U.S. patent application number 11/610230 was filed with the patent office on 2007-05-17 for pyrazole derivatives.
This patent application is currently assigned to FUJISAWA PHARMACEUTICAL CO., LTD.. Invention is credited to Hidenori Azami, Natsuko Kayakiri, Katsuya Nakamura, Kazuo Okumura, Fumiyuki SHIRAI.
Application Number | 20070112037 11/610230 |
Document ID | / |
Family ID | 32474716 |
Filed Date | 2007-05-17 |
United States Patent
Application |
20070112037 |
Kind Code |
A1 |
SHIRAI; Fumiyuki ; et
al. |
May 17, 2007 |
Pyrazole Derivatives
Abstract
A compound of the formula (I): ##STR1## wherein R.sup.1 is
hydrogen or lower alkyl; R.sup.2 is lower alkyl, etc.; R.sup.3 is
lower alkoxy, etc.; R.sup.4 is hydroxy, etc.; X is O, S, etc.; Y is
CH or N; Z is lower alkylene or lower alkenylene; and m is 0 or 1;
or salts thereof, which are useful as a medicament.
Inventors: |
SHIRAI; Fumiyuki; (Osaka,
JP) ; Azami; Hidenori; (Osaka, JP) ; Kayakiri;
Natsuko; (Osaka, JP) ; Okumura; Kazuo; (Osaka,
JP) ; Nakamura; Katsuya; (Osaka, JP) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
FUJISAWA PHARMACEUTICAL CO.,
LTD.
Osaka-shi
JP
|
Family ID: |
32474716 |
Appl. No.: |
11/610230 |
Filed: |
December 13, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10706999 |
Nov 14, 2003 |
7183306 |
|
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11610230 |
Dec 13, 2006 |
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Current U.S.
Class: |
514/341 ;
514/406; 546/275.4; 548/377.1 |
Current CPC
Class: |
A61P 29/00 20180101;
C07D 231/12 20130101; A61P 25/04 20180101; C07D 413/04 20130101;
A61P 37/00 20180101; A61P 7/02 20180101; C07D 403/14 20130101; A61P
25/00 20180101; C07D 401/04 20130101; A61P 43/00 20180101; C07D
231/22 20130101; A61P 19/02 20180101; A61P 35/00 20180101; C07D
231/14 20130101; A61P 37/06 20180101; C07D 231/24 20130101; C07D
403/10 20130101; A61P 25/28 20180101 |
Class at
Publication: |
514/341 ;
514/406; 548/377.1; 546/275.4 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439; A61K 31/415 20060101 A61K031/415; C07D 403/02
20060101 C07D403/02; C07D 231/12 20060101 C07D231/12 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 2, 2002 |
AU |
2002953019 |
Dec 30, 2002 |
AU |
2002-953602 |
Apr 29, 2003 |
AU |
2003902015 |
Claims
1. A compound of the formula (I): ##STR356## wherein R.sup.1 is
hydrogen or lower alkyl; R.sup.2 is lower alkyl optionally
substituted with halogen, hydroxy, lower alkoxyimino or lower
alkoxy; lower alkenyl; cycloalkyl; cyano; lower alkanoyl;
cycloalkylcarbonyl; N,N-di(lower)alkylcarbamoyl; carbamoyl; N-lower
alkoxy-N-lower alkylcarbamoyl; amino; di(lower)alkylamino; lower
alkoxycarbonylamino; N,N-di(lower)alkylcarbamoylamino;
N-(N,N-di(lower)alkylcarbamoyl)-N-lower alkylamino; halogen;
hydroxy; carboxy; lower alkoxycarbonyl; aroyl;
heterocycliccarbonyl; heterocyclic group; lower alkylsulfonyl;
lower alkoxy optionally substituted with lower alkoxy,
N,N-di(lower)alkylcarbamoyl or halogen; cycloalkyloxy; lower
alkylthio; or lower alkylsufinyl; R.sup.3 is lower alkyl optionally
substituted with amino, carbamoylamino or lower alkylsulfonylamino;
halogen; cyano; hydroxy; lower alkanoyloxy; lower alkylenedioxy;
lower alkoxy optionally substituted with aryl, hydroxy, cyano,
amino, lower alkoxycarbonylamino, lower alkylsulfonylamino or
carbamoylamino; nitro; amino; hetrocyclic group; lower alkylthio;
lower alkylsulfinyl; or lower alkylsufonyl; R.sup.4 is hydrogen;
cyano; amino optionally substituted with phthaloyl or lower alkyl;
aryl; heterocyclic group; lower alkoxy; hydroxy; lower
alkylsulfonyloxy; lower alkanoyloxy; lower alkyl substituted with
tritylamino and lower alkoxycarbonyl, amino and lower
alkoxycarbonyl, amino and carboxy, amino and carbamoyl, or amino
and hydroxy; N-lower alkoxycarbonyl-N-lower alkylamino; lower
alkanoyl optionally substituted with halogen; carboxy; lower
alkylsulfonyl; sulfo; lower alkylsilyloxy; lower alkoxycarbonyl;
sulfamoyl optionally substituted with lower alkyl; carbamoyl
optionally substituted with lower alkyl; lower alkylthio; lower
alkylsulfinyl; carbamoyloxy; thioureido; or a group of the formula:
R.sup.5-G-J- in which G is --CO-- or --SO.sub.2--; J is
--N(R.sup.6)-- (wherein R.sup.6 is hydrogen or lower alkyl); and
R.sup.5 is amino optionally substituted with lower alkoxycarbonyl
or lower alkyl; lower alkyl optionally substituted with hydroxy,
lower alkoxycarbonylamino, lower alkanoyloxy, amino or halogen;
lower alkoxy; hydrogen; heterocyclic group; or aryl; X is O, S, SO
or SO.sub.2; Y is CH or N; Z is lower alkylene or lower alkenylene;
and m is 0 or 1; provided that when R.sup.4 is hydrogen; then
R.sup.3 is lower alkyl substituted with amino, carbamoylamino or
lower alkylsulfonylamino; or lower alkoxy substituted with aryl,
hydroxy, cyano, amino, lower alkoxycarbonylamino, lower
alkylsulfonylamino or carbamoylamino; or salts thereof.
2. The compound of claim 1, wherein R.sup.1 is hydrogen; R.sup.2 is
lower alkyl optionally substituted with halogen, hydroxy, lower
alkyoxyimino or lower alkoxy; cycloalkyl; halogen; lower alkoxy
optionally substituted with halogen; or lower alkylthio; R.sup.3 is
lower alkoxy optionally substituted with aryl, hydroxy, cyano,
amino, lower alkoxyxcarbonylamino, lower alkylsulfonylamino or
carbamoylamino; R.sup.4 is a group of the formula: R.sup.5-G-J- in
which R.sup.5, G and J are each as defined in claim 1; X is O or S;
and Z is lower alkylene.
3. The compound of claim 2, wherein R.sup.2 is lower alkyl
optionally substituted with halogen; cycloalkyl; halogen; or lower
alkoxy optionally substituted with halogen; R.sup.3 is lower
alkoxy; R.sup.4 is a group of the formula: R.sup.5-G-J- in which G
is --CO-- or --SO.sub.2--, J is --NH-- and R.sup.5 is amino or
lower alkyl; and X is O.
4. The compound of claim 3, which is
N-(2-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethyl)urea-
,
N-{4-[3-(difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}met-
hanesulfonamide,
N-{4-[3-(difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}urea,
N-(2-{4-[3-(difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}-
ethyl)urea,
N-(2-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}-
ethyl)urea,
N-(2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phe-
noxy}ethyl)urea,
N-(2-{4-[3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)-
urea,
N-(2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5--
yl]phenoxy}ethyl)urea,
N-(2-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}-
ethyl)acetamide, or
N-(2-{4-[3-(2,2-difluoroethoxy)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl-
]phenoxy}ethyl)urea.
5. A process of preparing a compound of the formula: ##STR357##
wherein R.sup.1 is hydrogen or lower alkyl; R.sup.2 is lower alkyl
optionally substituted with halogen, hydroxy, lower alkoxyimino or
lower alkoxy; lower alkenyl; cycloalkyl; cyano; lower alkanoyl;
cycloalkylcarbonyl; N,N-di(lower)alkylcarbamoyl; carbamoyl; N-lower
alkoxy-N-lower alkylcarbamoyl; amino; di(lower)alkylamino; lower
alkoxycarbonylamino; N,N-di(lower)alkylcarbamoylamino;
N-(N,N-di(lower)alkylcarbamoyl)-N-lower alkylamino; halogen;
hydroxy; carboxy; lower alkoxycarbonyl; aroyl;
heterocycliccarbonyl; heterocyclic group; lower alkylsulfonyl;
lower alkoxy optionally substituted with lower alkoxy,
N,N-di(lower)alkylcarbamoyl or halogen; cycloalkyloxy; lower
alkylthio; or lower alkylsufinyl; R.sup.3 is lower alkyl optionally
substituted with amino, carbamoylamino or lower alkylsulfonylamino;
halogen; cyano; hydroxy; lower alkanoyloxy; lower alkylenedioxy;
lower alkoxy optionally substituted with aryl, hydroxy, cyano,
amino, lower alkoxycarbonylamino, lower alkylsulfonylamino or
carbamoylamino; nitro; amino; hetrocyclic group; lower alkylthio;
lower alkylsulfinyl; or lower alkylsufonyl; R.sup.4 is hydrogen;
cyano; amino optionally substituted with phthaloyl or lower alkyl;
aryl; heterocyclic group; lower alkoxy; hydroxy; lower
alkylsulfonyloxy; lower alkanoyloxy; lower alkyl substituted with
tritylamino and lower alkoxycarbonyl, amino and lower
alkoxycarbonyl, amino and carboxy, amino and carbamoyl, or amino
and hydroxy; N-lower alkoxycarbonyl-N-lower alkylamino; lower
alkanoyl optionally substituted with halogen; carboxy; lower
alkylsulfonyl; sulfo; lower alkylsilyloxy; lower alkoxycarbonyl;
sulfamoyl optionally substituted with lower alkyl; carbamoyl
optionally substituted with lower alkyl; lower alkylthio; lower
alkylsulfinyl; carbamoyloxy; thioureido; or a group of the formula:
R.sup.5-G-J- in which G is --CO-- or --SO.sub.2--; J is
--N(R.sup.6)-- (wherein R.sup.6 is hydrogen or lower alkyl); and
R.sup.5 is amino optionally substituted with lower alkoxycarbonyl
or lower alkyl; lower alkyl optionally substituted with hydroxy,
lower alkoxycarbonylamino, lower alkanoyloxy, amino or halogen;
lower alkoxy; hydrogen; heterocyclic group; or aryl; X is O, S, SO
or SO.sub.2; Y is CH or N; Z is lower alkylene or lower alkenylene;
and m is 0 or 1; provided that when R.sup.4 is hydrogen; then
R.sup.3 is lower alkyl substituted with amino, carbamoylamino or
lower alkylsulfonylamino; or lower alkoxy substituted with aryl,
hydroxy, cyano, amino, lower alkoxycarbonylamino, lower
alkylsulfonylamino or carbamoylamino; or salts thereof, which
comprises, 1) reacting a compound of the formula: ##STR358## or its
salt with a compound of the formula: ##STR359## or its salt in the
acidic condition to provide a compound of the formula: ##STR360##
or its salt, in the above formulas, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, X, Y, Z and m are each as defined above, or 2) reacting a
compound of the formula: ##STR361## or its salt with a compound (V)
of the formula: R.sup.4-Z-Q (V) or its salt to provide a compound
of the formula: ##STR362## or its salt, in the above formulas:
R.sup.1, R.sup.2, R.sup.3, R.sup.4, Y and Z are each as defined
above, Xa is O or S, and Q is hydroxy or an acid residue.
6. A pharmaceutical composition comprising the compound of claim 1,
as an active ingredient, in association with a pharmaceutically
non-toxic carrier or excipient.
7. A compound of claim 1 for use as a medicament
8. A method for treatment and/or prevention of inflammatory
conditions, various pains, collagen diseases, autoimmune diseases,
various immunity diseases, analgesic, thrombosis, cancer or
neurodegenerative diseases which comprises administering an
effective amount of the compound of claim 1 to human beings or
animals.
9. Use of the compound of claim 1 for the manufacture of a
medicament for treatment and/or prevention of inflammatory
conditions, various pains, collagen diseases, autoimmune diseases,
various immunity diseases, analgesic, thrombosis, cancer or
neurodegenerative diseases in human beings or animals.
10. The analgesic agent comprising the compound of claim 1, which
is usable for treating and/or preventing pains caused by or
associated with acute or chronic inflammations without causing
gastrointestinal disorders.
11. The analgesic agent of claim 10, which is usable for treating
or preventing pains caused by or associated with rheumatoid
arthritis, osteoarthritis, lumbar rheumatism, rheumatoid
spondylitis, gouty arthritis, or juvenile arthritis; lumbago;
cervico-omo-brachial syndrome; scapulohumeral periarthritis; pain
and tumescence after operation or injury without causing
gastrointestinal disorders.
12. A commercial package comprising the pharmaceutical composition
containing the compound (I) identified in claim 1 and a written
matter associated therewith, wherein the written matter states that
the compound (I) can or should be used for preventing or treating
inflammatory conditions, various pains, collagen diseases,
autoimmune diseases, various immunity diseases, analgesic,
thrombosis, cancer or neurodegenerative diseases.
Description
TECHNICAL FIELD
[0001] This invention relates to pyrazole compounds having
pharmacological activity, to a process for their production and to
a pharmaceutical composition containing the same.
BACKGROUND ART
[0002] The presence of two cyclooxygenase isoenzymes,
cyclooxygenase-I (COX-I) and cyclooxygenase-II (COX-II) is known
(Proc. Nat. Acad. Sci. USA 88, 2692-2696 (1991)).
[0003] Traditional non steroidal anti-inflammatory compounds
(NSAIDs) have inhibiting activities of both COX-I and COX-II (J.
Biol. Chem., 268, 6610-6614 (1993), etc). The therapeutic use
thereof involves undesired effects on the gastrointestinal tract,
such as bleeding, erosions, gastric and intestinal ulcers, etc.
[0004] It was reported that selective inhibition of COX-II shows
anti-inflammatory and analgesic activities comparable with
conventional NSAIDs but with a lower incidence of some
gastrointestinal undesired effects (Pro. Nat. Acad. Sci. USA, 91,
3228-3232(1994)). Accordingly, various selective COX-II inhibitors
have been prepared. However, it was reported that those "selective
COX-II inhibitor" show some side-effects on kidney and/or
insufficient efficacy on acute pains.
[0005] Further, some compounds such as SC-560, mofezolac, etc,
which have certain selective inhibiting activity against COX-I.
WO98/57910 shows some compounds having such activity. However,
their selectivity of inhibiting COX-I does not seem to be enough to
use them as a clinically acceptable and satisfactory analgesic
agent due to their gastrointestinal disorders.
[0006] WO02/055502 shows some pyridine derivatives having
cyclooxygenase inhibiting activity, particularly cyclooxygenase-I
inhibiting activity. Further, WO03/040110 shows some triazole
derivatives having cyclooxygenase inhibiting activity, particularly
cyclooxygenase-I inhibiting activity. And WO99/51580 shows some
triazole derivatives having an inhibiting activity of cytokine
production.
DISCLOSURE OF INVENTION
[0007] This invention relates to pyrazole compounds, which have
pharmacological activity such as cyclooxygenase (hereinafter
described as COX) inhibiting activity, to a process for their
production, to a pharmaceutical composition containing the same and
to a use thereof.
[0008] Accordingly, one object of this invention is to provide the
pyrazole compounds, which have a COX inhibiting activity.
[0009] Another object of this invention is to provide a process for
production of the pyrazole compounds.
[0010] A further object of this invention is to provide a
pharmaceutical composition containing, as active ingredients, the
pyrazole compounds.
[0011] Still further object of this invention is to provide a use
of the pyrazole compounds for manufacturing a medicament for
treating or preventing various diseases.
[0012] The new pyrazole compounds of this invention can be
represented by the following general formula (I): ##STR2## wherein
[0013] R.sup.1 is hydrogen or lower alkyl; [0014] R.sup.2 is lower
alkyl optionally substituted with halogen, hydroxy, lower
alkoxyimino or lower alkoxy; lower alkenyl; cycloalkyl; cyano;
lower alkanoyl; cycloalkylcarbonyl; N,N-di(lower)alkylcarbamoyl;
carbamoyl; N-lower alkoxy-N-lower alkylcarbamoyl; amino;
di(lower)alkylamino; lower alkoxycarbonylamino;
N,N-di(lower)alkylcarbamoylamino;
N-(N,N-di(lower)alkylcarbamoyl)-N-lower alkylamino; halogen;
hydroxy; carboxy; lower alkoxycarbonyl; aroyl;
heterocycliccarbonyl; heterocyclic group; lower alkylsulfonyl;
lower alkoxy optionally substituted with lower alkoxy,
N,N-di(lower)alkylcarbamoyl or halogen; cycloalkyloxy; lower
alkylthio; or lower alkylsufinyl; [0015] R.sup.3 is lower alkyl
optionally substituted with amino, carbamoylamino or lower
alkylsulfonylamino; halogen; cyano; hydroxy; lower alkanoyloxy;
lower alkylenedioxy; lower alkoxy optionally substituted with aryl,
hydroxy, cyano, amino, lower alkoxycarbonylamino, lower
alkylsulfonylamino or carbamoylamino; nitro; amino; hetrocyclic
group; lower alkylthio; lower alkylsulfinyl; or lower alkylsufonyl;
[0016] R.sup.4 is hydrogen; cyano; amino optionally substituted
with phthaloyl or lower alkyl; aryl; heterocyclic group; lower
alkoxy; hydroxy; lower alkylsulfonyloxy; lower alkanoyloxy; lower
alkyl substituted with tritylamino and lower alkoxycarbonyl, amino
and lower alkoxycarbonyl, amino and carboxy, amino and carbamoyl,
or amino and hydroxy; N-lower alkoxycarbonyl-N-lower alkylamino;
lower alkanoyl optionally substituted with halogen; carboxy; lower
alkylsulfonyl; sulfo; lower alkylsilyloxy; lower alkoxycarbonyl;
sulfamoyl optionally substituted with lower alkyl; carbamoyl
optionally substituted with lower alkyl; lower alkylthio; lower
alkylsulfinyl; carbamoyloxy; thioureido; or [0017] a group of the
formula: R.sup.5-G-J- [0018] in which G is --CO-- or --SO.sub.2--;
[0019] J is --N(R.sup.6)-- [0020] (wherein R.sup.6 is hydrogen or
lower alkyl); and [0021] R.sup.5 is amino optionally substituted
with lower alkoxycarbonyl or lower alkyl; lower alkyl optionally
substituted with hydroxy, lower alkoxycarbonylamino, lower
alkanoyloxy, amino or halogen; lower alkoxy; hydrogen; heterocyclic
group; or aryl; [0022] X is O, S, SO or SO.sub.2; [0023] Y is CH or
N; [0024] Z is lower alkylene or lower alkenylene; and [0025] m is
0 or 1; provided that when R.sup.4 is hydrogen; [0026] then R.sup.3
is lower alkyl substituted with amino, carbamoylamino or lower
alkylsulfonylamino; or lower alkoxy substituted with aryl, hydroxy,
cyano, amino, lower alkoxycarbonylamino, lower alkylsulfonylamino
or carbamoylamino; or salts thereof.
[0027] The object compound (I) of the present invention can be
prepared by the following processes. Process (1) ##STR3## Process
(2) ##STR4##
[0028] In the above processes, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
X, Y, Z and m are each as defined above,
[0029] Xa is O or S, and
[0030] Q is hyroxy or an acid residue.
[0031] The compounds of formula (I) may contain one or more
asymmetric centers and thus they can exist as enantiomers or
diastereoisomers. This invention includes both mixtures and
separate individual isomers.
[0032] The compounds of the formula (I) may also exist in
tautomeric forms and the invention includes both mixtures and
separate individual tautomers.
[0033] The compounds of the formula (I) and its salts can be in a
form of a solvate, which is included within the scope of the
present invention. The solvate preferably include a hydrate and an
ethanolate.
[0034] Also included in the scope of invention are radiolabelled
derivatives of compounds of formula (I) which are suitable for
biological studies.
[0035] In the above and subsequent description of the present
specification, suitable examples of the various definitions to be
included within the scope of the invention are explained in detail
in the following.
[0036] The term "lower" is intended to mean a group having 1 to 6
carbon atom(s), unless otherwise provided.
[0037] So, the "lower alkyl" and lower alkyl moiety in the terms
"lower alkylthio", "lower aklylsufinyl", "lower alkylsulfonyl" and
"lower alkylsulfonylamino" means a straight or branched chain
aliphatic hydrocarbon, such as methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, tert-butyl, pentyl, isoamyl, hexyl, and the like,
and it is preferably (C.sub.1-C.sub.4)alkyl, more preferably
(C.sub.2-C.sub.2)alkyl, most preferably methyl.
[0038] The "halogen" may include a fluorine atom, a chlorine atom,
a bromine atom and an iodine atom, and it is preferably a fluorine
atom or a chlorine atom, more preferably a chlorine atom.
[0039] The "lower alkyl substituted with halogen" means a
monovalent group in which the above lower alkyl is substituted by
one or more (more preferably 1 to 5, most preferably 1 to 3) above
halogen atom(s), such as fluoromethyl, chloromethyl,
difluoromethyl, dichloro-methyl, dibromomethyl, trifluoromethyl,
trichloromethyl, fluoroethyl, chloroethyl, 2,2,2-trifluoroethyl,
2,2,2-trichloroethyl, 2,2,3,3,3-pentafluoroethyl, fluoropropyl,
fluorobutyl, fluorohexyl, or the like, and it is preferably
(C.sub.1-C.sub.4)alkyl substituted with halogen, more preferably
(C.sub.1-C.sub.2)alkyl substituted with halogen, more preferably
(C.sub.1-C.sub.2)alkyl substituted with fluorine, more preferably
methyl substituted with fluorine, most preferably difluoromethyl or
trifluoromethyl.
[0040] The "lower alkyl substituted with hydroxy" means a
monovalent group in which the above lower alkyl is substituted by a
OH group, such as hydroxymethyl, hydroxyethyl, hydroxypropyl,
1-hydroxyisopropyl, 2-hydroxyisopropyl, hydroxybutyl,
hydroxyisobutyl, hydroxy-tert-butyl, hydroxyhexyl, or the like, and
it is preferably (C.sub.1-C.sub.4)alkyl substituted with hydroxy,
more preferably (C.sub.1-C.sub.3)alkyl substituted with
hydroxy.
[0041] The "lower alkenyl" means a straight or branched chain
aliphatic hydrocarbon having more than one double bond between two
carbon atom, such as ethenyl, propenyl, isopropenyl, butenyl,
isobutenyl, pentenyl, hexenyl, and the like, and it is preferably
(C.sub.2-C.sub.4)alkenyl, more preferably
(C.sub.2-C.sub.3)alkenyl.
[0042] The "lower alkoxy" means a straight or branched chain
aliphatic hydrocarbon oxy group, such as methoxy, ethoxy, propoxy,
isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, or the
like, and it is preferably (C.sub.1-C.sub.4)alkoxy, more preferably
(C.sub.1-C.sub.2)alkoxy, most preferably methoxy.
[0043] The "cycloalkyl" and cycloalky moiety in the terms
"cycloalkylcarbonyl" and "cycloalkyloxy" means C.sub.3-C.sub.10
cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, norbornyl, adamantyl, and the like, and it
is preferably C.sub.3-C.sub.6 cycloalkyl, more preferably
C.sub.3-C.sub.5 cycloalkyl, most preferably cyclopropyl or
cyclopentyl.
[0044] The "di(lower)alkylamino" means a amino group substituted by
the same or different above (lower)alkyl groups, such as
dimethylamino, diethylamino, dipropylamino, diisopropylamino,
dibutylamino, diisobutylamino, dipentylamino, dihexylamino,
ethylmethylamino, methylpropylamino, butylmethylamino,
ethylpropylamino, butylethylamino, or the like, and it is
preferably [di(C.sub.1-C.sub.4)alkyl]amino, more preferably
[di(C.sub.1-C.sub.4)alkyl]amino, most preferably dimethylamino.
[0045] The "lower alkoxycarbonyl" and lower alkoxycarbonyl moiety
in the term "lower alkoxycarbonylamino" means a
--CO.sub.2-[(lower)alkyl] group, such as methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,
butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl,
pentoxycarbonyl, hexoxycarbonyl, and the like, and it is preferably
[(C.sub.1-C.sub.4)alkoxy]carbonyl, more preferably ethoxycarbonyl
or tert-butoxycarbonyl.
[0046] The "lower alkanoyl" means carbonyl group which is
substituted by hydrogen or the above (lower)alkyl groups, such as
formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl,
2,2-dimethylpropanoyl, hexanoyl, or the like, and it is preferably
(C.sub.1-C.sub.5)alkanoyl, more preferably
(C.sub.2-C.sub.3)alkanoyl, most preferably acetyl.
[0047] The "cycloalkylcarbonyl" means a carbonyl group substituted
with cycloalkyl group mentioned above, such as cyclopropylcarbonyl,
cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl,
cycloheptylcarbonyl, norbornylcarbonyl, adamantylcarbonyl, and the
like, and it is preferably [(C.sub.3-C.sub.6)cycloalkyl]carbonyl,
more preferably [(C.sub.3-C.sub.5)cycloalkyl]carbonyl, most
preferably cyclopropylcarbonyl.
[0048] The "N,N-di(lower)alkylcarbamoyl" and
N,N-di(lower)alkylcarbamoyl moiety in the term
"N,N-di(lower)alkylcarbamoylamino" means a carbamonyl group
substituted with the same or different lower alkyl groups mentioned
above, such as dimethylcarbamoyl, diethylcarbamoyl,
dipropylcarbamoyl, diisopropylcarbamoyl, dibutylcarbamoyl,
diisobutylcarbamoyl, dipentylcarbamoyl, dihexylcarbamoyl,
ethylmethylcarbamoyl, methylpropylcarbamoyl, butylmethylcarbamoyl,
ethylpropylcarbamoyl, butylethylcarbamoyl, and the like, and it is
preferably [di(C.sub.1-C.sub.4)alkyl]carbamoyl, more preferably
[di(C.sub.1-C.sub.2)alkyl]carbamoyl, most preferably
dimethycarbamoyl or ethylmethylcarbamoyl.
[0049] The "lower alkoxy substituted with halogen" means a
monovalent group in which the above lower alkoxy is substituted by
one or more (more preferably 1 to 5, most preferably 1 to 3) above
halogen atom(s), such as fluoromethoxy, chloromethoxy,
difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy,
trichloromethoxy, fluoroethoxy, chloroethoxy, 2,2-difluoroethoxy,
2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy,
2,2,3,3,3-pentafluoroethoxy, fluoropropoxy, fluorobutoxy,
fluorohexyloxy, or the like, and it is preferably
(C.sub.1-C.sub.4)alkoxy substituted with halogen, more preferably
(C.sub.1-C.sub.2)alkoxy substituted with halogen, more preferably
(C.sub.1-C.sub.2)alkoxy substituted with fluorine, more preferably
ethoxy substituted with fluorine, most preferably
2,2-difluoroethoxy.
[0050] The "lower alkyl substituted with amino" means a monovalent
group in which the above lower alkyl is substituted by a amino
group, such as aminomethyl, 2-aminoethyl, aminopropyl,
1-aminoisopropyl, 2-aminoisopropyl, aminobutyl, aminoisobutyl,
amino-tert-butyl, aminohexyl, or the like, and it is preferably
(C.sub.1-C.sub.4)alkyl substituted with amino, more preferably
(C.sub.1-C.sub.2)alkyl substituted with amino.
[0051] The "lower alkyl substituted with carbamoylamino" means a
monovalent group in which the above (lower)alkyl is substituted by
a carbamoylamino group (urea group), such as carbamoylaminomethyl,
2-(carbamoylamino)ethyl, carbamoylaminopropyl,
1-(carbamoylamino)isopropyl, 2-(carbamoylamino)isopropyl,
carbamoylaminobutyl, carbamoylaminoisobutyl,
carbamoylamino-tert-butyl, carbamoylaminohexyl, or the like, and it
is preferably (C.sub.1-C.sub.4)alkyl substituted with
carbamoylamino, more preferably (C.sub.1-C.sub.2)alkyl substituted
with carbamoylamino.
[0052] The "aryl" and ar moiety in the term "aroyl" means an
aromatic hydrocarbon group, such as phenyl, naphtyl, indenyl, or
the like, and it is preferably (C.sub.6-C.sub.10)aryl, more
preferably phenyl.
[0053] The "aroyl" means a carbonyl group substituted with aryl
group mentioned above, such as benzoyl, naphthoyl, or the like, and
it is preferably benzoyol.
[0054] The "lower alkanoyloxy" means a monovalent group in which
oxygen atom is substituted with lower alkanoyl group mentioned
above, such as formyl, acetyl, propanoyl, butanoyl,
2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, or
the like, and it is preferably [(C.sub.1-C.sub.4)alkanoyl]oxy, more
preferably [(C.sub.1-C.sub.2)alkanoyl]oxy, most preferably
acetoxy.
[0055] The "lower alkylene" means a straight or branched chain
aliphatic hydrocarbon divalent group, such as methylene, ethylene,
1-methylethylene, 2-methylethylene, propylene, methylpropylene,
butylene, pentylene, hexylene, and the like, and it is preferably
(C.sub.1-C.sub.4) alkylene, more preferably (C.sub.1-C.sub.2)
alkylene.
[0056] The "lower alkylenedioxy" means --O-[(lower)alkylene]-O--
group. That is, in this case, R.sup.3 is divalent group and is also
substituted at the next carbon atom. This group may be exemplified
by methylenedioxy, ethylenedioxy, methylethylenedioxy,
propylenedioxy, and the like, and it is preferably
[(C.sub.1-C.sub.4)alkylene]dioxy, more preferably
[(C.sub.1-C.sub.2)alkylene]dioxy, most preferably
methylenedioxy.
[0057] The "lower alkoxy substituted with aryl" means a monovalent
group in which the above lower alkoxy is substituted by aryl group
mentioned above.
[0058] The "lower alkoxy substituted with hydroxy" means a
monovalent group in which the above lower alkoxy is substituted by
hydroxy.
[0059] The "lower alkoxy substituted with cyano" means a monovalent
group in which the above (lower)alkoxy is substituted by a cyano
group, such as cyanomethoxy, cyanoethoxy, cyanopropoxy,
cyanobutoxy, and the like, and it is preferably (C1-C4) alkoxy
substituted with cyano, more preferably (C1-C2)alkoxy substituted
with cyano, most preferably cyanomethoxy.
[0060] The "lower alkoxy substituted with amino" means a monovalent
group in which the above lower alkoxy is substituted with
amino.
[0061] The "lower alkoxy substituted with lower alkoxycarbonylamino
means a lower alkoxy substituted with amino group mentioned above
substituted with lower alkoxycarbonyl group mentioned above.
[0062] The "lower alkoxy substituted with lower alkylsulfonylamino
means a monovalent group in which the above lower alkoxy is
substituted with lower alkylsulfonylamino group mentioned
above.
[0063] The "lower alkoxy substituted with carbamoylamino" means a
monovalent group in which the above lower alkoxy is substituted by
a (carbamoyl)amino (urea) group, such as [(carbamoyl)amino]methoxy,
[(carbamoyl)amino]ethoxy, [(carbamoyl)amino]propoxy,
[(carbamoyl)amino]cyanobutoxy, and the like, and it is preferably
(C1-C4)alkoxy substituted with [(carbamoyl)amino], more preferably
(C.sub.1-C.sub.2)alkoxy substituted with [(carbamoyl)amino], most
preferably carbamoylaminomethoxy.
[0064] The "lower alkokycarbonylamino" means an amino group
substituted with lower alkokycarbonyl group mentioned above.
[0065] The "lower alkylsulfonylamino means a sulfonylamino group
substituted with lower alkyl group mentioned above.
[0066] Suitable "heterocyclic group" may be one containing at least
one hetero atom selected from nitrogen, sulfur and oxygen atom, and
may include saturated or unsaturated, monocyclic or polycyclic
heterocyclic group, and preferable heterocyclic group may be
N-containing heterocyclic group such as unsaturated 3 to 6-membered
heteromonocyclic group containing 1 to 4 nitrogen atoms, for
example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,
pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g.
4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.],
tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.;
saturated 3 to 7-membered heteromonocyclic group containing 1 to 4
nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidyl,
piperazinyl, homopiperazinyl, etc.];
[0067] unsaturated condensed heterocyclic group containing 1 to
nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl,
benzimidazolyl, quinolyl, isoquinolyl, imidazopyridyl, indazolyl,
benzotriazolyl, tetrazolopyridazinyl [e.g.
tetrazolo[1,5-b]pyridazinyl, etc.], quioxalinyl, etc.;
unsaturated 3 to 6-membered heteromonocyclic group containing an
oxygen atom, for example, pyranyl, furyl, etc.;
[0068] saturated 3 to 6-membered heteromonocyclic group containing
an oxygen atom, for example, 1H-tetrahydropyranyl,
tetrahydrofuranyl, etc.; unsaturated 3 to 6-membered
heteromonocyclic group containing 1 to 2 sulfur atoms, for example,
thienyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group
containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for
example, oxazolyl, isoxazolyl, oxadiazolyl [e.g. 1,2,4-oxadiazolyl,
1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.], oxazolinyl [e.g.
2-oxazolinyl, etc.], etc.; saturated 3 to 6-membered
heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms [e.g. morpholinyl, etc.];
unsaturated condensed heterocyclic group containing 1 to 2 oxygen
atoms and 1 to 3 nitrogen atoms [e.g. benzofurazanyl, benzoxazolyl,
benzoxadiazolyl, etc.];
unsaturated 3 to 6-membered heteromonocyclic group containing 1 to
2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,
thiadiazolyl [e.g. 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
1,2,5-thiadiazolyl, etc.], etc.;
saturated 3 to 6-membered heteromonocyclic group containing 1 to 2
sulfur atoms and 1 to 3 nitrogen atoms [e.g. thiazolidinyl,
etc.];
unsaturated condensed heterocyclic group containing 1 to 2 sulfur
atoms and 1 to 3 nitrogen atoms [e.g. benzothiazolyl,
benzothiadiazolyl, etc.];
unsaturated condensed heterocyclic group containing 1 to 2 oxygen
atoms [e.g. benzofuranyl, benzodioxolyl, chromanyl, etc.] and the
like.
[0069] Said "heterocyclic group" may be substituted with lower
alkyl as exemplified above or oxo, in which preferable one is
pieridyl, pyrrolyl, 3-metyl-1,2,4-oxadiazol-5-yl,
isoindole-1,3-dione-2-yl or 1-methyl-1H-imidazolyl.
[0070] The heterocyclic moiety in the term "heterocycliccarbonyl"
means heterocyclic group mentioned above and, it is preferably
piperidyl.
[0071] The "lower alkylsulfonyloxy" means a sulfonyloxy group
substituted with lower alkyl group mentioned above.
[0072] The "lower alkanoyl substituted with halogen" means a lower
alkanoyl group mentioned above substituted with halogen mentioned
above, such as trifluoroacetyl, and the like.
[0073] The "lower alkylsilyloxy" means silyloxy group substituted
by the same or different above (lower)alkyl groups, such as
trimethylsilyloxy, triethylsilyloxy, tert-butyldimethylsilyloxy, or
the like, and it is preferably tert-butyldimethylsilyloxy.
[0074] The "acid residue" means halogen (e.g. fluoro, chloro,
bromo, iodo), arenesulfonyloxy (e.g. benzenesulfonyloxy, tosyloxy,
etc.), alkanesulfonyloxy (e.g. mesyloxy, ethanesulfonyloxy, etc.),
and the like.
[0075] Preferred compound (I) is one having hydrogen for R.sup.1;
lower alkyl optionally substituted with halogen; cycloalkyl;
halogen; or lower alkoxy optionally substituted with halogen for
R.sup.2; lower alkoxy for R.sup.3; R.sup.5-G-J- (wherein --CO-- or
--SO.sub.2-- for G, --NH-- for J, amino or lower alkyl for R.sup.5)
for R.sup.4; O for X; CH or N for Y; lower alkylene for Z; and 0 or
1 for m.
[0076] Suitable salts of the compounds (I) are pharmaceutically
acceptable conventional non-toxic salts and include a metal salt
such as an alkali metal salt (e.g., sodium salt, potassium salt,
etc.) and an alkaline earth metal salt (e.g., calcium salt,
magnesium salt, etc.), an ammonium salt, an organic base salt
(e.g., trimethylamine salt, triethylamine salt, pyridine salt,
picoline salt, dicyclohexylamine salt, etc.), an organic acid salt
(e.g., acetate, maleate, tartrate, methanesulfonate,
benzenesulfonate, formate, toluenesulfonate, trifluoroacetate,
etc.), an inorganic acid salt (e.g., hydrochloride, hydrobromide,
sulfate, phosphate, etc.), a salt with an amino acid (e.g.,
arginine, aspartic acid, glutamic acid, etc.), or the like.
[0077] The processes for preparing the object compounds are
explained in detail in the following.
Process (1)
[0078] The object compound (Ia) or its salt can be prepared by
reacting a compound (II) or its salt with a compound (III) or its
salt in the acidic condition, for example, by using acetic
acid.
[0079] Suitable salts of the compounds (Ia) and (III) may be the
same as those exemplified for the compound (I).
[0080] Suitable salt of the compound (II) may be acid addition salt
exemplified for the compound (I).
[0081] The reaction is carried out in a conventional solvent such
as water, an alcohol (e.g. methanol, ethanol, propanol,
isopropanol, etc.), tetrahydrofuran, dioxane, etc. or a mixture of
thereof.
[0082] The reaction temperature is not critical and the reaction is
usually carried out under cooling to heating.
[0083] According to the starting material, the heterocyclic ring is
formed but not to form pyrazole ring. In this case, the dehydration
process is need to form pyrazole ring.
[0084] The hydration process is carried out under the higher
temperature.
Process (2)
[0085] The object compound (Ib) or its salt can be prepared by
reacting a compound (IV) or its salt with a compound (V) or its
salt.
[0086] Suitable salts of the compounds (Ia), (IV) and (V) may be
the same as those exemplified for the compound (I).
[0087] When the compound (V) having halogen for Q is used in this
reaction, the reaction is preferably carried out in the presence of
a base such as alkali metal (e.g. sodium, potassium, etc.), an
alkaline earth metal (e.g. magnesium, calcium, etc.), the hydride
or hydroxide or carbonate or bicarbonate thereof.
[0088] When the compound (V) having hydroxy for Q is used in this
reaction, the reaction is preferably carried out in the presence of
diethyl azodicarboxylate and triphenylphosphine.
[0089] The reaction is usually carried out in a conventional
solvent which does not adversely influence the reaction such as
water, dioxane, a alcohol (e.g. methanol, ethanol, etc.),
acetonitrile, tetrahydrofuran, acetic acid, N,N-dimethylformamide,
or a mixture thereof.
[0090] The reaction temperature is not critical and the reaction
can be carried out under cooling to heating.
[0091] In order to illustrate the usefulness of the object
compounds (I), the pharmacological test data of the compounds (I)
are shown in the following.
[A] Analgesic Activity:
[0092] Effect on Adjuvant Arthritis in Rats:
(i) Test Method:
[0093] Analgesic activity of a single dose of agents in arthritic
rats was studied.
[0094] Arthritis was induced by injection of 0.5 mg of
Mycobacterium tuberculosis (Difco Laboratories, Detroit, Mich.) in
50 .mu.l of liquid paraffin into the right hind footpad of Lewis
rats aged 7 weeks. Arthritic rats were randomized and grouped
(n=10) for drug treatment based on pain threshold of left hind paws
and body weight on day 22.
[0095] Drugs (Test compounds) were administered and the pain
threshold was measured 2 hrs after drug administration. The
intensity of hyperalgesia was assessed by the method of
Randall-Selitto. The mechanical pain threshold of the left hind paw
(uninjected hind paw) was determined by compressing the ankle joint
with a balance pressure apparatus (Ugo Basile Co. Ltd., Varese,
Italy). The threshold pressure of rats squeaking or struggling was
expressed in grams. The threshold pressure of rats treated with
drugs was compared with that of non-treated rats. A dose showing
the ratio of 1.5 is considered to be the effective dose.
TABLE-US-00001 (ii) Test Results: Test compound Dose The
coefficient of (Example No.) (mg/kg) analgesic 23 3.2 >1.5 28
3.2 >1.5 61 3.2 >1.5 181 3.2 >=1.5 240 3.2 >=1.5 248
3.2 >=1.5 250 3.2 >=1.5 254 3.2 >=1.5 267 3.2 >=1.5
[B] Inhibiting Activity Against COX-I and COX-II (Whole Blood
Assay): (i) Test Method Whole Blood Assay for COX-I
[0096] Fresh blood was collected by syringe without anticoagulants
from volunteers with consent. The subjects had no apparent
inflammatory conditions and had not taken any medication for at
least 7 days prior to blood collection.
[0097] 500 .mu.l Aliquots of human whole blood were immediately
incubated with 2 .mu.l of either dimethyl sulfoxide vehicle or a
test compound at final concentrations for 1 hr at 37.degree. C. to
allow the blood to clot. Appropriate treatments (no incubation)
were used as blanks. At the end of the incubation, 5 .mu.l of 250
mM Indomethacin was added to stop the reaction. The blood was
centrifuged at 6000.times.g for 5 min at 4.degree. C. to obtain
serum. A 100 .mu.l aliquot of serum was mixed with 400 .mu.l
methanol for protein precipitation. The supernatant was obtained by
centrifuging at 6000.times.g for 5 min at 4.degree. C. and was
assayed for TXB.sub.2 using an enzyme immunoassay kit according to
the manufacturer's procedure. For a test compound, the results were
expressed as percent inhibition of thromboxane B.sub.2(TXB.sub.2)
production relative to control incubations containing dimethyl
sulfoxide vehicle.
[0098] The data were analyzed by that a test compound at the
indicated concentrations was changed log value and was applied
simple linear regression. IC.sub.50 value was calculated by least
squares method.
Whole Blood Assay for COX-II
[0099] Fresh blood was collected in heparinized tubes by syringe
from volunteers with consent. The subjects had no apparent
inflammatory conditions and had not taken any medication for at
least 7 days prior to blood collection.
[0100] 500 .mu.l aliquots of human whole blood were incubated with
either 2 .mu.l dimethyl sulfoxide vehicle or 2 .mu.l of a test
compound at final concentrations for 15 min at 37.degree. C. This
was followed by incubation of the blood with 10 .mu.l of 5 mg/ml
lipopolysaccharide for 24 hrs at 37.degree. C. for induction of
COX-II. Appropriate PBS treatments (no LPS) were used as blanks. At
the end of the incubation, the blood was centrifuged at
6000.times.g for 5 min at 4.degree. C. to obtain plasma. A 100
.mu.l aliquot of plasma was mixed with 400 .mu.l methanol for
protein precipitation. The supernatant was obtained by centrifuging
at 6000.times.g for 5 min at 4.degree. C. and was assayed for
prostaglandin E.sub.2 (PGE.sub.2) using a radioimmunoassay kit
after conversion of PGE.sub.2 to its methyl oximate derivative
according to the manufacturer's procedure.
[0101] For a test compound, the results were expressed as percent
inhibition of PGE.sub.2 production relative to control incubations
containing dimethyl sulfoxide vehicle. The data were analyzed by
that a test compound at the indicated concentrations was changed
log value and was applied simple linear regression. IC.sub.50 value
was calculated by least squares method. TABLE-US-00002 (ii) Test
Results: Test Compound COX-I COX-II (Example No.) IC50 (.mu.M) IC50
(.mu.M) 23 <0.01 >0.1 28 <0.01 >0.1 61 <0.01 >0.1
181 <0.01 >0.1 240 <0.01 >0.1 248 <0.01 >0.1 250
<0.01 >0.1 254 <0.01 >0.1 267 <0.01 >0.1
[0102] It appeared, from the above-mentioned Test Results, that the
compound (I) or pharmaceutically acceptable salts thereof of the
present invention have an inhibiting activity against COX,
particularly a selective inhibiting activity against COX-I.
[C] Inhibiting Activity on Aggregation of Platelet
(i) Methods
Preparation of Platelet-Rich Plasma
[0103] Blood from healthy human volunteers was collected into
plastic vessels containing 3.8% sodium citrate ( 1/10 volume). The
subject had no taken any compounds for at least 7 days prior to
blood collection. Platelet-rich plasma was obtained from the
supernatant fraction of blood after centrifugation at 1200 rpm. for
10 min. Platelet-poor plasma was obtained by centrifugation of the
remaining blood at 3000 rpm for 10 min.
Measurement of Platelet Aggregation
[0104] Platelet aggregation was measured according to the
turbidimetric method with an aggregometer (Hema Tracer) In the
cuvette, platelet-rich plasma was pre-incubated for 2 min at
37.degree. C. after the addition of compounds or vehicle. In order
to quantify the inhibitory effects of each compound, the maximum
increase in light transmission was determined from the aggregation
curve for 7 min after the addition of agonist. We used collagen as
agonist of platelet aggregation in this study. The final
concentration of collagen was 0.5 .mu.g/mL. The effect of each
compound was expressed as percentage inhibition agonist-induced
platelet aggregation compared with vehicle treatment. Data are
presented as the mean.+-.S.E.M. for six experiments. The IC.sub.50
value was obtained by linear regression, and is expressed as the
compound concentration required to produce 50% inhibition of
agonist-induced platelet aggregation in comparison to vehicle
treatment.
[0105] It appeared, from the above-mentioned Test Result, that the
compound (I) or pharmaceutically acceptable salts thereof of the
present invention have an inhibiting activity against platelet
aggregation. Therefore, the compound (I) or pharmaceutically
acceptable salts thereof are useful for preventing or treating
disorders induced by platelet aggregation, such as thrombosis.
[0106] Additionally, it was further confirmed that the compounds
(I) of the present invention lack undesired side-effects of
non-selective NSAIDs, such as gastrointestinal disorders, bleeding,
renal toxicity, cardiovascular affection, etc.
[0107] As shown above, the object compound (I) or pharmaceutically
acceptable salts thereof of this invention possesses COX inhibiting
activity and possesses strong anti-inflammatory, antipyretic,
analgesic, antithrombotic, anti-cancer activities, and so on.
[0108] The object compound (I) and pharmaceutically acceptable salt
thereof, therefore, are useful for treating and/or preventing COX
mediated diseases, inflammatory conditions, various pains, collagen
diseases, autoimmune diseases, various immunological diseases,
thrombosis, cancer and neurodegenerative diseases in human beings
or animals by using administered systemically or topically.
[0109] More particularly, the object compound (I) and
pharmaceutically acceptable salts thereof are useful for treating
and/or preventing inflammation and acute or chronic pain in joint
and muscle [e.g. rheumatoid arthritis, rheumatoid spondylitis,
osteoarthritis, gouty arthritis, juvenile arthritis, scapulohumeral
periarthritis, cervical syndrome, etc.]; lumbago; inflammatory skin
condition [e.g. sunburn, burns, eczema, dermatitis, etc.];
inflammatory eye condition [e.g. conjunctivitis, etc.]; lung
disorder in which inflammation is involved [e.g. asthma,
bronchitis, pigeon fancier's disease, farmer's lung, etc.];
condition of the gastrointestinal tract associated with
inflammation [e.g. aphthous ulcer, Chrohn's disease, atopic
gastritis, gastritis varioloid, ulcerative colitis, coeliac
disease, regional ileitis, irritable bowel syndrome, etc.];
gingivitis; menorrhalgia; inflammation, pain and tumescence after
operation or injury [pain after odontectomy, etc.]; pyrexia, pain
and other conditions associated with inflammation, particularly
those in which lipoxygenase and cyclooxygenase products are a
factor, systemic lupus erythematosus, scleroderma, polymyositis,
tendinitis, bursitis, periarteritis nodose, rheumatic fever,
Sjogren's syndrome, Behcet disease, thyroiditis, type I diabetes,
nephrotic syndrome, aplastic anemia, myasthenia gravis, uveitis
contact dermatitis, psoriasis, Kawasaki disease, sarcoidosis,
Hodgkin's disease, Alzheimers disease, or the like.
[0110] Additionally, the object compound (I) or a salt thereof is
expected to be useful as therapeutical and/or preventive agents for
cardiovascular or cerebrovascular diseases, the diseases caused by
hyperglycemia and hyperlipemia.
[0111] The object compound (I) and a salt thereof can be used for
prophylactic and therapeutic treatment of arterial thrombosis,
arterial sclerosis, ischemic heart diseases [e.g. angina pectoris
(e.g. stable angina pectoris, unstable angina pectoris including
imminent infarction, etc.), myocardial infarction (e.g. acute
myocardial infarction, etc.), coronary thrombosis, etc.], ischemic
brain diseases [e.g. cerebral infarction (e.g. acute cerebral
thrombosis, etc.), cerebral thrombosis (e.g. cerebral embolism,
etc.), transient cerebral ischemia (e.g. transient ischemic attack,
etc.), cerebrovascular spasm after cerebral hemorrhage (e.g.
cerebrovascular spasm after subarachnoid hemorrhage, etc.), etc.],
pulmonary vascular diseases (e.g. pulmonary thrombosis, pulmonary
embolism etc.), peripheral circulatory disorder [e.g.
arteriosclerosis obliterans, thromboangiitis obliterans (i.e.
Buerger's disease), Raynaud's disease, complication of diabetes
mellitus (e.g. diabetic angiopathy, diabetic neuropathy, etc.),
phiebothrombosis (e.g. deep vein thrombosis, etc.), etc.],
complication of tumors (e.g. compression thrombosis), abortion
[e.g. placental thrombosis, etc.], restenosis and reocclusion [e.g.
restenosis and/or reocclusion after percutaneous transluminal
coronary angioplasty (PTCA), restenosis and reocclusion after the
administration of thrombolytic drug (e.g. tissue plasminogen
activator (TPA), etc.)], thrombus formation in case of vascular
surgery, valve replacement, extracorporeal circulation [e.g.
surgery (e.g. open heart surgery, pump-oxygenator, etc.)
hemodialysis, etc.] or transplantation, disseminated intravascular
coagulation (DIC), thrombotic thrombocytopenia, essential
thrombocytosis, inflammation (e.g. nephritis, etc.), immune
diseases, atrophic thrombosis, creeping thrombosis, dilation
thrombosis, jumping thrombosis, mural thrombosis, etc.
[0112] The object compound (I) and a salt thereof can be used for
the adjuvant therapy with thrombolytic drug (e.g. TPA, etc.) or
anticoagulant (e.g. heparin, etc.).
[0113] And, the compound (I) is also useful for inhibition of
thrombosis during extra corporeal circulation such as dialysis.
[0114] Particularly, the following diseases are exemplified: pains
caused by or associated with rheumatoid arthritis, osteoarthritis,
lumbar rheumatism, rheumatoid spondylitis, gouty arthritis,
juvenile arthritis, etc; lumbago; cervico-omo-brachial syndrome;
scapulohumeral periarthritis; pain and tumescence after operation
or injury; etc.
[0115] And on the commercial package comprising the pharmaceutical
composition mentioned above, the matter, which states above
mentioned effects, may be written.
[0116] For therapeutic purpose, the compound (I) and a
pharmaceutically acceptable salt thereof of the present invention
can be used in a form of pharmaceutical preparation containing said
compounds as an active ingredient, in admixture with a
pharmaceutically acceptable carrier such as an organic or inorganic
solid or liquid excipient suitable for oral, parenteral or external
administration. The pharmaceutical preparations may be capsules,
tablets, dragees, granules, inhalant, suppositories, solution,
lotion, suspension, emulsion, ointment, gel, cream, or the like. If
desired, there may be included in these preparations, auxiliary
substances, stabilizing agents, wetting or emulsifying agents,
buffers and other commonly used additives.
[0117] For therapeutic purpose, the analgesic agent of the present
invention can be used in a form of pharmaceutical preparation
suitable for oral, parenteral or external administration. The
pharmaceutical preparations may be capsules, tablets, dragees,
granules, inhalant, suppositories, solution, lotion, suspension,
emulsion, ointment, gel, or the like.
[0118] Particularly, the analgesic agent of this invention is
useful for treating or preventing acute or chronic pains associated
with acute or chronic inflammations in human beings or animals by
using administered systemically or topically.
[0119] While the dosage of therapeutically effective amount of the
compound (I) will vary depending upon the age and condition of each
individual patient, an average single dose of about 0.01 mg, 0.1
mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the
compound (I) may be effective for treating the above-mentioned
diseases. In general, amounts between 0.01 mg/body and about 1,000
mg/body may be administered per day.
[0120] In the above and subsequent description of the present
specification, the following abbreviations and acronyms mean ones
as shown in the following table. TABLE-US-00003 Abbreviations and
Acronyms Full Name AcOEt or EtOAc ethyl acetate AcOH acetic acid
BuOH, t-BuOH, butanol, t-butyl alcohol, etc. etc. DME
1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl
sulfoxide Et3N triethylamine EtOH ethanol IPE diisopropyl ether
MeOH methanol PrOH, i-PrOH propanol, isopropyl alcohol, etc. or
IPA, etc. TFA trifluoroacetic acid THF tetrahydrofuran EDCI or WSCD
1-ethyl-3-[3'-(dimethylamino)propyl]carbodiimide HOBt or HOBT
1-hydroxybenztriazole Pd/C palladium on carbon MCBA or mCPBA
3-Chloroperoxybenzoic acid or mcpba deg .degree. C. = degree
centigrade min minute(s) hr or h hour(s) conc. concentrated aq
aqueous (ex. aq NaHCO3 solution)
[0121] The following Examples and Preparations are given only for
the purpose of illustrating the present invention in more
detail.
EXAMPLE 1-1
(1E)-1-[4-(Methoxymethoxy)phenyl]-4-methyl-1-penten-3-one
[0122] 1M Sodium hydroxide aqueous solution (5.4 ml) was added to a
solution of 4-mehoxymethoxybenzaldehyde (4.52 g) and
3-methyl-2-butanone (4.69 g) in ethanol (27 ml), and the mixture
was stirred at room temperature overnight.
[0123] The mixture partitioned between ethylacetate and water. The
organic layer was washed with water, saturated aqueous sodium
chloride solution, dried over magnesium sulfate, and concentrated
in vacuo. The residue was purified by silica gel chromatography
eluted with 10% ethyl acetate/n-hexane to give the title compound
(4.03 g, 63.2%) as an oil.
[0124] 1H NMR (CDCl.sub.3): .delta. 1.18(6H, d, J=6.7 Hz), 2.92(1H,
m), 3.48(3H, s), 5.21(2H, s), 6.71 (1H, d, J=16.0 Hz), 7.05 (2H, d,
J=8.8 Hz), 7.51(2H, d, J=8.8 Hz), 7.58(1H, d, J=16.0 Hz).
[0125] MS (ESI+): m/z 257 (M+Na).
EXAMPLE 1-2
(1S,2R)- and
(1R,2S)-1,2-epoxy-1-[4-(methoxymethoxy)-phenyl]-4-methyl-3-pentanone
[0126] 30% H.sub.2O.sub.2 (1.7 ml) and 3M sodium hydroxide aqueous
solution (1.7 ml) was added to a solution of
(1E)-1-[4-(methoxymethoxy)phenyl]-4-methyl-1-penten-3-one obtained
by Example 1-1 (2.00 g) in ethanol:acetone=3:1 (34 ml). The mixture
was stirred at room temperature overnight.
[0127] The mixture was concentrated in vacuo, and partitioned
between ethyl acetate and water. The organic layer was washed with
water, saturated aqueous sodium chloride solution, dried over
magnesium sulfate, and concentrated in vacuo to give the target
compound (2.03 g, 95%) as an oil.
[0128] 1H NMR (DMSO-d6): .delta. 1.05(6H, d, J=6.9 Hz), 2.85(1H,
m), 3.36(3H, s), 3.93(1H, d, J=1.9 Hz), 4.00(1H, d, J=1.9 Hz),
5.20(2H, s), 7.03(2H, d, J=8.6 Hz), 7.30(2H, d, J=8.6 Hz).
[0129] MS (ESI): m/z 273 (M+Na).
EXAMPLE 1-3
4-[3-Isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenol
[0130] A mixture of (1S,2R)- and
(1R,2S)-1,2-epoxy-1-[4-(methoxymeth-oxy)phenyl]-4-methyl-3-pentanone
obtained by Example 1-2 (2.10 g) and 4-methoxyphenylhydrazine
hydrochloride (1.76 g) in ethanol:acetic acid=20:1 (20 ml) was
stirred at 60.degree. C. for 3 hrs.
[0131] The mixture was concentrated in vacuo. To the residue was
added ethyl acetate and 1M hydrochloric acid. The whole mixture was
treated with activated carbon, and was filtered through a celite
pad. The filtrate was partitioned. The organic layer was washed
successively with 1M hydrochloric acid, saturated aqueous sodium
bicarbonate solution, saturated aqueous sodium chloride solution,
dried over magnesium sulfate, and concentrated in vacuo. The
residual solid were collected and washed with ethyl acetate to give
the target compound (322.2 mg, 12.5%) as a white powder.
[0132] 1H NMR (CDCl.sub.3): .delta. 1.33 (6H, d, J=7.0 Hz), 3.07
(1H, m), 3.80 (3H, s), 5.18(1H, s), 6.26(1H, s), 6.72(2H, d, J=8.8
Hz), 6.83(2H, d, J=9.0 Hz), 7.08(2H, d, J=8.8 Hz), 7.20(2H, d,
J=9.0 Hz).
[0133] MS (ESI+): m/z 309 (M+H).
EXAMPLE 2
tert-Butyl
2-{4-[3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}-
ethylcarbamate
[0134] Diethylazodicarboxylate (259 mg) was added to a mixture of
4-[3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol obtained
by Example 1-3 (305 mg), 2-t-butoxycarbonylaminoethanol (479 mg),
and triphenylphosphine (390 mg) in tetrahydrofuran (3 ml). After
stirring at room temperature for 7 hrs, diethylazodicarboxylate (17
mg) and triphenylphosphine (26 mg) was added to the reaction
mixture.
[0135] After stirring at room temperature for 1 hr, the reaction
mixture was concentrated in vacuo. The residue was purified by
silica gel column chromatography eluted with 30% ethyl
acetate/n-hexane to give the target compound (396 mg, 88.5%) as a
solid.
[0136] 1H NMR (CDCl.sub.3): .delta. 1.34 (6H, d, J=7.0 Hz), 1.45
(9H, s), 3.07 (1H, m), 3.48-3.57(2H, m), 3.80(3H, s), 3.97-4.03(2H,
m), 4.97(1H, br-s), 6.26(1H, s), 6.76-6.87(4H, m), 7.14(2H, d,
J=8.9 Hz), 7.20(2H, d, J=9.0 Hz).
EXAMPLE 3
2-{4-[3-Isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethanamine
hydrochloride
[0137] 4M Hydrochloric acid/dioxane (2 ml) was added to a solution
of tert-butyl
2-{4-[3-isopropyl-1-(4-methoxy-phenyl)-1H-pyrazol-5-yl]-phenoxy}ethylcarb-
amate obtained by Example 2 (382 mg) in dichloromethane (3 ml) at
0.degree. C.
[0138] After stirring at room temperature for 1 hr, the reaction
mixture was concentrated in vacuo. The residue was crystallized
from a mixture of isopropanol and ethyl acetate to give the target
compound (311 mg, 94.7%) as a powder.
[0139] 1H NMR (DMSO-d6): .delta. 1.27(6H, d, J=6.9 Hz), 2.95(1H,
m), 3.14-3.22(2H, m), 3.76(3H, s), 4.14-4.20(2H, m), 6.41(1H, s),
6.93(4H, d, J=8.9 Hz), 7.16(4H, d, J=8.9 Hz), 8.22(2H, br-s).
[0140] MS (ESI+): m/z 352 (M+H).
EXAMPLE 4
N-(2-{4-[3-Isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}-ethyl)me-
thanesulfonamide
[0141] Methanesulfonyl chloride (32.2 mg) was added to a solution
of
2-{4-[3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethanamine
hydrochloride obtained by Example 3 (90.9 mg) and triethylamine
(71.1 mg) in dichloromethane (2 ml). The mixture was stirred at
room temperature for 2 hrs.
[0142] The mixture was concentrated in vacuo, and the residue was
partitioned between ethyl acetate and a mixture of 1M hydrochloric
acid and brine. The aqueous layer was reextracted with ethyl
acetate. The organic layer was washed with saturated aqueous sodium
bicarbonate solution, and saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo
The residue was crystallized from a mixture of ethyl acetate and
isopropylether to give the target compound (78.0 mg, 77.5%) as a
white powder.
[0143] MP: 162-163.degree. C.
[0144] 1H NMR (DMSO-d6): .delta. 126(6H, d, J=6.9 Hz), 2.94(3H, s),
2.94(1H, m), 3.25-3.39(2H, m), 3.76(3H, s), 3.98-4.04(2H, m),
6.40(1H, s), 6.90(2H, d, J=8.8 Hz), 6.93(2H, d, J=8.9 Hz), 7.13(2H,
d, J=8.8 Hz), 7.15(2H, d, J=8.9 Hz), 7.27(1H, s).
[0145] IR (KBr): 3122, 2966, 2897, 2871, 1614, 1514 cm.sup.-1.
EXAMPLE 5
N-(2-{4-[3-Isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)ure-
a
[0146] Trimethylsilylisocyanate (41.4 mg) was added to a solution
of
2-{4-[3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethanamine
hydrochloride obtained by Example 3 (93.0 mg) and triethylamine
(72.8 mg) in dichloromethane (3 ml) and the mixture was stirred at
room temperature for 3 hrs. Trimethylsilylisocyanate (8.3 mg) was
added and the mixture was stirred at room temperature for 1.5 hrs.
Trimethylsilylisocyanate (13.8 mg) and triethylamine (12.1 mg) was
added and the mixture was stirred at room temperature for 1.5
hrs.
[0147] The mixture was concentrated in vacuo, and the residue was
partitioned between chloroform and a mixture of 1M hydrochloric
acid and brine. The aqueous layer was extracted with chloroform.
The combined organic layer was washed with saturated aqueous sodium
bicarbonate solution and saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo.
The residue was purified by preparative thin layer silica gel
chromatography developed by 10% methanol/chloroform. The separated
silica gel was extracted with 10% methanol/chloroform and the
solvent was evaporated in vacuo. The residue was crystallized from
a mixture of ethyl acetate and isopropylether to give the target
compound (85.7 mg, 90.6%) as a white powder.
[0148] MP: 100-104.degree. C.
[0149] 1H NMR (DMSO-d6) .delta. 1.26(6H, d, J=6.9 Hz), 2.94(1H, m),
3.27-3.36(2H, m), 3.76(3H, s), 3.89-3.96(2H, m), 5.52(2H, s),
6.14(1H, t, J=5.6 Hz), 6.39(1H, s), 6.89(2H, d, J=8.7 Hz), 6.93(2H,
d, J=8.9 Hz), 7.12(2H, d, J=8.7 Hz), 7.15(2H, d, J=8.9 Hz).
[0150] IR (KBr): 3371, 3190, 2964, 2873, 1738, 1684, 1639, 1614,
1543, 1512 cm.sup.-1.
[0151] MS (ESI+): m/z 395 (M+H).
EXAMPLE 6
tert-Butyl
2-{4-[3-(1-hydroxy-1-methylethyl)-1-(4-methoxyphenyl)-1H-pyrazo-
l-5-yl]phenoxy}ethylcarbamate
[0152] tert-Butyl
2-{4-[3-ethoxycarbonyl-1-(4-methoxy-phenyl)-1H-pyrazol-5-yl]phenoxy}ethyl-
carbamate (1.37 g) in tetrahydrofuran (10 ml) was added dropwise to
0.93M solution of methyl magnesium bromide in tetrahydrofuran (16
ml) at 24-27.degree. C. with cooling in a water bath.
[0153] After stirring at room temperature for 1 hr, the mixture was
poured into a mixture of saturated aqueous ammonium chloride
solution and ice. The mixture was extracted with ethyl acetate. The
organic layer was washed with saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo.
The residue was purified by silica gel column chromatography eluted
with 70% ethyl acetate/n-hexane to give the target compound (1.17
g, 88%) as an amorphous powder.
[0154] MS (ESI+): m/z 468(M+H)
[0155] 1H NMR (CDCl.sub.3): .delta. 1.45(9H, s), 1.65(6H, s),
2.78(1H, s), 3.48-3.57(2H, m), 3.81(3H, s), 3.97-4.03(2H, m),
4.97(1H, br), 6.36(1H, s), 6.78-6.89(4H, m), 7.13(2H, d, J=8.7 Hz),
7.21(2H, d, J=8.9 Hz).
EXAMPLE 7
tert-Butyl
2-{4-[3-isopropenyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy-
}ethylcarbamate
[0156] Methanesulfonyl chloride (367 mg) and triethylamine (649 mg)
were added successively to a solution of tert-butyl
2-{4-[3-(1-hydroxy-1-methylethyl)-1-(4-methoxy-phenyl)-1H-pyrazol-5-yl]ph-
enoxy}ethylcarbamate obtained by Example 6 (11.0 g) and
N,N-dimethylformamide (91.5 mg) in dichloromethane (10 ml) and the
mixture was stirred at room temperature for 2 hrs. Additional
methanesulfonyl chloride and triethylamine were added until all
starting material was consumed with stirring at the same
temperature.
[0157] The reaction mixture was partitioned between ethyl acetate
and 1M hydrochloric acid, and the organic layer was washed with
saturated aqueous sodium bicarbonate solution and saturated aqueous
sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo. The residue was purified by silica gel
column chromatography eluted with 30% ethylacetate/n-hexane to give
the target compound (900 mg, 93.6%) as an amorphous powder.
[0158] 1H NMR (CDCl.sub.3): .delta. 1.95(9H, s), 2.21(3H, s),
3.48-3.57(2H, m), 3.81(3H, s), 3.97-4.03(2H, m), 4.98(1H, br-s),
5.12(1H, br-s), 5.59(1H, br-s), 6.56(1H, s), 6.77-6.87(4H, m),
7.14(2H, d, J=8.7 Hz), 7.22(2H, d, J=8.9 Hz).
[0159] MS (ESI+): m/z 450 (M+H).
