superficial
mycosis such as tinea unguium is required to have not only
antifungal activity, but also high permeability to a nail whereby
development of such a patch for external use has been earnestly
desired. Accordingly, an object of the present invention is to
provide a patch for nail and/or skin having an antifungal activity
against dermatophytes, and having higher nail permeability.
Means for Solving the Problems
[0020] The present inventors have found that a patch comprising the
compound having a 2-(1H-pyrazol-1-yl)phenol backbone represented by
the following formula (I) or a salt thereof in a pressure sensitive
adhesive layer has high nail permeability and storability, whereby
they have accomplished the present invention based on these
findings.
[0021] That is, the present invention relates to a patch for nail
and/or skin for prevention or treatment of dermatophytosis which
comprises in a pressure sensitive adhesive layer a compound
represented by the formula:
##STR00002##
wherein R.sup.1 represents a hydrogen atom, C.sub.1-6 alkyl, or
trifluoromethyl, R.sup.2 represents a hydrogen atom, C.sub.1-6
alkyl, halogen, --COO(C.sub.1-6 alkyl), or (CH.sub.2).sub.1-3COOR
(R represents a hydrogen atom or C.sub.1-6 alkyl), R.sup.3
represents a hydrogen atom, C.sub.1-6 alkyl, amino,
trifluoromethyl, or OR (R represents a hydrogen atom or C.sub.1-6
alkyl), R.sup.4 represents a hydroxyl group, R.sup.5 represents a
hydrogen atom, C.sub.1-6 alkyl, a hydroxyl group, or halogen,
R.sup.6 represents a hydrogen atom, C.sub.1-6 alkyl,
trifluoromethyl, halogen, amino, --NR.sup.aR.sup.b, nitro,
hydroxy-C.sub.1-6 alkyl, --CONR.sup.aR.sup.b, --COO(C.sub.1-6
alkyl), --COOH, --(CH.sub.2).sub.1-3COOR, or OR.sup.a (R represents
a hydrogen atom or C.sub.1-6 alkyl, R.sup.a and R.sup.b may be the
same or different from each other, and each represent a hydrogen
atom, C.sub.1-6 alkyl, or C.sub.1-6 acyl), R.sup.7 represents a
hydrogen atom, C.sub.1-6 alkyl, --OR (R represents a hydrogen atom
or C.sub.1-6 alkyl), or halogen, and R.sup.8 represents a hydrogen
atom, C.sub.1-6 alkyl, a hydroxyl group, amino, or nitro, or a salt
thereof.
Effects of the Invention
[0022] The patch of the present invention not only shows potent
antifungal activity against dermatophytes, but also has high
permeability to a nail, so that it is useful as a patch for nail
and/or skin for prevention or treatment of dermatophytosis,
particularly tinea unguium.
BEST MODE FOR CARRYING OUT THE INVENTION
[0023] The terms "C.sub.1-6 alkyl", and "C.sub.1-6 alkyl" as a part
of the group to be used in the present specification mean an alkyl
group having 1 to 6 carbon atoms. The alkyl group may be either a
linear, branched or cyclic one. There may be mentioned, for
example, a C.sub.1-6 alkyl group such as methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl,
etc., and a C.sub.3-6 cycloalkyl group such as cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl.
[0024] The terms "C.sub.1-6 acyl", and "C.sub.1-6 acyl" as a part
of the group to be used in the present specification mean an acyl
group having 1 to 6 carbon atoms. The acyl group may be either a
linear, branched or cyclic one. There may be mentioned, for
example, formyl, acetyl, propionyl, butyryl, isobutyryl, etc., and
preferably, formyl, acetyl, propionyl, butyryl, etc.
[0025] The term "halogen" used in the present specification means
fluorine, chlorine, bromine, iodine, etc.
[0026] The terms of a group "--OR where R represents a hydrogen
atom or C.sub.1-6 alkyl" or a part of the group to be used in the
present specification mean a hydroxyl group, or C.sub.1-6 alkyloxy.
Here, "C.sub.1-6 alkyl" is the same as the above-mentioned
"C.sub.1-6 alkyl".
[0027] In "--OR.sup.a" as a group or a part of the group to be used
in the present specification, R.sup.a represents a hydrogen atom,
C.sub.1-6 alkyl, or C.sub.1-6 acyl, and "--OR.sup.a" represents a
hydroxyl group, C.sub.1-6 alkyloxy, or C.sub.1-6 acyloxy. Here,
"C.sub.1-6 alkyl" is the same as the above-mentioned "C.sub.1-6
alkyl".
[0028] With regard to the compound of the formula (I) or a salt
thereof, a solvate thereof
[0029] As mentioned above, the present invention relates to a patch
for nail and/or skin for prevention or treatment of dermatophytosis
comprising the compound represented by the formula:
##STR00003##
or a salt thereof, in a pressure sensitive adhesive layer.
[0030] In the formula (I), R.sup.1 represents a hydrogen atom,
C.sub.1-6 alkyl, trifluoromethyl, preferably a hydrogen atom, or
C.sub.1-6 alkyl, and more preferably C.sub.1-6 alkyl. R.sup.1
specifically includes a hydrogen atom, methyl, ethyl, etc.
[0031] In the formula (I), R.sup.2 represents a hydrogen atom,
C.sub.1-6 alkyl, halogen, --COO(C.sub.1-6 alkyl), or
--(CH.sub.2).sub.1-3COOR (R represents a hydrogen atom or C.sub.1-6
alkyl), preferably a hydrogen atom, C.sub.1-6 alkyl, or halogen.
R.sup.2 specifically includes a hydrogen atom, methyl, ethyl,
propyl, butyl, a chlorine atom, or 2-carboxyethyl, etc.
[0032] In the formula (I), R.sup.3 represents a hydrogen atom,
C.sub.1-6 alkyl, amino, trifluoromethyl, --OR (R represents a
hydrogen atom or C.sub.1-6 alkyl), preferably a hydrogen atom, or
C.sub.1-6 alkyl, more preferably C.sub.1-6 alkyl. R.sup.3
specifically includes methyl, or ethyl.
[0033] In the formula (I), R.sup.4 represents a hydroxyl group.
[0034] In the formula (I), R.sup.5 represents a hydrogen atom,
C.sub.1-6 alkyl, a hydroxyl group, or halogen, preferably a
hydrogen atom.
[0035] In the formula (I), R.sup.6 represents a hydrogen atom,
C.sub.1-6 alkyl, trifluoromethyl, halogen, amino,
--NR.sup.aR.sup.b, nitro, hydroxy-C.sub.1-6 alkyl,
--CONR.sup.aR.sup.b, --COO(C.sub.1-6 alkyl), --COOH,
--(CH.sub.2).sub.1-3COOR, or OR.sup.a (R represents a hydrogen atom
or C.sub.1-6 alkyl, le and R.sup.b may be the same or different
from each other, and each represent a hydrogen atom, C.sub.1-6
alkyl, or C.sub.1-6 acyl), preferably a hydrogen atom, C.sub.1-6
alkyl, trifluoromethyl, halogen, amino, --NR.sup.aR.sup.b, nitro,
hydroxy-C.sub.1-6 alkyl, --CONR.sup.aR.sup.b, --COOH, or OR.sup.a
(R.sup.a and R.sup.b may be the same or different from each other,
and each represent a hydrogen atom, C.sub.1-6 alkyl, or C.sub.1-6
acyl), more preferably a hydrogen atom, C.sub.1-6 alkyl, halogen,
or OR.sup.a (R.sup.a represents a hydrogen atom, C.sub.1-6 alkyl,
or C.sub.1-6 acyl). R.sup.6 specifically includes a hydrogen atom,
methyl, ethyl, methoxy, a chlorine atom, a bromine atom, a fluorine
atom, a hydroxyl group, acetoxy, amino, nitro, carboxyl,
hydroxymethyl, trifluoromethyl, methylamino, carbamoyl, or
N,N-dimethylcarbamoyl.
[0036] R.sup.7 represents a hydrogen atom, C.sub.1-6 alkyl, --OR (R
represents a hydrogen atom or C.sub.1-6 alkyl), or halogen,
preferably a hydrogen atom.
[0037] R.sup.8 represents a hydrogen atom, C.sub.1-6 alkyl, a
hydroxyl group, amino, or nitro, preferably a hydrogen atom,
C.sub.1-6 alkyl, amino, or nitro, more preferably a hydrogen atom.
R.sup.8 specifically includes a hydrogen atom, methyl, nitro, or
amino.
[0038] In the patch for nail and/or skin for prevention or
treatment of dermatophytosis of the present invention, a preferred
compound of the formula (I) is a compound wherein
R.sup.1 is a hydrogen atom or C.sub.1-6 alkyl, R.sup.2 is a
hydrogen atom, C.sub.1-6 alkyl, halogen, or
--(CH.sub.2).sub.1-3COOR (R represents a hydrogen atom or C.sub.1-6
alkyl), R.sup.3 is a hydrogen atom, or C.sub.1-6 alkyl, R.sup.4 is
a hydroxyl group, R.sup.5 is a hydrogen atom, R.sup.6 is a hydrogen
atom, C.sub.1-6 alkyl, trifluoromethyl, halogen, amino,
--NR.sup.aR.sup.b, nitro, hydroxy-C.sub.1-6 alkyl,
--CONR.sup.aR.sup.b, --COOH, or OR (R.sup.a and R.sup.b may be the
same or different from each other, and each represent a hydrogen
atom, C.sub.1-6 alkyl, or C.sub.1-6 acyl), R.sup.7 is a hydrogen
atom, and R.sup.8 is a hydrogen atom, C.sub.1-6 alkyl, amino, or
nitro.
[0039] In the patch for nail and/or skin for prevention or
treatment of dermatophytosis of the present invention, a more
preferred compound of the formula (I) is a compound wherein
R.sup.1 is C.sub.1-6 alkyl, R.sup.2 is a hydrogen atom, C.sub.1-6
alkyl, or halogen, R.sup.3 is C.sub.1-6 alkyl, R.sup.4 is a
hydroxyl group, R.sup.5 is a hydrogen atom, R.sup.6 is a hydrogen
atom, C.sub.1-6 alkyl, halogen, or OR.sup.a (R.sup.a represents a
hydrogen atom, C.sub.1-6 alkyl, or C.sub.1-6 acyl), R.sup.7 is a
hydrogen atom, and R.sup.8 is a hydrogen atom.
[0040] In the patch for nail and/or skin for prevention or
treatment of dermatophytosis of the present invention, a further
preferred compound of the formula (I) is a compound wherein R.sup.1
is C.sub.1-6 alkyl, R.sup.2 is a hydrogen atom, R.sup.3 is
C.sub.1-6 alkyl, R.sup.4 is a hydroxyl group, R.sup.5 is a hydrogen
atom, R.sup.6 is C.sub.1-6 alkyl, R.sup.7 is a hydrogen atom, and
R.sup.8 is a hydrogen atom.
[0041] As the compound of the formula (I) to be comprised in the
patch for nail and/or skin for prevention or treatment of
dermatophytosis of the present invention, the following compounds
may be mentioned.
Preparation example 1: 2-(3,5-dimethyl-1H-pyrazol-1-yl)phenol
Preparation example 2:
2-(3,5-dimethyl-1H-pyrazol-1-yl)-4-fluorophenol Preparation example
3: 2-(1H-pyrazol-1-yl)phenol Preparation example 4:
2-(5-hydroxy-3-methyl-1H-pyrazol-1-yl)phenol Preparation example 5:
2-(5-methyl-3-trifluoromethyl-1H-pyrazol-1-yl)phenol Preparation
example 6: 2-(3,5-bistrifluoromethyl-1H-pyrazol-1-yl)phenol
Preparation example 7: 2-(3-methyl-1H-pyrazol-1-yl)phenol
Preparation example 8: 2-(5-methyl-1H-pyrazol-1-yl)phenol
Preparation example 9: 2-(3,4,5-trimethyl-1H-pyrazol-1-yl)phenol
Preparation example 10:
2-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)phenol Preparation example
11: 4-chloro-2-(3,5-dimethyl-1H-pyrazol-1-yl)phenol Preparation
example 12: 2-chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)phenol
Preparation example 13:
2-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)phenol Preparation example
14: 2-(3,5-diethyl-1H-pyrazol-1-yl)phenol Preparation example 15:
3-(3,5-dimethyl-1H-pyrazol-1-yl)benzene-1,2-diol Preparation
example 16: 2-(3,5-dimethyl-1H-pyrazol-1-yl)benzene-1,4-diol
Preparation example 17:
2-(4-ethyl-3,5-dimethyl-1H-pyrazol-1-yl)phenol Preparation example
18: 5-fluoro-2-(3,4,5,-trimethyl-1H-pyrazol-1-yl)phenol Preparation
example 19:
2-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)benzene-1,4-diol
Preparation example 20:
4-fluoro-2-(3,4,5,-trimethyl-1H-pyrazol-1-yl)phenol Preparation
example 21:
2-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)-5-fluorophenol
Preparation example 22: ethyl
1-(2-hydroxyphenyl)-3,5-dimethyl-1H-pyrazol-4-carboxylate
Preparation example 23: methyl
3-(1-(2-hydroxyphenyl)-3,5-dimethyl-1H-pyrazol-4-yl)propanoate
Preparation example 24:
2-(4-butyl-3,5-dimethyl-1H-pyrazol-1-yl)phenol Preparation example
25: 2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-fluorophenol Preparation
example 26: 5-chloro-2-(3,5-dimethyl-1H-pyrazol-1-yl)phenol
Preparation example 27:
2-(3,5-dimethyl-1H-pyrazol-1-yl)-3-nitrophenol Preparation example
28: 2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-nitrophenol Preparation
example 29:
3-(1-(2-hydroxyphenyl)-3,5-dimethyl-1H-pyrazol-4-yl)propionic acid
Preparation example 30:
5-chloro-2-(3,4,5-trimethyl-1H-pyrazol-1-yl)phenol Preparation
example 31: 5-amino-2-(3,5-dimethyl-1H-pyrazol-1-yl)phenol
Preparation example 32:
5-nitro-2-(3,4,5-trimethyl-1H-pyrazol-1-yl)phenol Preparation
example 33: 4-(3,5-dimethyl-1H-pyrazol-1-yl)benzene-1,3-diol
Preparation example 34:
5-amino-2-(3,4,5-trimethyl-1H-pyrazol-1-yl)phenol Preparation
example 35: methyl
4-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzenecarboxylate
Preparation example 36:
3-amino-2-(3,5-dimethyl-1H-pyrazol-1-yl)phenol Preparation example
37: 4-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzenecarboxylic
acid Preparation example 38:
4-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxy-N,N-dimethylbenzamide
Preparation example 39:
4-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzamide Preparation
example 40:
3-hydroxy-4-(3,4,5-trimethyl-1H-pyrazol-1-yl)benzenecarboxylic acid
Preparation example 41:
3-hydroxy-4-(3,4,5-trimethyl-1H-pyrazol-1-yl)benzamide Preparation
example 42:
4-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzamide
Preparation example 43:
2-(3,5-dimethyl-1H-pyrazol-1-yl)benzene-1,3-diol Preparation
example 44: 2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-methylphenol
Preparation example 45:
2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-methoxyphenol Preparation
example 46: 2-(3,5-dimethyl-1H-pyrazol-1-yl)-3-methylphenol
Preparation example 47:
2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-hydroxymethylphenol Preparation
example 48: 2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-methylaminophenol
Preparation example 49:
2-(3,5-dimethyl-1H-pyrazol-1-yl)-4-methylphenol Preparation example
50: 2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-trifluoromethylphenol
Preparation example 51:
2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methylphenol Preparation example
52: 2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-ethylphenol Preparation
example 53: 2-(4-fluoro-3,5-dimethyl-1H-pyrazol-1-yl)phenol
Preparation example 54:
5-bromo-2-(3,5-dimethyl-1H-pyrazol-1-yl)phenol Preparation example
55: 5-bromo-2-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)phenol
Preparation example 56:
5-bromo-2-(3,4,5-trimethyl-1H-pyrazol-1-yl)phenol Preparation
example 57: 4-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxyphenyl
acetate Preparation example 58:
4-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxyphenyl acetate
Preparation example 59:
3-hydroxy-4-(3,4,5-trimethyl-1H-pyrazol-1-yl)phenyl acetate
Preparation example 60:
2-(3,5-dimethyl-1H-pyrazol-1-yl)-4-methoxy-5-methylphenol
Preparation example 61:
4-chloro-2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-methylphenol
Preparation example 62:
2-(3,5-dimethyl-1H-pyrazol-1-yl)-4,5-dimethylphenol Preparation
example 63:
4-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)-benzene-1,3-diol
[0042] Among these, 2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-methylphenol
is most preferably mentioned.
[0043] The compound of the formula (I) to be comprised in the patch
for nail and/or skin for prevention or treatment of dermatophytosis
of the present invention can be also used as a salt. As such a
salt, there may be used a pharmaceutically acceptable optional
salt, and may be specifically mentioned a pharmaceutically
acceptable salt derived from an inorganic acid, an organic acid or
a base. The "pharmaceutically acceptable salt" is known in this
field of the art. For example, S. M. Berge et al. describe
pharmaceutically acceptable salts in Journal of Pharmaceutical
Sciences, 66, p. 1 et seq. (1977) in detail. Representative acid
addition salts may include an inorganic acid salt such as
hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide,
phosphate, etc.; an organic carboxylic acid salt such as acetate,
trifluoroacetate, lactate, citrate, oxalate, succinate, glutarate,
malate, tartrate, fumarate, mandelate, maleate, benzoate,
nicotinate, phthalate, etc.; an organic sulfonate such as
methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate,
benzenesulfonate, p-toluenesulfonate, 2-naphthalenesulfonate,
camphor sulfonate, etc.; an acidic amino acid salt such as
aspartate, glutamate, etc., but the invention is not limited to
these. The acid addition salt preferably includes a salt with an
inorganic acid such as hydrochloric acid, hydrobromic acid,
sulfuric acid and phosphoric acid; and a salt with an organic acid
such as oxalic acid, maleic acid, methanesulfonic acid,
p-toluenesulfonic acid and citric acid, more preferably a salt with
hydrochloric acid, hydrobromic acid, sulfuric acid and
methanesulfonic acid.
[0044] The base addition salt can be prepared by reacting a
carboxylic acid or a phenolic-hydroxyl group-containing portion
with a suitable base during the final isolation or purification
process of the present invention compound to obtain the objective
material at that time. The pharmaceutically acceptable salt may
include an alkali metal salt such as lithium salt, sodium salt,
potassium salt, etc.; an alkaline earth metal salt such as calcium
salt, magnesium salt, etc.; aluminum salt, ammonium salt, and
further an organic base salt such as methylamine salt,
dimethylamine salt, ethylamine salt, diethylamine salt,
trimethylamine salt, triethylamine salt, tetramethylammonium salt,
tetraethylammonium salt, pyridine salt, picoline salt, ethanolamine
salt, diethanolamine salt, triethanolamine salt,
trishydroxymethylaminomethane salt, piperidine salt, piperazine
salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt,
etc.; a basic amino acid salt such as arginine salt, lysine salt,
ornithine salt, etc., but the invention is not limited to these.
The base addition salt preferably includes an addition salt with
sodium, potassium, calcium, ethanolamine and
trishydroxymethylaminomethane, more preferably an addition salt
with sodium, potassium and trishydroxymethylaminomethane.
[0045] Further, the compound of the formula (I) comprised in the
patch for nail and/or skin for prevention or treatment of
dermatophytosis of the present invention can be also used in the
form of a solvate. The term "solvate" used in the present
specification means complexes with various stoichiometry formed by
a solute (the compound of the formula (I) or a salt thereof in the
present invention) and a solvent. The solvent for the purpose of
the present invention is preferably a solvent which does not
interfere the biological activities of the above-mentioned solute
and is preferably a pharmaceutically acceptable material. The
suitable solvent for the solvate may be exemplified by water,
methanol, ethanol, ethylene glycol, propylene glycol, ethyl acetate
and butyl acetate, and the present invention is not limited by
these. As a solvent for the solvate, water, ethanol and ethyl
acetate are preferably mentioned.
[0046] Preparation Method of Compound Represented by the Formula
(I)
[0047] The 2-(1H-pyrazol-1-yl)phenol derivative represented by the
formula (I) which is comprised in the patch of the present
invention can be synthesized by an optional method, and, for
example, it can be synthesized by the method shown in Scheme 1 or a
method in accordance with the method. Incidentally, in Scheme 1,
each symbol of the compound is the same as that mentioned above, P
and P' each represent hydrogen or a suitable protective group, X
represents a halogen or a suitable boronic acid group, and Y
represents a dissociated ion of an acid used in the reaction. In
the present specification, "suitable boronic acid" means boronic
acid or a boronic acid ester.
[0048] [Formula 3]
##STR00004##
[0049] The method of obtaining a hydrazine derivative (V) or a salt
thereof from a 2-hydroxyaniline derivative (IIIa) or a salt thereof
via a diazonium compound (IVa) can be carried out in accordance
with the method described in Organic Synthesis Collective Volume 1,
pp. 442-445, J. Org. Chem., vol. 21, pp. 394-399, 1956, WO
2007/083320, or U.S. Pat. No. 6,852,890.
[0050] The diazotization reaction can be carried out by using a
nitrite such as potassium nitrite, calcium nitrite, silver nitrite,
sodium nitrite, barium nitrite, etc.; nitrosylsulfuric acid or a
nitrite ester such as ethyl nitrite, isoamyl nitrite, isobutyl
nitrite, isopropyl nitrite, tert-butyl nitrite, n-butyl nitrite,
n-propyl nitrite, etc., and preferably sodium nitrite, or a nitrite
ester such as isoamyl nitrite, tert-butyl nitrite, etc. are
mentioned.
[0051] When a protective group is used, any group may be used so
long as it is inactive in the steps other than the deprotection,
and as P and P', there may be mentioned, for example, an alkyl
group such as a methyl group, an isopropyl group, an allyl group, a
tert-butyl group, a methoxymethyl group, a methylthiomethyl group,
a benzyl group and a 9-anthrylmethyl group, an acyl group such as a
pivaloyl group and a benzoyl group, or a sulfonyl group such as a
p-toluenesulfonyl group and a methanesulfonyl group, and the
present invention is not limited by these. Preferred protective
group may be mentioned a methyl group, a p-toluenesulfonyl group
and a methanesulfonyl group.
[0052] The amount of the reagent to be used in the diazotization
reaction is preferably 1 to 10 equivalents, more preferably 1 to 3
equivalents based on the amount of the 2-hydroxyaniline derivative
(IIIa).
[0053] When a nitrite is used in the above-mentioned diazotization
reaction, water, or an organic solvent mixed with water in an
optional ratio, for example, methanol, ethanol, 2-propanol, acetic
acid, trifluoroacetic acid, tetrahydrofuran, 1,4-dioxane,
dimethylformamide and dimethylsulfoxide may be used. In addition,
these solvents may be used in combination of two or more.
Preferably used are water, a water-methanol mixed solution, and a
water-methanol-acetic acid mixed solution. Further, the
diazotization reaction is carried out under acidic conditions to
ensure solubility of the aniline derivative used as a substrate and
to generate nitric acid in the reaction system. The acid to be used
may include hydrochloric acid, hydrobromic acid, sulfuric acid,
nitric acid, acetic acid, trifluoroacetic acid and phosphoric acid.
Preferably used are hydrochloric acid, acetic acid and
trifluoroacetic acid. Moreover, these acids may be also used as a
solvent.
[0054] When a nitrite ester is used in the above-mentioned
diazotization reaction, there may be used an alcohol such as
methanol, ethanol, methoxyethanol, ethoxyethanol, I-propanol,
2-propanol, 1-butanol, 2-butanol and 2-methyl-2-propanol, an ether
solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran,
methyl-tert-butyl ether, diphenyl ether and 1,4-dioxane, an acetic
acid ester such as methyl acetate, ethyl acetate, propyl acetate
and butyl acetate, an aprotic solvent such as
N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone
and dimethylsulfoxide, and a halogenated solvent such as
dichloromethane, chloroform and 1,2-dichloroethane. In addition,
these solvents may be used in combination of two or more.
Preferably used are methanol, ethanol and a mixed solution of
ethanol-diethyl ether.
[0055] The temperature of the above-mentioned diazotization
reaction is in either of the case where a nitrite is used or the
case where a nitrite ester is used both preferably -50.degree. C.
to 50.degree. C., more preferably between -30.degree. C. and
10.degree. C., further preferably between -10.degree. C. and
5.degree. C.
[0056] The above-mentioned diazotization reaction may vary
depending on the substrate and the reaction conditions, and
completes within 5 minutes to 12 hours, generally within 3 hours in
many cases.
[0057] The concentration of the substrate in the solution of the
above-mentioned diazotization reaction is not particularly limited
and it can be carried out within the range of 0.1 mM to 10 M,
preferably within the range of 1 mM to 1 M.
[0058] Reduction of the diazonium compound (IVa) to the hydrazine
derivative (V) can be carried out by using stannous chloride or a
hydrate thereof, a sulfite, a hydrogen sulfite, a dithionite, or
triphenylphosphine (Organic Synthesis Collective Volume 1, p.
442-445, J. Org. Chem., vol. 21, pp. 394-399, 1956, WO2007/083320,
U.S. Pat. No. 6,852,890, US2007/0105866, J. Am. Chem. Soc., vol.
92, pp. 853-859, 1970). Preferred is a method using stannous
chloride, a dithionite, or a sulfite.
[0059] The above-mentioned reduction reaction can be carried out
subsequently to the diazotization reaction. That is, without
isolating diazonium compound which is generally unstable, a
reducing reagent is added to the reaction solution, or the
diazotization reaction solution is added to the solution of the
reducing reagent whereby the hydrazine derivative (V) or a salt
thereof can be synthesized.
[0060] The amount of the above-mentioned reducing agent is
preferably 1 to 30 equivalents, more preferably 1 to 10 equivalents
based on the amount of the corresponding diazonium compound.
[0061] The solvent to be used in the above-mentioned reduction may
be the same as that used in the diazotization reaction, also, may
be optionally added, and preferably the same as that used in the
diazotization reaction.
[0062] The temperature of the above-mentioned reduction may vary
depending on the kind of the reducing agent, and preferably
-50.degree. C. to 120.degree. C., and the reduction may be more
preferably carried out between -10.degree. C. and 70.degree. C.,
and further preferably between -10.degree. C. and 30.degree. C.
[0063] The hydrazine derivative (V) or a salt thereof can be
synthesized from the compound (Mb) without through the diazonium
compound (IVa). That is, the compound (Mb) is reacted with a
hydrazine or a hydrazine protected by P' in the presence of a
suitable catalyst, or in the absence thereof to obtain the
hydrazine derivative (V) or a salt thereof.
[0064] The phenylpyrazole derivative (VI) can be similarly
synthesized by reacting the compound (Mb) with a suitable pyrazole
in the presence of a suitable catalyst, or in the absence
thereof.
[0065] When a hydrazine to which the protective group P' has bonded
is used, the protective group may be any group so long as it is
inactive in the steps other than the deprotection. As the P', there
may be mentioned, for example, an alkyloxycarbonyl group such as a
methoxycarbonyl group, an ethoxycarbonyl group, a
tert-butoxycarbonyl group and a benzyloxycarbonyl group, etc., an
acyl group such as a pivaloyl group and a benzoyl group, or a
sulfonyl group such as a p-toluenesulfonyl group and a
methanesulfonyl group, and the present invention is not limited by
these. As the preferred protective group, there may be mentioned a
t-butoxycarbonyl group.
[0066] When X of the compound (IIIb) is halogen, the reaction can
be carried out in accordance with the method disclosed in Organic
Letters vol. 3, pp. 3803-3805, 2001, J. Org. Chem., vol. 72, pp.
6190-6199, 2007, or J. Org. Chem., vol. 70, pp. 5164-5173, 2005.
When X of the compound (IIIb) is boronic acid, the reaction can be
carried out in accordance with the method disclosed in Bioorg. Med.
Chem. Lett., vol. 18, pp. 4438-4441, 2008.
[0067] The amount of the hydrazine or the hydrazine protected by P'
to be used in the above-mentioned reaction, or an amount of the
pyrazole is preferably 1 to 30 equivalents, more preferably 1 to 5
equivalents based on the amount of the compound (IIIb).
[0068] The solvent suitable for the above-mentioned reaction may
vary depending on the substrate or the reaction conditions, and
there may be mentioned an aprotic solvent such as
N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone,
dimethyl sulfoxide, sulfolane, acetonitrile and propionitrile, an
ether solvent such as 1,4-dioxane, 1,2-dimethoxyethane and
1,2-diethoxyethane, and a halogenated solvent such as chloroform,
1,2-dichloroethane, 1,1,2,2-tetrachloroethane and
1,1,1-trichloroethane, and the present invention is not limited by
these. In addition, these solvents may be used in combination of
two or more. When the substrate is a liquid, it is possible to
react the materials without using any solvent. The reaction is
preferably carried out by using N,N-dimethylformamide,
N-methylpyrrolidone, propionitrile or dimethylsulfoxide, or without
any solvent.
[0069] In the above-mentioned reaction, in addition to the salt of
copper or palladium, a material in which a suitable ligand is
coordinated to copper or palladium may be used with a catalytic
amount or with a stoichiometric amount or more. At that time, it is
preferred to also use an organic base such as
1,4-diazabicyclo[2,2,2]octane, 1,8-diazabicyclo[5,4,0]undecene,
pyridine and N,N-dimethylaminopyridine, or an inorganic base such
as potassium tert-butoxide, sodium tert-butoxide, or potassium
carbonate, cesium carbonate and potassium phosphate. Pyridine,
potassium carbonate, cesium carbonate, potassium phosphate, etc.
are more preferred.
[0070] As a suitable ligand, there may be mentioned
tributylphosphine, triphenylphosphine, N-methylglycine,
N,N-dimethylglycine, 1,2-diaminocyclohexane, 1,10-phenanthroline
derivative, 8-hydroxyquinoline, picolinic acid and 2,2'-bipyridine,
and the present invention is not limited by these.
N,N-dimethylglycine, 1,2-diaminocyclohexane or 8-hydroxyquinoline
are more preferred.
[0071] When a small amount of water, Polyethylene glycol, etc., is
added good results can be sometimes obtained in the above-mentioned
reaction.
[0072] When X of the compound (IIIb) is boronic acid, good results
can be sometimes obtained if air or oxygen is optionally blown into
the reaction system.
[0073] The temperature of the above-mentioned reaction may vary
depending on the kind of the substrate, presence or absence of the
catalyst or the kind of the same, and is preferably 10.degree. C.
to 200.degree. C., more preferably 20.degree. C. to 150.degree. C.
At this time, when a microwave is irradiated, the reaction is
sometimes accelerated.
[0074] The above-mentioned reaction may vary depending on the kind
of the substrate, presence or absence of the catalyst or the kind
of the same, and completes within 15 minutes to 96 hours, generally
within 48 hours in many cases.
[0075] The concentration of the substrate in the above-mentioned
reaction is not particularly limited, and the reaction is generally
carried out with a concentration of 1 mM to neat (without solvent).
It is preferably 10 mM to 10 M.
[0076] The deprotection of the compound (IVb) to the compound (V)
or a salt thereof may be carried out by using a suitable method
depending on the P' used in view of Green, Protective Groups in
Organic Synthesis (5th), 1999, John Wieley & Sons.
Specifically, when the P' is a tert-butoxycarbonyl group, an acid
such as hydrochloric acid and trifluoroacetic acid is preferably
used. At that time, when anisole or thioanisole co-exists, good
results can be sometimes obtained.
[0077] The obtained hydrazine derivative (V) or a salt thereof is
reacted with 1,3-diketone or its chemical equivalent to synthesize
a phenylpyrazole derivative (VI) in which a pyrazole ring is
formed. Here, the chemical equivalent means a compound in which the
carbonyl group is protected by an acetal group, which can be easily
converted into a ketone group by an acid existing in the system
during the pyrazole ring-forming reaction.
[0078] The amount of the 1,3-diketone or its chemical equivalent to
be used in the above-mentioned reaction is preferably 1 to 20
equivalents, more preferably 1 to 5 equivalents based on the amount
of the compound (V).
[0079] The solvent suitable for the above-mentioned reaction may
vary depending on the substrate or the reaction conditions, and may
include an alcohol such as methanol, ethanol, methoxyethanol,
ethoxyethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol,
2-methyl-2-propanol, glycerol and 1,3-propanediol, an ether solvent
such as diethyl ether, diisopropyl ether, tetrahydrofuran,
methyl-tert-butyl ether, diphenyl ether, 1,4-dioxane, diethylene
glycol dimethyl ether, 1,2-dimethoxyethane and 1,2-diethoxyethane,
an acetic acid ester such as methyl acetate, ethyl acetate, propyl
acetate and butyl acetate, an aprotic solvent such as
N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone,
dimethyl sulfoxide, acetonitrile and propionitrile, and a
halogenated solvent such as dichloromethane, chloroform,
1,2-dichloroethane, 1,1,2,2-tetrachloroethane and
1,1,1-trichloroethane, and the present invention is not limited by
these. In addition, these solvents may be used in combination of
two or more. It is preferred to use methanol, ethanol, 2-propanol,
1,2-dimethoxyethane and N,N-dimethylformamide.
[0080] When the hydrazine derivative (V) is used as a free material
in the above-mentioned reaction, a suitable acid may be added in an
amount of a catalytic amount or 1 equivalent or more.
[0081] As a suitable acid, there may be mentioned hydrochloric
acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid,
trifluoroacetic acid and phosphoric acid, preferably hydrochloric
acid and trifluoroacetic acid.
[0082] The temperature of the above reaction may vary depending on
the kind of the substrates, and is preferably at 10.degree. C. to
200.degree. C., more preferably 40.degree. C. to 120.degree. C.
[0083] The above-mentioned reaction may vary depending on the kind
of the substrate, and completes within 15 minutes to 24 hours,
generally within 12 hours in many cases.
[0084] The concentration of the substrate in the above-mentioned
reaction is not particularly limited, and the reaction is generally
carried out with a concentration of 0.1 mM to 1 M, preferably 10 mM
to 1 M.
[0085] The obtained phenylpyrazole derivative (VI) can be led to
the compound (I) of the present invention, by deprotection of the
protective group if necessary. The deprotection reaction may be
carried out by using a suitable method depending on the P used in
view of Green, Protective Groups in Organic Synthesis (5th), 1999,
John Wieley & Sons. When P is a methyl group, boron tribromide,
aluminum chloride, etc., is preferably used, when P is a benzyl
group, catalytic hydrogenation and reduction, etc., is preferably
used, and when P is a p-toluenesulfonyl group, sodium hydroxide or
potassium hydroxide, etc., is preferably used.
[0086] The compound (I) of the present invention may be further
chemically modified to one or both of the benzene ring side chain
and the pyrazole ring side chain by an organic chemical reaction
generally used. For example, the compound having a carboxyl group
may be subjected to esterification, amidation, or reduction to
alcohol, the compound having an amino group may be subjected to
alkylation, acylation, or carbamation reaction, which are the
reactions easily conceived of by those skilled in the art having
knowledge in organic chemistry.
[0087] Also, the compound (I) of the present invention can be
synthesized by using a 2-nitro aniline derivative (IIIc), or a
nitrobenzene derivative (IIId) having a halogen or a boronic acid
group at the 2-position as shown in Scheme 2. Incidentally, in
Scheme 2, P' represents hydrogen or a suitable protective group, X
represents halogen or a suitable boronic acid group, and Y
represents a dissociated ion of an acid used in the reaction.
[0088] [Formula 4]
##STR00005##
[0089] Diazotization of the 2-nitroaniline derivative (IIIc),
reduction of the obtained diazonium compound, and cyclization of
the pyrazole ring can be carried out in accordance with the
preparation method of the above-mentioned reaction from (IIIa) to
(V), and, from (V) to (VI).
[0090] The reaction from the nitrobenzene derivative (IId) to the
2-nitrophenylpyrazole derivative (VIII) can be carried out in
accordance with the preparation method of the above-mentioned
reaction from (IIIb) to (VI). Or else, it can be synthesized in
accordance with the method described in J. Org. Chem., vol. 76, pp.
654-660, 2011.
[0091] Reduction from the 2-nitrophenylpyrazole derivative (VIII)
to the 2-aminophenylpyrazole derivative (IX) can be carried out in
view of Experimental Chemistry, fourth edition, pp. 159 to 266, and
utilizing the catalytic hydrogenation and reduction, in the
presence of an acid, reduction by a metal, reduction by a metal
hydride, and the like.
[0092] In the case of the catalytic hydrogenation and reduction,
the reaction is carried out with a hydrogen pressure of 1 to 80
atm, preferably to 5 atm.
[0093] The solvent suitable for the above-mentioned reaction may
vary depending on the substrate or the reaction conditions, and
there may be mentioned an alcohol such as methanol, ethanol,
methoxyethanol, ethoxyethanol, 1-propanol, 2-propanol, 1-butanol,
2-butanol and 2-methyl-2-propanol, an ether solvent such as diethyl
ether, diisopropyl ether, tetrahydrofuran, methyl-t-butyl ether,
diphenyl ether, diethylene glycol dimethyl ether and 1,4-dioxane,
an acetic acid ester such as methyl acetate, ethyl acetate, propyl
acetate and butyl acetate, and N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide,
glycerol, 1,3-propanediol, 1,2-dimethoxyethane, 1,2-diethoxyethane,
water and acetic acid, and the present invention is not limited by
these. In addition, these solvents may be used in combination of
two or more. It is preferred to use methanol, ethanol, 2-propanol
and 1,2-dimethoxyethane.
[0094] As the catalyst to be used in the catalytic hydrogenation
and reduction, there may be mentioned a metal such as palladium,
platinum, rhodium and nickel, and a complex thereof, these
compounds or a salt thereof which are adsorbed to activated carbon,
etc., and preferably palladium carbon and Raney nickel.
[0095] The temperature of the above-mentioned catalytic
hydrogenation reduction may vary depending on the kind of the
substrates and catalysts, and is preferably 0.degree. C. to
100.degree. C., more preferably 10.degree. C. to 50.degree. C.
[0096] The above-mentioned catalytic hydrogenation and reduction
may vary depending on the kind of the substrate, and completes
within 15 minutes to 24 hours, generally within 12 hours in many
cases.
[0097] The concentration of the substrate in the above-mentioned
catalytic hydrogenation and reduction is not particularly limited,
and the reaction is generally carried out with a concentration of
0.1 mM to 1M, preferably 1 mM to 100 mM.
[0098] When a metal is used as a reducing agent, the metal to be
used is iron, tin, zinc, etc., and it is necessary to add an acid
in either of the cases. As the acid to be used there may be
mentioned hydrochloric acid, sulfuric acid, acetic acid,
trifluoroacetic acid and phosphoric acid, preferably hydrochloric
acid. Moreover, these acids may be used also as a solvent.
[0099] The amount of the metal to be used in the above-mentioned
reaction is preferably 1 to 100 equivalents, more preferably 3 to
15 equivalents based on the amount of the compound (VIII).
[0100] The solvent suitable for the above-mentioned reaction may
vary depending on the substrate or the reaction conditions, and
there may be mentioned water, acetic acid, an alcohol such as
methanol, ethanol, methoxyethanol, ethoxyethanol, 1-propanol,
2-propanol, 1-butanol, 2-butanol and 2-methyl-2-propanol, an ether
solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran,
diphenyl ether, diethylene glycol dimethyl ether and 1,4-dioxane,
an acetic acid ester such as methyl acetate, ethyl acetate, propyl
acetate and butyl acetate, and N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide,
glycerol, 1,3-propanediol, 1,2-dimethoxyethane and
1,2-diethoxyethane, and the present invention is not limited by
these. In addition, these solvents may be used in combination of
two or more. It is preferred to use hydrochloric acid, acetic acid,
ethanol, 2-propanol and a mixture thereof.
[0101] The temperature of the above-mentioned reaction may vary
depending on the kind of the substrates or conditions, and is
preferably 0.degree. C. to 100.degree. C., more preferably
20.degree. C. to 50.degree. C.
[0102] The above-mentioned reaction may vary depending on the kind
of the substrate and the conditions, and completes within 1 hour to
24 hours, generally within 12 hours in many cases.
[0103] The concentration of the substrate in the above-mentioned
reaction is not particularly limited, and the reaction is generally
carried out with a concentration of 0.1 mM to 1 M, preferably 1 mM
to 100 mM.
[0104] In the case of the reduction reaction using a metal hydride,
there may be used, as a reagent, lithium borohydride, sodium
borohydride, potassium borohydride, zinc borohydride, lithium
triethoxyborane and diisobutylaluminum hydride, preferably lithium
borohydride or sodium borohydride. At that time, good results can
be sometimes be obtained when stannous chloride, nickel(II)
chloride, etc., co-exists.
[0105] The amount of the reducing agent to be used in the
above-mentioned reaction is preferably 1 to 50 equivalents, more
preferably 1 to 5 equivalents based on the amount of the compound
(VIII).
[0106] The solvent suitable for the above-mentioned reaction may
vary depending on the kinds of the substrate or the reducing agent,
and there may be mentioned an ether solvent such as diethyl ether,
diisopropyl ether, tetrahydrofuran, diphenyl ether, 1,4-dioxane,
diethylene glycol dimethyl ether, 1,2-dimethoxyethane and
1,2-diethoxyethane, and an alcohol such as methanol, ethanol,
methoxyethanol, ethoxyethanol, 1-propanol, 2-propanol, 1-butanol,
2-butanol and 2-methyl-2-propanol, and the present invention is not
limited by these. In addition, these solvents may be used in
combination of two or more. It is preferred to use methanol and a
mixture of methanol and diethylene glycol dimethyl ether.
[0107] The temperature of the above-mentioned reaction may vary
depending on the kind of the substrates or conditions, and is
preferably -80.degree. C. to 100.degree. C., more preferably
-20.degree. C. to 80.degree. C.
[0108] The above-mentioned reaction may vary depending on the kind
of the substrate and the conditions, and completes within 15
minutes to 24 hours, generally within 12 hours in many cases.
[0109] The concentration of the substrate in the above-mentioned
reaction is not particularly limited, and the reaction is generally
carried out with a concentration of 0.1 mM to 1 M, preferably 1 mM
to 100 mM.
[0110] The obtained 2-aminophenylpyrazole derivative (IX) can be
diazotized in accordance with the above-mentioned preparation
method of from (IIIa) to (IVa) and Japanese Unexamined Patent
Publication Hei 8-53401.
[0111] The reaction from the diazonium compound to (I) can be
carried out in accordance with the method described in Japanese
Unexamined Patent Publication Hei 8-188545 and Japanese Unexamined
Patent Publication Hei 11-60528.
[0112] Hydrolysis of the above-mentioned diazonium salt can be
carried out under acidic conditions and heating in water or in a
solvent containing water.
[0113] The solvent suitable for the above-mentioned reaction may
vary depending on the substrate or the reaction conditions, and
there may be mentioned water, acetic acid, trifluoroacetic acid, an
alcohol such as methanol, ethanol, methoxyethanol, ethoxyethanol,
glycerol, 1,3-propanediol, 1-propanol, 2-propanol, 1-butanol,
2-butanol and 2-methyl-2-propanol, an ether solvent such as
tetrahydrofuran, diethylene glycol dimethyl ether,
1,2-dimethoxyethane, 1,2-diethoxyethane and 1,4-dioxane, and an
aprotic solvent such as N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpynolidone and dimethylsulfoxide,
and the present invention is not limited by these. In addition,
these solvents may be used in combination of two or more. It is
preferred to use water, sulfuric acid, hydrochloric acid,
trifluoroacetic acid, acetic acid, methanol, ethanol and a mixture
of optional combination thereof.
[0114] The temperature of the above-mentioned reaction may vary
depending on the kind of the substrates or conditions, and is
preferably 20.degree. C. to 200.degree. C., more preferably
50.degree. C. to 150.degree. C.
[0115] The above-mentioned reaction may vary depending on the kind
of the substrate and the conditions, and completes within 10
minutes to 24 hours, generally within 12 hours in many cases.
[0116] The concentration of the substrate in the above-mentioned
reaction is not particularly limited, and the reaction is generally
carried out with a concentration of 0.1 mM to 1 M, preferably 1 mM
to 100 mM.