EXAMPLE 8
tert-Butyl
2-{4-[3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}e-
thylcarbamate
[0160] A mixture of 10% Pd--C 50% wet (65 mg) and tert-butyl
2-{4-[3-isopropenyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethylcarb-
amate obtained by Example 7 (645 mg) in tetrahydrofuran (2 ml) and
methanol (4 ml) was hydrogenated under H.sub.2 1 atm at room
temperature for 3 hrs.
[0161] The catalyst was removed by filtration. The filtrate and
combined washings were concentrated in vacuo. The residue was
crystallized from a mixture of ethyl acetate and isopropyl ether to
give the target compound (370 mg, 57.1%) as a white powder.
[0162] 1H NMR (CDCl.sub.3): .delta. 1.34(6H, d, J=7.0 Hz), 1.45(9H,
s), 3.07(1H, m), 3.48-3.57(2H, m), 3.80(3H, s), 3.97-4.03(2H, m),
4.97(1H, br-s), 6.26(1H, s), 6.76-6.87(4H, m), 7.14(2H, d, J=8.9
Hz), 7.20(2H, d, J=9.0 Hz).
[0163] MS (ESI+): m/z 452 (M+H).
EXAMPLE 9
tert-Butyl
2-{4-[3-(1-hydroxy-1-methylethyl)-1-(6-methoxy-3-pyridinyl)-1H--
pyrazol-5-yl]phenoxy)ethyl-carbamate
[0164] The title compound (624.4 mg, 42.9%) was prepared as an
amorphous powder from tert-butyl
2-{4-[3-(1-hydroxy-1-methylethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5--
yl]phenoxy}ethylcarbamate in a similar manner to that of Example
6.
[0165] 1H NMR (CDCl.sub.3): .delta. 1.45(9H, s), 1.65(6H, s),
3.49-3.57(3H, m), 3.93(3H, s), 3.98-4.04(2H, m), 4.98(1H, br),
6.39(1H, s), 6.72(1H, d, J=8.8 Hz), 6.83(2H, d, J=8.8 Hz), 7.15(2H,
d, J=8.8 Hz), 7.54(1H, dd, J=2.8, 8.8 Hz), 8.07(1H, d, J=2.8
Hz).
[0166] MS (ESI+): 469 (M+H).
EXAMPLE 10
tert-Butyl
2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]p-
henoxy}ethylcarbamate
[0167] The title compound (495 mg, 85.7%) was prepared as an oil
from tert-butyl
2-{4-[3-(1-hydroxy-1-methylethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5--
yl]phenoxy}-ethylcarbamate obtained by Example 9 in a similar
manner to that of Example 7.
[0168] 1H NMR (CDCl.sub.3): .delta. 1.45(9H, s), 2.20(3H, s),
3.49-3.57(2H, m), 3.92(3H, s), 3.98-4.04(2H, m), 4.99(1H, br-s),
5.15(1H, br-s), 5.60(1H, br-s), 6.58(1H, s), 6.72(1H, d, J=8.8 Hz),
6.83(2H, d, J=8.7 Hz), 7.15(2H, d, J=8.7 Hz), 7.55(1H, dd, J=2.6,
8.8 Hz), 8.09(1H, d, J=2.6 Hz).
[0169] MS (ESI+): m/z 451 (M+H).
EXAMPLE 11
tert-Butyl
2-{4-[3-isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phe-
noxy}ethylcarbamate
[0170] The title compound (220 mg, quant.) was prepared as a n
amorphous powder from tert-butyl
2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}-et-
hylcarbamate obtained by Example 10 in a similar manner to that of
Example 8.
[0171] 1H NMR (CDCl.sub.3): .delta. 1.34(6H, d, J=6.8 Hz), 1.45(9H,
s), 3.07(1H, m), 3.48-3.57(2H, m), 3.92(3H, s), 3.98-4.04(2H, m),
4.98(1H, br), 6.28(1H, s), 6.71(1H, d, J=8.9 Hz), 6.82(2H, d, J=8.9
Hz), 7.14(2H, d, J=8.9 Hz), 7.56(1H, dd, J=2.6, 8.9 Hz), 8.05(1H,
d, J=2.6 Hz).
[0172] MS (ESI+): m/z 453 (M+H).
EXAMPLE 12
2-{4-[3-Isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethana-
mine dihydrochloride
[0173] The title compound (257 mg, quant.) was prepared as an
amorphous powder from tert-butyl
2-{4-[3-isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl-
-carbamate obtained by Example 11 in a similar manner to that of
Example 3.
[0174] 1H NMR (DMSO-d6): .delta. 1.27(6H, d, J=6.9 Hz), 2.96(1H,
m), 3.15-3.23(2H, m), 3.85(3H, s), 4.15-4.21(2H, m), 6.47(1H, s),
6.86(1H, d, J=8.8 Hz), 6.97(2H, d, J=8.8 Hz), 7.20(2H, d, J=8.8
Hz), 7.62(1H, dd, J=2.7, 8.8 Hz), 8.01(1H, d, J=2.7 Hz), 8.19(2H,
s).
[0175] MS (ESI+): m/z 353 (M+H).
EXAMPLE 13
N-(2-{4-[3-Isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}eth-
yl)urea
[0176] The title compound (49.9 mg, 51.6%) was prepared as a white
powder from
2-{4-[3-isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}-
ethanamine obtained by Example 12 in a similar manner to that of
Example 5.
[0177] MP: 106-107.degree. C.
[0178] 1H NMR (DMSO-d6): .delta. 1.27(6H, d, J=6.9 Hz), 2.96(1H,
m), 3.27-3.36 (2H, m), 3.85(3H, s), 3.94 (2H, t, J=5.5 Hz), 5.52
(2H, s), 6.15(1H, t, J=5.6 Hz), 6.45(1H, s), 6.85(1H, d, J=8.8 Hz),
6.93(2H, d, J=8.7 Hz), 7.16(2H, d, J=8.7 Hz), 7.60(1H, dd, J=2.6,
8.8 Hz), 8.02(1H, d, J=2.6 Hz).
[0179] IR (KBr): 3400, 3390, 3379, 3352, 2960, 1657, 1608, 1547,
1512, 1500 cm.sup.-1
[0180] MS (ESI+): m/z 396 (M+H).
EXAMPLE 14-1
5-[4-(Benzyloxy)phenyl]-1-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-amine
[0181] Sodium (3.19 g) was added portionwise to ethanol (160 ml).
After all sodium was dissolved, 4-methoxyphenylhydrazine
hydrochloride (14.5 g) was added in one portion to the solution.
The mixture was stirred at room temperature for 10 min. To this
mixture was added 3-(4-benzyloxyphenyl)acrylonitrile (16.3 g) in
one portion, and the mixture was refluxed for 3 days.
[0182] Insoluble matter was filtered off, and the filtrate was
concentrated in vacuo. Ethyl acetate and water were added to the
residue and the mixture was stirred at room temperature for 1 hr.
Precipitates were collected and washed successively with water,
ethyl acetate, and air dried to give the target compound (12.57 g,
48.6%) as a powder.
[0183] 1H NMR (DMSO-d6): .delta. 2.49(1H, dd, J=8.3, 16.1 Hz),
3.29(1H, dd, J=10.2, 16.1 Hz), 3.60(3H, s), 4.69(1H, dd, J=8.3,
10.2 Hz), 5.06(2H, s), 5.62(2H, s), 6.65(4H, s), 6.97(2H, d, J=8.6
Hz), 7.25(2H, d, J=8.6 Hz), 7.31-7.48(5H, m).
[0184] MS: (ESI+): m/z 374 (M+H).
EXAMPLE 14-2
5-[4-(Benzyloxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-amine
[0185] MnO.sub.2 (3.5 g) was added to a solution of
5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-amin-
e obtained by Example 14-1 (12.54 g) in N,N-dimethylformamide (65
ml) and the mixture was stirred at 60.degree. C. for 2 hrs.
MnO.sub.2 (5.3 g) was added and the mixture was stirred at
60.degree. C. for 1 hr.
[0186] The mixture was filtered through a celite pad and the pad
was washed with N,N-dimethylformamide. To the filtrate were added
ethyl acetate and water, and the mixture was stirred at room
temperature for 1 hr. Precipitates were collected and washed with
water and air dried. The obtained powder was suspended in hot
isopropylether cooled with stirring, collected and washed with
isopropylether to give the target compound (11.70 g, 93.8%) as a
powder.
[0187] 1H NMR (DMSO-d6): .delta. 3.74(3H, s), 4.84(2H, s), 5.08(2H,
s), 5.73(1H, s), 6.87(2H, d, J=9.0 Hz), 6.96(2H, d, J=9.0 Hz),
7.03-7.13(4H, m), 7.34-7.47(5H, m).
[0188] MS (ESI+): m/z 372 (M+H).
EXAMPLE 15
5-[4-(Benzyloxy)phenyl]-1-(4-methoxyphenyl)-N,N-dimethyl-1H-pyrazol-3-amin-
e
[0189] 37% Aqueous formamide solution (6 ml) and sodium
cyanoborohydride (1.39 g) were added successively to a solution of
5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-amine
obtained by Example 14-2 (2.75 g) in methanol 30 ml. The reaction
mixture was stirred at room temperature for 3 days, occasionally
adding 37% aqueous formamide solution and sodium cyanoborohydride
appropriate amount to consume all starting material.
[0190] The reaction mixture was concentrated in vacuo, and the
residue was partitioned between ethyl acetate and water. The
organic layer was washed with saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo.
The residue was purified by silica gel column chromatography eluted
with 20% ethyl acetate/chloroform to give the target compound (0.88
g, 29.8%) as an oil.
[0191] 1H NMR (DMSO-d6): .delta. 2.81(6H, s), 3.75(3H, s), 5.08(2H,
s), 6.03(1H, s), 6.90(2H, d, J=8.9 Hz), 6.97(2H, d, J=8.8 Hz),
7.06-7.16(4H, m), 7.32-7.46(5H, m).
[0192] MS (ESI+): m/z 400 (M+H).
EXAMPLE 16
4-[3-(Dimethylamino)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol
[0193] A mixture of
5-[4-(benzyloxy)phenyl]-1-(4-methoxy-phenyl)-N,N-dimethyl-1H-pyrazol-3-am-
ine obtained by Example 15 (0.83 g) and 10% Pd--C 50% wet (160 mg)
in acetic acid (8 ml) was hydrogenated under H.sub.2 1 atm at room
temperature for 10 hrs.
[0194] The catalyst was removed by filtration. The filtrate and
combined washings were concentrated in vacuo. The residue was
purified by silica gel column chromatography eluted with 20% ethyl
acetate/chloroform and was crystallized from a mixture of
isopropylether and ethyl acetate to give the target compound (455
mg, 70.8%) as a white powder.
[0195] 1H NMR (DMSO-d6): .delta. 2.80(6H, s), 3.74(3H, s), 5.96(1H,
s), 6.69(2H, d, J=8.5 Hz), 6.89(2H, d, J=9.0 Hz), 7.01(2H, d, J=8.5
Hz), 7.09(2H, d, J=9.0 Hz), 9.64(1H, s).
[0196] MS (ESI+): m/z 310 (M+H).
EXAMPLE 17
tert-Butyl
2-{4-[3-(dimethylamino)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phe-
noxy}ethylcarbamate
[0197] The title compound (477.1 mg, 99.7%) was prepared as an oil
from
4-[3-(dimethylamino)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol
obtained by Example 16 in a similar manner to that of Example
2.
[0198] 1H NMR (CDCl.sub.3): .delta. 1.45(9H, s), 2.93(6H, s),
3.48-3.54(2H, m), 3.79(3H, s), 3.97-4.03(2H, m), 4.97(1H, br), 5.85
(1H, s), 6.79(2H, d, J=8.7 Hz), 6.81(2H, d, J=9.0 Hz),
7.10-7.27(4H, m).
EXAMPLE 18
5-[4-(2-Aminoethoxy)phenyl]-1-(4-methoxyphenyl)-N,N-dimethyl-1H-pyrazol-3--
amine hydrochloride
[0199] The title compound (454 mg, quant.) was prepared as an
amorphous from tert-butyl
2-{4-[3-(dimethylamino)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl-
-carbamate obtained by Example 17 in a similar manner to that of
Example 3.
[0200] 1H NMR (DMSO-d6): .delta. 2.83(6H, s), 3.16-3.25(2H, m),
3.75(3H, s), 4.13-4.18(2H, m), 6.06(1H, s), 6.91(2H, d, J=9.0 Hz),
6.94(2H, d, J=8.8 Hz), 7.12(2H, d, J=9.0 Hz), 7.17(2H, d, J=8.8
Hz), 8.05(2H, br-s).
[0201] MS (ESI+): m/z 353 (M+H).
EXAMPLE 19
N-(2-{4-[3-(Dimethylamino)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}eth-
yl)urea
[0202] The title compound (116 mg, 55.7%) was prepared as an
amorphous from
5-[4-(2-aminoethoxy)phenyl]-1-(4-methoxyphenyl)-N,N-dimethyl-1H-pyra-
zol-3-amine hydrochloride obtained by Example 18 in a similar
manner to that of Example 75 described later.
[0203] 1H NMR (DMSO-d6): .delta. 2.81(6H, s), 3.29-3.34(2H, m),
3.74(3H, s), 3.92(2H, t, J=5.6 Hz), 5.53(2H, s), 6.03(1H, s),
6.15(1H, t, J=5.6 Hz), 6.88-6.92(4H, m), 7.04-7.14(4H, m).
[0204] IR (neat): 3344, 3330, 3321, 1658, 1651, 1643, 1612, 1579,
1564, 1554, 1529, 1514 cm.sup.-1.
[0205] MS (ESI+): m/z 396 (M+H).
EXAMPLE 20-1
5-[4-(Methoxymethoxy)phenyl]-1-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3--
amine
[0206] The title compound (4.0 g, 57.8%) was prepared as a powder
from 3-(4-methoxymethoxyphenyl)acrylonitrile in a similar manner to
that of Example 14-1.
[0207] 1H NMR (DMSO-d6): .delta. 2.49(1H, dd, J=8.3, 16.1 Hz),
3.30(1H, dd, J=10.3, 16.1 Hz), 3.36(3H, s), 3.59(3H, s), 4.70(1H,
dd, J=8.3, 10.3 Hz), 5.16(2H, s), 5.62(2H, s), 6.65(4H, s),
6.97(2H, d, J=8.6 Hz), 7.25(2H, d, J=8.6 Hz).
[0208] MS (ESI+): m/z 328 (M+H).
EXAMPLE 20-2
5-[4-(Methoxymethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-amine
[0209] The title compound (4.80 g, quant.) was prepared as an oil
from
5-[4-(methoxymethoxy)phenyl]-1-(4-methoxy-phenyl)-4,5-dihydro-1H-pyrazol--
3-amine obtained by Example 20-1 in a similar manner to that of
Example 14-2.
[0210] 1H NMR (DMSO-d6): .delta. 3.36(3H, s), 3.74(3H, s), 4.85(2H,
s), 5.18(2H, s), 5.74(1H, s), 6.88(2H, d, J=9.0 Hz), 6.96 (2H, d,
J=8.8 Hz), 7.02-7.13(4H, m).
[0211] MS (ESI+): m/z 326 (M+H).
EXAMPLE 21
3-Chloro-5-[4-(methoxymethoxy)phenyl]-1-(4-methoxy-phenyl)-1H-pyrazole
[0212] A mixture of
5-[4-(methoxymethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-amine
obtained by Example 20-2 (3.79 g), lithium chloride (2.47 g), and
copper(II) chloride (3.13 g) in acetonitrile (60 ml) was stirred at
room temperature for 10 min. To this mixture was added isoamyl
nitrite (2.73 g), and the mixture was stirred at room temperature
for 1 hr.
[0213] The mixture was partitioned between ethyl acetate and
saturated aqueous ammonium chloride solution. The organic layer was
washed with saturated aqueous ammonium chloride solution and
saturated aqueous sodium chloride solution, dried over magnesium
sulfate, and concentrated in vacuo. The residue was purified by
silica gel column chromatography eluted with 30% ethyl
acetate/n-hexane. The solvent was evaporated in vacuo. The residue
was crystallized from a mixture of isopropyl ether and ethyl
acetate to give the target compound (2.38 g, 59.3%) as a white
powder.
[0214] 1H NMR (CDCl.sub.3): .delta. 3.48(3H, s), 3.82(3H, s),
5.17(2H, s), 6.36(1H, s), 6.85(2H, d, J=9.0 Hz), 6.95(2H, d, J=8.9
Hz), 7.12(2H, d, J=8.9 Hz), 7.20(2H, d, J=9.0 Hz).
[0215] MS (ESI+): m/z 345(M+H).
EXAMPLE 22
4-[3-Chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol
[0216] To a solution of
3-chloro-5-[4-(methoxymethoxy)-phenyl]-1-(4-methoxyphenyl)-1H-pyrazole
obtained by Example 21 (2.35 g) in tetrahydrofuran (10 ml) and
methanol (10 ml) was added 36% hydrochloric acid (0.34 ml). The
reaction mixture was stirred at room temperature for 1 hr, at
50.degree. C. for 1.5 hrs, and at 60.degree. C. for 1.5 hrs.
[0217] The mixture was partitioned between ethyl acetate and water.
The organic layer was washed with saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo.
The residue solid was collected and washed with a mixture of
isopropylether and n-hexane to give the target compound (1.99 g,
97.1%) as a white powder.
[0218] 1H NMR (DMSO-d6): .delta. 3.78(3H, s), 6.62(1H, s), 6.71(2H,
d, J=8.7 Hz), 6.96(2H, d, J=9.0 Hz), 7.03(2H, d, J=8.7 Hz),
7.19(2H, d, J=9.0 Hz), 9.80(1H, s).
[0219] 200 MHz 1H NMR (CDCl.sub.3): .delta. 3.82(3H, s), 5.24(1H,
s), 6.35(1H, s), 6.75(2H, d, J=8.6 Hz), 6.84(2H, d, J=9.0 Hz),
7.07(2H, d, J=8.6 Hz), 7.18(2H, d, J=9.0 Hz).
[0220] MS (ESI+): m/z 301 (M+H).
EXAMPLE 23
2-(4-[3-Chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethanol
[0221] Sodium hydride 60% dispersion in mineral oil (31.1 mg) was
added to a solution of
4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol obtained by
Example 22 (180 mg) in N,N-dimethylformamide (2 ml) under cooling
in an ice bath. The reaction mixture was stirred at room
temperature for 1 hr. To the reaction mixture was added a solution
of 2-bromoethyl tert-butyl(dimethyl)silyl ether (258 mg) in
N,N-dimethylformamide (2 ml).
[0222] After stirring at room temperature overnight, the mixture
was poured into ice water. The mixture was extracted with ethyl
acetate. The organic layer was washed with water and saturated
aqueous sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo. The residue was dissolved in ethanol (3.6
ml). To this solution was added 36% aqueous hydrochloric acid (0.3
ml). After stirring at room temperature for 3 hrs, the mixture was
concentrated in vacuo. The residue was partitioned between ethyl
acetate and saturated aqueous sodium bicarbonate solution. The
organic layer was washed with saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo.
The residue was purified by preparative thin layer silica gel
chromatography developed by 70% ethyl acetate/n-hexane. The
separate silica gel was extracted with 10% methanol/chloroform and
the solvent was evaporated in vacuo. The residue was crystallized
from a mixture of isopropylether and ethyl acetate to give the
target compound (136.4 mg, 66.1%) as a white powder.
[0223] MP: 114.7-115.5.degree. C.
[0224] 1H NMR (DMSO-d6): .delta. 3.64-3.73(2H, m), 3.77(3H, s),
3.97(2H, t, J=4.9 Hz), 4.86(1H, t, J=5.4 Hz), 6.68(1H, s), 6.91(2H,
d, J=8.9 Hz), 6.96(2H, d, J=8.9 Hz), 7.15(2H, d, J=8.9 Hz),
7.20(2H, d, J=8.9 Hz).
[0225] IR(KBr): 3521, 1610, 1518 cm.sup.-1.
[0226] MS (ESI+): m/z 345 (M+H).
EXAMPLE 24
tert-Butyl
2-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethy-
lcarbamate
[0227] The title compound (329.5 mg, 22.3%) was prepared as an
amorphous from
4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol obtained by
Example 22 in a similar manner to that of Example 73 described
later.
[0228] 1H NMR (CDCl.sub.3): .delta. 1.45(9H, s), 3.48-3.57(2H, m),
3.81(3H, s), 4.00(2H, t, J=5.1 Hz), 4.96(1H, br), 6.35(1H, s),
6.81(2H, d, J=8.8 Hz), 6.84(2H, d, J=8.9 Hz), 7.12(2H, d, J=8.8
Hz), 7.18(2H, d, J=8.9 Hz).
[0229] MS (ESI+): m/z 444 (M+H).
EXAMPLE 25
tert-Butyl
2-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethy-
lcarbamate
[0230] The title compound (1.31 g, 97.8%) was prepared from
4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol obtained by
Example 22 in a similar manner to that of Example 2.
[0231] MS (ESI+): m/z 444 (M+H).
EXAMPLE 26
2-{4-[3-Chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethanamine
hydrochloride
[0232] The title compound (605.2 mg, 85.4%) was prepared as a white
powder from tert-butyl
2-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate
obtained by Example 25 in a similar manner to that of Example
3.
[0233] 1H NMR (DMSO-d6): .delta. 3.14-3.23(2H, m), 3.78(3H, s),
4.14-4.20(2H, m), 6.70(1H, s), 6.96(2H, d, J=8.8 Hz), 6.97(2H, d,
J=8.9 Hz), 7.19(2H, d, J=8.8 Hz), 7.21(2H, d, J=8.9 Hz), 8.19(2H,
br-s).
[0234] MS (ESI+): m/z 344 (M+H).
EXAMPLE 27
N-(2-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethyl)metha-
nesulfonamide
[0235] The title compound (137.8 mg, 82.8%) was prepared as a white
powder from
2-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethanamine
hydrochloride obtained by Example 26 in a similar manner to that of
Example 4.
[0236] MP: 117-119.degree. C.
[0237] 1H NMR (DMSO-d6): .delta. 294(3H, s), 3.27-3.34(2H, m),
3.76(3H, s), 4.02(2H, t, J=5.5 Hz), 6.69(1H, s), 6.90-7.01(4H, m),
7.14-7.25(4H, m), 7.28(1H, t, J=5.7 Hz).
[0238] IR (KBr): 1612, 1516 cm.sup.-1.
[0239] MS (ESI+): m/z 422(M+H).
EXAMPLE 28
N-(2-{4-[3-Chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethyl)urea
[0240] The title compound (174.6 mg, 85.8%) was prepared as a white
powder from
2-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethanamine
hydrochloride obtained by Example 26 in a similar manner to that of
Example 75 described later.
[0241] MP: 144.8-145.4.degree. C.
[0242] 1H NMR (DMSO-d6): .delta. 3.27-3.34(2H, m), 3.77(3H, s),
3.93(2H, t, J=5.5 Hz), 5.52(2H, s), 6.15(1H, t, J=5.7 Hz), 6.68(1H,
s), 6.92(2H, d, J=9.0 Hz), 6.97(2H, d, J=9.0 Hz), 7.15(2H, d, J=9.0
Hz) 7.20(2H, d, J=9.0 Hz).
[0243] IR (ATR): 3423, 3402, 3203, 3143, 3010, 2976, 2943, 2885,
1651, 1610, 1583, 1516 cm.sup.-1.
[0244] MS (ESI+): m/z 387 (M+H).
EXAMPLE 29-1
5-[4-(Methoxymethoxy)phenyl]-1-(6-methoxy-3-pyridinyl)-4,5-dihydro-1H-pyra-
zol-3-amine
[0245] The title compound (1.63 g, 41.2%) was prepared as a powder
from 3-(4-methoxymethoxyphenyl)acrylonitrile and
2-methoxy-5-pyridinylhydrazine dihydrochloride in a similar manner
to that of Example 14-1.
[0246] H NMR (DMSO-d6): .delta. 2.48-2.60(1H, dd, overlapping),
3.23-3.34(1H, dd, overlapping), 3.36(3H, s), 3.68(3H, s), 4.75(1H,
dd, J=8.6, 10.0 Hz), 5.16(2H, s), 5.77(2H, s), 6.56(1H, d, J=8.8
Hz), 6.98(2H, d, J=8.6 Hz), 7.15(1H, dd, J=2.8, 8.8 Hz), 7.27(2H,
d, J=8.6 Hz), 7.49(1H, d, J=2.8 Hz).
[0247] MS (ESI+): m/z 329 (M+H).
EXAMPLE 29-2
5-[4-(Methoxymethoxy)phenyl]-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-3-amine
[0248] The title compound (1.77 g, quant.) was prepared as an oil
from
5-[4-(methoxymethoxy)phenyl]-1-(6-methoxy-3-pyridinyl)-4,5-dihydro-1H-pyr-
azol-3-amine obtained by Example 29-1 in a similar manner to that
of Example 14-2.
[0249] 1H NMR (DMSO-d6): .delta. 3.37(3H, s), 3.83(3H, s), 4.97(2H,
s), 5.19(2H, s), 5.78(1H, s), 6.81(1H, d, J=8.9 Hz), 6.99(2H, d,
J=8.8 Hz), 7.15(2H, d, J=8.8 Hz), 7.51(1H, dd, J=2.7, 8.9 Hz),
7.92(1H, d, J=2.7 Hz).
[0250] MS (ESI+): m/z 327 (M+H).
EXAMPLE 30
5-{3-Chloro-5-[4-(methoxymethoxy)phenyl]-1H-pyrazol-1-yl}-2-methoxypyridin-
e
[0251] The title compound (981.7 mg, 57.9%) was prepared as a
powder from
5-[4-(methoxymethoxy)phenyl]-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-3-amine
obtained by Example 29-2 in a similar manner to that of Example
21.
[0252] 1H NMR (CDCl.sub.3): .delta. 3.48(3H, s), 3.93(3H, s),
5.18(2H, s), 6.39(1H, s), 6.74(1H, d, J=8.8 Hz), 6.99(2H, d, J=8.8
Hz), 7.13(2H, d, J=8.8 Hz), 7.55(1H, dd, J=2.7, 8.8 Hz), 8.05 (1H,
d, J=2.7 Hz).
[0253] MS (ESI+): m/z 346 (M+H).
EXAMPLE 31
4-[3-Chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]-phenol
[0254] The title compound (2.15 g, 80.5%) was prepared as a white
powder from
5-{3-chloro-5-[4-(methoxymethoxy)-phenyl]-1H-pyrazol-1-yl}-2-methoxy-
pyridine obtained by Example 30 in a similar manner to that of
Example 22.
[0255] 1H NMR (DMSO-d6): .delta. 3.87(3H, s), 6.68(1H, s), 6.74(2H,
d, J=8.6 Hz), 6.89(1H, d, J=8.8 Hz), 7.07(2H, d, J=8.6 Hz),
7.65(1H, dd, J=2.7, 8.8 Hz), 8.09(1H, d, J=2.7 Hz), 9.86 (1H,
br-s).
[0256] MS (ESI+): m/z 302 (M+H).
EXAMPLE 32
2-{4-[3-Chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethanol
[0257] The title compound (140.9 mg, 86%) was prepared as a white
powder from
4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenol
obtained by Example 31 in a similar manner to that of Example
23.
[0258] MP: 136.5-138.2.degree. C.
[0259] 1H NMR (DMSO-d6): .delta. 3.65-3.74(2H, m), 3.87(3H, s),
3.98(2H, t, J=4.9 Hz), 4.87(1H, t, J=5.5 Hz), 6.74(1H, s),
6.86-6.98(3H, m), 7.19(2H, d, J=8.8 Hz), 7.67(1H, dd, J=2.8, 8.8
Hz), 8.10(1H, d, J=2.8 Hz).
[0260] IR (KBr): 3369, 2960, 1610, 1502 cm.sup.-1.
[0261] MS (ESI+): m/z 346 (M+H).
EXAMPLE 33
tert-Butyl
2-{4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenox-
y}ethylcarbamate
[0262] The title compound (964 mg, 93.4%) was prepared as a white
solid from
4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenol
obtained by Example 31 in a similar manner to that of Example
2.
[0263] 1H NMR (DMSO-d6): .delta. 1.37(9H, s), 3.22-3.33(2H, m),
3.87(3H, s), 3.95(2H, t, J=5.7 Hz), 6.74(1H, s), 6.86-7.04(4 H, m),
7.19(2H, d, J=8.7 Hz), 7.67(1H, dd, J=2.7, 8.8 Hz), 8.11(1H, d,
J=2.7 Hz).
[0264] MS (ESI+): m/z 445 (M+H).
EXAMPLE 34
2-{4-[3-Chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}-ethanami-
ne dihydrochloride
[0265] The title compound (842 mg, 98.6%) was prepared as an
amorphous from tert-butyl
2-{4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethylcar-
bamate obtained by Example 33 in a similar manner to that of
Example 3.
[0266] 1H NMR (DMSO-d6): .delta. 3.15-3.24(2H, m), 3.87(3H, s),
4.19(2H, t, J=4.9 Hz), 6.76(1H, s), 6.90(1H, d, J=8.8 Hz), 6.99(2H,
d, J=8.8 Hz), 7.23(2H, d, J=8.8 Hz), 7.68(1H, d, J=2.7, 8.8 Hz),
8.10(1H, d, J=2.7 Hz), 8.20(2H, br-s).
[0267] MS (ESI+): m/z 345 (M+H).
EXAMPLE 35
N-(2-{4-[3-Chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)-
urea
[0268] The title compound (119.5 mg, 62.4%) was prepared as a white
powder from
2-{4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethanami-
ne dihydrochloride obtained by Example 34 in a similar manner to
that of Example 75 described later.
[0269] MP: 155.6-157.9.degree. C.
[0270] 1H NMR (DMSO-d6): .delta. 3.27-3.34(2H, m), 3.87(3H, s),
3.94(2H, t, J=50.5 Hz), 5.53(2H, s), 6.15(1H, t, J=5.5 Hz),
6.75(1H, s), 6.89(1H, d, J=8.8 Hz), 6.95(2H, d, J=8.8 Hz), 7.19(2H,
d, J=8.8 Hz), 7.66(1H, dd, J=2.7, 8.8 Hz), 8.11(1H, d, J=2.7
Hz).
[0271] IR (KBr): 3425, 3415, 3319, 1657, 1610, 1591, 1581, 1574,
1500 cm.sup.-1.
EXAMPLE 36
5-[4-(Benzyloxy)phenyl]-3-isopropoxy-1-(4-methoxy-phenyl)-1H-pyrazole
[0272] A mixture of
5-[4-(benzyloxy)phenyl]-3-hydroxy-1-(4-methoxyphenyl)-1H-pyrazol
(2.4 g), 2-iodopropane (5.48 g), and potassium carbonate (2.67 g)
in N,N-dimethyl-formamide (1 ml) was stirred at 100.degree. C. for
3 hrs.
[0273] The reaction mixture was poured into ice water and the
mixture was extracted with ethylacetate. The organic layer was
washed with water and saturated aqueous sodium chloride solution,
dried over magnesium sulfate, and concentrated in vacuo. The
residue was purified by silica gel column chromatography eluted
with 20% ethyl acetate/n-hexane and the solvent was evaporated in
vacuo. The residue was recrystallized from a mixture of ethyl
acetate and n-hexane to give the target compound (2.14 g, 80.1%) as
a white powder.
[0274] 1H NMR (DMSO-d6): .delta. 1.31 (6H, d, J=6.1 Hz), 3.76(3H,
s), 4.75(1H, m), 5.08(2H, s), 6.00(1H, s), 6.92(2H, d, J=9.0 Hz),
6.97(2H, d, J=8.9 Hz), 7.10-7.16(4H, m), 7.34-7.43(5H, m).
[0275] MS (ESI+): m/z 415 (M+H).
EXAMPLE 37
4-[3-Isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenol
[0276] To a solution of ammonium formate (954 mg) in water (2 ml)
were added ethanol (10 ml), a solution of
5-[4-(benzyl-oxy)phenyl]-3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazole
obtained by Example 36 (2.09 g) in tetrahydrofuran (10 ml), and 10%
palladium on carbon 50% wet (200 mg) successively. The mixture was
refluxed for 1 hr.
[0277] The catalyst was removed by filtration and washed with ethyl
acetate. The filtrate and combined washings were concentrated in
vacuo. Ethyl acetate and water were added to the residue.
Precipitates were collected and washed with water and ethyl acetate
to give the first crop of the target compound (419 mg) as a white
powder. The filtrate was partitioned, and the organic layer was
saturated aqueous sodium chloride solution, dried over magnesium
sulfate, and concentrated in vacuo. The residue crystals were
collected and washed with isopropylether to give the second crop of
the target compound (1.19 g, 72.5%) as a white powder.
[0278] 1H NMR (DMSO-d6): .delta. 1.31(6H, d, J=6.2 Hz), 3.75(3H,
s), 4.75(1H, m), 5.93(1H, s), 6.70(2H, d, J=8.6 Hz), 6.91(2H, d,
J=9.0 Hz), 7.01(2H, d, J=8.6 Hz), 7.11(2H, d, J=9.0 Hz), 9.70(1H,
s).
[0279] MS (ESI+): m/z 325(M+H).
EXAMPLE 38
2-{4-[3-Isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethanol
[0280] The title compound (147.3 mg, 88.2%) was prepared as an oil
from 4-[3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol
obtained by Example 37 in a similar manner to that of Example
23.
[0281] 1H NMR (CDCl.sub.3): .delta. 1.40(6H, d, J=6.2 Hz), 2.02(1H,
t, J=5.8 Hz), 3.79(3H, s), 3.94-4.00(2H, m), 4.04-4.10(2H, m),
4.87(1H, m), 5.85(1H, s), 6.81(2H, d, J=9.0 Hz), 6.82(2H, d, J=8.9
Hz), 7.10-7.21(4H, m).
[0282] IR (neat): 3400, 3369, 2974, 2933, 1612, 1514 cm.sup.-1.
[0283] MS (ESI+): m/z 369 (M+H).
EXAMPLE 39
tert-Butyl
2-{4-[3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}-
ethylcarbamate
[0284] The title compound (520 mg, 72.2%) was prepared as a white
powder from
4-[3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol obtained
by Example 37 in a similar manner to that of Example 2.
[0285] 1H NMR (DMSO-d6): .delta. 1.31(6H, d, J=6.2 Hz), 1.37(9H,
s), 3.22-3.31(2H, m), 3.75(3H, s), 3.90-3.97(2H, m), 4.76(1H, m),
5.99(1H, s), 6.86-6.96(4H, m), 7.01(1H, t, J=5.66 Hz),
7.09-7.15(4H, m).
[0286] MS (ESI+): m/z 467 (M+H).
EXAMPLE 40
2-{4-[3-Isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethanamine
hydrochloride
[0287] The title compound (557 mg, quant.) was prepared as an
amorphous from tert-butyl
2-{4-[3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethylcarba-
mate obtained by Example 39 in a similar manner to that of Example
3.
[0288] 1H NMR (DMSO-d6): .delta. 1.31(6H, d, J=6.1 Hz),
3.12-3.28(2H, m), 3.76(3H, s), 4.00-4.18(2H, m), 4.76(1H, m),
6.01(1H, s), 6.92(2H, d, J=9.0 Hz), 6.94(2H, d, J=8.7 Hz),
7.10-7.19(4H, m), 8.06(2H, br-s).
[0289] MS (ESI+): m/z 368 (M+H).
EXAMPLE 41
N-(2-{4-[3-Isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)me-
thanesulfonamide
[0290] The title compound (125 mg, 79.8%) was prepared as a white
powder from
2-{4-[3-isopropoxy-1-(4-methoxy-phenyl)-1H-pyrazol-5-yl]phenoxy}etha-
namine hydrochloride obtained by Example 40 in a similar manner to
that of Example 4.
[0291] MP: 167.9-168.0.degree. C.
[0292] 1H NMR (DMSO-d6): .delta. 1.31(6H, d, J=6.1 Hz), 2.94(3H,
s), 3.27-3.36 (2H, m), 3.75(3H, s), 3.98-4.05(2H, m), 4.76(1H, m),
6.00 (1H, s), 6.88-6.94(4H, m), 7.12(2H, d, J=9.0 Hz), 7.14(2H, d,
J=8.9 Hz), 7.29(1H, t, J=5.8 Hz).
[0293] IR (KBr): 3132, 2979, 2939, 1612, 1556, 1518 cm.sup.-1.
[0294] MS (ESI+) m/z 446 (M+H).
EXAMPLE 42
N-(2-{4-[3-Isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)ur-
ea
[0295] The title compound (76.3 mg, 50.1%) was prepared as a white
powder from
2-{4-[3-isopropoxy-1-(4-methoxy-phenyl)-1H-pyrazol-5-yl]phenoxy}etha-
namine hydrochloride obtained by Example 40 in a similar manner to
that of Example 75 described later.
[0296] MP: 139-140.degree. C.
[0297] 1H NMR (DMSO-d6): .delta. 1.31(6H, d, J=6.1 Hz),
3.27-3.35(2H, m), 3.75(3H, s), 3.89-3.96(2H, m), 4.76(1H, m),
5.53(2H, s), 6.00(1H, s), 6.15(1H, t, J=5.7 Hz), 6.90(2H, d, J=8.9
Hz), 6.92(2H, d, J=9.0 Hz), 7.08-7.15(4H, m).
[0298] IR (KBr): 3388, 3350, 3332, 1658, 1612, 1579, 1562, 1554,
1518 cm.sup.-1.
[0299] MS (ESI+): m/z 411 (M+H).
EXAMPLE 43
5-[4-(Benzyloxy)phenyl]-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-3-ol
[0300] To a solution of 3-(4-benzyloxyphenyl)propiolic acid (1 g)
and 1-hydroxybenzotriazole hydrate (643 mg) in N-methylpyrrolidone
(10 ml) was added WSCD.HCl (912 mg) and the mixture was stirred at
room temperature for 10 min. In another flask,
diisopropylethylamine (2.31 g) was added to a suspension of
5-hydrazino-2-methoxypyridine dihydrochloride (1.26 g) in
N-methylpyrrolidone (4 ml) and stirred at room temperature until
all 5-hydrazino-2-methoxypyridine dihydrochloride was dissolved.
Thus obtained hydrazine solution was added to the reaction flask
and the mixture was stirred at room temperature for 1.5 hrs.
[0301] The mixture was partitioned between ethyl acetate and 0.1M
hydrochloric acid, and the aqueous layer was reextracted with ethyl
acetate. The combined organic layers were washed with saturated
aqueous sodium bicarbonate solution and saturated aqueous sodium
chloride solution, dried over magnesium sulfate, and concentrated
in vacuo. The residue was dissolved in dichloroethane (15 ml) and
tetrakis(triphenylphosphine)palladium(0) (45.8 mg) was added. The
mixture was refluxed for 1 hr and then concentrated in vacuo. The
residue was crystallized from ethyl acetate to give the target
compound (739 mg, 49.9%) as a powder.
[0302] 1H NMR (DMSO-d6): .delta. 3.84(3H, s), 5.10(2H, s), 5.87(1H,
s), 6.83(1H, d, J=8.7 Hz), 7.00(2H, d, J=8.7 Hz), 7.16(2H, d, J=8.7
Hz), 7.29-7.48(5H, m), 7.54(1H, dd, J=2.6, 8.7 Hz), 7.97(1H, d,
J=2.6 Hz), 10.13(1H, s).
[0303] MS (ESI+): m/z (M+H).
EXAMPLE 44
5-{5-[4-(Benzyloxy)phenyl]-3-isopropoxy-1H-pyrazol-1-yl}-2-methoxypyridine
[0304] The title compound (1.33 g, quant.) was prepared as a powder
from
5-[4-(benzyloxy)phenyl]-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-3-ol
obtained by Example 43 in a similar manner to that of Example
36.
[0305] 1H NMR (CDCl.sub.3): .delta. 1.40(6H, d, J=6.2 Hz), 3.92(3H,
s), 4.86(1H, m), 5.05(2H, s), 5.87(1H, s), 6.69(1H, d, J=8.8H z),
6.91(2H, d, J=8.8 Hz), 7.15(2H, d, J=8.8 Hz), 7.35-7.43(5H, m),
7.51(1H, dd, J=2.7, 8.8 Hz), 8.04(1H, d, J=2.7H z).
[0306] MS (ESI+): m/z 416 (M+H).
EXAMPLE 45
4-[3-Isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenol
[0307] The title compound (442.5 mg, 54.9%) was prepared as a
powder from
5-{5-[4-(benzyloxy)phenyl]-3-isopropoxy-1H-pyrazol-1-yl}-2-methoxypyridin-
e obtained by Example 44 in a similar manner to that of Example
37.
[0308] 1H NMR (CDCl.sub.3): .delta. 1.40(6H, d, J=6.2 Hz), 3.91(3H,
s), 4.84(1H, m), 5.80(1H, s), 5.87(1H, s), 6.71(1H, d, J=8.8H z),
6.75(2H, d, J=8.6 Hz), 7.08(2H, d, J=8.6 Hz), 7.55(1H, dd, J=2.7,
8.8 Hz), 8.00(1H, d, J=2.7 Hz).
[0309] MS (ESI+): m/z 326 (M+H).
EXAMPLE 46
2-{4-[3-Isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethan-
ol
[0310] The title compound (940.6 mg, 52.2%) was prepared as a white
powder from
4-[3-isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenol
obtained by Example 45 in a similar manner to that of Example
23.
[0311] MP: 74-75.degree. C.
[0312] 1H NMR (CDCl.sub.3): .delta. 1.40(6H, d, J=6.1 Hz), 1.99(1H,
t, J=6.1 Hz), 3.91(3H, s), 3.94-4.00(2H, m), 4.05-4.11(2H, m),
4.86(1H, m), 5.88(1H, s), 6.69(1H, d, J=8.7 Hz), 6.85(2H, d, J=8.7
Hz), 7.15(2H, d, J=8.7 Hz), 7.51(1H, dd, J=2.7, 8.7 Hz), 8.03(1H,
d, J=2.7 Hz).
[0313] IR (KBr): 3350, 1612, 1512, 1500 cm.sup.-1.
[0314] MS (ESI+) m/z 370 (M+H).
EXAMPLE 47
tert-Butyl
2-{4-[3-isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]ph-
enoxy}ethylcarbamate
[0315] The title compound (515.3 mg, 87.6%) was prepared as a
powder from
4-[3-isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenol
obtained by Example 45 in a similar manner to that of Example
2.
[0316] 1H NMR (DMSO-d6) .delta. 1.32(6H, d, J=6.2 Hz), 1.37(9H, s),
3.22-3.34(2H, m), 3.84(3H, s), 3.92(2H, t, J=5.7 Hz), 4.77(1H, m),
6.06(1H, s), 6.84(1H, d, J=8.8 Hz), 6.91(2H, d, J=8.8 Hz), 7.01(1H,
t, J=5.5 Hz), 7.16(2H, d, J=8.8 Hz), 7.58(1H, dd, J=2.7, 8.8 Hz),
7.99(1H, d, J=2.7 Hz).
EXAMPLE 48
2-{4-[3-Isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethan-
amine dihydrochloride
[0317] The title compound (531 mg, quant.) was prepared as an
amorphous from tert-butyl
2-{4-[3-isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethy-
l-carbamate obtained by Example 47 in a similar manner to that of
Example 3.
[0318] 1H NMR (DMSO-d6): .delta. 1.32(6H, d, J=6.1 Hz),
3.15-3.24(2H, m), 3.84(3H, s), 4.19(2H, t, J=4.9 Hz), 4.77(1H, m),
6.07(1H, s), 6.85(1H, d, J=8.8 Hz), 6.97(2H, d, J=8.8 Hz), 7.21(2H,
d, J=8.8 Hz), 7.60(1H, dd, J=2.7, 8.8 Hz), 7.99(1H, d, J=2.7 Hz),
8.22(2H, br-s).
[0319] MS (ESI+): m/z 369 (M+H).
EXAMPLE 49
N-(2-{4-[3-Isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}et-
hyl)urea
[0320] The title compound (81.4 mg, 60.2%) was prepared as a white
powder from
2-{4-[3-isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy-
}ethanamine dihydrochloride obtained by Example 48 in a similar
manner to that of Example 75 described later.
[0321] MP: 120.degree. C.
[0322] 1H NMR (DMSO-d6): .delta. 1.32(6H, d, J=6.2 Hz),
3.27-3.36(2H, m), 3.84(3H, s), 3.94(2H, t, J=5.5 Hz), 4.77(1H, m),
5.52(2H, s), 6.06(1H, s), 6.15(1H, t, J=5.6 Hz), 6.84(1H, d, J=8.8
Hz), 6.93(2H, d, J=8.8 Hz), 7.17(2H, d, J=8.8 Hz), 7.58(1H, dd,
J=2.7, 8.8 Hz), 7.99(1H, d, J=2.7 Hz).
[0323] IR (KBr): 3400, 3330, 1658, 1612, 1514, 1500 cm.sup.-1.
[0324] MS (ESI+) m/z 412 (M+H).
EXAMPLE 50
N-(2-{4-[3-Isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}et-
hyl)methanesulfonamide
[0325] The title compound (94.4 mg, 58.4%) was prepared from
2-{4-[3-isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}etha-
namine dihydrochloride obtained by Example 48 in a similar manner
to that of Example 4.
[0326] MP: 121.0-121.6.degree. C.
[0327] 1H NMR (DMSO-d6): .delta. 1.32(6H, d, J=6.1 Hz), 2.94(3H,
s), 3.29-3.34(2H, m), 3.84(3H, s), 4.00-4.06(2H, m), 4.77(1H, m),
6.06(1H, s), 6.85(1H, d, J=8.7 Hz), 6.94(2H, d, J=8.8 Hz), 7.18(2H,
d, J=8.8 Hz), 7.28(1H, br-s), 7.58(1H, dd, J=2.7, 8.7 Hz), 7.99(1H,
d, J=2.7 Hz).
[0328] IR (KBr) 3242, 1612, 1514, 1502 cm.sup.-1.
[0329] MS (ESI+): m/z 447 (M+H).
EXAMPLE 51
2-{4-[1-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethyl
methanesulfonate
[0330] To a solution of
2-{4-[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethan-
ol (2.72 g) and triethylamine (1.55 ml) in dichloromethane (30 ml)
was added dropwise methanesulfonyl chloride (0.86 ml) under
ice-cooling. The reaction mixture was allowed to warm to room
temperature and stirred for 1 hr.
[0331] The reaction mixture was quenched with water. The organic
layer was separated and washed with 1N hydrochloric acid and water,
dried over sodium sulfate, filtered and evaporated under reduced
pressure to give the target compound (3.25 g, 98.5%).
[0332] 1 HNMR (CDCl.sub.3): .delta. 2.929(3H, s), 3.072(2H, t,
J=6.7 Hz), 4.427(2H, t, J=6.7 Hz), 6.739(1H,), 7.175(2H, d, J=8.4H
z), 7.234(2H, d, J=8.4 Hz), 7.253(2H, d, J=8.9 Hz), 7.344 (2H, d,
J=8.8 Hz).
[0333] MS (ESI+): m/z 467 (M+Na).
EXAMPLE 52
2-(2-{4-[1-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}eth-
yl)-1H-isoindole-1,3(2H)-dione
[0334] A mixture of
2-{4-[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethyl
methanesulfonate obtained by Example 51 (3.2 g) and Potassium
phthalimide (1.6 g) was stirred at 80.degree. C. for 5 hrs.
[0335] After cooling, the mixture was diluted with water and ethyl
acetate. The aqueous layer was separated and extracted with ethyl
acetate (twice). The combined organic layer was washed with water
(twice) and brine, dried over magnesium sulfate, filtered and
evaporated under reduced pressure to give the target compound (1.55
g, 43.5%) as a powder.
[0336] 1H NMR (CDCl.sub.3): .delta. 1.59(3H, s), 3.02(2H, t, J=7.3
Hz), 3.94(2H, t, J=7.3 Hz), 6.71(1H, s), 7.11(2H, d, J=8.2 Hz),
7.21(2H, d, J=7.6 Hz), 7.24(2H, d, J=8.4 Hz), 7.32(2H, d, J=8.9
Hz), 7.70-7.86(4H, m).
[0337] MS (ESI+): m/z 518 (M+Na).
EXAMPLE 53
2-{4-[1-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethana-
mine
[0338] A mixture of
2-(2-{4-[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}et-
hyl)-1H-isoindole-1,3(2H)-dione obtained by Example 52 (1.5 g) and
hydrazine (2.93 ml) in acetonitrile (30 ml) was stirred at
60.degree. C. for 5 hrs.
[0339] After cooling, the mixture was filtered and washed with
acetonitrile. The filtrate was evaporated under reduced pressure to
give the target compound (1.1 g, quant.) as an oil.
[0340] 1H NMR (CDCl.sub.3): .delta. 3.09(2H, dd, J=5.6 Hz, 9.3 Hz),
3.24 (2H, dd, J=5.6 Hz, 8.6 Hz), 5.47(2H, s), 6.69(1H, s), 7.12(1H,
d, J=8.2 Hz), 7.21(1H, d, J=8.2 Hz), 7.22(1H, d, J=8.9 Hz),
7.32(1H, d, J=8.9 Hz).
[0341] MS (ESI+): m/z 366 (M+1).
EXAMPLE 54
N-(2-{4-[1-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}eth-
yl)methanesulfonamide
[0342] To a solution of
2-{4-[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethan-
amine obtained by Example 53 (400 mg) and triethylamine (0.46 ml)
in dichloromethane (20 ml) was added dropwise methanesulfonyl
chloride (0.25 ml) at room temperature.
[0343] After stirring for 1 hr, the reaction mixture was quenched
with 1N hydrochloric acid. The aqueous layer was separated and
extracted twice with chloroform. The combined organic layer was
washed with 1N hydrochloric acid, sodium hydrogencarbonate
solution, water, dried over sodium sulfate, filtered and evaporated
under reduced pressure. The residue was column chromatographed on
silica gel (chloroform/methanol=4:1) to give the target compound
(166 mg, 34.2%) as an oil.
[0344] 1H NMR (CDCl.sub.3): .delta. 2.899(3H, s), 2.904(2H, t,
J=6.9 Hz), 3.417(2H, dt, J=6.7, 6.8 Hz), 4.272(1H, t, J=6.1 Hz),
6.737 (1H, s), 7.178(2H, d, J=8.4 Hz), 7.21(2H, d, J=8.4 Hz),
7.255(2H, d, J=8.8 Hz), 7.35(2H, d, J=8.8 Hz).
[0345] IR (Film): 3346, 1657, 1597, 1552, 1496, 1471, 1236, 1163,
1136, 1092, 978, 835, 756 cm.sup.-1.
[0346] MS (ESI-): 442 (M-1).
EXAMPLE 55
N-(2-{4-[1-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}eth-
yl)urea
[0347] To a solution of
2-{4-[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethan-
amine obtained by Example 53 (300 mg) and triethylamine (0.57 ml)
in dichloromethane (10 ml) was added dropwise trimethylsilyl
isocyanate (0.555 ml) at room temperature.
[0348] After stirring overnight, the reaction mixture was quenched
with 1N hydrochloric acid. Aqueous layer was separated and
extracted twice with chloroform. The combined organic layer was
washed with 1N hydrochloric acid, sodium hydrogencarbonate
solution, water, dried over sodium sulfate, filtered and evaporated
under reduced pressure. The residue was column chromatographed on
silica gel (chloroform/methanol=4:1) to give the target compound
(205 mg, 61.1%) as an amorphous.
[0349] 1H NMR (CDCl.sub.3) .delta. 2.83(2H, t, J=7 Hz), 3.43(2H,
dt, J=6.6 Hz, 6.8 Hz), 4.41(2H, s), 4.61(1H, t, J=5.4 Hz), 6.72(1H,
s), 7.16(4H, s), 7.25(2H, d, J=8.8 Hz), 7.34(2H, d, J=8.8 Hz).
[0350] IR (Film): 3346, 1657, 1597, 1552, 1496, 1471, 1448, 1375,
1271, 1236, 1163, 1136, 1092, 978, 835, 756 cm.sup.-1.
[0351] MS (ESI+): m/z 431 (M+Na).
EXAMPLE 56
4-[1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzonitrile
[0352] A mixture of 4-(4,4,4-trifluoro-3-oxobutanoyl)-benzonitrile
(1.0 g), 4-methoxyphenylhydrazine hydrochloride (760 mg), and
sodium acetate (357 mg) in acetic acid (10 ml) was stirred at
80.degree. C. for 4 hrs.
[0353] After cooling, the reaction mixture was poured into water
and ethyl acetate. The aqueous layer was extracted twice with ethyl
acetate. Combined organic layers were washed with saturated sodium
hydrogencarbonate solution (twice), water and brine, dried over
sodium sulfate, and evaporated under reduced pressure to give crude
product. The crude product was column chromatographed on silica gel
(50 ml, n-hexane:ethyl acetate=5:1-4:1) and triturate with
petroleum ether to give the target compound (553 mg, 38.8%).
[0354] 1H NMR (CDCl.sub.3): .delta. 3.84(3H, s), 6.82(1H, s),
6.9(2H, d, J=9 Hz), 7.2(2H, d, J=9 Hz), 7.33(2H, d, J=8.6 Hz),
7.62(2H, d, J=8.6 Hz).
[0355] IR (Film): 2229, 1610, 1512, 1468, 1240, 1161, 1132, 839
cm.sup.-1.
[0356] MS (ESI+): m/z 366 (M+Na).
EXAMPLE 57
4-[1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzyl-amine
hydrochloride
[0357] A mixture of
4-[1-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]benzonitrile
obtained by Example 56 (430 mg), Pd/C (100 mg) and 1N hydrochloric
acid (1.3 ml) in methanol (43 ml) was stirred under Hydrogen
atmosphere for 5 hrs.
[0358] The reaction mixture was filtered with paper filter, and
filtrate was evaporated. After dissolving in methanol, the solution
was filtered with membrane filter. The filtrate was evaporated to
give the target compound (450 mg, 93.6%) as crystals.
[0359] 1H NMR (CDCl.sub.3): .delta. 3.79(3H, s), 4.04(2H, br-s),
6.69(1H, s), 6.85(2H, d, J=8.9 Hz), 7.13(2H, d, J=8.9 Hz), 7.24(2H,
d, J=9 Hz), 7.42(2H, d, J=9 Hz).
[0360] IR (Film): 2964, 1512, 1468, 1238, 1161, 1130, 976, 837
cm.sup.-1.
[0361] MS (ESI+): m/z 331 (M-Cl--NH.sub.3).
EXAMPLE 58
N-{4-[1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzyl}metha-
nesulfonamide
[0362] To a solution of
4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzylamine
hydrochloride obtained by Example 57 (100 mg) and triethylamine
(0.073 ml) in chloroform (10 ml) was added dropwise methanesulfonyl
chloride (0.04 ml) at room temperature.
[0363] After stirring for 1 hr, the reaction mixture was
partitioned between chloroform and water. The organic layer was
washed with water, sodium bicarbonate solution, brine, dried over
magnesium sulfate, filtered and evaporated under reduced pressure
to give the target compound (90 mg, 81.2%) as an oil.
[0364] 1H NMR (CDCl.sub.3): .delta. 2.93(3H, s), 3.82(3H, s),
4.32(2H, d, J=6.2 Hz), 4.71(1H, t, J=6.2 Hz), 6.73(1H, s), 6.86(2H,
d, J=9 Hz), 7.21(2H, d, J=9 Hz), 7.21(2H, d, J=8.3 Hz), 7.31 (2H,
d, J=8.3 Hz).
[0365] IR (Film): 3282, 1514, 1321, 1240, 1151, 974, 837
cm.sup.-1.
[0366] MASS (ESI+): m/z 426 (M+1).
EXAMPLE 59
4-[3-(Difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzonitrile
[0367] The title compound (4.5 g, 20.6%) was prepared from
4-(4,4-difluoro-3-oxobutanoyl)benzonitrile in a similar manner to
that of Example 56.
[0368] 1H NMR (CDCl.sub.3): .delta. 3.84(3H, s), 6.77(1H, t, J=54.9
Hz), 6.8(1H, s), 6.9(2H, d, J=9 Hz), 7.19(2H, d, J=9 Hz), 7.33(2H,
d, J=8.6 Hz), 7.61(2H, d, J=8.6 Hz).
[0369] MS (ESI+): m/z 348 (M+Na).
EXAMPLE 60
1-{4-[3-(Difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenyl}methan-
amine hydrochloride
[0370] The title compound (510 mg, 45.4%) was prepared from
4-[3-(difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzonitrile
obtained by Example 59 in a similar manner to that of Example
57.
[0371] 1H NMR (DMSO-d6): .delta. 3.35(3H, s), 3.79(2H, s), 7.1(1H,
t, J=54.5 Hz), 6.95(1H, s), 6.99(2H, d, J=8.8 Hz), 7.26(2H, d,
J=8.8 Hz), 7.3(2H, d, J=8.3 Hz), 7.49(2H, d, J=8.3 Hz).
[0372] MS (ESI-): m/z 365 (M-HCl).
EXAMPLE 61
N-{4-[3-(Difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}methan-
esulfonamide
[0373] The title compound (146 mg, 65.5%) was prepared from
1-{4-[3-(difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenyl}metha-
namine hydrochloride obtained by Example 60 in a similar manner to
that of Example 58.
[0374] 1H NMR (CDCl.sub.3): .delta. 2.90(3H, s), 3.82(3H, s),
4.31(2H, d, J=6.2 Hz), 4.73(1H, t, J=6.2 Hz), 6.72(1H, s), 6.77(1H,
t, J=55 Hz), 6.86(2H, d, J=9 Hz), 7.19(2H, d, J=9 Hz), 7.22(2H, d,
J=8.4 Hz), 7.30(2H, d, J=8.4 Hz).
[0375] IR (film): 3143, 1518, 1508, 1452, 1325, 1244, 1151, 1074,
1022, 972, 843, 793 cm.sup.-1.
[0376] MS (ESI-): m/z 406 (M-1).
EXAMPLE 62
N-{4-[3-(Difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}urea
[0377] To a solution of
1-{4-[3-(difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenyl}metha-
namine hydrochloride obtained by Example 60 (100 mg) in
dichloromethane (1 ml) was added dropwise triethylamine (0.163 ml)
and trimethylsilyl isocyanate (0.11 ml) at room temperature.
[0378] The mixture was stirred at room temperature overnight and
quenched by adding saturated sodium hydrogencarbonate solution (0.5
ml). The mixture was filtered by Chemelute. The elution was
evaporated and purified by preparative thin layer chromatography
(0.5 mm, 10% methanol/chloroform) to give solid. The solid was
added ethyl acetate and n-hexane, and the precipitate was collected
by filtration to give the target compound (160 mg, 62.9%).
[0379] 1H NMR(CDCl.sub.3): .delta. 3.82(3H, s), 4.35(2H, d, J=6
Hz), 4.46(2H, br-s), 4.99(1H, t, J=6 Hz), 6.69(1H, s), 6.76(1H, t,
J=55.1 Hz), 6.86(2H, d, J=9 Hz), 7.14-7.21(6H, m).
[0380] MS (ESI+): m/z 395 (M+Na).
[0381] IR (film) 1657, 1608, 1593, 1550, 15120, 1510, 1467, 1338,
1252, 1171, 1088, 1030, 837, 796 cm.sup.-1.
EXAMPLE 63
4-[1-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzonitrile
[0382] The title compound (942 mg, 86.8%) was prepared from
4-(4,4,4-trifluoro-3-oxobutanoyl)benzonitrile in a similar manner
to that of Example 56.
[0383] 1H NMR (CDCl.sub.3): .delta. 2.39(3H, s), 6.82(1H, s),
7.15(2H, d, J=8.9 Hz), 7.21(2H, d, J=8.8 Hz), 7.33(2H, d, J=8.3
Hz), 7.62(2H, d, J=8.3 Hz).
[0384] MS (ESI+): m/z 328 (M+1).
EXAMPLE 64
1-{4-[1-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}methan-
amine hydrochloride
[0385] The title compound (414 mg, 92.1%) was prepared from
4-[1-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzonitrile
obtained by Example 63 in a similar manner to that of Example
57.
[0386] 1H NMR (DMSO-d6): .delta. 2.35(3H, d, J=4.2 Hz), 3.35(2H,
s), 7.17(1H, s), 7.17-7.29(4H, m), 7.32(2H, d, J=8.1 Hz), 7.51(2H,
d, J=8.2 Hz).
[0387] MS (ESI+): m/z 332 (M+1).
EXAMPLE 65
N-{4-[1-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzyl}urea
[0388] The title compound (81 mg, 31.8%) was prepared from
1-{4-[1-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}metha-
namine hydrochloride obtained by Example 64 in a similar manner to
that of Example 62.
[0389] 1H NMR (CDCl.sub.3): .delta. 2.36(3H, s), 4.35(2H, d, J=5.9
Hz), 4.50(2H, br-s), 5.02(1H, t, J=5.5 Hz), 6.71(1H, s), 7.16(4H,
s), 7.20(4H, d, J=5.7 Hz).
[0390] IR (film): 3344, 1658, 1600, 1552, 1518, 1236, 1159, 1134
cm.sup.-1.
[0391] MS (ESI+): m/z 397 (M+Na).
EXAMPLE 66
4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile
[0392] The title compound (1.05 g, 73.8%) was prepared from
4-methyl-1-(4,4,4-trifluoro-3-oxobutanoyl)benzene in a similar
manner to that of Example 69 described later.
[0393] MP: 125.0-125.5.degree. C.
[0394] 1H NMR (CDCl3): .delta. 2.39(3H, s), 6.74(1H, s), 7.10(2H,
d, J=8.1 Hz), 7.19(2H, d, J=8.2 Hz), 7.45(2H, d, J=8.7 Hz),
7.65(2H, d, J=8.7 Hz).
[0395] MASS (ESI+): m/z 350 (M+Na).
EXAMPLE 67
1-{4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}methan-
amine hydrochloride
[0396] The title compound (830 mg, 92.3%) was prepared from
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile
obtained by Example 66 in a similar manner to that of Example 70
described later.
[0397] 1H NMR (DMSO-d6): .delta. 2.30(3H, d, J=2.3 Hz), 4.07(2H,
s), 7.15(1H, s), 7.15(2H, d, J=9.0 Hz), 7.21(2H, d, J=8.9 Hz),
7.39(2H, d, J=8.5 Hz), 7.58(2H, d, J=8.5 Hz).
[0398] MS (ESI+): m/z 332 (M+1).
EXAMPLE 68
N-{4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzyl}urea
[0399] The title compound (65 mg, 31.9%) was prepared from
1-{4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}metha-
namine hydrochloride obtained by Example 67 in a similar manner to
that of Example 72 described later.
[0400] 1H NMR (CDCl.sub.3): .delta. 2.34(3H, s), 4.34(2H, d, J=5.8
Hz), 4.56(2H, br-s), 5.23(1H, t, J=5.8 Hz), 6.71(1H, s), 7.07(2H,
d, J=8.7 Hz), 7.13(2H, d, J=8.7 Hz), 7.24(4H, s).
[0401] IR (film): 3344, 1658, 1604, 1552, 1234, 1159, 1134
cm.sup.-1.
[0402] MS (ESI+): 397 (M+Na).
EXAMPLE 69
4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile
[0403] A mixture of
4-methoxy-1-(4,4,4-trifluoro-3-oxobutanoyl)benzene (1.0 g),
4-methoxyphenylhydrazine hydrochloride (758 mg) and sodium acetate
(367 mg) in acetic acid (5 ml) was stirred overnight at room
temperature.
[0404] After then, the reaction mixture was poured into water and
ethyl acetate. The aqueous layer was extracted twice with ethyl
acetate. Combined organic layers were washed with water, saturated
sodium hydrogencarbonate (twice) and brine, dried over sodium
sulfate, and evaporated under reduced pressure to give crude
product. The crude product was column chromatographed on silica gel
(50 ml, n-hexane:ethyl acetate=10:1-5:1) to give the target
compound (930 mg, 66.7%).
[0405] 1H NMR (CDCl.sub.3): .delta. 3.84(3H, s), 6.72(1H, s),
6.9(2H, d, J=8.9 Hz), 7.14(2H, d, J=8.9 Hz), 7.46(2H, d, J=8.7 Hz),
7.66(2H, d, J=8.7 Hz).
[0406] MS (ESI+): m/z 366 (M+Na).
EXAMPLE 70
4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzylamine
hydrochloride
[0407] A mixture of
4-[5-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-1-yl]benzonitrile
obtained by Example 69 (400 mg) and 50% wet pd/C (400 mg) in
ethanol (10 ml) and 1N hydrochloric acid (1.2 ml) was stirred under
hydrogen atmosphere for 8 hrs.
[0408] The mixture was filtered and filtrate was evaporated under
reduced pressure. The residue was washed with isopropyl ether to
give the target compound (400 mg, 89.4%) as a powder.
[0409] 1H NMR (CDCl.sub.3): .delta. 3.36(s, 3H), 3.76(d, J=2.4, 2
Hz), 6.94(d, J=8.7, 2 Hz), 7.12(s, 1H), 7.23(d, J=8.7, 2 Hz), 7.39
(d, J=8.4, 2 Hz), 7.59(d, J=8.4, 2 Hz).
[0410] MS (ESI+): m/z 348 (M+1).
EXAMPLE 71
N-{4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzyl}metha-
nesulfonamide
[0411] To a solution of
4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzylamine
hydrochloride obtained by Example 70 (150 mg) and triethylamine
(0.1 ml) in dichloromethane (10 ml) was added dropwise
methanesulfonyl chloride (0.06 ml) under ice cooling.
[0412] After stirring for 1 hr, the reaction mixture was quenched
and partitioned between chloroform and water. The aqueous layer was
extracted with chloroform. The combined organic layer was washed
with water, 1N hydrochloric acid, saturated sodium
hydrogencarbonate solution and brine, dried over magnesium sulfate,
filtered and evaporated under reduced pressure. The residue was
chromatographed by high performanced thin layer chromatography to
give the target compound (67 mg, 40.3%).
[0413] 1H NMR (CDCl.sub.3): .delta. 2.91(3H, s), 3.82(s, 3H),
4.35(2H, d, J=6.1 Hz), 4.69(1H, t, J=6.1 Hz), 6.69(1H, s), 6.84(2H,
d, J=8.6 Hz), 7.13(2H, d, J=8.6 Hz), 7.32(2H, d, J=9 Hz), 7.37(2H,
d, J=9 Hz).
[0414] IR (film): 3207, 1479, 1456, 1323, 1252, 1234, 1146, 1122,
984, 968, 962, 841, 802 cm.sup.-1.
[0415] MS (ESI+): m/z 448 (M+Na).
EXAMPLE 72
N-{4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzyl}urea
[0416] To a solution of
4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzylamine
hydrochloride obtained by Example 70 (150 mg) in water (8 ml) and
ethanol (4 ml) was added sodium cyanate (100 mg) under ice
cooling.
[0417] After stirring for 3 hrs, the reaction mixture was
partitioned between chloroform and water. The aqueous layer was
extracted with chloroform. The combined organic layer was washed
with water and brine, dried over magnesium sulfate, filtered and
evaporated under reduced pressure. The residue was chromatographed
by high performanced thin layer chromatography to give the target
compound (105 mg, 69%).
[0418] 1H NMR (CDCl.sub.3): .delta. 3.80(3H, s), 4.35(2H, d, J=5.9
Hz), 4.53(2H, br-s), 5.171(1H, t, J=5.7 Hz), 6.68(1H, s), 6.84(2H,
d, J=8.7 Hz), 7.12(2H, d, J=8.7 Hz), 7.25(4H, s).
[0419] MS (ESI+): m/z 413 (M+Na).
EXAMPLE 73
tert-Butyl
2-{4-[1-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]-
phenoxy}ethylcarbamate
[0420] To solution of
4-[1-(4-methoxyphenyl)-3-trifluoro-methyl-1H-pyrazol-5-yl]phenol
(500 g) in N,N-dimethyl-formamide (1.5 L) was added sodium hydride
(dispersion in mineral oil, 77.8 g) over 25 min under ice cooling.
The mixture was warmed to room temperature over 10 min and then
stirred at room temperature for 30 min. A solution of
2-tert-butoxycabonylaminoethyl bromide (469 g) (prepared by
reacting di-ter-butyl dicarbonate with 2-bromoethylamine
hydrobromide) reaction in N,N-dimethylformamide (300 ml) was added
to the mixture over 10 min at 25-28.degree. C., and the whole
mixture was stirred at 60.degree. C. for 6 hrs.
[0421] After allowed to stand overnight, the mixture was poured
into a mixture of water (4.5 L) and toluene (3 L). The organic
layer was separated, and the aqueous layer was extracted with
toluene (1.5 L). The combined organic layers were washed with water
(1.5 L.times.3) and brine (1.5 L), dried over magnesium sulfate,
filtered and evaporated to give the oil (1.02 kg). The oil was
purified with silica gel column chromatography [5 L, n-hexane (10
L), 50% ethyl acetate/n-hexane (30 L)] to give the target compound
(680 g, 95%) as a pale yellow oil.
[0422] MP: 104.7-105.1.degree. C.
[0423] 1H NMR (CDCl.sub.3): .delta. 1.45(3H, s), 3.53(2H, dt, J=4
Hz), 3.82 (3H, s), 4.01(2H, t, J=4 Hz), 6.67(1H, s), 6.83(2H, d,
J=8 Hz), 6.87(2H, d, J=8 Hz), 7.13(2H, d, J=8 Hz), 7.23(2H, d, J=8
Hz).
EXAMPLE 74
2-{4-[1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}etha-
namine hydrochloride
[0424] To a solution of hydrogen chloride in ethyl acetate (4N, 1.0
L) was added powdered tert-Butyl
2-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-phenoxy}et-
hylcarbamate obtained by Example 73 (500 g) at 5.degree. C. over 20
min.
[0425] After stirring at the same temperature for 30 min and then
at room temperature for 1 hr, the mixture was evaporated to give
oil (543.12 g). The oil was dissolved in toluene (1.5 L). And then,
n-hexane (200 ml) and the target compound (as seeds for
crystallization) were added to the solution. The mixture was
stirred at room temperature overnight. And the precipitate was
filtered, washed with toluene (500 ml.times.2) and isopropylether
(650 ml), and dried to give the target compound (420.5 g, 97%) as a
white powder.
[0426] MP: 166.8-168.0.degree. C.
[0427] 1HNMR (DMSO-d6): .delta. 3.185(2H, t, J=5 Hz), 3.8(3H, s),
4.215(2H, t, J=5 Hz), 6.96-7.05(4H, m), 7.1(1H, s), 7.22-7.33(4H,
m).
EXAMPLE 75
N-(2-{4-[1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}e-
thyl)urea
[0428]
2-{4-[1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phen-
oxy}ethanamine hydrochloride obtained by Example 74 (400 g) and
sodium acetate (159 g) was dissolved in a mixture of
N,N-dimethylformamide (1.4 L) and water (0.52 L) at 50.degree. C. A
solution of potassium cyanate (157 g) in water (520 ml) was added
dropwise to the solution over 15 min at 38-40.degree. C. The whole
solution was stirred at 50.degree. C. for 2 hrs.
[0429] The solution was filtered and washed with
N,N-dimethylformamide (0.68 L) at the same temperature. The
filtrate was cooled to room temperature, and then water (0.4 L) and
the target compound (A04 type crystal) was added as seeds for
crystallization to the filtrate, and the mixture was stirred at
room temperature for 30 min. Then water (2.76 L) was added dropwise
to the mixture over 30 min, and the mixture was stirred at room
temperature for 30 min. The precipitate was filtered, washed with
water (0.8 L.times.3), and dried under reduced pressure at
45.degree. C. overnight to give the target compound (A04 type
crystals, 442.01 g) as a white powder.
[0430] 1H NMR (CDCl.sub.3): .delta. 3.555(2H, dt, J=5, 6 Hz),
3.81(3H, s), 3.995(2H, t, J=5 Hz), 4.67(2H, s), 5.37(1H, t, J=6
Hz), 6.66(1H, br-s), 6.79(2H, d, J=8 Hz), 6.845(2H, d, J=6 Hz),
7.11(2H, d, J=8 Hz), 7.19(2H, d, J=8 Hz).
[0431] 1H NMR (DMSO-d6): .delta. 3.28-3.36(2H, m), 3.79(3H, s),
3.945(2H, t, J=5 Hz), 5.54 (2H, br-s), 6.165(1H, t, J=5 Hz),
6.92-7.08(5H, m), 7.2(2H, d, J=8 Hz), 7.28(2H, d, J=8 Hz).
EXAMPLE 76
2-Hydroxy-N-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]be-
nzyl}acetamide
[0432] To a solution of
4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzylamine
hydrochloride obtained by Example 57 (46.5 mg) in dichloromethane
(1.5 ml) was added diisopropylethylamine (135 .mu.L) and
acetoxyacetylchloride (41.6 .mu.L) at 0.degree. C.
[0433] After stirring at room temperature for 3 hrs, the mixture
was quenched with water. The whole mixture was extracted with
ethylacetate. The organic layer was washed with brine, dried over
magnesium sulfate, filtered and evaporated to give oil (67 mg). The
oil was dissolved in methanol (1.5 ml). Potassium carbonate (55 mg)
was added to the solution. After stirring at room temperature for 3
hrs, the mixture was filtered and evaporated to give oil which was
purified with preparative thin layer chromatography (0.5
mm.times.2, 10% methanol/chloroform) to give colorless oil (42.5
mg). The oil was crystallized from a mixture of ethyl acetate,
diisopropylether, and n-hexane with stirring at room temperature.
The precipitate was filtered and dried to give the target compound
(33.9 mg, 64.8%) as a white powder.
[0434] 1HNMR (CDCl.sub.3): .delta. 2.32(1H, t, J=5.2 Hz), 3.83(3H,
s), 4.20(2H, d, J=5.2 Hz), 4.51(2H, d, J=6.1 Hz), 6.72(1H, s),
6.87(2H, d, J=8.9 Hz), 7.16-7.24(6H, m).
[0435] MS (ESI+): 428.2(M+Na).
EXAMPLE 77
2-Hydroxy-N-(2-{4-[1-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-y-
l]phenyl}ethyl)ethanesulfonamide
[0436] To a solution of
2-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}etha-
namine hydrochloride and triethylamine in chloroform was added
methanesulfonyl chloride at room temperature.
[0437] After stirring for 1 hr, the reaction mixture was poured
into water and chloroform. The aqueous layer was separated and
extracted with chloroform. The combined organic layer was washed
with water and brine, dried over sodium sulfate, filtered and
evaporated under reduced pressure. The residue was column
chromatographed on silica gel and crystallized to give the target
compound (27.7 mg, 23.5%).
[0438] 1H NMR (CDCl.sub.3): .delta. 2.78-2.91(2H, m), 3.16(2H, t,
J=5.1 Hz), 3.32-3.43(2H, m), 3.82(3H, s), 3.96(2H, t, J=5.1 Hz),
4.65(1H, t, J=6.2 Hz), 6.72 (1H, s), 6.87 (2H, d, J=9.0 Hz),
7.12-7.27 (6H, m).
[0439] MS(LC, ESI+), 470.21(MH+), 511.17(MHMeCN).
EXAMPLE 78-1
tert-Butyl 2-(4-acetylphenoxy)ethylcarbamate
[0440] To a solution of 4-hydroxyacetophenone (10 g) and
2-tert-butoxycarbonylaminoethylbromide (24.7 g) in
N,N-dimethylformamide (50 ml) was added potassium iodide (12.2 g)
and potassium carbonate (15.2 g).
[0441] After stirring at 50.degree. C. overnight, the mixture was
quenched with water and extracted with ethyl acetate (3 times). The
combined organic layers were washed with 1N sodium hydroxide
aqueous solution (2 times) and brine, dried over magnesium sulfate,
and evaporated to give oil. The oil was purified with silica gel
column chromatography [500 ml, 20% ethyl acetate/n-hexane (100 ml),
30% ethyl acetate/n-hexane (1000 ml)] to give the target compound
(19.89 g, 96.9%) as a white solid.
[0442] 1H NMR(CDCl.sub.3): .delta. 1.46(9H, s), 2.56(3H, s),
3.52-3.60(2H, m), 4.09(2H, t, J=5.1 Hz), 6.93(2H, d, J=8.9 Hz),
7.93(2H, d, J=8.9 Hz).
[0443] MS (ESI+): 280.09(MH+).
EXAMPLE 78-2
tert-Butyl
2-[4-(4,4,4-trifluoro-3-oxobutanoyl)-phenoxy]ethylcarbamate
[0444] A mixture of tert-butyl 2-(4-acetylphenoxy)ethyl-carbamate
obtained by Example 78-1 (15 g), trifluoroacetic acid (8.95 ml),
and sodium ethoxide (8.77 g) in ethanol (45 ml) was stirred at
70.degree. C. for 2.5 hrs.
[0445] The mixture was poured into a mixture of aqueous hydrogen
chloride solution (1N) and ethyl acetate. The whole mixture was
extracted with ethyl acetate (2 times). The organic layer was
separated, washed with saturated sodium hydrogencarbonate and
brine, dried over magnesium sulfate, and evaporated to give oil (25
g). The oil was purified with silica gel column chromatography [500
ml, 30% ethyl acetate/n-hexane (1000 ml)] to give oil. The oil was
dissolved in ethyl acetate (5 ml) under heating by water bath.
n-Hexane (100 ml) was added to the solution, and the solution was
cooled to room temperature over 30 min under stirring. And n-hexane
(100 ml) was added to the mixture. The precipitate was filtered and
dried to give the target compound (15.956 g, 79.2%) as an orange
powder.
[0446] 1H NMR (CDCl.sub.3): .delta. 3.40-3.70(2H, m), 4.00-4.20(2H,
m), 5.00(1H, br-s), 6.50(1H, s), 6.98(2H, d, J=8.6 Hz), 7.93(2H, d,
J=8.6 Hz).
EXAMPLE 78-3
tert-Butyl
2-{4-[1-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]-
phenoxy}ethylcarbamate
[0447] To a suspension of 4-methoxyaniline (100 mg) in a mixture of
acetic acid (2 ml) and concentrated hydrogen chloride (0.4 ml) was
added dropwise a solution of sodium nitrite (61.6 mg) in water (0.1
ml) over 5 min at 3.degree. C., and the mixture was stirred at
3.degree. C. for 1 hr. To the mixture was added dropwise a solution
of tin chloride (641 mg) in concentrated hydrogen chloride (0.3 ml)
at 0.degree. C. over 10 min, and then the mixture was stirred at
0.degree. C. for 1 hr. Acetic acid (5 ml) was added dropwise to the
mixture at between -20 and -10.degree. C. over 2 min, and then the
mixture was quenched with a solution of sodium hydroxide (336 mg)
in water (2.24 ml) at -10.degree. C. over 2 min and warmed to room
temperature to give a solution containing 4-methoxyphenylhydrazine
hydrochloride.
[0448] A solution of tert-butyl
2-[4-(4,4,4-trifluoro-3-oxobutanoyl)-phenoxy]ethylcarbamate
obtained by Example 78-2 (305 mg) was added to the former solution
at -10.degree. C., and then the mixture was stirred at room
temperature for 3 hrs. The mixture was poured into a mixture of
saturated sodium hydrogen carbonate aqueous solution (150 ml) and
ethyl acetate (100 ml), and adjusted pH to basic by sodium
hydrogencarbonate powder.
[0449] The organic layer was separated and the aqueous layer was
extracted with ethyl acetate (50 ml.times.2). The combined organic
layers were washed with saturated sodium hydrogen carbonate aqueous
solution and brine, dried over magnesium sulfate, filtered, and
evaporated to give oil (450 mg). The oil was purified with silica
gel column chromatography [35 ml, 15% ethyl acetate/n-hexane (800
ml)] to give an oil. (343.2 mg, 88.5%). The oil was dissolved in
isopropylether (2 ml), and then n-hexane (6 ml) was added to the
solution. The whole mixture was stirred at room temperature for 1
hr. And then the precipitate was filtered, washed with n-hexane (10
ml), and dried under reduced pressure for 2 hrs to give the target
compound (280.6 mg, 72.4%) as a white powder.
[0450] 1HNMR (CDCl.sub.3) data was identical to authentic
sample.
[0451] 1HNMR (CDCl.sub.3): .delta. 1.45(3H, s), 3.53(2H, dt, J=4.4
Hz), 3.82(3H, s), 4.01(2H, t, J=4 Hz), 6.67(1H, s), 6.83(2H, d, J=8
Hz), 6.87(2H, d, J=8 Hz), 7.13(2H, d, J=8 Hz), 7.23(2H, d, J=8
Hz).
EXAMPLE 79-1
1-[4-(Benzyloxy)phenyl]hydrazine hydrochloride
[0452] To the suspension of 4-benzyloxyaniline (10 g) in
concentrated hydrogen chloride (100 ml) was added dropwise a
solution of sodium nitrite (3.2 g) in water (10 ml) over 10 min at
between -15 and -10.degree. C., and then the mixture was stirred at
3.degree. C. for 1 hr. To the mixture was added dropwise a solution
of tin chloride (33.5 g) in concentrated hydrogen chloride (80 ml)
at between -20 and -10.degree. C. over 30 min, and then the mixture
stirred at 0.degree. C. for 1 hr.
[0453] After cooling to -20.degree. C., the precipitate was
filtered, washed with water (25 ml), ethanol (25 ml) and ether (50
ml), and dried to give the target compound (10.637 g, 100%) as a
pale brown powder.
[0454] NMR(DMSO-d6): .delta. 5.05(2H, s), 6.93-7.03(4H, m),
7.46-7.28(4H, m).
EXAMPLE 79-2
2-{4-[1-(4-Benzyloxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxyl}e-
thanamine hydrochloride
[0455] The title compound (12.9 g, 87.5%) was prepared from
1-[4-(benzyloxy)phenyl]hydrazine hydrochloride obtained by Example
79-1 and tert-butyl
2-[4-(4,4,4-trifluoro-3-oxobutanoyl)phenoxy]ethylcarbamate obtained
by Example 78-2 in a similar manner to that of Example 78-3.
[0456] 1H NMR (DMSO-d6): .delta. 3.10-3.30(2H, m), 4.19(2H, t,
J=6.3 Hz), 5.14(2H, s), 6.98(2H, d, J=8.7 Hz), 7.09(1H, s),
7.09(2H, d, J=8.9 Hz), 7.49-7.22(9H, m).
EXAMPLE 80
N-(2-{4-[1-[4-(Benzyloxy)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]pheno-
xy}ethyl)urea
[0457] The title compound (10.57 g, 84.3%) was prepared from
2-{4-[1-(4-benzyloxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxyl}-
-ethanamine hydrochloride obtained by Example 79-2 in a similar
manner to that of Example 75.
[0458] 1H NMR (CDCl.sub.3): .delta. 3.57(2H, td, J=5.7, 50 Hz),
4.01(2H, t, J=5.0 Hz), 4.57(1H, br-s), 5.06(2H, s), 5.20(1H, t,
J=5.7 Hz), 6.66(1H, s), 6.80(2H, d, J=8.7 Hz), 6.93(2H, d, J=9.0
Hz), 7.12(2H, d, J=8.7 Hz), 7.21(2H, d, J=9.0 Hz), 7.35-7.42(5H,
m).
EXAMPLE 81
N-(2-{4-[1-(4-Hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-phenoxy}-
ethyl)urea
[0459] To a solution of
N-(2-{4-[1-[4-(benzyloxy)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phen-
oxy}ethyl)urea obtained by Example 80 (10.33 g) in methanol (100
ml) was added palladium on carbon (10% wet, 2 g), and the mixture
was stirred vigorously at room temperature under hydrogen
atmosphere for 3 hrs. The whole mixture was filtered and evaporated
to give oil (8.23 g) The oil was purified with silica gel column
chromatography [250 ml, 3% methanol/chloroform (500 ml), 5%
methanol/chloroform (500 ml), and 10% methanol/chloroform (500 ml)]
to give the target compound (8.07 g, 95.4%) as an oil.
[0460] 1H NMR (DMSO-d6): .delta. 3.28-3.33(2H, m), 3.94(2H, t,
J=5.5 Hz), 5.52(2H, br-s), 6.14(1H, br-t, J=5.7 Hz), 6.80(2H, d,
J=8.7 Hz), 6.93(2H, d, J=8.9 Hz), 7.05(1H, s), 7.14(2H, d, J=8.7
Hz), 7.19(2H, d, J=8.9 Hz).
[0461] MS (ESI+): 407.10(MH+).
EXAMPLE 82
4-[5-(4-{2-[(Aminocarbonyl)amino]ethoxy}phenyl)-3-(trifluoromethyl)-1H-pyr-
azol-1-yl]phenyl acetate
[0462] To a mixture of
N-(2-{4-[1-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}-
ethyl)urea obtained by Example 81 (148.5 mg) in dichloromethane
(1.5 ml) was added pyridine (163 .mu.L) and acetic anhydride (45
.mu.L), and the mixture was stirred at room temperature for 1 hr
and stirred under reflux for 3 hrs.
[0463] After evaporation, the mixture was purified with preparative
thin layer chromatography (11.0 mm, 10% methanol/chloroform) to
give oil. The oil was crystallized from a mixture of
dichloromethane and isopropylether at room temperature to give the
target compound (138.6 mg, 84.6%) as a white powder.
[0464] 1H NMR (CDCl.sub.3): .delta. 2.30(3H, s), 3.59(2H, td,
J=5.5, 4.9H z), 4.04(2H, t, J=4.9 Hz), 4.51(2H, br-s), 5.22(1H,
br-t, J=5.5 Hz), 6.69(1H, s), 6.84(2H, d, J=8.7 Hz), 7.10(2H, d,
J=8.8 Hz), 7.14(2H, d, J=8.7 Hz), 7.31(2H, d, J=8.9 Hz).
[0465] MS(LC, ESI+): 449.24(MH.sup.+), (ESI-)
492.5(M-H+HCO.sub.2.sup.-).
EXAMPLE 83-1
1-(1,3-Benzodioxol-5-yl)hydrazine hydrochloride
[0466] The title compound (1.811 g, quant.) was prepared from
3,4-(methylenedioxy)aniline in a similar manner to that of Example
79-1.
[0467] 1H NMR (DMSO-d6): .delta. 594(2H, s), 6.53(1H, dd, J=2.2 8.2
Hz), 6.80(1H, s), 6.83(1H, d, J=8.2 Hz).
[0468] MS(LS, ESI+): 153.9(MH+) 193.99(MH+CH.sub.3CN).
EXAMPLE 83-2
tert-Butyl
2-{4-[1-(1,3-benzodioxol-5-yl)-3-(trifluoro-methyl)-1H-pyrazol--
5-yl]phenoxy}ethylcarbamate
[0469] The title compound (371.3 mg, 56.7%) was prepared from
tert-butyl
2-[4-(4,4,4-trifluoro-3-oxobutanoyl)-phenoxy]ethylcarbamate
obtained by Example 78-2 and 1-(1,3-benzodioxol-5-yl)hydrazine
hydrochloride obtained by Example 83-1 in a similar manner to that
of Example 78-3.
[0470] NMR (CDCl.sub.3) MA12.048: .delta. 1.75(9H, s),
3.45-3.60(2H, m), 4.02(2H, t, J=5.1 Hz), 6.02(2H, s), 6.66-6.88(1H,
m), 7.16(2H, d, J=8.8 Hz).
[0471] MS(LC, ESI+): 492.22 (MH+), 533.26 (MHMeCN+).
EXAMPLE 84
2-{4-[1-(1,3-Benzodioxol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy-
}ethanamine
[0472] The title compound (181.2 mg, 61.5%) was prepared from
tert-butyl
2-{4-[1-(1,3-benzodioxol-5-yl)-3-(tri-fluoromethyl)-1H-pyrazol-5-yl]pheno-
xy}ethylcarbamate obtained by Example 83-2 in a similar manner to
that of Example 74.
[0473] 1H NMR (CDCl.sub.3): .delta. 1.75(9H, s), 3.45-3.60(2H, m),
4.02(2H, t, J=5.1 Hz), 6.02(2H, s), 6.66-6.88(1H, m), 7.16(2H, d,
J=8.8 Hz).
[0474] MS (LC, ESI+): 392.09(MH+), 433.16(MHMeCN+).
EXAMPLE 85
N-(2-{4-[1-(1,3-Benzodioxol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phen-
oxy}ethyl)urea
[0475] The title compound (181.2 mg, 90.1%) was prepared from
2-{4-[1-(1,3-benzodioxol-5-yl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]pheno-
xy}ethanamine obtained by Example 84 in a similar manner to that of
Example 75.
[0476] 1H NMR (CDCl.sub.3): .delta. 3.6(2H, td, J=5.0, 5.0 Hz),
4.045(2H, t, J=5 Hz), 4.5(2H, br-s), 5.095(1H, br-t, J=5 Hz),
6.01(2H, s), 6.66(1H, s), 6.75-6.86(3H, m), 6.84(2H, d, J=8 Hz),
7.16(2H, d, J=8 Hz).
[0477] MS (LC, ESI+): 435.08(MH+).
EXAMPLE 86
tert-Butyl
2-({4-[1-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl-
]benzyl}amino)-2-oxoethyl-carbamate
[0478] A mixture of
4-[1-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]benzylamine
hydrochloride obtained by Example 57,
N-tert-butoxycarbonyl-glycine, WSCD and 1-hydroxybenzotriazole
hydrate in triethylamine and dichloromethane was stirred at room
temperature.
[0479] After stirring for 15 hrs, the reaction mixture was poured
onto water and chloroform. The aqueous layer was separated and
extracted with chloroform. The combined organic layer was washed
with water and brine, dried over sodium sulfate, filtered and
evaporated under reduced pressure. The residue was column
chromatographed on silica gel and crystallized to give the target
compound (93.5 mg, 88.9%).
[0480] 1HNMR (CDCl.sub.3): .delta. 1.43(9H, s), 3.82(3H, s),
3.82-3.85(2H, m), 4.475(2H, d, J=6 Hz), 6.71(1H, s), 6.87(2H, d,
J=8 Hz), 7.14-7.26(6H, m).
[0481] MS (ESI+): 505(MH+).
EXAMPLE 87
2-Amino-N-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benz-
yl}acetamide hydrochloride
[0482] The title compound (62.3 mg, 82.9%) was prepared from
tert-butyl
2-({4-[1-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]benzyl}am-
ino)-2-oxoethyl-carbamate obtained by Example 86 in a similar
manner to that of Example 74.
[0483] 1H NMR (DMSO-d6): .delta. 3.61(2H, s), 3.79(3H, s),
4.345(2H, d, J=6 Hz), 7.005(2H, d, J=10 Hz), 7.15(1H, s), 7.22-7.32
(6H, m), 8.09(2H, br-s), 8.93(1H, br-t, J=6 Hz).
[0484] MS (ESI+): 405.33 (free, MH+).
EXAMPLE 88
N-{4-[1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzyl}aceta-
mide
[0485] To a solution of
4-[1-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]benzylamine
hydrochloride obtained by Example 57 and triethylamine in
dichloromethane was added dropwise acetyl chloride at 0.degree.
C.
[0486] After stirring at room temperature for 1 hr, the mixture was
quenched with saturated sodium hydrogen carbonate aqueous solution
and extracted with ethyl acetate (3 times). The combined organic
layers were washed with 1N hydrochloric acid, water, and brine,
dried over magnesium sulfate, and evaporated to give oil, which was
purified with silica gel column chromatography (eluted with 50%
ethyl acetate/n-hexane) to give oil. The oil was crystallized from
a mixture of ethyl acetate and n-hexane at 5.degree. C. to give the
target compound (52.2 mg, 69.3%) as a solid.
[0487] 1H NMR (CDCl.sub.3): .delta. 2.04(3H, s), 3.83(3H, s),
4.435(2H, d, J=6 Hz), 6.71(1H, s), 6.87(2H, d, J=8 Hz),
7.15-7.26(6H, m).
[0488] IR (KBr): 1647 cm.sup.-1.
[0489] MS (ESI+): 412.1(M+Na).
EXAMPLE 89
N-(2-{4-[1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-phenyl}e-
thyl)-1-methyl-1H-imidazole-4-sulfonamide
[0490] The title compound (72 mg, 70.8%) was prepared from
2-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}etha-
namine hydrochloride in a similar manner to that of Example 77.
[0491] 1H NMR (CDCl.sub.3): .delta. 2.83(2H, t, J=8 Hz), 3.26(2H,
dt, J=6H z), 3.75(3H, s), 3.83(3H, s), 5.005(1H, t, J=6 Hz),
6.7(1H, s), 6.88(2H, d, J=8 Hz), 7.13(4H, s), 7.22(2H, d, J=8H z),
7.45-7.47(2H, m).
[0492] MS (ESI+): 528.1 (MNa+).
EXAMPLE 90
N-((1R)-2-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phen-
oxy}-1-methylethyl)urea
[0493] To a solution of
(1R)-2-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenox-
y}-1-methyl-ethanamine hydrochloride in dichloromethane was added
triethylamine and trimethylsilyl isocyanate at 0.degree. C.
[0494] After stirring for 5 hrs, the mixture was quenched with
water and extracted with dichloromethane. The combined organic
layers were washed with brine, dried over magnesium sulfate, and
evaporated under reduced pressure to give oil, which was purified
with preparative thin layer chromatography (1 mm, ethyl acetate) to
give oil. The oil was crystallized from a mixture of isopropyl
ether, ethyl acetate, and n-hexane to give the target compound as a
white solid (22.8 mg, 88.1%).
[0495] 1H NMR (CDCl.sub.3): .delta. 1.29(3H, d, J=8 Hz), 3.82(3H,
s), 3.87-3.94(2H, m), 4.07-4.19(1H, m), 4.51(2H, s), 4.87(1H, d,
J=8 Hz), 6.67(1H, s), 6.8-6.89(4H, m), 7.12(2H, d, J=8 Hz),
7.215(2H, d, J=10 Hz).
[0496] MS (ESI+): 435.3 (MH+), 476.3(MH+MeCN).
EXAMPLE 91
N-(2-{4-[1-(6-Methoxy-3-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phe-
noxy}ethyl)methanesulfonamide
[0497] The title compound (130 mg, 71.8%) was prepared from
2-{4-[1-(6-methoxy-3-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]pheno-
xy}ethanamine dihydrochloride in a similar manner to that of
Example 77.
[0498] 1HNMR (CDCl.sub.3): .delta. 3.03(3H, s), 3.555(2H, dt, J=5,
5 Hz), 3.94(3H, s), 4.115(2H, t, J=5 Hz), 4.785(1H, br-t, J=5 Hz),
6.71(1H, s), 6.76(1H, d, J=8 Hz), 6.85(2H, d, J=8 Hz), 7.16(2H, d,
J=8 Hz), 7.555(2H, dd, J=8, 2 Hz), 8.085(1H, d, J=2 Hz).
[0499] MS (ESI+): 479.1 (M+Na)+.
EXAMPLE 92
4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenol
[0500] A mixture of
4-methoxy-1-(4,4,4-trifluoro-3-oxo-butanoyl)benzene (5.0 g) and
p-hydroxyphenyl hydrazine hydrochloride (3.59 g) in acetic acid (30
ml) was stirred at room temperature.
[0501] After stirring for 15 hrs, toluene and water was added. The
aqueous layer was separated and extracted twice with toluene. The
combined organic layer was washed with water (twice) and brine,
dried over sodium sulfate, filtered and evaporated under reduced
pressure. The residue was column chromatographed on silica gel to
give the target compound (4.88 g, 71.9%) as crystals.
[0502] 1H NMR (CDCl.sub.3): .delta. 3.80(3H, s), 6.68(1H, s),
6.72(2H, d, J=8.8 Hz), 6.83(2H, d, J=8.8 Hz), 7.12(2H, d, J=8.8
Hz), 7.13(2H, d, J=8.8 Hz).
[0503] MS (ESI+): m/z 357 (M+Na).
EXAMPLE 93
2-{4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}etha-
nol
[0504] A suspension of
4-[5-(4-methoxyphenyl)-3-(tri-fluoromethyl)-1H-pyrazol-1-yl]phenol
obtained by Example 92 (500 mg), potassium carbonate (1.24 g),
potassium iodide (1.49 g), and 2-chloro-1-ethanol (0.60 ml) was
stirred at 80.degree. C. for 5 hrs.
[0505] After cooling, the reaction mixture was poured into water.
The mixture was extracted twice with ethyl acetate, washed with
water and brine, dried over sodium sulfate, filtered and evaporated
under reduced pressure. The residue was column chromatographed on
silica gel to give the target compound (545 mg, 96.4%).
[0506] 1H NMR (CDCl.sub.3): 2.03(1H, t, J=5.8 Hz), 3.81(3H, s),
3.94-4.01(2H, m), 4.09(2H, dd, J=3.5, 4.6 Hz), 4.52(3H, s),
6.68(1H, s), 6.84(2H, d, J=8.9 Hz), 6.89(2H, d, J=9 Hz), 7.13(2H,
d, J=8.9 Hz), 7.24(2H, d, J=9 Hz).
[0507] MASS (ESI+): m/z 401 (M+Na).
EXAMPLE 94
{4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}aceton-
itrile
[0508] A suspension of
4-[5-(4-methoxyphenyl)-3-(tri-fluoromethyl)-1H-pyrazol-1-yl]phenol
obtained by Example 92 (2.0 g), potassium carbonate (992 mg),
potassium iodide (993 mg), and chloroacetonitrile (0.57 ml) was
stirred at 80.degree. C. for 4 hrs.
[0509] After cooling, the reaction mixture was poured into water.
The mixture was extracted twice with ethyl acetate, washed with
water and brine, dried over sodium sulfate, filtered and evaporated
under reduced pressure. The residue was column chromatographed on
silica gel to give the target compound (1.75 g, 78.3%) as an
oil.
[0510] 1H NMR (CDCl.sub.3): .delta. 3.81(3H, s), 4.79(2H, s),
6.69(1H, s), 6.86(2H, d, J=8.8 Hz), 6.96(2H, d, J=9 Hz), 7.14(2H,
d, J=8.8 Hz), 7.31(2H, d, J=9 Hz).
[0511] MS (APCI+): m/z 374 (M+1).
EXAMPLE 95
tert-Butyl
2-{4-[5-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-1-yl]-
phenoxy}ethylcarbamate
[0512] The title compound (420 mg, 21%) was prepared from
4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenol
obtained by Example 92 in a similar manner to that of Example
73.
[0513] 1H NMR (CDCl.sub.3): .delta. 1.46(9H, s), 3.501-3.58(2H, m),
4.02 (2H, t, J=5.1 Hz), 4.99(1H, br-s), 6.67(1H, s), 6.84(2H, d,
J=8.9 Hz), 6.85(2H, d, J=9 Hz), 7.13(2H, d, J=8.9 Hz), 7.23(2H, d,
J=9 Hz).
[0514] MS (ESI+): m/z 500 (M+Na).
EXAMPLE 96
2-{4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}etha-
namine hydrochloride
[0515] The title compound (0.35 g, 96.2%) was prepared from
tert-butyl
2-{4-[5-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-1-yl]phenoxy}et-
hylcarbamate obtained by Example 95 in a similar manner to that of
Example 74.
[0516] 1H NMR (CDCl.sub.3+CD.sub.3OD): .delta. 3.2-3.5(4H, m),
3.81(3H, s), 4.2-4.35(2H, m), 6.70(1H, s), 6.84(2H, d, J=8.6 Hz),
6.95(2H, d, J=8.6 Hz), 7.13(2H, d, J=8.6 Hz), 7.25(2H, d, J=8.6H
z).
[0517] MS (ESI+): m/z 378 (M-Cl).
EXAMPLE 97
N-(2-{4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}e-
thyl)methanesulfonamide
[0518] To a solution of
2-{4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}eth-
anamine hydrochloride obtained by Example 96 (100 mg) in
dichloromethane (5 ml) and triethylamine (0.1 ml) was added
dropwise methanesulfonyl chloride (38 .mu.l) at room
temperature.
[0519] After stirring for 2 hrs, the reaction mixture was
partitioned between chloroform and water. The aqueous layer was
extracted with chloroform. The combined organic layer was washed
with water and brine, dried over magnesium sulfate, filtered and
evaporated under reduced pressure. The residue was purified with
high performanced thin layer chromatography to give the target
compound (35 mg, 31.8%) as crystals.
[0520] 1H NMR (CDCl.sub.3): .delta. 3.03(3H, s), 3.56(2H, dt, J=5,
5.7 Hz), 3.81(3H, s), 4.11(2H, t, J=5 Hz), 4.82(1H, t, J=5.7 Hz),
6.68(1H, s), 6.85(2H, d, J=7.9 Hz), 6.85(2H, d, J=8.7 Hz), 7.13(2H,
d, J=8.7 Hz), 7.24(2H, d, J=7.9 Hz).
[0521] MS (ESI+): m/z 478 (M+Na).
EXAMPLE 98
N-(2-{4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenoxy}-
ethyl)urea
[0522] To a solution of
2-{4-[5-(4-methoxyphenyl)-3-(tri-fluoromethyl)-1H-pyrazol-1-yl]phenoxy}et-
hanamine hydrochloride obtained by Example 96 (200 mg) in water (10
ml) and ethanol (5 ml) was added sodium cyanate (314 mg) at room
temperature.
[0523] After stirring for 15 hrs, the reaction mixture was
partitioned between ethyl acetate and water. The aqueous layer was
extracted with ethyl acetate. The combined organic layer was washed
with water, dried over sodium sulfate, filtered and evaporated
under reduced pressure. The residue was column chromatography by
high performanced thin layer chromatography
(chloroform:methanol=8:1) to give the target compound (0.148 g,
72.8%).
[0524] 1H NMR (CDCl.sub.3): .delta. 3.60(2H, dt, J=5.6, 5.0 Hz),
3.81(3H, s), 4.04(2H, t, J=5.0 Hz), 4.50(2H, br-s), 5.12(1H, t,
J=5.6 Hz), 6.68(1H, s), 6.84(2H, d, J=8.8 Hz), 6.85(2H, d, J=8.9
Hz), 7.13(2H, d, J=8.8 Hz), 7.22(2H, d, J=8.9 Hz).
[0525] MS (ESI+): m/z 443 (M+Na).
EXAMPLE 99
N-(2-{4-[3-(Difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenyl}eth-
yl)-2-hydroxyethanesulfonamide
[0526] To a solution of
2-(2-{4-[1-(4-methoxyphenyl)-3-difluoromethyl-1H-pyrazol-5-yl]phenyl}ethy-
l)-1H-isoindole-1,3(2H)-dione in acetonitrile was added hydrazine
monohydrate.
[0527] After stirring at 60.degree. C. overnight, the mixture was
filtered. And the filtrate was evaporated to give
2-{4-[1-(4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl]phenyl}ethan-
amine as an orange oil.
[0528] To a solution of the oil and triethylamine in chloroform was
added 2-hydroxyethanesulfonyl chloride at room temperature.
[0529] After stirring for 1 hr, the reaction mixture was poured
onto water and chloroform. The aqueous layer was separated and
extracted with chloroform. The combined organic layer was washed
with water and brine, dried over sodium sulfate, filtered and
evaporated under reduced pressure. The residue was column
chromatographed on silica gel and crystallized to give the target
compound (220 mg, 76.1%).
[0530] 1H NMR (CDCl.sub.3): .delta. 2.875(2H, t, J=7 Hz),
2.91-3.19(2H, m), 3.395(2H, dt, J=6 Hz), 3.83(3H, s), 3.985(2H, t,
J=5 Hz), 4.44(1H, br-t, J=6 Hz), 6.7(1H, s), 6.765(1H, t, J=55 Hz),
6.875(2H, d, J=10 Hz), 7.12(6H, s).
[0531] MS (ESI+): 452.19(MH+). Preparation 1 ##STR5##
[0532] To a suspension of AlCl3 (45.9 g) was added dropwise acetyl
chloride (13.4 ml) (About 5.degree. C.), and then I (25.7 g)
mentioned above under ice-cooling (5-10.degree. C.). After stirring
for 8 hours, the reaction mixture was poured onto ice-water. The
organic layer was separated and washed with water (twice) and
1NHCl, sat. NaHCO3 and brine, dried over MgSO4, filtered and
evaporated under reduced pressure to give crude product. The
product was distilled under reduced pressure to give 105.8 g (84%)
of the following compound (P0001) ##STR6##
[0533] (P0001)
[0534] TLC Check: Ninhydrin/UV
[0535] b.p. 1> 91-117.degree. C./0.7 mmHg. E111271-1 12.6 g
[0536] 2> 117.degree. C./0.7 mmHg. E111271-2 105.8 g Preparation
2 ##STR7##
[0537] (P0002)
[0538] The above compound P0002 was prepared in a similar manner to
that of P0001.
[0539] Mass (API-ES positive): 243 (M+Na)+
[0540] 200 MHz 1H NMR (CDCl.sub.3, d): 1.91-2.05(2H, m), 2.06(3H,
s), 2.59(3H, s), 2.76(2H, t, J=7.7 Hz), 4.09(2H, t, J=6.5 Hz),
7.28(2H, d, J=8.2 Hz), 7.90(2H, d, J=8.2 Hz). Preparation 3
##STR8##
[0541] (P0003)
[0542] 60% Sodium hydride 427 mg was added to a solution of the
compound P0001 (2 g) and ethyl trifluoroacetate 2.6 ml in DMF 10 ml
portionwise (in three portions) under ice bath cooling. The
reaction mixture was stirred at same temperature for 45 minutes.
Then ice bath was replaced to water bath. The temperature of
reaction mixture was raised to 24.5.degree. C., then slowly fall
down to 22.degree. C. over 1 hour. The mixture was stirred at r.t.
for 1 hour, then poured into a mixture of 1M HCl 12 ml and ice 40
ml. The whole mixture was extracted with AcOEt 20 ml. The organic
layer was washed with H2O 30 ml, saturated aqueous sodium chloride
solution, dried over magnesium sulfate, concentrated in vacuo. The
residue was purified by silica gel column chromatography eluted
with toluene. Obtained crystals were washed with chilled n-hexane
10 ml and petroleum ether 5 ml by decantation to give a compound
P0003 as white crystals.
[0543] mp. 87-88.degree. C.
[0544] Mass (API-ES negative): 301(M-H)+
[0545] 200 MHz 1HNMR (DMSO-d6, d): 3.00(2H, t, J=6.7 Hz), 4.27(2H,
t, J=6.7 Hz), 6.99(1H, s), 7.48(2H, d, J=8.3 Hz), 8.08(2H, d, J=8.3
Hz). Preparation 4 ##STR9##
[0546] (P0004)
[0547] P0004 was prepared in a similar manner to that of P0003 as
shown in Preparation 3.
[0548] Mass (API-ES negative) 315 (M-H)+
[0549] NMR JA24.112
[0550] 200 MHz 1H NMR (CDCl.sub.3, d): 1.92-2.06(2H, m), 2.06(3H,
s), 2.74-2.82(2H, m), 4.10(2H, t, J=6.5 Hz), 6.55(1H, s), 7.33(2H,
d, J=8.3 Hz), 7.89(2H, d, J=8.3 Hz) Preparation 5 ##STR10##
[0551] (P0005)
[0552] P0005 was prepared in a similar manner to that of P0003 as
shown in Preparation 3.
[0553] yellow crystals
[0554] Mass (API-ES positive): 259 (M+Na)+
[0555] 400 MHz 1H NMR (CDCl.sub.3, d): 1.41(3H, t, J=7.1 Hz),
4.40(2H, q, J=7.1 Hz), 6.93(2H, d, J=8.9 Hz), 7.02(1H, s), 7.96(2H,
d, J=8.9 Hz) Preparation 6 ##STR11##
[0556] (P0006)
[0557] P0006 was obtained according to a similar manner to that of
P0003. (PREPARATION 3) Preparation 7 ##STR12##
[0558] (P0007)
[0559] 60% Sodium hydride 233 mg was added to a solution of P0001 1
g and ethyl pentafluoropropionate 0.93 ml in three portions under
ice bath cooling. The reaction mixture was stirred at 24-27.degree.
C. with cooling in a water bath for several hours, then poured into
a mixture of ice and 1M HCl 50 ml. The whole mixture was extracted
with AcOEt twice. The combined organic layer was washed with
saturated aqueous sodium chloride solution, dried over magnesium
sulfate, and concentrated in vacuo to give P0007 1.94 g as an
oil.
[0560] Mass (API-ES negative): 309 (M-H)+
[0561] 200 MHz 1H NMR (CDCl3, d): 2.90-3.05(2H, m), 3.85-4.00(2H,
m), 6.62(1H, s), 7.39(2H, d, J=8.3 Hz), 7.92(2H, d, J=8.3 Hz).
Preparation 8 ##STR13##
[0562] (P0008)
[0563] 20% solution of sodium ethoxide in EtOH 18 ml was added
dropwise to a solution of P0001 (4.00 g) and diethyl oxalate 5.95 g
in DMF 12 ml at 4-6.degree. C. After stirring at same temperature
for 1 hour, the reaction mixture was poured into a mixture of
ice-water 100 ml and conc. HCl 5 ml, and extracted with AcOEt. The
organic layer was washed successively with 1M HCl, H2O, and
saturated aqueous sodium chloride solution, dried over magnesium
sulfate, treated with activated carbon, then filtered through a
SiO2 (20 ml) pad. The pad was washed with AcOEt. The filtrate and
combined washings were concentrated in vacuo to give P0008 (6.05 g)
as an oil.
[0564] Mass (API-ES positive): 287(M+Na).sup.+, (API-ES negative)
263(M-H)+
[0565] 200 MHz 1H NMR (CDCl.sub.3, d): 1.42(3H, t, J=7.1 Hz),
2.96(2H, t, j=6.5 Hz), 3.93(2H, t, J=6.5 Hz), 4.40(2H, q, J=7.1
Hz), 7.06(1H, s), 7.38(2H, d, J=8.3 Hz), 7.96(2H, d, J=8.3 Hz).
Preparation 9 ##STR14##
[0566] (P0009).
[0567] To a solution of 4-Hydroxybenzophenone (160 g), Ethyl
trifluoroacetate (182 ml), and ethanol (11 ml) in
N,N-dimethylformamide (670 ml) was added portionwise sodium hydride
(suspension in mineral oil, 103 g) over 15 minutes at
0.about.35.degree. C. The mixture was stirring at room temperature
for 2 hours, and then at 35.about.40.degree. C. for 3 hours. The
mixture was poured into a mixture of ice and concentrated hydrogen
chloride (320 ml) (aqueous layer total 4 L) and diisopropyl ether
(2 L). The aqueous layer was separated and extracted with
diisopropyl ether (500 ml.times.2). The combined organic layers
were washed with water (500 ml.times.4) and brine, dried over
magnesium sulfate, and evaporated to give 415 g of solid. The solid
was dissolved in diisopropyl ether (200 ml) at 65.degree. C. The
solution was added dropwise hexane (1.5 L) under stirring at room
temperature. After stirring at room temperature for 1 hour, The
suspension was filtered and dried under reduced pressure to give
solid (first crop, 109.53 g, 40%) The mother liquid evaporated and
similarly treated diisopropyl ether (20 ml) and hexane (250 ml) to
give second crop (71.11 g, 26%) P0009 (first corp and second corp
total, 66.2%).
[0568] NMR(CDCl3); 5.65(1H, brs), 6.50(1H, s), 6.94(2H, d, J=8.8
Hz), 7.91 (2H, d, J=8.8 Hz).
[0569] MS(ESI+), 255.1(M+Na)+. Preparation 10 ##STR15##
[0570] (P0010)
[0571] This compound was obtained according to a similar manner to
that of P0009 (S0203744) as a powder (56.195 g, 102%).
[0572] NMR(CDCl3); 6.01(1H, t, J=54 Hz), 6.49(1H, s), 6.92(2H, d,
J=8.8 Hz), 7.90(2H, d, J=8.8 Hz).
[0573] MS(ESI-), 213.3(M-H)+ Preparation 11 ##STR16##
[0574] (P0011)
[0575] A mixture of P0009 (100 g), 4-Methoxyphenylhydrazine
hydrochloride (82.4 g), and sodium acetate (42.6 g) in acetic acid
(550 ml) was stirring at 70.degree. C. for 3 hours. After cooling
to room temperature, the mixture was poured into water (4 L) and
stirred at room temperature for 1 hour. The precipitate was
filtered, washed with water (250 ml.times.3) and Hex (500
ml.times.2), and dried at room temperature overnight to give powder
(157.86 g). The powder was purified by recrystallization from ethyl
acetate and hexane to give P0011 as a powder 121.34G (77%).
[0576] NMR(CDCl.sub.3); 3.82(3H, s), 5.08(1H, brs), 6.67(1H, s),
6.77(2H, d, J=8.6 Hz), 6.87(2H, d, J=9.0 Hz), 7.09(2H, d, J=8.6
Hz), 7.23(2H, d, J=9.0 Hz).
[0577] MS(ESI+); 357.1(M+Na)+. Preparation 12 ##STR17##
[0578] (P0012)
[0579] This compound was obtained according to a similar manner to
that of P0011 as a solid (3.2028 g, 72%).
[0580] NMR(DMSO-d6); 3.88 (3H, s), 6.74 (2H, d, J=8.6 Hz), 6.82
(1H, s), 6.90(1H, d, J=8.6 Hz), 7.10(2H, d, J=8.6 Hz), 7.09(1H, t,
J=55 Hz), 7.68(1H, dd, J=8.6, 2.7 Hz), 8.12(1H, d, J=2.7 Hz).
[0581] MS(ESI+); 316.1(M-H)+, 633.3(2M-H). Preparation 13
##STR18##
[0582] (P0013)
[0583] This compound was obtained according to a similar manner to
that of P0011. Preparation 14 ##STR19##
[0584] (P0014).
[0585] To a solution of 4-methoxyphenylhydrazine hydrochloride
(3.43 g) in water (7.7 ml) was added a solution of P0009 in acetic
acid (50 ml). The mixture was then allowed to stand at room
temperature overnight. The mixture was poured into water (500 ml)
and stirred at room temperature for 1 hour. The precipitate was
filtered, washed with water (100 ml), and dried at room temperature
to give P0014 as a brown solid (3.26 g, 90%).
[0586] NMR(DMSO-d6); 3.88(3H, s), 6.75(2H, d, J=8.6 Hz), 6.92(1H,
d, J=8.5 Hz), 7.06-7.15(3H, m), 7.73(1H, dd, J=8.5, 2.8 Hz),
8.16(1H, d, J=2.8 Hz), 9.86(1H, s, OH).
[0587] MS(ESI-); 334.1(M-H)+, 669.2(2M-1)+. Preparation 15
##STR20##
[0588] (P0015)
[0589] This compound was obtained according to a similar manner to
that of P0014 as a pale brown powder (13.58 g, 91.7%).
[0590] NMR(DMSO-d6); 3.94(3H, s), 6.67(1H, s), 6.75(1H, t, J=55
Hz), 6.73-6.80(3H, m), 7.09(2H, d, J=8.6 Hz), 7.57(1H, dd, J=8.6,
2.6 Hz), 8.07(1H, d, J=2.6 Hz).
[0591] MS(ESI-); 316.1(M-H), 633.3(2M-H). Preparation 16
##STR21##
[0592] (P0016) (P0016-1)
[0593] 1M NaOH 1 ml was added to a solution of P0016-1 (reported in
WO9427973) 1.31 g and in EtOH 5 ml and the mixture was stirred at
ambient temperature overnight. The mixture partitioned between
AcOEt and H2O. The organic layer was washed with H2O, saturated
aqueous sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo. The residue was purified by silica gel
column chromatography eluted with AcOEt/n-hexane to give P0016 (900
mg) as an oil.
[0594] Mass (ESI+): 331 (M+H)+
[0595] 200 MHz 1H NMR (DMSO-d6, d): -0.05(6H, s), 0.82(9H, s),
0.94(4H, d, J=6.0 Hz), 2.38-2.52(1H, m), 2.78(2H, t, J=6.6 Hz),
3.79(2H, t, J=66 Hz), 7.01(1H, d, J=16.2 Hz), 7.29(2H, d, J=8.1
Hz), 7.65(2H, d, J=8.1 Hz), 7.65(1H, d, J=16.2 Hz) Preparation 17
##STR22##
[0596] (P0017)
[0597] P0017 6.41 g was prepared in a similar manner to that of
P0016.
[0598] Mass (API-ES positive): 255 (M+Na)+
[0599] 200 MHz 1H NMR (CDCl.sub.3, d): 0.90-1.01(2H, m),
1.11-1.20(2H, m), 2.22 (1H, m), 3.49 (3H, s), 5.21 (2H, s), 6.78
(1H, d, J=16.0 Hz), 7.05(2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7 Hz),
7.58 (1H, d, J=16.0 Hz). Preparation 18 ##STR23##
[0600] (P0018)
[0601] 30% H2O2 0.64 ml and 3M NaOH 0.64 ml was added to a 0.25M
solution of P0016 1.03 g in EtOH:acetone=3:1. The mixture was
stirred at ambient temperature overnight. The mixture was
concentrated in vacuo, and partitioned between AcOEt and H2O. The
organic layer was washed with H2O, saturated aqueous sodium
chloride solution, dried over magnesium sulfate, and concentrated
in vacuo to give P0018 (792 mg) as an oil.
[0602] Mass (ESI+): 347 (M+H)+
[0603] 200 MHz 1H NMR (DMSO-d6, d): -0.05(6H, s), 0.82(9H, s),
0.92-1.04(4H, m), 2.24(1H, m), 2.75(2H, t, J=6.7 Hz), 3.76(2H, t,
J=6.7 Hz), 3.86(1H, d, J=1.9 Hz), 4.19(1H, d, J=1.9 Hz), 7.24(2H,
d, J=8.4 Hz), 7.30(2H, d, J=8.4 Hz) Preparation 19 ##STR24##
[0604] (P0019)
[0605] P0019 1.082 g was prepared from P0017 1.0 g in a similar
manner to that of P0018.
[0606] Mass (API-ES positive): 271(M+Na)+
[0607] 200 MHz 1H NMR (DMSO-d6, d): 0.90-1.04(4H, m), 2.24(1H, m),
3.37(3H, s), 3.88(1H, d, J=1.9 Hz), 4.17(1H, d, J=1.9 Hz), 5.20(2H,
s), 7.03(2H, d, J=8.7 Hz), 7.32(2H, d, J=8.7 Hz) 200 MHz 1H NMR
(CDCl.sub.3, d): 0.90-1.07(2H, m), 1.12-1.26(2H, m), 2.18 (1H, m),
3.48 (3H, s), 3.58 (1H, d, J=1.9 Hz), 4.05(1H, d, J=1.9 Hz),
5.18(2H, s), 7.04(2H, d, J=8.7 Hz), 7.23(2H, d, J=8.7 Hz).
Preparation 20 ##STR25##
[0608] (P0020)
[0609] P0005 17.00 g was dissolved in warm EtOH 68 ml and AcOH 170
ml at 70.degree. C. To this solution was added P0005, suspended in
H2O 20 ml, in one portion. The mixture was stirred at 70.degree. C.
for 1.5 hours and then poured into a mixture of ice 500 ml and
conc.HCl 10 ml. Diisopropyl ether 100 ml was added and the mixture
was stirred at ambient temperature for 20 minutes. The precipitates
were collected and washed successively with 1M HCl, H2O, and
diisopropylether. This was air dried overnight to give P0020 21.28
g was a pale yellow powder.
[0610] Mass (ESI+): 339 (M+H)+
[0611] 400 MHz 1H NMR (CDCl.sub.3, d): 1.41(3H, t, J=7.1 Hz),
3.82(3H, s), 4.44(2H, q, J=7.1 Hz), 6.76(2H, d, J=8.7 Hz), 6.85(2H,
d, J=9.0 Hz), 6.96(1H, s), 7.08(2H, d, J=8.7 Hz), 7.24(2H, d, J=9.0
Hz). Preparation 21 ##STR26##
[0612] (P0021)
[0613] P0021 was prepared from P0005 in a similar manner to that of
P0020.
[0614] white powder
[0615] Mass (ESI+): 340 (M+H)+
[0616] 200 MHz 1H NMR (DMSO-d6, d): 1.31 (3H, t, J=7.1 Hz), 3.88
(3H, s), 4.32(2H, q, J=7.1 Hz), 6.74(2H, d, J=8.6 Hz), 6.92(1H, d,
J=8.8 Hz), 7.00(1H, s), 7.09(2H, d, J=8.6 Hz), 7.71(1H, dd,
J=8.8,2.7 Hz), 8.13(1H, d, J=2.7 Hz), 9.82(1H, s). Preparation 22
##STR27##
[0617] (P0022).
[0618] A solution of triphenylphosphine 831 mg in THF 5 ml was
added dropwise to a solution of E0118 521.8 mg and carbon
tetrabromide 1.15 g in THF 5 ml at ambient temperature. The
reaction mixture was stirred at ambient temperature for 1 hour.
Carbon tetrabromide 573 mg and triphenylphosphine 415 mg were added
in one portion and stirred for further 1 hour. Unsoluble matter was
filtered off and washed with THF. The filtrate and combined
washings were concentrated in vacuo. The residue was purified by
silica gel column chromatography eluted with AcOEt/n-hexane=5%,
then 25% to give P0022 647.2 mg as pale yellow wax.
[0619] mp. 60-70.degree. C.
[0620] Mass (API-ES positive): 425, 427 (M+H)+, 447, 449(M+Na)+
[0621] 200 MHz 1H NMR (CDCl.sub.3, d): 3.12-3.19(2H, m),
3.52-3.60(2H, m), 3.82(3H, s), 6.72(1H, s), 6.87(2H, d, J=9.0 Hz),
7.16-7.30(6H, m). Preparation 23 ##STR28##
[0622] (P0023)
[0623] P0023 was prepared in a similar manner to that of P0022.
colorless oil
[0624] Mass (API-ES positive): 448, 450 (M+Na)+
[0625] 400 MHz 1H NMR (DMSO-d6, d) 3.14(2H, t, J=7.2 Hz), 3.74(2H,
t, J=7.2 Hz), 3.88(3H, s), 6.92(1H, d, J=8.8 Hz), 7.20(1H, s),
7.27(2H, d, J=8.4 Hz), 7.32(2H, d, J=8.4 Hz), 7.76(1H, dd,
J=2.7,8.8 Hz), 8.19(1H, d, J=2.7 Hz), Preparation 24 ##STR29##
[0626] (P0024-0) (P0024).
[0627] To a solution of P0001 (20.0 g) and P0024-0 (53.4 g) in DMF
(200 ml) was added portionwise NaH (4.27 g) under ice-cooling. The
reaction mixture was warmed at room temperature and the temperature
was kept under 40.degree. C. After stirring for 5 hours, the
reaction mixture was poured onto ice-cooled dilHCl and extracted
twice with ethylacetate. The combined organic layer was washed with
water (twice) and brine, dried over MgSO4, filtered and evaporated
under reduced pressure. The residue was column chromatographed on
silica gel (500 ml, Hex:EtOAc) to give 12.12 g of P0024 as
crystal.
[0628] mp: 52.6-53.6.degree. C.
EXAMPLE 100
[0629] ##STR30##
[0630] (E0100).
[0631] To a solution of 4-hydroxybenzophenone (4.16 g) and
chloromethyl methyl ether (2.46 g) in N,N-dimethylacetoamide (15
ml) was added portionwise sodium hydride (suspension in mineral oil
(60%), 1.22 g) over 15 minutes at 0.degree. C. The mixture was
stirred for 30 minutes at ambient temperature. To the reaction
mixture was added 2-propanole (0.5 ml), carbon disulfide (2.56 g)
and portionwise sodium hydride (suspension in mineral oil (60%),
2.50 g) over 15 minutes at 25.degree. C. The mixture was stirred at
ambient temperature for 1.5 hours, diluted with toluene (20 ml) and
poured into a mixture of ice and concentrated hydrogen chloride (8
ml) (aqueous layer total 68 ml). The resultant mixture was
extracted with ethyl acetate, washed with brine, dried over
magnesium sulfate, and evaporated. To the mixture of the resultant
residue and sodium hydrogen carbonate (13 g) in ethyl acetate (30
ml) and water (20 ml) was added portionwise the solution of iodine
(3.88 g) and sodium iodide (8.0 g) in water at 0.degree. C. To the
mixture was added portionwise 4-Methoxyphenylhydrazine
hydrochloride (3.80 g) at 0.degree. C. under nitrogen. The mixture
was stirred at ambient temperature for 3 hours and the organic
layer was separated, washed with water and brine, dried over
magnesium sulfate, and evaporated. To the solution of the residue
in ethyl acetate (30 ml) was added methyl iodide (4.0 ml) and
triethylamine (1 ml) at 0.degree. C. The mixture was stirred for 30
minutes at ambient temperature, washed with water and aqueous
potassium carbonate, dried over magnesium sulfate, and evaporated.
The residue was column chromatographed on silica gel (80 g),
eluting with a mixture of ethyl acetate and toluene (1:20) to give
7.56 g of
5-[4-(methoxymethoxy)-phenyl]-1-(4-methoxyphenyl)-3-(methylthio)-1H-pyraz-
ole.
[0632] To the solution of methyl sulfide (7.56 g) in
dichloromethane (30 ml) was added a solution of m-chloroperbenzoic
acid (80%, 4.4 g) in dichloromethane (15 ml) at 0.degree. C., and
the mixture was stirred at 0.degree. C. for 1 hour. The mixture was
washed with aqueous potassium carbonate, dried over magnesium
sulfate, and evaporated. The residue was column chromatographed on
silica gel (80 g), eluting with ethyl acetate to give 5.43 g of
5-[4-(methoxymethoxy)phenyl]-1-(4-methoxyphenyl)-3-(methylsulfinyl)-1H-py-
razole (E0100).
[0633] mp. 136.9-137.3.degree. C.
[0634] Mass; 373(M+1)
[0635] IR(KBr); 1054 cm-1
[0636] NMR(CDCl3,.delta.); 3.00 (H, s), 3.48 (H, s), 3.83 (H, s),
5.17 (H, s), 6.88 (H, d, J=9.0 Hz), 6.92 (H, s), 6.97 (H, d, J=8.8
Hz), 7.14(H, d, J=8.8 Hz), 7.22(H, d, J=9.0 Hz),
EXAMPLE 101
[0637] ##STR31##
[0638] (E0101)
[0639] To the solution of
5-[4-(methoxymethoxy)phenyl]-1-(4-methoxyphenyl)-3-(methylsulfinyl)-1H-py-
razole (7.56 g) in dichloromethane (20 ml) was added
m-chloroperbenzoic acid (60%, 3.76 g) at 0.degree. C., and the
mixture was stirred at 0.degree. C. for 3 hour. The mixture was
washed with aqueous sodium hydrogen carbonate, dried over magnesium
sulfate, and evaporated. The residue was purified by
recrystallization with toluene to give 5.07 g of
5-[4-(methoxymethoxy)phenyl]-1-(4-methoxyphenyl)-3-(methylsulfonyl)-1H-py-
razole(E0101).
[0640] mp. 128.0-128.1.degree. C.
[0641] Mass; 389(M+1)
[0642] IR(KBr); 1300 cm-1
[0643] NMR(CDCl.sub.3,.delta.); 3.29(3H, s), 3.48(3H, s), 3.83(3H,
s), 5.17(2H, s), 6.88(2H, d, J=9.0 Hz), 6.93(1H, s), 6.98(2H, d,
J=8.8 Hz), 7.13(2H, d, J=8.8 Hz), 7.24(2H, d, J=9.0 Hz),
Preparation 25 ##STR32##
[0644] (P0024)
[0645] To the solution of
5-[4-(methoxymethoxy)phenyl]-1-(4-methoxyphenyl)-3-(methylsulfonyl)-1H-py-
razole (0.93 g) in a mixture of tetrahydrofuran (10 ml) and
isopropyl alcohol (5 ml) was added hydrogen chloride aqueous
solution (20%, 8 ml) at ambient temperature. The solution was
stirred for 3 hours, extracted with ethyl acetate, washed with
brine, dried over magnesium sulfate, and evaporated to give 0.82 g
of 4-[1-(4-methoxyphenyl)-3-(methylsulfonyl)-1H-pyrazol-5-yl]phenol
(P0025).
[0646] Mass; 345 (M+1)
[0647] NMR(DMSO-d6,.delta.); 3.32(3H, s), 3.79(3H, s), 6.73(2H, d,
J=8.6 Hz), 7.01(2H, d, J=8.9 Hz), 7.05(1H, s), 7.08(2H, d, J=8.6
Hz), 7.27(2H, d, J=8.9 Hz), 9.84(1H, s), Preparation 26
##STR33##
[0648] (P0026-0) (P0026).
[0649] To a solution of P0026-0 (5.0 g) and imidazole (3.3 g) in
DMF (40 ml) was added portionwise TBDMSCl (6.69 g) at room
temperature. After stirring overnight, water and hexane was added.
The aqueous layer was separated and extracted twice with hexane.
The combined organic layer was washed with water (twice) and brine,
dried over MgSO4, filtered and evaporated under reduced pressure to
give 9.49 g (98.3%) of P0026.
[0650] IR (film): 2952.5, 2935.1, 1467.6, 1255.4, 1124.3, 1097.3,
838.9, 777.2 cm-1. Preparation 27 ##STR34##
[0651] (P0027-0) (P0027).
[0652] To a solution of P0027-0 (10 g) and dimethylcarbonate 5.97 g
in DMF was added sodium methoxide 4.77 g. The mixture was stirred
at ambient temperature for 2 hours. The mixture was poured into
water with 8 ml of conc. HCl, and extracted with AcOEt. The organic
layer was dried over magnesium sulfate, and concentrated in vacuo.
The residue was purified by silica gel column chromatography to
give orange solid. Which was recrystallized from MeOH to give P0027
as white crystals.
[0653] NMR (200 MHz, CDCl.sub.3) 3.75(3H, s), 3.96(2H, s), 5.14(2H,
s), 7.02(2H, d, J=8.9 Hz), 7.34-7.45(5H, m), 7.93(2H, d, J=8.9
Hz)
[0654] Mass ESI 285(M+H)+ (file platform 7366-1). Preparation 28
##STR35##
[0655] (P0028).
[0656] To a solution of triphenylphosphin oxide 294 mg in
1,2-dichloroethane 3 ml was added trifluoromethanesulfonic
anhydride 198 mg dropwise under cooling in an ice bath. The mixture
was stirred at same temperature for 15 minutes, when white
precipitates were came out. To this mixture was added P0027 (300
mg) in 1,2-dichloroethane 2 ml dropwise, followed by addition of
Et3N 214 mg. The mixture was refluxed for 2 hours. The mixture was
allowed to cool to ambient temperature and was washed with H2O,
sat.aq NaCl, dried over MgSO4, concentrated in vacuo. The residue
was purified by silica gel column chromatography eluted with
AcOEt/n-hexane=5%, and 10%. The residue was crystallized from IPE
to give P0028 (166 mg) as a white powder.
[0657] Mass (ESI+): 289 (M+Na)+
[0658] 200 MHz 1H NMR (DMSO-d6, d): 3.76(3H, s), 5.18(2H, s),
7.11(2H, d, J=8.8 Hz), 7.33-7.48(5H, m), 7.62(2H, d, J=8.8 Hz).
Preparation 29 ##STR36##
[0659] (P0029)
[0660] Solid KOH 124 mg was dissolved in EtOH 5 ml at 50.degree. C.
To this solution was added P0028 (196 mg). After stirring at same
temperature for 2 hours, the reaction mixture was allowed to cool
to ambient temperature. The mixture was partitioned between 1M HCl
and CHCl3. The aqueous layer was reextracted with CHCl3. The
combined organic layers were dried over MgSO4, evaporated in vacuo.
The residual crystals were collected and washed with IPE to give
1st crop of P0029 (87 mg) as a white powder. The mother liqour was
concentrated in vacuo and the residual crystals were collected and
washed with n-hexane to give 2nd crop of P0029 (39 mg) as a
slightly reddish powder.
[0661] Mass (ESI-): 251 (M-H)+
[0662] 200 MHz 1H NMR (CDCl.sub.3, d): 5.10(3H, s), 6.97(2H, d,
J=8.9 Hz), 7.34-7.43(5H, m), 7.56(2H, d, J=8.9 Hz). Preparation 30
##STR37##
[0663] (P0030-0) (P0030).
[0664] To a solution of P0030-0 (2 g) and triethylphosphonoacetate
2.32 g in DMF 20 ml was added 60% NaH 490 mg in two portions with
cooling on ice bath. The mixture was stirred at same temperature
for 1 hour, and then poured into ice water containing NH4Cl. The
mixture was stirred for a while, and white precipitates were
collected and washed with water and 10% aqueous IPA to give
P0030.