[0117] With Regard to Pressure Sensitive Adhesive
[0118] The patch for nail and/or skin for prevention or treatment
of dermatophytosis of the present invention comprises the
above-mentioned compound represented by the formula (I) or a salt
thereof in a pressure sensitive adhesive layer. As such a pressure
sensitive adhesive layer, there may be mentioned an optional
pressure sensitive adhesive to be generally used for a patch for
nail or skin. As the pressure sensitive adhesive, there may be
mentioned, for example, an acrylic-based pressure sensitive
adhesive, a silicone-based pressure sensitive adhesive, a
rubber-based pressure sensitive adhesive, a urethane-based pressure
sensitive adhesive, etc.
(1) Acrylic-Based Pressure Sensitive Adhesive
[0119] As the acrylic-based pressure sensitive adhesive, there may
be mentioned an optional acrylic-based pressure sensitive adhesive
to be generally used for a patch for nail or skin. Among these,
those comprising, as a base material, a (meth)acrylic acid ester
copolymer containing a (meth)acrylic acid alkyl ester having an
alkyl group with 4 to 12 carbon atoms as a monomer component. As
the monomer component of the (meth)acrylic acid alkyl ester, there
may be mentioned an acrylic acid alkyl ester such as n-butyl
acrylate, n-hexyl acrylate, n-octyl acrylate, 2-ethylhexyl
acrylate, isooctyl acrylate, isononyl acrylate, n-decyl acrylate,
isodecyl acrylate, 1,6-hexanediol diacrylate, etc.; and a
methacrylic acid alkyl ester such as 2-ethylhexyl methacrylate,
n-decyl methacrylate, isodecyl methacrylate, dodecyl methacrylate,
lauryl methacrylate, etc.
[0120] In such an acrylic-based pressure sensitive adhesive, for
example, a vinyl monomer having a functional group may be also
formulated as the monomer component in addition to the
above-mentioned (meth)acrylic acid alkyl ester. Specific examples
thereof may include a monomer having a hydroxyl group such as
2-hydroxyethyl acrylate, 3-hydroxypropyl acrylate, and
4-hydroxybutyl acrylate, etc.; a monomer having a carboxyl group
such as acrylic acid, methacrylic acid, etc.; a monomer having an
amino group such as acrylamide, dimethyl acrylamide, diethyl
acrylamide, methacrylamide and N-methylol acrylamide, etc.; a
monomer having an epoxy group such as glycidyl acrylate and
glycidyl methacrylate, etc.; and a non-functional group type
monomer, etc.
[0121] The monomer component of the acrylic-based pressure
sensitive adhesive is particularly preferably 2-ethylhexyl
acrylate, acrylic acid, 1,6-hexaneglycol dimethacrylate,
2-ethylhexyl methacrylate, dodecyl methacrylate, etc.
[0122] These monomer components may be used each singly, or in
admixture of two or more kinds in combination.
[0123] Other Monomer Component which can be Contained in the
Monomer Component
[0124] To the acrylic-based pressure sensitive adhesive may, be
formulated other monomer component(s) which can be contained in
addition to the above-mentioned monomer components. As such a
component, there may be mentioned a vinyl monomer having a lactam
ring such as N-vinyl pyrrolidine, etc.; a vinyl ester such as vinyl
acetate, an unsaturated nitrile such as acrylonitrile and
methacrylonitrile, etc.; and, a vinyl aromatic compound such as
styrene, etc. The other monomer components which can be contained
may be used each singly, or in admixture of two or more kinds in
combination.
[0125] Preferred Formulation Example of Acrylic-Based Pressure
Sensitive Adhesive
[0126] As the specific acrylic-based pressure sensitive adhesive,
preferred is a copolymer of 2-ethylhexyl acrylate and acrylic acid,
and their formulation ratio is preferably 99:1 to 90:10 (mass
ratio). Also preferred is a copolymer of 2-ethylhexyl acrylate and
N-vinylpyrrolidone, and their formulation ratio is preferably 70:30
to 90:10 (mass ratio).
[0127] Also preferred is a copolymer comprising 2-ethylhexyl
acrylate, 2-ethylhexyl methacrylate and dodecyl methacrylate, and
their formulation ratio is preferably 5:90:5 to 20:60:20 (molar
ratio).
[0128] Synthesis of Acrylic-Based Pressure Sensitive Adhesive
[0129] The acrylic-based pressure sensitive adhesive can be
generally synthesized by a radical polymerization. The
polymerization method may include a solution polymerization method,
an emulsion polymerization method or a bulk polymerization method,
etc., and a solution polymerization method is preferred since good
adhesive characteristics can be obtained.
[0130] The polymerization reaction can be carried out by adding a
radical polymerization initiator with a ratio of 0.1 to 1% by mass
or so based on the whole mass of the monomer components and
polymerizing these under nitrogen atmosphere, at a temperature of
40 to 90.degree. C. or so under stirring for several hours to
several ten hours. The polymerization initiator herein used may
include an organic peroxide such as benzoyl peroxide and lauroyl
peroxide, etc., and an azo series initiator such as
azobisisobutyronitrile, etc.
(2) Silicone-Based Pressure Sensitive Adhesive
[0131] As the silicone-based pressure sensitive adhesive, there may
be used, for example, a silicone-based pressure sensitive adhesive
disclosed in Japanese Unexamined Patent Publication 2006-213650.
Such a silicone-based pressure sensitive adhesive may include a
mixture of a silicone rubber and a silicone resin or a partial
condensate thereof. As the silicone rubber, there may be mentioned
a linear polydiorganosiloxane with a high molecular weight having a
silicon functional group such as a silanol group at the both
terminals, and the silicone resin may include a branched
polyorganosiloxane or those having a network structure, which
contains a 1-functional siloxane unit and a 4-functional siloxane
unit, and has a silicon functional group such as a silanol group or
a methoxy group in the molecule. More specifically, there may be
mentioned, as the silicone rubber, a copolymer of a long chain
polydimethylsiloxane, and as the silicone resin, an MQ resin (a
three-dimensional structure silicone resin comprising an M unit
((CH.sub.3).sub.3SiO.sub.1/2) and a Q unit (SiO.sub.2)).
[0132] A mixture ratio of the silicone rubber/silicone resin
constituting the silicone-based pressure sensitive adhesive is not
particularly limited, and it is preferably 30:70 to 60:40, more
preferably 35:65 to 45:55 (mass ratio). Particularly preferred
mixture ratio of the silicone rubber/silicone resin in the present
invention may be mentioned 40/60 (w/w) (BIO-PSA7-4501, available
from Dow Corning Corp.), 45/55 (w/w) (BIO-PSA7-4601, available from
Dow Corning Corp.), etc.
[0133] The silicone-based pressure sensitive adhesive is an
adhesive having a pressure-sensitive adhesiveness due to the
silicon functional group existing in the molecule. The organic
group bonded to the silicon atom may include various kinds of
monovalent hydrocarbon group such as methyl, ethyl, vinyl, phenyl,
etc., and the viscosity thereof can be controlled by selecting the
kind of the substituents. The silicone-based pressure sensitive
adhesive comprises a polyorganosiloxane as a main component which
has a long intermolecular distance, so that it is enriched in air
permeability and moisture permeability.
(3) Rubber-Based Pressure Sensitive Adhesive
[0134] As the rubber-based pressure sensitive adhesive, there may
be used, for example, a base material in which a tackifier, for
example, a hydrogenated rosin ester resin, a terpene resin, a
coumarone-indene resin, a petroleum-based resin, etc., is added to
a rubbery elastomer such as natural rubber, a
styrene-isoprene-styrene block copolymer, polyisobutylene,
polybutene, polyisoprene, etc. Preferred is a rubber-based pressure
sensitive adhesive in which a styrene-isoprene-styrene block
copolymer is formulated as the rubbery elastomer, and a
hydrogenated rosin ester resin or a terpene resin is formulated as
the tackifier. More specifically, there may preferably include a
rubber-based pressure sensitive adhesive in which a hydrogenated
rosin ester resin or terpene resin is formulated into a
styrene-isoprene-styrene block copolymer with the ratio of 1:1.
(4) Urethane-Based Pressure Sensitive Adhesive
[0135] As the urethane-based pressure sensitive adhesive, there may
be used, for example, either of the urethane-based pressure
sensitive adhesives which have been used as a pressure sensitive
adhesive for a percutaneous absorption patch, which are not
particularly limited. More specifically, there may preferably
include a urethane-based pressure sensitive adhesive obtained by
reacting polyether polyol and polyether monool in the presence of
an urethanization catalyst.
[0136] Formulation Ratio of the Compound of the Formula (I) or a
Salt Thereof to the Pressure Sensitive Adhesive Layer
[0137] The formulation ratio of the compound of the formula (I) or
a salt thereof in the pressure sensitive adhesive layer can be
optionally determined based on the kinds of the compounds. When the
compound of the formula (I) or a salt thereof is to be formulated
into the acrylic-based pressure sensitive adhesive layer, the
compound of the formula (I) or a salt thereof is formulated in an
amount of preferably 5 to 50% by mass, more preferably 5 to 30% by
mass, further more preferably 5 to 20% by mass, particularly
preferably 5 to 15% by mass into the whole acrylic-based pressure
sensitive adhesive layer with a total mass standard.
[0138] When the compound of the formula (I) or a salt thereof is to
be formulated into the silicone-based pressure sensitive adhesive
layer, the compound of the formula (I) or a salt thereof is
formulated in an amount of preferably 5 to 50% by mass, more
preferably 5 to 30% by mass, further more preferably 5 to 20% by
mass, particularly preferably 5 to 15% by mass into the whole
silicone-based pressure sensitive adhesive layer with a total mass
standard.
[0139] When the compound of the formula (I) or a salt thereof is
formulated into the rubber-based pressure sensitive adhesive layer,
the compound of the formula (I) or a salt thereof is formulated in
an amount of preferably 5 to 50% by mass, more preferably 5 to 30%
by mass, further more preferably 5 to 20% by mass, particularly
preferably 5 to 15% by mass into the whole rubber-based pressure
sensitive adhesive layer with a total mass standard.
[0140] When the compound of the formula (I) or a salt thereof is
formulated into the urethane-based pressure sensitive adhesive
layer, the compound of the formula (I) or a salt thereof is
formulated in an amount of preferably 5 to 50% by mass, more
preferably 5 to 30% by mass, further more preferably 5 to 20% by
mass, particularly preferably 5 to 15% by mass into the whole
urethane-based pressure sensitive adhesive layer with a total mass
standard:
[0141] Other Additives
[0142] In the pressure sensitive adhesive layer of the patch for
nail and/or skin of the present invention, a preservative, a
solubilizing agent, a permeation enhancer, a filler, an
antioxidant, a curing agent, etc., which are generally used for a
patch may be contained in addition to the components for the
above-mentioned pressure sensitive adhesive.
[0143] As the antiseptic, there may be formulated, for example,
organic preservatives (cationic activator, phenols, sorbate,
salicylate, dehydroacetate and benzoate, etc.), and inorganic
preservatives (antibacterial zeolite in which an antibacterial
metal ion such as silver, copper, zinc, etc., is ion-exchanged with
zeolite, etc.). As the solubilizing agent, there may be mentioned a
solubilizing agent including, for example, polyvalent alcohols
(glycerine, sorbitol, ethylene glycol, propylene glycol,
dipropylene glycol, 1,3-butylene glycol, 1,3-tetramethylene glycol,
polyethylene glycol, etc.), phenols (thymol, safrole, isosafrole,
eugenol, isoeugenol, etc.), higher alcohols (benzyl alcohol, oleyl
alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol,
octyldodecanol, etc.), ester type surfactants (sesquioleic acid
sorbitane, polyoxyethylene hydrogenated castor oil, polyoxyl
stearate, etc.), fatty acid esters (isopropyl myristate,
octyldodecyl myristate, oleyl oleate, diethyl phthalate, dibutyl
phthalate, etc.), (meth)acrylates (aminoalkyl methacrylate
copolymer, etc.), and organic acids (lactic acid, citric acid,
tartaric acid, maleic acid, malic acid, etc.).
[0144] As the permeation enhancer, there may be mentioned a
permeation enhancer including, for example, an aliphatic acid, an
aliphatic acid ester (isopropyl myristate, isopropyl palmitate,
diisopropyl sebacate, diethyl sebacate, diisopropyl adipate,
diethyl adipate, etc.), an aliphatic acid amide, an aliphatic
alcohol, 2-(2-ethoxyethoxy)-ethanol, an ester of glycerol, glycerol
monolaurate, propylene glycol, polyethylene glycol, an unsaturated
polyglycolated glyceride, saturated polyglyceride, .alpha.-hydroxy
acid, dimethyl sulfoxide, decylmethyl sulfoxide, pyrrolidones,
salicylic acid, lactic acid, dimethylformamide, dimethylacetamide,
sodium dodecyl sulfate, phospholipid, oleic acid, oleic
acid/2-(2-ethoxyethoxyl)ethanol, protease and N-acetylcysteine.
[0145] Also, as the filler, there may be specifically formulated
calcium carbonate, magnesium carbonate, silicate, zinc oxide,
titanium oxide, magnesium sulfate, calcium sulfate, etc., and as
the antioxidant, there may be specifically formulated dibutyl
hydroxy toluene, etc.
[0146] As the curing agent, there may be formulated a
polyisocyanate (for example, COLONATE L (trimethylolpropane adduct
of tolylene diisocyanate, available from NIPPON POLYURETHANE
INDUSTRY CO., LTD.)), etc.
[0147] Also, for the purpose of enhancing the cohesive force of the
acrylic-based pressure sensitive adhesive to be used in the
pressure sensitive adhesive layer of the patch for nail and/or skin
of the present invention, various kinds of cross-linking agents may
be further added to the pressure sensitive adhesive layer. As the
cross-linking agent, there may be mentioned a polyfunctional
isocyanate compound, a polyfunctional epoxy compound and a
polyvalent metal salt. More specifically, there may be preferably
used a polyisocyanate (for example, COLONATE HL (trimethylolpropane
adduct of hexamethylene diisocyanate, available from NIPPON
POLYURETHANE INDUSTRY CO., LTD.)).
[0148] Furthermore, for the purpose of improving the adhesiveness
of the silicone-based pressure sensitive adhesive to be used in the
pressure sensitive adhesive layer of the patch for nail and/or skin
of the present invention, various kinds of silicone fluids may be
added. As the silicone fluid, there may be formulated
polydimethylsiloxane fluid,
dimethylsiloxane.cndot.methylphenylsiloxane copolymer fluid,
dimethylsiloxane.cndot.methylvinylsiloxane copolymer fluid,
dimethylsiloxane.cndot.diphenylsiloxane copolymer fluid,
dimethylsiloxane.cndot.methyl(2-phenylpropyl)siloxane copolymer
fluid,
dimethylsiloxane.cndot.methyl(2-phenylpropyl)siloxane.cndot.methyloctylsi-
loxane copolymer fluid, and polyoxyalkylene-modified
polydimethylsiloxane fluid, each of both molecular ends of which
are sealed by trimethylsiloxy groups.
[0149] Preparation Method of the Patch of the Present Invention
[0150] For preparing the patch of the present invention, a mixture
of the compound of the formula (I) or a salt thereof which is an
effective ingredient, and the pressure sensitive adhesive and other
additive(s) if desired is applied on a suitable release liner, a
suitable support is adhered thereon, and cut to a suitable size, if
necessary, to prepare a final product.
[0151] The support usable for the patch of the present invention
can be optionally selected depending on the purposes in
consideration with flexibility, elasticity and a thickness, etc.,
in view of followability to the affected part and the easiness of
affixing it at the time of pasting, etc. Such a support may include
paper such as impregnated paper, coated paper, fine paper, kraft
paper, Japanese paper and glassine paper, etc.; a plastic film such
as a polyethylene terephthalate, polyester film, polyethylene film,
polypropylene film, polyvinyl chloride film, polycarbonate film,
polyurethane film and cellophane film, etc.; foam body; a cloth
base material such as non-woven fabric, woven fabric and knitted
fabric comprising polyester fiber, polyethylene fiber and
polypropylene fiber, etc.; and a laminated material thereof.
[0152] The thickness of the support to be used is preferably from 1
.mu.m to 200 .mu.m, more preferably from 10 .mu.m to 100 .mu.m,
further preferably from 20 to 50 .mu.m.
[0153] The release liner which can be used for the patch of the
present invention can be optionally selected depending on the
purposes in consideration with detacheability from the pressure
sensitive adhesive layer, air permeability, water permeability and
flexibility, etc. It is preferred to use a film having a thickness
of 10 to 200 .mu.m or so, comprising a polymer material such as
polyethylene, polypropylene and polyester, etc., and it may be used
after subjecting the film surface to a silicone treatment or a
fluorocarbon treatment to enhance detachability. Among these, a
polyethylene terephthalate film having a thickness of 75 .mu.m and
one surface of which is subjected to a silicone treatment is
preferably used.
[0154] For preparing the patch of the present invention, a general
method for preparing a patch can be optionally used. More
specifically, the preparation method described hereinbelow may be
mentioned.
[0155] When an acrylic-based pressure sensitive adhesive is used,
the acrylic-based pressure sensitive adhesive is firstly
synthesized by, for example, the above-mentioned solution
polymerization method, and by using a solution of the obtained
acrylic-based pressure sensitive adhesive, a patch is prepared by
the solution coating method.
[0156] In the solution coating method, firstly, a solution to which
the prepared acrylic-based pressure sensitive adhesive solution and
the compound of the formula (I) or a salt thereof, and if desired,
a permeation enhancer, a solubilizing agent, a preservatives, a
cross-linking agent, and other additive(s) were added is prepared.
To the solution, it is possible to add an organic solvent as a
diluent to optionally adjust the concentration thereof.
[0157] The organic solvent herein used may be mentioned n-hexane,
toluene, ethyl acetate, acetone, methyl ethyl ketone, etc. When
these organic solvents are added as a diluent, by using these
organic solvents, a solution containing the acrylic-based pressure
sensitive adhesive and the compound of the formula (I) or a salt
thereof in an amount of preferably 10 to 50% by mass, more
preferably 20 to 40% by mass based on the total mass of the whole
solution is prepared.
[0158] The amount of the compound of the formula (I) or a salt
thereof to be formulated in said solution can be optionally
determined depending on the kind of the compound of the formula
(I), the desired formulation amount of the compound of the formula
(I) in the finally obtained patch, and the amount of the
acrylic-based pressure sensitive adhesive.
[0159] The amount of the permeation enhancer, the solubilizing
agent, the preservative, the cross-linking agent and the other
additives can be optionally determined depending on the amounts of
the respective components.
[0160] Next, the above-mentioned solution (diluent) containing the
respective components is stirred to uniformly dissolve and disperse
the respective components. The solution thus obtained is uniformly
applied by using a coating machine such as a knife coater, a comma
coater or a reverse coater, etc., on, for example, a release liner
(a silicone-treated polyethylene terephthalate film, etc.). The
applied amount of above-mentioned solution can be optionally
determined depending on the thickness of the objective pressure
sensitive adhesive layer, the kind of the pressure sensitive
adhesive to be used, the kind of the compound of the formula (I),
and an amount thereof. For example, in the case of the solution
containing 30% by mass of the acrylic-based pressure sensitive
adhesive based on the total mass of the solution, and 3.5% by mass
of the compound of the formula (I) based on the total mass of the
solution, it is preferably applied with a thickness of 10 to 300
.mu.m, more preferably 20 to 200 .mu.m.
[0161] After applying, the liner is maintained at a temperature of
about 40.degree. C. to 130.degree. C. under dry-heat atmosphere for
about 30 seconds to 10 minutes to volatilize the organic solvent.
The drying conditions are optionally selected depending on the kind
of the organic solvent to be used and the thickness of the pressure
sensitive adhesive to be applied.
[0162] A patch can be obtained by laminating a support on the
surface of the obtained pressure sensitive adhesive layer.
Depending on the kind of the support, after forming the pressure
sensitive adhesive layer on the support, a release liner may be
laminated on the surface of the pressure sensitive adhesive
layer.
EXAMPLES
[0163] Although the following provides a more detailed explanation
of the present invention through Examples, the present invention is
not limited by these Examples. In addition, "%" and "parts" in
Examples mean "% by mass" and "part by mass", respectively.
Furthermore, "room temperature" in Examples indicates usually from
about 1.degree. C. to about 40.degree. C.
1. Preparation of Compounds of General Formula (I)
Preparation Example 1
2-(3,5-Dimethyl-1H-pyrazol-1-yl)phenol
a) 1-(2-Methoxyphenyl)-3,5-dimethyl-1H-pyrazole
[0164] 3.50 g of 2-methoxyphenylhydrazine hydrochloride was
dissolved in 60 ml of ethanol and 2.06 ml of acetylacetone was
added, followed by heating to reflux for 1 hour. To the reaction
mixture was added 150 ml of water, followed by neutralizing with a
saturated aqueous sodium carbonate solution and extracting with 150
ml of ethyl acetate. The organic layer was dried over anhydrous
magnesium sulfate, subsequently the solvent was distilled off under
reduced pressure, and purification by silica gel column
chromatography (hexane:ethyl acetate=2:1) afforded 3.88 g of the
title compound.
[0165] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.08 (3H, s), 2.29
(3H, s), 3.78 (3H, s), 5.95 (1H, s), 6.98-7.03 (2H, m), 7.29-7.32
(1H, m), 7.34-7.39 (1H, m).
[0166] MS (ESI); m/z 203 (M+H).sup.+
b) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)phenol
[0167] 3.88 g of 1-(2-methoxyphenyl)-3,5-dimethyl-1H-pyrazole was
dissolved in 40 ml of methylene chloride and 32 ml of a 1M solution
of boron tribromide in methylene chloride was added, followed by
stirring at room temperature for 1.5 hours. The reaction mixture
was added to 150 ml of water, followed by neutralizing with
1N-sodium hydroxide and extracting with 150 ml of ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate,
subsequently the solvent was distilled off under reduced pressure,
and purification by silica gel column chromatography (hexane:ethyl
acetate=3:1) afforded 2.83 g of the title compound.
[0168] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.29 (3H, s), 2.38
(3H, s), 6.02 (1H, s), 6.87-6.6.91 (1H, m), 7.06-7.09 (1H, m),
7.16-7.20 (1H, m).
[0169] MS (ESI); m/z 189 (M+H).sup.+
Preparation Example 2
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-4-fluorophenol
a) 2-Amino-4-fluorophenol
[0170] 300 mg of 4-fluoro-2-nitrophenol was dissolved in 3 ml of
ethanol and 120 mg of 10% palladium/carbon was added, followed by
stirring under a hydrogen atmosphere at room temperature for 1
hour. The insoluble material was filtered and subsequently the
filtrate was distilled off under reduced pressure to afford 211 mg
of the title compound.