[0665] 200 MHz 1H NMR (CDCl.sub.3, d): 1.33(3H, t, J=7.2 Hz),
4.25(2H, q, J=7.2 Hz), 5.10(2H, s), 6.31(1H, d, J=16.0 Hz),
6.97(2H, d, J=8.7 Hz), 7.32-7.50(7H, m), 7.64(1H, d, J=16.0 Hz).
Preparation 31 ##STR38##
[0666] (P0031)
[0667] To a solution of P0030 (2.79 g) in CH2Cl2 28 ml was added
bromine 1.66 g dropwise under ice bath cooling. The mixture was
stirred at same temperature for 30 minutes. The reaction mixture
was poured into 5% aqueous solution of Na2S2O3, and partitioned.
The organic layer was washed with sat.aqNaHCO3, sat.aqNaCl, dried
over MgSO4, concentrated in vacuo. The residual crystals were
collected and washed with n-hexane to give P0031 (3.07 g) as a pale
yellow powder.
[0668] 200 MHz 1H NMR (CDCl.sub.3, d): 1.38(3H, t, J=7.2 Hz),
4.35(2H, q, J=7.2 Hz), 4.81(1H, d, J=11.8 Hz), 5.07(2H, s),
5.35(1H, d, J=11.8 Hz), 6.98 (2H, d, J=8.7 Hz), 7.34 (2H, d, J=8.7
Hz), 7.32-7.45(5H, m). Preparation 32 ##STR39##
[0669] (P0032)
[0670] 85% solid KOH 1.73 g was dissolved in 95% aqueous EtOH 20 ml
at 50.degree. C. P0031 (3.05 g) was added in one portion and the
mixture was refluxed for 9 hours. To this mixture was added a
solution of 85% KOH 0.32 g dissolved in 95% aqueous EtOH 10 ml and
refluxed for 5 hours. The mixture was cooled in an ice bath,
precipitates were collected and washed with EtOH. The crystals were
suspended in AcOEt and H2O, cooled in an ice bath, acidified by 3M
HCl and 1M HCl. The mixture was partitioned and the organic layer
was washed with H2O, dried over MgSO4, concentrated in vacuo. The
residual solid was collected and washed with IPE-n-hexane to give
P0032 (0.67 g) as a white powder.
[0671] 200 MHz 1H NMR (CDCl.sub.3, d): 5.10(3H, s), 6.97(2H, d,
J=8.9 Hz), 7.34-7.43(5H, m), 7.56(2H, d, J=8.9 Hz)
EXAMPLE 102
[0672] ##STR40##
[0673] (E0102-0) (E0102).
[0674] To a solution of P0032(99.9 mg) and HOBT 64.2 mg in
N-methylpyrrolidone 1 ml was added WSCD.HCl 91.1 mg and the mixture
was stirred at ambient temperature for 20 minutes. In another
flask, diisopropylethylamine 76.8 mg was added to a suspension of
E0102-0 (83.0 mg) in N-methylpyrrolidone 1 ml and stirred at
ambient temperature until all E0102-0 was dissolved. The solution
of E0102-0 was added to the reaction flask and the mixture was
stirred at ambient temperature for 1 hour. The mixture was
partitioned between AcOEt and H2O, washed with sat.aqNaHCO3,
sat.aqNaCl, dried over MgSO4, and concentrated in vacuo. The
residue was dissolved in CH2Cl2 3 ml, and stirred at ambient
temperature for 24 hours. The mixture was concentrated in vacuo.
The residual crystals were suspended in hot AcOEt, cooled with
stirring, collected and washed with AcOEt to give E0102 (90.9 mg)
as a white powder.
[0675] Mass (ESI+): 373 (M+H)+
[0676] 200 MHz 1H NMR (DMSO-d6, d): 3.75(3H, s), 5.08(2H, s),
5.81(1H, s), 6.90(2H, d, J=9.0 Hz), 6.96(2H, d, J=9.0 Hz), 7.10(2H,
d, J=9.0 Hz), 7.12(2H, d, J=9.0 Hz), 7.32-7.47(5H, m), 10.00(1H,
s)
EXAMPLE 103
[0677] ##STR41##
[0678] (E0103)
[0679] To a suspension of E0102 (20.9 mg) and K2CO3 23.3 mg in DMSO
0.5 ml was added dimethylsulfate 10.6 mg and the mixture was
stirred at ambient temperature for 1 hour. The mixture was
partitioned between AcOEt and H2O, and the organic layer was washed
with sat.aqNaCl, dried over MgSO4, concentrated in vacuo. The
residue was purified by preparative thin layer chromatography
developed with AcOEt/n-hexane=25%. The obtained crystals were
crystallized from IPE to give E0103 (12.0 mg) as white
crystals.
[0680] Mass (ESI+): 387 (M+H)+
[0681] 200 MHz 1H NMR (DMSO-d6, d): 3.76(3H, s), 3.83(3H, s),
5.08(2H, s), 6.04(1H, s), 6.92(2H, d, J=9.0 Hz), 6.97(2H, d, J=9.0
Hz), 7.11-7.17(4H, m), 7.30-7.50(5H, m)
[0682] 200 MHz 1H NMR (CDCl.sub.3, d): 3.80(3H, s), 3.97(3H, s),
5.04(2H, s), 5.88(1H, s), 6.82(2H, d, J=9.0 Hz), 6.88(2H, d, J=8.9
Hz), 7.11-7.21(4H, m), 7.34-7.43(5H, m)
EXAMPLE 104
[0683] ##STR42##
[0684] (E0104)
[0685] To suspension of E0102 (818 mg) and K2CO3 911 mg in DMF 6 ml
was added dimethylcarbonate 0.56 ml. The mixture was stirred at
120.degree. C. for 2 hours. Additional dimethylcarbonate 1 ml was
added and stirred at 120.degree. C. for 8 hours. The mixture was
partitioned between AcOEt and H2O, and the aq layer was reextracted
with AcOEt. The combined organic layers were washed with
sat.aqNaCl, dried over MgSO4, concentrated in vacuo. The residue
was purified by silica gel column chromatography eluted with
AcOEt/n-hexane=30%. The residue was crystallized from AcOEt 2.5 ml
and n-hexane 5 ml to give E0104 (583 mg) as white crystals.
[0686] 200 MHz 1H NMR (DMSO-d6, d): 3.76(3H, s), 3.83(3H, s),
5.08(2H, s), 6.04(1H, s), 6.92(2H, d, J=9.0 Hz), 6.97(2H, d, J=9.0
Hz), 7.11-7.17(4H, m), 7.30-7.50(5H, m)
[0687] 200 MHz 1H NMR (CDCl.sub.3, d): 3.80(3H, s), 3.97(3H, s),
5.04(2H, s), 5.88(1H, s), 6.82(2H, d, J=9.0 Hz), 6.88(2H, d, J=8.9
Hz), 7.11-7.21(4H, m), 7.34-7.43(5H, m). Preparation 33
##STR43##
[0688] (P0033).
[0689] A mixture of 10% Pd--C 50% wet 50 mg and E0104 (261 mg) in
AcOEt 2 ml and MeOH 2 ml was hydrogenated under H.sub.2 1 atm at
ambient temperature for 1 day. The additional 10% Pd--C 50% wet 50
mg was added and the mixture was hydrogenated under H2 3.5 atm at
ambient temperature for 3 hours. The catalyst was filtered off and
the filtrate and combined washings were concentrated in vacuo. The
residue was dissolved in AcOEt, dried over MgSO4, and concentrated
in vacuo. The residue was crystallized from AcOEt-n-hexane to give
P0033 (146 mg) as a white powder.
[0690] Mass (ESI+): 297 (M+H)+
[0691] 200 MHz 1H NMR (DMSO-d6, d): 3.75(3H, s), 3.83(3H, s),
5.98(1H, s), 6.70(2H, d, J=8.6 Hz), 6.91(2H, d, J=8.9 Hz), 7.01(2H,
d, J=8.6 Hz), 7.12(2H, d, J=8.9 Hz), 9.69(1H, s). Preparation 34
##STR44##
[0692] (P0034).
[0693] To a solution of ammonium formate 455 mg in H2O 1 ml was
added EtOH 6 ml, E0104 (558 mg), THF 1 ml, and 10% Pd--C 50% wet 60
mg successively. The mixture was refluxed for 1 hour. The catalyst
was removed by filtration. The filtrate and combined washings were
concentrated in vacuo. The residue was partitioned between AcOEt
and H2O, and the organic layer was washed with sat.aqNaCl, dried
over MgSO4, concentrated in vacuo. The residual crystals were
recrystallized from AcOEt 3 ml and n-hexane 3 ml to give P0034 (335
mg) as white crystals.
[0694] Mass (ESI+): 297 (M+H)+
EXAMPLE 105
[0695] ##STR45##
[0696] (E0105)
[0697] A mixture of P0003 (2.9 g) and 4-methoxyphenylhydrazine
(1.68 g) in acetic acid (30 ml) was stirred at room temperature for
15 hours. After addition of water, the mixture was extracted twice
with toluene. The combined organic layer was washed with water
(twice), sat.NaHCO3, water and brine, dried over MgSO4, filtered
and evaporated under reduced pressure. The residue was column
chromatographed on silica gel (Hex/EtOAc=8:1-4:1) to give 2.2 g
(57%) of E0105 as an oil.
[0698] IR (film): 1737.6, 1511.9, 1240.0, 1159.0, 1130.1 cm-1.
EXAMPLE 106
[0699] ##STR46##
[0700] (E0106)
[0701] E0106 was prepared from P0004 in a similar manner to that of
E0105.
[0702] Mass (ESI+): 420 (M+H)+
[0703] 200 MHz 1H NMR (DMSO-d6, d): 1.79-1.94(2H, m), 1.98(3H, s)
2.60-2.68(2H, m), 3.88(3H, s), 3.98(2H, t, J=6.5 Hz), 6.92(1H, d,
J=8.9 Hz), 7.18(1H, s), 7.24(4H, s), 7.75(1H, dd, J=2.7,8.9 Hz),
8.48(1H, d, J=2.7 Hz)
EXAMPLE 107
[0704] ##STR47##
[0705] (E0107)
[0706] E0107 (175.7 mg) was prepared from P0007 (590 mg) and
4-methoxyphenylhydrazine hydrochloride (332 mg) in a similar manner
to that of E0105.
[0707] Mass (ESI+): 455 (M+H)+
[0708] 200 MHz 1H NMR (DMSO-d6, d): 1.96(3H, s), 2.88(2H, t, J=6.8
Hz), 3.79(3H, s), 4.20(2H, t, J=6.8 Hz), 6.99(2H, d, J=8.9 Hz),
7.15(1H, s), 7.17-7.30(6H, m)
EXAMPLE 108
[0709] ##STR48##
[0710] (E0108)
[0711] E0108 was prepared from P0007 in a similar manner to that of
E0105.
[0712] Mass (API-ES positive): 456 (M+H)+, 478 (M+Na)+
[0713] 200 MHz 1H NMR (DMSO-d6, d) 1.96(3H, s), 2.89(2H, t, J=6.8
Hz), 3.88(3H, s), 4.21(2H, t, J=6.8 Hz), 6.92(1H, d, J=8.8 Hz),
7.15-7.35(4H, m), 7.21(1H, s), 7.76(1H, dd, J=2.7,8.8 Hz), 8.17(1H,
d, J=2.7 Hz)
EXAMPLE 109
[0714] ##STR49##
[0715] (E0109)
[0716] E0109 was prepared in a similar manner to that of E0105.
[0717] Mass (ESI+) 409(M+H)+, 431(M+Na)+
[0718] NMR: SE20.059 200 MHz 1H NMR (DMSO-d6, d): 1.31(3H, t, J=7.1
Hz), 1.96(3H, s), 2.87(2H, t, J=6.8 Hz), 3.79(3H, s), 420(2H, t,
J=6.8 Hz), 4.32(2H, q, J=7.1 Hz), 6.99(2H, d, J=9.0 Hz), 7.08(1H,
s), 7.16-7.28(6H, m)
EXAMPLE 110
[0719] ##STR50##
[0720] (E0110)
[0721] E0110 was prepared in a similar manner to that of E0105.
[0722] Mass (ESI+): 410 (M+H)+
[0723] 200 MHz 1H NMR (DMSO-d6, d): 1.32 (3H, t, J=7.1 Hz), 1.96
(3H, s), 2.89(2H, t, J=6.8 Hz), 3.88(3H, s), 4.21(2H, t, J=6.8 Hz),
4.33(2H, q, J=7.1 Hz), 6.92(1H, d, J=8.8 Hz), 7.12(1H, s),
7.19-7.32(4H, m), 7.73(1H, dd, J=2.7,8.8 Hz), 8.14(1H, d, J=2.7
Hz)
EXAMPLE 111
[0724] ##STR51##
[0725] (E0111)
[0726] E0111 was prepared in a similar manner to that of E0105.
[0727] Mass (API-ES positive) 406(M+H)+, 428(M+Na)+
[0728] 200 MHz 1H NMR (DMSO-d6, d): 1.96(3H, s), 2.89(2H, t, J=6.7
Hz), 3.88(3H, s), 4.21(2H, t, J=6.7 Hz), 6.92(1H, d, J=8.8 Hz),
7.20(1H, s), 7.24(2H, d, J=8.7 Hz), 7.30(2H, d, J=8.7 Hz), 7.76(1H,
dd, J=2.7, 8.8 Hz), 8.18(1H, d, J=27 Hz)
EXAMPLE 112
[0729] ##STR52##
[0730] (E0112)
[0731] E0112 was obtained according to a similar manner to that of
E0105.
EXAMPLE 113
[0732] ##STR53##
[0733] (E0113)
[0734] E0113 was obtained according to a similar manner to that of
E0105.
EXAMPLE 114
[0735] ##STR54##
[0736] (E0114)
[0737] E0114 was obtained according to a similar manner to that of
E0105.
EXAMPLE 115
[0738] ##STR55##
[0739] (E0115)
[0740] E0115 was obtained according to a similar manner to that of
E0105.
EXAMPLE 116
[0741] ##STR56##
[0742] (E0116)
[0743] E0116 was obtained according to a similar manner to that of
E0105.
EXAMPLE 117
[0744] ##STR57##
[0745] (E0117)
[0746] E0117 was obtained according to a similar manner to that of
E0105.
EXAMPLE 118
[0747] ##STR58##
[0748] (E0118).
[0749] A mixture of E0105 (2.0 g) and 1N NaOH (15 ml) in THF (40
ml) was stirred at room temperature for 5 hours. After the reaction
was completed, the mixture was neutralized with 1N HCl (15 ml),
extracted twice with ethylacetate, washed with 1N HCl, sat.NaHCO3,
and brine, dried over NA2SO4, filtered and evaporated under reduced
pressure. The residue was column chromatographed on silica gel
(H/EA 2:1-1:1) to give 1.14 g (64%) of E0118 as a crystal.
[0750] mp: 103-104.degree. C.
[0751] IR (film): 3396.0, 1513.9, 1467.6, 1238.1, 1160.9, 1132.0
cm-1.
EXAMPLE 119
[0752] ##STR59##
[0753] (E0119)
[0754] E0119 was prepared from E0217 in a similar manner to that of
E0118.
[0755] IR (neat): 3359, 3332, 3325, 1658, 1651, 1624, 1614, 1545,
1533, 1500 cm-1
[0756] Mass (ESI+): 421 (M+H)+
[0757] 200 MHz 1H NMR (DMSO-d6, d): 2.71-2.79(2H, m), 3.28-3.39(2H,
m), 3.76(2H, brs), 3.88(3H, s), 5.47(1H, br), 6.92(1H, d, J=8.9
Hz), 7.18(1H, s), 7.24(4H, s), 7.74(1H, dd, J=2.7, 8.9 Hz) 7.80(1H,
t, J=5.9 Hz), 8.19(1H, d, J=2.7 Hz)
EXAMPLE 120
[0758] ##STR60##
[0759] (E0120)
[0760] E0120 was prepared from E0002 in a similar manner to that of
E0118.
[0761] IR (neat): 3433, 3423, 3398, 3367, 2945, 1612, 1500 cm-1
[0762] Mass (ESI+): 378 (M+H)+
[0763] 200 MHz 1H NMR (DMSO-d6, d): 1.62-1.77(2H, m), 2.57-3.65(2H,
m), 3.34-3.44(2H, m), 3.88(3H, s), 4.48(1H, t, J=5.1 Hz), 6.92(1H,
d, J=8.9 Hz), 7.17(1H, s), 7.23(4H, s), 7.76(1H, dd, J=8.9,2.8 Hz),
8.18(1H, d, J=2.8 Hz)
EXAMPLE 121
[0764] ##STR61##
[0765] (E0121)
[0766] E0121 was prepared from E0268 in a similar manner to that of
E0118.
[0767] white powder
[0768] mp. 91-92.degree. C.
[0769] IR (KBr): 3491, 3471, 3437, 2941, 2239, 1610, 1508
cm.sup.-1
[0770] Mass (ESI+): 336 (M+H)+
[0771] 200 MHz 1H NMR (DMSO-d6, d): 3.65-3.73(2H, m), 3.79(3H, s),
3.95-4.05(2H, m), 4.87(1H, t, J=5.4 Hz), 6.93(2H, d, J=8.8 Hz),
7.00(2H, d, J=9.0 Hz), 7.16(2H, d, J=8.8 Hz), 7.28(2H, d, J=9.0
Hz), 7.32(1H, s)
EXAMPLE 122
[0772] ##STR62##
[0773] (E0122)
[0774] E0122 was prepared from E0353 in a similar manner to that of
E0118.
[0775] white powder
[0776] mp. 158-159.degree. C.
[0777] IR (KBr): 3399, 2955, 1707, 1693, 1647, 1614, 1566, 1547,
1529, 1512 cm-1
[0778] Mass (ESI+): 393 (M+H)+
[0779] 200 MHz 1H NMR (DMSO-d6, d): 2.44(3H, s), 3.66-3.74(2H, m),
3.80(3H, s), 3.96-4.02(2H, m), 4.88(1H, t, J=5.4 Hz), 6.94(2H, d,
J=8.7 Hz), 7.02(2H, d, J=8.9 Hz), 7.22(2H, d, J=8.7 Hz), 7.26(1H,
s), 7.31(2H, d, J=8.9 Hz)
EXAMPLE 123
[0780] ##STR63##
[0781] (E0123)
[0782] E0123 was prepared from E0358 in a similar manner to that of
E0118.
[0783] white powder
[0784] mp. 105-107.degree. C.
[0785] IR (KBr): 3529, 3437, 2956, 1610, 1570, 1547, 1529 cm-1
[0786] Mass (ESI+): 337 (M+H)+
[0787] 200 MHz 1H NMR (DMSO-d6, d): 3.65-3.73(2H, m), 3.88(3H, s),
3.96-4.02(2H, m), 4.87(1H, t, J=5.3 Hz), 6.93(1H, d, J=8.8 Hz),
6.96(2H, d, J=8.7 Hz), 7.21(2H, d, J=8.7 Hz), 7.35(1H, s), 7.73(1H,
dd, J=2.7,8.8 Hz), 8.20(1H, d, J=2.7 Hz)
EXAMPLE 124
[0788] ##STR64##
[0789] (E0124)
[0790] E0124 was prepared from E0107 in a similar manner to that of
E0118.
[0791] white powder
[0792] mp. 97-98.degree. C.
[0793] IR (KBr): 3427, 2960, 1608, 1516 cm-1
[0794] Mass (ESI+): 413 (M+H)+
[0795] 200 MHz 1H NMR (DMSO-d6, d): 2.71(2H, t, J=6.9 Hz),
3.54-3.65(2H, m), 3.79(3H, s), 4.64(1H, t, J=5.1 Hz), 7.00(2H, d,
J=9.0 Hz), 7.12(1H, s), 7.15-7.33(4H, m), 7.29(2H, d, J=9.0 Hz)
EXAMPLE 125
[0796] ##STR65##
[0797] (E0125)
[0798] E0125 was prepared in a similar manner to that of E0118.
[0799] IR (neat): 3435, 3425, 3406, 3398, 3367, 1691, 1658, 1647,
1614, 1547, 1512 cm-1
[0800] Mass (ESI+): 320 (M+H)+, 361(M+CH3CN+H)+
[0801] 200 MHz 1H NMR (DMSO-d6, d): 2.71(2H, t, J=6.8 Hz),
3.54-3.64(2H, m), 3.79(3H, s), 4.64(1H, t, J=5.2 Hz), 7.00(2H, d,
J=8.9 Hz), 7.15(2H, d, J=8.3 Hz), 7.23(2H, d, J=8.3 Hz), 7.29(2H,
d, J=8.9 Hz), 7.34(1H, s)
EXAMPLE 126
[0802] ##STR66##
[0803] (E0126)
[0804] is E0126 was prepared from E0111 in a similar manner to that
of E0118.
[0805] white powder
[0806] mp 89-92.degree. C.
[0807] IR (KBr): 3481, 2947, 1608, 1496 cm-1
[0808] Mass (ESI+): 364 (M+H)+
[0809] 200 MHz 1H NMR (DMSO-d6, d): 2.72(2H, t, J=6.8 Hz),
3.55-3.65(2H, m), 3.88(3H, s), 4.65(1H, t, J=5.2 Hz), 6.92(1H, d,
J=8.8 Hz), 7.16(1H, s), 7.19-7.28(4H, m), 7.77(1H, dd, J=2.6,8.8
Hz), 8.19(1H, d, J=2.6 Hz)
EXAMPLE 127
[0810] ##STR67##
[0811] (E0127)
[0812] E0127 was prepared from E0108 in a similar manner to that of
E0118.
[0813] IR (neat): 3400, 2951, 1610, 1502 cm-1
[0814] Mass (API-ES positive): 414 (M+H).sup.+, 436 (M+Na)+
[0815] 200 MHz 1H NMR (DMSO-d6, d): 2.72(2H, t, J=6.9 Hz),
3.51-3.65(2H, m), 3.88(3H, s), 4.65(1H, t, J=5.1 Hz), 6.93(1H, d,
J=8.8 Hz), 7.15-7.35(4H, m), 7.18(1H, s), 7.77(1H, dd, J=2.7,8.8
Hz), 8.18(1H, d, J=2.7 Hz)
EXAMPLE 128
[0816] ##STR68##
[0817] (E0128)
[0818] E0128 104.4 mg was prepared in a similar manner to that of
E0118.
[0819] IR (neat): 3433, 3423, 3398, 2947, 2873, 2243, 1608 cm-1
[0820] Mass (ESI+): 321 (M+H)+
[0821] 200 MHz 1H NMR (DMSO-d6, d): 2.72(2H, t, J=6.8 Hz),
3.55-3.65(2H, m), 3.88(3H, s), 4.65(1H, t, J=5.1 Hz), 6.93(1H, d,
J=8.8 Hz), 7.19(2H, d, J=8.4 Hz), 7.26(2H, d, J=8.4 Hz), 7.38(1H,
s), 7.76(1H, dd, J=2.7,8.8 Hz), 8.21(1H, d, J=2.7 Hz)
EXAMPLE 129
[0822] ##STR69##
[0823] (E0129)
[0824] E0129 was obtained according to a similar manner to that of
E0118.
EXAMPLE 130
[0825] ##STR70##
[0826] (E0130)
[0827] E0130 was obtained according to a similar manner to that of
E0118.
EXAMPLE 131
[0828] ##STR71##
[0829] (E0131)
[0830] E0131 was obtained according to a similar manner to that of
E0118.
EXAMPLE 132
[0831] ##STR72##
[0832] (E0132)
[0833] E0132 was obtained according to a similar manner to that of
E0118.
[0834] IR (film): 3392.2, 1494.6, 1236.2, 1160.9, 1133.9, 1095.4,
975.8, 833.1 cm-1.
EXAMPLE 133
[0835] ##STR73##
[0836] (E0133)
[0837] E0133 was obtained according to a similar manner to that of
E0118.
[0838] IR (film): 3374.8, 1511.9, 1471.4, 1274.7, 1232.3, 1160.9,
1133.9, 977.7, 842.7, 811.9 cm-1.
[0839] mp: 82-83.degree. C.
EXAMPLE 134
[0840] ##STR74##
[0841] (E0134)
[0842] E0134 was obtained according to a similar manner to that of
E0118.
[0843] IR (film): 3386.4, 1511.9, 1471.4, 1236.2, 1159.0, 1132.0,
1047.2, 975.8, 817.7 cm-1.
EXAMPLE 135
[0844] ##STR75##
[0845] (E0135)
[0846] E0135 was obtained according to a similar manner to that of
E0118.
[0847] IR (film): 3399.9, 1610.3, 1513.9, 1459.9, 1251.6, 1172.5,
1083.8, 1033.7, 836.9, 802.2 cm-1. (FS7081)
EXAMPLE 136
[0848] ##STR76##
[0849] (E0136)
[0850] P0018 (277 mg) and 4-methoxyphenylhydrazine hydrochloride
(209 mg) in EtOH:AcOH=20:1 6 ml was refluxed for 2 hours. The
mixture was partitioned between AcOEt and H2O. The organic layer
was washed successively with 1M HCl, saturated aqueous sodium
bicarbonate solution, and saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo.
The residue was purified by silica gel column chromatography eluted
with AcOEt/n-hexane=30%, 40%, 50%. The pure fraction was collected
and concentrated in vacuo. The residue was crystallized from
AcOEt/n-hexane to give E0136 (95.6 mg) as a white powder.
[0851] mp. 111-112.degree. C.
[0852] IR (KBr): 3325, 2931, 1707, 1693, 1685, 1658, 1647, 1564,
1549, 1514 cm-1
[0853] Mass (ESI+): 335 (M+H)+
[0854] 200 MHz 1H NMR (DMSO-d6, d): 0.69-0.77(2H, m), 0.86-0.96(2H,
m), 1.93(1H, m), 2.69(2H, t, J=6.9 Hz), 3.53-3.64(2H, m), 3.76(3H,
s), 4.64(1H, t, J=5.2 Hz), 6.28(1H, s), 6.92(2H, d, J=9.0 Hz),
7.05-7.19(6H, m)
EXAMPLE 137
[0855] ##STR77##
[0856] (E0137)
[0857] E0137 was prepared from P0018 498.5 mg in a similar manner
to that of E0136. Preparation 34 ##STR78##
[0858] (P0034)
[0859] P0034 was prepared in a similar manner to that of E0137.
[0860] white powder
[0861] Mass (ESI+): 306 (M+H)+
[0862] 200 MHz 1H NMR (DMSO-d6, d): 0.67-0.76(2H, m), 0.84-0.94(2H,
m), 1.91(1H, m), 3.76(3H, s), 6.18(1H, s), 6.68(2H, d, J=8.7 Hz),
6.91(2H, d, J=9.0 Hz), 6.98(2H, d, J=8.7 Hz), 7.12(2H, d, J=9.0
Hz), 9.63(1H, s)
EXAMPLE 138
[0863] ##STR79##
[0864] (E0138).
[0865] To a solution of E0118 (11.0 g) and Et3N (0.6 ml) in CH2Cl2
(20 ml) was added dropwise methanesulfonyl chloride (0.26 ml) under
ice-cooling. After stirring for 1 hour, the reaction mixture was
quenched with water and extracted with CHCl3. The organic layer was
washed with water, dried over Na2SO4, filtered and evaporated to
give 1.2 g (99%) of crude E0138 as an off-white solid.
[0866] IR (film): 1513.9, 1469.5, 1351.9, 1240.0, 1166.7, 1130.1,
971.9, 835.0, 804.2 cm-1.
EXAMPLE 139
[0867] ##STR80##
[0868] (E0139)
[0869] E0139 was prepared in a similar manner to that of
E00138.
[0870] Mass (ESI+): 459 (M+H)+
[0871] 200 MHz 1H NMR (DMSO-d6, d) 1.09-1.23(3H, m), 2.98, 3.29(3H,
s), 3.01(2H, t, J=6.6 Hz), 3.09(3H, s), 3.43-3.77(2H, m), 3.87(3H,
s), 4.42(2H, t, J=6.6 Hz), 6.88-6.92(2H, m), 7.25(2H, d, J=8.3 Hz),
7.33(2H, d, J=8.3 Hz), 7.65-7.73(1H, m), 8.15(1H, d, J=2.6 Hz)
EXAMPLE 140
[0872] ##STR81##
[0873] (E0140)
[0874] E0140 was prepared in a similar manner to that of E0138.
[0875] Mass (APCI+): 458 (M+H)+
[0876] 200 MHz 1H NMR (DMSO-d6, d): 1.05-1.25(3H, m), 2.96-3.03(2H,
m), 2.98, 3.29(3H, s), 3.08(3H, s), 3.40-3.85(2H, m), 3.78(3H, s),
4.42(2H, t, J=6.6 Hz), 6.86, 6.88(1H, s), 6.98(2H, d, J=8.9 Hz),
7.18-7.32(6H, m)
EXAMPLE 141
[0877] ##STR82##
[0878] (E0141)
[0879] E0141 was prepared in a similar manner to that of E0138.
[0880] Mass (ESI+): 456 (M+H)+
[0881] 200 MHz 1H NMR (DMSO-d6, d): 1.89-2.04 (2H, m), 2.52-2.73
(2H, m), 3.16(3H, s), 3.88(3H, s), 4.19(2H, t, J=6.3 Hz), 6.92(1H,
d, J=8.9 Hz), 7.18(1H, s), 7.21-7.31(4H, m), 7.76(1H, dd, J=2.6,8.9
Hz), 8.19(1H, d, J=2.6 Hz)
EXAMPLE 142
[0882] ##STR83##
[0883] (E0142)
[0884] E0142 was obtained according to a similar manner to that of
E0138.
EXAMPLE 143
[0885] ##STR84##
[0886] (E0143)
[0887] E0143 was obtained according to a similar manner to that of
E0138.
EXAMPLE 144
[0888] ##STR85##
[0889] (E0144)
[0890] This compound was obtained according to a similar manner to
that of E0138.
EXAMPLE 145
[0891] ##STR86##
[0892] (E0145)
[0893] This compound was obtained according to a similar manner to
that of E0138.
EXAMPLE 146
[0894] ##STR87##
[0895] (E0146)
[0896] This compound was obtained according to a similar manner to
that of E0138.
EXAMPLE 147
[0897] ##STR88##
[0898] (E0147)
[0899] This compound was obtained according to a similar manner to
that of E0138.
EXAMPLE 148
[0900] ##STR89##
[0901] (E0148).
[0902] A mixture of E0138 (900 mg) and potassium phthalimide (454
mg) in DMF (18 ml) was stirred at 60.degree. C. for 3.0 hours.
After addition of water, the reaction mixture was extracted with
EtOAc and washed twice with water and with brine. The organic layer
was dried over Na2SO4, filtered and evaporated under reduced
pressure. The residue was column chromatographed on silica gel (50
ml) to give 930 mg (93%) of E0148 as a powder.
[0903] IR (film): 1772.3, 1712.5, 1240.0, 1160.9, 1130.1 cm-1.
EXAMPLE 149
[0904] ##STR90##
[0905] (E0149)
[0906] E0149 was prepared from E0139 in a similar manner to that of
E0148.
[0907] amorphous powder
[0908] Mass (ESI+): 510 (M+H)+
[0909] 200 MHz 1H NMR (DMSO-d6, d): 1.08-1.22(3H, m), 2.89-2.98(2H,
m), 2.98, 3.27(3H, s), 3.48, 3.70(2H, q, J=7.1,6.9 Hz), 3.82(2H, t,
J=7.3 Hz), 3.88(3H, s), 6.83-6.88(2H, m), 7.23(2H, d, J=8.7 Hz),
7.18(2H, d, J=8.7 Hz), 7.53-7.63(1H, m), 7.79-7.89(4H, m), 8.15(1H,
d, J=2.6 Hz)
EXAMPLE 150
[0910] ##STR91##
[0911] (E0150)
[0912] E0150 was prepared from E0140 in a similar manner to that of
E0148.
[0913] amorphous powder
[0914] Mass (ESI+): 509 (M+H)+
[0915] 200 MHz 1H NMR (DMSO-d6, d): 1.12, 1.18(3H, t, J=7.0,7.1
Hz), 2.92(2H, t, J=7.0 Hz), 2.97, 3.28(3H, s), 3.47, 3.71(2H, q,
J=7.1,7.0 Hz), 3.78(3H, s), 3.81(2H, t, J=7.0 Hz), 6.82, 6.84(1H,
s), 6.94(2H, d, J=9.0 Hz), 7.11-7.20(6H, m), 7.79-7.89(4H, m)
EXAMPLE 151
[0916] ##STR92##
[0917] (E0151)
[0918] E0151 was prepared from E0038 in a similar manner to that of
E0148.
[0919] Mass (ESI+): 507 (M+H)+
[0920] 200 MHz 1H NMR (DMSO-d6, d): 1.82-1.97 (2H, m), 2.59-2.67
(2H, m), 3.60(2H, t, J=7.0 Hz), 3.88(3H, s), 6.91(1H, d, J=8.8 Hz),
7.14(1H, s), 7.20(2H, d, J=8.5 Hz), 7.26(2H, d, J=8.5 Hz), 7.73(1H,
dd, J=8.8,2.8 Hz), 7.78-7.89(4H, m), 8.17 (1H, d, J=2.8 Hz)
EXAMPLE 152
[0921] ##STR93##
[0922] (E0152)
[0923] This compound was obtained according to a similar manner to
that of E0148.
EXAMPLE 153
[0924] ##STR94##
[0925] (E0153)
[0926] This compound was obtained according to a similar manner to
that of E0148.
EXAMPLE 154
[0927] ##STR95##
[0928] (E0154)
[0929] This compound was obtained according to a similar manner to
that of E0148.
EXAMPLE 155
[0930] ##STR96##
[0931] (E0155).
[0932] This compound was obtained according to a similar manner to
that of E0148.
EXAMPLE 156
[0933] ##STR97##
[0934] (E0156)
[0935] This compound was obtained according to a similar manner to
that of E0148.
EXAMPLE 157
[0936] ##STR98##
[0937] (E0157)
[0938] This compound was obtained according to a similar manner to
that of E0148.
EXAMPLE 158
[0939] ##STR99##
[0940] (E0158).
[0941] To a solution of E0148 (800 mg) in CH3CN (10 ml) was added
hydrazine hydroxide (87 .mu.l) at room temperature. After stirring
for 1 hour, the reaction mixture was filtered and evaporated. After
addition of dichloromethane, the mixture was stirred for an hour,
filtered and evaporated. The residue was treated with 4NHCl/EtOAc
to give 518 mg (80%) of E0158.
[0942] IR (Film); 3403.74, 1610.27, 1511.92, 1467.56, 1238.08,
1160.94, 1130.08, 1027.87, 975.80, 836.96, 806.10 cm-1.
EXAMPLE 159
[0943] ##STR100##
[0944] (E0159)
[0945] This compound was obtained according to a similar manner to
that of E0158.
EXAMPLE 160
[0946] ##STR101##
[0947] (E0160)
[0948] This compound was obtained according to a similar manner to
that of E0158.
EXAMPLE 161
[0949] ##STR102##
[0950] (E0161)
[0951] This compound was obtained according to a similar manner to
that of E00158.
[0952] IR (film): 3428.8, 1511.9, 1467.6, 1238.1, 1160.9, 1132.0
cm-1.
EXAMPLE 162
[0953] ##STR103##
[0954] (E0162)
[0955] This compound was obtained according to a similar manner to
that of E0158.
[0956] IR (film): 3371.0, 1511.9, 1471.4, 1272.8, 1230.4, 1160.9,
1133.9, 975.8, 842.7, 810.0 cm-1.
EXAMPLE 163
[0957] ##STR104##
[0958] (E0163)
[0959] This compound was obtained according to a similar manner to
that of E0158.
[0960] mp: 163.1-165.1.degree. C.
[0961] IR (film): 2973.7, 1511.9, 1471.4, 1236.2, 1159.0, 1133.9
cm-1.
EXAMPLE 164
[0962] ##STR105##
[0963] (E0164)
[0964] This compound was obtained according to a similar manner to
that of E0158.
[0965] IR(film): 3369.0, 1604.5, 1513.9, 1459.9, 1251.6, 1172.5,
1083.8, 1029.8, 837.0, 800.3 cm-1.
EXAMPLE 165
[0966] ##STR106##
[0967] (E0165).
[0968] To a solution of E0395 (1.08 g) in acetonitril (15 ml) was
added hydrazine monohydrate (0.53 ml). After stirring at 60.degree.
C. overnight, the mixture was filtered. And the filtrate was
evaporated to give E0165 as an orange oil (814 mg, 102%).
[0969] NMR(CDCl3), 2.76(2H, t, J=6.5 Hz), 2.98(2H, t, J=6.5 Hz),
3.94 (3H, s), 6.73(1H, s), 6.76(1H, d, J=8.9 Hz), 7.22-7.12(4H, m),
7.57(1H, dd, J=8.9, 2.7 Hz), 8.09(1H, d, J=2.7 Hz).
[0970] MS(ESI+); 363.3(MH+).
EXAMPLE 166
[0971] ##STR107##
[0972] (E0166)
[0973] E0166 was prepared from E0046 in a similar manner to that of
E0165.
[0974] Mass (ESI+): 380 (M+H)+
[0975] 200 MHz 1H NMR (DMSO-d6, d): 1.91-1.23(3H, m), 2.59-2.79(4H,
m), 2.98, 3.28(3H, s), 3.48, 3.71(2H, q, J=7.2,7.0 Hz), 3.87(3H,
s), 6.86-6.93(2H, m), 7.16-7.26(4H, m), 7.64-7.73(1H, m), 8.15(1H,
d, J=2.5 Hz)
EXAMPLE 167
[0976] ##STR108##
[0977] (E0167)
[0978] E0167 was prepared from E0150 in a similar manner to that of
E0165.
[0979] Mass (ESI+): 379 (M+H)+
[0980] 200 MHz 1H NMR (DMSO-d6, d): 1.08-1.22(3H, m), 2.57-2.78(4H,
m), 2.97, 3.29(3H, s), 3.48, 3.72(2H, q, J=7.2,7.0 Hz), 3.78(3H,
s), 6.83, 6.85(1H, s), 6.98(2H, d, J=8.9 Hz), 7.06-7.26(6H, m)
EXAMPLE 168
[0981] ##STR109##
[0982] (E0168)
[0983] E0168 was prepared from E0048 in a similar manner to that of
E0165.
[0984] Mass (ESI+): 377 (M+H)+
[0985] 200 MHz 1H NMR (DMSO-d6, d): 1.54-1.69(2H, m), 2.49-2.64(4H,
m), 3.88(3H, s), 6.92(1H, d, J=8.7 Hz), 7.17(1H, s), 7.22(4H, s),
7.75(1H, dd, J=8.7,2.6 Hz), 8.18(1H, d, J=2.6 Hz)
EXAMPLE 169
[0986] ##STR110##
[0987] (E0169)
[0988] To a solution of E0165 (180 mg) in tetrahydrofuran (2 ml)
was added triethylamine (0.242 ml) and t-butoxycarbonyl anhydride
(325 mg) at room temperature. After stirring at room temperature
overnight, the mixture was quenched with water and extracted with
ethyl acetate (.times.3) The organic layer was washed with hydrogen
chloride aqueous solution (1N), saturated sodium hydrogen carbonate
aqueous solution, and brine, dried over magnesium sulfate, and
evaporated to give oil, which was purified with column
chromatography (SiO2 25 ml, 20% ethyl acetate/hexane) to give E0169
as an oil (224 mg, 97.5%).
[0989] NMR(CDCl3); 1.35(9H, s), 2.69(2H, t, J=7.7 Hz),
3.09-3.19(2H, m), 3.88(3H, s), 6.91(1H, d, J=8.8 Hz), 7.17(1H, s),
7.18-7.27(4H, m), 7.75(1H, dd, J=8.8, 2.7 Hz), 8.19(1H, d, J=2.7
Hz).
[0990] MS(ESI+); 485.2(M+Na).
EXAMPLE 170
[0991] ##STR111##
[0992] (E0170)
[0993] This compound was obtained according to a similar manner to
that of E0169.
[0994] NMR(CDCl3), 1.45(9H, s), 3.49-3.57(2H, m), 3.82(3H, s),
4.01(2H, t, J=5.1 Hz), 6.67(1H, s), 6.82(2H, d, J=8.7 Hz), 6.87(2H,
d, J=9.0 Hz), 7.13(2H, d, J=8.7 Hz), 7.22(2H, d, J=9.0 Hz).
[0995] MS(ESI+), 500.2(M+Na).
EXAMPLE 171
[0996] ##STR112##
[0997] (E0171).
[0998] A mixture of E0158 (650 mg), Boc2O (428 mg) and 1NNaOH (3.3
ml) in THF (20 ml) was stirred at room temperature for 15 hours.
Water and EtOAc was added and the aqueous layer was separated and
extracted with EtOAc. The combined organic layer was washed with
sat NaHCO3, water and brine, dried over NA2SO4, filtered and
evaporated under reduced pressure. The residue was column
chromatographed on silica gel (Hex/EtOAc) to give 700 mg (93%) of
E0171 as an oil.
EXAMPLE 172
[0999] ##STR113##
[1000] (E0172)
[1001] This compound was obtained according to a similar manner to
that of E0171.
EXAMPLE 173
[1002] ##STR114##
[1003] (E0173)
[1004] This compound was obtained according to a similar manner to
that of E0171.
EXAMPLE 174
[1005] ##STR115##
[1006] (E0174)
[1007] This compound was obtained according to a similar manner to
that of E0171.
[1008] IR (film): 1702.8, 1513.9, 1241.9, 1164.8, 1132.0 cm-1.
EXAMPLE 175
[1009] ##STR116##
[1010] (E0175).
[1011] To a solution of E0171 (200 mg) and MeI (0.14 ml) in THF (20
ml) was added portionwise NaH (35 mg) at room temperature. Then the
reaction mixture was heated at 70.degree. C. for 1 hour. Almost no
reaction.
[1012] MeI (0.3 ml) and NaH (40 mg) was added, and DMF was
added.
[1013] The mixture was stirred at 70.degree. C. for 12 hours, and
then cooled, quenched with water. The aqueous layer was extracted
twice with EtOAc. The combined organic layer was washed with water
and brine, dried over MgSO4, filtered and evaporated. The residue
was column chromatographed on silica gel to give 151 mg (73%) of
E0175 as an oil.
EXAMPLE 176
[1014] ##STR117##
[1015] (E0176)
[1016] This compound was obtained according to a similar manner to
that of E0175.
EXAMPLE 177
[1017] ##STR118##
[1018] (E0177)
[1019] To a mixture of E0158 (150 mg) and HCHO (46 .mu.l) in Et3N
(53 .mu.l) and CH3CN (5 ml) was added portionwise NaBH(OAc)2 (240
mg) at room temperature. After stirring for 15 hours, the mixture
was quenched with water and extracted three times with EtOAc. The
combined organic layer was washed with water and brine, dried over
Na2SO4, filtered and evaporated under reduced pressure. The residue
was column chromatographed on silica gel (CHCl3/MeOH) and treated
with 4NHCl/dioxane to give 108 mg (70%) of E0177.
EXAMPLE 178
[1020] ##STR119##
[1021] (E0178)
[1022] Methylisocyanate 36.2 mg was added to a solution of E0165
(199.3 mg) and triethylamine 48.6 mg in CH2Cl2 2 ml under ice bath
cooling. The reaction mixture was stirred at same temperature for 1
hour and concentrated in vacuo. The residue was partitioned between
AcOEt and 1M HCl The organic layer was washed with saturated
aqueous sodium bicarbonate solution and saturated aqueous sodium
chloride solution, dried over magnesium sulfate, and concentrated
in vacuo The residue was recrystallized from AcOEt-n-hexane.
Obtained powder was dissolved in CHCl3 and further purified by
preparative thin layer silica gel chromatography developed by
MeOH/CHCl3=10%. The separated silica gel was extracted with 10%
MeOH/CHCl3 and the solvent was evaporated in vacuo. The residual
solid was collected and washed with diisopropyl ether to give E0178
(101.3 mg) as a white powder.
[1023] mp. 149.degree. C.
[1024] IR (KBr): 3348, 2947, 2885, 1626, 1583, 1529, 1500
cm.sup.-1
[1025] Mass (ESI+): 420 (M+H)+
[1026] 200 MHz 1H NMR (DMSO-d6, d): 2.49-2.53(3H, overlapping),
2.64-2.72(2H, m), 3.15-3.26(2H, m), 3.88(3H, s), 5.72(1H, q, J=4.5
Hz), 5.89(1H, t, J=5.7 Hz), 6.92(1H, d, J=8.8 Hz), 7.17(1H, s),
7.24(4H, s), 7.76(1H, dd, J=2.7, 8.8 Hz), 8.19(1H, d, J=2.7 Hz)
EXAMPLE 179
[1027] ##STR120##
[1028] (E0179)
[1029] E0179 80.7 mg was prepared from E0166 in a similar manner to
that of E0178.
[1030] amorphous powder
[1031] IR (neat): 3350, 2950, 2930, 1707, 1691, 1674, 1645, 1641,
1622, 1614, 1566, 1549, 1533, 1510 cm-1
[1032] Mass (ESI+): 437 (M+H)+
[1033] 200 MHz 1H NMR (DMSO-d6, d): 1.09-1.23(3H, m), 2.49-2.54(3H,
overlapping), 2.67(2H, t, J=7.2 Hz), 2.98, 3.28(3H, s),
3.15-3.28(2H, m), 3.48, 3.71(2H, q, J=6.8,6.9 Hz), 3.88(3H, s),
5.73(1H, q, J=4.6 Hz), 5.90(1H, t, J=5.6 Hz), 6.86-6.93(2H, m),
7.22(4H, s), 7.64-7.73(1H, m), 8.15(1H, d, J=2.6 Hz)
EXAMPLE 180
[1034] ##STR121##
[1035] (E0180)
[1036] E0180 was prepared from E0294 in a similar manner to that of
E0178.
[1037] white powder
[1038] mp. 155-157.degree. C.
[1039] IR (KBr): 3336, 2968, 1707, 1693, 1674, 1621, 1576, 1533
cm-1
[1040] Mass (ESI+): (M+H)+
[1041] 200 MHz 1H NMR (DMSO-d6, d): 0.96(3H, t, J=7.1 Hz),
2.64-2.72(2H, m), 2.91-3.05(2H, m), 3.15-3.26(2H, m), 3.88 (3H, s),
5.76-5.84 (2H, m), 6.92 (1H, d, J=8.8 Hz), 7.17 (1H, s), 7.24(4H,
s), 7.76(1H, dd, J=8.8,2.7 Hz), 8.19(1H, d, J=2.7 Hz)
EXAMPLE 181
[1042] ##STR122##
[1043] (E0181)
[1044] This compound was obtained according to a similar manner to
that of E0178.
[1045] IR (film): 3343.9, 1658.5, 1608.3, 1513.9, 1457.9, 1249.6,
1029.8, 836.9 cm-1.
EXAMPLE 182
[1046] ##STR123##
[1047] (E0182)
[1048] This compound was obtained according to a similar manner to
that of E0178.
[1049] IR (Film): 1659.0, 1608.8, 1554.8, 1485.4, 1470.0, 1240.4,
1165.1, 1134.3, 1097.6, 835.3 cm-1.
EXAMPLE 183
[1050] ##STR124##
[1051] (E0183)
[1052] This compound was obtained according to a similar manner to
that of E0178.
[1053] IR (film): 3249.8, 1658.5, 1608.3, 1554.3, 1469.5, 1240.0,
1164.8, 1133.9, 1097.3, 975.8, 835.0 cm-1.
EXAMPLE 184
[1054] ##STR125##
[1055] (E0184)
[1056] AcCl 23.3 mg was added to E0158 (107.4 mg) and triethylamine
68.3 mg in CH2Cl2 2 ml with cooling in an ice bath. After stirring
at same temperature for 1 hour, the reaction mixture was
concentrated in vacuo. The residue was partitioned between AcOEt
and 1M HCl. The organic layer was washed with saturated aqueous
sodium bicarbonate solution and saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo.
The residual solid were collected and washed with diisopropyl ether
to give E0184 (84 mg) as a white powder.
[1057] mp. 79-80.degree. C.
[1058] IR (KBr): 3307, 3221, 3093, 2964, 1689, 1639, 1554, 1514
cm-1
[1059] Mass (ESI+): 404 (M+H)+
[1060] 200 MHz 1H NMR (DMSO-d6, d): 1.76(3H, s), 2.65-2.73(2H, m),
3.18-3.31(2H, m), 3.79(3H, s), 6.99(2H, d, J=8.9 Hz), 7.12(1H, s),
7.20(4H, s), 7.28(2H, d, J=8.9 Hz), 7.92(1H, t, J=5.4 Hz)
EXAMPLE 185
[1061] ##STR126##
[1062] (E0185)
[1063] E0185 (143.4 mg) was prepared from E0232 (155.3 mg), methyl
chloroformate 35.8 mg, and triethylamine 105 mg in a similar manner
to that of E0184.
[1064] amorphous powder
[1065] IR (neat): 3319, 2954, 1718, 1711, 1668, 1660, 1612, 1545,
1533, 1500 cm-1
[1066] Mass (ESI+): 178 (M+H)+
[1067] 200 MHz 1H NMR (DMSO-d6, d): 2.67-2.75(2H, m), 3.22-3.33(2H,
m), 3.50-3.60(2H, overlapping), 3.53(3H, s), 3.88(3H, s), 6.92(1H,
d, J=8.8 Hz), 7.18(1H, s), 7.24(4H, s), 7.28(1H, t, J=6 Hz),
7.75(1H, dd, J=2.7,8.8 Hz), 7.94(1H, t, J=5.6 Hz), 8.19(1H, d,
J=2.7 Hz)
EXAMPLE 186
[1068] ##STR127##
[1069] (E0186)
[1070] E0186 (59.3 mg) was prepared from E0158 (96.2 mg), methyl
chloroformate 25.1 mg and triethylamine 61.2 mg in a similar manner
to that of E0184.
[1071] mp. 78-80.degree. C.
[1072] IR (KBr): 3352, 1739, 1695, 1658, 1647, 1549, 1514 cm-1
[1073] Mass (ESI+): 420 (M+H)+
[1074] 200 MHz 1H NMR (DMSO-d6, d): 2.66-2.74 (2H, m), 3.14-3.25
(2H, m), 3.49(3H, s), 3.79(3H, s), 6.99(2H, d, J=8.9 Hz), 7.12(1H,
s), 7.12-7.32(1H, m), 7.20(4H, s), 7.28(2H, d, J=8.9 Hz)
EXAMPLE 187
[1075] ##STR128##
[1076] (E0187)
[1077] E0187 (63.4 mg) was prepared from E0165 (113.6 mg), acetyl
chloride 29.5 mg, and triethylamine 41.2 mg in a similar manner to
that of E0184.
[1078] white powder
[1079] mp. 97-98.degree. C.
[1080] IR (KBr): 3311, 2956, 1674, 1641, 1543, 1500 cm-1
[1081] Mass (ESI+): 405 (M+H)+
[1082] 200 MHz 1H NMR (DMSO-d6, d): 1.76(3H, s), 2.66-2.74(2H, m),
3.19-3.30(2H, m), 3.88(3H, s), 6.92(1H, d, J=8.8 Hz), 7.18(1H, s),
7.24(4H, s), 7.75(1H, dd, J=8.8,2.6 Hz), 7.92(1H, t, J=5.3 Hz),
8.19(1H, d, J=2.6 Hz)
EXAMPLE 188
[1083] ##STR129##
[1084] (E0188)
[1085] E0188 was prepared from E0165 in a similar manner to that of
E0184.
[1086] IR (neat): 3338, 3020, 2951, 1716, 1610, 1527, 1500 cm-1
[1087] Mass (ESI+): 421 (M+H)+
[1088] 200 MHz 1H NMR (DMSO-d6, d): 2.67-2.75(2H, m), 3.14-3.25(2H,
m), 3.49(3H, s), 3.88(3H, s), 6.92(1H, d, J=8.9 Hz), 7.15-7.35(5H,
m), 7.18(1H, s), 7.75(1H, dd, J=2.7,8.9 Hz), 8.19(1H, d, J=2.7
Hz)
EXAMPLE 189
[1089] ##STR130##
[1090] (E0189)
[1091] E0189 was prepared from E0294 in a similar manner to that of
E0184.
[1092] IR (neat): 3352, 2939, 1691, 1639, 1533, 1500 cm-1
[1093] Mass (ESI+): 434 (M+H)+
[1094] 200 MHz 1H NMR (DMSO-d6, d): 2.67-2.74(2H, m), 2.74(6H, s),
3.15-3.26(2H, m), 3.88(3H, s), 6.34(1H, t, J=5.4 Hz), 6.92(1H, d,
J=8.9 Hz), 7.17(1H, s), 7.23(4H, s), 7.75(1H, dd, J=8.9,2.7 Hz),
8.19(1H, d, J=2.7 Hz)
EXAMPLE 190
[1095] ##STR131##
[1096] (E0190)
[1097] This compound was obtained according to a similar manner to
that of E0189
[1098] NMR(CDCl3); 2.78 (3H, d, J=5.0 Hz), 3.56-3.64 (2H, m), 3.82
(3H, s), 4.03(2H, t, J=5.1 Hz), 4.2-4.4(1H, m, NH), 4.6-4.9(1H, m,
NH), 6.67(1H, s), 6.80-6.91(4H, m), 7.13(2H, d, J=8.8 Hz), 7.22(2H,
d, J=9.0 Hz).
[1099] MS(ESI+). 457.1(M+Na).
[1100] IR(NBr), 1627.6 cm-1
EXAMPLE 191
[1101] ##STR132##
[1102] (E0191)
[1103] This compound was obtained according to a similar manner to
that of E0184.
[1104] IR (film): 3299.6, 1658.5, 1550.5, 1515.8, 1467.6, 1240.0,
1164.8, 1132.0, 975.8, 829.2, 755.9 cm-1.
EXAMPLE 192
[1105] ##STR133##
[1106] (E0192)
[1107] E0158 (250 mg) was suspended in AcOEt 5 ml and was
partitioned between AcOEt and saturated aqueous sodium bicarbonate
solution. The organic layer was washed with aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo.
The residue was dissolved in dimethoxyethane 5 ml, sulfamide 181 mg
was added and refluxed for 2 days. The reaction mixture was
concentrated in vacuo, and the residue was purified by silica gel
column chromatography eluted with MeOH/CHCl3=1%, 2%, then 3%.
Obtained amorphous powder was crystallized from EtOH-diisopropyl
ether to give E0192 153 mg as a white powder.
[1108] mp. 127-128.degree. C.
[1109] IR (KBr): 3357, 1707, 1693, 1647, 1564, 1549, 1529, 1514
cm-1
[1110] Mass (ESI+): 441 (M+H)+
[1111] 400 MHz 1H NMR (DMSO-d6, d): 2.76-2.80(2H, m), 3.06-3.11(2H,
m), 3.79(3H, s), 6.53(2H, s), 6.53-6.61(1H, broad), 7.00(2H, d,
J=8.9 Hz), 7.12 (1H, s), 7.21 (2H, d, J=8.5 Hz), 7.24 (2H, d, J=8.5
Hz), 7.29(2H, d, J=8.9 Hz)
EXAMPLE 193
[1112] ##STR134##
[1113] (E0193)
[1114] E0193 was prepared from E0294 in a similar manner to that of
E0192.
[1115] white powder
[1116] mp. 114-115.degree. C.
[1117] IR (KBr): 3489, 3469, 3458, 3435, 3425, 3398, 3363, 3280,
1647, 1500 cm-1
[1118] Mass (ESI+): 442 (M+H)+
[1119] 200 MHz 1H NMR (DMSO-d6, d): 2.75-2.83(2H, m), 3.00-3.20(2H,
m), 3.88(3H, s), 6.45-6.67(3H, m), 6.92(1H, d, J=8.7 Hz), 7.18(1H,
s), 7.21-7.31(4H, m), 7.76(1H, dd, J=2.6,8.7 Hz), 8.19(1H, d, J=2.6
Hz)
EXAMPLE 194
[1120] ##STR135##
[1121] (E0194)
[1122] E0194 was prepared from E0322 in a similar manner to that of
E0192.
[1123] white powder
[1124] mp. 142-143.degree. C.
[1125] IR (KBr): 3415, 3323, 3111, 3093, 3010, 2962, 1614, 1516
cm-1
[1126] Mass (ESI+): 429 (M+H)+
[1127] 200 MHz 1H NMR (DMSO-d6, d): 0.68-0.76(2H, m), 0.85-0.95(2H,
m), 1.92(1H, m), 3.15-3.31(2H, m), 3.76(3H, s), 4.00-4.07(2H, m),
6.25 (1H, 1), 6.60 (2H, brs), 6.72 (1H, brs), 6.86-6.96 (4H, m),
7.10(2H, d, J=8.7 Hz), 7.13(2H, d, J=8.9 Hz)
EXAMPLE 195
[1128] ##STR136##
[1129] (E0195)
[1130] This compound was obtained according to a similar manner to
that of E0192.
[1131] NMR(CDCl3), 3.50-3.59(2H, m), 3.82(3H, s), 4.14(2H, t, J=4.9
Hz), 6.68(1H, s), 6.80-6.90(4H, m), 7.15(2H, d, J=8.8 Hz), 7.22(2H,
d, J=9.0 Hz).
[1132] IR(KBr); 1612, 1552 cm-1.
[1133] MS(ESI+), 479.1(M+Na).
EXAMPLE 196
[1134] ##STR137##
[1135] (E0196).
[1136] To a solution of E0158 (100 mg) and Et3N (53 .mu.l) in CHCl3
(10 ml) was added MsCl (29 .mu.l) at room temperature. After
stirring for 1 hour, the reaction mixture was poured onto water and
CHCl3. The aqueous layer was separated and extracted with CHCl3.
The combined organic layer was washed with water and brine, dried
over Na2SO4, filtered and evaporated under reduced pressure. The
residue was column chromatographed on silica gel (50 ml) and
crystallized to give 75 mg (68%) of E0196 as a powder.
[1137] IR (film): 3284.2, 1513.9, 1319.1, 1240.0, 1151.3, 973.9
cm-1.
EXAMPLE 197
[1138] ##STR138##
[1139] (E0197)
[1140] E0197 was prepared from E0166 in a similar manner to that of
E0196.
[1141] mp. 137-138.degree. C.
[1142] IR (KBr): 3222, 1691, 1684, 1658, 1645, 1610, 1566, 1547,
1531 cm-1
[1143] Mass (ESI+): 458 (M+H)+
[1144] 200 MHz 1H NMR (DMSO-d6, d) 1.09-1.22(3H, m), 2.73-2.81(2H,
m), 2.80(3H, s), 2.98, 3.28(3H, s), 3.09-3.30(2H, m), 3.48,
3.71(2H, q, J=7.0,6.8 Hz), 3.87(3H, s), 6.88-6.93(2H, m), 7.10(1H,
brs), 7.22(2H, d, J=8.5 Hz), 7.28(2H, d, J=8.5 Hz), 7.64-7.73(1H,
m), 8.15(1H, d, J=2.5 Hz)
EXAMPLE 198
[1145] ##STR139##
[1146] (E0198)
[1147] E0198 was prepared from E0167 in a similar manner to that of
E0196.
[1148] mp. 162-163.degree. C.
[1149] IR (KBr): 3224, 1610, 1547, 1512 cm-1
[1150] Mass (ESI+): 457 (M+H)+
[1151] 200 MHz 1H NMR (DMSO-d6, d): 1.08-1.22(3H, m), 2.76(2H, t,
J=7.2 Hz), 2.80(3H, s), 2.98, 3.29(3H, s), 3.12-3.23(2H, m), 3.48,
3.73(2H, q, J=7.2,6.9 Hz), 3.78(3H, s), 6.84, 6.87(1H, s), 6.98(2H,
d, J=9.0 Hz), 7.09(1H, t, J=5.7 Hz), 7.16-7.26(6H, m)
EXAMPLE 199
[1152] ##STR140##
[1153] (E0199)
[1154] E0199 was prepared from E0234 in a similar manner to that of
E0196.
[1155] white powder,
[1156] mp. 155.degree. C.
[1157] IR (KBr): 3265, 2974, 2937, 1682, 1612, 1512 cm-1
[1158] Mass (ESI+): 458 (M+H)+
[1159] 200 MHz 1H NMR (DMSO-d6, d): 1.15(6H, d, J=6.8 Hz), 2.94(3H,
s), 3.27-3.36(2H, m), 3.68(1H, m), 3.79(3H, s), 4.03(2H, t, J=5.5
Hz), 6.93(2H, d, J=8.8 Hz), 6.98(1H, s), 7.00(2H, d, J=8.9 Hz),
7.19(2H, d, J=8.8 Hz), 7.28(2H, d, J=8.9 Hz), 7.17-7.30(1H,
overlapping)
EXAMPLE 200
[1160] ##STR141##
[1161] (E0200)
[1162] E0200 was prepared from E0235 in a similar manner to that of
E0196.
[1163] white powder
[1164] mp. 149-153.degree. C.
[1165] IR (KBr): 3321, 1693, 1658, 1647, 1610, 1547, 1510
cm.sup.-1
[1166] Mass (ESI+): 413 (M+H)+
[1167] 200 MHz 1H NMR (DMSO-d6, d): 2.93(3H, s), 3.27-3.35(2H, m),
3.79(3H, s), 4.03(2H, t, J=5.5 Hz), 6.95(2H, d, J=8.7 Hz), 7.01(2H,
d, J=9.0 Hz), 7.18(2H, d, J=8.7 Hz), 7.28(2H, d, J=9.0 Hz),
7.31(1H, s), 7.15-7.31(1H, overlapping)
EXAMPLE 201
[1168] ##STR142##
[1169] (E0201)
[1170] E0201 was prepared from E0294 in a similar manner to that of
E0196.
[1171] IR (neat): 3298, 2952, 2885, 1612, 1566, 1547, 1529 cm-1
[1172] Mass (ESI+): 470 (M+H)+
[1173] 200 MHz 1H NMR (DMSO-d6, d): 2.56(6H, s), 2.71-2.79(2H, m),
3.07-3.17(2H, m), 3.88(3H, s), 6.92(1H, d, J=8.7 Hz), 7.18(1H, s),
7.19-7.30(5H, m), 7.77(1H, dd, J=8.7,2.6 Hz), 8.18(1H, d, J=2.6
Hz)
EXAMPLE 202
[1174] ##STR143##
[1175] (E0202)
[1176] E0202 was prepared from E0322 in a similar manner to that of
E0196.
[1177] white powder
[1178] mp. 166-168.degree. C.
[1179] IR (KBr): 3093, 2964, 2873, 2854, 1614, 1516 cm-1
[1180] Mass (ESI+): 428 (M+H)+
[1181] 200 MHz 1H NMR (DMSO-d6, d): 0.68-0.76(2H, m), 0.85-0.95(2H,
m), 1.92(1H, m), 2.93(3H, s), 3.27-3.36(2H, m), 3.76(3H, s),
3.98-4.04(2H, m), 6.25(1H, s), 6.90(2H, d, J=8.7 Hz), 6.92(2H, d,
J=8.9 Hz), 7.11(2H, d, J=8.7 Hz), 7.13(2H, d, J=8.9 Hz), 7.27(1H,
t, J=5.8 Hz)
EXAMPLE 203
[1182] ##STR144##
[1183] (E0203)
[1184] This compound was obtained according to a similar manner to
that of E00196.
[1185] MS(ESI+); 454.1(MH+).
[1186] IR(KBr); 1612.2, 1515.8 cm-1.
[1187] NMR(CDCl3), 3.03(3H, s), 3.51-3.59(2H, m), 3.82(3H, s),
4.10(2H, t, J=4.9 Hz), 6.68(1H, s), 6.82(1H, d, J=8.7 Hz), 6.88(1H,
d, J=8.9 Hz), 7.15(1H, d, J=8.7 Hz), 7.22(1H, d, J=8.9 Hz).
EXAMPLE 204
[1188] ##STR145##
[1189] (E0204)
[1190] This compound was obtained according to a similar manner to
that of E0196.
[1191] NMR(DMSO-d6); 2.80(3H, s), 2.73-2.84(2H, m), 3.13-3.22(2H,
m), 3.88(3H, s), 6.92(1H, d, J=9.0 Hz), 7.08-7.13(1H, m), 7.19(1H,
s), 7.22-7.33(4H, m), 7.76(1H, dd, J=9.0, 2.6 Hz), 8.19(1H, d,
J=2.6 Hz).
[1192] MS(ESI+), 463.1(M+Na).
[1193] IR(KBr), 3136, 1614, 1554, 1144 cm-1.
EXAMPLE 205
[1194] ##STR146##
[1195] (E0205)
[1196] This compound was obtained according to a similar manner to
that of E0196.
EXAMPLE 206
[1197] ##STR147##
[1198] (E0206)
[1199] This compound was obtained according to a similar manner to
that of E0196.
[1200] mp: 134.2-134.5.degree. C.
[1201] IR (film): 3284.2, 1610.3, 1513.9, 1457.9, 1321.0, 1251.6,
1151.3, 1083.8, 1031.7, 838.9, 802.2, 757.9 cm-1.
EXAMPLE 207
[1202] ##STR148##
[1203] (E0207)
[1204] This compound was obtained according to a similar manner to
that of E00196.
[1205] IR (film): 3286.11, 1606.41, 1513.85, 1457.92, 1319.07,
1251.58, 1153.22, 1081.87, 1029.80, 836.955 cm-1.
EXAMPLE 208
[1206] ##STR149##
[1207] (E0208)
[1208] This compound was obtained according to a similar manner to
that of E0196.
[1209] IR(film): 3284.2, 1513.9, 1317.1, 1240.0, 1153.2 cm-1.
EXAMPLE 209
[1210] ##STR150##
[1211] (E0209)
[1212] This compound was obtained according to a similar manner to
that of E0196.
[1213] IR (film): 3286.1, 1511.9, 1321.0, 1230.4, 1155.2, 975.8,
842.7, 756.0 cm-1.
EXAMPLE 210
[1214] ##STR151##
[1215] (E0210)
[1216] This compound was obtained according to a similar manner to
that of E0196.
[1217] IR (film): 3284.2, 1511.9, 1469.5, 1321.0, 1236.2, 1153.2,
975.8, 821.5, 756.0 cm-1.
EXAMPLE 211
[1218] ##STR152##
[1219] (E0211)
[1220] This compound was obtained according to a similar manner to
that of E0196.
[1221] IR (film): 3289.9, 1612.2, 1513.9, 1322.9, 1251.6, 1155.1,
1085.7, 1029.8, 975.8, 836.9, 796.4 cm-1.
EXAMPLE 212
[1222] ##STR153##
[1223] (E0212)
[1224] This compound was obtained according to a similar manner to
that of E0196.
[1225] IR (film): 3266.8, 1612.2, 1469.5, 1321.0, 1240.0, 1153.2,
1097.3, 975.8, 835.0 cm-1.
EXAMPLE 213
[1226] ##STR154##
[1227] (E0213)
[1228] This compound was obtained according to a similar manner to
that of E0196.
[1229] IR (film): 3288.0, 1612.2, 1322.9, 1240.0, 1153.2, 975.8,
946.9 cm-1.
EXAMPLE 214
[1230] ##STR155##
[1231] (E0214).
[1232] A mixture of E0158 (180 mg), formic acid (38 .mu.l), and
WSCD (155 mg) in Et3N (0.3 ml) and THF (5 ml) was stirred at room
temperature for 1 hour. After addition of water and EtOAc, the
aqueous layer was separated and extracted twice with EtOAc. The
combined organic layer was washed with 1NHCl, sat.NaHCO3, water and
brine, dried over Na2SO4, filtered and evaporated under reduced
pressure. The residue was column chromatographed on silica gel
(Hex/EtOAc=2:1) to give 136 mg (70%) of E0214 as a powder.
[1233] IR (film): 1670.1, 1513.9, 1238.1, 1160.9, 1130.1 cm-1.
EXAMPLE 215
[1234] ##STR156##
[1235] (E0215).
[1236] A mixture of E0158 (250 mg), BocGly (132 mg), WSCD (127 mg)
and HOBt (110 mg) in Et3N (114 .mu.l) and CH2Cl2 (30 ml) was
stirred at room temperature. After stirring for 15 hour, the
reaction mixture was poured onto water and CHCl3. The aqueous layer
was separated and extracted with CHCl3. The combined organic layer
was washed with water and brine, dried over Na2SO4, filtered and
evaporated under reduced pressure. The residue was column
chromatographed on silica gel (50 ml) and crystallized to give 325
mg (99%) of E0215 as an oil.
EXAMPLE 216
[1237] ##STR157##
[1238] (E0216)
[1239] E0216 was prepared in a similar manner to that of E0215.
[1240] oil
[1241] IR (neat): 3431, 3421, 3404, 3400, 2939, 1614, 1570, 1547
cm-1
[1242] Mass (ESI+): 381(M+H)+
[1243] 200 MHz 1H NMR (DMSO-d6, d): 1.09-1.23(3H, m), 2.72(2H, t,
J=6.9 Hz), 2.98, 3.29(3H, s), 3.42-3.77(4H, m), 3.88(3H, s),
6.86-6.93(2H, m), 7.19(2H, d, J=8.5 Hz), 7.24(2H, d, J=8.5 Hz),
7.65-7.74(1H, m), 8.15(1H, d, J=2.6 Hz)
EXAMPLE 217
[1244] ##STR158##
[1245] (E0217)
[1246] E0217 was prepared from E0294 and acetoxyacetic acid in a
similar manner to that of E0215.
[1247] oil
[1248] Mass (ESI+): 463(M+H)+
[1249] 200 MHz 1H NMR (DMSO-d6, d): 2.07(3H, s), 2.69-2.77(2H, m),
3.24-3.33(2H, m), 3.88(3H, s), 4.40(2H, s), 6.92(1H, d, J=8.7 Hz),
7.18(1H, s), 7.24(4H, s), 7.75(1H, dd, J=2.7,8.7 Hz), 8.10(1H, t,
J=5.6 Hz), 8.19(1H, d, J=2.7 Hz)
EXAMPLE 218
[1250] ##STR159##
[1251] (E0218)
[1252] E0218 was prepared from E0294 and N-tert-butoxycarbonyl
glycine in a similar manner to that of E0215 using
N-methylmorpholine 55.8 mg instead of triethylamine.
[1253] amorphous powder
[1254] IR (neat): 3315, 1707, 1693, 1684, 1676, 1658, 1649, 1624,
1614, 1564, 1547, 1533, 1510, 1500 cm-1
[1255] Mass (ESI+): 520 (M+H)+
[1256] 200 MHz 1H NMR (DMSO-d6, d): 1.37(9H, s), 2.67-2.75(2H, m),
3.22-3.33(2H, m), 3.47(2H, d, J=6.0 Hz), 3.88(3H, s), 6.80-7.00(1H,
overlapping), 6.92(1H, d, J=8.8 Hz), 7.17(1H, s), 7.24(4H, s),
7.75(1H, dd, J=8.8,2.7 Hz), 7.86(1H, t, J=5.6 Hz), 8.19(1H, d,
J=2.7 Hz)
EXAMPLE 219
[1257] ##STR160##
[1258] (E0219)
[1259] E0219 was prepared in a similar manner to that of E0215.
[1260] oil
[1261] IR (KBr): 3329, 3313, 3303, 1620, 1564, 1547, 1512 cm-1
[1262] Mass (ESI+): 380 (M+H)+
[1263] 200 MHz 1H NMR (DMSO-d6, d): 1.08-1.22(3H, m), 2.71(2H, t,
J=6.9 Hz), 2.97, 3.29(3H, s), 3.42-3.78(4H, m), 3.78(3H, s),
4.65(1H, t, J=5.1 Hz), 6.82, 6.85(1H, s), 6.98(2H, d, J=8.9 Hz),
7.12-7.27(6H, m)
EXAMPLE 220
[1264] ##STR161##
[1265] (E0220)
[1266] E0220 was prepared in a similar manner to that of E0215.
EXAMPLE 221
[1267] ##STR162##
[1268] (E0221)
[1269] E0221 was prepared in a similar manner to that of E0215.
[1270] white powder
[1271] mp. 95-101.degree. C.
[1272] IR (KBr): 3421, 1693, 1647, 1603, 1566, 1549, 1516 cm-1
[1273] Mass (ESI+): 396 (M+H)+
[1274] 200 MHz 1H NMR (DMSO-d6, d): 1.08-1.22(3H, m), 2.97,
3.29(3H, s), 3.42-3.74(4H, m), 3.78(3H, s), 3.95-4.00(2H, m),
4.86(1H, t, J=5.4 Hz), 6.78, 6.81(1H, s), 6.91(2H, d, J=8.8 Hz),
6.98(2H, d, J=8.8 Hz), 7.16(2H, d, J=8.8 Hz), 7.23(2H, d, J=8.8
Hz)
EXAMPLE 222
[1275] ##STR163##
[1276] (E0222)
[1277] E0222 was prepared in a similar manner to that of E0215.
[1278] white powder
[1279] Mass (ESI+) 398 (M+H)+
[1280] 200 MHz 1H NMR (DMSO-d6, d): 3.38(3H, s), 3.65-3.74(2H, m),
3.77(3H, s), 3.78(3H, s), 3.95-4.01(2H, m), 4.87(1H, t, J=5.4 Hz),
6.89(1H, s), 6.92(2H, d, J=8.8 Hz), 6.99(2H, s, J=8.9 Hz), 7.17(2H,
d, J=8.8 Hz), 7.24(2H, d, J=8.9 Hz)
EXAMPLE 223
[1281] ##STR164##
[1282] (E0223)
[1283] E0223 was prepared in a similar manner to that of E0215.
[1284] white powder
[1285] mp. 110-111.degree. C.
[1286] IR (KBr): 3425, 2979, 2945, 1606, 1570, 1549 cm-1
[1287] Mass (ESI+): 397 (M+H)+
[1288] 200 MHz 1H NMR (DMSO-d6, d): 1.09-1.23(3H, m), 2.98,
3.28(3H, s), 3.42-3.73(4H, m), 3.87(3H, s), 3.96-4.02(2H, m),
4.87(1H, t, J=5.3 Hz), 6.82-6.97(4H, m), 7.21(2H, d, J=8.7 Hz),
7.63-7.72(1H, m), 8.14(1H, d, J=2.6 Hz)
EXAMPLE 224
[1289] ##STR165##
[1290] (E0224)
[1291] E0224 was prepared in a similar manner to that of E0215.
[1292] white powder
[1293] Mass (ESI+): 399 (M+H)+
[1294] 200 MHz 1H NMR (DMSO-d6, d): 3.37(3H, s), 3.66-3.74(2H, m),
3.77(3H, s), 3.88(3H, s), 3.96-4.02(2H, m), 4.87(1H, t, J=5.5 Hz),
6.88-6.97(4H, m), 7.21(2H, d, J=8.7 Hz), 7.69(1H, dd, J=2.7,8.8
Hz), 8.16(1H, d, J=2.7 Hz)
EXAMPLE 225
[1295] ##STR166##
[1296] (E0225)
[1297] E0225 was prepared in a similar manner to that of E0215.
[1298] white powder
[1299] Mass (ESI+): 495(M+H)+
[1300] 400 MHz 1H NMR (DMSO-d6, d): 1.12, 1.18(3H, t, J=7.0 Hz),
1.37(9H, s), 2.97, 3.29(3H, s), 3.24-3.28(2H, m), 3.48, 3.45(2H, q,
J=7.0 Hz), 3.78(3H, s), 3.95(2H, t, J=5.7 Hz), 6.78, 6.81(1H, s),
6.91(2H, d, J=8.8 Hz), 6.98(2H, d, J=8.8 Hz), 7.00(1H,
overlapping), 7.16(2H, d, J=8.8 Hz), 7.23(2H, d, J=8.9 Hz)
EXAMPLE 226
[1301] ##STR167##
[1302] (E0226)
[1303] E0226 was prepared in a similar manner to that of E0215.
[1304] white powder
[1305] Mass (ESI+): 497 (M+H)+
[1306] 400 MHz 1H NMR (DMSO-d6, d): 1.37(9H, s), 3.25-3.29(2H, m),
3.37(3H, brs), 3.76(3H, s), 3.78(3H, s), 3.95(2H, t, J=5.7 Hz),
6.88(1H, s), 6.91(2H, d, J=8.8 Hz), 6.99(2H, d, J=8.9 Hz),
6.97-7.00(1H, br), 7.17(2H, d, J=8.8 Hz), 7.24(2H, d, J=8.9 Hz)
EXAMPLE 227
[1307] ##STR168##
[1308] (E0227)
[1309] E0227 was prepared in a similar manner to that of E0215.
[1310] white powder
[1311] Mass (ESI+): 498 (M+H)+
[1312] 200 MHz 1H NMR (DMSO-d6, d): 1.37(9H, s), 3.22-3.33(2H, m),
3.37(3H, s), 3.77(3H, s), 3.88(3H, s), 3.93-3.99(2H, m),
6.88-7.05(5H, m), 7.22(2H, d, J=8.6 Hz), 7.69(1H, dd, J=2.7,8.8
Hz), 8.16(1H, d, J=2.7 Hz)
EXAMPLE 228
[1313] ##STR169##
[1314] (E0228)
[1315] This compound was obtained according to a similar manner to
that of E0215 as an oil (371.9 mg, 96%).
[1316] NMR(CDCl3); 1.43(9H, s), 3.65-3.73(2H, m), 3.79-3.82(2H, m),
3.82(3H, s), 4.03(2H, t, J=5.2 Hz), 6.67(1H, s), 6.79-6.89(4H, m),
7.14(2H, d, J=8.7 Hz), 7.22(2H, d, J=9.0 Hz).
[1317] MS(ESI+); 557.2(M+Na).
EXAMPLE 229
[1318] ##STR170##
[1319] (E0229)
[1320] This compound was obtained according to a similar manner to
that of E0289 as a white powder.
[1321] NMR(DMSO-d6), 3.49-3.63(4H, m), 3.79(3H, s), 4.03(2H, t,
J=4.8 Hz), 6.92-7.08(5H, m), 7.21(2H, d, J=8.7 Hz), 7.28(2H, d,
J=8.9 Hz).
[1322] MS(ESI-), 433.2(M-H).
[1323] IR(KBr); 1683 cm-1
EXAMPLE 230
[1324] ##STR171##
[1325] (E0230)
[1326] This compound was obtained according to a similar manner to
that of E0215.
[1327] IR (film): 3320.82, 1706.69, 1668.12, 1515.77, 1249.65,
1168.65, 1031.73 cm-1.
EXAMPLE 231
[1328] ##STR172##
[1329] (E0231).
[1330] A mixture of E0215 (300 mg) and 4NHCl in dioxane (5.8 ml)
was stirred at room temperature for 1.0 hour. After then, the
reaction mixture was evaporated under reduced pressure to give 260
mg (99%) of E0231 as an amorphous.
[1331] IR(film): 3226.3, 1679.7, 1513.9, 1251.6, 1083.8, 1029.8,
837.0 cm-1.
EXAMPLE 232
[1332] ##STR173##
[1333] (E0232)
[1334] E0232 was prepared in a similar manner to that of E0231.
[1335] white powder
[1336] IR (KBr): 3458, 3435, 3404, 3244, 3078, 3026, 1671, 1614,
1579, 1566, 1554, 1500 cm-1
[1337] Mass (ESI+): 420 (M+H)+
[1338] 200 MHz 1H NMR (DMSO-d6, d): 2.71-2.79(2H, m), 3.30-3.41(2H,
m), 3.44-3.54(2H, m), 3.88(3H, s), 6.93(1H, d, J=8.7 Hz), 7.22(1H,
s), 7.22-7.33(4H, m), 7.77(1H, dd, J=2.7,8.7 Hz), 8.10(2H, br),
8.19(1H, d, J=2.7 Hz), 8.55(1H, t, J=5.4 Hz)
EXAMPLE 233
[1339] ##STR174##
[1340] (E0233)
[1341] E0233 was prepared in a similar manner to that of E0231.
[1342] white powder
[1343] mp. 207-209.degree. C.
[1344] IR (KBr): 2966, 2933, 2871, 2750, 1606, 1566, 1549, 1512
cm-1
[1345] Mass (ESI+): 395 (M+H)+
[1346] 200 MHz 1H NMR (DMSO-d6, d): 108-1.22(3H, m), 2.97, 3.29(3H,
s), 3.17-3.22(2H, m), 3.40-3.80(2H, m), 3.78(3H, s), 4.14-4.20(2H,
m), 6.80, 6.83(1H, s), 6.94-7.01(4H, m), 7.18-7.26(4H, m), 8.13(2H,
brs)
EXAMPLE 234
[1347] ##STR175##
[1348] (E0234)
[1349] E0234 was prepared in a similar manner to that of E0231.
[1350] white powder
[1351] mp. 129-142.degree. C.
[1352] IR (KBr): 3471, 3437, 2968, 2933, 1674, 1639, 1631, 1612,
1545, 1512 cm-1
[1353] Mass (ESI+): 380 (M+H)+
[1354] 200 MHz 1H NMR (DMSO-d6, d): 1.15(6H, d, J=6.9 Hz),
3.16-3.22(2H, m), 3.68(1H, m), 3.79(3H, s), 4.15-4.20(2H, m),
6.94-7.05(5H, m), 7.22(2H, d, J=8.8 Hz), 7.29(2H, d, J=8.9 Hz),
8.15(2H, brs)
EXAMPLE 235
[1355] ##STR176##
[1356] (E0235)
[1357] E0235 was prepared and in a similar manner to that of
E0231.
[1358] white powder
[1359] mp. 186-189.degree. C.
[1360] IR (KBr): 3209, 3136, 2968, 2873, 1647, 1610, 1547, 1512
cm-1
[1361] Mass (ESI+): 335 (M+H)+
[1362] 200 MHz 1H NMR (DMSO-d6, d): 3.19(2H, t, J=4.9 Hz), 3.79(3H,
s), 4.18(2H, t, J=4.9 Hz), 6.96-7.05(4H, m), 7.21(2H, d, J=8.8 Hz),
7.29(2H, d, J=9.0 Hz), 7.32(1H, s), 8.16(2H, brs)
EXAMPLE 236
[1363] ##STR177##
[1364] (E0236)
[1365] E0236 was prepared in a similar manner to that of E0231.
[1366] white powder
[1367] Mass (ESI+): 378 (M+H)+
[1368] 200 MHz 1H NMR (DMSO-d6, d): 1.04(4H, d, J=6.1 Hz), 3.04(1H,
m), 3.14-3.22(2H, m), 3.80(3H, s), 4.15-4.21(2H, m), 6.93-7.05(5H,
m), 7.23(2H, d, J=8.6 Hz), 7.31(2H, d, J=8.9 Hz), 8.15(2H, brs)
EXAMPLE 237
[1369] ##STR178##
[1370] (E0237)
[1371] E0237 was prepared in a similar manner to that of E0231.
[1372] amorphous powder
[1373] IR (KBr): 3433, 3425, 3404, 3043, 3028, 3022, 2962, 1658,
1612 cm-1
[1374] Mass (ESI+): 336 (M+H)+
[1375] 200 MHz 1H NMR (DMSO-d6, d): 3.15-3.24(2H, m), 3.88(3H, s),
4.16-4.22(2H, m), 6.94(1H, d, J=8.8 Hz), 7.01(2H, d, J=8.7 Hz),
7.25(2H, d, J=8.7 Hz), 7.36(1H, s), 7.75(1H, dd, J=2.6,8.8 Hz),
8.10-8.30(2H, br), 8.20(1H, d, J=2.6 Hz)
EXAMPLE 238
[1376] ##STR179##
[1377] (E0238)
[1378] E0238 was prepared in a similar manner to that of E0231.
[1379] white powder
[1380] mp. 156-161.degree. C.
[1381] IR (KBr): 2970, 1676, 1647, 1612, 1550, 1500 cm-1
[1382] Mass (ESI+): 381 (M+H)+
[1383] 200 MHz 1H NMR (DMSO-d6, d): 1.16(6H, d, J=6.9 Hz),
3.15-3.24(2H, m), 3.68(1H, m), 3.88(3H, s), 4.16-4.22(2H, m),
6.91-7.06(4H, m), 7.26(2H, d, J=8.7 Hz), 7.75(1H, dd, J=2.7,8.9
Hz), 8.18(1H, d, J=2.7 Hz), 8.22(2H, brs)
EXAMPLE 239
[1384] ##STR180##
[1385] (E0239)
[1386] This compound was obtained according to a similar manner to
that of E0231.
[1387] IR (film): 3220.5, 1679.7, 1513.9, 1461.8, 1251.6, 1081.9,
1029.8, 837.0, 800.3 cm-1.
EXAMPLE 240
[1388] ##STR181##
[1389] (E0240).
[1390] To a solution of E0267 (75.2 mg) in dichloromethane (1 ml)
was added triethylamine (30.4 ml) and trimethylsilyl isocyanate
(36.9 ml) at 0.degree. C. After stirring for 5 hours, the mixture
was quenched with water and extracted with dichloromethane. The
combined organic layers were washed with brine, dried over
magnesium sulfate, and evaporated under reduced pressure to give
oil, which was purified with preparative TLC (1 mm, ethyl acetate)
to give oil. The oil was crystallized from a mixture of isopropyl
ether, ethyl acetate, and hexane to give E0240 as a white solid
(39.1 mg, 51.2%).
[1391] NMR(DMSO-d6); 3.27-3.32(2H, m), 3.79(3H, s), 3.94(2H, t,
J=5.6 Hz), 5.52(2H, brs, NH2), 6.15(1H, t, J=5.6 Hz, NH), 6.94 (2H,
d, J=8.8 Hz), 7.00(2H, d, J=8.9 Hz), 7.07(1H, s), 7.20(2H, d, J=8.8
Hz), 7.28(2H, d, J=8.9 Hz).
[1392] MS(ESI+); 443.2(M+Na).
[1393] IR(KBr), 1685.5, 1656.6 cm-1.
EXAMPLE 241
[1394] ##STR182##
[1395] (E0241)
[1396] E0241 was prepared from E0194 in a similar manner to that of
E0240
[1397] white powder
[1398] mp. 139-140.degree. C.
[1399] IR (KBr): 3458, 3342, 1691, 1647, 1604, 1572, 1529 cm-1
[1400] Mass (ESI+): 404 (M+H)+
[1401] 200 MHz 1H NMR (DMSO-d6, d): 3.28-3.36(2H, m), 3.87(3H, s),
3.92-3.98(2H, m), 5.52(2H, brs), 6.15(1H, t, J=5.5 Hz),
6.88-6.98(4H, m), 7.10(1H, t, J=54.4 Hz), 7.22(2H, d, J=8.7 Hz),
7.69(1H, dd, J=2.7,8.8 Hz), 8.14(1H, d, J=2.7 Hz)
EXAMPLE 242
[1402] ##STR183##
[1403] (E0242)
[1404] E0242 was prepared in a similar manner to that of E0240.
[1405] white powder mp. 108-113.degree. C.
[1406] IR (KBr): 3492, 3435, 3425, 3359, 3298, 1647, 1614, 1564,
1549, 1512 cm-1
[1407] Mass (ESI+): 438 (M+H)+
[1408] 200 MHz 1H NMR (DMSO-d6, d): 1.08-1.22(3H, m), 2.97,
3.29(3H, s), 3.20-3.85(4H, m), 3.78(3H, s), 3.94(2H, t, J=5.5 Hz),
5.53(2H, s), 6.15(1H, t, J=5.6 Hz), 6.79, 6.81(1H, s), 6.92(2H, d,
J=8.8 Hz), 6.99(2H, d, J=8.9 Hz), 7.17(2H, d, J=8.8 Hz), 7.23(2H,
d, J=8.9 Hz)
EXAMPLE 243
[1409] ##STR184##
[1410] (E0243)
[1411] E0243 was prepared from E0234 in a similar manner to that of
E0240.
[1412] white powder
[1413] mp. 144-145.degree. C.
[1414] IR (KBr): 3435, 3369, 3176, 2970, 1674, 1612, 1547, 1514
cm-1
[1415] Mass (ESI+): 423 (M+H)+
[1416] 200 MHz 1H NMR (DMSO-d6, d): 1.15(6H, d, J=6.9 Hz),
3.27-3.36(2H, m), 3.68(1H, m), 3.79(3H, s), 3.90-3.97(2H, m),
5.53(2H, s), 6.15(1H, t, J=5.6 Hz), 6.92(2H, d, J=8.7 Hz), 6.98(1H,
s), 7.00(2H, d, J=8.9 Hz), 7.18(2H, d, J=8.7 Hz), 7.28(2H, d, J=8.9
Hz)
EXAMPLE 244
[1417] ##STR185##
[1418] (E0244)
[1419] E0244 was prepared from E0235 in a similar manner to that of
E0240.
[1420] white powder
[1421] mp. 187-190.degree. C.
[1422] IR (KBr): 3379, 3201, 1649, 1614, 1579, 1527, 1506 cm-1
[1423] Mass (ESI+): 378 (M+H)+
[1424] 200 MHz 1H NMR (DMSO-d6, d): 3.27-3.34(2H, m), 3.79(3H, s),
3.94(2H, t, J=5.5 Hz), 5.52(2H, brs), 6.14(1H, t, J=5.6 Hz),
6.94(2H, d, J=8.8 Hz), 7.00(2H, d, J=9.0 Hz), 7.17(2H, d, J=8.8
Hz), 7.24-7.31(3H, m)
EXAMPLE 245
[1425] ##STR186##
[1426] (E0245)
[1427] E0245 was prepared in a similar manner to that of E0240.
[1428] white powder
[1429] mp. 136-137.degree. C.
[1430] IR (KBr): 3433, 3342, 3221, 1658, 1612, 1581, 1549, 1512
cm-1
[1431] Mass (ESI+): 421 (M+H)+
[1432] 200 MHz H NMR (DMSO-d6, d): 1.04(4H, d, J=6.2 Hz), 3.03(1H,
m), 3.27-3.36(2H, m), 3.80(3H, s), 3.90-3.97(2H, m), 5.52(2H, s),
6.14(1H, t, J=5.6 Hz), 6.93(2H, d, J=8.8 Hz), 6.97(1H, s), 7.01(2H,
d, J=8.9 Hz), 7.19(2H, d, J=8.8 Hz), 7.30(2H, d, J=8.9 Hz)
EXAMPLE 246
[1433] ##STR187##
[1434] (E0246)
[1435] E0246 was prepared in a similar manner to that of E0240.
[1436] white powder
[1437] mp. 173-176.degree. C.
[1438] IR (KBr): 3473, 3334, 1630, 1624, 1601, 1583 cm-1
[1439] Mass (ESI+): 379 (M+H)+
[1440] 200 MHz 1H NMR (DMSO-d6, d): 3.27-3.36(2H, m), 3.88(3H, s),
3.92-3.98(2H, m), 5.52(2H, s), 6.14(1H, t, J=5.7 Hz), 6.93(1H, d,
J=8.8 Hz), 6.97(2H, d, J=8.8 Hz), 7.21(2H, d, J=8.8 Hz), 7.35(1H,
s), 7.73(1H, dd, J=2.7,8.8 Hz), 8.20(1H, d, J=2.7 Hz)
EXAMPLE 247
[1441] ##STR188##
[1442] (E0247)
[1443] E0247 was prepared in a similar manner to that of E0240.
[1444] white powder
[1445] mp. 145-147.degree. C.
[1446] IR (KBr): 3367, 3174, 2972, 1689, 1674, 1610, 1566, 1502
cm-1
[1447] Mass (ESI+): 424 (M+H)+
[1448] 200 MHz 1H NMR (DMSO-d6, d): 1.16(6H, d, J=6.9 Hz),
3.28-3.37(2H, m), 3.68(1H, m), 3.88(3H, s), 3.92-3.98(2H, m),
5.52(2H, s), 6.15(1H, t, J=5.6 Hz), 6.93(1H, d, J=8.7 Hz), 6.95(2H,
d, J=8.8 Hz), 7.02(1H, s), 7.22(2H, d, J=8.8 Hz), 7.73(1H, dd,
J=2.7,8.7 Hz), 8.19(1H, d, J=2.7 Hz)
EXAMPLE 248
[1449] ##STR189##
[1450] (E0248)
[1451] E0248 was prepared in a similar manner to that of E0240.
[1452] white powder
[1453] mp. 150.8-151.0.degree. C.
[1454] IR (KBr): 3496, 3361, 3294, 1705, 1674, 1647, 1603, 1581,
1568, 1554, 1516 cm-1
[1455] Mass (ESI+): 393 (M+H)+
[1456] 200 MHz 1H NMR (DMSO-d6, d): 0.71-0.77(2H, m), 0.85-0.92(2H,
m), 1.92(1H, m), 3.27-3.37(2H, m), 3.76(3H, s), 3.92(2H, t, J=5.5
Hz), 5.51(2H, s), 6.14(1H, t, J=5.5 Hz), 6.24(1H, s), 6.86-6.96(4H,
m), 7.07-7.15(4H, m)
EXAMPLE 249
[1457] ##STR190##
[1458] (E0249)
[1459] This compound was obtained according to a similar manner to
that of E0240 as an amorphous.
[1460] NMR(CDCl3), 3.56-3.64(2H, m), 3.94(3H, s), 4.04(2H, t, J=4.9
Hz), 4.50(2H, brs, NH2), 6.69(1H, s), 6.76(1H, d, J=8.8 Hz),
6.84(2H, d, J=8.8 Hz), 7.12(2H, d, J=8.8 Hz), 7.58(1H, dd, J=8.8,
2.8 Hz), 8.05(1H, d, J=2.8 Hz).
[1461] MS(ESI+), 444.1 (M+Na)+. IR(KBr); 1650.8, 1608.3 cm-1.
[1462] LCMS(ESI+), 422.27(MH+).
EXAMPLE 250
[1463] ##STR191##
[1464] (E0250)
[1465] This compound was obtained according to a similar manner to
that of E0240 as a white powder.
[1466] NMR(CDCl3), 3.55-3.63(2H, m), 3.93(3H, s), 4.04(2H, t, J=5.1
Hz), 4.55(2H, brs, NH2), 5.23(1H, brt, J=5.4 Hz, NH), 6.67(1H, s),
6.75(1H, t, J=55 Hz), 6.75(1H, d, J=8.4 Hz), 6.88(2H, d, J=8.8 Hz),
7.13(2H, d, J=8.8 Hz), 7.56(1H, d, J=8.4, 2.9 Hz), 8.04(1H, d,
J=2.9 Hz).
[1467] LCMS(ESI+), 404.39(MH+).
[1468] IR(KBr) 1649 cm-1
[1469] MP, 141.5-142.1.degree. C.
EXAMPLE 251
[1470] ##STR192##
[1471] (E0251)
[1472] This compound was obtained according to a similar manner to
that of E0240 as a powder.
[1473] NMR (CDCl3), 3.6-364(2H, m), 382(3H, s), 4.03(2H, t, J=5.0
Hz), 4.42(2H, brs), 6.65(1H, s), 6.76(1H, t, J=55 Hz),
6.79-6.89(4H, m), 7.14(2H, d, J=8.7 Hz), 7.20(2H, d, J=9.0 Hz).
[1474] MS(ESI+), 425(M+Na)+.
EXAMPLE 252
[1475] ##STR193##
[1476] (E0252)
[1477] To a solution of E0267 (15.3 g) in ethanol (75 ml) and
hydrogen chloride aqueous solution (1N, 220 ml) was added dropwise
a solution of sodium cyanate (14.4 g) in water (300 ml) at
45.degree. C. over 5 minutes. After stirring at 45.degree. C. for 4
hours, the mixture was quenched with saturated sodium hydrogen
carbonate aqueous solution and extracted with ethyl acetate. The
combined organic layers were washed with brine, dried over
magnesium sulfate, and evaporated to give powder. The powder was
crystallized from ethyl acetate and hexane at room temperature
.about.70.degree. C. to give E0252 as a powder (12.628 g,
81.2%).
[1478] The physical data of this compound was identical to
previously obtained authentic sample.
EXAMPLE 253
[1479] ##STR194##
[1480] (E0253).
[1481] To a solution of E0267 (200 mg) in methanol (1 ml) was added
sodium methoxide methanol solution (5.2M, 0.1 ml) at room
temperature. After stirring for 20 minutes, the mixture was
evaporated to give residue. To the residue was added
tetrahydrofuran, and the mixture was filtered and evaporated to
give oil. The oil was dissolved in ethyl formate (2 ml) and stirred
at room temperature overnight. The mixture was evaporated and
purified with preparative TLC (1 mm, 50% ethyl acetate/hexane) to
give oil, which was crystallized from isopropyl ether, ethyl
acetate, and hexane to give E0253 as a white powder (162.8 mg,
83%).
[1482] NMR(CDCl3), 3.68-3.76(2H, m), 3.82(3H, s), 4.06(2H, t, J=5.0
Hz), 6.68(1H, s), 6.80-6.89(4H, m), 7.14(2H, d, J=8.7 Hz), 7.22(2H,
d, J=9.0 Hz), 8.22(1H, s).
[1483] MS(ESI+), 428.2(M+Na).
[1484] IR(KBr), 1660.4, 1614.1 cm-1.
EXAMPLE 254
[1485] ##STR195##
[1486] (E0254).
[1487] To a solution of E0267 (800 mg) and triethylamine (0.7 ml)
in dichloromethane (9 ml) was added dropwise acetyl chloride (0.18
ml) at 0.degree. C. After stirring at room temperature for 1 hour,
the mixture was quenched with saturated sodium hydrogen carbonate
aqueous solution and extracted with ethyl acetate (.times.3). The
combined organic layers were washed with hydrogen chloride aqueous
solution (1N), water, and brine, dried over magnesium sulfate, and
evaporated to give oil, which was purified with column
chromatography (SiO2 100 ml, eluted with 50% ethyl acetate/hexane)
to give oil. The oil was crystallized from a mixture of ethyl
acetate and hexane at 50.degree. C. to give E0254 as a solid (768.6
mg, 94.8%).
[1488] NMR(CDCl3). 2.01(3H, s), 3.62-3.70(2H, m), 3.82(3H, s),
4.03(2H, t, J=5.0 Hz), 6.67(1H, s), 6.80-6.91(4H, m), 7.14(2H, d,
J=8.7 Hz), 7.22(2H, d, J=9.0 Hz).
[1489] MP; 109.8-110.2.degree. C.
[1490] IR(KBr), 1649 cm-1.
[1491] MS(ESI+). 442.1(M+Na).
EXAMPLE 255
[1492] ##STR196##
[1493] (E0255)
[1494] This compound was obtained according to a similar manner to
that of E0254 as an oil.
[1495] NMR(CDCl3), 3.69(3H, s), 3.65-3.73(2H, m), 3.82(3H, s),
3.86(2H, d, J=5.9 Hz), 4.04(2H, t, J=5.1 Hz), 6.67(1H, s),
6.80-6.89(4H, m), 7.14(2H, d, J=8.5 Hz), 7.22(2H, d, J=8.9 Hz),
[1496] MS(ESI+). 515.2(M+Na).
[1497] IR(KBr, 20727-10), 1722.1, 1710.6, 1673.9 cm-1.
EXAMPLE 256
[1498] ##STR197##
[1499] (E0256)
[1500] This compound was obtained according to a similar manner to
that of E0254 as an oil (82 mg, 78%).
[1501] MS(ESI+). 458.2(M+Na).
[1502] IR(Neat), 1699 cm-1.
[1503] NMR(CDCl3); 3.54-3.62(2H, m), 3.69(3H, s), 3.82(3H, s),
4.02(2H, t), 6.67(1H, s), 6.80-6.89(4H, m), 7.13(2H, d, J=8.9 Hz),
7.22(2H, d, J=9.0 Hz)
EXAMPLE 257
[1504] ##STR198##
[1505] (E0257).
[1506] To a solution of E0275 (97.5 mg) and pyridine (0.14 ml) in
dichloromethane (1 ml) was added trifluoroacetic anhydride (60.6
ml) at 0.degree. C. After stirring at room temperature overnight,
the mixture was quenched with saturated sodium hydrogen carbonate
aqueous solution (0.5 ml), filtered with chemelute 1001 (Varian),
and purified with preparative TLC (1 mm, 50% ethyl acetate/hexane)
to give E0257 as a solid (92.5 mg, 76%).
[1507] MS(ESI+), 496.1(M+Na).
[1508] IR(KBr), 1705 cm-1.
[1509] NMR(CDCl3), 3.75-3.87(2H, m), 3.82(3H, s), 4.10(4.8H, t),
6.68(1H, s), 6.83(2H, d, J=8.8 Hz), 6.88(2H, d, J=8.9 Hz), 7.16(2H,
d, J=8.8 Hz), 7.22(2H, d, J=8.9 Hz).
EXAMPLE 258
[1510] ##STR199##
[1511] (E0258).
[1512] To a solution of E0327 (400 mg) in THF (5 ml) was added
dropwise 1N NaOH (2.5 ml) at room temperature. The mixture was
stirred overnight, and then quenched with 1N HCl and CHCl3. The
organic layer was separated and water layer was extracted twice
with CHCl3. The combined organic layer was washed with water and
brine, dried over Na2SO4, and evaporated under reduced pressure.
The residue was washed with IPE to give 273 mg (70.7%) of
E0258.
[1513] IR (film): 2971.8, 1683.6, 1629.6, 1515.8, 1315.2, 1230.4,
1159.0, 1132.0, 977.7, 835.0 cm-1.
EXAMPLE 259
[1514] ##STR200##
[1515] (E0259)
[1516] E0259 was prepared in a similar manner to that of E0258.
[1517] white powder
[1518] Mass (ESI+): 355 (M+H)+
[1519] 200 MHz 1H NMR (DMSO-d6, d): 3.63-3.78(2H, m), 3.79(3H, s),
3.95-4.00(2H, m), 4.86(1H, brs), 6.91(2H, d, J=8.7 Hz), 6.95(1H,
s), 6.99(2H, d, J=8.9 Hz), 7.16(2H, d, J=8.7 Hz), 7.24(2H, d, J=8.9
Hz), 12.88(1H, brs)
EXAMPLE 260
[1520] ##STR201##
[1521] (E0260)
[1522] E0260 was prepared in a similar manner to that of E0258.
[1523] white powder
[1524] Mass (ESI+): 356 (M+H)+
[1525] 200 MHz 1H NMR (DMSO-d6, d): 3.69-3.79(2H, m), 3.88(3H, s),
3.96-4.02(2H, m), 4.87(1H, br), 6.89-7.00(4H, m), 7.20(2H, d, J=8.8
Hz), 7.70(1H, dd, J=2.6,8.8 Hz), 8.14(1H, d, J=2.6 Hz), 12.97(1H,
br)
EXAMPLE 261
[1526] ##STR202##
[1527] (E0261)
[1528] E0261 was prepared from E0109 in a similar manner to that of
E0258.
[1529] white powder
[1530] Mass (ESI+): 339(M+H)+
[1531] 200 MHz 1H NMR (DMSO-d6, d): 2.70(2H, t, J=6.9 Hz), 3.59(2H,
t, J=6.9 Hz), 3.79(3H, s), 4.64(1H, brs), 6.96-7.03(3H, m),
7.12-7.28(6H, m), 12.90(1H, br)
EXAMPLE 262
[1532] ##STR203##
[1533] (E0262)
[1534] E0262 was prepared in a similar manner to that of E0258.
[1535] white powder
[1536] Mass (ESI+): 454 (M+H)+
[1537] 200 MHz 1H NMR (DMSO-d6, d): 1.37(9H, s), 3.22-3.32(2H, m),
3.79(3H, s), 3.91-3.98(2H, m), 6.90(2H, d, J=8.7 Hz), 6.90-7.03(1H,
overlapping), 6.95(1H, s), 6.99(2H, d, J=8.9 Hz), 7.16(2H, d, J=8.7
Hz), 7.24(2H, d, J=8.9 Hz)
EXAMPLE 263
[1538] ##STR204##
[1539] (E0263)
[1540] E0263 was prepared in a similar manner to that of E0258.
[1541] amorphous powder
[1542] Mass (ESI+): 455 (M+H)+
[1543] 200 MHz 1H NMR (DMSO-d6, d): 1.37(9H, s), 3.22-3.32(2H, m),
3.88(3H, s), 3.93-3.98(2H, m), 6.89-7.05(5H, m), 7.20(2H, d, J=8.7
Hz), 7.70(1H, dd, J=2.7,8.8 Hz), 8.14(1H, d, J=2.7 Hz), 12.98(1H,
br)
EXAMPLE 264
[1544] ##STR205##
[1545] (E0264)
[1546] E0264 was prepared from E0006 in a similar manner to that of
E0258.
[1547] white powder
[1548] Mass (ESI+): 340 (M+H)+
[1549] 200 MHz 1H NMR (DMSO-d6, d): 2.71(2H, t, J=6.9 Hz),
3.56-3.64(2H, m), 3.88(3H, s), 4.64(1H, br), 6.92(1H, d, J=8.8 Hz),
7.03(1H, s), 7.16-7.28(4H, m), 7.72(1H, dd, J=8.8,2.7 Hz), 8.15(1H,
d, J=2.7 Hz), 12.94 (1H, br)
EXAMPLE 265
[1550] ##STR206##
[1551] (E0265)
[1552] 4M HCl/AcOEt 0.4 ml was added to a solution of E0378 (73 mg)
in AcOEt 1 ml. The mixture was concentrated and dried in vacuo to
give E0265 68.4 mg as an amorphous powder.
[1553] IR (neat): 3440, 2960, 1739, 1707, 1691, 1674, 1647, 1624,
1614, 1566, 1549, 1533, 1500 cm-1
[1554] Mass (ESI+): 400 (M+H)+
[1555] 200 MHz 1H NMR (DMSO-d6, d): 2.73(2H, t, J=6.9 Hz), 3.62(2H,
t, J=6.9 Hz), 3.89(3H, s), 6.94(1H, d, J=8.8 Hz), 7.19-7.32(5H, m),
7.52-7.70(3H, m), 7.80(1H, dd, J=8.8,2.7 Hz), 8.22-8.28(3H, m)
EXAMPLE 266
[1556] ##STR207##
[1557] (E0266)
[1558] E0266 was prepared in a similar manner to that of E0265.
[1559] oil
[1560] IR (neat): 3435, 2966, 2935, 1678, 1662, 1649, 1612, 1581,
1566, 1547, 1533, 1500 cm-1
[1561] Mass (ESI+): 366 (M+H)+
[1562] 200 MHz 1H NMR (DMSO-d6, d): 1.16(6H, d, J=6.9 Hz), 2.72(2H,
t, J=6.9 Hz), 3.54-3.75(3H, m), 3.89(3H, s), 6.93(1H, d, J=8.8 Hz),
7.05(1H, s), 7.13-7.35(4H, m), 7.76(1H, dd, J=2.7,8.8 Hz), 8.19(1H,
d, j=2.7 Hz)
EXAMPLE 267
[1563] ##STR208##
[1564] (E0267).
[1565] To a solution of E0275 (765 mg) in ethyl acetate (1.9 ml)
was added a solution of hydrogen chloride in ethyl acetate (4N,
0.56 ml). The mixture was evaporated to give oil, which was
crystallized from diisopropyl ether and ethyl acetate at 65.degree.
C. to give E0267 as a solid (766.8 mg, 91.4%).
[1566] NMR(CDCl3), 3.30(2H, t, J=5.0 Hz), 3.79(3H, s), 4.18(2H, t,
J=5.0 Hz), 6.62(1H, s), 6.83-6.88(4H, m), 7.10(2H, d, J=8.8 Hz),
7.18(2H, d, J=8.8 Hz).
[1567] NMR(DMSO-d6), 3.19(2H, brs), 3.79(3H, s), 4.18(2H, t, J=5.0
Hz), 6.96-7.01(4H, m), 7.08(1H, s), 7.23-7.29(4H, m).
[1568] MS(ESI+), 378.3(MH+, free).
[1569] IR(KBr, 20727-2), 1612.2, 1513.9 cm-1.
EXAMPLE 268
[1570] ##STR209##
[1571] (E0268).
[1572] A mixture of P0011 (30 g), chloroacetonitrile (8.52 ml),
potassium iodide (4.47 g), and potassium carbonate (14.9 g) in
acetone (150 ml) was stirring under reflux at 80.degree. C. for 2.5
hours. After cooling to room temperature, the mixture as quenched
with water (600 ml) and extracted with ethyl acetate (300
ml.times.2, 150 ml). The combined organic layers were washed with
brine (300 ml), dried over magnesium sulfate, and evaporated to
give solid (36.34 g). The solid was recrystallized from
diisopropylether (60 ml) and hexane (200 ml) at room temperature to
give E0268 as a powder (31.5 g, 94%).
[1573] NMR(CDCl3), 3.83(3H, s), 4.78(2H, s), 6.70(1H, s),
6.86-6.97(4H, m), 7.18-7.24(4H, m).
[1574] IR(KBr), 2051.9 cm-1.
EXAMPLE 269
[1575] ##STR210##
[1576] (E0269)
[1577] E0269 was obtained according to a similar manner to that of
E0268.
[1578] white powder
[1579] Mass (ESI+) 346(M+H)+
[1580] 200 MHz 1H NMR (DMSO-d6, d): 0.69-0.77(2H, m), 0.86-0.96(2H,
m), 1.92(1H, m), 3.76(3H, s), 5.16(2H, s), 6.30(1H, s), 6.93(2H, d,
J=9.0 Hz), 7.02(2H, d, J=8.8 Hz), 7.10-7.21(4H, m)
EXAMPLE 270
[1581] ##STR211##
[1582] (E0270)
[1583] This compound was obtained according to a similar manner to
that of E0268 as a powder.
[1584] NMR(CDCl3), 3.95(3H, s), 4.78(2H, s), 6.71(1H, s), 6.76(1H,
t, J=55 Hz), 6.76(1H, d, J=8.4 Hz), 6.96(2H, d, J=8.9 Hz), 7.23(2H,
d, J=8.9 Hz), 7.53(1H, dd, J=8.4, 2.6 Hz), 8.08(1H, d, J=2.6
Hz).
[1585] MS (ESI+) 379 (M+Na).
EXAMPLE 271
[1586] ##STR212##
[1587] (E0271)
[1588] This compound was obtained according to a similar manner to
that of E0268.
EXAMPLE 272
[1589] ##STR213##
[1590] (E0272)
[1591] This compound was obtained according to a similar manner to
that of E0268.
[1592] IR (film): 1612.2, 1482.9, 1234.2, 1162.8, 1132.0, 1095.3,
973.8, 835.0 cm-1.
EXAMPLE 273
[1593] ##STR214##
[1594] (E0273)
[1595] This compound was obtained according to a similar manner to
that of E0268.
EXAMPLE 274
[1596] ##STR215##
[1597] (E0274)
[1598] This compound was obtained according to a similar manner to
that of E0268.
[1599] mp. 96-99.degree. C.
[1600] Mass; 389(M+1)
[1601] NMR (CDCl3,.delta.); 1.98(1H, t, J=6.1 Hz), 3.29(3H, s),
3.83(3H, s), 3.93-4.01(2H, m), 4.06-4.11(2H, m), 6.86(2H, d, J=8.8
Hz), 6.88(2H, d, J=9.0 Hz), 6.93(1H, s), 7.14(2H, d, J=8.8 Hz),
7.23(2H, d, J=9.0 Hz)
EXAMPLE 275
[1602] ##STR216##
[1603] (E0275)
[1604] To a suspension of lithium aluminum hydride (250 mg) in
ether (14 ml) was added E0268 (1.38 g) in ether (5 ml) and
tetrahydrofuran (1 ml) under ice-bath. The mixture was stirred at
room temperature for 1 hour. Lithium aluminum hydride (50 mg) was
added to the mixture under ice-bath, and then the mixture was
stirred at room temperature for 1 hour. The mixture was quenched
with water (0.3 ml), sodium hydroxide aqueous solution (15%, 0.3
ml), and water (0.9 ml), and then stirred at room temperature for
30 minutes. Magnesium sulfate and celite was added to the mixture,
then the suspension was filtered and washed with ether. The
filtrate was evaporated to give 1.307 g of oil. The oil purified
with column chromatography (SiO2, 100 ml, eluted with 20%
methanol/chloroform (500 ml)) to give E0275 as an oil (1.156 g,
82.9%).
[1605] NMR(CDCl3), 3.09(2H, t, J=5.1 Hz), 3.82(3H, s), 3.99(2H, t,
J=5.1 Hz), 6.67(1H, s), 6.82-6.89(4H, m), 7.14(2H, d, J=8.9 Hz),
7.23(2H, d, J=9.0 Hz).
[1606] MS(ESI+), 378(MH+).
EXAMPLE 276
[1607] ##STR217##
[1608] (E0276).
[1609] To a solution of E0268 (27.43 g) in tetrahydrofuran (270 ml)
was added borane methylsulfide complex (10M, 15 ml) at room
temperature. The mixture was stirred at room temperature overnight.
Then borane methylsulfide complex (7.5 ml) was added to the
mixture. After stirring at room temperature overnight, the mixture
was quenched with methanol (100 ml) and evaporated under reduced
pressure to give oil. The oil was dissolved in a mixture of
tetrahydrofuran (150 ml) and hydrochloric acid (6N, 100 ml), and
then stirred at 40.about.50.degree. C. for 1 hour. To the mixture
was added dropwise aqueous sodium hydroxide solution (30%, 80 ml),
and then sodium hydrogen carbonate, and sodium chloride. The
mixture was extracted with ethyl acetate (.times.4). The organic
layer was evaporated to give oil (31.86 g), which was purified with
column chromatography (SiO2, 1 L, eluted with 20%
methanol/dichloromethane and concentrated
ammonia/methanol/chloroform (0.025:1:4)) to give oil. A solution of
hydrogen chloride in ethyl acetate (4N, 22 ml) was added to the
solution of the oil in ethyl acetate (50 ml), and the mixture was
evaporated to give E0276 as an amorphous (22.87 g, 69.4%).
EXAMPLE 277
[1610] ##STR218##
[1611] (E0277)
[1612] E0277 was prepared in a similar manner to that of E0276.
[1613] white powder
[1614] mp. 229-231.degree. C.
[1615] IR (KBr): 3084, 2960, 2885, 2800, 2731, 2563, 2519, 2482,
1606, 1576, 1516 cm-1
[1616] Mass (ESI+): 350 (M+H)+
[1617] 200 MHz 1H NMR (DMSO-d6, d): 0.69-0.77 (2H, m),
0.84-0.96(2H, m), 1.93(1H, m), 3.14-3.22(2H, m), 3.76(3H, s),
4.14-4.20(2H, m), 6.26(1H, s), 6.94(4H, d, J=8.8 Hz), 7.14(4H, d,
J=8.8 Hz), 8.21(2H, brs)
EXAMPLE 278
[1618] ##STR219##
[1619] (E0278)
[1620] This compound was obtained according to a similar manner to
that of E0276 without formation of hydrogen chloride salt
(oil).
[1621] NMR(CDCl3), 3.09(2H, t, J=5.2 Hz), 3.94(3H, s), 3.99(2H, t,
J=5.2 Hz), 6.77(1H, t, J=54.9 Hz), 6.67(1H, s), 6.74(2H, d, J=7.5
Hz), 6.87(2H, d, J=8.9 Hz), 7.15(2H, d, J=8.7 Hz), 7.55(1H, dd,
J=8.9, 2.8 Hz), 8.09(1H, d, J=2.8 Hz).
[1622] MS(ESI+), 361(MH+).
EXAMPLE 279
[1623] ##STR220##
[1624] (E0279)
[1625] This compound was obtained according to a similar manner to
that of E0276.
EXAMPLE 280
[1626] ##STR221##
[1627] (E0280)
[1628] This compound was obtained according to a similar manner to
that of E0276.
[1629] IR (film): 3423.0, 1612.2, 1469.5, 1240.0, 1164.8, 1132.0,
1095.4, 975.8, 836.9 cm-1.
EXAMPLE 281
[1630] ##STR222##
[1631] (E0281)
[1632] This compound was obtained according to a similar manner to
that of E0276.
[1633] mp. 104-106.degree. C.
[1634] Mass; 388(M+1)
[1635] IR(KBr); 1310 cm-1
[1636] NMR(CDCl3,.delta.); 3.09(2H, t, J=5.1 Hz), 3.29(3H, s),
3.83(3H, s), 3.99(2H, t, J=5.1 Hz), 6.83(2H, d, J=8.8 Hz), 6.88(2H,
d, J=8.9 Hz), 6.93(1H, s), 7.13(2H, d, J=8.8 Hz), 7.24(2H, d, J=8.9
Hz),
EXAMPLE 282
[1637] ##STR223##
[1638] (E0282) (P0015-1)
[1639] Diethylazodicarboxylate 82.3 mg was added to a solution of
P0015 (100 mg), P0015-1 (152 mg), and triphenylphosphine 124 mg in
THF 2 ml. After stirring at ambient temperature for 5 hours, The
reaction mixture was concentrated in vacuo. The residue was
purified by silica gel column chromatography eluted with
AcOEt/CHCl3=5% viscous oil to give E0282.
[1640] Mass (ESI+): 461 (M+H)+
[1641] 200 MHz 1H NMR (DMSO-d6, d): 1.37(9H, s), 3.22-3.33(2H, m),
3.87(3H, s), 3.93-3.99(2H, m), 6.88-7.04(5H, m), 7.10(1H, t, J=54.4
Hz), 7.21(2H, d, J=8.7 Hz), 7.69(1H, dd, J=2.7,8.8 Hz), 8.14(1H, d,
J=2.7 Hz)
EXAMPLE 283
[1642] ##STR224##
[1643] (E0283)
[1644] E0283 was prepared from P0020 in a similar manner to that of
E0282.
[1645] white powder
[1646] Mass (ESI+): 482 (M+H)+
[1647] 200 MHz 1H NMR (DMSO-d6, d): 1.31(3H, t, J=7.1 Hz), 1.37(9H,
s), 3.22-3.32(2H, m), 3.79(3H, s), 3.91-3.98(2H, m), 4.32(2H, q,
J=7.1 Hz), 6.90(2H, d, J=8.7 Hz), 6.95-7.06(1H, overlapping),
6.99(2H, d, J=8.9 Hz), 7.01(1H, s), 7.17(2H, d, J=8.7 Hz), 7.25(2H,
d, J=8.9 Hz)
EXAMPLE 284
[1648] ##STR225##
[1649] (E0284)
[1650] E0284 was prepared in a similar manner to that of E0282.
[1651] white powder
[1652] Mass (ESI+): 483 (M+H)+
[1653] 200 MHz 1H NMR (DMSO-d6, d): 1.31(3H, t, J=7.1 Hz), 1.37(9H,
s), 3.22-3.33(2H, m), 3.88(3H, s), 3.96(2H, t, J=5.7 Hz), 4.33(2H,
q, J=7.1 Hz), 6.89-7.05(1H, overlapping), 6.92(1H, d, J=8.9 Hz),
6.93(2H, d, J=8.7 Hz), 7.05(1H, s), 7.21(2H, d, J=8.7 Hz), 7.72(1H,
dd, J=2.7,8.9 Hz), 8.15(1H, d, J=2.7 Hz)
EXAMPLE 285
[1654] ##STR226##
[1655] (E0285)
[1656] This compound was obtained according to a similar manner to
that of E0282 as an oil.
[1657] NMR(CDCl3), 1.45(9H, s), 3.50-3.58(2H, m), 3.94(3H, s),
4.02(2H, t, J=5.1 Hz), 6.70(1H, s), 6.75(1H, d, J=8.4 Hz), 6.85(2H,
d, J=8.9 Hz), 7.15(2H, d, J=8.9 Hz), 7.56(1H, dd, J=8.4, 2.9 Hz),
8.08(1H, d, J=2.9 Hz).
[1658] MS(ESI+), 501.2(M+Na).
EXAMPLE 286
[1659] ##STR227##
[1660] (E0286)
[1661] This compound was obtained according to a similar manner to
that of E0282 as a powder.
[1662] NMR(CDCl3), 2.89(1H, d, J=10.4 Hz, NH), 3.23(3H, s),
3.67-3.78(1H, m), 3.81(3H, s), 3.99(1H, dd, J=9.2, 6.4 Hz),
4.22(1H, dd, J=9.2, 5.0 Hz), 6.67(1H, s), 6.81(2H, d, J=8.9 Hz),
6.86(2H, d, J=6.0 Hz), 7.10-7.29(13H, m), 7.49-7.54(6H, m).
[1663] MS(ESI+), 678.4(MH+).
EXAMPLE 287
[1664] ##STR228##
[1665] (E0287)
[1666] This compound was obtained according to a similar manner to
that of E0282 as an oil.
[1667] NMR(CDCl3), 1.28(3H, d, J=6.6 Hz), 1.45(9H, s), 3.82(3H, s),
3.92(2H, d, J=4.1 Hz), 3.90-4.14(1H, m), 6.67(1H, s), 6.84(2H, d,
J=8.9 Hz), 6.86(2H, d, J=9.0 Hz), 7.13(2H, d, J=8.9 Hz), 7.23(2H,
d, J=9.0 Hz).
[1668] MS(ESI+), 514.2(M+Na).
EXAMPLE 288
[1669] ##STR229##
[1670] (E0288)
[1671] This compound was obtained according to a similar manner to
that of E0282 as an oil.
[1672] NMR(CDCl3), 1.28(3H, d, J=6.6 Hz), 1.45(9H, s), 3.82(3H, s),
3.92(2H, d, J=4.1 Hz), 3.90-4.14(1H, m), 6.67(1H, s), 6.84(2H, d,
J=8.9 Hz), 6.86(2H, d, J=9.0 Hz), 7.13(2H, d, J=8.9 Hz), 7.23(2H,
d, J=9.0 Hz).
[1673] MS(ESI+), 514.2(M+Na).
EXAMPLE 289
[1674] ##STR230##
[1675] (E0289)
[1676] 4M HCl/AcOEt 1 ml was added to a solution of E0282 (129 mg)
in AcOEt 1 ml, and the mixture was stirred at ambient temperature
for 1 hour. The supernatant was removed by decantation. The
residual oily solid was washed with AcOEt 1 ml by decantation. To
the residue was added acetone 2 ml, and oily residual solid became
white powder on stirring. This was stirred at ambient temperature
for 20 minutes. The precipitates were collected and washed with
acetone to give E0289 (91.4 mg) as a white powder.
[1677] IR (neat): 2964, 1705, 1668, 1660, 1614, 1581, 1566, 1531,
1512 cm-1
[1678] Mass (ESI+): 361 (M+H)+
[1679] 200 MHz 1H NMR (DMSO-d6, d): 3.11-3.23(2H, m), 3.87(3H, s),
4.12-4.28(2H, m), 6.90-7.02(4H, m), 7.11(1H, t, J=54.3 Hz),
7.26(2H, d, J=8.6 Hz), 7.71(1H, dd, J=2.7,8.8 Hz), 8.14(1H, d,
J=2.7 Hz), 8.24(2H, brs)
EXAMPLE 290
[1680] ##STR231##
[1681] (E0290)
[1682] This compound was obtained according to a similar manner to
that of E0289 as a white powder.
[1683] NMR(DMSO-d6), 3.17-3.21(2H, m), 3.95(3H, s), 4.19(2H, t,
J=5.0 Hz), 6.93(1H, d, J=8.8 Hz), 7.00(2H, d, J=8.8 Hz), 7.15(1H,
s), 7.28(2H, d, J=8.8 Hz), 7.76(1H, dd, J=8.8, 2.6 Hz), 8.18(1H, d,
J=2.6 Hz).
[1684] MS(ESI+), 379.1(MH+).
[1685] IR(KBr), 1612.2 cm-1.
EXAMPLE 291
[1686] ##STR232##
[1687] (E0291)
[1688] This compound was obtained according to a similar manner to
that of E0289 as a white powder.
[1689] NMR(DMSO-d6), 2.60(3H, s), 3.28-3.33(2H, m), 3.79(3H, s),
4.25(2H, t, J=4.7 Hz), 7.04-6.96(4H, m), 7.09(1H, s), 7.22-7.31
(4H, m).
[1690] MS(ESI-), 426.2 (M+Cl)+.
[1691] IR(KBr); 1610.2, 1515.8 cm-1.
[1692] MP; 189-189.2.degree. C.
EXAMPLE 292
[1693] ##STR233##
[1694] (E0292)
[1695] This compound was obtained according to a similar manner to
that of E0289 as a white amorphous.
[1696] NMR(DEMSO-d6), 1.04(3H, d, j=6.0 Hz), 3.5-3.7(1H, m),
3.79(3H, s), 3.98(1H, dd, J=10.1, 6.9 Hz), 4.11(1H, dd, J=10.1, 6.5
Hz), 6.96-7.04(4H, m), 7.09(1H, s), 7.22-7.31(4H, m).
[1697] MS(ESI+), 392.2(MH+).
EXAMPLE 293
[1698] ##STR234##
[1699] (E0293)
[1700] This compound was obtained according to a similar manner to
that of E0289 as a white amorphous.
[1701] NMR(DEMSO-d6), 1.04(3H, d, J=6.0 Hz), 3.5-3.7(1H, m),
3.79(3H, s), 3.98(1H, dd, J=10.1, 6.9 Hz), 4.11(1H, dd, J=10.1, 6.5
Hz), 6.96-7.04(4H, m), 7.09(1H, s), 7.22-7.31(4H, m).
[1702] MS(ESI+), 392.2(MH+). IR(Neat) 1612.2 cm-1.
EXAMPLE 294
[1703] ##STR235##
[1704] (E0294)
[1705] This compound was obtained according to a similar manner to
that of E0289 as a white powder.
[1706] NMR(DMSO-d6); 2.84-3.20(4H, m), 3.88(3H, s), 6.93(1H, d,
J=8.9 Hz), 7.19(1H, s), 7.30-7.36(4H, m), 7.86(1H, dd, J=8.9, 2.7
Hz), 8.19(1H, d, J=2.7 Hz).
[1707] MS(ESI+); 363.3(MH+).
[1708] IR(KBr); 1612.2, 1500.3 cm-1.
EXAMPLE 295
[1709] ##STR236##
[1710] (E0295).
[1711] A mixture of P0012 (0.5 g), chloroacetonitrile (0.2 ml),
potassium iodide (525 mg), and potassium carbonate (437 mg) in
N,N-dimethylformamide (6 ml) was stirring at 75.degree. C. for 6
hours. After cooling to room temperature, the mixture was quenched
with water, and extracted with ethyl acetate (.times.3). The
combined organic layers were washed with water (.times.3) and
brine, dried over magnesium sulfate, and evaporated to give E0295
as a solid (631.6 mg, 112%).
[1712] NMR(CDCl3), 3.83(3H, s), 4.77(2H, s), 6.69(1H, s), 6.76(1H,
t, J=55 Hz), 6.96-6.86(4H, m), 7.18-7.24(4H, m).
[1713] MS(ESI+), 378.1(M+Na).
EXAMPLE 296
[1714] ##STR237##
[1715] (E0296)
[1716] This compound was obtained according to a similar manner to
that of E0295 as an oil.
[1717] NMR(CDCl3); 1.63(1H, t, J=5.2 Hz), 1.99-2.11(2H, m),
3.82(3H, s), 3.82-3.91(2H, m), 4.12(2H, t, J=6.0 Hz), 6.67(1H, s),
6.84(2H, d, J=8.8 Hz), 6.87(2H, d, J=8.9 Hz), 7.13(2H, d, J=8.8
Hz), 7.32(2H, d, J=8.9 Hz).
[1718] IR(Neat); 1612, 1514 cm-1.
[1719] MS(ESI+); 393.1(MH+), 415.1(M+Na).
EXAMPLE 297
[1720] ##STR238##
[1721] (E0297)
[1722] This compound was obtained according to a similar manner to
that of E0205 as an oil.
[1723] NMR(CDCl3); 3.03(3H, s), 3.83(3H, s), 4.97(2H, s), 6.70(1H,
s), 6.88(2H, d, J=9.0 Hz), 7.01(2H, d, J=8.8 Hz), 7.17-7.26(4H,
m).
[1724] IR(KBr); 1612.2, 1513.9 cm-1.
[1725] MS(ESI+), 449.1(M+Na).
EXAMPLE 298
[1726] ##STR239##
[1727] (E0298)
[1728] This compound was obtained according to a similar manner to
that of E0295 as a white solid.
[1729] NMR(DMSO-d6), 3.65-3.73(2H, m), 3.79(3H, s), 3.98(2H, t,
J=4.7 Hz), 4.87(1H, t, J=5.4 Hz), 6.93(2H, d, J=8.7 Hz), 7.00(2H,
d, J=8.9 Hz), 7.07(1H, s), 7.19(2H, d, J=8.7 Hz), 7.28(2H, d, J=8.9
Hz).
[1730] MS(ESI+), 401.2(M+Na).
[1731] IR(KBr); 1610.3, 1511.9 cm-1.
EXAMPLE 299
[1732] ##STR240##
[1733] (E0299)
[1734] This compound was obtained according to a similar manner to
that of E0295 as a white solid.
[1735] NMR(CDCl3), 2.01(1H, t, J=6.1 Hz), 3.82(3H, s),
3.93-4.10(4H, m), 6.66(1H, s), 6.76(1H, t, J=55.1 Hz), 6.85(2H, d,
J=8.7 Hz), 6.87(2H, d, J=9.0 Hz), 7.15(2H, d, J=8.7 Hz), 7.21(2H,
d, J=9.0 Hz).
[1736] MS(ESI+); 383.2(M+Na).
[1737] IR(KBr); 1610.3, 1513.9, 1454.1 cm-1.
EXAMPLE 300
[1738] ##STR241##
[1739] (E0300)
[1740] This compound was obtained according to a similar manner to
that of E0295 as a white powder.
[1741] NMR(DMSO-d6); 3.78 (3H, s), 4.43(2H, s), 6.80-753(12H, m,
NH2),
[1742] MS(ESI+); 396.3(M+Na)+.
[1743] IR(KBr); 16816, 1606.4 cm-1.
EXAMPLE 301
[1744] ##STR242##
[1745] (E0301)
[1746] Alkylation of this compound was achieved by a similar manner
to that of E0295 to give salt free compound as an oil. Hydrogen
chloride salt formation was achieved successively by a similar
manner to that of E0172 to give E0301 as a white powder (498.7 mg,
49.6%).
[1747] NMR(DMSO-d6), 3.69(2H, t, J=5.0 Hz), 3.88(3H, s), 3.99(2H,
t, J=5.0 Hz), 6.92 (1H, d, J=8.7 Hz), 6.96 (2H, d, J=8.8 Hz), 7.13
(1H, s), 7.23 (2H, d, J=8.8 Hz), 7.53 (1H, dd, J=8.7, 2.9 Hz),
8.18(1H, d, J=2.9 Hz).
[1748] MS(ESI+), 402.1(M+Na)+, (Free).
[1749] IR(Neat), 1614, 1552 cm-1.
EXAMPLE 302
[1750] ##STR243##
[1751] (E0302)
[1752] This compound was obtained according to a similar manner to
that of E0295 as a white solid.
[1753] NMR(CDCl3); 3.88(3H, s), 4.45(2H, s), 6.92(1H, d, J=8.9 Hz),
6.96(2H, d, J=8.8 Hz), 7.14(1H, s), 7.26(2H, d, J=8.8 Hz), 7.41(1H,
brs, NH2), 7.56(1H, brs, NH2), 7.76(1H, dd, J=8.9, 2.5 Hz),
8.18(1H, d, J=2.5 Hz).
[1754] MS(ESI+); 415.1(M+Na).
[1755] IR(KBr); 1693.2, 1608.3 cm-1.
EXAMPLE 303
[1756] ##STR244##
[1757] (E0303)
[1758] This compound was obtained according to a similar manner to
that of E0295 as an oil.
[1759] NMR(CDCl3); 3.94(3H, s), 3.94-4.14(4H, m), 6.68(1H, s),
6.74(1H, d, J=8.7 Hz), 6.86(1H, t, J=55.0 Hz), 6.88(2H, d, J=8.9
Hz), 7.16(2H, d, J=8.9 Hz), 7.53(1H, dd, J=2.6, 8.7 Hz), 8.08(1H,
d, J=2.6 Hz).
[1760] MS(ESI+); 384.2(M+Na).
[1761] IR(KBr), 1805.1, 1612.2 cm-1.
EXAMPLE 304
[1762] ##STR245##
[1763] (E0304)
[1764] This compound was obtained according to a similar manner to
that of E0295 as a white powder.