[0171] .sup.1H-NMR (DMSO-d6); .delta. (ppm) 4.80 (2H, s), 6.09-6.14
(1H, m), 6.34-6.37 (1H, m), 6.53-6.57 (1H, m), 8.93 (1H, s).
[0172] MS (FAB); m/z 128 (M+H).sup.+
b) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-4-fluorophenol
[0173] To 100 mg of 2-amino-4-fluorophenol was added 0.8 ml of
5N-hydrochloric acid and a solution of 65 mg of sodium nitrite
dissolved in 0.2 ml of water was added dropwise at 0.degree. C.,
followed by stirring for 30 minutes. Then, a solution of 249 mg of
stannous chloride dissolved in 0.46 ml of 5N-hydrochloric acid was
added dropwise at 0.degree. C., followed by stirring at 0.degree.
C. for 30 minutes and then at room temperature for 2 hours. The
solvent was distilled off under reduced pressure and 2.5 ml of
ethanol and 81 .mu.l of acetylacetone were added, followed by
heating to reflux for 4 hours. To the reaction mixture was added 50
ml of water, followed by neutralizing with saturated sodium
hydrogen carbonate solution and extracting with 50 ml of ethyl
acetate. The organic layer was dried over anhydrous magnesium
sulfate, subsequently the solvent was distilled off under reduced
pressure, and purification by silica gel column chromatography
(hexane:ethyl acetate=2:1) afforded 20.6 mg of the title
compound.
[0174] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.24 (3H, s), 2.33
(3H, s), 5.99 (1H, s), 6.82-6.90 (2H, m), 6.95-6.98 (1H, m).
[0175] MS (FAB); m/z 207 (M+H).sup.+
Preparation Example 3
2-(1H-Pyrazol-1-yl)phenol
a) 1-(2-Methoxyphenyl)-1H-pyrazole
[0176] 200 mg of 2-methoxyphenylhydrazine hydrochloride was
dissolved in 5 ml of ethanol and 189 .mu.l of malonaldehyde
bisdimethylacetal was added, followed by heating to reflux for 2
hours. To the reaction mixture was added 50 ml of water, followed
by neutralizing with a saturated aqueous sodium carbonate solution
and extracting with 60 ml of ethyl acetate. The organic layer was
dried over anhydrous magnesium sulfate and subsequently the solvent
was distilled off under reduced pressure to afford 179.4 mg of the
title compound.
[0177] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 3.87 (3H, s), 6.42
(1H, d, J=2.4 Hz), 7.02-7.07 (2H, m), 7.27-7.32 (1H, m), 7.68-7.72
(2H, m), 8.01 (1H, d, J=2.4 Hz).
[0178] MS (FAB); m/z 175 (M+H).sup.+
b) 2-(1H-Pyrazol-1-yl)phenol
[0179] 121 mg of the title compound was afforded from 178 mg of
1-(2-methoxyphenyl)-1H-pyrazole in a manner similar to Preparation
example 1b).
[0180] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 6.49 (1H, d, J=2.4
Hz), 6.88-6.92 (1H, m), 7.08-7.10 (1H, m), 7.14-7.18 (1H, m),
7.35-7.37 (1H, m), 7.72 (1H, s), 7.99 (1H, d, J=2.4 Hz).
[0181] MS (ESI); m/z 161 (M+H).sup.+
Preparation Example 4
2-(5-Hydroxy-3-methyl-1H-pyrazol-1-yl)phenol
a) 5-Hydroxy-1-(2-methoxyphenyl)-3-methyl-1H-pyrazole
[0182] 55.1 mg of the title compound was afforded from 150 mg of
2-methoxyphenylhydrazine hydrochloride and 93 .mu.l of methyl
acetoacetate in a manner similar to Preparation example 1a).
[0183] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.11 (3H, s), 3.76
(3H, s), 6.88-6.94 (3H, m), 7.19-7.34 (2H, m).
[0184] MS (ESI); m/z 204 (M+H).sup.+
b) 2-(5-Hydroxy-3-methyl-1H-pyrazol-1-yl)phenol
[0185] 32.4 mg of the title compound was afforded from 52 mg of
5-hydroxy-1-(2-methoxyphenyl)-3-methyl-1H-pyrazole in a manner
similar to Preparation example 1b).
[0186] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.17 (3H, s), 5.30
(1H, s), 6.88-6.95 (2H, m), 7.15 (1H, t, J=7.6 Hz), 7.37 (1H, d,
J=7.6 Hz).
[0187] MS (FAB); m/z 191 (M+H).sup.+
Preparation Example 5
2-(5-Methyl-3-trifluoromethyl-1H-pyrazol-1-yl)phenol
a) 1-(2-Methoxyphenyl)-5-methyl-3-trifluoromethyl-1H-pyrazole
[0188] 300 mg of 2-methoxyphenylhydrazine hydrochloride was
dissolved in 1.3 ml of 2-methoxyethanol, and 2.5 ml of acetic acid
and 208 .mu.l of 1,1,1-trifluoro-2,4-pentanedione were added,
followed by heating to reflux for 1 hour and 40 minutes. The
solvent was distilled off under reduced pressure, 50 ml of ethyl
acetate was added, the organic layer washed with 50 ml of saturated
sodium hydrogen carbonate solution and 50 ml of saturated brine was
dried over anhydrous magnesium sulfate, and the solvent was
distilled off under reduced pressure to afford 485.6 mg of the
title compound.
[0189] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.14 (3H, s), 3.78
(3H, s), 6.40 (1H, s), 7.00-7.07 (2H, m), 7.31-7.33 (1H, m),
7.41-7.45 (1H, m).
[0190] MS (ESI); m/z 257 (M+H).sup.+
b) 2-(5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenol
[0191] 320.1 mg of the title compound was afforded from
1-(2-methoxyphenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole in a
manner similar to Preparation example 1b).
[0192] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.41 (3H, s), 6.52
(1H, s), 6.95-6.99 (1H, m), 7.11-7.13 (1H, m), 7.20-7.24 (1H, m),
7.28-7.32 (1H, m).
[0193] MS (FAB); m/z 243 (M+H).sup.+
Preparation Example 6
2-(3,5-Bistrifluoromethyl-1H-pyrazol-1-yl)phenol
a) 1-(2-Methoxyphenyl)-3,5-bistrifluoromethyl-1H-pyrazole
[0194] The title compound was afforded from 300 mg of
2-methoxyphenylhydrazine hydrochloride and 243 .mu.l of
hexafluoroacetylacetone in a manner similar to Preparation example
5a).
[0195] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 3.77 (3H, s),
7.01-7.06 (3H, m), 7.33 (1H, d, J=7.6 Hz), 7.49 (1H, d, J=7.6
Hz).
[0196] MS (ESI); m/z 311 (M+H).sup.+
b) 2-(3,5-Bistrifluoromethyl-1H-pyrazol-1-yl)phenol
[0197] 455.6 mg of the title compound was afforded from
1-(2-methoxyphenyl)-3,5-bistrifluoromethyl-1H-pyrazole obtained in
the above a) in a manner similar to Preparation example 1b).
[0198] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 6.99-7.04 (1H, m),
7.07-7.08 (1H, m), 7.10 (1H, s), 7.32-7.41 (2H, m).
[0199] MS (FAB); m/z 297 (M+H).sup.+
Preparation Example 7
2-(3-Methyl-1H-pyrazol-1-yl)phenol
a) 1-(2-Methoxyphenyl)-3-methyl-1H-pyrazole
[0200] 115.1 mg of the title compound was afforded from 200 mg of
2-methoxyphenylhydrazine hydrochloride and 151 .mu.l of
4,4-dimethoxybutan-2-one in a manner similar to Preparation example
1a).
[0201] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.31 (3H, s), 3.80
(3H, s), 6.14 (1H, d, J=2.4 Hz), 6.95-6.99 (2H, m), 7.18-7.22 (1H,
m), 7.61-7.63 (1H, m), 7.84 (1H, d, J=2.4 Hz).
[0202] MS (FAB); m/z 189 (M+H).sup.+
b) 2-(3-Methyl-1H-pyrazol-1-yl)phenol
[0203] 76 mg of the title compound was afforded from 115 mg of
1-(2-methoxyphenyl)-3-methyl-1H-pyrazole in a manner similar to
Preparation example 1b).
[0204] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.36 (3H, s), 6.24
(1H, d, J=2.4 Hz), 6.85-6.89 (1H, m), 7.05-7.14 (2H, m), 7.29-7.31
(1H, m), 7.86 (1H, d, J=2.4 Hz).
[0205] MS (FAB); m/z 175 (M+H).sup.+
Preparation Example 8
2-(5-Methyl-1H-pyrazol-1-yl)phenol
a) 1-(2-Methoxyphenyl)-5-methyl-1H-pyrazole
[0206] 70 mg of the title compound was afforded from 200 mg of
2-methoxyphenylhydrazine hydrochloride and 151 .mu.l of
4,4-dimethoxybutan-2-one in a manner similar to Preparation example
1a).
[0207] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.07 (3H, s), 3.71
(3H, s), 6.09 (1H, s), 6.94-6.99 (2H, m), 7.24-7.26 (1H, m),
7.31-7.35 (1H, m), 7.52 (1H, s).
[0208] MS (FAB); m/z 189 (M+H).sup.+
b) 2-(5-Methyl-1H-pyrazol-1-yl)phenol
[0209] 45.5 mg of the title compound was afforded from 69 mg of
1-(2-methoxyphenyl)-5-methyl-1H-pyrazole in a manner similar to
Preparation example 1b).
[0210] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.41 (3H, s), 6.27
(1H, d, J=1.6 Hz), 6.90-6.94 (1H, m), 7.10-7.12 (1H, m), 7.19-7.24
(2H, m), 7.66 (1H, d, J=1.6 Hz).
[0211] MS (FAB); m/z 175 (M+H).sup.+
Preparation Example 9
2-(3,4,5-Trimethyl-1H-pyrazol-1-yl)phenol
a) 1-(2-Methoxyphenyl)-3,4,5-trimethyl-1H-pyrazole
[0212] 200 mg of 2-methoxyphenylhydrazine hydrochloride was
dissolved in 4 ml of ethanol and 134 .mu.l of
3-methyl-2,4-pentanedione was added, followed by heating to reflux
for 3 hours. To the reaction mixture was added 50 ml of water,
followed by neutralizing with a saturated aqueous sodium carbonate
solution and extracting with 60 ml of ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate and subsequently
the solvent was distilled off under reduced pressure to afford
209.8 mg of the title compound.
[0213] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 1.98 (3H, s), 2.02
(3H, s), 2.24 (3H, s), 3.80 (3H, s), 6.99-7.04 (2H, m), 7.29-7.31
(1H, m), 7.34-7.39 (1H, m).
[0214] MS (FAB); m/z 217 (M+H).sup.+
b) 2-(3,4,5-Trimethyl-1H-pyrazol-1-yl)phenol
[0215] 104 mg of the title compound was afforded from 209 mg of
1-(2-methoxyphenyl)-3,4,5-trimethyl-1H-pyrazole in a manner similar
to Preparation example 1b).
[0216] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 1.99 (3H, s), 2.25
(3H, s), 2.31 (3H, s), 6.90 (1H, t, J=8.0 Hz), 7.08 (1H, d, J=8.0
Hz), 7.06-7.20 (2H, m), 9.89 (1H, s).
[0217] MS (ESI); m/z 203 (M+H).sup.+
Preparation Example 10
2-(5-Amino-3-tert-butyl-1H-pyrazol-1-yl)phenol
a) 3-tert-Butyl-1-(2-methoxyphenyl)-1H-pyrazol-5-amine
[0218] 310.3 mg of the title compound was afforded from 300 mg of
2-methoxyphenylhydrazine hydrochloride and 215 mg of
4,4-dimethyl-3-oxopentanenitrile and 40 .mu.l of acetic acid in a
manner similar to Preparation example 1a).
[0219] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 1.32 (9H, s), 3.80
(2H, s), 3.86 (3H, s), 5.51 (1H, s), 7.01-7.08 (2H, m), 7.30-7.35
(1H, m), 7.45-7.47 (1H, m).
[0220] MS (FAB); m/z 246 (M+H).sup.+
b) 2-(5-Amino-3-tert-butyl-1H-pyrazol-1-yl)phenol
[0221] 66.2 mg of the title compound was afforded from 100 mg of
3-tert-butyl-1-(2-methoxyphenyl)-1H-pyrazol-5-amine in a manner
similar to Preparation example 1b).
[0222] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 1.30 (9H, s), 3.93
(2H, s), 5.55 (1H, s), 6.90 (1H, dt, J=1.6, 8.0 Hz), 7.08 (1H, dd,
J=1.6, 8.0 Hz), 7.17 (1H, dt, J=1.6, 8.0 Hz), 7.47 (1H, dd, 8.0
Hz), 10.39 (1H, brs).
[0223] MS (FAB); m/z 232 (M+H).sup.+
Preparation Example 11
4-Chloro-2-(3,5-dimethyl-1H-pyrazol-1-yl)phenol
a) 1-(5-Chloro-2-methoxyphenyl)-3,5-dimethyl-1H-pyrazole
[0224] 104.8 mg of the title compound was afforded from 388 mg of
5-chloro-2-methoxyaniline hydrochloride in a manner similar to
Preparation example 2b).
[0225] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.11 (3H, s), 2.29
(3H, s), 3.79 (3H, s), 5.96 (1H, s), 6.93 (1H, dd, J=2.4, 7.2 Hz),
7.33-7.35 (2H, m).
[0226] MS (FAB); m/z 237 (M+H).sup.+
b) 4-Chloro-2-(3,5-dimethyl-1H-pyrazol-1-yl)phenol
[0227] 67.3 mg of the title compound was afforded from 104.8 mg of
1-(5-chloro-2-methoxyphenyl)-3,5-dimethyl-1H-pyrazole in a manner
similar to Preparation example 1b).
[0228] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.30 (3H, s), 2.43
(3H, s), 6.05 (1H, s), 7.02 (1H, d, J=8.8 Hz), 7.14-7.20 (2H, m),
10.08 (1H, s).
[0229] MS (FAB); m/z 223 (M+H).sup.+
Preparation Example 12
2-Chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)phenol
a) 1-(3-Chloro-2-methoxyphenyl)-3,5-dimethyl-1H-pyrazole
[0230] 30.6 mg of the title compound was afforded from 158 mg of
3-chloro-o-anisidine in a manner similar to Preparation example
2b).
[0231] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.14 (3H, s), 2.29
(3H, s), 3.49 (3H, s), 5.99 (1H, s), 7.12 (1H, t, J=8.0 Hz),
7.27-7.31 (1H, m), 7.43-7.46 (1H, m).
[0232] MS (ESI); m/z 236 (M+H).sup.+
b) 2-Chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)phenol
[0233] 27.4 mg of the title compound was afforded from 63.4 mg of
1-(3-chloro-2-methoxyphenyl)-3,5-dimethyl-1H-pyrazole in a manner
similar to Preparation example 1b).
[0234] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.30 (3H, s), 2.40
(3H, s), 6.05 (1H, s), 6.86 (1H, t, J=8.0 Hz), 7.13-7.15 (1H, m),
7.26-7.31 (1H, m), 10.66 (1H, s).
[0235] MS (FAB); m/z 223 (M+H).sup.+
Preparation Example 13
2-(4-Chloro-3,5-dimethyl-1H-pyrazol-1-yl)phenol
a) 4-Chloro-1-(2-methoxyphenyl)-3,5-dimethyl-1H-pyrazole
[0236] 193.9 mg of the title compound was afforded from 174.6 mg of
2-methoxyphenylhydrazine hydrochloride and 114 .mu.l of
3-chloropentane-2,4-dione in a manner similar to Preparation
example 1a).
[0237] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.09 (3H, s), 2.29
(3H, s), 3.81 (3H, s), 7.00-7.06 (2H, m), 7.30 (1H, dd, J=1.6, 7.6
Hz), 7.38-7.43 (1H, m).
[0238] MS (FAB); m/z 237 (M+H).sup.+
b) 2-(4-Chloro-3,5-dimethyl-1H-pyrazol-1-yl)phenol
[0239] 151.9 mg of the title compound was afforded from 193 mg of
4-chloro-1-(2-methoxyphenyl)-3,5-dimethyl-1H-pyrazole in a manner
similar to Preparation example 1b).
[0240] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.30 (3H, s), 2.37
(3H, s), 6.91-6.95 (1H, m), 7.09 (1H, dd, J=1.6, 8.0 Hz), 7.17 (1H,
dd, J=1.6, 8.0 Hz), 7.21-7.25 (1H, m), 9.23 (1H, s).
[0241] MS (FAB); m/z 223 (M+H).sup.+
Preparation Example 14
2-(3,5-Diethyl-1H-pyrazol-1-yl)phenol
a) 3,5-Diethyl-1-(2-methoxyphenyl)-1H-pyrazole
[0242] 209.8 mg of the title compound was afforded from 174.6 mg of
2-methoxyphenylhydrazine hydrochloride and 135.5 .mu.l of
3,5-heptanedione in a manner similar to Preparation example
1a).
[0243] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 1.14-1.18 (3H, m),
1.25-1.31 (3H, m), 2.42 (2H, q, J=7.2 Hz), 2.67-2.73 (2H, m), 3.78
(3H, s), 6.03 (1H, s), 6.99-7.04 (2H, m), 7.31-7.40 (2H, m).
[0244] MS (FAB); m/z 231 (M+H).sup.+
b) 2-(3,5-Diethyl-1H-pyrazol-1-yl)phenol
[0245] 159.2 mg of the title compound was afforded from 207 mg of
3,5-diethyl-1-(2-methoxyphenyl)-1H-pyrazole in a manner similar to
Preparation example 1b).
[0246] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 1.24-1.31 (6H, m),
2.69 (2H, q, J=7.6 Hz), 2.76 (2H, q, J=7.6 Hz), 6.11 (1H, s), 6.90
(1H, q, J=7.6 Hz), 7.09 (1H, d, J=7.6 Hz), 7.19-7.22 (2H, m), 9.69
(1H, s).
[0247] MS (FAB); m/z 217 (M+H).sup.+
Preparation Example 15
3-(3,5-Dimethyl-1H-pyrazol-1-yl)benzene-1,2-diol
a) 1-(2,3-Dimethoxyphenyl)-3,5-dimethyl-1H-pyrazole
[0248] 189 mg of the title compound was afforded from 306 mg of
2,3-dimethoxyaniline in a manner similar to Preparation example
2b).
[0249] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.14 (3H, s), 2.29
(3H, s), 3.53 (3H, s), 3.91 (3H, s), 5.96 (1H, s), 6.96-6.70 (2H,
m), 7.12 (1H, t, J=8.0 Hz).
[0250] MS (FAB); m/z 233 (M+H).sup.+
b) 3-(3,5-Dimethyl-1H-pyrazol-1-yl)benzene-1,2-diol
[0251] 28.9 mg of the title compound was afforded from 186 mg of
1-(2,3-dimethoxyphenyl)-3,5-dimethyl-1H-pyrazole in a manner
similar to Preparation example 1b).
[0252] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.26 (3H, s), 2.38
(3H, s), 5.99 (1H, s), 6.75-6.85 (3H, m).
[0253] MS (FAB); m/z 205 (M+H).sup.+
Preparation Example 16
2-(3,5-Dimethyl-1H-pyrazol-1-yl)benzene-1,4-diol
a) 1-(2,5-Dimethoxyphenyl)-3,5-dimethyl-1H-pyrazole
[0254] 260.3 mg of the title compound was afforded from 306 mg of
2,5-dimethoxyaniline in a manner similar to Preparation example
2b).
[0255] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.11 (3H, s), 2.30
(3H, s), 3.73 (3H, s), 3.78 (3H, s), 5.96 (1H, s), 6.91-6.93 (3H,
in).
[0256] b) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)benzene-1,4-diol 162.6 mg
of the title compound was afforded from 260.3 mg of
1-(2,5-dimethoxyphenyl)-3,5-dimethyl-1H-pyrazole in a manner
similar to Preparation example 1b).
[0257] .sup.1H-NMR (DMSO-d6); .delta. (ppm) 2.07 (3H, s), 2.14 (3H,
s), 5.93 (1H, s), 6.56 (1H, d, J=2.8 Hz), 6.66-6.69 (1H, m), 6.80
(1H, d, J=8.8 Hz), 9.02 (1H, s), 9.17 (1H, s).
[0258] MS (FAB); m/z 205 (M+H).sup.+
Preparation Example 17
2-(4-Ethyl-3,5-dimethyl-1H-pyrazol-1-yl)phenol
a) 4-Ethyl-1-(2-methoxyphenyl)-3,5-dimethyl-1H-pyrazole
[0259] 236.6 mg of the title compound was afforded from 200 mg of
2-methoxyphenylhydrazine hydrochloride and 155 .mu.l of
3-ethyl-2,4-pentanedione in a manner similar to Preparation example
1a).
[0260] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 1.13 (3H, t, J=7.6
Hz), 2.03 (3H, s), 2.27 (3H, s), 2.42 (2H, q, J=7.6 Hz), 3.79 (3H,
s), 6.99-7.04 (2H, m), 7.30-7.39 (2H, m).
[0261] MS (FAB); m/z 231 (M+H).sup.+
b) 2-(4-Ethyl-3,5-dimethyl-1H-pyrazol-1-yl)phenol
[0262] 196.2 mg of the title compound was afforded from 232 mg of
4-ethyl-1-(2-methoxyphenyl)-3,5-dimethyl-1H-pyrazole in a manner
similar to Preparation example 1b).
[0263] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 1.12 (3H, t, J=7.6
Hz), 2.27 (3H, s), 2.33 (3H, s), 2.43 (2H, q, J=7.6 Hz), 6.88-6.92
(1H, m), 7.08-7.10 (1H, m), 7.06-7.19 (2H, m), 9.90 (1H, s).
[0264] MS (FAB); m/z 217 (M+H).sup.+
Preparation Example 18
5-Fluoro-2-(3,4,5-trimethyl-1H-pyrazol-1-yl)phenol
[0265] 114.7 mg of the title compound was afforded from 201.2 mg of
2-amino-5-fluorophenol and 184 .mu.l of 3-methyl-2,4-pentanedione
in a manner similar to Preparation example 1b).