[1765] NMR(DMSO-d6); 3.88(3H, s), 4.44(2H, s), 6.98-9.89(4H, m),
7.10(1H, t, J=54.3 Hz), 7.24(2H, d, J=8.8 Hz), 7.39(1H, brs, NH2),
7.54(1H, brs, NH2), 7.70(1H, dd, J=8.9, 2.8 Hz), 8.14(1H, d, J=2.8
Hz).
[1766] MS(ESI-); 373 (M-H)+.
[1767] IR(KBr); 1662.3, 1610.3 cm-1.
EXAMPLE 305
[1768] ##STR246##
[1769] (E0305)
[1770] This compound was obtained according to a similar manner to
that of E0298.
[1771] IR (film): 3388.3, 1494.6, 1236.2, 1160.9, 1133.9, 1095.4,
975.8, 833.1 cm-1.
EXAMPLE 306
[1772] ##STR247##
[1773] (E0306)
[1774] This compound was obtained according to a similar manner to
that of E0295.
[1775] Mass; 384(M+1)
EXAMPLE 307
[1776] ##STR248##
[1777] (E0307)
[1778] To a suspension of lithium aluminum hydride (250 mg) in
ether (5 ml) was added E0295 (630 mg) in tetrahydrofuran (1 ml)
under ice-bath. After stirring at room temperature for 1 hour. the
mixture was quenched with water (0.125 ml), sodium hydroxide
aqueous solution (15%, 0.125 ml), and water (0.375 ml), and then
stirred at room temperature for 30 minutes. Magnesium sulfate and
celite was added to the mixture, then the suspension was filtered
and washed with ether. The filtrate was evaporated to give 0.5 g of
oil. The oil was purified with column chromatography (SiO2, 50 ml,
eluted with methanol/dichloromethane/concentrated ammonia water
(1/10/0.05)) to give oil (300 mg). The oil was dissolved in ethyl
acetate and added a solution of hydrogen chloride in ethyl acetate
(4N, 1.6 ml) The mixture was evaporated to give oil, which was
crystallized from methanol and diisopropyl ether to give E0307 as a
powder (300 mg, 42.7%).
[1779] NMR(DMSO-d6), 3.20(2H, t, J=4.9 Hz), 3.78 (3H, s), 4.16(2H,
t, J=4.9 Hz), 6.85(1H, s), 6.94-7.01(4H, m), 7.08(1H, t, J=54.6
Hz), 7.20-7.26(4H, m).
[1780] MS(ESI+), 360.3(MH+, free).
[1781] IR(KBr, 20727-7), 1612, 1513.9 cm-1.
EXAMPLE 308
[1782] ##STR249##
[1783] (E0308)
[1784] This compound was obtained according to a similar manner to
that of E0307.
[1785] IR (film): 3401.8, 1610.3, 1511.9, 1469.5, 1240.0, 1162.9,
1130.1, 975.8, 827.3 cm-1.
EXAMPLE 309
[1786] ##STR250##
[1787] (E0309)
[1788] A mixture of P0011 (200 mg), Chloromethylsulfonic acid
sodium salt (274 mg), potassium iodide (298 mg), and potassium
carbonate (248 mg) in 1-methyl-2-pyrrolidinone (2 ml) was stirring
at 150.degree. C. overnight. After cooling to room temperature, the
mixture was poured into a mixture of aqueous hydrogen chloride
solution (1 N), brine, and ethyl acetate. The aqueous layer was
separated and extracted with ethyl acetate (.times.3). The combined
organic layers were dried over magnesium sulfate, and evaporated
under reduced pressure to give oil. The oil was purified with
column chromatography (SiO2 100 ml, eluted with 15%
methanol/dichloromethane) to give E0309 as a brown amorphous (154.3
mg, 60%).
[1789] MS (ESI-); 427.1(M-H).
[1790] NMR(DMSO-d6), 3.79(3H, s), 4.52(2H, s), 7.00(2H, d, J=9.0
Hz), 7.01(2H, d, J=8.9 Hz), 7.07(1H, s), 7.18(2H, d, J=9.0 Hz),
7.27(2H, d, J=8.9 Hz).
EXAMPLE 310
[1791] ##STR251##
[1792] (E0310).
[1793] To a solution of P0011 (1.0 g) in DMF (10 ml) under water
cooling was added portionwise NaH (60% in Oil, 144 mg) and stirred
for 1 hour. After then, III (787 mg) was added and the reaction
mixture was stirred at 50.degree. C. for 5 hours. The mixture was
quenched with water and extracted twice with EtOAc. The organic
layer was washed three times with water and once with brine, dried
over MgSO4, filtered and evaporated under reduced pressure. The
residue was column chromatographed on silica gel (50 ml) to give
803 mg (55%) of E0310 as a oil.
EXAMPLE 311
[1794] ##STR252##
[1795] (E0311)
[1796] This compound was obtained according to a similar manner to
that of E0310.
EXAMPLE 312
[1797] ##STR253##
[1798] (E0312)
[1799] The mixture of E0310 (800 mg) and cHCl (100 .mu.l) in EtOH
(10 ml) was stirred at room temperature f or 3 hours. After
addition of aqueous sodium bicarbonate, the mixture was evaporated,
and extracted twice with EtOAc. The organic layer was washed with
water and brine, dried over MgSO4, filtered and evaporated under
reduced pressure. The residue (710 mg) was column chromatographed
on silica gel (50 ml) to give 570 mg (93%) of E0312.
[1800] IR (film): 3409.5, 1612.2, 1513.9, 1467.6, 1243.9, 1162.9,
1130.1, 835.0, 835.0 cm-1.
EXAMPLE 313
[1801] ##STR254##
[1802] (E0313)
[1803] This compound was obtained according to a similar manner to
that of E0312.
[1804] mp: 122.3-122.5.degree. C.
[1805] IR (film): 3399.9, 1612.2, 1513.9, 1456.0, 1251.6, 1174.4,
1083.8, 1033.7, 836.9, 800.3 cm-1.
EXAMPLE 314
[1806] ##STR255##
[1807] (E0314)
[1808] 60% Sodium hydride 39.7 mg was added to a solution of P0011
(255 mg) in DMF 1.5 ml. The mixture was stirred at ambient
temperature for 1 hour. To this was added ethyl bromoacetate 153
mg. The reaction mixture was stirred at ambient temperature for 1
hour, and then quenched by adding saturated ammonium chloride
solution, and whole mixture was extracted with AcOEt. The organic
layer was washed with H2O, aqueous sodium chloride solution, dried
over magnesium sulfate, and concentrated in vacuo. The residue was
purified by silica gel column chromatography eluted with
AcOEt/n-hexane=30% to give E0314 (217 mg) as an oil.
[1809] Mass (ESI+) 421(M+H)+
[1810] 200 MHz 1H NMR (DMSO-d6, d): 1.94(3H, t, J=7.1 Hz), 3.79(3H,
s), 4.15(2H, q, J=7.1 Hz), 4.79(2H, s), 6.92(2H, d, J=8.8 Hz),
6.99(2H, d, J=8.9 Hz), 7.09 (1H, s), 7.20 (2H, d, J=8.8 Hz),
7.28(2H, d, J=8.9 Hz)
EXAMPLE 315
[1811] ##STR256##
[1812] (E0315)
[1813] 1M solution of diisobutylaluminum hydride in toluene 0.5 ml
was added dropwise to a solution of E0314 (98 mg) in THF 3 ml at
-50.degree. C. The mixture was stirred at -50.degree. C. for 1
hour, then at 5.degree. C. for 1 hour. Additional 1M solution of
diisobutylaluminum hydride in toluene 0.5 ml was added dropwise.
After stirring at 5.degree. C. for one more hour, the reaction was
quenched by adding 10% aqueous potassium sodium tartaric acid salt,
and the mixture was filtered through a celite pad. The filtrate was
extracted with AcOEt. The organic layer was washed with saturated
aqueous sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo. The residue was purified by preparative thin
layer silica gel chromatography developed by AcOEt/n-hexane=60%.
The separated silica gel was extracted with 10% MeOH/CHCl3 and the
solvent was evaporated in vacuo to give E0315 (54.5 mg) as an oil,
which became solid on standing.
[1814] IR (KBr): 3431, 2931, 1612, 1564, 1549, 1512 cm-1
[1815] Mass (ESI+): 379 (M+H)+
[1816] 400 MHz 1H NMR (DMSO-d6, d): 3.67-3.72(2H, m), 3.79(3H, s),
3.84-3.99(2H, m), 4.87(1H, t, J=5.4 Hz), 6.93(2H, d, J=8.7 Hz),
7.00(2H, d, J=8.9 Hz), 7.10(1H, s), 7.19(2H, d, J=8.7 Hz), 7.27(2H,
d, J=8.9 Hz)
EXAMPLE 316
[1817] ##STR257##
[1818] (E0316)
[1819] 60% Sodium hydride 52 mg was added to a solution of P0020
(200 mg) in DMF 2 ml under ice bath cooling. The mixture was
stirred at same temperature for 30 minutes. To this was added
bromoacetic acid 90.3 mg. The reaction mixture was stirred at
ambient temperature for 2 hours, and then quenched by adding s1M
HCl 3 ml. H2O 3 ml and diisopropyl ether 2 ml were added and the
mixture was stirred in an ice bath f or 30 minutes. The
precipitates were collected and washed with H2O and diisopropyl
ether to give E0316 (231.2 mg) as a white powder
[1820] Mass (ESI+): 397 (M+H)+
[1821] 200 MHz 1H NMR (DMSO-d6, d): 1.31(3H, t, J=7.1 Hz), 3.79
(3H, s), 4.32(2H, q, J=7.1 Hz), 4.68(2H, s), 6.88(2H, d, J=8.8 Hz),
7.00(2H, d, J=8.9 Hz), 7.02(1H, s), 7.18(2H, d, J=8.8 Hz), 7.26(2H,
d, J=8.9 Hz), 13.05(1H, brs)
EXAMPLE 317
[1822] ##STR258##
[1823] (E0317)
[1824] E0317 was prepared in a similar manner to that of E0316.
[1825] white powder
[1826] Mass (ESI+): 398 (M+H)+
[1827] 200 MHz 1H NMR (DMSO-d6, d): 1.31(3H, t, J=7.1 Hz), 3.88(3H,
s), 4.33(2H, q, J=7.1 Hz), 4.70(2H, s), 6.92(2H, d, J=8.8 Hz),
6.89-7.00(1H, m), 7.06(1H, s), 7.22(2H, d, J=8.8 Hz), 7.73(1H, dd,
J=2.8,8.8 Hz), 8.15(1H, d, J=2.8 Hz), 13.04(1H, brs)
EXAMPLE 318
[1828] ##STR259##
[1829] (E0318)
[1830] E0318 was obtained according to a similar manner to that of
E0316.
[1831] oil
[1832] Mass (ESI+): 365 (M+H)+
[1833] 200 MHz 1H NMR (DMSO-d6, d): 0.70-0.93(4H, m), 1.70-2.00(1H,
m), 3.76(3H, s), 4.66(2H, s), 6.25(1H, s), 6.85(2H, d, J=8.9 Hz),
6.92(2H, d, J=9.0 Hz), 7.06-7.16(4H, m), 13.00(1H, brs)
EXAMPLE 319
[1834] ##STR260##
[1835] (E0319)
[1836] To a suspension of sodium borohydride 19.1 mg in THF 2 ml
was added boron trifluoride diethyl etherate 89.5 mg dropwise under
ice bath cooling 2.5 eq. The mixture was stirred at same
temperature for 30 minutes. E0316 (100 mg) was added in one portion
and the mixture was stirred at ambient temperature for 5 hours. 1M
HCl 5 ml was added and the mixture was stirred at ambient
temperature for 30 minutes. The mixture was extracted with AcOEt.
The organic layer was washed with saturated aqueous sodium
bicarbonate solution and saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo.
The residue was crystallized from diisopropyl ether to give E0319
(68.9 mg) as a white powder.
[1837] Mass (ESI+): 383 (M+H)+
[1838] 200 MHz 1H NMR (DMSO-d6, d): 1.31(3H, t, J=7.1 Hz),
3.65-3.73(2H, m), 3.79(3H, s), 3.94-4.00(2H, m), 4.32(2H, q, J=7.1
Hz), 4.87(1H, t, J=5.5 Hz), 6.91(2H, d, J=8.8 Hz), 6.99(2H, d,
J=8.9 Hz), 7.01(1H, s), 7.17(2H, d, J=8.8 Hz), 7.25(2H, d, J=8.9
Hz)
EXAMPLE 320
[1839] ##STR261##
[1840] (E0320)
[1841] E0320 was prepared in a similar manner to that of E0319.
[1842] white powder
[1843] Mass (ESI+): 384 (M+H)+
[1844] 200 MHz 1H NMR (DMSO-d6, d): 1.31(3H, t, J=7.1 Hz),
3.65-3.74(2H, m), 3.88(3H, s), 3.96-4.02(2H, m), 4.33(2H, q, J=7.1
Hz), 4.87(1H, t, J=5.4 Hz), 6.89-6.96(3H, m), 7.05(1H, s), 7.21(2H,
d, J=8.7 Hz), 7.72(1H, dd, J=2.7,8.8 Hz), 8.14(1H, d, J=2.7 Hz)
EXAMPLE 321
[1845] ##STR262##
[1846] (E0321)
[1847] E0321 was prepared in a similar manner to that of E0319.
[1848] white powder
[1849] mp. 142-144.degree. C.
[1850] IR (KBr): 3246, 2924, 1612, 1566, 1547, 1516 cm-1
[1851] Mass (ESI+): 351 (M+H)+
[1852] 200 MHz 1H NMR (DMSO-d6, d): 0.68-0.77(2H, m), 0.85-0.95(2H,
m), 1.92(1H, m), 3.64-3.73(2H, m), 3.76(3H, s), 3.96(2H, t, J=4.9
Hz), 4.85(1H, t, J=5.5 Hz), 6.24(1H, s), 6.85-6.96(4H, m),
7.05-7.17(4H, m)
EXAMPLE 322
[1853] ##STR263##
[1854] (E0322)
[1855] E0322 was prepared in a similar manner to that of E0319.
[1856] white powder
[1857] mp. 228-231.degree. C.
[1858] IR (KBr): 3082, 2958, 2885, 2802, 2733, 2480, 1606, 1572,
1512 cm-1
[1859] Mass (ESI+): 350 (M+H)+
[1860] 200 MHz 1H NMR (DMSO-d6, d): 0.69-0.77(2H, m), 0.83-0.96(2H,
m), 1.93(1H, m), 3.14-3.22 (2H, m), 3.76(3H, s), 4.14-4.20(2H, m),
6.27(1H, s), 6.93(4H, d, J=8.8 Hz), 7.14(4H, d, J=8.8 Hz), 8.24(2H,
brs)
EXAMPLE 323
[1861] ##STR264##
[1862] (E0323).
[1863] A solution of sodium sulfite 84.2 mg in H2O 1 ml was added
to a solution of P0022 (258.1 mg) in EtOH 3 ml and stirred at
70.degree. C. for 2 hours. At which time, white precipitates were
appeared and H2O 1 ml was added to dissolve the precipitates. The
mixture was stirred at 80.degree. C. overnight to give a clear
solution. This was stirred at 80.degree. C. further for 28 hours.
The reaction mixture was acidified by 1M HCl 0.7 ml, concentrated
and dried under vacuo. The residue was dissolved in CHCl3, dried
over magnesium sulfate, all of unsoluble matter was filtered off,
and concentrated in vacuo to give E0323 (245 mg) as an amorphous
powder.
[1864] Mass (API-ES negative) 425(M-H)+
[1865] 200 MHz 1H NMR (DMSO-d6, d): 2.61-2.69(2H, m), 2.78-2.91(2H,
m), 3.79(3H, s), 7.00(2H, d, J=8.9 Hz), 7.12(1H, s), 7.17(2H, d,
J=8.6 Hz), 7.22(2H, d, J=8.6 Hz), 7.29(2H, d, J=8.9 Hz)
EXAMPLE 324
[1866] ##STR265##
[1867] (E0324)
[1868] E0324 was prepared from P0023 in a similar manner to that of
E0323.
[1869] amorphous powder
[1870] Mass (API-ES negative): 426 (M-H)+
[1871] 200 MHz 1H NMR (DMSO-d6, d): 2.61-2.69(2H, m), 2.83-2.92(2H,
m), 3.88(3H, s), 6.92(1H, d, J=8.8 Hz), 7.17(1H, s), 7.23(4H, s),
7.75(1H, dd, J=8.8,2.7 Hz), 8.20(1H, d, J=2.7 Hz)
EXAMPLE 325
[1872] ##STR266##
[1873] (E0325)
[1874] DMF 41 mg was added to a solution of E0319 (239 mg) in
thionyl chloride 0.6 ml and the mixture was stirred at 50.degree.
C. for 30 minutes. The reaction mixture was concentrated in vacuo.
To the residue was added toluene 3 ml, and concentrated in vacuo.
The residue was dissolved in THF 10 ml and was added dropwise to a
solution of 28% aqueous ammonium hydroxide solution 0.5 ml and
tetrabutylammonium hydrogensulfate 19 mg in THF 4 ml under ice bath
cooling. After stirring at ambient temperature for 30 minutes, the
reaction mixture was partitioned between AcOEt and aqueous sodium
chloride solution. The organic layer was washed with aqueous sodium
chloride solution, dried over magnesium sulfate. The residue was
purified by silica gel column chromatography eluted with
MeOH/CHCl3=2%, 5%. Pure fraction was collected and concentrated in
vacuo. The residual solid was recrystallized from EtOH-diisopropyl
ether to give E0325 (72.6 mg) as a white powder.
[1875] mp. 131-132.degree. C.
[1876] IR (KBr): 3354, 3184, 3126, 1707, 1693, 1676, 1647, 1564,
1549, 1516 cm-1
[1877] Mass (ESI+): 426 (M+H)+
[1878] 200 MHz 1H NMR (DMSO-d6, d): 2.95-3.04(2H, m), 3.21-3.30(2H,
m), 3.79(3H, s), 6.87(2H, s), 7.00(2H, d, J=8.9 Hz), 7.14(1H, s),
7.23-7.33(6H, m)
EXAMPLE 326
[1879] ##STR267##
[1880] (E0326)
[1881] E0326 was prepared in a similar manner to that of E0325.
[1882] white powder
[1883] mp. 139-140.degree. C.
[1884] IR (KBr): 3230, 3132, 1610, 1568, 1527, 1500 cm-1
[1885] Mass (ESI+): 441 (M+H)+
[1886] 200 MHz 1H NMR (DMSO-d6, d): 2.58(3H, s), 2.90-3.00(2H, m),
3.25-3.33(2H, m), 3.88(3H, s), 6.93(1H, d, J=8.9 Hz), 6.97(1H,
brs), 7.19(1H, s), 7.26(2H, d, J=8.3 Hz), 7.34(2H, d, J=8.3 Hz),
7.77(1H, dd, J=8.9,2.8 Hz), 8.19(1H, d, J=2.8 Hz)
EXAMPLE 327
[1887] ##STR268##
[1888] (E0327-0) (E0327-1) (E0327).
[1889] A mixture of E0327-0 (800 mg) and E0327-1, methyl
(triphenylphosphoranylidene)-acetate (850 mg) in toluene (10 ml)
was stirred under reflux condition for 5 hrs. The mixture was
evaporated under reduced pressure and column chromatographed on
silica gel (50 ml, Hex:EtOAc=5:1) to give 795 mg (85.5%) of
E0327.
[1890] IR (film): 1718.3, 1637.3, 1513.9, 1241.9, 1166.7, 1132.0,
977.7, 837.0 cm-1
EXAMPLE 328
[1891] ##STR269##
[1892] (E0328)
[1893] To a suspension of E0258 (180 mg) in toluene (5 ml) was adde
thionylchloride (0.17 ml) at room temperature. The reaction mixture
was stirred at 100.degree. C. for 5 hours until the mixture become
clear solution. After then, the mixture was evaporated under
reduced pressure. (become solid) THF was added, and then aqueous
NH3 (37%) was added. The mixture was stirred for 1 hour, and
quenched with water, and extracted twice with EtOAc. The combined
organic layer was washed with sat.NaHCO3, water and brine, dried
over Na2SO4, filtered and evaporated under reduced pressure to give
170 mg (95%) of E0328 as a powder.
[1894] IR (KBr): 3347.8, 1671.9, 1606.4, 1513.9, 1467.6, 1388.5,
1236.2, 1164.8, 1132.0, 979.7, 837.0 cm-1.
EXAMPLE 329
[1895] ##STR270##
[1896] (E0329)
[1897] T a suspension of E0258 (200 mg) in toluene (4 ml) was added
thionylchloride (0.19 ml) at room temperature. The reaction mixture
was stirred at 10.degree. C. for 5 hours until the mixture become
clear solution. After then, the mixture was evaporated under
reduced pressure. (become solid) THF was added, and then Me2NH (116
mg) was added. The mixture was stirred for 1 hour, and quenched
with water, and extracted twice with EtOAc. The combined organic
layer was washed with sat.NaHCO3, water and brine, dried over
Na2SO4, filtered and evaporated under reduced pressure to give 45
mg (21%) of E0329 as a powder.
[1898] Filtrate (58 mg).
[1899] mp: 118-120.degree. C.
[1900] IR (film): 1650.8, 1608.3, 1511.9, 1469.5, 1240.0, 1159.0,
1133.9 cm-1.
EXAMPLE 330
[1901] ##STR271##
[1902] (E0330).
[1903] A mixture of E0328 (125 mg) and Pd/C (10 mg) in EtOH (10m)
was stirred under H2 atmosphere for 3.0 hours. After filtration, a
filtrate was evaporated under reduced pressure. The residue was
dissolved in EtOH and filtered with syringe driven filter, and
evaporated to give 85 mg of E0330.
[1904] IR (KBr): 3342.0, 1670.0, 1511.9, 1240.0, 1160.9, 1130.1
cm-1.
EXAMPLE 331
[1905] ##STR272##
[1906] (E0331).
[1907] A mixture of E0138 (300 mg) and MeSNa (72 mg) in DMF (6 ml)
was heated at 70.degree. C. for 5 hours. After cooling, the
reaction mixture was partitioned between EtOAc and water. The
aqueous layer was separated and extracted with EtOAc. The combined
organic layer was washed with water (twice) and brine, dried over
Na2SO4, filtered and evaporated. The residue was column
chromatographed on silica gel to give 270 mg (quant) of E0331.
EXAMPLE 332
[1908] ##STR273##
[1909] (E0332)
[1910] E0332 was prepared from E0141 in a similar manner to that of
E0331.
[1911] Mass (ESI+): 408 (M+H)+
[1912] 200 MHz 1H NMR (DMSO-d6, d): 1.73-1.89(2H, m), 2.03(3H, s),
2.40-2.52(2H, m), 2.62-2.70(2H, m), 3.88(3H, s), 6.92(1H, d, J=8.8
Hz), 7.18(1H, s), 7.24(4H, s), 7.76(1H, dd, J=8.8,2.7 Hz), 8.18(1H,
d, J=2.7 Hz)
EXAMPLE 333
[1913] ##STR274##
[1914] (E0333)
[1915] This compound was obtained according to a similar manner to
that of E0331.
EXAMPLE 334
[1916] ##STR275##
[1917] (E0334)
[1918] This compound was obtained according to a similar manner to
that of E0331.
EXAMPLE 335
[1919] ##STR276##
[1920] (E0335)
[1921] This compound was obtained according to a similar manner to
that of E0331
EXAMPLE 336
[1922] ##STR277##
[1923] (E0336)
[1924] This compound was obtained according to a similar manner to
that of E0331.
EXAMPLE 337
[1925] ##STR278##
[1926] (E0337)
[1927] A mixture of E0331 (250 mg) and mcpba (165 mg) in CH2Cl2 was
stirred under ice-cooling for 1 hour, and then mcpba (55 mg) was
added. After stirring for 1 hour under ice cooling, the reaction
mixture was partitioned between CHCl3 and sat.NaHCO3. The organic
layer was separated, washed with sat.NaHCO3, water and brine, dried
over Na2SO4, filtered and evaporated under reduced pressure. The
residue was column chromatographed on silica gel (Hex/EtOAc) to
give 11 mg (52%) of E0337.
[1928] IR (film): 1511.9, 1303.6, 1240.0, 1130.1 cm-1.
[1929] Oxide: FR267958
[1930] NMR (CDCl.sub.3): 2.599(s, 3H), 2.85-3.21(m, 4H), 3.828(s,
3H), 6.721(s, 1H), 6.872(d,J=9.0 Hz,2H), 7.141(s, 4H),
7.179(d,J=9.0 Hz, 2H).
[1931] MS: (M+Na)+431.1 (M110092-2)
EXAMPLE 338
[1932] ##STR279##
[1933] (E0338)
[1934] This compound was obtained according to a similar manner to
that of E0337.
[1935] IR (film): 1511.9, 1469.5, 1311.4, 1282.4, 1236.2, 1126.2,
973.9, 823.5, 759.8 cm-1.
EXAMPLE 339
[1936] ##STR280##
[1937] (E0339)
[1938] This compound was obtained according to a similar manner to
that of E0337.
[1939] IR (film): 1511.9, 1469.5, 1311.4, 1282.4, 1236.2, 1128.2,
973.9, 823.5, 759.8 cm-1.
EXAMPLE 340
[1940] ##STR281##
[1941] (E0340)
[1942] This compound was obtained according to a similar manner to
that of E0337.
[1943] IR(film): 1673.9, 1616.1, 1498.4, 1477.2, 1467.6, 1390.4,
1307.5, 1290.1, 1240.0, 1160.9, 1132.0, 971.9, 756.0 cm-1.
[1944] NMR (CDCl3): 2.76-2.94(m, 4H), 3.927(s, 3H), 3.943(s, 3H),
6.728(s, 1H), 6.752(d, J=8.9 Hz, 1H), 7.12-7.26(m, 4H),
7.46-7.59(m, 1H), 8.04-8.10(m, 1H).
[1945] MASS (M+Na)+445.1 (FR267958-N)
EXAMPLE 341
[1946] ##STR282##
[1947] (E0341).
[1948] To a solution of E0336 (450 mg) in dichloromethane (45 ml)
was added MCPBA (306 mg) at room temperature. After stirring for 1
hour, the reaction mixture was washed with sat.NaHCO3 (twice) and
water, dried over Na2SO4, filtered and evaporated under reduced
pressure. The residue was column chromatographed on silica gel (50
ml) to give 470 mg of E0341 as an oil.
EXAMPLE 342
[1949] ##STR283##
[1950] (E0342)
[1951] E0342 was prepared in a similar manner to that of E0341.
[1952] white powder.
[1953] mp. 92-93.degree. C.
[1954] IR (KBr): 3080, 2952, 1612, 1566, 1547, 1529, 1500 cm-1
[1955] Mass (ESI+): 424 (M+H)+
[1956] 200 MHz 1H NMR (DMSO-d6, d): 1.87-2.00(2H, m), 2.51(3H, s),
2.56-2.78(4H, m), 3.88(3H, s), 6.92(1H, d, J=8.9Hz), 7.19(1H, s),
7.21-7.31(4H, m), 7.76(1H, dd, J=2.7,8.9 Hz), 8.19(1H, d, J=2.7
Hz)
EXAMPLE 343
[1957] ##STR284##
[1958] (E0343).
[1959] To a solution of E0336 (450 mg) in dichloromethane (45 ml)
was added MCPBA (306 mg) at room temperature. After stirring for 1
hour, the reaction mixture was washed with sat.NaHCO3 (twice) and
water, dried over Na2SO4, filtered and evaporated under reduced
pressure. The residue was column chromatographed on silica gel (50
ml) and recrystallized from EtOH to give 168 mg (44%) of E0343.
EXAMPLE 344
[1960] ##STR285##
[1961] (E0344)
[1962] 3-Chloroperoxybenzoic acid (407 mg) was added to a solution
of E0342 (666.3 mg) in CH2Cl2 6 ml under ice bath cooling. The
reaction mixture was stirred at ambient temperature for 1 hour. The
mixture was diluted with CHCl3, washed with 1M NaOH, 5% aqueous
sodium thiosulfate solution, and saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo.
The residue was recrystallized from AcOEt-n-hexane to give E0344
(565.2 mg) as a white powder.
[1963] mp. 121-122.degree. C.
[1964] IR (KBr): 3120, 2954, 1707, 1693, 1647, 1612, 1566, 1547,
1529, 1500 cm-1
[1965] Mass (ESI+): 440 (M+H)+
[1966] 200 MHz 1H NMR (DMSO-d6, d): 1.93-2.06(2H, m), 2.67-2.75(2H,
m), 2.96(3H, s), 3.04-3.13(2H, m), 3.88(3H, s), 6.92(1H, d, J=8.8
Hz), 7.19(1H, s), 7.19-7.31(4H, m), 7.76(1H, dd, J=8.8,2.8 Hz),
8.19(1H, d, J=2.8 Hz)
EXAMPLE 345
[1967] ##STR286##
[1968] (E0345)
[1969] Oxalylchloride 286 mg was added to a suspension of E0363
(0.43 g) in CH2Cl2 3 ml under ice bath cooling. DMF 5 drop was
added and the mixture was stirred at same temperature for 1 hour,
and then concentrated in vacuo. To the residue, was added toluene
and concentrated in vacuo. The residue was dissolved in THF 5 ml
and was added to a solution of aqueous ammonium hydroxide solution
5 ml with under ice bath cooling. The mixture was stirred at same
temperature for 1 hour, diluted with AcOEt, washed successively
with 1M HCl, saturated aqueous sodium bicarbonate solution, and
saturated aqueous sodium chloride solution, dried over magnesium
sulfate, and concentrated in vacuo. The residue was purified by
silica gel column chromatography eluted with AcOEt/n-hexane=60%.
The pure fraction was collected and concentrated in vacuo and the
residue was crystallized from diisopropylether to give E0345 (287.8
mg) as a white powder.
[1970] Mass (ESI+): 381 (M+H)+
[1971] 200 MHz 1H NMR (DMSO-d6, d): 1.97(3H, s), 2.89(2H, t, J=6.8
Hz), 3.87(3H, s), 4.21(2H, t, J=6.8 Hz), 6.91(1H, d, J=8.8 Hz),
6.98(1H, s), 7.22(2H, d, J=8.4 Hz), 7.28(2H, d, J=8.4 Hz), 7.38(1H,
brs), 7.63-7.75(1H, brs), 7.72(1H, dd, J=2.7,8.8 Hz), 8.16(1H, d,
J=2.7 Hz)
EXAMPLE 346
[1972] ##STR287##
[1973] (E0346).
[1974] A mixture of E0109 (449.1 mg) and sodium methoxide 238 mg in
formamide 5 ml was heated at 70.degree. C. for 5 hours. The mixture
was allowed to cool to ambient temperature, and was partitioned
between ethyl acetate and H2O. The organic layer was washed with
saturated aqueous sodium chloride solution, dried over magnesium
sulfate, and concentrated in vacuo. The residue was purified by
silica gel column chromatography eluted with CHCl3, then
MeOH/CHCl3=2%, 5% to give E0346 (235.7 mg) as a white powder.
[1975] Mass (ESI+): 338(M+H)+
[1976] 400 MHz 1H NMR (DMSO-d6, d): 2.70(2H, t, J=6.9 Hz),
3.56-3.62(2H, m), 3.79(3H, s), 4.65(1H, t, J=5.1 Hz), 6.92(1H, s),
6.99(2H, d, J=8.9 Hz), 7.15(2H, d, J=8.3 Hz), 7.20(2H, d, J=8.3
Hz), 7.27(2H, d, J=8.9 Hz), 7.33(1H, s), 7.64(1H, s)
EXAMPLE 347
[1977] ##STR288##
[1978] (E0347)
[1979] E0347 was prepared in a similar manner to that of E0346.
[1980] white powder
[1981] Mass (ESI+): 454 (M+H)+
[1982] 200 MHz 1H NMR (DMSO-d6, d): 3.65-3.73(2H, m), 3.78(3H, s),
3.94-4.00(2H, m), 4.86(1H, t, J=5.5 Hz), 6.88(1H, s), 6.91(2H, d,
J=8.8 Hz), 6.99(2H, d, J=8.9 Hz), 7.16(2H, d, J=8.8 Hz), 7.26(2H,
d, J=8.9 Hz), 7.32(1H, s), 7.63(1H, s)
EXAMPLE 348
[1983] ##STR289##
[1984] (E0348)
[1985] E0348 was prepared in a similar manner to that of E0346.
[1986] white powder
[1987] Mass (ESI+): 355 (M+H)+
[1988] 200 MHz 1H NMR (DMSO-d6, d): 3.65-3.74(2H, m), 3.87(3H, s),
3.96-4.05(2H, m), 4.87(1H, t, J=5.5 Hz), 6.88-6.97(4H, m), 7.20(2H,
d, J=8.7 Hz), 7.37(1H, brs), 7.67-7.73(1H, brs, overlapping),
7.71(1H, dd, J=2.6,8.8 Hz), 8.16(1H, d, J=2.6 Hz)
EXAMPLE 349
[1989] ##STR290##
[1990] (E0349)
[1991] E0349 was prepared in a similar manner to that of E0346.
[1992] white powder
[1993] Mass (ESI+): 453 (M+H)+
[1994] 400 MHz 1H NMR (DMSO-d6, d): 1.37(9H, s), 3.24-3.29(2H, m),
3.78(3H, s), 3.94(2H, t, J=5.8 Hz), 6.88(1H, s), 6.90(2H, d, J=8.8
Hz), 6.99(2H, d, J=9.0 Hz), 6.97-7.00(1H, br), 7.16(2H, d, J=8.8
Hz), 7.25(2H, d, J=9.0 Hz), 7.32(1H, brs), 7.62(1H, brs)
EXAMPLE 350
[1995] ##STR291##
[1996] (E0350)
[1997] E0350 was prepared in a similar manner to that of E0346.
[1998] white powder
[1999] Mass (ESI+): 454 (M+H)+
[2000] 200 MHz 1H NMR (DMSO-d6, d): 1.37(9H, s), 3.22-3.33(2H, m),
3.88(3H, s), 3.93-3.99(2H, m), 6.88-7.10(4H, m), 6.91(1H, s),
7.20(2H, d, J=8.7 Hz), 7.36(1H, brs), 7.68(1H, brs), 7.71(1H, dd,
J=2.7,8.8 Hz), 8.16(1H, d, J=2.7 Hz)
EXAMPLE 351
[2001] ##STR292##
[2002] (E0351)
[2003] E0351 was prepared in a similar manner to that of E0346.
[2004] mp. 168-169.degree. C.
[2005] IR (KBr): 3381, 3192, 1705, 1695, 1674, 1643, 1614, 1564,
1549, 1516 cm-1
[2006] Mass (ESI+): 392 (M+H)+
[2007] 400 MHz 1H NMR (DMSO-d6, d): 3.79(3H, s), 4.43(2H, s),
6.93(2H, d, J=8.9 Hz), 7.00(2H, d, J=9.0 Hz), 7.08(1H, s), 7.21(2H,
d, J=8.9 Hz), 7.28(2H, d, J=9.0 Hz), 7.40(1H, brs), 7.54 (1H,
brs)
EXAMPLE 352
[2008] ##STR293##
[2009] (E0352).
[2010] A mixture of E0346 (433.5 mg) and N,N-dimethylacetamide
dimethyl acetal 856 mg in toluene 5 ml was heated at 100.degree. C.
for 40 minutes. The reaction mixture was concentrated in vacuo To
the residue was added toluene and concentrated in vacuo. The
residue was dissolved in toluene 5 ml, hydroxylamine hydrochloride
893 mg and AcOH 3 ml was added and the mixture was heated at
100.degree. C. for 1 hour. The mixture was cooled to ambient
temperature, and partitioned between AcOEt and H2O, The organic
layer was washed with H2O, saturated aqueous sodium bicarbonate
solution, and saturated aqueous sodium chloride solution, dried
over magnesium sulfate, and concentrated in vacuo. The residue was
purified by silica gel column chromatography eluted with
AcOEt/n-hexane=40%, 60%, 80%. The pure fraction was collected and
concentrated in vacuo. The residue was crystallized from
AcOEt/n-hexane to give E0352 (203 mg) as a white powder.
[2011] mp. 148-150.degree. C.
[2012] IR (KBr): 3431, 3425, 3406, 1614, 1547, 1510 cm-1
[2013] Mass (ESI+) 377 (M+H)+
[2014] 200 MHz 1H NMR (DMSO-d6, d): 2.44(3H, s), 2.72(2H, t, J=6.9
Hz), 3.55-3.65(2H, m), 3.80(3H, s), 4.66(1H, t, J=5.1 Hz), 7.02(2H,
d, J=8.9 Hz), 7.20(2H, d, J=9.0 Hz), 7.24(2H, d, J=9.0 Hz),
7.28-7.36(3H, m)
EXAMPLE 353
[2015] ##STR294##
[2016] E0353 was prepared in a similar manner to that of E0352,
[2017] oil
[2018] Mass (ESI+): 435 (M+H)+
[2019] 200 MHz 1H NMR (DMSO-d6, d): 2.03 (3H, s), 2.44(3H, s),
3.80(3H, s), 4.17-4.22(2H, m), 4.25-4.35(2H, m), 6.97(2H, d, J=8.7
Hz), 7.02(2H, d, J=9.0 Hz), 7.23(2H, d, J=8.7 Hz), 7.27(1H, s),
7.31(2H, d, J=9.0 Hz)
EXAMPLE 354
[2020] ##STR295##
[2021] (E0354)
[2022] Acetic anhydride 124 mg was added to a solution of E0346
(102.6 mg) and pyridine 241 mg in CH 2Cl2 1 ml. The reaction
mixture was stirred at ambient temperature for 1 hour. Acetic
anhydride 62 mg and pyridine 1 ml was added and stirred at ambient
overnight. Acetic anhydride 62 mg was added and stirred at ambient
for 4 hours. The mixture was concentrated in vacuo, and the residue
was partitioned between ethyl acetate and 1M HCl. The organic layer
was washed with saturated aqueous sodium bicarbonate solution and
saturated aqueous sodium chloride solution, dried over magnesium
sulfate, and concentrated in vacuo. The residual solid was
collected and washed with diisopropyl ether to give E0354 (76.3 mg)
as a white powder.
[2023] Mass (ESI+): 380 (M+H)+
[2024] 200 MHz 1H NMR (DMSO-d6, d): 1.96(3H, s), 2.87(2H, t, J=6.8
Hz), 3.78(3H, s), 4.20(2H, t, J=6.8 Hz), 6.94(1H, s), 6.98(2H, d,
J=8.9 Hz), 7.15-7.30(6H, m), 7.33(1H, s), 7.64(1H, s)
EXAMPLE 355
[2025] ##STR296##
[2026] (E0355)
[2027] E0355 was prepared in a similar manner to that of E0354.
[2028] white powder
[2029] Mass (ESI+): 397 (M+H)+
[2030] 200 MHz 1H NMR (DMSO-d6, d): 2.03(3H, s), 3.87(3H, s),
4.16-4.21(2H, m), 4.29-4.34(2H, m), 6.88-6.98(4H, m), 7.21(2H, d,
J=8.7 Hz), 7.37(1H, brs), 7.68-7.70(1H, brs, overlapping), 7.71(1H,
dd, J=2.7,8.8 Hz), 8.16(1H, d, J=2.7 Hz)
EXAMPLE 356
[2031] ##STR297##
[2032] E0356)
[2033] Phosphorus oxychloride 40.4 mg was added to DMF 0.5 ml under
ice bath cooling. After stirring at same temperature for 5 minutes,
E0354 (50 mg) was added in one portion. The reaction mixture was
stirred at same temperature for 1 hour, and quenched by adding
aqueous sodium bicarbonate solution. The mixture was extracted with
ethyl acetate. The organic layer was washed with H2O, saturated
aqueous sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo to give E0356 (45.0 mg) as an oil.
[2034] Mass (ESI+): 403 (M+CH3CN+H)+
[2035] Mass (API-ES positive): 362 (M+H)+, 384 (M+Na)+
[2036] 200 MHz 1H NMR (DMSO-d6, d): 1.96(3H, s), 2.88(2H, t, J=6.8
Hz), 3.79(3H, s), 4.20(2H, t, J=6.8 Hz), 7.00(2H, d, J=8.9 Hz),
7.15-7.31(6H, m), 7.36(1H, s)
EXAMPLE 357
[2037] ##STR298##
[2038] (E0357)
[2039] E0357 was prepared in a similar manner to that of E0356.
[2040] oil
[2041] Mass (ESI+): 378 (M+H)+
[2042] 200 MHz 1H NMR (DMSO-d6, d): 2.02(3H, s), 3.79(3H, s),
4.15-4.21(2H, m), 4.29-4.34(2H, m), 6.93-7.04(4H, m), 7.18(2H, d,
J=8.8 Hz), 7.24-7.31(3H, m)
EXAMPLE 358
[2043] ##STR299##
[2044] (E0358)
[2045] E0358 was prepared in a similar manner to that of E0356.
[2046] oil
[2047] Mass (ESI+) 379 (M+H)+
[2048] 200 MHz 1H NMR (DMSO-d6, d): 2.02(3H, s), 3.88(3H, s),
4.17-4.21(2H, m), 4.29-4.34(2H, m), 6.90-7.03(3H, m), 7.22(2H, d,
J=8.8 Hz), 7.36(1H, s), 7.74(1H, dd, J=2.7,8.9 Hz), 8.20(1H, d,
J=2.7 Hz)
EXAMPLE 359
[2049] ##STR300##
[2050] (E0359)
[2051] E0359 was prepared in a similar manner to that of E0356.
[2052] amorphous powder
[2053] Mass (ESI+): 435 (M+H)+
[2054] 200 MHz 1H NMR (DMSO-d6, d): 1.37(9H, s), 3.22-3.32(2H, m),
3.79(3H, s), 3.92-3.98(2H, m), 6.90-7.08(1H, br,overlapping),
6.92(2H, d, J=8.8 Hz), 7.00(2H, d, J=9.0 Hz), 7.16(2H, d, J=8.8
Hz), 7.28(2H, d, J=9.0 Hz), 7.30(1H, s)
EXAMPLE 360
[2055] ##STR301##
[2056] E0360)
[2057] E0360 was prepared in a similar manner to that of E0356.
[2058] white powder
[2059] Mass (ESI+): 436 (M+H)+
[2060] 200 MHz 1H NMR (DMSO-d6, d): 1.37 (9H, s), 3.22-3.32(2H, m),
3.88(3H, s), 3.93-3.99(2H, m), 6.90-7.01(1H, overlapping), 6.92(1H,
d, J=8.8 Hz), 6.95(2H, d, J=8.8 Hz), 7.21(2H, d, J=8.8 Hz),
7.34(1H, s), 7.73(1H, d, J=2.7,8.8 Hz), 8.20(1H, d, J=2.7 Hz)
EXAMPLE 361
[2061] ##STR302##
[2062] (E0361)
[2063] E0361 was prepared from E0345 in a similar manner to that of
E0356.
[2064] oil
[2065] Mass (ESI+): 363 (M+H)+
[2066] 200 MHz 1H NMR (DMSO-d6, d): 1.96(3H, s), 2.89(2H, t, J=6.8
Hz), 3.88(3H, s), 4.21(2H, t, J=6.8 Hz), 6.92(1H, d, J=8.8 Hz),
7.22(2H, d, J=8.3 Hz), 7.30(2H, d, J=8.3 Hz), 7.41(1H, s), 7.75(1H,
dd, J=8.8,2.7 Hz), 8.20(1H, d, J=2.7 Hz)
EXAMPLE 362
[2067] ##STR303##
[2068] (E0362)
[2069] A solution of acetyl chloride 0.28 ml in was added to a
solution of E0261 (441.6 mg) in CH2Cl2 4 ml and pyridine 2 ml under
ice bath cooling. The reaction mixture was stirred at ambient
temperature for 1 hour. Acetyl chloride 0.14 ml was added and
stirred at ambient temperature for 1 hour. The reaction was
quenched by adding aqueous sodium bicarbonate solution and the
mixture was stirred at ambient temperature overnight. The mixture
was acidified to pH 2 by 6M HCl and extracted with ethyl acetate.
The organic layer was washed with H2O and saturated aqueous sodium
chloride solution, dried over magnesium sulfate, and concentrated
in vacuo. The residue was crystallized from diisopropyl ether to
give E0362 (405.3 mg) as a white powder.
[2070] Mass (ESI+): 381(M+H)+
[2071] 200 MHz 1H NMR (DMSO-d6, d): 1.96(3H, s), 2.87(2H, t, J=6.8
Hz), 3.79(3H, s), 4.20(2H, t, J=6.8 Hz), 6.96-7.02(3H, m),
7.15-7.27(6H, m), 12.91(1H, br)
EXAMPLE 363
[2072] ##STR304##
[2073] (E0363)
[2074] E0363 was prepared in a similar manner to that of E0362.
[2075] oil
[2076] Mass (ESI+): 382 (M+H)+
[2077] 200 MHz 1H NMR (DMSO-d6, d): 2.04(3H, s), 2.94(2H, t, J=7.0
Hz), 3.95(3H, s), 4.29(2H, t, J=7.0 Hz), 6.76(1H, d, J=8.8 Hz),
7.08(1H, s), 7.04-7.35(4H, m), 7.59(1H, dd, J=2.7,8.8 Hz), 8.12(1H,
d, J=2.7 Hz)
EXAMPLE 364
[2078] ##STR305##
[2079] (E0364)
[2080] Oxalyl chloride 264 mg was added to a suspension of E0362
(395 mg) in CH2Cl2 5 ml under ice bath cooling. DMF 5 drop was
added and the mixture was stirred at ambient temperature for 1
hour.
[2081] The mixture was concentrated in vacuo. To the residue was
added toluene, and concentrated in vacuo. The residue was dissolved
in CH2Cl2 30 ml, cooled in an ice bath, N,O-dimethylhydroxylamine
hydrochloride 203 mg and triethylamine 525 mg were added and the
mixture was stirred at ambient temperature overnight. The mixture
was diluted with AcOEt, washed successively with 1M HCl, aqueous
sodium bicarbonate solution, and saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo.
The residue was purified by silica gel column chromatography eluted
with CHCl3, then AcOEt/CHCl3=10%, 20% to give E0364 (418.4 mg) as
an oil.
[2082] Mass (ESI+): 424 (M+H)+
[2083] 200 MHz 1H NMR (DMSO-d6, d): 1.97(3H, s), 2.88(2H, t, J=6.8
Hz), 3.38(3H, s), 3.77(3H, s), 3.78(3H, s), 4.20(2H, t, J=6.8 Hz),
6.94-7.03(3H, m), 7.16-7.27(6H, m)
EXAMPLE 365
[2084] ##STR306##
[2085] (E0365)
[2086] E0365 was prepared from E0363 and N,O-dimethylhydroxylamine
hydrochloride in a similar manner to that of E0364.
[2087] oil
[2088] Mass (ESI+): 425 (M+H)+
[2089] 200 MHz 1H NMR (DMSO-d6, d): 1.97(3H, s), 2.89(2H, t, J=6.8
Hz), 3.37(3H, s), 3.77(3H, s), 3.88(3H, s), 4.21(2H, t, J=6.8 Hz),
6.91(1H, d, J=8.8 Hz), 6.98(1H, s), 7.20-7.33(4H, m), 7.70(1H, dd,
J=2.8,8.8 Hz), 8.15(1H, d, J=2.8 Hz)
EXAMPLE 366
[2090] ##STR307##
[2091] (E0366).
[2092] To a solution of 1.0 M phenylmagnesium bromide in THF 3.4 ml
was added a solution of E0364 (106.5 mg) in THF 2 ml under ice bath
cooling. After stirring at same temperature for 1 hour, the mixture
was poured into sat.aqNH4Cl, and extracted with AcOEt. The organic
layer was washed with saturated aqueous sodium chloride solution,
dried over magnesium sulfate, and concentrated in vacuo. The
residue was purified by silica gel column chromatography eluted
with AcOEt/n-hexane 30%, 40%, 50% to give E0366 (107 mg) as an
oil.
[2093] IR (neat) 3469, 3435, 3425, 3406, 3398, 3369, 2937, 1647,
1606, 1512 cm-1
[2094] Mass (ESI+): 399 (M+H)+
[2095] 200 MHz 1H NMR (DMSO-d6, d): 2.72(2H, t, J=6.9 Hz),
3.56-3.66(2H, m), 3.80(3H, s), 4.65(1H, t, J=5.1 Hz), 7.02(2H, d,
J=8.9 Hz), 7.20(1H, s), 7.22(4H, s), 7.34(2H, d, J=8.9 Hz),
7.52-7.68(3H, m), 8.25(2H, d, J=8.5 Hz)
EXAMPLE 367
[2096] ##STR308##
[2097] (E0367)
[2098] E0367 was prepared in a similar manner to that of E0366.
[2099] white powder
[2100] mp. 95-96.degree. C.
[2101] IR (KBr): 3498, 3476, 2966, 1678, 1649, 1612, 1547, 1512
cm-1
[2102] Mass (ESI+) 381 (M+H)+
[2103] 200 MHz 1H NMR (DMSO-d6, d): 1.15(6H, d, J=6.8 Hz),
3.61-3.75(3H, m), 3.79(3H, s), 3.95-4.00(2H, m), 4.87(1H, t, J=5.3
Hz), 6.91(2H, d, J=8.7 Hz), 6.98(1H, s), 7.00(2H, d, J=8.9 Hz),
7.17(2H, d, J=8.7 Hz), 7.28(2H, d, J=8.9 Hz)
EXAMPLE 368
[2104] ##STR309##
[2105] (E0368)
[2106] E0368 was prepared in a similar manner to that of E0366.
[2107] white powder
[2108] mp. 132-133.degree. C.
[2109] IR (KBr): 3390, 3334, 3288, 1707, 1670, 1612, 1564, 1549,
1512 cm-1
[2110] Mass (ESI+): 379 (M+H)+
[2111] 200 MHz 1H NMR (DMSO-d6, d): 1.04(4H, d, J=6.2 Hz), 3.03(1H,
m), 3.65-3.73(2H, m), 3.80(3H, s), 3.95-4.00(2H, m), 4.87(1H, t,
J=5.4 Hz), 6.92(2H, d, J=8.7 Hz), 6.96(1H, s), 7.01(2H, d, J=8.9
Hz), 7.18(2H, d, J=8.7 Hz), 7.31(2H, d, J=8.9 Hz)
EXAMPLE 369
[2112] ##STR310##
[2113] (E0369)
[2114] E0369 was prepared in a similar manner to that of E0366.
[2115] white powder
[2116] mp. 108-109.degree. C.
[2117] IR (KBr): 3440, 2966, 1678, 1610, 1566, 1549, 1533, 1502
cm-1
[2118] Mass (ESI+) 382 (M+H)+
[2119] 200 MHz 1H NMR (DMSO-d6, d): 1.16(6H, d, J=6.9 Hz),
3.64-3.74(3H, m), 3.88(3H, s), 3.96-4.02(2H, m), 4.87(1H, t, J=5.4
Hz), 6.93(1H, d, J=8.9 Hz), 6.94 (2H, d, J=8.7 Hz), 7.02(1H, s),
7.21(2H, d, J=8.7 Hz), 7.74(1H, dd, J=2.7,8.9 Hz), 8.18(1H, d,
J=2.7 Hz)
EXAMPLE 370
[2120] ##STR311##
[2121] (E0370)
[2122] E0370 was prepared in a similar manner to that of E0368.
[2123] white powder
[2124] mp. 104-106.degree. C.
[2125] IR (KBr): 3367, 2947, 1668, 1610, 1566, 1549, 1531 cm-1
[2126] Mass (ESI+): 380 (M+H)+
[2127] 2500 MHz 1H NMR (DMSO-d6, d): 1.05(4H, d, J=6.2 Hz),
3.04(1H, m), 3.65-3.73(2H, m), 3.89(3H, s), 3.96-4.02(2H, m),
4.87(1H, t, J=5.4 Hz), 6.93(1H, d, J=8.8 Hz), 6.95(2H, d, J=8.8
Hz), 7.06(1H, s), 7.22(2H, d, J=8.8 Hz), 7.76(1H, dd, J=2.6,8.8
Hz), 8.21(1H, d, J=2.6 Hz)
EXAMPLE 371
[2128] ##STR312##
[2129] (E0371)
[2130] E0371 was prepared in a similar manner to that of E0366.
[2131] white powder
[2132] Mass (ESI+): 480 (M+H)+
[2133] 200 MHz 1H NMR (DMSO-d6, d): 1.15(6H, d, J=6.9 Hz), 1.37(9H,
s), 3.25-3.33(2H, m), 3.68(1H, m), 3.79(3H, s), 3.91-398(2H, m),
6.90(2H, d, J=8.7 Hz), 6.90-7.05(1H, overlapping), 6.97(1H, s),
7.00(2H, d, j=8.9 Hz), 7.17(2H, d, J=8.7 Hz), 7.28(2H, d, J=8.9
Hz)
EXAMPLE 372
[2134] ##STR313##
[2135] (E0372)
[2136] E0372 was prepared in a similar manner to that of E0368.
[2137] white powder
[2138] Mass (ESI+) 477 (M+H)+
[2139] 200 MHz 1H NMR (DMSO-d6, d): 1.04(4H, d, J=6.2 Hz), 1.37(9H,
s), 3.04(1H, m), 3.22-3.33(2H, m), 3.80(3H, s), 3.95(2H, t, J=5.7
Hz), 6.88-7.03(1H, overlapping), 6.91(2H, d, J=8.7 Hz), 6.97(1H,
s), 7.01(2H, d, J=8.9 Hz), 7.18(2H, d, J=8.7 Hz), 7.31(2H, d, J=8.9
Hz)
EXAMPLE 373
[2140] ##STR314##
[2141] (E0373)
[2142] E0373 was prepared in a similar manner to that of E0366.
[2143] white powder
[2144] Mass (ESI+): 481 (M+H)+
[2145] 200 MHz 1H NMR (DMSO-d6, d): 1.16(6H, d, J=6.9 Hz), 1.37(9H,
s), 3.22-3.32(2H, m), 3.68(1H, m), 3.88(3H, s), 3.93-3.99(2H, m),
6.90-7.02(5H, m), 7.22(2H, d, J=8.7 Hz), 7.73(1H, dd, J=2.7,8.8
Hz), 8.18(1H, d, J=2.7 Hz)
EXAMPLE 374
[2146] ##STR315##
[2147] (E0374)
[2148] E0374 was prepared in a similar manner to that of E0368.
[2149] white powder
[2150] Mass (ESI+): 479 (M+H)+
[2151] 200 MHz 1H NMR (DMSO-d6, d): 1.05(4H, d, J=6.2 Hz), 1.37(9H,
s), 3.04(1H, m), 3.23-3.33(2H, m), 3.89(3H, s), 3.93-3.99(2H, m),
6.89-7.08(5H, m), 7.22(2H, d, J=8.7 Hz), 7.76(1H, dd, J=2.7,8.8
Hz), 8.21(1H, d, J=2.7 Hz)
EXAMPLE 375
[2152] ##STR316##
[2153] (E0375)
[2154] E0375 was prepared from E0364 in a similar manner to that of
E0366.
[2155] oil
[2156] IR (neat): 3487, 3469, 3435, 3408, 3398, 3369, 2966, 2933,
1678, 1512 cm-1
[2157] Mass (ESI+): 365 (M+H)+
[2158] 200 MHz 1H NMR (DMSO-d6, d): 1.19(6H, d, J=7.9 Hz), 2.70(2H,
t, J=6.9 Hz), 3.54-3.75(3H, m), 3.79(3H, s), 4.64(1H, t, J=5.1 Hz),
7.00(2H, d, J=8.9 Hz), 7.02(1H, s), 7.16(2H, d, J=8.6 Hz), 7.21(2H,
d, J=8.6 Hz), 7.29(2H, d, J=8.9 Hz)
EXAMPLE 376
[2159] ##STR317##
[2160] (E0376).
[2161] To a solution of 1.0M methylmagnesium bromide in diethyl
ether 2.8 ml was added a solution of E0364 (237.6 mg) in THF 4 ml
dropwise under ice bath cooling. After stirring at same temperature
for 30 minutes the mixture was poured into sat.aqNH4Cl, and
extracted with AcOEt. The organic layer was washed successively
with a mixture of 1M HCl and saturated aqueous sodium chloride
solution, saturated aqueous sodium bicarbonate solution, and
saturated aqueous sodium chloride solution, dried over magnesium
sulfate, and concentrated in vacuo. The residue was dissolved in
THF 1 ml, 1M NaOH 0.4 ml was added and the mixture was stirred at
ambient temperature for several hours. The mixture was neutralized
with 1M HCl 0.4 ml, and partitioned between AcOEt and saturated
aqueous sodium chloride solution. The organic layer was dried over
magnesium sulfate, and concentrated in vacuo. The residue was
purified by silica gel column chromatography eluted with
AcOEt/n-hexane=50% to give E0376 (139.1 mg) as a white powder.
[2162] Mass (ESI+): 337 (M+H)+
[2163] 200 MHz 1H NMR (DMSO-d6, d): 2.54(3H, s), 2.70(2H, t, J=6.9
Hz), 3.55-3.64(2H, m), 3.80(3H, s), 4.65(1H, t, J=5.1 Hz), 7.00(2H,
d, J=8.9 Hz), 7.01 (1H, s), 7.15 (2H, d, J=8.5 Hz), 7.21(2H, d,
J=8.5 Hz), 7.29(2H, d, J=8.9 Hz)
EXAMPLE 377
[2164] ##STR318##
[2165] (E0377)
[2166] E0377 was prepared in a similar manner to that of E0376.
[2167] oil
[2168] Mass (ESI+): 366 (M+H)+
[2169] 200 MHz 1H NMR (DMSO-d6, d): 1.16(6H, d, J=6.9 Hz), 2.72(2H,
t, J=6.9 Hz), 3.55-3.75(3H, m), 3.88(3H, s), 4.65(1H, t, J=5.1 Hz),
6.93(1H, d, J=8.8 Hz), 7.05(1H, s), 7.17-7.29(4H, m), 7.76(1H, dd,
J=8.8,2.7 Hz), 8.19(1H, d, J=2.7 Hz)
EXAMPLE 378
[2170] ##STR319##
[2171] (E0378)
[2172] E0378 was prepared in a similar manner to that of E0376.
[2173] oil
[2174] 200 MHz 1H NMR (DMSO-d6, d): 2.73(2H, t, J=6.9 Hz),
3.57-3.66(2H, m), 3.89(3H, s), 4.66(1H, t, J=5.0 Hz), 6.94(1H, d,
J=8.8 Hz), 7.23(1H, s), 7.15-7.35(4H, m), 7.52-7.72(3H, m),
7.80(1H, dd, J=2.7,8.8 Hz), 8.23-8.32(3H, m)
EXAMPLE 379
[2175] ##STR320##
[2176] (E0379)
[2177] E0379 was prepared in a similar manner to that of E0376.
[2178] white powder
[2179] Mass (ESI+): 338 (M+H)+
[2180] 00 MHz 1H NMR (DMSO-d6, d): 2.55(3H, s), 2.71(2H, t, J=6.9
Hz), 3.55-3.65(2H, m), 3.89(3H, s), 4.65(1H, t, J=5.1 Hz), 6.93(1H,
d, J=8.8 Hz), 7.05(1H, s), 7.19(2H, d, J=8.6 Hz), 7.24(2H, d, J=8.6
Hz), 7.75(1H, dd, J=2.7,8.8 Hz), 8.19(1H, d, J=2.7 Hz)
EXAMPLE 380
[2181] ##STR321##
[2182] (E0380).
[2183] A mixture of E0376 (127 mg), O-methylhydroxylamine
hydrochloride 47.3 mg and pyridine in EtOH 3 ml was heated at
60.degree. C. for 1 hour. The mixture was concentrated in vacuo and
the residue was purified by silica gel column chromatography eluted
with AcOEt/n-hexane=40%. The pure fraction was collected and
concentrated in vacuo. The residue was crystallized from
diisopropyl ether to give E0380 (103.2 mg) as a white powder.
[2184] mp. 82-86.degree. C.
[2185] IR (KBr): 3359, 3269, 3246, 2939, 1549, 1512 cm-1
[2186] Mass (ESI+): 366(M+H)+
[2187] 200 MHz 1H NMR (DMSO-d6, d): 2.20(3H, s), 2.70(2H, t, J=6.9
Hz), 3.54-3.65(2H, m), 3.78(3H, s), 3.92(3H, s), 4.65(1H, t, J=5.0
Hz), 6.77(1H, s), 6.97(2H, d, J=8.9 Hz), 7.12-7.26(6H, m)
EXAMPLE 381
[2188] ##STR322##
[2189] (E0381)
[2190] E0381 was prepared in a similar manner to that of E0380.
[2191] white powder
[2192] mp. 94-95.degree. C.
[2193] IR (KBr): 3469, 3433, 3423, 3404, 3400, 3371, 1647, 1549
cm.sup.-1
[2194] Mass (ESI+): 267(M+H)+
[2195] 200 MHz 1H NMR (DMSO-d6, d): 2.20(3H, s), 2.71(2H, t, J=6.8
Hz), 3.55-3.65(2H, m), 3.87(3H, s), 3.92(3H, s), 4.65(1H, t, J=5.0
Hz), 6.81(1H, s), 6.90(1H, d, J=8.8 Hz), 7.18(2H, d, J=8.7 Hz),
7.23(2H, d, J=8.7 Hz), 7.69(1H, dd, J=8.8,2.7 Hz), 8.11(1H, d,
J=2.7 Hz)
EXAMPLE 382
[2196] ##STR323##
[2197] (E0382)
[2198] To a solution of E0314 (100 mg) in methanol (21 ml) was
added a solution of methyl amine in methanol (40%, 92 ml) After
stirring at room temperature overnight, the mixture was evaporated
to give oil, which was purified with preparative TLC (1 mm, 60%
ethyl acetate/hexane) to give E0382 as an oil (97 mg, 100%).
[2199] NMR(CDCl3), 2.92(3H, d, J=50 Hz), 3.83(3H, s), 4.49(2H, s),
6.69(1H, s), 6.82-6.91(4H, m), 7.14-7.24(4H, m).
[2200] MS(ESI+); 428.2(M+Na).
[2201] IR(Neat, 20727-11), 1693.2 cm-1.
EXAMPLE 383
[2202] ##STR324##
[2203] (50383)
[2204] Trichloroacetyl isocyanate 62.4 mg was added to a solution
of E0118 100 mg in CH2Cl2 2 ml under ice bath cooling. After
stirring at ambient temperature for 3 hours, the reaction mixture
was concentrated in vacuo. The residue was dissolved in THF 1 ml,
MeOH 1 ml, and H2O 1 ml. Potassium carbonate 153 mg was added to
the reaction mixture, and stirred at ambient temperature overnight.
The reaction mixture was partitioned between AcOEt and H2O. The
organic layer was washed with saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo.
The residual solid was recrystallized from AcOEt-n-hexane to give
E0383 84.1 mg as a white powder.
[2205] mp. 169-170.degree..degree. C.
[2206] IR (KBr): 3435, 3332, 3263, 3209, 1684, 1610, 1516 cm-1
[2207] Mass (ESI+): 406 (M+H)+
[2208] 400 MHz 1H NMR (DMSO-d6, d): 2.84(2H, t, J=6.8 Hz), 3.79(3H,
s), 4.10(2H, t, J=6.8 Hz), 6.30-6.70(2H, br), 7.00(2H, d, J=9.0
Hz), 7.14 (1H, s), 7.21 (2H, d, J=8.4 Hz), 7.26(2H, d, J=8.4 Hz),
7.29(2H, d, J=9.0 Hz)
EXAMPLE 384
[2209] ##STR325##
[2210] (E0384)
[2211] Trimethylsilyl isocyanate 42.7 mg was added to a solution of
E0158 98.2 mg and triethylamine 30 mg in CH2Cl2 1 ml under ice bath
cooling. The reaction mixture was stirred at same temperature for 1
hour and concentrated in vacuo. The residue was purified by
preparative thin layer silica gel chromatography developed by
MeOH/CHCl3=10%. The separated silica gel was extracted with 10%
MeOH/CHCl3, filtered, and the solvent was evaporated in vacuo. The
residue was crystallized from ethylacetate-diisopropyl ether to
give E0384 (59.7 mg) as a white powder.
[2212] mp. 157-158.degree. C.
[2213] IR (KBr): 3406, 3357, 3330, 3209, 1704, 1662, 1614, 1529,
1520 cm-1
[2214] Mass (ESI+): 405 (M+H)+
[2215] 200 MHz 1H NMR (DMSO-d6, d) NO06.067: 2.62-2.70(2H, m),
3.13-3.24(2H, m), 3.79(3H, s), 5.42(2H, s), 5.93(1H, t, J=5.4 Hz),
7.00(2H, d, J=8.8 Hz), 7.12(1H, s), 7.21(4H, s), 7.29(2H, d, J=8.8
Hz)
EXAMPLE 385
[2216] ##STR326##
[2217] (E0385)
[2218] This compound was obtained according to a similar manner to
that of E0384.
[2219] IR (film): 3343.9, 1656.6, 1604.5, 1550.5, 1515.8, 1457.9,
1342.2, 1251.6, 1029.8 cm-1.
EXAMPLE 386
[2220] ##STR327##
[2221] (E0386)
[2222] This compound was obtained according to a similar manner to
that of E0384.
[2223] IR (film): 3345.9, 1654.6, 1604.5, 1556.3, 1513.9, 1465.6,
1240.0, 1160.9, 1132.0 cm-1.
EXAMPLE 387
[2224] ##STR328##
[2225] (E0387)
[2226] This compound was obtained according to a similar manner to
that of E0384.
[2227] IR (film): 3345.9, 1658.5, 1602.6, 1552.4, 1236.2, 1159.0,
1133.9 cm-1.
EXAMPLE 388
[2228] ##STR329##
[2229] (E0388)
[2230] This compound was obtained according to a similar manner to
that of E0384.
[2231] IR(film): 3345.9, 1658.5, 1602.6, 1552.4, 1517.7, 1236.2,
1159.0, 1133.9 cm-1.
EXAMPLE 389
[2232] ##STR330##
[2233] (E0389).
[2234] A mixture of E0175 (150 mg) and 6 ml of 4N HCl/dioxane was
stirred at room temperature. After 2 hours, the reaction mixture
was evaporated under reduced pressure to give 128 mg (quant.) of
E0389 as an oil.