[0266] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 1.99 (3H, s), 2.23
(3H, s), 2.28 (3H, s), 6.59-6.64 (1H, m), 6.78-6.81 (1H, m),
7.10-7.14 (1H, m).
[0267] MS (ESI); m/z 221 (M+H).sup.+
Preparation Example 19
2-(4-Chloro-3,5-dimethyl-1H-pyrazol-1-yl)benzene-1,4-diol
a) 4-Chloro-1-(2,5-dimethoxyphenyl)-3,5-dimethyl-1H-pyrazole
[0268] 333.7 mg of the title compound was afforded from 306 mg of
2,5-dimethoxyaniline and 228 of 3-chloropentane-2,4-dione in a
manner similar to Preparation example 2b).
[0269] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.10 (3H, s), 2.29
(3H, s), 3.74 (3H, s), 3.78 (3H, s), 6.94-6.97 (2H, m), 7.26 (1H,
s).
[0270] MS (FAB); m/z 267 (M+H).sup.+
b) 2-(4-Chloro-3,5-dimethyl-1H-pyrazol-1-yl)benzene-1,4-diol
[0271] 184.8 mg of the title compound was afforded from 329 mg of
4-chloro-1-(2,5-dimethoxyphenyl)-3,5-dimethyl-1H-pyrazole in a
manner similar to Preparation example 1b).
[0272] .sup.1H-NMR (DMSO-d6); .delta. (ppm) 2.05 (3H, s), 2.15 (3H,
s), 6.58 (1H, d, J=2.8 Hz), 6.72 (1H, dd, J=2.8, 8.8 Hz), 6.82 (1H,
d, J=8.8 Hz), 9.11 (1H, s), 9.33 (1H, s).
[0273] MS (FAB); m/z 239 (M+H).sup.+
Preparation Example 20
4-Fluoro-2-(3,4,5-trimethyl-1H-pyrazol-1-yl)phenol
[0274] 84.8 mg of the title compound was afforded from 111 mg of
2-amino-4-fluorophenol and 102 .mu.l of 3-methyl-2,4-pentanedione
in a manner similar to Preparation example 2b).
[0275] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 1.99 (3H, s), 2.23
(3H, s), 2.24 (3H, s), 2.34 (3H, s), 6.87-6.95 (2H, m), 7.00-7.03
(1H, m), 9.90 (1H, s).
[0276] MS (FAB); m/z 221 (M+H).sup.+
Preparation Example 21
2-(4-Chloro-3,5-dimethyl-1H-pyrazol-1-yl)-5-fluorophenol
[0277] 62 mg of the title compound was afforded from 100 mg of
2-amino-5-fluorophenol and 90 .mu.l of 3-chloropentane-2,4-dione in
a manner similar to Preparation example 2b).
[0278] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.29 (3H, s), 2.35
(3H, s), 6.62-6.67 (1H, m), 6.78-6.81 (1H, m), 7.10-7.14 (1H, m),
9.44 (1H, s).
[0279] MS (FAB); m/z 241 (M+H).sup.+
Preparation Example 22
Ethyl 1-(2-hydroxyphenyl)-3,5-dimethyl-1H-pyrazol-4-carboxylate
a) Ethyl
1-(2-methoxyphenyl)-3,5-dimethyl-1H-pyrazol-4-carboxylate
[0280] 82.6 mg of the title compound was afforded from 175 mg of
2-methoxyphenylhydrazine hydrochloride and 156 .mu.l of ethyl
2-acetyl-3-oxobutanoate in a manner similar to Preparation example
1a).
[0281] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 1.38 (3H, t, J=7.6
Hz), 2.33 (3H, s), 2.50 (3H, s), 0.80 (3H, s), 4.32 (2H, q, J=7.6
Hz), 7.02-7.08 (2H, m), 7.30-7.32 (1H, m), 7.41-7.45 (1H, m).
[0282] MS (ESI); m/z 275 (M+H).sup.+
b) Ethyl
1-(2-hydroxyphenyl)-3,5-dimethyl-1H-pyrazol-4-carboxylate
[0283] 21 mg of the title compound was afforded from 82 mg of ethyl
1-(2-methoxyphenyl)-3,5-dimethyl-1H-pyrazol-4-carboxylate in a
manner similar to Preparation example 1b).
[0284] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 1.39 (3H, t, J=7.2
Hz), 2.50 (3H, s), 2.61 (3H, s), 4.34 (2H, q, J=7.2 Hz), 6.96 (1H,
t, J=8.4 Hz), 7.10 (1H, d, J=8.4 Hz), 7.17 (1H, d, J=8.4 Hz),
7.26-7.30 (1H, m), 8.76 (1H, s).
[0285] MS (FAB); m/z 261 (M+H).sup.+
Preparation Example 23
Methyl
3-(1-(2-hydroxyphenyl)-3,5-dimethyl-1H-pyrazol-4-yl)propanoate
a) Methyl
3-(1-(2-methoxyphenyl)-3,5-dimethyl-1H-pyrazol-4-yl)propanoate
[0286] 96 mg of the title compound was afforded from 174.6 mg of
2-methoxyphenylhydrazine hydrochloride and 175 .mu.l of methyl
4-acetyl-5-oxohexanoate in a manner similar to Preparation example
1a).
[0287] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.04 (3H, s), 2.27
(3H, s), 2.49-2.54 (2H, m), 2.74-2.78 (2H, m), 3.68 (3H, s), 3.79
(3H, s), 6.99-7.02 (2H, m), 7.28-7.31 (1H, m), 7.35-7.39 (1H,
m).
[0288] MS (FAB); m/z 289 (M+H).sup.+
b) Methyl
3-(1-(2-hydroxyphenyl)-3,5-dimethyl-1H-pyrazol-4-yl)propanoate
[0289] 36.8 mg of the title compound was afforded from 96 mg of
methyl
3-(1-(2-methoxyphenyl)-3,5-dimethyl-1H-pyrazol-4-yl)propanoate in a
manner similar to Preparation example 1b).
[0290] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.28 (3H, s), 2.34
(3H, s), 2.51 (2H, t, J=8.0 Hz), 2.77 (2H, t, J=8.0 Hz), 3.69 (3H,
s), 6.91 (1H, t, J=6.8 Hz), 7.08-7.10 (1H, m), 7.17-7.26 (2H, m),
9.73 (1H, s).
[0291] MS (ESI); m/z 275 (M+H).sup.+
Preparation Example 24
2-(4-Butyl-3,5-dimethyl-1H-pyrazol-1-yl)phenol
a) 4-Butyl-1-(2-methoxyphenyl)-3,5-dimethyl-1H-pyrazole
[0292] 273 mg of the title compound was afforded from 175 mg of
2-methoxyphenylhydrazine hydrochloride and 168 .mu.l of 3-n-butyl
2,4-pentanedione in a manner similar to Preparation example
1a).
[0293] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 0.94 (3H, t, J=7.2
Hz), 1.32-1.39 (2H, m), 1.45-1.50 (2H, m), 2.01 (3H, m), 2.26 (3H,
s), 2.39 (2H, q, J=7.2 Hz), 3.79 (3H, s), 6.99-7.04 (2H, m),
7.30-7.38 (2H, m).
[0294] MS (FAB); m/z 259 (M+H).sup.+
b) 2-(4-Butyl-3,5-dimethyl-1H-pyrazol-1-yl)phenol
[0295] 208.8 mg of the title compound was afforded from 273 mg of
4-butyl-1-(2-methoxyphenyl)-3,5-dimethyl-1H-pyrazole in a manner
similar to Preparation example 1b).
[0296] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 0.95 (3H, t, J=7.6
Hz), 1.33-1.39 (2H, m), 1.43-1.48 (2H, m), 2.26 (3H, s), 2.32 (3H,
s), 2.40 (2H, t, J=7.6 Hz), 6.88-6.92 (1H, m), 7.08 (1H, d, J=8.4
Hz), 7.16-7.20 (2H, m), 9.93 (1H, s).
[0297] MS (FAB); m/z 245 (M+H).sup.+
Preparation Example 25
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-fluorophenol
a) 2-Amino-5-fluorophenol
[0298] 252.5 mg of the title compound was afforded from 314 mg of
5-fluoro-2-nitrophenol in a manner similar to Preparation example
2a).
[0299] .sup.1H-NMR (DMSO-d6); .delta. (ppm) 6.33-6.38 (1H, in),
6.45-6.48 (1H, m), 6.51-6.55 (1H, m).
[0300] MS (FAB); m/z 128 (M+H).sup.+
b) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-fluorophenol
[0301] 89.6 mg of the title compound was afforded from 150 mg of
2-amino-5-fluorophenol in a manner similar to Preparation example
2b).
[0302] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.29 (3H, s), 2.37
(3H, s), 6.03 (1H, s), 6.60-6.65 (1H, m), 6.78-6.81 (1H, m),
7.13-7.16 (1H, m).
[0303] MS (ESI); m/z 207 (M+H).sup.+
Preparation Example 26
5-Chloro-2-(3,5-dimethyl-1H-pyrazol-1-yl)phenol
[0304] 168.8 mg of the title compound was afforded from 287 mg of
2-amino-5-chlorophenol in a manner similar to Preparation example
2b).
[0305] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.30 (3H, s), 2.40
(3H, s), 6.05 (1H, s), 6.87-6.90 (1H, m), 7.10-7.14 (2H, m), 10.23
(1H, s).
[0306] MS (FAB); m/z 223 (M+H).sup.+
Preparation Example 27
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-nitrophenol
[0307] 75.4 mg of the title compound was afforded from 308 mg of
2-amino-3-nitrophenol in a manner similar to Preparation example
2b).
[0308] .sup.1H-NMR (CD.sub.3OD); .delta. (ppm) 2.14 (3H, s), 2.19
(3H, s), 6.04 (1H, s), 7.27 (1H, dd, J=1.6, 7.6 Hz), 7.44 (1H, dd,
J=1.6, 7.6 Hz), 7.50 (1H, t, J=7.61 Hz).
[0309] MS (FAB); m/z 234 (M+H).sup.+
Preparation Example 28
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-nitrophenol
[0310] 101 mg of the title compound was afforded from 308 mg of
2-amino-5-nitrophenol in a manner similar to Preparation example
2b).
[0311] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.33 (3H, s), 2.50
(3H, s), 6.13 (1H, s), 7.38 (1H, d, J=7.6 Hz), 7.79-7.81 (1H, m),
7.95 (1H, s).
[0312] MS (ESI); m/z 234 (M+H).sup.+
Preparation Example 29
3-(1-(2-Hydroxyphenyl)-3,5-dimethyl-1H-pyrazol-4-yl)propionic
acid
[0313] 29.9 mg of methyl 3-(1-(2-hydroxyphenyl)-3,5-dimethyl-1H
pyrazol-4-yl)propanoate was dissolved in 0.6 ml of methanol and
0.29 ml of 1N-sodium hydroxide was added, followed by stirring at
room temperature for 3.5 hours. To the reaction mixture was added
20 ml of water, followed by neutralizing with 1N-hydrochloric acid
and extracting with 20 ml of ethyl acetate. The organic layer was
dried over anhydrous magnesium sulfate and subsequently the solvent
was distilled off under reduced pressure to afford 7.5 mg of the
title compound.
[0314] (CDCl.sub.3); .delta. (ppm) 2.29 (3H, s), 2.34 (3H, s), 2.56
(2H, t, J=7.6 Hz), 2.78 (2H, t, J=7.6 Hz), 6.89-6.93 (1H, m),
7.08-7.10 (1H, m), 7.16-7.22 (2H, m).
[0315] MS (FAB); m/z 261 (M+H).sup.+
Preparation Example 30
5-Chloro-2-(3,4,5-trimethyl-1H-pyrazol-1-yl)phenol
[0316] 152 mg of the title compound was afforded from 287 mg of
2-amino-5-chlorophenol and 233 .mu.l of 3-methyl-2,4-pentanedione
in a manner similar to Preparation example 2b).
[0317] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 1.99 (3H, s), 2.24
(3H, s), 2.31 (3H, s), 6.86-6.89 (1H, m), 7.09-7.11 (2H, m).
[0318] MS (FAB); m/z 227 (M+H).sup.+
Preparation Example 31
5-Amino-2-(3,5-dimethyl-1H-pyrazol-1-yl)phenol
[0319] 86 mg of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-nitrophenol was
dissolved in 1.7 ml of ethanol and 43 mg of 10% palladium/carbon
was added, followed by stirring under a hydrogen atmosphere at room
temperature for 45 minutes. The insoluble material was filtered and
subsequently the solvent was distilled off under reduced pressure
to afford 30.4 mg of the title compound.
[0320] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.28 (3H, s), 2.33
(3H, s), 3.72 (2H, s), 5.99 (1H, s), 6.22 (1H, dd, J=2.4, 8.4 Hz),
6.40 (1H, d, J=2.4 Hz), 6.97 (1H, d, J=8.4 Hz), 9.27 (1H, s).
[0321] MS (FAB); m/z 204 (M+H).sup.+
Preparation Example 32
5-Nitro-2-(3,4,5-trimethyl-1H-pyrazol-1-yl)phenol
[0322] 289.5 mg of the title compound was afforded from 308 mg of
2-amino-5-nitrophenol and 233 .mu.l of 3-methyl-2,4-pentanedione in
a manner similar to Preparation example 2b).
[0323] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.02 (3H, s), 2.24
(3H, s), 2.40 (3H, s), 7.33 (1H, d, J=8.8 Hz), 7.79 (1H, dd, J=2.4,
8.8 Hz), 7.94 (1H, d, J=2.4 Hz).
[0324] MS (FAB); m/z 248 (M+H).sup.+
Preparation Example 33
4-(3,5-Dimethyl-1H-pyrazol-1-yl)benzene-1,3-diol
a) 2,4-Dimethoxyphenylboronic acid
[0325] 576 .mu.l of 1-bromo-2,4-dimethoxybenzene was dissolved in
5.8 ml of tetrahydrofuran and 3 ml of a 1.6 mol/l solution of
n-butyllithium in hexane was added dropwise under an argon
atmosphere at -78.degree. C. Then, 1.1 ml of triisopropyl borate
was added, followed by stirring at -78.degree. C. for 40 minutes
and then stirring at room temperature for 2 hours. To the reaction
mixture were added 40 ml of water and 1 ml of 5N-hydrochloric acid,
followed by extracting with 50 ml of ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate, subsequently the
solvent was distilled off under reduced pressure, and purification
using silica gel column chromatography (hexane:ethyl acetate=2:1)
afforded 610.2 mg of the title compound.
[0326] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 3.85 (3H, s), 3.89
(3H, s), 5.81 (2H, s), 6.46 (1H, s), 6.56 (1H, dd, J=2.0, 8.4 Hz),
7.77 (1H, d, J=8.4 Hz).
b) 1-(2,4-Dimethoxyphenyl)-3,5-dimethyl-1H-pyrazole
[0327] 610.2 mg of 2,4-dimethoxyphenylboronic acid was dissolved in
6 ml of methylene chloride, 387 mg of 3,5-dimethylpyrazole, 730 mg
of copper(II) acetate and 948 .mu.l of pyridine were added,
followed by stirring at room temperature overnight. To the reaction
mixture was added 60 ml of water, followed by extracting with 60 ml
of ethyl acetate. The organic layer was dried over anhydrous
magnesium sulfate, subsequently the solvent was distilled off under
reduced pressure, and purification using silica gel column
chromatography (hexane:ethyl acetate=3:2) afforded 81.7 mg of the
title compound.
[0328] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.07 (3H, s), 2.29
(3H, s), 3.77 (3H, s), 3.85 (3H, s), 5.94 (1H, s), 6.52-6.54 (2H,
m), 7.22-7.24 (1H, m).
[0329] MS (FAB); m/z 233 (M+H).sup.+
c) 4-(3,5-Dimethyl-1H-pyrazol-1-yl)benzene-1,3-diol
[0330] 118.4 mg of 1-(2,4-dimethoxyphenyl)-3,5-dimethyl-1H-pyrazole
was dissolved in 2.3 ml of methylene chloride and 1.7 ml of a 1M
solution of boron tribromide in methylene chloride was added,
followed by stirring at room temperature for 1 hour. The reaction
mixture was added to 30 ml of water, followed by neutralizing with
1N-sodium hydroxide and extracting with 50 ml of ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate,
subsequently the solvent was distilled off under reduced pressure,
and purification using preparative thin-layer silica gel column
chromatography (hexane:ethyl acetate=1:2) afforded 71.7 mg of the
title compound.
[0331] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.29 (3H, s), 2.33
(3H, s), 6.01 (1H, s), 6.37 (1H, dd, J=2.8, 8.8 Hz), 6.53 (1H, d,
J=2.8 Hz), 7.03 (1H, d, J=8.8 Hz).
[0332] MS (ESI); m/z 205 (M+H).sup.+
Preparation Example 34
5-Amino-2-(3,4,5-trimethyl-1H-pyrazol-1-yl)phenol
[0333] 118.4 mg of the title compound was afforded from 200 mg of
5-nitro-2-(3,4,5-trimethyl-1H-pyrazol-1-yl)phenol in a manner
similar to Preparation example 31.
[0334] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 1.97 (3H, s), 2.23
(3H, s), 2.24 (3H, s), 3.70 (2H, s), 6.22 (1H, dd, J=2.4, 8.4 Hz),
6.40 (1H, d, J=2.4 Hz), 6.95 (1H, d, J=8.4 Hz), 9.34 (1H, s).
[0335] MS (FAB); m/z 218 (M+H).sup.+
Preparation Example 35
Methyl
4-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzenecarboxylate
[0336] 239.4 mg of the title compound was afforded from 334 mg of
methyl 4-amino-3-hydroxybenzenecarboxylate in a manner similar to
Preparation example 2b).
[0337] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.31 (3H, s), 2.45
(3H, s), 3.92 (3H, s), 6.08 (1H, s), 7.26-7.29 (1H, m), 7.60 (1H,
dd, J=1.6, 8.0 Hz), 7.76 (1H, d, J=1.6 Hz).
[0338] MS (ESI); m/z 247 (M+H).sup.+
Preparation Example 36
3-Amino-2-(3,5-dimethyl-1H-pyrazol-1-yl)phenol
[0339] 38.9 mg of the title compound was afforded from 56.6 mg of
2-(3,5-dimethyl-1H-pyrazol-1-yl)-3-nitrophenol in a manner similar
to Preparation example 31.
[0340] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.14 (3H, s), 2.25
(3H, s), 3.57 (2H, s), 6.02 (1H, s), 6.32-6.37 (2H, m), 7.02 (1H,
t, J=8.0 Hz).
[0341] MS (FAB); m/z 204 (M+H).sup.+
Preparation Example 37
4-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzene carboxylic
acid
[0342] 100 mg of methyl
4-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzenecarboxylate was
dissolved in 1 ml of methanol and 1.6 ml of 1N-sodium hydroxide was
added, followed by stirring at room temperature for 3.5 hours. To
the reaction mixture was added 20 ml of water, followed by
neutralizing with 1N-hydrochloric acid and extracting with 20 ml of
ethyl acetate. The organic layer was dried over anhydrous magnesium
sulfate and subsequently the solvent was distilled off under
reduced pressure to afford 40.8 mg of the title compound.
[0343] .sup.1H-NMR (CD.sub.3OD); .delta. (ppm) 2.16 (3H, s), 2.24
(3H, s), 6.04 (1H, s), 7.30 (1H, d, J=8.4 Hz), 7.59 (1H, dd, J=2.0,
8.4 Hz), 7.64 (1H, d, J=2.0 Hz).
[0344] MS (ESI); m/z 233 (M+H).sup.+
Preparation Example 38
4-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-hydroxy-N,N-dimethylbenzamide
[0345] 36 mg of 4-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzene
carboxylic acid was dissolved in 0.4 ml of dimethylformamide, and
36 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride, 25 mg of 1-hydroxybenzotriazole and 93 .mu.l of
dimethylamine (a 2.0M THF solution) were added, followed by
stirring at room temperature for 4 hours. To the reaction mixture
was added 10 ml of water, followed by extracting with 15 ml of
ethyl acetate. The organic layer was dried over anhydrous magnesium
sulfate, subsequently the solvent was distilled off under reduced
pressure, and purification using preparative thin-layer silica gel
column chromatography (ethyl acetate) afforded 11.4 mg of the title
compound.
[0346] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.31 (3H, s), 2.41
(3H, s), 3.02 (3H, s), 3.11 (3H, s), 6.06 (1H, s), 6.97 (1H, d,
J=8.0 Hz), 7.23 (1H, d, J=8.0 Hz), 7.26 (1H, s).
[0347] MS (ESI); m/z 259 (M+H).sup.+
Preparation Example 39
4-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzamide
[0348] 34.3 mg of the title compound was afforded from 73.1 mg of
4-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzene carboxylic acid
and 38 .mu.l of aqueous ammonia in a manner similar to Preparation
example 38.
[0349] .sup.1H-NMR (CD.sub.3OD); .delta. (ppm) 2.16 (3H, s), 2.24
(3H, s), 6.04 (1H, s), 7.29 (1H, d, J=8.4 Hz), 7.41 (1H, dd, J=2.0,
8.4 Hz), 7.50 (1H, d, J=2.0 Hz).
[0350] MS (ESI); m/z 232 (M+H).sup.+
Preparation Example 40
3-Hydroxy-4-(3,4,5-trimethyl-1H-pyrazol-1-yl)benzene carboxylic
acid
a) Methyl
3-hydroxy-4-(3,4,5-trimethyl-1H-pyrazol-1-yl)-benzenecarboxylate
[0351] 110.4 mg of the title compound was afforded from 167 mg of
methyl 4-amino-3-hydroxybenzenecarboxylate and 116 .mu.l of
3-methyl-2,4-pentanedione in a manner similar to Preparation
example 2b).
[0352] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.00 (3H, s), 2.26
(3H, s), 2.36 (3H, s), 3.92 (3H, s), 7.23-7.26 (1H, m), 7.58-7.60
(1H, m), 7.49 (1H, s), 10.53 (1H, s).
[0353] MS (ESI); m/z 261 (M+H).sup.+
b) 3-Hydroxy-4-(3,4,5-trimethyl-1H-pyrazol-1-yl)benzene carboxylic
acid
[0354] 68.7 mg of the title compound was afforded from 110 mg of
methyl 3-hydroxy-4-(3,4,5-trimethyl-1H-pyrazol-1-yl)-benzene
carboxylate in a manner similar to Preparation example 37.
[0355] .sup.1H-NMR (CD.sub.3OD); .delta. (ppm) 1.99 (3H, s), 2.09
(3H, s), 2.20 (3H, s), 7.28 (1H, d, J=8.0 Hz), 7.59 (1H, dd, J=2.0,
8.0 Hz), 7.63 (1H, d, J=2.0 Hz).
[0356] MS (ESI); m/z 247 (M+H).sup.+
Preparation Example 41
3-Hydroxy-4-(3,4,5-trimethyl-1H-pyrazol-1-yl)benzamide
[0357] 33.3 mg of the title compound was afforded from 65 mg of
3-hydroxy-4-(3,4,5-trimethyl-1H-pyrazol-1-yl)benzene carboxylic
acid and 32 .mu.l of aqueous ammonia in a manner similar to
Preparation example 38.
[0358] .sup.1H-NMR (CD.sub.3OD); .delta. (ppm) 1.99 (3H, s), 2.09
(3H, s), 2.19 (3H, s), 7.27 (1H, d, J=8.0 Hz), 7.40 (1H, dd, 8.0
Hz), 7.57 (1H, d, 0.1=2.0 Hz).
[0359] MS (ESI); m/z 246 (M+H).sup.+
Preparation Example 42
4-(4-Chloro-3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzamide
a) Methyl 4-(4-chloro
3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzoate
[0360] 69.1 mg of the title compound was afforded from 167 mg of
methyl 4-amino-3-hydroxybenzoate and 114 .mu.l of
3-chloropentane-2,4-dione in a manner similar to Preparation
example 2b).
[0361] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.32 (3H, s), 2.42
(3H, s), 3.93 (3H, s), 7.24-7.26 (1H, m), 7.60-7.66 (1H, m), 7.77
(1H, s).
b) 4-(4-Chloro-3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzoic
acid
[0362] 39.2 mg of the title compound was afforded from 6 9.1 mg of
methyl 4-(4-chloro 3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzoate
in a manner similar to Preparation example 37.
[0363] .sup.1H-NMR (CD.sub.3OD); .delta. (ppm) 2.15 (3H, s), 2.24
(3H, s), 7.32-7.35 (1H, m), 7.59-7.66 (2H, m).
[0364] MS (ESI); m/z 267 (M+H).sup.+
c) 4-(4-Chloro-3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzamide
[0365] 12.3 mg of the title compound was afforded from 37.9 mg of
4-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzoic acid and
17 .mu.l of aqueous ammonia in a manner similar to Preparation
example 38.
[0366] .sup.1H-NMR (CD.sub.3OD); .delta. (ppm) 2.14 (3H, s), 2.24
(3H, s), 7.29-7.32 (1H, m), 7.41-7.44 (1H, m), 7.50 (1H, s).
[0367] MS (ESI); m/z 266 (M+H).sup.+
Preparation Example 43
2-(3,5-Dimethyl-1H-pyrazol-1-yl)benzene-1,3-diol
a) 2-Aminobenzene-1,3-diol
[0368] 465 mg of 2-nitroresorcinol was dissolved in 9.3 ml of
ethanol, 230 mg of 10% palladium/carbon was added, followed by
stirring under a hydrogen atmosphere at room temperature for 1
hour. The insoluble material was filtered and subsequently the
solvent was distilled off under reduced pressure to afford 338.5 mg
of the title compound.
[0369] .sup.1H-NMR (DMSO-d6); .delta. (ppm) 6.20-6.28 (3H, m).
[0370] MS (ESI); m/z 126 (M+H).sup.+
b) 2-Amino-1,3-phenylene bis(4-methylbenzenesulfonate)
[0371] 100 mg of 2-aminobenzene-1,3-diol was dissolved in 2 ml of
dichloromethane, 234 .mu.l of triethylamine and 320 mg of
p-toluenesulfonyl chloride were added, followed by stirring at room
temperature for 1.5 hours. To the reaction mixture was added 20 ml
of water, followed by extracting with 20 ml of ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate,
subsequently the solvent was distilled off under reduced pressure,
and purification using silica gel column chromatography
(hexane:ethyl acetate=4:1) afforded 278.1 mg of the title
compound.
[0372] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.46 (6H, s), 3.83
(2H, s), 6.48 (1H, t, J=8.1 Hz), 6.79 (2H, d, J=8.3 Hz), 7.32 (4H,
d, J=8.1 Hz), 7.72 (4H, d, J=8.3 Hz).
[0373] MS (ESI); m/z 434 (M+H).sup.+
c) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-hydroxyphenyl
4-methylbenzenesulfonate
[0374] To 278 mg of 2-amino-1,3-phenylene
bis(4-methylbenzenesulfonate) was added 0.64 ml of 5N-hydrochloric
acid, and a solution of 58 mg of sodium nitrite dissolved in 0.4 ml
of water was added dropwise at 0.degree. C., followed by stirring
for 30 minutes. Then, a solution of 289 mg of stannous chloride
dissolved in 0.32 ml of 5N-hydrochloric acid was added dropwise at
0.degree. C., followed by stirring for 1 hour. The solvent was
distilled off under reduced pressure, and 1.3 ml of ethanol and 66
.mu.l of acetylacetone were added, followed by heating to reflux
for 2 hours. To the reaction mixture was added 50 ml of water,
followed by neutralizing with saturated sodium hydrogen carbonate
solution and extracting with 50 ml of ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate, subsequently the
solvent was distilled off under reduced pressure, and purification
using silica gel column chromatography (hexane:ethyl
acetate=4:1-1:1) afforded 62.9 mg of the title compound.
[0375] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.15 (3H, s), 2.17
(3H, s), 2.41 (3H, s), 5.91 (1H, s), 6.93-6.96 (2H, m), 7.14 (2H,
d, J=8.0 Hz), 7.18-7.26 (1H, m), 7.35 (2H, d, J=8.0 Hz).
[0376] MS (ESI); m/z 359 (M+H).sup.+
d) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)benzene-1,3-diol
[0377] To 62 mg of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxyphenyl
4-methylbenzenesulfonate was added a solution of 97 mg of potassium
hydroxide dissolved in 1.5 ml of ethanol and 1.5 ml of water,
followed by heating to reflux for 3.5 hours. To the reaction
mixture was added 20 ml of water, followed by extracting with 20 ml
of ethyl acetate. The organic layer was dried over anhydrous
magnesium sulfate, subsequently the solvent was distilled off under
reduced pressure, and purification using preparative thin-layer
silica gel column chromatography (hexane:ethyl acetate=1:1)
afforded 20.8 mg of the title compound.
[0378] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.15 (3H, s), 2.16
(3H, s), 5.98 (1H, s), 6.45 (2H, d, J=8.4 Hz), 7.00 (1H, t, J=8.4
Hz).
[0379] MS (ESI); m/z 205 (M+H).sup.+
Preparation Example 44
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-methylphenol
a) 2-Amino-5-methylphenyl 4-methylbenzenesulfonate
[0380] 400 mg of 2-amino-5-methylphenol was dissolved in 6.5 ml of
dichloromethane, and 476 .mu.l of triethylamine and 619 mg of
p-toluenesulfonyl chloride were added, followed by stirring at room
temperature for 1 hour. To the reaction mixture was added 60 ml of
water, followed by extracting with 60 ml of ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate,
subsequently the solvent was distilled off under reduced pressure,
and purification using silica gel column chromatography
(hexane:ethyl acetate=3:1) afforded 730.1 mg of the title
compound.
[0381] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.15 (3H, s), 2.46
(3H, s), 3.63 (2H, brs), 6.61-6.63 (1H, m), 6.67 (1H, s), 6.82-6.85
(1H, m), 6.33 (2H, d, J=8.4 Hz), 7.78 (2H, d, J=8.4 Hz).
[0382] MS (ESI); m/z 278 (M+H).sup.+
b) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-methylphenyl
4-methylbenzenesulfonate
[0383] To 453 mg of 2-amino-5-methylphenyl 4-methylbenzenesulfonate
was added 1.6 ml of 5N-hydrochloric acid, and a solution of 146 mg
of sodium nitrite dissolved in 1 ml of water was added dropwise at
0.degree. C., followed by stirring for 30 minutes. Then, a solution
of 736 mg of stannous chloride dissolved in 0.8 ml of
5N-hydrochloric acid was added dropwise at 0.degree. C., followed
by stirring for 1 hour. The solvent was distilled off under reduced
pressure and 3.2 ml of ethanol and 167 .mu.l of acetylacetone were
added, followed by heating to reflux for 2 hours. To the reaction
mixture was added 50 ml of water, followed by neutralizing with
saturated sodium hydrogen carbonate solution and extracting with 80
ml of ethyl acetate. The organic layer was dried over anhydrous
magnesium sulfate, subsequently the solvent was distilled off under
reduced pressure, and purification using silica gel column
chromatography (hexane:ethyl acetate=2:1) afforded 199.6 mg of the
title compound.
[0384] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.09 (3H, s), 2.11
(3H, s), 2.41 (3H, s), 2.43 (3H, s), 5.82 (1H, s), 7.15-7.21 (4H,
m), 7.36-7.38 (3H, m).
[0385] MS (ESI); m/z 357 (M+H).sup.+
c) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-methylphenol
[0386] To 199.6 mg of
2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-methylphenyl
4-methylbenzenesulfonate was added a solution of 314 mg of
potassium hydroxide dissolved in 4 ml of ethanol and 4 ml of water,
followed by heating to reflux for 1 hour. To the reaction mixture
was added 20 ml of water, followed by extracting with 20 ml of
ethyl acetate. The organic layer was dried over anhydrous magnesium
sulfate, subsequently the solvent was distilled off under reduced
pressure, purification was carried out using preparative thin-layer
silica gel column chromatography (hexane:ethyl acetate=4:1), the
desired fraction was dissolved in 1,4-dioxane, and subsequently
lyophilization afforded 66.2 mg of the title compound.
[0387] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.29 (3H, s), 2.33
(3H, s), 2.37 (3H, s), 6.01 (1H, s), 6.70 (1H, d, J=8.0 Hz), 6.90
(1H, s), 7.07 (1H, d, J=8.0 Hz), 9.64 (1H, brs).
[0388] MS (ESI); m/z 203 (M+H).sup.+
Preparation Example 45
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-methoxyphenol
a) 2-Amino-5-methoxyphenyl 4-methylbenzenesulfonate
[0389] 220.1 mg of the title compound was afforded from 176 mg of
2-hydroxy-4-methoxyaniline hydrochloride in a manner similar to
Preparation example 44 a).
[0390] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.46 (3H, s), 3.62
(3H, s), 6.41 (1H, s), 6.65-6.66 (2H, m), 7.34 (2H, d, J=8.8 Hz),
7.79 (2H, d, J=8.8 Hz).
b) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-methoxyphenyl
4-methylbenzenesulfonate
[0391] 93.7 mg of the title compound was afforded from 220 mg of
2-amino-5-methoxyphenyl 4-methylbenzenesulfonate in a manner
similar to Preparation example 44b).
[0392] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.08 (3H, s), 2.11
(3H, s), 2.41 (3H, s), 3.85 (3H, s), 5.82 (1H, s), 6.87 (1H, dd,
J=2.4, 8.4 Hz), 7.06 (1H, d, J=2.4 Hz), 7.17 (2H, d, J=8.4 Hz),
7.20-7.24 (1H, m), 7.39 (2H, d, J=8.4 Hz).
[0393] MS (ESI); m/z 373 (M+H).sup.+
c) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-methoxyphenol
[0394] 30.1 mg of the title compound was afforded from 93 mg of
2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-methoxyphenyl
4-methylbenzenesulfonate in a manner similar to Preparation example
44c).
[0395] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.27 (3H, s), 2.33
(3H, s), 3.80 (3H, s), 6.00 (1H, s), 6.45 (1H, dd, J=2.8, 8.4 Hz),
6.61 (1H, d, J=2.8 Hz), 7.08 (1H, d, J=8.4 Hz), 9.67 (1H, brs).
[0396] MS (ESI); m/z 219 (M+H).sup.+
Preparation Example 46
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-methylphenol
a) 2-Amino-3-methylphenyl 4-methylbenzenesulfonate
[0397] 374.1 mg of the title compound was afforded from 200 mg of
2-amino-3-methylphenol in a manner similar to Preparation example
43b).
[0398] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.14 (3H, s), 2.46
(3H, s), 3.79 (2H, s), 6.51 (1H, t, J=8.0 Hz), 6.63 (1H, d, J=8.0
Hz), 6.91 (1H, d, J=8.0 Hz), 7.32 (2H, d, J=8.4 Hz), 7.78 (2H, d,
J=8.4 Hz).
[0399] MS (ESI); m/z 278 (M+H).sup.+
b) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-methylphenyl
4-methylbenzenesulfonate
[0400] 269.9 mg of the title compound was afforded from 374 mg of
2-amino-3-methylphenyl 4-methylbenzenesulfonate in a manner similar
to Preparation example 43c).
[0401] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.01 (3H, s), 2.02
(3H, s), 2.16 (3H, s), 2.43 (3H, s), 5.88 (1H, s), 7.19-7.24 (3H,
m), 7.32 (2H, d, J=5.2 Hz), 7.51 (2H, d, J=8.4 Hz).
[0402] MS (ESI); m/z 357 (M+H).sup.+
c) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-methylphenol
[0403] 79.2 mg of the title compound was afforded from 269 mg of
2-(3,5-dimethyl-1H-pyrazol-1-yl)-3-methylphenyl
4-methylbenzenesulfonate in a manner similar to Preparation example
43d).
[0404] .sup.1H-NMR (CD.sub.3OD); .delta. (ppm) 1.92 (3H, s), 2.01
(3H, s), 2.24 (3H, s), 6.02 (1H, s), 6.79 (2H, d, J=7.6 Hz), 7.18
(1H, t, J=7.6 Hz).
[0405] MS (ESI); m/z 203 (M+H).sup.+
Preparation Example 47
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-hydroxymethylphenol
[0406] 132 mg of methyl
4-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzenecarboxylate was
dissolved in 2.6 ml of tetrahydrofuran and 58 mg of lithium
borohydride was added, followed by stirring at 50.degree. C. for
3.5 hours. To the reaction mixture was added 20 ml of water,
followed by extracting with 20 ml of ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate, subsequently the
solvent was distilled off under reduced pressure, and purification
using preparative thin-layer silica gel column chromatography
(hexane:ethyl acetate=1:2) afforded 12.4 mg of the title
compound.
[0407] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.28 (3H, s), 2.44
(3H, s), 4.64 (2H, s), 6.02 (1H, s), 6.90 (1H, d, J=8.0 Hz), 7.02
(1H, s), 7.17 (1H, d, J=8.0 Hz).
[0408] MS (ESI); m/z 219 (M+H).sup.+
Preparation Example 48
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-methylaminophenol
a) 1-(2-Methoxy-4-nitrophenyl)-3,5-dimethyl-1H-pyrazole
[0409] 498 mg of the title compound was afforded from 700 mg of
2-methoxy-4-nitroaniline in a manner similar to Preparation example
43c).
[0410] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.13 (3H, s), 2.30
(3H, s), 3.93 (3H, s), 6.02 (1H, s), 7.53 (1H, d, J=8.4 Hz), 7.89
(1H, d, J=2.0 Hz), 7.95 (1H, dd, J=2.0, 8.4 Hz).
[0411] MS (ESI); m/z 248 (M+H).sup.+
b) 4-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-methoxyaniline
[0412] 417.6 mg of the title compound was afforded from 495 mg of
1-(2-methoxy-4-nitrophenyl)-3,5-dimethyl-1H-pyrazole in a manner
similar to Preparation example 31.
[0413] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.06 (3H, s), 2.28
(3H, s), 3.72 (3H, s), 3.81 (2H, brs), 5.92 (1H, s), 6.28-6.31 (2H,
m), 7.06 (1H, d, J=8.4 Hz).
[0414] MS (ESI); m/z 218 (M+H).sup.+
c) 4-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-methoxy-N-methylaniline
[0415] 200 mg of 4-(3,5-dimethyl-1H-pyrazol-1-yl)-3-methoxyaniline
was dissolved in 6 ml of dimethylformamide, and 160 .mu.l of methyl
iodide and 636 mg of potassium carbonate were added, followed by
stirring at room temperature for 2.5 hours. To the reaction mixture
was added 50 ml of water, followed by extracting with 50 ml of
ethyl acetate. The organic layer was dried over anhydrous magnesium
sulfate, subsequently the solvent was distilled off under reduced
pressure, and purification using preparative thin-layer silica gel
column chromatography (hexane:ethyl acetate=1:3) afforded 48.7 mg
of the title compound.
[0416] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.07 (3H, s), 2.28
(3H, s), 2.86 (3H, s), 3.74 (3H, s), 3.95 (1H, brs), 5.92 (1H, s),
6.17 (1H, d, J=2.4 Hz), 6.21 (1H, dd, J=2.4, 8.4 Hz), 7.09 (1H, d,
J=8.4 Hz).
[0417] MS (ESI); m/z 232 (M+H).sup.+
d) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-methylaminophenol
[0418] 25 mg of the title compound was afforded from 58.7 mg of
4-(3,5-dimethyl-1H-pyrazol-1-yl)-3-methoxy-N-methylaniline in a
manner similar to Preparation example 33c).
[0419] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.28 (3H, s), 2.32
(3H, s), 2.83 (3H, d, J=1.2 Hz), 5.98 (1H, s), 6.13-6.16 (1H, m),
6.31-6.32 (1H, m), 6.99 (1H, dd, J=1.2, 8.4 Hz).
[0420] MS (ESI); m/z 218 (M+H).sup.+
Preparation Example 49
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-4-methylphenol
a) 2-Amino-4-methylphenyl 4-methylbenzenesulfonate
[0421] 770.1 mg of the title compound was afforded from 479 mg of
2-amino-4-methylphenol hydrochloride in a manner similar to
Preparation example 43b).
[0422] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.21 (3H, s), 2.46
(3H, s), 3.74 (2H, brs), 6.39 (1H, d, J=8.0 Hz), 6.53 (1H, s), 6.62
(1H, d, J=8.0 Hz), 7.32 (2H, d, J=8.0 Hz), 7.77 (2H, d, J=8.0
Hz).
[0423] MS (ESI); m/z 278 (M+H).sup.+
b) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-4-methylphenyl
4-methylbenzenesulfonate
[0424] 137.3 mg of the title compound was afforded from 400 mg of
2-amino-4-methylphenyl 4-methylbenzenesulfonate in a manner similar
to Preparation example 43c).
[0425] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.10 (3H, s), 2.12
(3H, s), 2.35 (3H, s), 2.41 (3H, s), 5.82 (1H, s), 7.13-7.15 (3H,
m), 7.20-7.22 (1H, m), 7.33-7.36 (2H, m), 7.42 (2H, d, J=8.4
Hz).
[0426] MS (ESI); m/z 357 (M+H).sup.+
c) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-4-methylphenol
[0427] 60.4 mg of the title compound was afforded from 167 mg of
2-(3,5-dimethyl-1H-pyrazol-1-yl)-4-methylphenyl
4-methylbenzenesulfonate in a manner similar to Preparation example
43d).
[0428] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.29 (3H, s), 2.31
(3H, s), 2.39 (3H, s), 6.02 (1H, s), 6.97-7.02 (3H, m), 9.43 (1H,
s).
[0429] MS (ESI); m/z 203 (M+H).sup.+
Preparation Example 50
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-trifluoromethylphenol
a)
1-(2-Methoxy-4-(trifluoromethylphenyl)-3,5-dimethyl-1H-pyrazole
[0430] 95.5 mg of the title compound was afforded from 191 mg of
2-methoxy-4-trifluoromethylaniline in a manner similar to
Preparation example 43c).
[0431] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.05 (3H, s), 2.30
(3H, s), 3.86 (3H, s), 5.99 (1H, s), 7.22 (1H, s), 7.31 (1H, d,
J=8.0 Hz), 7.46 (1H, d, J=8.0 Hz).
[0432] MS (ESI); m/z 271 (M+H).sup.+
b) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-trifluoromethylphenol
[0433] 25.7 mg of the title compound was afforded from 95.5 mg of
1-(2-methoxy-4-trifluoromethylphenyl)-3,5-dimethyl-1H-pyrazole in a
manner similar to Preparation example 33c).
[0434] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.31 (3H, s), 2.45
(3H, s), 6.08 (1H, s), 7.15-7.18 (1H, m), 7.30-7.35 (2H, m), 10.64
(1H, s).
[0435] MS (ESI); m/z 257 (M+H).sup.+
Preparation Example 51
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-methylphenol
a) 2-Amino-6-methylphenyl 4-methylbenzenesulfonate
[0436] 159.9 mg of the title compound was afforded from 200 mg of
6-amino-o-cresol hydrochloride in a manner similar to Preparation
example 43b).
[0437] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.06 (3H, s), 2.48
(3H, s), 3.96 (2H, s), 6.53-6.55 (1H, m), 6.59-6.61 (1H, m), 6.93
(1H, t, J=7.6 Hz), 7.37 (2H, d, J=8.0 Hz), 7.90 (2H, d, J=8.0
Hz).
[0438] MS (ESI); m/z 278 (M+H).sup.+
b) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-methylphenyl
4-methylbenzenesulfonate
[0439] 48.8 mg of the title compound was afforded from 159.5 mg of
2-amino-6-methylphenyl 4-methylbenzenesulfonate in a manner similar
to Preparation example 43c).
[0440] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.09 (3H, s), 2.10
(3H, s), 2.43 (3H, s), 2.49 (3H, s), 5.67 (1H, s), 7.13-7.32 (5H,
m), 7.48 (2H, d, J=8.0 Hz).
[0441] MS (ESI); m/z 357 (M+H).sup.+
c) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-methylphenol
[0442] 12 mg of the title compound was afforded from 48.5 mg of
2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methylphenyl
4-methylbenzenesulfonate in a manner similar to Preparation example
43d).
[0443] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.30 (3H, s), 2.31
(3H, s), 2.38 (3H, s), 6.03 (1H, s), 6.81 (1H, t, J=8.0 Hz),
7.03-7.09 (2H, m), 9.79 (1H, s).