[2235] IR(film): 3403.7, 1513.9, 1467.6, 1241.9, 1162.9, 1130.1
cm-1.
EXAMPLE 390
[2236] ##STR331##
[2237] (E0390)
[2238] This compound was obtained according to a similar manner to
that of E0389.
[2239] IR(film): 3428.8, 1662.34, 1612.2, 1500.4, 1461.8, 1390.4,
1292.1, 1166.7, 1087.7, 1029.8 cm-1.
EXAMPLE 391
[2240] ##STR332##
[2241] (E0391)
[2242] This compound was obtained according to a similar manner to
that of E0389.
[2243] IR (film): 3403.74, 2965.98, 1610.27, 1513.85, 1461.78,
1251.58, 1170.58, 1085.73, 1029.80, 836.955, 800.314 cm-1.
EXAMPLE 392
[2244] ##STR333##
[2245] (E0392)
[2246] This compound was obtained according to a similar manner to
that of E0389.
[2247] IR (film): 3432.7, 1511.9, 1467.6, 1240.0, 1160.9, 1130.1
cm-1.
EXAMPLE 393
[2248] ##STR334##
[2249] (E0393).
[2250] A mixture of E0258 (100 mg) and Pd/C (10 mg) in EtOH (10m)
was stirred under H2 atmosphere for 3.0 hours. After filtration, a
filtrate was evaporated under reduced pressure. The residue was
dissolved in EtOH and filtered with syringe driven filter, and
evaporated to give 93 mg (93%) of E0393.
[2251] IR (film): 3019.9, 1704.8, 1513.9, 1303.6, 1238.1, 1133.9
cm-1.
EXAMPLE 394
[2252] ##STR335##
[2253] (E0394)
[2254] T a suspension of E0258 (200 mg) in toluene (4 ml) was added
thionylchloride (0.19 ml) at room temperature. The reaction mixture
was stirred at 100.degree. C. for 5 hours until the mixture become
clear solution. After then, the mixture was evaporated under
reduced pressure. (become solid) THF was added, and then aqueous
MeNH2 (37%) was added. The mixture was stirred for 1 hour, and
quenched with water, and extracted twice with EtOAc. The combined
organic layer was washed with sat.NaHCO3, water and brine, dried
over Na2SO4, filtered and evaporated under reduced pressure to give
63 mg (31%) of E0394 as a powder.
[2255] mp: 155-157.degree. C.
[2256] IR(film) 3297.7, 1662.3, 1617.9, 1513.9, 1236.2, 1162.9,
1133.9 cm-1
EXAMPLE 395
[2257] ##STR336##
[2258] (E0395)
[2259] A suspension of E0399 (1.8 g) and potassium phtalimido (1.13
g) in N,N-dimethylformamide (6.6 ml) was stirred at 80.degree. C.
for 3 hours. The mixture was added water (700 ml) and extracted
with a mixture of ethyl acetate and hexane (2:1) (.times.4). The
combined organic layers were washed with aqueous sodium hydroxide
(1N) (.times.2) and brine, dried over magnesium sulfate, and
evaporated to give oil, which was purified with column
chromatography (SiO2 100 ml, eluted with 30% ethyl acetate/hexane)
to give oil (1.83 g, 91.1%). Ethanol (15 ml) was added to the oil,
then the mixture was stirred at room temperature for 10 minutes.
The precipitate was filtered, washed with ethanol (3 ml), and dried
under reduced pressure to give E0395 as a white solid (1.16 g,
58%).
[2260] NMR(CDCl3), 3.00(2H, t, J=7.6 Hz), 3.93(2H, t, J=7.6 Hz),
3.94(3H, s), 6.73(1H, s), 6.73(1H, d, J=8.7 Hz), 7.13-7.26(4H, m),
7.49(1H, dd, J=8.7, 2.5 Hz), 7.70-7.86(4H, m), 8.10(1H, d, J=2.5
Hz).
[2261] MS (ESI+), 515 (M+Na)
EXAMPLE 396
[2262] ##STR337##
[2263] (E0396)
[2264] 6M HCl 0.045 ml was added to a solution of E0168 (101.5 mg)
in AcOEt 1 ml and EtOH 1 ml. The mixture was concentrated and dried
in vacuo to give E0396 (94.8 mg) as an amorphous powder.
[2265] IR (neat): 3433, 3020, 2956, 1668, 1658, 1612, 1572, 1543,
1500 cm-1
[2266] Mass (ESI+): 377 (M+H)+
[2267] 200 MHz 1H NMR (DMSO-d6, d): 1.76-1.92(2H, m), 2.52-2.81(4H,
m), 3.88(3H, s), 6.93(1H, d, J=8.9 Hz), 7.19(1H, s), 7.26(4H, s),
7.76(1H, dd, J=8.9,2.7 Hz), 8.19(1H, d, J=2.7 Hz)
EXAMPLE 397
[2268] ##STR338##
[2269] (E0397)
[2270] To a mixture of P0002 (5.0 g) and CF3COOEt (3.5 ml) in DMF
(30 ml) was added NaH (1.1 g) under ice-cooling. The reaction
mixture was allowed to warm to room temperature, and stirred under
40.degree. C. for 1 hour. The reaction mixture was extracted twice
with EtOAc. The organic layer was washed with water and brine,
dried over MgSO4, filtered and evaporated under reduced pressure.
The residue, sodium acetate (2.23 g) and 4-methoxyphenylhydrazine
(3.96 g) in acetic acid (20 ml) was stirred at room temperature for
15 hours. The mixture was extracted twice with ethyl acetate. The
combined organic layer was washed with water (twice), sat.NaHCO3,
water and brine, dried over MgSO4, filtered and evaporated under
reduced pressure. The residue was column chromatographed on silica
gel (Hex/EtOAc=8:1-4:1) to give 2.58 g (36%) of E0397 as an
oil.
EXAMPLE 398
[2271] ##STR339##
[2272] (E0398).
[2273] To a solution of E0312 (326.7 mg) in ethyl acetate (3 ml)
was added methanesulfonyl chloride (86.9 ml) and triethylamine
(0.181 ml) at 0.degree. C. After stirring for 40 minutes at
0.degree. C., the mixture was quenched with water and extracted
with ethyl acetate (.times.3). The combined organic layers were
washed with water and brine, dried over sodium sulfate, and
evaporated under reduced pressure to give E0398 as an oil (351.3
mg, 89%).
[2274] NMR(CDCl3); 3.09(3H, s), 3.82(3H, s), 4.22-4.26(2H, m),
4.52-4.59(2H, m), 6.68(1H, s), 6.75(2H, d, J=8.7 Hz), 6.87(2H, d,
J=8.9 Hz), 7.16(2H, d, J=8.7 Hz), 7.22(2H, d, J=8.9 Hz)
EXAMPLE 399
[2275] ##STR340##
[2276] (E0399)
[2277] This compound was obtained according to a similar manner to
that of E0398 as a pale yellow oil (1.82 g, 98.6%).
[2278] NMR(CDCl3), 2.91(3H, s), 3.07(2H, t, J=6.8 Hz), 3.94(3H, s),
4.43(2H, t, J=6.8 Hz), 6.75(1H, s), 6.78(1H, d, J=8.2 Hz),
7.17-7.26 (4H, m), 7.58 (1H, dd, J=9.0, 2.9 Hz), 8.05 (1H, d, J=2.8
Hz).
[2279] MS(ESI+), 442.1(MH+), 464.0(M+Na).
EXAMPLE 400
[2280] ##STR341##
[2281] (E0400)
[2282] A suspension of E0398 (351.3 mg) and sodium thiomethoxide
(162 mg) in N,N-dimethylformamide (3 ml) was stirred at 60.degree.
C. for 3.5 hours. The mixture was quenched with water and extracted
with ethyl acetate (.times.3). The combined organic layers were
washed with water and brine, dried over magnesium sulfate, and
evaporated to give oil. The oil was purified with column
chromatography (SiO2 50 ml, eluted with 10% ethyl acetate/hexane)
to give E0400 as an oil (236.7 mg, 75.3%).
[2283] NMR(CDCl3); 2.24(3H, s), 2.88(2H, t, J=6.6 Hz), 3.82(3H, s),
4.15(2H, t, J=6.6 Hz), 6.67(1H, s), 6.83(2H, d, J=8.8 Hz), 6.88(2H,
d, J=9.0 Hz), 7.13(2H, d, J=8.8 Hz), 7.23(2H, d, J=9.0 Hz).
[2284] MS(ESI+); 431(M+Na).
EXAMPLE 401
[2285] ##STR342##
[2286] (E0401).
[2287] To a solution of E0400 (103.5 mg) in dichloromethane (1 ml)
was added m-chloroperbenzoic acid (134 mg) at room temperature.
After stirring at room temperature for 1 hour, the mixture was
added saturated sodium hydrogen sulfate aqueous solution (0.5 ml)
and sodium thiosulfate pentahydrate (100 mg), and stirred for 30
minutes at room temperature. The mixture was filtered by Chemelut
1001(Varian) and evaporated to give oil, which was purified with
preparative TLC (1 mm, 50% ethyl acetate/hexane) to give E0401 as
an amorphous (105.9 mg, 94.9%).
[2288] NMR(CDCl3); 3.07(3H, s), 3.45(2H, t, J=5.3 Hz), 4.44(2H, t,
J=5.3 Hz), 3.83(3H, s), 6.69(1H, s), 6.69-6.90(4H, m),
7.15-7.26(4H, m).
[2289] MS(ESI+); 463.1 (M+Na).sup.+. IR(KBr, 20727-8), 1612.2,
1515.8 cm-1.
EXAMPLE 402
[2290] ##STR343##
[2291] (E0402).
[2292] To a solution of E0400 (104.8 mg) in dichloromethane (1 ml)
was added m-chloroperbenzoic acid (44.7 mg) at 0.degree. C., and
the mixture was stirred at 0.degree. C. for 1 hour. Then
m-chloroperbenzoic acid (35 mg) was added to the mixture. After
stirring at 0.degree. C. for 30 minutes, the mixture was quenched
with saturated sodium hydrogen sulfate aqueous solution (0.5 ml)
and sodium thiosulfate pentahydrate (100 mg), and stirred for 30
minutes at room temperature. The mixture was filtered by Chemelut
1001 (Varian) and evaporated to give oil, which was purified with
preparative TLC (1 mm, ethyl acetate) to give 2 fractions of E0401
(TLC upper) as an amorphous (40.7 mg, 37.4%) and E0402 (TLC lower)
as a powder (60 mg, 55%).
[2293] NMR(CDCl3); 2.70(3H, s), 2.99-3.27(2H, m), 3.83(3H, s),
4.40-4.46(2H, m), 6.68(1H, s), 6.84-6.90(4H, m), 7.15(2H, d, J=8.7
Hz), 7.22(2H, d, J=9.0 Hz).
[2294] MS(ESI+); 447.1 (M+Na).
[2295] IR(KBr); 1612.2, 1513.9 cm-1.
EXAMPLE 403
[2296] ##STR344##
[2297] (E0403).
[2298] To a solution of E0286 (500 mg) in dichloromethane (1.5 ml)
was added successively anisol (0.5 ml) and triflutoroacetic acid (1
ml). After stirring at room temperature for 2 hours, the mixture
was quenched with saturated sodium hydrogen carbonate aqueous
solution and extracted with ethyl acetate (.times.3). The organic
layers were dried over magnesium sulfate and evaporated to give
oil, which was purified with column chromatography (SiO2 50 ml,
eluted with ethyl acetate) to give E0403 as an oil (302.5 mg,
94.2%).
[2299] NMR(CDCl3), 3.77(3H, s), 3.80(3H, s), 3.80-3.87(1H, m),
4.21-4.28(2H, m), 6.67(1H, s), 6.80-6.89(4H, m), 7.13(2H, d, J=8.7
Hz), 7.22(2H, d, J=8.9 Hz).
[2300] MS(ESI+), 436.1(MH+).
EXAMPLE 404
[2301] ##STR345##
[2302] (E0404).
[2303] A solution of E0403 (104.6 mg) in methanol (3 ml) and sodium
hydroxide aqueous solution (1N, 2 ml) was stirred at room
temperature for 3 hours. The mixture was evaporated, and methanol
was added to the residue and evaporated to give white powder, which
was purified with preparative TLC (1 mm, 20% methanol/chloroform)
to give E0404 as a powder (29.9 mg, 29.5%).
[2304] NMR(DMSO-d6), 3.50-3.54(1H, m), 3.79(3H, s), 4.13-4.30(2H,
m), 6.91-7.07(5H, m), 7.21(2H, d, J=8.7 Hz), 7.27(2H, d, J=8.9
Hz).
[2305] MS(ESI-). 420.4(M-H).
[2306] IR(KBr), 1641, 1616 cm-1.
EXAMPLE 405
[2307] ##STR346##
[2308] (E0405).
[2309] To a solution of E0403 (106.6 mg) in methanol (2 ml) was
added concentrated ammonia solution (1 ml). After stirring at room
temperature overnight, the mixture was evaporated to give solid,
which was purified with preparative TLC (1 mm, 20%
methanol/chloroform) to give E0405 as a solid (58.2 mg, 56.5%).
[2310] NMR(CDCl3), 3.75-3.82(1H, m), 3.82(3H, s), 4.15-4.29(2H, m),
6.67(1H, s), 6.83-6.91(4H, m), 7.14(2H, d, J=6.7 Hz), 7.22(2H, d,
J=9.0 Hz).
[2311] MS(ESI+). 421.4(MH+), 462.4(MHMeCN)+.
[2312] IR(KBr), 1658 cm-1.
EXAMPLE 406
[2313] ##STR347##
[2314] (E0406).
[2315] To a solution of E0403 (87.5 mg) in tetrahydrofuran (1 ml)
was added lithium aluminum hydride (30.5 mg) at room temperature.
After stirring at room temperature for 2 hours, the mixture was
quenched with water (30 ml), sodium hydroxide aqueous solution
(15%, 30 ml), and water (90 ml), and then stirred at room
temperature for 30 minutes. Magnesium sulfate and celite was added
to the mixture, then the suspension was filtered and washed with
tetrahydrofuran.
[2316] The filtrate was evaporated to give oil, which was purified
with preparative TLC (0.5 mm, 20% methanol/chloroform) to give
oil.
[2317] To a solution of the oil in ethyl acetate was added a
solution of hydrogen chloride in ethyl acetate (4N, 0.5 ml), and
then the mixture was evaporated to give E0406 as an oil (43.5 mg,
49%).
[2318] NMR(CDCl3), 3.64-4.13(5H, m), 3.76(3H, s), 6.60(1H, s),
6.73-6.85(4H, m), 7.07(2H, d, J=8.5 Hz), 7.16(2H, d, J=8.9 Hz).
[2319] MS(ESI+), 408.1(MH+) (Free). IR(Neat, 20727-5), 1614.1
cm-1.
EXAMPLE 407
[2320] ##STR348##
[2321] (E0407)
[2322] To a suspension of sodium hydride (34.8 mg) in
terahydrofuran (2 ml) was added a solution of E0347 (208 mg) in
tetrahydrofuran (1 ml) at 0.degree., and then the mixture was
stirred at room temperature for 20 minutes. Then iodomethane (54.2
ml) was added to the mixture. After stirring at room temperature
overnight, the mixture was quenched with water, extracted with
ethyl acetate (.times.3). The combined organic layers were washed
with water (.times.3) and brine, dried over magnesium sulfate, and
evaporated under reduced pressure to give oil, which was purified
with preparative TLC (1 mm, 30% ethyl acetate/hexane) to give E0407
as an oil (160 mg, 74.7%).
[2323] NMR(CDCl3), 1.45(9H, s), 2.97(3H, s), 3.59(2H, t, J=5.5 Hz),
3.82(3H, s), 4.0-4.15(2H, m), 6.67(1H, s), 6.80-6.91(4H, m),
7.13(2H, d, J=8.8 Hz), 7.23(2H, d, J=9.0 Hz).
[2324] MS(ESI+). 514.2(M+Na).
EXAMPLE 408
[2325] ##STR349##
[2326] (E0408)
[2327] AcCl 0.31 ml was added to a suspension of E0347 (1.29 g) and
Et3N0.66 ml in CH2Cl2 10 ml under ice bath cooling. The mixture was
stirred at ambient temperature for 2 hours. AcCl 0.31 ml and
Et3N0.66 ml was added and stirred at ambient temperature for 3
hours. To this mixture was added H2O and stirred at ambient
temperature for a while. White precipitates were appeared, which
was collected and washed with H2O and diisopropyl ether to give
E0408 (879.3 mg) as a white powder.
[2328] Mass (ESI+): 396(M+H)+
[2329] 200 MHz 1H NMR (DMSO-d6, d): 2.03(3H, s), 3.78(3H, s),
4.15-4.19(2H, m), 4.29-4.33(2H, m), 6.89(1H, s), 6.93(2H, d, J=8.8
Hz), 6.98(2H, d, J=8.9 Hz), 7.17(2H, d, J=8.8 Hz), 7.26(2H, d,
J=8.9 Hz), 7.32(1H, s), 7.63(1H, s)
EXAMPLE 409
[2330] ##STR350##
[2331] (E0409).
[2332] To a solution of E0374 (61.4 mg) in CH2Cl2 2 ml was added
trimethylsilyl trifluoromethanesulfonate 85.6 mg at 0.degree. C.,
followed by an addition of triethylamine 39 mg. The mixture was
stirred at 0.degree. C. for 30 minutes, and partitioned between
AcOEt and H2O. The organic layer was washed with saturated aqueous
sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo. The residue was purified by preparative thin
layer silica gel chromatography developed by 28%
NH3aq:MeOH:CHCl3=1:10:100. The separated silica gel was extracted
with 28% NH3aq:MeOH:CHCl3=1:10:100 and the solvent was evaporated
in vacuo. The residue was dried under vacuo and then dissolved in
EtOH 3 ml. To this solution was added 1M HCl 0.0892 ml and
concentrated in vacuo. The residue was dried under vacuo to give
E0409 (37 mg) as an amorphous powder.
[2333] IR (KBr): 2958, 1668, 1662, 1612, 1581, 1568, 1549, 1531,
1500 cm-1
[2334] Mass (ESI+): 379 (M+H)+
[2335] 200 MHz 1H NMR 1.05(4H, d, J=6.2 Hz), 3.04 (1H, m),
3.15-3.24 (2H, m), 3.89(3H, s), 4.16-4.22(2H, m), 6.94(1H, d, J=8.8
Hz), 7.00(2H, d, J=8.7 Hz), 7.02(1H, s), 7.27(2H, d, J=8.7 Hz),
7.78(1H, dd, J=2.7,8.8 Hz), 8.14(2H, brs), 8.21(1H, d, J=2.7
Hz)
EXAMPLE 410
[2336] ##STR351##
[2337] (E0410).
[2338] To a solution of
2-{4-[1-(4-methoxyphenyl)-3-(methylsulfonyl)-1H-pyrazol-5-yl]phenoxy}etha-
namine (133 mg, 0.342 mmol) in methylene chloride (5 ml) was added
trimethylsilyl isocyanate (118 mg, 1.03 mmol) and triethylamine
(1.39 mg, 1.37 mmol) at ambient temperature and stirred for two
days. The reaction mixture was washed with water and brine, dried
over magnesium sulfate, filtered and evaporated. Purification by
column chromatography (silica gel, methylene
chloride/methanol=20/1) followed by recrystallization from
ethylacetate gave 102 mg (69%) of E0410 as white crystals.
[2339] mp. 165-167.degree. C.
[2340] Mass; 431(M+1)
[2341] IR(KBr); 1650, 1310 CM-1
[2342] NMR(DMSO-d6,.delta.); 3.32(2H, q, J=5.5 Hz), 3.33(3H, s),
3.79(3H, s), 3.94(2H, t, J=5.5 Hz), 5.52(2H, s), 6.14(1H, t, J=5.5
Hz), 6.94(2H, d, J=8.7 Hz), 7.01(2H, d, J=8.9 Hz), 7.11(1H, s),
7.20(2H, d, J=8.7 Hz), 7.28(2H, d, J=8.9 Hz),
EXAMPLE 411
[2343] ##STR352##
[2344] (E0411).
[2345] A solution of P0034 64 mg in DMF 1 ml was added 60% NaH 11.4
mg at 4.degree. C. and the mixture was stirred at same temperature
for 30 minutes. To the mixture was added bromoacetic acid 33 mg and
the mixture was stirred at ambient temperature for 2 hours. The
reaction was quenched by adding 1M HCl 2 ml, and the mixture was
extracted with AcOEt. The organic layer was washed with H2O,
sat.aqNaCl, dried over MgSO4, concentrated in vacuo to give E0411
(73 mg) as crystals.
[2346] Mass (ESI+): 355 (M+H)+
[2347] 200 MHz 1H NMR (DMSO-d6, d): 3.79(3H, s), 3.96(3H, s),
4.63(2H, s), 5.88(1H, s), 6.82(4H, d, J=9.0 Hz), 7.14(2H, d, J=9.0
Hz), 7.17 (2H, d, J=9.0 Hz)
EXAMPLE 412
[2348] ##STR353##
[2349] (E0412)
[2350] Boron trifluoride diethyl etherate 137 mg was added to a
suspension of sodium borohydride 29.3 mg in THF 3 ml with cooling
in an ice bath, and the mixture was stirred at same temperature for
30 minutes. To the reaction mixture was added E0411 (137 mg) in THF
3 ml in one portion and the mixture was stirred at ambient
temperature for 4 hours. The reaction was quenched by adding ice
water containing 1M HCl 1 ml, and the mixture was stirred at
ambient temperature for 1 hour. The mixture was extracted with
AcOEt for 2 times, the combined organic layers were washed with
sat.aqNaHCO3, sat.aqNaCl, dried over MgSO4, evaporated in vacuo.
The residue was purified by preparative thin layer chromatography
developed with AcOEt/n-hexane=50%. The residue was crystallized
from IPE to give E0412 (79.2 mg) as a white powder.
[2351] mp. 107-109.degree. C.
[2352] IR (KBr): 3334, 2935, 1693, 1612, 1564, 1520 cm-1
[2353] Mass (ESI+): 341 (M+H)+
[2354] 200 MHz 1H NMR (DMSO-d6, d): 2.02(1H, t, J=6.1 Hz), 3.80(3H,
s), 3.91-3.99(2H, m), 3.97(3H, s), 4.04-4.09(2H, m), 5.88(1H, s),
6.82(4H, d, J=9.0 Hz), 7.14(2H, d, J=9.0 Hz), 7.17(2H, d, J=9.0
Hz)
EXAMPLE 413
[2355] ##STR354##
[2356] (E0413) (E0413-0).
[2357] To a solution of P0034 (237 mg) in DMF 2 ml was added 60%
NaH 41.6 mg with cooling in an ice bath, and the mixture was
stirred at ambient temperature for 1 hour. To the mixture was added
E0413-0 (287 mg) in DMF 1 ml and the mixture was stirred at ambient
temperature for 13 hours, and at 60.degree. C. for 3 hours. The
reaction was quenched by adding sat.NH4Claq, and the mixture was
extracted with AcOEt. The organic layer was washed with H2O,
sat.aqNaCl, dried over MgSO4, concentrated in vacuo. The residue
was dissolved in EtOH 4 ml, and conc.HCl 40 .mu.L was added. After
stirring at ambient temperature for 2 hours, the mixture was
concentrated in vacuo. The residue was partitioned between AcOEt
and sat.aqNaHCO3, and the organic layer was washed with sat.aqNaCl,
dried over MgSO4, concentrated in vacuo. The residue was purified
by silica gel column chromatography eluted with AcOEt/n-hexane=40%,
60%. The residue was crystallized from AcOEt 1 ml and IPE 2 ml. The
obtained crystals were recrystallized from AcOEt 0.7 ml and IPE 1.5
ml to give E0413 (196.9 mg) as white crystals.
[2358] mp. 114.9-116 (115).degree. C. Mass (ESI+): 341 (M+H)+
[2359] 200 MHz 1H NMR (DMSO-d6, d): 3.65-3.73(2H, m), 3.75(3H, s),
3.83(3H, s), 3.94-3.99(2H, m), 4.86(1H, t, J=5.4 Hz), 6.04(1H, s),
6.87-6.96(4H, m), 7.10-7.16(4H, m)
EXAMPLE 414
[2360] ##STR355##
[2361] (E0414).
[2362] To a solution of P0034 (100 mg) in DMF 1 ml was added 60%
NaH 17.5 mg with cooling in an ice bath. The mixture was stirred at
ambient temperature for 1 hour. The mixture was cooled to 0.degree.
C. To the mixture was added 2-bromoethyl acetate 113 mg and the
mixture was stirred at ambient temperature for 24 hours. The
reaction was quenched by adding sat.NH4Claq, and the mixture was
extracted with AcOEt. The organic layer was washed with H2O,
sat.aqNaCl, dried over MgSO4, concentrated in vacuo. The residue
was dissolved in THF 0.9 ml and MeOH 0.9 ml. To this solution was
added 1M NaOH 0.4 ml. The mixture was stirred at ambient
temperature for 1 hour. The mixture was partitioned between AcOEt
and H2O, and the aqueous layer was reextracted with AcOEt. The
combined organic layers were washed with sat.aqNaCl, dried over
MgSO4, concentrated in vacuo. The residue was crystallized from
AcOEt 0.3 ml-IPE 0.9 ml to give E0414 (82.4 mg) as white
crystals.
[2363] Mass (ESI+): 341 (M+H)+
Preparation 35
[2364] To a solution of
N'-[5-[4-(benzyloxy)phenyl]-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-N,N-dim-
ethylurea (1.19 g) in EtOH (10 ml) and THF (10 ml) were added a
solution of ammonium formate (509 mg) in H2O (2 ml) and 10% Pd--C
50% wet (150 mg). The mixture was refluxed for 1 hour. The catalyst
was filtered off through a celite pad and the pad was washed with
EtOH. The filtrate and combined washings were concentrated in
vacuo. To the residue were added AcOEt and H2O. White precipitates
were appeared and collected and washed with H2O and IPE
successively to give
N'-[5-(4-hydroxyphenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N-dimethyl-
urea (555 mg) as a white powder.
[2365] Mass (ESI+): 353 (M+H)+
[2366] 200 MHz 1H NMR (DMSO-d6, d): 2.91(6H, s), 3.76(3H, s),
6.57(1H, s), 6.71(2H, d, J=8.6 Hz), 6.93(2H, d, J=9.0 Hz), 7.01(2H,
d, J=8.6 Hz), 7.14(2H, d, J=9.0 Hz), 8.99(1H, s), 9.68(1H, s)
[2367] The following compound(s) was(were) obtained in a similar
manner to that of Preparation 35.
Preparation 36
N-[5-(4-hydroxyphenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N',N'-trimet-
hylurea
[2368] white powder
[2369] Mass (ESI+): 367 (M+H)+
[2370] 200 MHz 1H NMR (DMSO-d6, d): 2.78(6H, s), 3.11(3H, s),
3.76(3H, s), 6.19(1H, s), 6.70(2H, d, J=8.6 Hz), 6.93(2H, d, J=9.0
Hz), 7.03(2H, d, J=8.6 Hz), 7.15(2H, d, J=9.0 Hz), 9.72(1H, s)
Preparation 37
4-[3-ethoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol
[2371] powder
[2372] Mass (ESI+): 311(M+H)+
[2373] 200 MHz 1H NMR (DMSO-d6, d): 1.32(3H, t, J=7.0 Hz), 3.75(3H,
s), 4.16(2H, q, J=7.0 Hz), 5.96(1H, s), 6.70(2H, d, J=8.6 Hz),
6.91(2H, d, J=8.9 Hz), 7.01(2H, d, J=8.6 Hz), 7.11(2H, d, J=8.9
Hz), 9.74(1H, brs).
Preparation 38
4-[3-isobutoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenol
[2374] white powder
[2375] Mass (ESI+): 339 (M+H)+
[2376] 200 MHz 1H NMR (CDCl3, d): 1.02(6H, d, J=6.6 Hz), 2.10(1H,
m), 3.79(3H, s), 3.98(6.6H, d, J=2 Hz), 5.38(1H, s), 5.87(1H, s),
6.72(2H, d, J=8.6 Hz), 6.81(2H, d, J=9.0 Hz), 7.07(2H, d, J=8.6
Hz), 7.16(2H, d, J=9.0 Hz).
Preparation 39
4-[3-(2-methoxyethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol
[2377] white powder
[2378] Mass (ESI+): 341 (M+H)+
[2379] 200 MHz 1H NMR (DMSO-d6, d): 3.30(3H, s), 3.62-3.67(2H, m),
3.75(3H, s), 4.21-4.26(2H, m), 5.98 (1H, s), 6.70(2H, d, J=8.6 Hz),
6.91(2H, d, J=9.0 Hz), 7.01(2H, d, J=8.6 Hz), 7.12(2H, d, J=9.0
Hz), 9.69(1H, s).
Preparation 40
4-[3-(2-ethoxyethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol
[2380] white powder
[2381] Mass (ESI+): 355 (M+H)+
[2382] 200 MHz 1H NMR (DMSO-d6, d): 1.13(3H, t, J=7.0 Hz), 3.49(2H,
q, J=7.0 Hz), 3.65-3.71(2H, m), 3.75(3H, s), 4.20-4.25(2H, m),
5.99(1H, s), 6.70(2H, d, J=8.6 Hz), 6.91(2H, d, J=9.0 Hz), 7.01(2H,
d, J=8.6 Hz), 7.12(2H, d, J=9.0 Hz), 9.72(1H, s)
Preparation 41
2-{[5-(4-hydroxyphenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]oxy}-N,N-dimet-
hylacetamide
[2383] white powder
[2384] Mass (ESI+): 368 (M+H)+
[2385] 200 MHz 1H NMR (DMSO-d6, d): 2.84(3H, s), 2.97(3H, s),
3.75(3H, s), 4.87(2H, s), 6.01(1H, s), 6.70(2H, d, J=8.6 Hz),
6.92(2H, d, J=9.0 Hz), 7.01(2H, d, J=8.6 Hz), 7.10(2H, d, J=9.0
Hz), 9.71(1H, s).
Preparation 42
4-[3-methoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenol
[2386] white powder
[2387] MS (ESI+): m/z 298 (M+H)+
[2388] 200 MHz 1H NMR (DMSO-d6, d): 3.84(6H, s), 6.05(1H, s),
6.73(2H, d, J=8.6 Hz), 6.85(1H, d, J=8.8 Hz), 7.05(2H, d, J=8.6
Hz), 7.59(1H, dd, J=8.8,2.7 Hz), 7.98 (1H, d, J=2.7 Hz), 9.77 (1H,
s)
Preparation 43
4-[3-ethoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenol
[2389] white powder
[2390] MS (ESI+): m/z 312 (M+H)+
[2391] 200 MHz 1H NMR (DMSO-d6, d): 1.33(3H, t, J=7.0 Hz), 3.84(3H,
s), 4.18(2H, q, J=7.0 Hz), 6.03(1H, s), 6.73(2H, d, J=8.6 Hz), 6.84
(1H, d, J=8.7 Hz), 7.05(2H, d, J=8.6 Hz), 7.57 (1H, dd, J=2.6,8.7
Hz), 7.97(1H, d, J=2.6 Hz), 9.76(1H, s).
Preparation 44
4-[1-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenol
[2392] MASS (ESI+): m/z=371.2 (M+Na).
[2393] 1HNMR (400 MHz, CDCl.sub.3): 2.15 (3H, s), 3.78 (3H, s),
6.79 (2H, d, J=8.9 Hz), 6.8 (2H, d, J=8.6 Hz), 7.01 (2H, d, J=8.6
Hz), 7.13 (2H, d, J=8.9 Hz).
Preparation 45
4-[3-cyclopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenol
[2394] white powder
[2395] MS(ESI+): m/z 308 (M+H).
[2396] 1HNMR (200 MHz, CDCl.sub.3): 0.76-0.85 (2H, m), 0.93-1.06
(2H, m), 1.97-2.08 (1H, m), 3.91 (3H, s), 6.08 (1H, s), 6.15 (1H,
s), 6.68-6.76 (3H, m), 7.04 (2H, d, J=8.6 Hz), 7.56 (1H, dd, J=2.7,
6.2 Hz), 8.02 (1H, d, J=2.7 Hz
Preparation 46
4-[3-(cyclopentyloxy)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenol
[2397] white powder
[2398] MS (ESI+): m/z 352 (M+H).
[2399] 1H NMR (200 MHz, DMSOd6): 1.09-2.41 (8H, m), 3.84 (3H, s),
4.92-5 (1H, m), 6.01 (1H, s), 6.73 (2H, d, J=8.6 Hz) 6.84 (1H, d,
J=8.8 Hz), 7.05 (2H, d, J=8.6 Hz), 7.57 (1H, dd, J=2.7, 8.8 Hz),
7.97 (1H, d, J=2.7 Hz), 9.76 (1H, brs).
Preparation 47
4-[1-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]phenol
[2400] white powder
[2401] MS (ESI+): m/z 365 (M+H).
[2402] 1H NMR (200 MHz, DMSOd6): 3.76 (3H, s), 4.8 (1H, d, J=9 Hz),
4.89 (1H, d, J=9 Hz), 6.15 (1H, s), 6.71 (2H, d, J=8.6 Hz), 6.93
(2H, d, J=8.9 Hz), 7.03 (2H, d, J=8.6 Hz), 7.14 (2H, d, J=8.9 Hz),
9.74 (1H, brs).
Preparation 48
4-[3-(2,2-difluoroethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol
[2403] white powder
[2404] MS (ESI+): m/z 347 (M+H).
[2405] 1HNMR (200 MHz, DMSOd6): 3.76 (3H, s), 4.43 (2H, dt,
J=3.5,14.9 Hz), 6.08 (1H, s), 6.40 (1H, tt, J=3.5, 54.6 Hz), 6.71
(2H, d, J=8.6 Hz), 6.92 (2H, d, J=9.0 Hz), 7.02 (2H, d, J=8.6 Hz),
7.14 (2H, d, J=9.0 Hz
Preparation 49
4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]phe-
nol
[2406] white powder
[2407] MS (ESI+): m/z 366 (M+H).
[2408] 1H NMR (200 MHz, CDCl3): 3.92 (3H, s), 4.61 (1H, d, J=8.5
Hz), 4.69 (1H, d, J=8.5 Hz), 5.39 (1H, brs), 5.97 (1H, s), 6.72
(1H, d, J=8.9 Hz), 6.76 (2H, d, J=8.5 Hz), 7.09 (2H, d, J=8.5 Hz),
7.51 (1H, dd, J=2.7, 8.9 Hz), 8.01 (1H, d, J=2.7 Hz)
Preparation 50
4-[3-(2,2-difluoroethoxy)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenol
[2409] white powder
[2410] MS (ESI+): m/z 348 (M+H).
[2411] 1HNMR (200 MHz, CDCl3): 3.92 (3H, s), 4.46 (2H, dt, J=4.2,
13.5 Hz), 5.42 (1H, brs), 5.93 (1H, s), 6.16 (1H, tt, J=4.2, 55.4
Hz), 6.72 (1H, d, J=8.7 Hz), 6.76 (2H, d, J=8.6 Hz), 7.09 (2H, d,
J=8.6 Hz), 7.51 (1H, dd, J=2.7, 8.7 Hz), 8.01 (1H, d, J=2.7 Hz
Preparation 51
4-[1-(4-methoxyphenyl)-4-methyl-1H-pyrazol-5-yl]phenol
[2412] white powder
[2413] MS (ESI+): m/z 281 (M+H)
[2414] 200 MHz 1H NMR (DMSO-d6, d): 2.00(3H, s), 3.74 (3H, s), 6.74
(2H, d, J=8.5 Hz), 6.88(2H, d, J=9.0 Hz), 6.96(2H, d, J=8.5 Hz),
7.09(2H, d, J=9.0 Hz), 7.53(1H, s), 9.66(1H, s).
Preparation 52
4-[1-(6-methoxy-3-pyridinyl)-4-methyl-1H-pyrazol-5-yl]phenol
[2415] white powder
[2416] MS (ESI+): m/z 282 (M+H).
[2417] 1HNMR (200 MHz, DMSOd6): 2.01 (3H, s), 3.83 (3H, s),
6.75-6.85 (3H, m), 7.01 (2H, d, J=8.6 Hz), 7.53 (1H, dd, J=2.7, 8.8
Hz), 7.6 (1H, s), 7.96 (1H, d, J=2.7 Hz), 9.73 (1H, brs)
Preparation 53
[2418] To a solution of 4'-benzyloxypropiophenone (6.0 g) in THF
(120 ml) at -60.degree. C. was added 38 ml of 1N lithium
bis(trimethylsilyl)amide (LiHMDS), and the mixture was stirred at
under -60.degree. C. for 45 mins. 1-(Trifluoroacetyl)-imidazole
(3.4 ml) was added and the mixture was stirred at -60.degree. C.
for 1 hour and at 0.degree. C. for 30 min. The reaction mixture was
quenched with 0.5N HCl, the mixture was poured into EtOAc and
water, and the EtOAc layer was separated, washed with brine, died
over MgSO4, and concentrated to give
1-[4-(benzyloxy)phenyl]-4,4,4-trifluoro-2-methyl-1,3-butanedione.
[2419] MASS (ESI+): m/z=359.2 (m+Na).
[2420] 1H NMR (400 MHz, CDCl3): 1.36 (1H, d, J=7.2 Hz), 1.52 (2H,
d, J=7 Hz), 5.16 (2H, s), 7.02-7.08 (2H, m), 7.37-7.44 (5H, m),
7.92-7.98 (2H, m).
Preparation 54
[2421] To a mixture of 4-(methylthio)aniline (6.3 g) and conc.HCl
(45 ml) was added dropwise NaNO2 (3.6 g) in water (18 ml) under
ice-cooling. After stirring for 30 min., SnClH2O (28.6 g) in
conc.HCl (24 ml) was added under ice cooling over 1 hour. After
stirring for 1 hour, filtrate, washed with conc.HCl and water, and
dried to give 14.1 g of [4-(methylthio)phenyl]hydrazine
hydrochloride as a solid.
[2422] MASS (ESI+): m/z=139.3 (M-NH2+1).
[2423] 1HNMR (400 MHz, DMSOd6): 2.42 (3H, s), 3.75 (2H, b.s), 6.97
(2H, d, J=8.7 Hz), 7.24 (2H, d, J=8.7 Hz), 10.24 (1H, b.s).
Preparation 55
[2424] A mixture of 4-hydroxypropiophenone (20 g), benzyl chloride
(16.1 ml), K2CO3 (12.9 g) and KI (2.21 g) in EtOH (80 ml) and H2O
(1 ml) was stirred under reflux condition for 4 hours. The reaction
mixture was cooled and filtered. Appeared crystal was dissovled
with EtOAc and water. Organic layer was separated and washed with
water and brine, dried over MgSO4 and filtered. Filtrate was
evaporated under reduced pressure to give 30.0 g (94%) of
1-[4-(benzyloxy)phenyl]-1-propanone as a crystal.
[2425] MASS (ESI+): m/z=263.2 (M+Na).
[2426] 1HNMR (400 MHz, CDCl3): 1.21 (3H, t, J=7.3 Hz), 2.95 (2H, q,
J=7.3 Hz), 5.13 (2H, s), 7 (2H, d, J=8.9 Hz), 7.34-7.45 (5H, m),
7.95 (2H, d, J=8.9 Hz
Preparation 56
[2427] 1M NaOH (4.8 ml) was added to a solution of
4-benzyloxybenzaldehyde (5 g) and cyclopropyl methyl ketone (3.96
g) in EtOH (24 ml) and the mixture was stirred at ambient
temperature overnight. The reaction mixture was diluted with H2O
and EtOH. The mixture was stirred at ambient temperature for 20
minutes. Pale yellow crystals were collected and washed with H2O
and 50% aqueous EtOH to give
(2E)-3-[4-(benzyloxy)phenyl]-1-cyclopropyl-2-propen-1-one (6.29
g).
[2428] Pale yellow crystals
[2429] MS (ESI+): m/z 301 (M+Na).
[2430] 1HNMR (200 MHz, CDCl3): 0.9-1.00 (2H, m), 1.11-1.19 (2H, m),
2.16-2.29 (1H, m), 5.11 (2H, s), 6.77 (1H, d, J=16.1 Hz), 6.99 (2H,
d, J=8.8 Hz), 7.32-7.46 (4H, m), 7.52 (2H, d, J=8.8 Hz), 7.58 (2H,
d, J=16.1 Hz
Preparation 57
[2431] (2E)-3-[4-(Benzyloxy)phenyl]-1-cyclopropyl-2-propen-1-one
(6.259) was suspended in EtOH (67.5 ml), acetone (22.5 ml) To this
mixture was added hydrogen peroxide 30% aqueous solution (4.5 ml),
and 3M NaOH (4.5 ml), and the mixture was stirred at ambient
temperature for 1 day. The mixture was diluted with H2O. White
precipitates were collected and washed with H2O, and air dried to
give
{(2R,3S)-3-[4-(benzyloxy)phenyl]-2-oxiranyl}(cyclopropyl)methanone
(6.27 g).
[2432] powder
[2433] MS (ESI+): m/z 317 (M+Na).
[2434] 1HNMR (200 MHz, DMSOd6): 0.96-1.07 (2H, m), 1.12-1.19 (2H,
m), 2.11-2.22 (1H, m), 3.59 (1H, d, J=1.8 Hz), 4.04 (1H, d, J=1.8
Hz), 5.08 (2H, s), 6.97 (2H, d, J=8.8 Hz), 7.23 (2H, d, J=8.8 Hz),
7.35-7.43 (5H, m).
Preparation 58
[2435] To a solution of
4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol (501 mg) in
CH2Cl2 (5 ml) was added trifluoromethanesulfonic anhydride (300
.mu.l) and diisopropylethylamine (324 .mu.l) under ice-bath
cooling. The mixture was stirred at same temperature for 2 hours.
Additional trifluoromethanesulfonic anhydride (57 .mu.l) and
diisopropylethylamine (147 .mu.l) were added and stirring at same
temperature was continued for 1 hour. The mixture was washed with
1M HCl, saturated aqueous sodium bicarbonate solution and saturated
aqueous sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo. The residue was purified by silica gel
column chromatography eluted with AcOEt/n-hexane=20% to give
4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenyl
trifluoromethanesulfonate (712.3 mg) as an oil.
[2436] MS (ESI+): m/z 429 (M+H)
[2437] 1HNMR (200 MHz, CDCl.sub.3): 3.81 (3H, s) 3.98 (3H, s), 5.97
(1H, s), 6.85 (2H, d, J=9.0 Hz), 7.11-7.32 (6H, m)
[2438] The following compound(s) was(were) obtained in a similar
manner to that of Preparation 58.
Preparation 59
4-[3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenyl
trifluoromethanesulfonate
[2439] oil
[2440] MS ESI+): m/z 457 (M+H).
[2441] 1HNMR (200 MHz, CDCl3): 1.40 (6H, d, J=6.1 Hz 3.81 (3H, s),
4.89 (1H, m), 5.94 (1H, s), 6.84 (2H, d, J=9.0 Hz 7.14 (2H, d,
J=9.0 Hz), 7.20-7.32 (4H, m).
Preparation 60
4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenyl
trifluoromethanesulfonate
[2442] oil
[2443] MS (ESI+): m/z 433 (M+H).
[2444] 1H NMR (200 MHz, CDCl3): 3.82 (3H, s), 6.46 (1H, s), 6.86
(2H, d, J=9.0 Hz), 7.17 (2H, d, J=9.0 Hz), 7.23-7.32 (4H, m).
Preparation 61
[2445] A mixture of
4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenyl
trifluoromethanesulfonate (679 mg), zinc cyanide (279 mg), and
tetrakis(triphenylphosphine)-palladium(0) (183 mg) in DMF (4 ml)
was stirred at 85.degree. C. for 5 hours. The reaction mixture was
cooled to ambient temperature and AcOEt and H2O were added.
Unsoluble matter was filtered off through a celite pad. The
filtrate was partitioned, and the organic layer was washed with
saturated aqueous sodium chloride solution, dried over magnesium
sulfate, and concentrated in vacuo. The residue was purified by
silica gel column chromatography eluted with AcOEt/n-hexane=20%.
The pure fractions were collected and concentrated in vacuo to give
4-[3-methoxy-1-(4-methoxy-phenyl)-1H-pyrazol-5-yl]benzonitrile (326
mg) as a powder.
[2446] mp. 112-113.degree. C.
[2447] MS (ESI+): m/z 306 (M+H), 328 (M+Na).
[2448] IR (KBr) 2929, 2227, 1568, 1552, 1541, 1518 cm-1
[2449] 1HNMR (200 MHz, CDCl3): 3.81 (3H, s), 3.98 (3H, s), 6.01
(1H, s), 6.85 (2H, d, J=8.9 Hz), 7.15 (2H, d, J=8.9 Hz 7.30 (2H, d,
J=8.5 Hz), 7.57 (2H, d, J=8.5 Hz)
[2450] The following compound(s) was(were) obtained in a similar
manner to that of Preparation 61.
Preparation 62
4-[3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-benzonitrile
[2451] mp. 96-97.degree. C.
[2452] MS (ESI+): m/z 334 (M+H), 356 (M+Na).
[2453] 1HNMR (200 MHz, CDCl.sub.3): 1.40 (6H, d, J=6.1 Hz), 3.81
(3H, s), 4.89 (1H, m), 5.98 (1H, s), 6.84 (2H, d, J=9.0 Hz), 7.14
(2H, d, J=9.0 Hz), 7.30 (2H, d, J=8.6 Hz), 7.56 (2H, d, J=8.6
Hz)
Preparation 63
4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]ben-
zonitrile
[2454] oil
[2455] MS (ESI+): m/z 375 (M+H)
[2456] 1HNMR (200 MHz, CDCl3): 3.94 (3H, s), 4.62 (1H, d, J=8.4
Hz), 4.71 (1H, d, J=8.4 Hz), 6.12 (1H, s), 6.76 (1H, d, J=8.7 Hz),
7.33 (2H, d, J=8.4 Hz), 7.5 (1H, dd, J=2.7, 8.7 Hz), 7.62 (2H, d,
J=8.4 Hz), 7.97 (1H, d, J=2.7 Hz).
Preparation 64
4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-benzonitrile
[2457] powder
[2458] MS (ESI+): m/z 310 (M+H), 332 (M+Na).
[2459] 1HNMR (200 MHz, CDCl.sub.3): 3.83 (3H, s), 6.50 (1H, s),
6.87 (2H, d, J=9.0 Hz), 7.16 (2H, d, J=9.0 Hz) 7.30 (2H, d, J=8.5
Hz), 7.60 (2H, d, J=8.5 Hz
Preparation 65
4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]-benzonitrile
[2460] powder
[2461] MS (ESI+): m/z 311 (M+H), 333 (M+Na).
[2462] 1HNMR (200 MHz, CDCl3): 3.94 (3H, s), 6.53 (1H, s), 6.78
(1H, d, J=8.9 Hz), 7.33 (2H, d, J=8.4 Hz), 7.54 (1H, dd, J=2.7, 8.9
Hz), 7.64 (2H, d, J=8.4 Hz), 7.99 (1H, d, J=2.7 Hz
Preparation 66
[2463] A solution of trifluoromethanesulfonic anhydride (207 .mu.l)
in CH2Cl2 (1 ml) was added to a solution of
4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]ph-
enol (300 mg) and pyridine (199 .mu.l) in CH2Cl2 (3 ml) under
ice-bath cooling. The mixture was stirred at same temperature for 1
hour. The reaction was quenched by adding saturated aqueous
ammonium chloride solution (5 ml). The mixture was partitioned
between AcOEt and 1M HCl. The mixture was washed with saturated
aqueous sodium bicarbonate solution and saturated aqueous sodium
chloride solution, dried over magnesium sulfate, and concentrated
in vacuo to give
4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro-ethoxy)-1H-pyrazol-5-yl]p-
henyl trifluoromethane-sulfonate (439 mg) as an oil.
[2464] MS (ESI+): m/z 498 (M+H).
[2465] 1HNMR (200 MHz, CDCl3): 3.94 (3H, s), 4.62 (1H, d, J=8.4
Hz), 4.71 (1H, d, J=8.4 Hz), 6.08 (1H, s), 6.74 (1H, d, J=8.7 Hz),
7.22-7.38 (4H, m), 7.47 (1H, dd, J=2.7, 8.7 Hz), 8.01 (1H, d, J=2.7
Hz)
[2466] The following compound(s) was(were) obtained in a similar
manner to that of Preparation 66.
Preparation 67
4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]-phenyl
trifluoromethanesulfonate
[2467] oil
[2468] MS (ESI+): m/z 434 (M+H).
[2469] 1HNMR (200 MHz, CDCl3): 3.94 (3H, s), 6.49 (1H, s), 6.76
(1H, d, J=8.9 Hz), 7.23-7.34 (4H, m), 7.52 (1H, dd, J=2.8, 8.9 Hz),
8.02 (1H, d, J=2.8 Hz
Preparation 68
[2470] A solution of
4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenyl benzyl ether
(2.79 g) and thioanisole (3.56 g) in trifluoroacetic acid (25 ml)
was stirred at ambient temperature overnight. The mixture was
concentrated in vacuo. The residue was recrystallized from AcOEt
(15 ml) and n-hexane (12 ml) to givr 1st crop of FR282117 (1.48 g).
The mother liqour was washed with H2O, saturated aqueous sodium
chloride solution, dried over magnesium sulfate, and concentrated
in vacuo. The residue was purified by silica gel column
chromatography eluted with AcOEt/n-hexane=30%. The pure fractions
were collected and concentrated in vacuo. The residual crystals
were collected and washed with IPE to give 2nd crop of
4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol (457.2 mg)
white powder
[2471] Mass (ESI+): m/z 301 (M+H)
[2472] 200 MHz 1H NMR (DMSO-d6, d): 3.78 (3H, s), 6.62 (1H, s),
6.71 (2H, d, J=8.7 Hz), 6.96(2H, d, J=9.0 Hz), 7.03(2H, d, J=8.7
Hz), 7.19(2H, d, J=9.0 Hz), 9.80(1H, s)
[2473] The following compound(s) was(were) obtained in a similar
manner to that of Preparation 68.
Preparation 69
4-[1-(4-methoxyphenyl)-3-(methylthio)-1H-pyrazol-5-yl]-phenol
[2474] powder
[2475] MS (ESI+): m/z 313 (M+H).
[2476] 1HNMR (200 MHz, DMSOd6): 2.50 (3H, s), 3.77 (3H, s), 6.49
(1H, s), 6.70 (2H, d, J=8.6 Hz), 6.94 (2H, d, J=9.0 Hz), 7.02 (2H,
d, J=8.6 Hz), 7.16 (2H, d, J=9.0 Hz), 9.71 (1H, brs).
[2477] The following compound(s) was(were) obtained in a similar
manner to that of Example 596.
Preparation 70
4-[1-[4-(methylthio)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenol
[2478] MASS (ESI+): m/z=373.1 (M+Na).
[2479] 1HNMR (400 MHz, CDCl3): 2.49 (3H, s), 5.13 (1H, b.s), 6.67
(1H, s), 6.79 (2H, d, J=8.7 Hz), 7.1 (2H, d, J=8.7 Hz), 7.2 (2H, d,
J=9.1 Hz), 7.23 (2H, d, J=9.1 Hz
Preparation 71
4-{3-(difluoromethyl)-1-[4-(methylthio)phenyl]-1H-pyrazol-5-yl}phenol
[2480] MASS (ESI+) m/z=355.1 (M+Na).
[2481] 1HNMR (400 MHz, CDCl3): 2.49 (3H, s), 5.17 (1H, b.s), 6.65
(1H, s), 6.76 (1H, t, J=55 Hz), 6.78 (2H, d, J=8.7 Hz), 7.1 (2H, d,
J=8.7 Hz) 7.2 (4H, s).
Preparation 72
4-[1-(6-methoxy-3-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzonitr-
ile
[2482] MASS (ESI+): m/z=345.1, 367.1 (m+H, m+Na).
[2483] 1HNMR (400 MHz, CDCl3): 3.96 (3H, s), 6.8 (1H, d, J=8.8 Hz),
6.85 (1H, s), 7.36 (2H, d, J=8.4 Hz), 7.57 (1H, dd, J=2.7, 8.8 Hz),
7.66 (2H, d, J=8.4 Hz), 8.04 (1H, d, J=2.7 Hz).
Preparation 73
4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]benzonitri-
le
[2484] MASS (ESI+): m/z=327.1 (m+1).
[2485] 1HNMR (400 MHz, CDCl3): 3.95 (3H, s), 6.77 (1H, t, J=54.8
Hz) 6.79 (1H, d, J=8.8 Hz) 6.82 (1H, s), 7.36 (2H, d, J=8.4 Hz),
7.54 (1H, dd, J=2.8, 8.8 Hz), 7.65 (2H, d, J=8.4 Hz) 8.04 (1H, d,
J=2.8 Hz).
EXAMPLE 415
[2486] 4M HCl in dioxane (3 ml) was added to a solution of
tert-butyl
(2-{4-[3-(1-hydroxy-1-methylethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-
-yl]phenoxy}ethyl)-carbamate (236 mg) in CH2Cl2 (3 ml). The
reaction mixture was stirred at ambient temperature for 3 hours.
2-Propanol (2 ml) was added to dissolve unsoluble oil, and stirred
at ambient temperature for 4 hours. The mixture was concentrated in
vacuo. The residue was suspended in CH2Cl2 (3 ml). Methanesulfonyl
chloride (127 mg) was added and then Et3N was added to adjust pH of
the reaction mixture to neutral. After stirring for 1 hour, the
reaction mixture was concentrated in vacuo. The residue was
partitioned between ethyl acetate and water. The mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated aqueous sodium bicarbonate solution and saturated aqueous
sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo. The residue was purified by silica gel
column chromatography eluted with 50% AcOEt/n-hexane to give
N-(2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy)-
ethyl)methane-sulfonamide (118 mg) as an oil.
[2487] 1H NMR (CDCl.sub.3) .delta. 2.20(3H, s), 3.03(3H, s),
3.51-3.60(2H, m), 3.93(3H, s), 4.07-4.13(2H, m), 4.77(1H, t, J=6.0
Hz), 5.15(1H, brs), 5.60(1H, brs), 6.59(1H, s), 6.73(1H, d, J=8.9
Hz), 6.83(2H, d, J=8.8 Hz), 7.17(2H, d, J=8.8 Hz), 7.55(1H, dd,
J=2.6,8.8 Hz), 8.09(1H, d, J=2.6 Hz)
EXAMPLE 416
[2488] A mixture of 10% Pd--C 50% wet (20 mg) and
N-(2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}-
ethyl)methanesulfonamide (118 mg) in THF (1 ml) and MeOH (1 ml) was
hydrogenated under H2 1 atm at ambient temperature for 1 day. The
catalyst was removed by filtration. The filtrate and combined
washings were concentrated in vacuo. The residue was purified by
preparative thin layer silica gel chromatography developed by
AcOEt/n-hexane=70%. The separated silica gel was extracted with 10%
MeOH/CHCl3 and the solvent was evaporated in vacuo. The residue was
recrystallized from AcOEt-IPE to give
N-(2-[4-(3-isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]pheno-
xy}ethyl)methanesulfonamide (68.6 mg) as white powder.
[2489] white powder
[2490] mp. 96-97.degree. C.
[2491] IR (KBr): 3269, 2970, 1612, 1512 cm-1
[2492] MS (ESI+): m/z 431 (M+H).
[2493] 1H NMR (DMSO-d6) .delta. 1.27(6H, d, J=6.9 Hz),
2.88-2.99(1H, m), 2.92(3H, s), 3.92-3.35(2H, m), 3.85(3H, s),
3.99-4.06(2H, m), 6.46(1H, s), 6.88(1H, d, J=8.7 Hz), 6.94(2H, d,
J=8.8 Hz), 7.17(2H, d, J=8.8 Hz), 7.28(1H, s), 7.60(1H, dd,
J=2.7,8.7 Hz), 8.02(1H, d, J=2.7 Hz)
[2494] The following compound(s) was(were) obtained in a similar
manner to that of Example 416.
EXAMPLE 417
tert-butyl
{4-[3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}carb-
amate
[2495] oil
[2496] MS (ESI+): m/z 422 (M+H).
[2497] 1HNMR (200 MHz,): 1.34 (6H, d, J=7.0 Hz), 1.46 (9H, s), 3.08
(1H, m), 3.80 (3H, s), 4.30 (2H, d, J=5.9 Hz), 4.81 (1H, brs), 6.31
(1H, s), 6.83(2H, d, J=9.0 Hz), 7.15-7.26 (6H, m)
EXAMPLE 418
tert-butyl
{4-[3-isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]benzy-
l}carbamate
[2498] oil
[2499] MS (ESI+): m/z 423 (M+H).
[2500] 1HNMR (200 MHz, CDCl3) 1.34 (6H, d, J=7 Hz) 1.46 (9H, s),
3.07 (1H, m), 3.92 (3H, s), 4.30 (2H, d, J=6.0 Hz), 4.84 (1H, brs),
6.33 (1H, s), 6.72 (1H, d, J=8.8 Hz), 7.15-7.26 (4H, m), 7.56 (1H,
dd, J=2.7, 8.8 Hz), 8.04 (1H, d, J=2.7 Hz
EXAMPLE 419
[2501] A 4M solution of HCl in dioxane (2 ml) was added to a
solution of ter-butyl
(2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]-
phenoxy}ethyl)carbamate (269.7 mg) in CH2Cl2 (2 ml). The reaction
mixture was stirred at ambient temperature for 2 hours, then, was
concentrated in vacuo to give
(2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}et-
hyl)amine dihydrochloride (259 mg) as an amorphous powder.
[2502] MS (ESI+): m/z 351 (M+H).
[2503] 1H NMR (DMSO-d6) .delta. 2.10(3H, s), 3.15-3.23(2H, m),
3.86(3H, s), 4.16-4.24 (2H, m), 5.15(1H, brs), 5.63(1H, brs),
6.85(1H, s), 6.86-7.00(3H, m), 7.18-7.25(2H, m), 7.66(1H, dd,
J=2.8,8.7 Hz), 8.06(1H, d, J=2.8 Hz), 8.24(2H, brs)
[2504] The following compound(s) was(were) obtained in a similar
manner to that of Example 419.
EXAMPLE 420
(2-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethyl)amine
hydrochloride
[2505] white powder
[2506] Mass (ESI+): 340 (M+H)+
[2507] 200 MHz 1H NMR (DMSO-d6, d): 3.16-3.23(2H, m), 3.76(3H, s),
3.84(3H, s), 4.14-4.20(2H, m), 6.06(1H, s), 6.93(2H, d, J=8.9 Hz),
6.94 (2H, d, J=8.7 Hz), 7.14 (2H, d, J=8.9 Hz), 7.17 (2H, d, J=8.7
Hz), 8.16(2H, brs)
EXAMPLE 421
(2-{4-[3-ethoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethyl)amine
hydrochloride
[2508] white powder
[2509] Mass (ESI+): 354 (M+H)+
[2510] 200 MHz 1H NMR (DMSO-d6, d): 1.33(3H, t, J=7.0 Hz),
3.14-3.23(2H, m), 3.76(3H, s), 4.12-4.23(4H, m), 6.04(1H, s),
6.92(2H, d, J=9.0 Hz), 6.94(2H, d, J=8.8 Hz), 7.12(2H, d, J=9.0
Hz), 7.16(2H, d, J=8.8 Hz), 8.24(2H, brs)
EXAMPLE 422
(2-{4-[3-isobutoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)amine
hydrochloride amorphous
[2511] Mass (ESI+): 382 (M+H)+
[2512] 200 MHz 1H NMR (DMSO-d6, d): 0.97(6H, d, J=6.7 Hz), 2.03(1H,
m), 3.14-3.23(2H, m), 3.76(3H, s), 3.90(2H, d, J=6.6 Hz),
4.14-4.20(2H, m), 6.06(1H, s), 6.92(2H, d, J=9.0 Hz), 6.94(2H, d,
J=8.8 Hz), 7.08-7.19(4H, m), 8.23(2H, brs)
EXAMPLE 423
(2-{4-[3-(2-methoxyethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}eth-
yl)amine hydrochloride amorphous
[2513] Mass (ESI+): 384 (M+H)+
[2514] 200 MHz 1H NMR (DMSO-d6, d): 3.15-3.23(2H, m), 3.31(3H, s),
3.62-3.67(2H, m), 3.75(3H, s), 4.14-4.27(4H, m), 6.06(1H, s),
6.92(2H, d, J=8.9 Hz), 6.95(2H, d, J=8.8 Hz), 7.13(2H, d, J=8.9
Hz), 7.17(2H, d, J=8.8 Hz), 8.20(2H, brs)
EXAMPLE 424
(2-{4-[3-(2-ethoxyethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethy-
l)amine hydrochloride amorphous
[2515] Mass (ESI+): 398 (M+H)+
[2516] 200 MHz 1H NMR (DMSO-d6, d): 1.13(3H, t, J=7.0 Hz),
3.15-3.24 (2H, m), 3.50 (2H, q, J=7.0 Hz), 3.66-3.71 (2H, m),
3.76(3H, s), 4.13-4.27(4H, m), 6.07(1H, s), 6.93(2H, d, J=8.9 Hz),
6.95(2H, d, J=8.7 Hz), 7.13(2H, d, J=8.9 Hz), 7.17(2H, d, J=8.7
Hz), 8.13(2H, brs)
EXAMPLE 425
(2-{4-[3-methoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)a-
mine dihydrochloride amorphous
[2517] MS (ESI+): m/z 341 (M+H)+
[2518] 200 MHz 1H NMR (DMSO-d6, d): 3.16-3.23(2H, m), 3.84 (3H, s),
3.85(3H, s), 4.16-4.21(2H, m), 6.12(1H, s), 6.86(1H, d, J=8.7 Hz),
6.98(2H, d, J=8.7 Hz), 7.21(2H, d, J=8.7 Hz), 7.62(1H, dd,
J=2.5,8.7 Hz), 7.99(1H, d, J=2.5 Hz), 8.24(2H, brs)
EXAMPLE 426
(2-{4-[3-ethoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)am-
ine dihydrochloride amorphous
[2519] MS (ESI+): m/z 355 (M+H)+
[2520] 200 MHz 1H NMR (DMSO-d6, d): 1.33(3H, t, J=7.0 Hz),
3.15-3.24(2H, m), 3.84(3H, s), 4.13-4.24(2H, m), 4.19(2H, q, J=7.0
Hz), 6.10(1H, s), 6.86(1H, d, J=8.9 Hz), 6.98(2H, d, J=8.8 Hz),
7.21(2H, d, J=8.8 Hz), 7.60(1H, dd, J=2.7,8.9 Hz), 7.98(1H, d,
J=2.7 Hz), 8.19(2H, brs)
EXAMPLE 427
(2-{4-[1-(4-methoxyphenyl)-4-methyl-3-(trifluoro-methyl)-1H-pyrazol-5-yl]p-
henoxy}ethyl)amine hydrochloride
[2521] MASS (ESI+): m/z=392.2 (M+H).
[2522] 1HNMR (400 MHz, DMSOd6): 2.09 (3H, s), 3.1-3.3 (2H, m), 3.36
(2H, b.s), 3.57 (3H, s), 4.20 (2H, t, J=5 Hz), 6.94 (2H, d, J=8.9
Hz), 7.01 (2H, d, J=8.8 Hz), 7.2 (2H, d, J=8.9 Hz), 7.21 (2H, d,
J=8.8 Hz), 8.29 (2H, br.s).
EXAMPLE 428
(2-{4-[1-[4-(methylthio)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenox-
y}ethyl)amine hydrochloride
[2523] MASS (ESI+): m/z=394.1 (M(Free)+1, HCl salt).
[2524] 1HNMR (200 MHz, DMSOd6): 2.5 (3H, s), 3.15-3.25 (2H, m),
4.22 (2H, t, J=5 Hz), 7 (2H, d, J=8.7 Hz), 7.1 (1H, s), 7.26 (2H,
d, J=8.7 Hz), 7.27 (2H, d, J=9.8 Hz 7.33 (2H, d, J=9.8 Hz), 8.35
(2H, b.s).
EXAMPLE 429
[2-(4-{3-(difluoromethyl)-1-[4-(methylthio)phenyl]-1H-pyrazol-5-yl}phenoxy-
)ethyl]amine hydrochloride
[2525] MASS (ESI-): m/z=410.0 (M-1).
[2526] 1HNMR (400 MHz, DMSOd6): 2.49 (3H, s), 3.2 (2H, t, J=5 Hz),
4.19 (2H, t, J=5 Hz), 6.87 (1H, s), 6.99 (1H, d, J=8.7 Hz), 7.09
(1H, t, J=53.5 Hz), 7.24 (4H, d, J=9.6 Hz), 7.3 (2H, d, J=8.7 Hz),
8.17 (2H, b.s)
EXAMPLE 430
(2-{4-[3-cyclopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}eth-
yl)amine dihydrochloride
[2527] amorphous powder
[2528] MS (ESI+): m/z 351 (M+H).
[2529] 1HNMR (200 MHz, DMSOd6): 0.70-0.78 (2H, m), 0.86-1.02 (2H,
m), 1.88-1.99 (1H, m), 3.10-3.20 (2H, m), 3.85 (3H, s), 4.15-4.21
(2H, m), 6.31 (1H, s), 6.86 (1H, d, J=8.9 Hz), 6.96 (2H, d, J=8.8
Hz), 7.17 (2H, d, J=8.8 Hz), 7.60 (1H, dd, J=2.7, 8.9 Hz), 8.00
(1H, d, J=2.7 Hz), 8.24 (2H, brs)
EXAMPLE 431
(2-{4-[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl)-1H-pyrazol-5-yl]pheno-
xy}ethyl)amine hydrochloride
[2530] amorphous powder
[2531] MS (ESI+): m/z 421 (M+H).
[2532] 1HNMR (200 MHz, DMSOd6): 1.43-1.72 (6H, m), 3.14-3.24 (2H,
m), 3.52-3.70 (2H, m), 3.77-3.95 (2H, m), 3.78 (3H, s), 4.15-4.20
(2H, m), 6.79 (1H, s), 6.96 (2H, d, J=8.8 Hz), 6.99 (2H, d, J=8.9
Hz), 7.21 (2H, d, J=8.8 Hz), 7.24 (2H, d, J=8.9 Hz), 8.14 (2H,
brs)
EXAMPLE 432
(2-{4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl-carbonyl)-1H-pyrazol-5-y-
l]phenoxy}ethyl)amine dihydrochloride
[2533] amorphous powder
[2534] MS (ESI+): m/z 422 (M+H).