[0444] MS (ESI); m/z 203 (M+H).sup.+
Preparation Example 52
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-ethylphenol
a) 4-Chloro-5-ethyl-2-nitrophenyl methanesulfonate
[0445] 150 mg of 4-chloro-5-ethyl-2-nitrophenol was dissolved in
1.5 ml of dichloromethane, and 156 .mu.l of triethylamine and 69
.mu.l of methanesulfonyl chloride were added, followed by stirring
at room temperature for 30 minutes. To the reaction mixture was
added 50 ml of water, followed by extracting with 60 ml of ethyl
acetate. The organic layer was dried over anhydrous magnesium
sulfate, and subsequently the solvent was distilled off under
reduced pressure to afford 200.7 mg of the title compound.
[0446] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 1.28 (3H, t, J=7.6
Hz), 2.83 (2H, q, J=7.6 Hz), 3.37 (3H, s), 7.42 (1H, s), 8.09 (1H,
s).
b) 2-Amino-5-ethylphenyl methanesulfonate
[0447] 200 mg of 4-chloro-5-ethyl-2-nitrophenyl methanesulfonate
was dissolved in 4 ml of ethanol and 200 mg of 10% palladium/carbon
was added, followed by stirring under a hydrogen atmosphere at room
temperature for 4 hours. The insoluble material was filtered, and
subsequently the solvent was distilled off under reduced pressure
to afford 74.9 mg of the title compound.
[0448] .sup.1H-NMR (CD.sub.3OD); .delta. (ppm) 1.26 (3H, t, J=7.6
Hz), 2.73 (2H, q, J=7.6 Hz), 3.47 (3H, s), 7.28-7.46 (3H, m).
[0449] MS (ESI); m/z 216 (M+II).sup.+
c) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-ethylphenyl
methanesulfonate
[0450] 28.1 mg of the title compound was afforded from 74.5 mg of
2-amino-5-ethylphenyl methanesulfonate in a manner similar to
Preparation example 43c).
[0451] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 1.28 (3H, t, J=7.6
Hz), 2.17 (3H, s), 2.26 (3H, s), 2.65 (3H, s), 2.73 (2H, q, J=7.6
Hz), 6.00 (1H, s), 7.24-7.26 (1H, m), 7.33-7.37 (2H, m).
[0452] MS (ESI); m/z 295 (M+H).sup.+
d) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-ethylphenol
[0453] 28 mg of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-ethylphenyl
methanesulfonate was dissolved in 0.1 ml of methanol and 0.07 ml of
5N-hydrochloric acid was added, followed by heating to reflux for
30 minutes. To the reaction mixture was added 15 ml of water,
followed by extracting with 15 ml of ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate, subsequently the
solvent was distilled off under reduced pressure, and purification
using preparative thin-layer silica gel column chromatography
(hexane:ethyl acetate=4:1) afforded 7.4 mg of the title
compound.
[0454] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 1.24 (3H, t, J=7.6
Hz), 2.29 (3H, s), 2.38 (3H, s), 2.63 (2H, q, J=7.6 Hz), 6.02 (1H,
s), 6.73-6.75 (1H, m), 6.94 (1H, s), 7.10 (1H, d, J=8.0 Hz), 9.67
(1H, s).
[0455] MS (ESI); m/z 217 (M+H).sup.+
Preparation Example 53
2-(4-Fluoro-3,5-dimethyl-1H-pyrazol-1-yl)phenol
a) 1-(2-Benzyloxyphenyl)-4-fluoro-3,5-dimethyl-1H-pyrazole
[0456] 500 mg of 2-benzyloxyphenylhydrazine hydrochloride and 251
mg of 3-fluoropentane-2,4-dione were added to 12 ml of ethanol,
followed by heating to reflux for 1.5 hours. The reaction solution
was concentrated under reduced pressure as such, and purification
using silica gel column chromatography (hexane:ethyl
acetate=6:1-5:1) afforded 417 mg of the title compound.
[0457] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.07 (3H, s), 2.30
(3H, s), 5.04 (2H, s), 7.03-7.07 (2H, m), 7.24-7.37 (7H, m).
[0458] MS (ESI); m/z 297 (M+H).sup.+
b) 2-(4-Fluoro-3,5-dimethyl-1H-pyrazol-1-yl)phenol
[0459] 416 mg of
1-(2-benzyloxyphenyl)-4-fluoro-3,5-dimethyl-1H-pyrazole was
dissolved in 16 ml of methanol and 42.6 mg of 10% palladium/carbon
was added, followed by stirring under a hydrogen atmosphere at room
temperature for 24 hours. The insoluble material was filtered,
subsequently the filtrate was distilled off under reduced pressure,
and the resulting residue was purified using silica gel column
chromatography (hexane:ethyl acetate=5:1) to give 290 mg of the
title compound.
[0460] .sup.1H-NMR (CDCl.sub.3); .delta. (ppm) 2.28 (3H, s), 2.33
(3H, s), 6.90 (1H, t, J=8.0 Hz), 7.06 (1H, d, J=8.0 Hz), 7.15 (1H,
d, J=8.0 Hz), 7.19 (1H, t, J=8.0 Hz).
[0461] MS (ESI); m/z 207 (M+H).sup.+
Preparation Example 54
5-Bromo-2-(3,5-dimethyl-1H-pyrazol-1-yl)phenol
a) 5-Bromo-2-hydrazinylphenol 4-methylbenzenesulfonate
[0462] 1.0 g of 2-amino-5-bromophenol was suspended in 7 ml of
ethanol and 1.5 ml of concentrated hydrochloric acid was added
dropwise at -10.degree. C. Furthermore, 636 mg of tert-butyl
nitrite was added dropwise at the same temperature, followed by
stirring at the same temperature for 1 hour to afford a diazonium
salt solution. Another flask was charged with 2.49 g of stannous
chloride dihydrate, 1.08 g of p-toluenesulfonic acid monohydrate
and 15 ml of ethanol, followed by stirring at -10.degree. C. for 15
minutes. Into this solution was added dropwise the above prepared
diazonium salt solution at -10.degree. C., followed by stirring at
the same temperature for 1 hour. 30 ml of tert-butyl methylether
was added, followed by stirring for 15 minutes. Subsequently, the
resulting precipitate was filtered off to afford 0.9 g of the title
compound.
b) 5-Bromo-2-(3,5-dimethyl-1H-pyrazol-1-yl)phenol
[0463] 0.9 g of 5-bromo-2-hydrazinylphenol 4-methylbenzenesulfonate
and 0.8 g of acetylacetone were added into 25 ml of ethanol,
followed by heating to reflux for 1 hour. The reaction was cooled
to room temperature and concentrated under reduced pressure as
such, and the resulting residue was dissolved in 50 ml of ethyl
acetate, followed by washing twice with 20 ml of saturated aqueous
sodium bicarbonate. The organic layer was dehydrated with anhydrous
sodium sulphate and subsequently concentrated under reduced
pressure, and the resulting residue was purified by silica gel
column chromatography (hexane:ethyl acetate=4:1) to afford 650 mg
of the title compound.
[0464] 1H-NMR (CDCl.sub.3); .delta. (ppm) 2.30 (3H, s), 2.40 (3H,
s), 6.05 (1H, s), 7.01-7.08 (2H, m), 7.26 (1H, s).
[0465] MS (ESI); m/z 267 (M+H).sup.+
Preparation Example 55
5-Bromo-2-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)phenol
[0466] 558 mg of the title compound was afforded from 0.9 g of
5-bromo-2-hydrazinylphenol 4-methylbenzenesulfonate prepared in
analogy to Preparation example 54a) and 1.07 g of
3-chloropentane-2,4-dione in a manner similar to Preparation
example 54b).
[0467] 1H-NMR (CDCl.sub.3); .delta. (ppm) 2.30 (3H, s), 2.38 (3H,
s), 7.02-7.08 (2H, m), 7.27 (1H, d, J=2.0 Hz), 9.62 (1H, s).
[0468] MS (ESI); m/z 303 (M+H).sup.+
Preparation Example 56
5-Bromo-2-(3,4,5-trimethyl-1H-pyrazol-1-yl)phenol
[0469] 320 mg of the title compound was afforded from 0.9 g of
5-bromo-2-hydrazinylphenol 4-methylbenzenesulfonate prepared in
analogy to Preparation example 54a) and 0.9 g of
3-methylpentane-2,4-dione in a manner similar to Preparation
example 54b). 1H-NMR (CDCl.sub.3); .delta. (ppm) 1.98 (3H, s), 2.24
(3H, s), 2.31 (3H, s), 7.00-7.06 (2H, m), 7.25 (1H, d, J=1.6 Hz)),
10.34 (1H, s).
[0470] MS (ESI); m/z 281 (M+H).sup.+
Preparation Example 57
4-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-hydroxyphenyl acetate
a) 4-Nitro-1,3-phenylene diacetate
[0471] Under a nitrogen atmosphere, 5.0 g of
4-nitrobenzene-1,3-diol was dissolved in 50 ml of methylene
chloride, and under ice cooling, 5.35 g of pyridine, 0.39 g of
4-dimethylaminopyridine and 8.12 g of acetic anhydride were
sequentially added. The temperature of the reaction was raised to
room temperature, followed by stirring for 1 hour. The reaction
solution was washed with 50 ml of water, 100 ml of 1N-hydrochloric
acid, 100 ml of saturated aqueous sodium bicarbonate, and 100 ml of
saturated brine sequentially, dehydrated with anhydrous sodium
sulphate, and subsequently concentrated under reduced pressure to
afford 7.4 g of the title compound. 1H-NMR (CDCl.sub.3); .delta.
(ppm) 2.33 (3H, s), 2.37 (3H, s), 7.09 (1H, d, J=2.4 Hz), 7.18 (1H,
dd, J=2.4, 9.2 Hz), 8.16 (1H, d, J=9.2 Hz).
b) 3-Hydroxy-4-nitrophenyl acetate
[0472] Under a nitrogen atmosphere, 1.0 g of 4-nitro-1,3-phenylene
diacetate was dissolved in 25 ml of chloroform, and under ice
cooling, 2.23 g of aluminium chloride was added. The temperature of
the reaction was raised to room temperature, followed by stirring
for 3 hours. 100 ml of water was added, followed by extracting
three times with 30 ml of methylene chloride. The organic layers
were combined, washed with 25 ml of 1N-hydrochloric acid and 25 ml
of saturated brine sequentially, dehydrated with anhydrous sodium
sulphate, and subsequently concentrated under reduced pressure. The
resulting residue was purified by silica gel column chromatography
(hexane:ethyl acetate=20:1) to afford 610 mg of the title
compound.
[0473] 1H-NMR (CDCl.sub.3): .delta. (ppm) 2.32 (3H, s), 6.77 (1H,
dd, J=2.4 Hz, J=9.2 Hz), 6.95 (1H, d, J=2.4 Hz), 8.14 (1H, d, J=9.2
Hz), 10.70 (1H, s).
[0474] MS (ESI); m/z 196 (M-H).sup.-
c) 4-Amino-3-hydroxyphenyl acetate
[0475] 3.0 g of 3-hydroxy-4-nitrophenyl acetate was dissolved in 50
ml of ethyl acetate and 300 mg of 10% palladium/carbon was added,
followed by stirring under a hydrogen atmosphere at room
temperature for 10 hours. The insoluble material was filtered,
subsequently the filtrate was distilled off under reduced pressure,
and the resulting residue was purified by silica gel column
chromatography (hexane:ethyl acetate-1:1) to afford 2.48 g of the
title compound.
[0476] 1H-NMR (DMSO-d6); .delta. (ppm) 2.17 (3H, s), 4.45 (2H,
brs), 6.28 (1H, dd, J=2.4, 8.4 Hz), 6.40 (1H, d, J=2.4 Hz), 6.53
(1H, d, J=8.4 Hz), 9.26 (1H, brs).
[0477] MS (ESI); m/z 167 (M+)
d) 4-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-hydroxyphenyl acetate
[0478] 330 mg of the title compound was afforded from 0.9 g of
4-hydrazinyl-3-hydroxyphenyl acetate 4-methylbenzenesulfonate
prepared using 1.0 g of 4-amino-3-hydroxyphenyl acetate in analogy
to Preparation example 54a) and 0.9 g of acetylacetone, in a manner
similar to Preparation example 54b).
[0479] 1H-NMR (CDCl.sub.3); .delta. (ppm) 2.29 (3H, s), 2.30 (3H,
s), 2.41 (3H, s), 6.04 (1H, s), 6.68 (1H, dd, J=2.4, 8.8 Hz), 6.85
(1H, d, J=2.4 Hz), 7.19 (1H, d, J=8.8 Hz), 10.14 (1H, s).
[0480] MS (ESI); m/z 247 (M+H).sup.+
Preparation Example 58
4-(4-Chloro-3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxyphenyl
acetate
[0481] 30 mg of the title compound was afforded from 0.9 g of
4-hydrazinyl-3-hydroxyphenyl acetate 4-methylbenzenesulfonate
prepared using 1.0 g of 4-amino-3-hydroxyphenyl acetate in analogy
to Preparation example 54a) and 1.2 g of 3-chloropentane-2,4-dione,
in a manner similar to Preparation example 54b).
[0482] 1H-NMR (CDCl.sub.3); .delta. (ppm) 2.30 (3H, s), 2.31 (3H,
s), 2.39 (3H, s), 6.70 (1H, dd, J=2.8, 8.8 Hz), 6.86 (1H, d, J=2.8
Hz), 7.17 (1H, d, J=8.8 Hz), 9.50 (1H, s).
[0483] MS (ESI); m/z 281 (M+H).sup.+
Preparation Example 59
3-Hydroxy-4-(3,4,5-trimethyl-1H-pyrazol-1-yl)phenyl acetate
[0484] 230 mg of the title compound was afforded from 0.6 g of
4-hydrazinyl-3-hydroxyphenyl acetate 4-methylbenzenesulfonate
prepared using 1.0 g of 4-amino-3-hydroxyphenyl acetate in analogy
to Preparation example 54a) and 1.0 g of 3-methylpentane-2,4-dione,
in a manner similar to Preparation example 54b).
[0485] 1H-NMR (CDCl.sub.3); .delta. (ppm) 1.99 (3H, s), 2.24 (3H,
s), 2.30 (3H, s), 2.32 (3H, s), 6.66 (1H, dd, J=2.8, 8.4 Hz), 6.83
(1H, d, J=2.8 Hz), 7.17 (1H, d, J=8.4 Hz), 10.22 (1H, s).
[0486] MS (ESI); m/z 261 (M+H).sup.+
Preparation Example 60
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-4-methoxy-5-methylphenol
a) 1,4-Dimethoxy-2-methyl-5-nitrobenzene
[0487] 6.0 g of 2,5-dimethoxytoluene was dissolved in 20 ml of
acetic acid, and at 40.degree. C., a solution of 4.32 g of fuming
nitric acid (d=1.50) in 10 ml of acetic acid was added dropwise
over 5 minutes. The reaction was stirred at the same temperature
for 30 minutes, cooled to room temperature, and subsequently
stirred for another 30 minutes. The reaction solution was diluted
with 300 ml of cold water, and the resulting precipitate was
filtering off and washed with 100 ml of cold water. Drying under
reduced pressure gave 7.5 g of the title compound. 1H-NMR (CDCl3);
.delta. (ppm) 2.28 (3H, s), 3.84 (3H, s), 3.92 (3H, s), 6.90 (1H,
s), 7.40 (1H, s).
[0488] MS (ESI); m/z 198 (M+H).sup.+
b) 4-Methoxy-5-methyl-2-nitrophenol
[0489] A solution of 6.0 g of 1,4-dimethoxy-2-methyl-5-nitrobenzene
in 30 ml of methylene chloride was cooled to -20.degree. C. and 30
ml of 1M solution of boron trichloride in methylene chloride was
added dropwise at the same temperature. The temperature of the
reaction was raised to room temperature and subsequently the
reaction solution was stirred for 16 hours and added to 50 ml of
saturated aqueous sodium bicarbonate, followed by extracting three
times with 100 ml of ethyl acetate. The organic layers were
combined, washed with 100 ml of water and 50 ml of saturated brine,
subsequently dehydrated with anhydrous sodium sulphate, and
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=9:1) to afford 4.25 g of the title compound. 1H-NMR
(CDCl.sub.3); .delta. (ppm) 2.26 (3H, s), 3.84 (3H, s), 6.94 (1H,
s), 7.39 (1H, s), 10.46 s).
[0490] MS (ESI); m/z 182 (M-H).sup.-
c) 4-Methoxy-5-methyl-2-nitrophenyl 4-methylbenzenesulfonate
[0491] Under a nitrogen atmosphere, to a solution of 8.0 g of
4-methoxy-5-methyl-2-nitrophenol in 80 ml of methylene chloride was
added 9.15 g of p-toluenesulfonyl chloride at room temperature,
followed by cooling to 0.degree. C. 4.86 g of triethylamine was
added thereto, followed by stirring for 2 hours. The reaction
solution was poured to 150 ml of water, followed by extracting with
150 ml of methylene chloride. The organic layer was washed with 100
ml of water and 50 ml of saturated brine, dehydrated with anhydrous
sodium sulphate, and subsequently concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (hexane:ethyl acetate-9:1) to afford 12.0 g of the
title compound.
[0492] 1H-NMR (CDCl.sub.3); .delta. (ppm) 2.26 (3H, s), 2.46 (3H,
s), 3.87 (3H, s), 7.19 (1H, s), 7.33 (1H, s), 7.34 (2H, d, J=8.4
Hz), 7.77 (2H, d, J=8.4 Hz).
[0493] MS (ESI); m/z 336 (M-H).sup.-
d) 2-Amino-4-methoxy-5-methylphenyl 4-methylbenzenesulfonate
[0494] 3.2 g of the title compound was afforded in a manner similar
to Preparation example 57c) using 4.0 g of
4-methoxy-5-methyl-2-nitrophenyl 4-methylbenzenesulfonate. 1H-NMR
(DMSO-d.sub.6); .delta. (ppm) 1.91 (3H, s), 2.41 (3H, s), 3.64 (3H,
s), 4.73 (2H, brs), 6.25 (1H, s), 6.64 (1H, s), 7.43 (2H, d, J=8.4
Hz), 7.79 (2H, d, J=8.4 Hz).
[0495] MS (ESI); m/z 308 (M+H).sup.+
e) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-4-methoxy-5-methylphenyl
4-methylbenzenesulfonate
[0496] 400 mg of the title compound was afforded in a manner
similar to Preparation examples 54a) and 54b) using 1.0 g of
2-amino-4-methoxy-5-methylphenyl 4-methylbenzenesulfonate.
[0497] 1H-NMR (CDCl.sub.3); .delta. (ppm) 2.10 (6H, s), 2.25 (3H,
s), 2.41 (3H, s), 3.79 (3H, s), 5.80 (1H, s), 6.71 (1H, s), 7.15
(2H, d, J=8.4 Hz), 7.27 (1H, s), 7.35 (2H, d, J=8.4 Hz).
[0498] MS (ESI); m/z 387 (M+H).sup.+
f) 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-4-methoxy-5-methylphenol
[0499] 70 mg of the title compound was afforded in a manner similar
to Preparation example 29 using 200 mg of
2-(3,5-dimethyl-1H-pyrazol-1-yl)-4-methoxy-5-methylphenyl
4-methylbenzenesulfonate.
[0500] 1H-NMR (CDCl.sub.3); .delta. (ppm) 2.21 (3H, s), 2.29 (3H,
s), 2.39 (3H, s), 3.78 (3H, s), 6.02 (1H, s), 6.67 (1H, s), 6.89
(1H, s), 8.87 (1H, s).
[0501] MS (ESI); m/z 233 (M+H).sup.+
Preparation Example 61
4-Chloro-2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-methylphenol
a) 2-Amino-4-chloro-5-methylphenol
[0502] Into a solution of 5.0 g of 4-chloro-5-methyl-2-nitrophenol
in 100 ml of methanol were added 8.71 g of zinc dust activated by
hydrochloric acid and a solution of 7.1 g of ammonium chloride in
20 ml of water at 0.degree. C. This suspension was stirred at room
temperature for 4 hours and subsequently the insoluble material was
filtered through Celite, followed by washing with 100 ml of ethyl
acetate. The filtrate and washings were combined and concentrated
under reduced pressure. The resulting residue was purified by
silica gel column chromatography (hexane:ethyl acetate=3:2) to
afford 1.4 g of the title compound.
[0503] 1H-NMR (DMSO-d.sub.6); .delta. (ppm) 2.10 (3H, s), 4.57 (2H,
brs), 6.54 (1H, s), 6.58 (1H, s), 9.11 (1H, s).
[0504] MS (ESI); m/z 157 (M).sup.+
b) 4-Chloro-2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-methylphenol
[0505] 120 mg of the title compound was afforded using 1.0 g of
2-amino-4-chloro-5-methylphenol in a manner similar to Preparation
examples 54a) and 54b).
[0506] 1H-NMR (CDCl.sub.3); .delta. (ppm) 2.29 (3H, s), 2.34 (3H,
s), 2.41 (3H, s), 6.03 (1H, s), 6.96 (1H, s), 7.19 (1H, s), 9.88
(1H, s).
[0507] MS (ESI); m/z 237 (M+H).sup.+
Preparation Example 62
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-4,5-dimethylphenol
[0508] 630 mg of the title compound was afforded using 1.0 g of
2-amino-4,5-dimethylphenol in a manner similar to Preparation
examples 54a) and 54b).
[0509] 1H-NMR (CDCl.sub.3); .delta. (ppm) 2.21 (3H, s), 2.24 (3H,
s), 2.29 (3H, s), 2.38 (3H, s), 6.00 (1H, s), 6.88 (1H, s), 6.94
(1H, s), 9.28 (1H, s).
[0510] MS (ESI); m/z 217 (M+H).sup.+
Preparation Example 63
4-(4-Chloro-3,5-dimethyl-1H-pyrazol-1-yl)-benzene-1,3-diol
[0511] 200 mg of the title compound was afforded as a by-product
during the silica gel column chromatography purification in
Preparation example 58.
[0512] 1H-NMR (CD.sub.3OD); .delta. (ppm) 2.07 (3H, s), 2.20 (3H,
s), 6.36 (1H, dd, J=2.4, 8.4 Hz), 6.42 (1H, d, J=2.4 Hz), 6.98 (1H,
d, J=8.4 Hz).
[0513] MS (ESI); m/z 239 (M+H).sup.+
2. Preparation Example of a Pressure Sensitive Adhesive in the
Patch of the Present Invention
[0514] Preparation examples of the various kinds of pressure
sensitive adhesives to be used in the patch of the present
invention are shown below. Incidentally, all "%" and "parts" mean
"% by mass" and "part by mass", respectively.
Pressure Sensitive Adhesive Preparation Example 1
Acrylic-Based Pressure Sensitive Adhesive A
[0515] 99% of 2-ethylhexyl acrylate and 1% of acrylic acid were
polymerized according to a conventional solution polymerization
method using 0.5 part of lauroyl peroxide as a polymerization
initiator in ethyl acetate at a concentration of 50% to obtain
Acrylic-based pressure sensitive adhesive A.
Pressure Sensitive Adhesive Preparation Example 2
Acrylic-Based Pressure Sensitive Adhesive B
[0516] 96% of 2-ethylhexyl acrylate and 4% of acrylic acid were
polymerized according to a conventional solution polymerization
method using 0.5 part of lauroyl peroxide as a polymerization
initiator in ethyl acetate at a concentration of 50% to obtain
Acrylic-based pressure sensitive adhesive B.
Pressure Sensitive Adhesive Preparation Example 3
Acrylic-Based Pressure Sensitive Adhesive C
[0517] 92% of 2-ethylhexyl acrylate and 8% of acrylic acid were
polymerized according to a conventional solution polymerization
method using 0.5 part of lauroyl peroxide as a polymerization
initiator in ethyl acetate at a concentration of 50% to obtain
Acrylic-based pressure sensitive adhesive C.
Pressure sensitive adhesive preparation example 4
Acrylic-based pressure sensitive adhesive D
[0518] a 2-ethylhexyl acrylate.cndot.N-vinylpyrrolidone copolymer
solution (product listed in Japanese Pharmaceutical Excipients) was
adjusted to 35% of solid content concentration in ethyl acetate to
obtain Acrylic-based pressure sensitive adhesive.
Pressure Sensitive Adhesive Preparation Example 5
Acrylic-Based Pressure Sensitive Adhesive E
[0519] By using 99.5% of a mixture comprising 2-ethylhexyl
acrylate, 2-ethylhexyl methacrylate and dodecyl methacrylate with a
molar ratio of 1:8:1, and 0.5% of lauroyl peroxide as a
polymerization initiator, the resulting mixture was polymerized
according to a conventional solution polymerization method in ethyl
acetate at a concentration of 35% to obtain Acrylic-based pressure
sensitive adhesive E.
Pressure Sensitive Adhesive Preparation Example 6
Acrylic-Based Pressure Sensitive Adhesive F
[0520] Non-functional acrylic-based pressure sensitive adhesive
GMS3253 (Cytec)
Pressure Sensitive Adhesive Preparation Example 7
Acrylic-Based Pressure Sensitive Adhesive G
[0521] Hydroxy functional acrylic-based pressure sensitive adhesive
GMS7883 (Cytec)
Pressure Sensitive Adhesive Preparation Example 8
Acrylic-Based Pressure Sensitive Adhesive H
[0522] Carboxylic acid functional acrylic-based pressure sensitive
adhesive GMS9083 (Cytec)
Pressure Sensitive Adhesive Preparation Example 9
Acrylic-Based Pressure Sensitive Adhesive I
[0523] carboxylic acid functional acrylic-based pressure sensitive
adhesive GMS9073 (Cytec)
Pressure Sensitive Adhesive Preparation Example 10
Silicone-Based Pressure Sensitive Adhesive
[0524] silicone-based pressure sensitive adhesive Bio-PSA 7-4501
(TORAY DOW CORNING Corp.)
Pressure Sensitive Adhesive Preparation Example 11
Rubber-Based Pressure Sensitive Adhesive A
[0525] By using 50% of a styrene-isoprene-styrene block copolymer
(SIS5002, JSR) and 50% of a hydrogenated rosin ester resin (Pine
Crystal KE-311, ARAKAWA CHEMICAL INDUSTRIES, LTD.), a
toluene/hexane (mixture ratio: 2/1) solution thereof was so
prepared that the solid component concentration of the solution
became 40%, and the mixture was stirred until the solution became
uniform to obtain rubber-based pressure sensitive adhesive A.
Pressure Sensitive Adhesive Preparation Example 12
Rubber-Based Pressure Sensitive Adhesive B
[0526] By using 50% of a styrene-isoprene-styrene block copolymer
(SIS5002, JSR) and 50% of a terpene resin (YS resin PX1150N,
YASUHARA CHEMICAL CO., LTD.), a toluene/hexane (mixture ratio: 2/1)
solution thereof was so prepared that the solid component
concentration of the solution became 40%, and the mixture was
stirred until the solution became uniform to obtain rubber-based
pressure sensitive adhesive B.
Pressure Sensitive Adhesive Preparation Example 13
Urethane-Based Pressure Sensitive Adhesive
[0527] Toluene and ethyl acetate were added to 43% of a polyether
polyol (1) (copolymer of ethylene oxide unit and propyleneoxide
unit using glycerine as an initiator, number average molecular
weight: 10,000, number of average functional group(s): 3), 21% of a
polyether polyol (2) (copolymer of propylene oxide units, number
average molecular weight: 10,000, number of average functional
group(s): 2), and 36% of a polyether monool (polymer of propylene
oxide units using methanol as an initiator, number average
molecular weight: 3,500, number of average functional group(s): 1),
to adjust the solid component to 50%, then, 0.02% of dibutyl tin
dilaurate was added as the urethanization catalyst to the
above-mentioned solid component, and hexamethylene diisocyanate
prepolymer (weight average molecular weight: 600, number of average
functional group(s): 2) was added as the organic diisocyanate so
that a molar ratio thereof become 90 of the isocyanate group in the
isocyanate prepolymer based on 100 of the hydroxyl group in the
active hydrogen compound to obtain Urethane-based pressure
sensitive adhesive.
3. Preparation Example of the Patch of the Present Invention
Preparation Examples of Patches 1 to 33 Using Acrylic-Based
Pressure Sensitive Adhesives
[0528] After weighing
2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-methylphenol (hereinafter
referred to as the compound of Preparation example 44) prepared in
Preparation example 44, and Acrylic-based pressure sensitive
adhesives A to I (weight as solid component) prepared in Pressure
sensitive adhesive preparation examples 1 to 9, the whole solid
component was adjusted to 35% in ethyl acetate, and the mixture was
stirred until it became uniform. The pressure sensitive adhesive
solution was applied onto a 75 .mu.m PET
(polyethyleneterephthalate) film (FILMBYNA 75E-0010BD, FUJIMORI
KOGYO CO., LTD.) one surface of which had been subjected to
silicone-treatment so that a thickness of the pressure sensitive
adhesive layer after drying became 70 .mu.m, and dried at
85.degree. C. for 3 minutes. Then, one surface of the pressure
sensitive adhesive layer was laminated with a 12 .mu.m PET film
(Lumirror S10, Toray Industries, Inc.) to obtain a patch using
acrylic-based pressure sensitive adhesive.
Preparation Examples of Patches 34 and 35 Using Silicone-Based
Pressure Sensitive Adhesives
[0529] In the same manner as in Preparation example of the patches
using the above-mentioned acrylic-based pressure sensitive adhesive
except that Acrylic-based pressure sensitive adhesive A was changed
to Silicone-based pressure sensitive adhesive prepared in pressure
sensitive adhesive preparation example 10, and the concentration of
the whole solid components was adjusted to 65% in ethyl acetate to
obtain a patch using silicone-based pressure sensitive
adhesive.
Preparation Examples of Patches 36 and 37 Using Rubber-Based
Pressure Sensitive Adhesives
[0530] In the same manner as in Preparation example of the patches
using the above-mentioned acrylic-based pressure sensitive adhesive
except that Acrylic-based pressure sensitive adhesive A was changed
to Rubber-based pressure sensitive adhesive A or B prepared in
Pressure sensitive adhesive preparation examples 11 and 12,
dibutylhydroxytoluene (SWANOX BHT, Seiko Chemical Co., Ltd.) (1%
based on the whole solid components) was added as an antioxidant,
and the concentration of the whole solid components was adjusted to
40% in a toluene/hexane (mixture ratio: 2/1) solution to obtain a
patch using Rubber-based pressure sensitive adhesive.
Preparation Example of Patch 38 Using Urethane-Based Pressure
Sensitive Adhesive
[0531] In the same manner as in Preparation example of the patches
using the above-mentioned acrylic-based pressure sensitive adhesive
except that Acrylic-based pressure sensitive adhesive A was changed
to Urethane-based pressure sensitive adhesive prepared in Pressure
sensitive adhesive preparation example 13, and a polyisocyanate
(COLONATE L, NIPPON POLYURETHANE INDUSTRY CO., LTD.) (1.7% based on
the whole solid components) was added as a curing agent to obtain a
patch using Urethane-based pressure sensitive adhesive.
[0532] Concrete prescriptions of the patches prepared in the
above-mentioned patch preparation examples are shown in the
following table.
TABLE-US-00001 TABLE 1 Patch No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14
15 16 17 18 19 Drug Compound of 5 5 5 5 5 5 5 5 5 10 10 10 10 10 10
10 10 30 30 Preparation example 44 Adhesive agent Acrylic-based 95
90 70 pressure sensitive adhesive A Acrylic-based 95 90 70 pressure
sensitive adhesive B Acrylic-based 95 90 pressure sensitive
adhesive C Acrylic-based 95 90 pressure sensitive adhesive D
Acrylic-based 95 90 pressure sensitive adhesive E Acrylic-based 95
90 pressure sensitive adhesive F Acrylic-based 95 90 pressure
sensitive adhesive G Acrylic-based 95 90 pressure sensitive
adhesive H Acrylic-based 95 pressure sensitive adhesive I
Silicone-based pressure sensitive adhesive Rubber-based pressure
sensitive adhesive A Rubber-based pressure sensitive adhesive B
Urethane-based pressure sensitive adhesive Antioxidant Curing agent
Thickness of (.mu.m) 70 70 70 70 70 70 70 70 70 70 70 70 70 70 70
70 70 70 70 pressure sensitive adhesive layer Patch No. 20 21 22 23
24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 Drug Compound of 30 30
30 30 30 30 50 50 50 50 50 50 50 50 5 10 10 10 10 Preparation
example 44 Adhesive agent Acrylic-based 50 pressure sensitive
adhesive A Acrylic-based 50 pressure sensitive adhesive B
Acrylic-based 70 50 pressure sensitive adhesive C Acrylic-based 70
50 pressure sensitive adhesive D Acrylic-based 70 50 pressure
sensitive adhesive E Acrylic-based 70 50 pressure sensitive
adhesive F Acrylic-based 70 50 pressure sensitive adhesive G
Acrylic-based 70 50 pressure sensitive adhesive H Acrylic-based
pressure sensitive adhesive I Silicone-based 95 90 pressure
sensitive adhesive Rubber-based 89 pressure sensitive adhesive A
Rubber-based 89 pressure sensitive adhesive B Urethane-based 88.3
pressure sensitive adhesive Antioxidant BHT 1 1 Curing agent
Polyisocyanate 1.7 Thickness of (.mu.m) 70 70 70 70 70 70 70 70 70
70 70 70 70 70 70 70 70 70 70 pressure sensitive adhesive layer
4. Antifungal Activity Test Against Dermatophytes
[0533] Measurement of the anti-trichophyton activity of the
compound of the formula (I) comprised in the patch of the present
invention was carried out by the following method. The compound to
be evaluated was used by dissolving in dimethyl sulfoxide (DMSO).
As a medium for the test, RPMI1640 medium containing 0.165M of
3-morpholinopropanesulfonic acid (MOPS) was used. As fungi to be
tested, Trichophyton mentagrophytes (T. mentagrophytes) ATCC18748
or Trichophyton rubrum (T. rubrum) ATCC10218 was used. The testing
fungal strain was apportioned to 100 .mu.l with a concentration of
1.times.10.sup.4 conidia/ml, mixed with a compound to be evaluated
on a 96-well half area plate so that the DMSO concentration became
1%, and cultured at a cultivation temperature of 28.degree. C. for
3 days (Trichophyton mentagrophytes) or 4 days (Trichophyton
rubrum). Thereafter, 5 .mu.l of Cell Counting Kit 8 (WST8) was
added thereto, and absorbances at 450 nm and 595 nm were measured
to use these as background values. Thereafter, these were
cultivated at 28.degree. C. for 5 hours (Trichophyton
mentagrophytes) or overnight (Trichophyton rubrum) to cause a
color, and absorbances at 450 nm and 595 nm were measured again. A
growth inhibiting rate was calculated from the difference to the
background values, and a 80% growth inhibiting concentration was
made an MIC value (.mu.h/ml).
TABLE-US-00002 TABLE 2 Preparation MIC MIC example No. (T.
mentagrophytes) (T. rubrum) 1 B B 5 C D 6 C E 7 C E 8 C E 9 A A 10
D E 11 C D 12 C E 13 A B 14 B B 15 C C 16 C E 17 A A 18 B B 19 C C
20 C D 21 A B 22 C D 23 C D 24 A C 25 B B 26 A A 28 B C 30 A A 31 B
B 32 B B 33 B A 34 B B 35 C C 36 E D 37 B B 38 C B 39 C C 40 E D 41
D D 42 C D 43 E D 44 A A 45 A A 46 E D 47 B B 48 B B 49 E D 50 B B
51 E D 52 A A 53 B B 54 A A 55 A A 56 A A 57 B B 58 B A 59 B B 61 C
C 63 A A Amorolfine hydrochloride A A Terbinafine hydrochloride A A
MIC (T. mentagrophytes) A .ltoreq.1 .mu.g/ml B 2 to 8 .mu.g/ml C 16
to 32 .mu.g/ml D Inhibited 50% or more and less than 80% with 32
.mu.g/ml E Inhibited less than 50% with 32 .mu.g/ml MIC (T. rubrum)
A .ltoreq.2 .mu.g/ml B 4-16 .mu.g/ml C 16-32 .mu.g/ml D >32-64
.mu.g/ml E >64 .mu.g/ml
5. Nail permeability test
Method
[0534] By using the same method as in Patch Preparation examples 1
to 33, the patches of the present invention with the formulations
shown in the following Table in which the compound of Preparation
example 44 had been used were prepared, and permeability of said
compound to human nail was evaluated.
[0535] To the center of a human nail formed to a round shape having
a diameter of 9 mm was adhered a patch formed to a round shape
having a diameter of 4 mm, and after covering the patch with a
cover tape.sup.*1, it was placed on a receiver layer.sup.*2, and
allowed to stand under the atmosphere at a temperature of
32.degree. C. and a relative humidity of 85% for one week. On the
second day and fifth day from allowing to stand, 30 .mu.l of a 20%
aqueous polyethylene glycol solution was added to the receiver
layer.
[0536] The patch and the cover tape were removed from the human
nail which had been allowed to stand for one week. The human nail
was dissolved in an aqueous sodium hydroxide solution, the compound
of Preparation example 44 was extracted and quantitated by high
performance liquid chromatography, which was made a nail storage
amount. The nail storage amount was converted to an amount of the
compound per 1 g weight of the respective nails which had
previously measured, and an average value of the three specimens
was calculated.
[0537] Also, said compound in the receiver layer was extracted with
methanol, and quantitated by high performance liquid
chromatography, which was made a nail permeated amount. The nail
permeated amount was converted to an amount of the compound per 1
cm.sup.2, and an average value of the three specimens was
calculated.
*1: It was prepared by forming a tape in which an acrylic-based
pressure sensitive adhesive had been applied on a PET film having a
thickness of 12 .mu.m to a round shape which has a diameter of 6.5
mm, and adhering a PET film having a thickness of 12 .mu.m formed
to a round shape which has a diameter of 4.5 mm to the center of
the pressure sensitive adhesive surface. *2: An absorbent cotton
formed to a round shape with the same size as that of the human
nail, to which 30 .mu.l of a 20% aqueous polyethylene glycol
solution had been added.
Results
[0538] As shown in the following Table, it could be confirmed that
the compound was transferred into the nail with a sufficient amount
in all the patches.
TABLE-US-00003 TABLE 3 Formulation (% by mass) Test Test Test Test
Test Test Example 1 Example 2 Example 3 Example 4 Example 5 Example
6 Compound of Preparation 5 10 10 10 20 20 example 44 Acrylic-based
pressure -- 90 70 -- 53.3 -- sensitive adhesive D Acrylic-based
pressure 63.3 -- -- 46.7 -- 46.7 sensitive adhesive H Acrylic-based
pressure 31.7 -- -- 23.3 26.7 23.3 sensitive adhesive I N-acetyl
cysteine -- -- 10 10 -- 10 Aminoalkyl methacrylate -- -- 10 10 --
-- copolymer E Nail storage amount (.mu.g/g) 427 466 837 593 1080
1204 Nail permeated 2.6 4.0 4.0 3.5 4.2 7.0 amount
(.mu.g/cm.sup.2)
6. Antimicrobial activity test of patches
Method
[0539] By using the same method as in Patch Preparation examples 1
to 38, the patches of the present invention with the formulation
shown in the following Table in which the compound of Preparation
example 44 had been used were prepared, and antimicrobial activity
of the patch to the human nail was confirmed.
[0540] To the center of a human nail formed to a round shape having
a diameter of 6 mm was adhered a patch formed to a round shape
having a diameter of 3 mm, and after covering the patch with a
cover tape.sup.*1, it was placed on a receiver layer.sup.*2, and
allowed to stand under the atmosphere at a temperature of
32.degree. C. and a relative humidity of 85% for one week. At the
second day and fifth day after allowed to stand, 30 .mu.l of a 20%
aqueous polyethylene glycol solution was added to the receiver
layer. The patch was removed from the human nail which had been
allowed to stand for one week, and the cover tape was changed,
then, the human nail was placed at the center of the test
medium.sup.*3, and cultivated under the atmosphere at a temperature
of 28.degree. C. for one week. For evaluation, the medium at the
human nail and peripheral thereof were observed, and lengths of the
inhibition zone were measured.sup.*4.
*1: It was prepared by forming a tape in which a pressure sensitive
adhesive had been applied on a PET film having a thickness of 12
.mu.m to a round shape which has a diameter of 6.5 mm, and adhering
a PET film having a thickness of 12 .mu.m formed to a round shape
which has a diameter of 4.5 mm to the center of the pressure
sensitive adhesive surface. *2: An absorbent cotton formed to a
round shape with the same size as that of the human nail, to which
30 .mu.l of a 20% aqueous polyethylene glycol solution had been
added. *3: On the surface of the Sabouraud's agar plating medium
(available from Japan Becton Dickinson and Company), 50 .mu.l of a
suspension containing 1.times.10.sup.7/mL of conidium of
trichophyton (Trichophyton mentagrophytes (T. mentagrophytes) NBRC
32410) was uniformly coated. *4: The length of the inhibition zone
was obtained by measuring a transparent portion around the human
nail in which growth of trichophyton had been inhibited, and
calculating an average value of three specimens.
Results
[0541] In all the human nails to which the patch comprising the
compound of Preparation example 44, inhibition zones in which
growth of trichophyton was inhibited were formed, whereby it could
be shown that a sufficient amount of the compound which is
sufficient for showing antimicrobial activity had been transferred
from the patch to the nail and stored. On the other hand, in the
nail to which the patch (placebo patch) comprising no compound of
Preparation example 44 was adhered, and in the nail to which no
patch was adhered, no inhibition zone was formed.
TABLE-US-00004 TABLE 4 Formulation (% by mass) Test Test Test Test
Test Test Test Example 7 Example 8 Example 9 Example 10 Example 11
Example 12 Example 13 Compound of Preparation 10 10 10 10 10 10 10
example 44 Acrylic-based pressure 90 -- 75 -- -- -- -- sensitive
adhesive D Acrylic-based pressure -- 90 -- -- -- -- -- sensitive
adhesive E Acrylic-based pressure -- -- 15 -- -- -- -- sensitive
adhesive I Silicone-based pressure- -- -- -- 90 -- -- -- sensitive
adhesive Rubber-based pressure- -- -- -- -- 90 -- -- sensitive
adhesive A Rubber-based pressure- -- -- -- -- -- 90 -- sensitive
adhesive B Urethane-based pressure- -- -- -- -- -- -- 90 sensitive
adhesive Inhibition zone (mm) 6.9 6.1 5.5 4.9 10.7 8.1 2.2
7. Adhesiveness Test of Patch
Method
[0542] By using the same method as in Patch Preparation examples 1
to 13, the patches comprising the compound of Preparation example
44 were prepared with the formulation shown in the following Table,
and their adhesive forces and adhesivenesses were measured by the
method regulated in Japanese Industrial Standard JIS Z0237. More
specifically, a patch with a width of 10 mm was adhered to a
stainless test plate with a surface finish of BA, and an adhesive
force thereof when it is peeled off by an Instron type tensile
tester with a peeling angle of 180.degree. was measured. Based on
the measurement of this adhesive force, evaluation was carried out
according to the following criteria.
[0543] I: Adhesive force is 2.0N/10 mm or more
[0544] II: Adhesive force is 0.1N/10 mm or more
[0545] III: Adhesive force is less than 0.1N/10 mm
[0546] Also, a patch test piece cut to a size of 10 mm.times.10 mm
was adhered to each toenail of four subjects, and the adhered
conditions for 7 days were evaluated by whether it is adhered
(good), or dropped out.
Results
[0547] As shown in the following Table, adhesive forces sufficient
as the patch were shown in all the patches. Also, these were
adhered for a long term of 7 days without dropping out, whereby
these were practically excellent in adhesiveness.
TABLE-US-00005 TABLE 5 Formulation (% by mass) Test Test Test Test
Test Test Test Example 14 Example 15 Example 16 Example 17 Example
18 Example 19 Example 20 Compound of Preparation 10 10 10 10 15 20
20 example 44 Acrylic-based pressure 85 75 60 45 46.7 53.3 46.7
sensitive adhesive D Acrylic-based pressure 5 15 30 25 23.3 26.7
23.3 sensitive adhesive I N-acetyl cysteine -- -- -- 10 10 -- 10
Aminoalkyl methacrylate -- -- -- 10 5 -- -- copolymer E Adhesive
force I I I I I I I Nail Adhesiveness Good Good Good Good Good Good
Good
INDUSTRIAL APPLICABILITY
[0548] According to the present invention, a patch for nail and/or
skin having antifungal activity against dermatophytes, and having
higher nail permeability can be provided.
* * * * *