[2535] 1HNMR (200 MHz, CDCl3): 1.42-1.75 (6H, m), 3.14-3.24 (2H,
m), 3.52-3.70 (2H, m), 3.73-3.94 (2H, m), 3.87 (3H, s), 4.16-4.22
(2H, m), 6.83 (1H, s), 6.91 (1H, d, J=8.9 Hz), 6.99 (2H, d, J=8.8
Hz), 7.25 (2H, d, J=8.8 Hz), 7.69 (1H, dd, J=2.7, 8.9 Hz), 8.14
(1H, d, J=2.7 Hz), 8.21 (2H, brs)
EXAMPLE 433
5-[4-(2-aminoethoxy)phenyl]-N-ethyl-1-(6-methoxy-3-pyridinyl)-N-methyl-1H--
pyrazole-3-carboxamide dihydrochloride
[2536] amorphous powder
[2537] Mass (ESI+): m/z 396 (M+H).
[2538] 1HNMR (200 MHz, DMSOd6): 1.09-1.23 (3H, m), 2.98, 3.29 (3H,
s), 3.13-3.25 (2H, m), 3.43-3.78 (4H, m), 3.87 (3H, s), 4.16-4.22
(2H, m), 6.84, 6.86 (1H, s), 6.91 (1H, d, J=8.7 Hz), 7.00(2H, d,
J=8.7 Hz), 7.25 (2H, d, J=8.7 Hz), 7.61-7.74 (1H, m), 8.13-8.20
(3H, m)
EXAMPLE 434
(2-{4-[3-(cyclopentyloxy)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenox-
y}ethyl)amine dihydrochloride
[2539] amorphous powder
[2540] MS (ESI+): m/z 395 (M+H).
[2541] 1HNMR (400 MHz, DMSOd6): 1.57-1.91 (8H, m), 3.16-3.21 (2H,
m), 3.84 (3H, s), 4.17-4.21 (2H, m), 4.95-5 (1H, m), 6.08 (1H, s),
6.85 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.2 (2H, d, J=8.8
Hz), 7.59 (1H, dd, J=2.8, 8.8 Hz), 7.98 (1H, d, J=2.8 Hz), 8.24
(2H, brs)
EXAMPLE 435
(2-{4-[1-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]pheno-
xy}ethyl)amine hydrochloride
[2542] oil
[2543] MS (ESI+): m/z 408 (M+H).
[2544] 1HNMR (200 MHz, DMSOd6): 3.13-3.24 (2H, m), 3.76 (3H, s),
4.15-4.21 (2H, m), 4.82 (1H, d, J=9.0 Hz), 4.91 (1H, d, J=9.0 Hz),
6.23 (1H, s), 6.92-6.99 (4H, m), 7.13-7.21 (4H, m), 8.20 (2H,
brs)
EXAMPLE 436
(2-{4-[3-(2,2-difluoroethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}-
ethyl)amine hydrochloride
[2545] amorphous powder
[2546] MS (ESI+): m/z 390 (M+H).
[2547] 1HNMR (200 MHz, DMSOd6): 3.13-3.23 (2H, m), 3.76 (3H, s),
4.14-4.20 (2H, m), 4.44 (2H, dt, J=3.5, 14.9 Hz), 6.16 (1H, s),
6.41 (1H, tt, J=3.5, 54.6 Hz), 6.94 (2H, d, J=8.9 Hz), 6.95 (2H, d,
J=8.9 Hz), 7.16 (2H, d, J=8.9 Hz), 7.18 (2H, d, J=8.9 Hz), 8.17
(2H, brs)
EXAMPLE 437
(2-{4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro-ethoxy)-1H-pyrazol-5-y-
l]phenoxy}ethyl)amine dihydrochloride
[2548] amorphous powder
[2549] MS (ESI+): m/z 409 (M+H).
[2550] 1HNMR (200 MHz, DMSOd6): 3.16-3.21 (2H, m), 3.85 (3H, s),
4.16-4.22 (2H, m), 4.83 (1H, d, J=9.0 Hz), 4.92 (1H, d, J=9.0 Hz),
6.29 (1H, s), 6.88 (1H, d, J=8.8 Hz), 6.99 (2H, d, J=8.8 Hz), 7.22
(2H, d, J=8.8 Hz), 7.63 (1H, dd, J=2.7, 8.8 Hz), 8.03 (1H, d, J=2.7
Hz), 8.19 (2H, brs)
EXAMPLE 438
(2-{4-[3-(2,2-difluoroethoxy)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]ph-
enoxy}ethyl)amine dihydrochloride
[2551] powder
[2552] MS (ESI+): m/z 391 (M+H).
[2553] 1HNMR (200 MHz, DMSOd6): 3.15-3.24 (2H, m), 3.85 (3H, s),
4.16-4.22 (2H, m), 4.46 (2H, dt, J=3.5, 14.9 Hz), 6.22 (1H, s),
6.42 (1H, tt, J=3.5, 54.5 Hz), 6.87 (1H, d, J=8.9 Hz), 6.99 (2H, d,
J=8.7 Hz), 7.22 (2H, d, J=8.7 Hz), 7.62 (1H, dd, J=2.7, 8.9 Hz),
8.02 (1H, d, J=2.7 Hz), 8.20 (2H, brs)
EXAMPLE 439
{4-[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl)-1H-pyrazol-5-yl]benzyl}a-
mine hydrochloride
[2554] amorphous powder
[2555] MS (ESI+): m/z 391 (M+H).
[2556] 1HNMR (200 MHz, DMSOd6): 1.43-1.74 (6H, m), 3.51-3.72 (2H,
m), 3.77-3.93 (2H, m), 3.79 (3H, s), 3.97-4.06 (2H, m), 6.90 (1H,
s), 6.99 (2H, d, J=8.9 Hz), 7.26 (2H, d, J=8.9 Hz), 7.30 (2H, d,
J=8.2 Hz), 7.46 (2H, d, J=8.2 Hz), 8.38 (2H, brs)
EXAMPLE 440
5-[4-(aminomethyl)phenyl]-N-ethyl-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-
-3-carboxamide hydrochloride
[2557] powder
[2558] MS (ESI+): m/z 365 (M+H).
[2559] 1HNMR (200 MHz, DMSOd6): 1.09-1.22 (3H, m), 2.98, 3.29 (3H,
s), 3.35-3.80 (2H, m), 3.79 (3H, s), 3.97-4.08 (2H, m), 6.91, 6.93
(1H, s), 6.99 (2H, d, J=8.9 Hz), 7.26 (2H, d, J=8.9 Hz), 7.30 (2H,
d, J=8.3 Hz), 7.46 (2H, d, J=8.3 Hz), 8.37 (2H, brs)
EXAMPLE 441
{4-[3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-benzyl}amine
hydrochloride
[2560] oil
[2561] MS (ESI+): m/z 322 (M+H).
[2562] 1HNMR (200 MHz, DMSOd6): 1.27 (6H, d, J=6.8 Hz), 2.96 (1H,
m), 3.77 (3H, s), 3.95-4.03 (2H, m), 6.51 (1H, s), 6.94 (2H, d,
J=8.9 Hz), 7.17 (2H, d, J=8.9 Hz), 7.25 (2H, d, J=8.2 Hz), 7.45
(2H, d, J=8.2 Hz), 8.45 (2H, brs)
EXAMPLE 442
1-[5-[4-(aminomethyl)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-2-methyl-
-1-propanone hydrochloride amorphous powder
[2563] MS (ESI+): m/z 350 (M+H).
[2564] 1HNMR (200 MHz, DMSOd6): 1.16 (6H, d, J=6.9 Hz), 3.68 (1H,
m), 3.80 (3H, s), 4.01 (2H, s), 7.01 (2H, d, J=8.9 Hz), 7.10 (1H,
s), 7.26-7.34 (4H, m) 7.46 (2H, d, J=8.2 Hz), 8.33 (2H, brs)
EXAMPLE 443
{4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl-carbonyl)-1H-pyrazol-5-yl]b-
enzyl}amine dihydrochloride
[2565] oil
[2566] MS (ESI+): m/z 392 (M+H).
[2567] 1HNMR (200 MHz, DMSO-d6): 1.45-1.73 (6H, m), 3.53-3.70 (2H,
m), 3.70-3.98 (2H, m), 3.98-4.08 (2H, m), 6.92 (1H, d, J=8.8 Hz),
6.93 (1H, s), 7.32-7.55 (4H, m), 7.74 (1H, dd, J=2.7, 8.8 Hz), 8.15
(1H, d, J=2.7 Hz), 8.38 (2H, brs)
EXAMPLE 444
5-[4-(aminomethyl)phenyl]-N-ethyl-1-(6-methoxy-3-pyridinyl)-N-methyl-1H-py-
razole-3-carboxamide dihydrochloride
[2568] oil
[2569] MS (ESI+): m/z 366 (M+H).
[2570] 1HNMR (200 MHz, DMSOd6): 1.09-1.23 (3H, m), 2.98, 3.29 (3H,
s), 3.43-3.77 (2H, m), 3.88 (3H, s), 3.97-4.06 (2H, m), 6.89-6.96
(2H, m), 7.32-7.80 (5H, m), 8.14-8.16 (1H, m), 8.52 (2H, brs)
EXAMPLE 445
{4-[3-isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]benzyl}amine
dihydrochloride
[2571] amorphous powder
[2572] MS (ESI+): m/z 323 (M+H).
[2573] 1HNMR (200 MHz, DMSOd6): 1.28 (6H, d, J=6.9 Hz), 2.86-3.05
(1H, m), 3.85 (3H, s), 3.96-4.06 (2H, m), 6.57 (1H, s), 6.88 (1H,
d, J=8.8 Hz), 7.26-7.53 (4H, m), 7.66 (1H, dd, J=2.7, 8.8 Hz), 8.02
(1H, d, J=2.7 Hz), 8.48 (2H, brs)
EXAMPLE 446
1-[5-[4-(aminomethyl)phenyl]-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-3-yl]-2--
methyl-1-propanone dihydrochloride
[2574] oil
[2575] MS (ESI+): m/z 351 (M+H).
[2576] 1HNMR (200 MHz, DMSOd6): 1.17 (6H, d, J=6.8 Hz), 3.68 (1H,
m), 3.89 (3H, s), 3.98-4.06 (2H, m), 6.95 (1H, d, J=8.8 Hz) 7.13
(1H, s), 7.36 (2H, d, J=8.2 Hz), 7.51 (2H, d, J=8.2 Hz), 7.80 (1H,
dd, J=2.7, 8.8 Hz), 8.19 (1H, d, J=2.7 Hz), 8.43 (2H, brs)
EXAMPLE 447
(2-{4-[1-(4-methoxyphenyl)-4-methyl-1H-pyrazol-5-yl]-phenoxy}ethyl)amine
hydrochloride
[2577] powder
[2578] MS (ESI+): m/z 324 (M+H)
[2579] 200 MHz 1H NMR (DMSO-d6, d): 2.02(3H, s), 3.17-3.26(2H, m),
3.74(3H, s), 4.13-4.19(2H, m), 6.89(2H, d, J=9.0 Hz), 6.98(2H, d,
J=8.7 Hz), 7.10(2H, d, J=8.9 Hz), 7.13(2H, d, J=8.7 Hz), 7.57(1H,
s), 8.05(2H, brs)
EXAMPLE 448
(2-{4-[1-(6-methoxy-3-pyridinyl)-4-methyl-1H-pyrazol-5-yl]phenoxy}ethyl)am-
ine dihydrochloride
[2580] oil
[2581] MS(ESI+): m/z 325 (M+H).
[2582] 1HNMR (200 MHz, DMSOd6): 2.03 (3H, s), 3.16-3.24 (2H, m),
3.83 (3H, s), 4.18-4.24 (2H, m), 6.84 (1H, d, J=8.7 Hz), 7.01 (2H,
d, J=8.8 Hz), 7.17 (2H, d, J=8.8 Hz), 7.56 (1H, dd, J=2.7, 8.7 Hz),
7.64 (1H, s), 7.98 (1H, d, J=2.7 Hz), 8.28 (2H, brs)
EXAMPLE 449
(2-{4-[1-(4-methoxyphenyl)-3-(methylthio)-1H-pyrazol-5-yl]phenoxy}ethyl)am-
ine hydrochloride
[2583] amorphous powder
[2584] MS (ESI+): m/z 356 (M+H).
[2585] 1HNMR (200 MHz, DMSOd6): 2.52 (3H, s), 3.14-3.23 (2H, m),
3.77 (3H, s), 4.15-4.21 (2H, m), 6.57 (1H, s) 6.95 (4H, d, J=8.9
Hz), 7.17 (4H, d, J=8.9 Hz), 8.22 (2H, brs)
[2586] The following compound(s) was(were) obtained in a similar
manner to that of Example 428.
EXAMPLE 450
5-[4-(aminomethyl)phenyl]-1-(4-methoxyphenyl)-1H-pyrazole-3-carbonitrile
hydrochloride
[2587] MASS (ESI+): m/z=304.2 (M+1).
EXAMPLE 451
[2588] To a solution of
(2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}et-
hyl)amine dihydrochloride (126.4 mg) and Et3N (125 .mu.l) in CH2Cl2
(2 ml) was added methanesulfonyl chloride (34.7 .mu.l) under ice
bath cooling. The mixture was stirred at ambient temperature for 1
hour. Additional methanesulfonyl chloride (6.9 .mu.l) and Et3N
(41.6 .mu.l) were added and the reaction mixture was stirred at
ambient temperature for 30 minutes. The mixture was concentrated in
vacuo, and the residue was partitioned between AcOEt and 1M HCl.
The aqueous layer was reextracted with AcOEt. The combined organic
layers were washed with saturated aqueous sodium bicarbonate
solution and saturated aqueous sodium chloride solution, dried over
magnesium sulfate, and concentrated in vacuo. The residue was
purified by preparative thin layer silica gel chromatography
developed by AcOEt/n-hexane=70%. The separated silica gel was
extracted with 10% MeOH/CHCl3 and the solvent was evaporated in
vacuo. The residue was crystallized from AcOEt-IPE to give
N-(2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}-
ethyl)methane-sulfonamide (48.0 mg) as white powder.
[2589] mp. 96-99.degree. C.
[2590] IR (KBr): 3205, 3140, 1612, 1502 cm-1
[2591] MS (ESI+) m/z 429 (M+H).
[2592] 1H NMR (CDCl.sub.3) .delta. 2.20(3H, s), 3.03(3H, s),
3.51-3.60(2H, m), 3.93(3H, s), 4.07-4.13(2H, m), 4.75(1H, t, J=5.8
Hz), 5.15(1H, brs), 5.60(1H, brs), 6.59(1H, s), 6.73(1H, d, J=8.9
Hz), 6.83(2H, d, J=8.8 Hz), 7.17(2H, d, J=8.8 Hz), 7.55(1H, dd,
J=2.6,8.8 Hz), 8.09(1H, d, J=2.6 Hz)
[2593] The following compound(s) was(were) obtained in a similar
manner to that of Example 451.
EXAMPLE 452
N-(2-{4-[3-{[(dimethylamino)carbonyl]amino}-1-(4-methoxyphenyl)-1H-pyrazol-
-5-yl]phenoxy}ethyl)methane-sulfonamide
[2594] powder: mp. 166-167.degree. C.
[2595] IR (KBr): 3309, 3188, 3182, 3174, 1657, 1651, 1643, 1568,
1514 cm-1
[2596] Mass (ESI+): 474 (M+H)+
[2597] 200 MHz 1H NMR (CDCl3, d): 3.02(3H, s), 3.04(6H, s),
3.49-3.57(2H, m), 3.81(3H, s), 4.07(2H, t, J=5.0 Hz), 4.84(1H, t,
J=5.5 Hz), 6.78(2H, d, J=8.9 Hz), 6.85(2H, d, J=9.0 Hz), 6.85(1H,
s), 7.05(1H, s), 7.15(2H, d, J=9.0 Hz), 7.18(2H, d, J=8.9 Hz)
EXAMPLE 453
N-(2-{4-[3-[[(dimethylamino)carbonyl](methyl)amino]-1-(4-methoxyphenyl)-1H-
-pyrazol-5-yl]phenoxy}ethyl)-methanesulfonamide
[2598] amorphous
[2599] IR (neat): 1658, 1649, 1641, 1631, 1620, 1612, 1518, 1502
cm-1
[2600] Mass (ESI+): 488 (M+H)+
[2601] 200 MHz 1H NMR (DMSO-d6, d): 2.79(6H, s), 2.94(3H, s),
3.12(3H, s), 3.30-3.34(2H, m), 3.76(3H, s), 4.02(2H, t, J=5.4 Hz),
6.26(1H, s), 6.92(2H, d, J=8.7 Hz), 6.94(2H, d, J=8.9 Hz), 7.16(2H,
d, J=8.7 Hz), 7.16(2H, d, J=8.9 Hz), 7.29(1H, s)
EXAMPLE 454
N-(2-{4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)-
methanesulfonamide
[2602] white powder: mp. 112-114.degree. C.
[2603] IR (KBr): 3280, 1612 cm-1
[2604] Mass (ESI+): 423 (M+H)+
[2605] 200 MHz 1H NMR (DMSO-d6, d): 2.94(3H, s), 3.29-3.34(2H, m),
3.87(3H, s), 4.03(2H, t, J=5.4 Hz), 6.75(1H, s), 6.89(1H, d, J=8.8
Hz), 6.96(2H, d, J=8.7 Hz), 7.20(2H, d, J=8.7 Hz), 7.29(1H, brs),
7.67(1H, dd, J=2.7,8.8 Hz), 8.11(1H, d, J=2.7 Hz)
EXAMPLE 455
N-(2-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)metha-
nesulfonamide
[2606] mp. 103-104.degree. C.
[2607] IR (KBr): 3271, 1612, 1579, 1560, 1520, 1514 cm-1
[2608] Mass (ESI+): 418 (M+H)+
[2609] 200 MHz 1H NMR (DMSO-d6, d): 2.94(3H, s), 3.28-3.33(2H, m),
3.76(3H, s), 3.83(3H, s), 3.98-4.05(2H, m), 6.05(1H, s),
6.88-6.96(4H, m), 7.09-7.17(4H, m), 7.27(1H, s)
EXAMPLE 456
N-(2-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)ethan-
esulfonamide
[2610] white powder: mp. 117.8-118.0.degree. C.
[2611] IR (KBr): 3269, 1612, 1552, 1520 cm-1
[2612] Mass (ESI+): 432 (M+H)+
[2613] 200 MHz 1H NMR (DMSO-d6, d): 1.18(3H, t, J=7.3 Hz), 3.04(2H,
q, J=7.3 Hz), 3.26-3.34(2H, m), 3.75(3H, s), 3.83(3H, s),
3.96-4.03(2H, m), 6.05(1H, s), 6.91(2H, d, J=8.9 Hz), 6.92(2H, d,
J=9.0 Hz), 7.09-7.17(4H, m), 7.32(1H, brs)
EXAMPLE 457
N-(2-{4-[3-ethoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethyl)metha-
nesulfonamide
[2614] white powder: mp. 146-147.degree. C.
[2615] IR (KBr): 3130, 1612, 1518 cm-1
[2616] Mass (ESI+): 432 (M+H)+
[2617] 200 MHz 1H NMR (DMSO-d6, d): 1.33 (3H, t, J=7.0 Hz), 2.94
(3H, s), 3.27-3.36(2H, m), 3.75(3H, s), 3.98-4.05(2H, m), 4.17(2H,
q, J=7.0 Hz), 6.03(1H, s), 6.91(2H, d, J=8.8 Hz), 6.92(2H, d, J=9.0
Hz), 7.12(2H, d, J=9.0 Hz), 7.14(2H, d, J=8.8 Hz), 7.29(1H, t,
J=5.8 Hz)
EXAMPLE 458
N-(2-{4-[3-isobutoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)met-
hanesulfonamide
[2618] white powder: mp. 164.3-165.2.degree. C.
[2619] IR (KBr): 3140, 2952, 2933, 2870, 1614, 1518 cm-1
[2620] Mass (ESI+): 460 (M+H)+
[2621] 200 MHz 1H NMR (DMSO-d6, d): 0.97(6H, d, J=6.8 Hz), 2.03(1H,
m), 2.94(3H, s), 3.27-3.36(2H, m), 3.75(3H, s), 3.90(2H, d, J=6.6
Hz), 3.99-4.05(2H, m), 6.05(1H, s), 6.88-6.96(4H, m), 7.12(2H, d,
J=9.0 Hz), 7.14(2H, d, J=8.8 Hz), 7.28(1H, t, J=5.8 Hz)
EXAMPLE 459
N-(2-{4-[3-(2-methoxyethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}e-
thyl)methanesulfonamide
[2622] white powder: mp. 94.5-94.7.degree. C.
[2623] IR (KBr): 3319, 2933, 2891, 1612, 1520 cm-1
[2624] Mass (ESI+): 462 (M+H)+
[2625] 200 MHz 1H NMR (DMSO-d6, d): 2.94(3H, s), 3.29-3.35(2H, m),
3.30(3H, s), 3.62-3.67(2H, m), 3.75(3H, s), 3.98-4.05(2H, m),
4.22-4.27(2H, m), 6.05(1H, s), 6.89-6.95(4H, m), 7.10-7.17(4H, m),
7.28(1H, s)
EXAMPLE 460
N-(2-{4-[3-(2-ethoxyethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}et-
hyl)methanesulfonamide
[2626] white powder: mp. 116.3-116.4.degree. C.
[2627] IR (KBr): 3141, 2873, 1612, 1518 cm-1
[2628] Mass (ESI+): 476 (M+H)+
[2629] 200 MHz 1H NMR (DMSO-d6, d): 1.13(3H, t, J=7.0 Hz), 2.94(3H,
s), 3.28-3.40(2H, m), 3.49(2H, q, J=7.0 Hz), 3.66-3.71(2H, m),
3.75(3H, s), 3.98-4.05(2H, m), 4.21-4.26(2H, m), 6.06(1H, s),
6.89-6.95(4H, m), 7.09-7.17(4H, m), 7.29(1H, brs)
EXAMPLE 461
N-(2-{4-[3-methoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl-
)methanesulfonamide
[2630] mp. 116-117.5.degree. C.
[2631] IR (KBr) 3126, 1614, 1520, 1500 cm-1
[2632] MS (ESI+) m/z 419 (M+H)+
[2633] 200 MHz 1H NMR (DMSO-d6, d): 2.94(3H, s), 3.28-3.36(2H, m),
3.85(3H, s), 4.00-4.06(2H, m), 6.11(1H, s), 6.85(1H, d, J=8.9 Hz),
6.94(2H, d, J=8.8 Hz), 7.18(2H, d, J=8.8 Hz), 7.29(1H, s), 7.60(1H,
dd, J=2.6,8.9 Hz), 8.00(1H, d, J=2.6 Hz)
EXAMPLE 462
N-(2-{4-[3-ethoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)-
methanesulfonamide
[2634] white powder: mp. 122.0-122.6.degree. C.
[2635] IR (KBr): 3242, 1614, 1518, 1502 cm-1
[2636] MS (ESI+): m/z 433 (M+H)+
[2637] 200 MHz 1H NMR (DMSO-d6, d): 1.33(3H, t, J=7.0 Hz), 2.94(3H,
s), 3.29-3.35(2H, m), 3.84(3H, s), 4.00-4.06(2H, m), 4.19(2H, q,
J=7.0 Hz), 6.10(1H, s), 6.85(1H, d, J=8.8 Hz), 6.94(2H, d, J=8.7
Hz), 7.18(2H, d, J=8.7 Hz), 7.29(1H, brs), 7.59(1H, dd, J=2.7,8.8
Hz), 7.99(1H, d, J=2.7 Hz)
EXAMPLE 463
N-(2-{4-[1-(4-methoxyphenyl)-4-methyl-3-(trifluoro-methyl)-1H-pyrazol-5-yl-
]phenoxy}ethyl)methane-sulfonamide
[2638] MASS (ESI+): m/z=492.1 (M+Na).
[2639] 1HNMR (400 MHz, CDCl3): 2.15 (3H, s), 3.03 (3H, s),
3.53-3.57 (2H, m), 3.79 (3H, s), 4.11 (2H, t, J=5.0 Hz), 4.78 (1H,
t, J=6.0 Hz), 6.81 (2H, d, J=9.0 Hz), 6.86 (2H, d, J=8.8 Hz), 7.08
(2H, d, J=8.8 Hz), 7.13 (2H, d, J=9.0 Hz)
EXAMPLE 464
N-[2-(4-{3-(difluoromethyl)-1-[4-(methylthio)phenyl]-1H-pyrazol-5-yl}pheno-
xy)ethyl]methanesulfonamide
[2640] mp: 122.7-122.8.degree. C.
[2641] MASS (ESI+): m/z=476.1 (M+Na).
[2642] 1HNMR (400 MHz, CDCl3): 2.49 (3H, s), 3.03 (3H, s), 3.55
(2H, dt, J=4.9, 6 Hz), 4.1 (2H, t, J=4.9 Hz), 4.8 (1H, t, J=6 Hz),
6.66 (1H, s), 6.76 (1H, t, J=55 Hz), 6.83 (2H, d, J=8.8 Hz), 7.16
(2H, d, J=8.8 Hz), 7.22 (4H, s).
EXAMPLE 465
N-{4-[1-(6-methoxy-3-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzyl-
}methanesulfonamide
[2643] Crystal. mp: 125-126.degree. C.
[2644] MASS (ESI+): 449.0 (M+Na).
[2645] 1HNMR (400 MHz, CDCl3): 2.91 (3H, s), 3.94 (3H, s), 4.34
(2H, d, J=6.2 Hz), 4.74 (1H, t, J=6.2 Hz), 6.74 (1H, s), 6.77 (1H,
d, J=8.8 Hz), 7.24 (2H, d, J=8.3 Hz), 7.35 (2H, d, J=8.3 Hz), 7.58
(1H, dd, J=2.7, 8.8 Hz), 8.03 (1H, d, J=2.7 Hz
EXAMPLE 466
N-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]benzyl}-
methanesulfonamide
[2646] mp: 125.7-126.1.degree. C.
[2647] MASS (ESI+): m/z=431.0 (M+Na).
[2648] 1HNMR (400 MHz, CDCl3): 2.92 (3H, s), 3.94 (3H, s), 4.33
(2H, d, J=6.1 Hz), 4.73 (1H, b.s), 6.74 (1H, s), 6.77 (1H, t, J=55
Hz), 7.24 (2H, d, J=8.8 Hz), 7.25 (1H, d, J=7.9 Hz), 7.34 (2H, d,
J=7.9 Hz), 7.55 (1H, dd, J=2.3, 8.8 Hz), 8.03 (1H, d, J=2.3 Hz)
EXAMPLE 467
N-(2-{4-[3-cyclopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}e-
thyl)methanesulfonamide
[2649] mp. 95-97.degree. C.
[2650] MS (ESI+): m/z 429 (M+H).
[2651] 1H NMR (200 MHz,): 0.70-0.78 (2H, m), 0.87-0.98 (2H, m),
1.87-1.99 (1H, m), 2.94 (3H, s), 3.20-3.52 (2H, m), 3.85 (3H, s),
3.99-4.05 (2H, m), 6.30 (1H, s), 6.85 (1H, d, J=8.8 Hz), 6.93 (2H,
d, J=8.7 Hz), 7.15 (2H, d, J=8.7 Hz), 7.27 (1H, brs), 7.59 (1H, dd,
J=2.7, 8.8 Hz), 8.00 (1H, d, J=2.7 Hz
EXAMPLE 468
N-(2-{4-[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl)-1H-pyrazol-5-yl]phe-
noxy}ethyl)methanesulfonamide
[2652] mp. 149.1-150.3.degree. C.
[2653] Mass (ESI+): 499 (M+H)
[2654] 1HNMR (200 MHz, DMSOd6): 1.43-1.74 (6H, m), 2.94 (3H, s),
3.25-3.39 (2H, m), 3.52-3.70 (2H, m), 3.77-3.92 (2H, m), 3.78 (3H,
s), 3.99-4.06 (2H, m), 6.78 (1H, s), 6.93 (2H, d, J=8.9 Hz), 6.98
(2H, d, J=8.9 Hz), 7.18 (2H, d, J=8.9 Hz), 7.23 (2H, d, J=8.9 Hz),
7.27 (1H, brs)
EXAMPLE 469
N-(2-{4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl-carbonyl)-1H-pyrazol-5-
-yl]phenoxy}ethyl)methane-sulfonamide
[2655] mp. 158.8-159.1.degree. C.
[2656] Mass (ESI+): m/z 500 (M+H).
[2657] 1H NMR (200 MHz, DMSOd6): 1.43-1.74 (6H, m), 2.94 (3H, s),
3.22-3.40 (2H, m), 3.52-3.69 (2H, m), 3.75-3.91 (2H, m), 3.87 (3H,
s), 4.00-4.07 (2H, m), 6.82 (1H, s), 6.90 (1H, d, J=8.8 Hz), 6.96
(2H, d, J=8.8 Hz), 7.22 (2H, d, J=8.8 Hz), 7.28 (1H, brs), 7.68
(1H, dd, J=2.7, 8.8 Hz), 8.14 (1H, d, J=2.7 Hz)
EXAMPLE 470
N-ethyl-1-(4-methoxyphenyl)-N-methyl-5-(4-{2-[(methyl-sulfonyl)amino]ethox-
y}phenyl)-1H-pyrazole-3-carboxamide
[2658] mp. 106.0-106.3.degree. C.
[2659] Mass (ESI+): m/z 473 (M+H).
[2660] 1HNMR (200 MHz, DMSOd6): 1.08-1.22 (3H, m), 2.94 (3H, s),
2.97, 3.29 (3H, s), 3.28-3.35 (2H, m), 3.42-3.53, 3.67-3.79 (2H,
m), 3.78 (3H, s), 3.99-4.06 (2H, m), 6.79, 6.81 (1H, s), 6.93 (2H,
d, J=8.9 Hz), 6.98 (2H, d, J=9 Hz), 7.15-7.26 (4H, m), 7.28 (1H,
brs)
EXAMPLE 471
N-ethyl-1-(6-methoxy-3-pyridinyl)-N-methyl-5-(4-{2-[(methylsulfonyl)amino]-
ethoxy}phenyl)-1H-pyrazole-3-carboxamide
[2661] mp. 110-111.degree. C.
[2662] Mass (ESI+): m/z 474 (M+H).
[2663] 1HNMR (200 MHz, DMSOd6): 1.09-1.23 (3H, m), 2.94 (3H, s),
2.98, 3.28 (3H, s), 3.28-3.36 (2H, m), 3.42-3.55, 3.66-3.78 (2H,
m), 3.87 (3H, s), 4.01-4.07 (2H, m), 6.83, 6.85 (1H, s), 6.90 (1H,
d, J=9.0 Hz), 6.96 (2H, d, J=8.7 Hz), 7.22 (2H, d, J=8.7 Hz), 7.28
(1H, brs), 7.61-7.75 (1H, m), 8.14-8.16 (1H, m)
EXAMPLE 472
N-(2-{4-[3-isobutyryl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}et-
hyl)methanesulfonamide
[2664] mp. 155.6-155.8.degree. C.
[2665] MS (ESI+): m/z 459 (M+H).
[2666] 1HNMR (200 MHz, DMSOd6): 1.16 (6H, d, J=6.9 Hz), 2.94 (3H,
s), 3.25-3.40 (2H, m), 3.68 (1H, m), 3.88 (3H, s), 4.01-4.07 (2H,
m) 6.93 (1H, d, J=8.7 Hz), 6.96 (2H, d, J=8.7 Hz), 7.02 (1H, s),
7.23 (2H, d, J=8.7 Hz), 7.28 (1H, brs), 7.74 (1H, dd, J=2.7, 8.7
Hz), 8.18 (1H, d, J=2.7 Hz)
EXAMPLE 473
N-(2-{4-[3-(cyclopentyloxy)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phen-
oxy}ethyl)methanesulfonamide
[2667] oil
[2668] MS (ESI+): m/z 473 (M+H).
[2669] 1HNMR (200 MHz, DMSOd6): 1.51-2.00 (8H, m), 2.94 (3H, s),
3.24-3.39 (2H, m), 3.84 (3H, s), 4-4.06 (2H, m), 4.98 (1H, m), 6.07
(1H, s), 6.84 (1H, d, J=8.8 Hz), 6.94 (2H, d, J=8.8 Hz), 7.18 (2H,
d, J=8.8 Hz), 7.28 (1H, brs), 7.58 (1H, dd, J=2.7, 8.8 Hz), 7.99
(1H, d, J=2.7 Hz)
EXAMPLE 474
N-(2-{4-[1-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]phe-
noxy}ethyl)methanesulfonamide
[2670] mp. 131.3-131.4.degree. C.
[2671] MS (ESI+): m/z 486 (M+H).
[2672] 1HNMR (200 MHz, DMSOd6): 2.94 (3H, s), 3.25-3.39 (2H, m),
3.76 (3H, s), 3.99-4.05 (2H, m), 4.81 (1H, d, J=9.0 Hz), 4.90 (1H,
d, J=9.0 Hz), 6.22 (1H, s), 6.90-6.98 (4H, m), 7.11-7.18 (4H, m),
7.28 (1H, brs)
EXAMPLE 475
N-(2-{4-[3-(2,2-difluoroethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenox-
y}ethyl)methanesulfonamide
[2673] mp. 145.0-145.1.degree. C.
[2674] MS (ESI+): m/z 468 (M+H)
[2675] 1HNMR (200 MHz, DMSOd6): 2.93 (3H, s), 3.28-3.34 (2H, m),
3.76 (3H, s), 3.99-4.05 (2H, m), 4.44 (2H, dt, J=3.5,14.9 Hz), 6.15
(1H, s), 6.41 (1H, tt, J=3.5, 54.6 Hz), 6.92 (2H, d, J=9.0 Hz),
6.93 (2H, d, J=9.0 Hz), 7.11-7.18 (4H, m), 7.27 (1H, brs)
EXAMPLE 476
N-(2-{4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro-ethoxy)-1H-pyrazol-5-
-yl]phenoxy}ethyl)methane-sulfonamide
[2676] oil
[2677] MS (ESI+): m/z 487 (M+H).
[2678] 1HNMR (200 MHz, DMSOd6): 2.94 (3H, s), 3.29-3.35 (2H, m),
3.85 (3H, s), 4.00-4.06 (2H, m), 4.83 (1H, d, J=9.0 Hz), 4.92 (1H,
d, J=9.0 Hz), 6.28 (1H, s), 6.87 (1H, d, J=8.8 Hz), 6.95 (2H, d,
J=8.8 Hz), 7.19 (2H, d, J=8.8 Hz), 7.28 (1H, brs), 7.61 (1H, dd,
J=2.7, 8.9 Hz), 8.03 (1H, d, J=2.7 Hz
EXAMPLE 477
N-(2-{4-[3-(2,2-difluoroethoxy)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]-
phenoxy}ethyl)methane-sulfonamide
[2679] solid
[2680] MS (ESI+): m/z 469 (M+H).
[2681] 1HNMR (200 MHz, CDCl3): 3.03 (3H, s), 3.51-3.60 (2H, m),
3.92 (3H, s), 4.07-4.13 (2H, m), 4.46 (2H, dt, J=4.2, 13.4 Hz),
4.76 (1H, t, J=6 Hz), 5.95 (1H, s), 6.17 (1H, tt, J=4.2, 55.4 Hz),
6.72 (1H, d, J=8.8 Hz), 6.83 (2H, d, J=8.8 Hz), 7.15 (2H, d, J=8.8
Hz), 7.49 (1H, dd, J=2.8, 8.8 Hz), 8.01 (1H, d, J=2.8 Hz)
EXAMPLE 478
N-(2-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethyl)-2-hy-
droxyethanesulfonamide
[2682] mp. 139.1-139.4.degree. C.
[2683] MS (ESI+): m/z 452 (M+H).
[2684] 1HNMR (200 MHz, DMSOd6): 3.18-3.35 (4H, m), 3.69-3.77 (2H,
m), 3.78 (3H, s), 3.97-4.04 (2H, m), 4.90 (1H, t, J=5.6 Hz), 6.69
(1H, s), 6.90-7.01 (4H, m), 7.14-7.26 (5H, m)
EXAMPLE 479
N-(2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phen-
oxy}ethyl)methanesulfonamide
[2685] oil
[2686] Mass (ESI+): m/z 439 (M+H).
[2687] 1HNMR (200 MHz, CDCl3): 3.03 (3H, s), 3.51-3.60 (2H, m),
3.94 (3H, s), 4.08-4.14 (2H, m), 4.75 (1H, t, J=5.6 Hz), 6.68 (1H,
s), 6.75 (1H, d, J=8.9 Hz), 6.76 (1H, t, J=55 Hz), 6.85 (2H, d,
J=8.8 Hz), 7.17 (2H, d, J=8.8 Hz), 7.53 (1H, dd, J=2.7, 8.9 Hz),
8.08 (1H, d, J=2.7 Hz)
EXAMPLE 480
N-{4-[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl)-1H-pyrazol-5-yl]benzyl-
}methanesulfonamide
[2688] mp. 179.3-179.6.degree. C.
[2689] MS (ESI+): m/z 469 (M+H).
[2690] 1HNMR (200 MHz, DMSOd6): 1.42-1.72 (6H, m), 2.85 (3H, s),
3.52-3.69 (2H, m), 3.75-3.92 (2H, m), 3.78 (3H, s), 4.15 (2H, s),
6.85 (1H, s), 6.98 (2H, d, J=9 Hz), 7.21-7.35 (6H, m), 7.58 (1H,
brs)
EXAMPLE 481
N-ethyl-1-(4-methoxyphenyl)-N-methyl-5-(4-{[(methyl-sulfonyl)amino]methyl}-
phenyl)-1H-pyrazole-3-carboxamide
[2691] mp. 149.8-150.8.degree. C.
[2692] MS (ESI+): m/z 443 (M+H).
[2693] 1HNMR (200 MHz, DMSOd6): 1.09-1.21 (3H, m), 2.86 (3H, s),
2.98, 3.29 (3H, s), 3.40-3.78 (2H, m), 3.78 (3H, s), 4.13-4.17 (2H,
m), 6.86, 6.88 (1H, s), 6.98 (2H, d, J=9 Hz), 7.21-7.35 (6H, m),
7.58 (1H, brs)
EXAMPLE 482
N-{4-[3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-benzyl}methanesulfo-
namide
[2694] mp. 130.9-131.0.degree. C.
[2695] MS (ESI+): m/z 400 (M+H)
[2696] 1HNMR (200 MHz, DMSOd6): 1.27 (6H, d, J=6.9 Hz), 2.84 (3H,
s), 2.96 (1H, m), 3.76 (3H, s), 4.14 (2H, s), 6.47 (1H, s), 6.93
(2H, d, J=8.9 Hz), 7.11-7.21 (4H, m), 7.30 (2H, d, J=8.2 Hz), 7.56
(1H, brs)
EXAMPLE 483
N-{4-[3-isobutyryl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}methanesulfo-
namide
[2697] mp. 155.8-155.9.degree. C.
[2698] MS (ESI+): m/z 428 (M+H).
[2699] 1HNMR (200 MHz,): 1.16 (6H, d, J=6.9 Hz), 2.86 (3H, s), 3.68
(1H, m), 3.79 (3H, s), 4.15 (2H, s), 7.00 (2H, d, J=8.9 Hz), 7.06
(1H, s), 7.22-7.35 (6H, m), 7.58 (1H, s)
EXAMPLE 484
N-{4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl-carbonyl)-1H-pyrazol-5-yl-
]benzyl}methanesulfonamide
[2700] mp. 182.6-182.9.degree. C.
[2701] MS (ESI+): m/z 470 (M+H).
[2702] 1HNMR (200 MHz, DMSOd6): 1.42-1.72 (6H, m), 2.86 (3H, s),
3.53-3.69 (2H, m), 3.75-3.9 (2H, m), 3.87 (3H, s), 4.16 (2H, s),
6.89 (1H, s), 6.90 (1H, d, J=8.8 Hz), 7.28 (2H, d, J=8.4 Hz), 7.36
(2H, d, J=8.4 Hz), 7.59 (1H, s), 7.70 (1H, dd, J=2.7, 8.8 Hz), 8.14
(1H, d, J=2.7 Hz)
EXAMPLE 485
N-ethyl-1-(6-methoxy-3-pyridinyl)-N-methyl-5-(4-{[(methylsulfonyl)amino]me-
thyl}phenyl)-1H-pyrazole-3-carboxamide
[2703] white powder
[2704] MS (ESI+): m/z 444 (M+H).
[2705] 1HNMR (200 MHz, DMSOd6): 1.09-1.23 (3H, m), 2.86 (3H, s),
2.98, 3.29 (3H, s), 3.49, 3.72 (2H, q, J=7.1 Hz), 3.87 (3H, s),
4.16 (2H, s), 6.88-6.93 (2H, m), 7.28 (2H, d, J=8.3 Hz), 7.36 (2H,
d, J=8.3 Hz), 7.56 (1H, brs), 7.65-7.74 (1H, m), 8.13-8.14 (1H,
m)
EXAMPLE 486
N-{4-[3-isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]benzyl}methane-
sulfonamide
[2706] oil
[2707] MS (ESI+): m/z 401 (M+H).
[2708] 1HNMR (200 MHz, CDCl3): 1.34 (6H, d, J=6.9 Hz), 2.86 (3H,
s), 3.03 (1H, m), 3.90 (3H, s), 4.28 (2H, d, J=6.1 Hz), 5.19 (1H,
t, J=6.1 Hz), 6.34 (1H, s), 6.72 (1H, d, J=8.8 Hz), 7.21 (2H, d,
J=8.2 Hz), 7.29 (2H, d, J=8.2 Hz). 7.56 (1H, dd, J=2.7, 8.8 Hz),
7.98 (1H, d, J=2.7 Hz)
EXAMPLE 487
N-{4-[3-isobutyryl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]benzyl}methan-
esulfonamide
[2709] mp. 160.8-161.2.degree. C.
[2710] MS (ESI+): m/z 429 (M+H).
[2711] 1HNMR (200 MHz, DMSOd6): 1.16 (6H, d, J=6.8 Hz), 2.86 (3H,
s), 3.68 (1H, m), 3.88 (3H, s), 4.16 (2H, d, J=5.5 Hz), 6.93 (1H,
d, J=8.8 Hz), 7.09 (1H, s), 7.29 (2H, d, J=8.3 Hz), 7.36 (2H, d,
J=8.3 Hz), 7.59 (1H, t, J=5.5 Hz), 7.76 (1H, dd, J=2.8, 8.8 Hz),
8.18 (1H, d, J=2.7 Hz)
EXAMPLE 488
N-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}methanesulfonam-
ide
[2712] mp. 94.0-94.3.degree. C.
[2713] MS (ESI+): m/z 388 (M+H).
[2714] 1HNMR (200 MHz, DMSOd6): 2.85 (3H, s), 3.76 (3H, s), 3.84
(3H, s), 4.14 (2H, s), 6.12 (1H, s), 6.92 (2H, d, J=8.9 Hz), 7.14
(2H, d, J=8.9 Hz), 7.20 (2H, d, J=8.2 Hz), 7.30 (2H, d, J=8.2 Hz),
7.57 (1H, s)
EXAMPLE 489
N-{4-[3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}methanesulfo-
namide
[2715] amorphous
[2716] MS (ESI+): m/z 416 (M+H).
[2717] 1HNMR (200 MHz, DMSOd6): 1.32 (6H, d, J=6.1 Hz), 2.85 (3H,
s), 3.75 (3H, s), 4.14 (2H, s), 4.77 (1H, m), 6.07 (1H, s), 6.91
(2H, d, J=8.9 Hz), 7.13 (2H, d, J=8.9 Hz), 7.19 (2H, d, J=8.2 Hz),
7.30 (2H, d, J=8.2 Hz), 7.57 1H, brs)
EXAMPLE 490
N-{4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro-ethoxy)-1H-pyrazol-5-yl-
]benzyl}methanesulfonamide
[2718] mp. 130-131.degree. C.
[2719] Mass (ESI+): 457 (M+H).
[2720] 1HNMR (200 MHz, CDCl3): 2.92 (3H, s), 3.93 (3H, s), 4.33
(2H, d, J=6.0 Hz), 4.54-4.71 (1H, m), 4.62 (1H, d, J=8.4 Hz), 4.70
(1H, d, J=8.4 Hz) 6.04 (1H, s), 6.73 (1H, d, J=8.8 Hz), 7.22 (2H,
d, J=8.3 Hz), 7.33 (2H, d, J=8.3 Hz), 7.52 (1H, dd, J=2.7, 8.8 Hz),
7.95 (1H, d, J=2.7 Hz)
EXAMPLE 491
N-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}methanesulfonami-
de
[2721] mp. 68.3-69.3.degree. C.
[2722] Mass (ESI+): 392 (M+H).
[2723] 1HNMR (200 MHz, DMSOd6): 2.85 (3H, s), 3.77 (3H, s), 4.14
(2H, s), 6.76 (1H, s), 6.96 (2H, d, J=8.9 Hz), 7.17-7.24 (4H, m),
7.32 (2H, d, J=8.2 Hz), 7.58 (1H, s)
EXAMPLE 492
N-{4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]benzyl}methanesul-
fonamide
[2724] oil
[2725] Mass (ESI+): 393 (M+H).
[2726] 1HNMR (200 MHz, DMSOd6): 2.86 (3H, s), 3.86 (3H, s), 4.16
(2H, s), 6.82 (1H, s), 6.89 (1H, d, J=8.8 Hz), 7.26 (2H, d, J=8.3
Hz), 7.35 (2H, d, J=8.3 Hz), 7.59 (1H, brs), 7.69 (1H, dd, J=2.7,
8.8 Hz), 8.1 (1H, d, J=2.7 Hz)
EXAMPLE 493
N-(2-{4-[1-(4-methoxyphenyl)-3-(methylthio)-1H-pyrazol-5-yl]phenoxy}ethyl)-
methanesulfonamide
[2727] mp. 165.0-166.0.degree. C.
[2728] MS (ESI+): m/z 434 (M+H).
[2729] 1HNMR (200 MHz, DMSOd6): 2.51 (3H, s), 2.94 (3H, s),
3.27-3.36 (2H, m), 3.77 (3H, s), 3.99-4.05 (2H, m), 6.56 (1H, s),
6.92 (2H, d, J=8.8 Hz), 6.95 (2H, d, J=8.9 Hz), 7.15 (2H, d, J=8.8
Hz), 7.17 (2H, d, J=8.9 Hz), 7.27 (1H, t, J=5.8 Hz)
EXAMPLE 494
N-(2-{4-[1-(6-methoxy-3-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phe-
nyl}ethyl)benzenesulfonamide
[2730] amorphous powder
[2731] Mass (ESI+): 503 (M+H)+
[2732] 200 MHz 1H NMR (DMSO-d6, d): 2.64-2.72(2H, m), 2.91-3.02(2H,
m), 3.88(3H, s), 6.91(1H, d, J=9.0 Hz), 7.03-7.21(5H, m),
7.56-7.80(7H, m), 8.18(1H, d, J=2.6 Hz)
EXAMPLE 495
N-methoxy-1-(4-methoxyphenyl)-N-methyl-5-(4-{2-[(methylsulfonyl)amino]ethy-
l}phenyl)-1H-pyrazole-3-carboxamide
[2733] oil
[2734] Mass (ESI+): m/z 459 (M+H)
[2735] 1HNMR (200 MHz, CDCl3): 2.84-2.91 (2H, m), 2.87 (3H, s),
3.35-3.46 (2H, m), 3.51 (3H, s), 3.83 (3H, s), 3.85 (3H, s), 4.26
(1H, t, J=6.2 Hz), 6.86 (2H, d, J=9.0 Hz), 6.97 (1H, s), 7.12-7.29
(6H, m)
EXAMPLE 496
N-methoxy-1-(6-methoxy-3-pyridinyl)-N-methyl-5-(4-{2-[(methylsulfonyl)amin-
o]ethyl}phenyl)-1H-pyrazole-3-carboxamide
[2736] oil
[2737] Mass (ESI+): m/z 460 (M+H).
[2738] 1HNMR (200 MHz, CDCl3): 2.80-2.93 (2H, m), 2.88 (3H, s),
3.36-3.47 (2H, m), 3.50 (3H, s), 3.85 (3H, s), 3.94 (3H, s), 4.28
(1H, t, J=6.2 Hz), 6.75 (1H, d, J=8.8 Hz), 6.98 (1H, s), 7.20 (4H,
s), 7.56 (1H, dd, J=2.7, 8.8 Hz), 8.10 (1H, d, J=2.7 Hz)
EXAMPLE 497
[2739] Trimethylsilyl isocyanate (73.8 .mu.l) was added to a
solution of
(2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}et-
hyl)amine dihydrochloride (115.4 mg) and Et3N (114 .mu.l) and the
mixture was stirred at ambient temperature for 1.5 hours. The
mixture was concentrated in vacuo and the residue was partitioned
between AcOEt and 1M HCl. The aqueous layer was reextracted with
AcOEt. The combined organic layers were washed with saturated
aqueous sodium bicarbonate solution and saturated aqueous sodium
chloride solution, dried over magnesium sulfate, and concentrated
in vacuo. The residue was purified by preparative thin layer silica
gel chromatography developed by 10% MeOH/CHCl3. The separated
silica gel was extracted with 10% MeOH/CHCl3 and the solvent was
evaporated in vacuo. The residue was crystallized from AcOEt-IPE to
give
N-(2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}-
ethyl)urea (40.1 mg) as a white powder.
[2740] white powder: mp. 94-98.degree. C.
[2741] IR (KBr): 3435, 3388, 3344, 3333, 1657, 1631, 1610, 1577,
1572, 1562, 1552, 1502 cm-1
[2742] 1H NMR (DMSO-d6) .delta. 2.10(3H, s), 3.28-3.27(2H, m),
3.86(3H, s), 3.91-3.97(2H, m), 5.15(1H, brs), 5.53(2H, s), 5.62(1H,
brs), 6.16(1H, t, J=5.5 Hz), 6.84(1H, s), 6.88(1H, d, J=8.8 Hz),
6.95(2H, d, J=8.8 Hz), 7.19(2H, d, J=8.8 Hz), 7.64(1H, dd,
J=2.7,8.8 Hz), 8.07(1H, d, J=2.7 Hz)
[2743] The following compound(s) was(were) obtained in a similar
manner to that of Example 497.
EXAMPLE 498
N-(2-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea
[2744] mp. 108-111.degree. C.
[2745] IR (KBr): 3388, 3342, 1657, 1631, 1612, 1593, 1577, 1562,
1522 cm-1
[2746] Mass (ESI+): 383 (M+H)+
[2747] 200 MHz 1H NMR (CDCl3, d): 3.54-3.62(2H, m), 3.79(3H, s),
3.96(3H, s), 3.98-4.04(2H, m), 4.44(2H, s), 5.03(1H, t, J=5.5 Hz),
5.88(1H, s), 6.78(2H, d, J=8.8 Hz), 6.82(2H, d, J=8.9 Hz), 7.12(2H,
d, J=8.8 Hz), 7.16(2H, d, J=8.9 Hz)
EXAMPLE 499
N-(2-{4-[3-ethoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea
[2748] white powder: mp. 154.2-154.4.degree. C.
[2749] IR (KBr): 3398, 3332, 1658, 1631, 1612, 1566, 1518 cm-1
[2750] Mass (ESI+): 397 (M+H)+
[2751] 200 MHz 1H NMR (DMSO-d6, d): 1.33(3H, t, J=7.0 Hz),
3.27-3.34(2H, m), 3.75(3H, s), 3.89-3.96(2H, m), 4.17(2H, q, J=7.0
Hz), 5.53(2H, s), 6.03(1H, s), 6.15(1H, t, J=5.6 Hz), 6.90(2H, d,
J=8.9 Hz), 6.92(2H, d, J=9.0 Hz), 7.10-7.15(4H, m)
EXAMPLE 500
[2752] Imidazole (680 mg) and t-butyldimethylsilyl chloride (903
mg) was added successively to a solution of ethyl
5-[4-{2-(hydroxy)ethoxy}phenyl]-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxy-
late (1.91 g) in DMF (15 ml) under cooling in an ice bath. After
stirring at ambient temperature for 2 hours, the mixture was
partitioned between AcOEt and H2O. The organic layer was washed
with H2O, saturated aqueous sodium chloride solution, dried over
MgSO4, concentrated in vacuo. The residual crystals were collected
and washed with n-hexane to give ethyl
5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-phenyl]-1-(4-methoxypheny-
l)-1H-pyrazole-3-carboxylate (2.34 g).
[2753] powder
[2754] mp. 86-87.degree. C.
[2755] MS (ESI+): m/z 497 (M+H).
[2756] 1H NMR (CDCl3) .delta. 0.09(6H, s), O 90(9H, s), 1.42(3H, t,
J=7.1 Hz), 3.82(3H, s), 3.94-3.97(2H, m), 4.01-4.04(2H, m),
4.44(2H, q, J=7.1 Hz), 6.83(2H, d, J=8.7 Hz), 6.85(2H, d, J=8.9
Hz), 6.96(1H, s), 7.11(2H, d, J=8.7 Hz), 7.24(2H, d, J=8.9 Hz)
EXAMPLE 501
[2757] A solution of ethyl
5-[4-(2-{[tert-butyl(dimethyl)silyl]-oxy}ethoxy)phenyl]-1-(4-methoxypheny-
l)-1H-pyrazole-3-carboxylate (0.3 g) in THF (3 ml) was added
dropwise to a 1M solution of methylmagnesium bromide (3 ml) at
ambient temperature. The reaction mixture was stirred at ambient
temperature for 1 hour, then was poured into a mixture of crushed
ice and saturated aqueous ammonium chloride solution The mixture
was extracted with AcOEt. The organic layer was washed with
saturated aqueous sodium bicarbonate solution and saturated aqueous
sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo to give
2-[5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-ethoxy)phenyl]-1-(4-methoxyph-
enyl)-1H-pyrazol-3-yl]-2-propanol (0.27 g) as an oil.
[2758] oil
[2759] MS (ESI+): m/z 483 (M+H).
[2760] 1H NMR (CDCl3) .delta. 0.09(6H, s), 0.90(9H, s), 1.65(6H,
s), 3.81(3H, s), 3.94-3.97(2H, m), 4.01-4.04(2H, m), 6.35(1H, s),
6.82(2H, d, J=8.8 Hz), 6.85(2H, d, J=8.9 Hz), 7.12(2H, d, J=8.8
Hz), 7.21(2H, d, J=8.9 Hz)
[2761] The following compound(s) was(were) obtained in a similar
manner to that of Example 501.
EXAMPLE 502
N-(2-{4-[3-(1-hydroxy-1-methylethyl)-1-(4-methoxy-phenyl)-1H-pyrazol-5-yl]-
phenoxy}ethyl)urea
[2762] white powder: mp. 147-152.degree. C.
[2763] IR (KBr): 3333, 3271, 2976, 1676, 1664, 1658, 1612, 1547,
1537, 1516, 1502 cm-1
[2764] MS (ESI+): m/z 411 (M+H).
[2765] 1H NMR (DMSO-d6) .delta. 1.48(6H, s), 3.22-3.40(2H, m),
3.76(3H, s), 3.90-3.96(2H, m), 4.98(1H, s), 5.52(2H, s), 6.14(1H,
t, J=5.6 Hz), 6.49(1H, s), 6.90(2H, d, J=8.7 Hz), 6.94(2H, d, J=8.8
Hz), 7.12(2H, d, J=8.7 Hz), 7.15(2H, d, J=8.8 Hz)
EXAMPLE 503
tert-butyl
{4-[3-(1-hydroxy-1-methylethyl)-1-(4-methoxyphenyl)-1H-pyrazol--
5-yl]benzyl}carbamate
[2766] powder
[2767] MS (ESI+): m/z 438 (M+H).
[2768] 1HNMR (200 MHz, DMSOd6): 1.39 (9H, s), 1.49 (6H, s), 3.76
(3H, s), 4.11 (2H, d, J=6.1 Hz), 5.01 (1H, s), 6.54 (1H, s), 6.94
(2H, d, J=8.9 Hz), 7.15 (2H, d, J=8.9 Hz), 7.17 (4H, brs), 7.4 (1H,
t, J=6.1 Hz)
EXAMPLE 504
tert-butyl
{4-[3-(1-hydroxy-1-methylethyl)-1-(6-methoxy-3-pyridinyl)-1H-py-
razol-5-yl]benzyl}-carbamate
[2769] powder
[2770] MS (ESI+): m/z 439 (M+H).
[2771] 1HNMR (200 MHz, DMSOd6): 1.39 (9H, s), 1.49 (6H, s), 3.85
(3H, s), 4.12 (2H, d, J=6.1 Hz), 5.05 (1H, s), 6.59 (1H, s), 6.86
(1H, d, J=8.8 Hz), 7.20 (4H, s), 7.40 (1H, t, J=6.1 Hz), 7.62 (1H,
dd, J=2.7, 8.8 Hz), 8.00 (1H, d, J=2.7 Hz)
EXAMPLE 505
[2772] A solution of
2-[5-[4-(2-{[tert-butyl(dimethyl)silyl]-oxy}ethoxy)phenyl]-1-(4-methoxyph-
enyl)-1H-pyrazol-3-yl]-2-propanol (180 mg) in DMF (2 ml) was added
dropwise to a suspension of sodium hydride 60% dispersion in
mineral oil (17 mg) in DMF (1 ml) under cooling in an ice bath.
After 10 minutes, iodemethane (63.5 mg) was added and the reaction
mixture was stirred at same temperature for 1 hour and at ambient
temperature for 1 hour. Additional iodomethane was added until all
starting material was consumed. The reaction was quenched by adding
saturated ammonium chloride. The mixture was extracted with ethyl
acetate. The organic layer was washed with H2O and saturated
aqueous sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo. The residue was purified by silica gel
column chromatography eluted with AcOEt/n-hexane, which polarity
was gradually changed from 20% to 80%, to give
5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)phenyl]-3-(1-methoxy-1-met-
hylethyl)-1-(4-methoxyphenyl)-1H-pyrazole (32.2 mg) as an oil.
[2773] Mass (ESI+): 497 (M+H).
[2774] 1H NMR (CDCl3) .delta. 0.09(6H, s), 0.90(9H, s), 1.58(3H,
s), 1.63(3H, s), 3.22(3H, s), 3.81(3H, s), 3.93-4.04(4H, m),
6.42(1H, s), 6.82(2H, d, J=8.8 Hz), 6.84(2H, d, J=9.0 Hz), 7.13(2H,
d, J=8.8 Hz), 7.22(2H, d, J=9.0 Hz)
EXAMPLE 506
[2775] A 1M solution of tetra-n-butylammonium fluoride in THF (0.24
ml) was added to a solution of
5-[4-(2-{[tert-butyl-(dimethyl)silyl]oxy}ethoxy)phenyl]-3-(1-methoxy-1-me-
thylethyl)-1-(4-methoxyphenyl)-1H-pyrazole (98 mg) in THF (2 ml)
under ice bath cooling. The reaction mixture was stirred at same
temperature for 1 hour. The mixture was partitioned between ethyl
acetate and H2O. The organic layer was washed with saturated
aqueous sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo. The residue was purified by preparative thin
layer silica gel chromatography developed by 50% AcOEt/n-hexane.
The separated silica gel was extracted with 10% MeOH/CHCl3 and the
solvent was evaporated in vacuo to give
2-{4-[3-(1-methoxy-1-methylethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phe-
noxy}ethanol (66 mg) as an oil.
[2776] IR (neat): 3423, 3398, 3371, 2976, 2935, 1647, 1612, 1566,
1549, 1512 cm-1
[2777] MS (ESI+): m/z 383 (M+H).
[2778] 1H NMR (CDCl3) .delta. 1.60(3H, s), 1.63(3H, s), 2.03(1H, t,
J=6.1 Hz), 3.22(3H, s), 3.81(3H, s), 3.91-4.00(2H, m),
4.05-4.10(2H, m), 6.43(1H, s), 6.83(2H, d, J=8.9 Hz), 6.84(2H, d,
J=8.9 Hz), 7.15(2H, d, J=8.9 Hz), 7.21(2H, d, J=8.9 Hz)
EXAMPLE 507
[2779] A 4M solution of HCl in dioxane (2 ml) was added to a
solution of ethyl
5-(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}-phenyl)-1-(4-methoxyphe-
nyl)-1H-pyrazole-3-carboxylate (300 mg) in CH2Cl2 (3 ml) under
cooling in an ice bath. After stirring at ambient temperature for 1
hour, the reaction mixture was concentrated in vacuo. The residue
was dissolved in CH2Cl2 (3 ml), Et3N (189 mg) and trimethylsilyl
isocyanate (108 mg) were added, and the mixture was stirred at
ambient temperature overnight. The stirring was continued for more
4 hours, adding more trimethylsilyl isocyanate and Et3N to consume
all starting material. The mixture was concentrated in vacuo and
the residue was partitioned between ethyl acetate and 1M HCl. The
organic layer was washed with saturated aqueous sodium bicarbonate
solution and saturated aqueous sodium chloride solution, dried over
magnesium sulfate, and concentrated in vacuo. The residual crystals
were suspended in hot ethyl acetate, cooled with stirring,
collected and washed with ethyl acetate to give ethyl
5-(4-{2-[(aminocarbonyl)amino]ethoxy}phenyl)-1-(4-methoxyphenyl)-1H-pyraz-
ole-3-carboxylate (217 mg) as a white powder.
[2780] MS (ESI+): m/z 425 (M+H).
[2781] 1H NMR (DMSO-d6) .delta. 1.31(3H, t, J=7.1 Hz),
3.27-3.36(2H, m), 3.79(3H, s), 3.90-3.96(2H, m), 4.32(2H, q, J=7.1
Hz), 5.52(2H, s), 6.14(1H, t, J=5.7 Hz), 6.92(2H, d, J=8.8 Hz),
6.99(2H, d, J=8.8 Hz), 7.01(1H, s), 7.17(2H, d, J=8.8 Hz), 7.25(2H,
d, J=8.8 Hz)
EXAMPLE 508
[2782] 1M NaOH (5 ml) was added to a solution of ethyl
5-(4-{2-[(aminocarbonyl)amino]ethoxy}phenyl)-1-(4-methoxyphenyl)-1H-pyraz-
ole-3-carboxylate (1.75 g) in THF (15 ml) and MeOH (10 ml). The
reaction mixture was stirred at ambient temperature and
concentrated in vacuo. The residue was dissolved in H2O and
acidified by 1M HCl. white precipitates were collected and washed
successively with H2O and IPE to give
5-(4-{2-[(aminocarbonyl)amino]-ethoxy}phenyl)-1-(4-methoxyphenyl)-1H-pyra-
zole-3-carboxylic acid (1.58 g) as a white powder.
[2783] MS (ESI+): m/z 397 (M+H).
[2784] 1H NMR (DMSO-d6) .delta. 3.15-3.55(2H, m), 3.90-3.97(2H, m),
5.52(2H, s), 6.14(1H, t, J=5.7 Hz), 6.89-7.03(5H, m), 7.17(2H, d,
J=8.8 Hz), 7.24(2H, d, J=8.9 Hz)
[2785] The following compound(s) was(were) obtained in a similar
manner to that of Example 508.
EXAMPLE 509
5-(4-{[(tert-butoxycarbonyl)amino]methyl}phenyl)-1-(4-methoxyphenyl)-1H-py-
razole-3-carboxylic acid
[2786] white powder
[2787] MS (ESI+): m/z 424(M+H).
[2788] 1HNMR (200 MHz, DMSOd6): 1.38 (9H, s), 3.79 (3H, s), 4.11
(2H, d, J=6.1 Hz), 6.99 (2H, d, J=8.9 Hz), 7.01 (1H, s), 7.20 (4H,
brs), 7.25 (2H, d, J=8.9 Hz), 7.41 (1H, t, J=6.1 Hz), 12.92 (1H,
brs
EXAMPLE 510
5-(4-{[(tert-butoxycarbonyl)amino]methyl}phenyl)-1-(6-methoxy-3-pyridinyl)-
-1H-pyrazole-3-carboxylic acid
[2789] powder
[2790] MS (ESI+): m/z 425 (M+H).
[2791] 1HNMR (200 MHz, CDCl3): 1.46 (9H, s), 3.95 (3H, s), 4.33
(2H, d, J=5.9 Hz), 4.9 (1H, brs), 6.76 (1H, d, J=8.8 Hz), 7.07 (1H,
s), 7.19 (2H, d, J=8.4 Hz), 7.27 (2H, d, J=8.4 Hz), 7.58 (1H, dd,
J=2.7, 8.8 Hz), 8.11 (1H, d, J=2.7 Hz)
EXAMPLE 511
[2792] A mixture of
5-(4-{2-[(aminocarbonyl)amino]ethoxy}-phenyl)-1-(4-methoxyphenyl)-1H-pyra-
zole-3-carboxylic acid (1.56 g), diphenylphosphoryl azide (1.62 g),
and Et3N (597 mg) in t-butanol (5 ml) was refluxed for 3 hours. The
mixture was concentrated in vacuo, and the residue was partitioned
between ethyl acetate and H2O. The combined organic layer was
washed twice with 1M HCl. and washed with saturated aqueous sodium
bicarbonate solution and saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo.
The residue was purified by silica gel column chromatography eluted
with ethyl acetate to give tert-butyl
[5-(4-{2-[(aminocarbonyl)amino]-ethoxy}phenyl)-1-(4-methoxyphenyl)-1H-pyr-
azol-3-yl]carbamate (519 mg) as an amorphous powder.
[2793] MS (ESI+): m/z 468 (M+H).
[2794] 1H NMR (DMSO-d6) .delta. 1.46(9H, s), 3.27-3.36(2H, m),
3.76(3H, s), 3.90-3.96(2H, m), 5.52(2H, s), 6.15(1H, t, J=5.6 Hz),
6.55(1H, s), 6.90(2H, d, J=8.9 Hz), 6.93(2H, d, J=8.9 Hz), 7.13(4H,
d, J=8.9 Hz), 9.74(1H, s)
EXAMPLE 512
[2795] A 4M solution of HCl in dioxane (3 ml) was added to a
solution of
tert-butyl[5-(4-{2-[(aminocarbonyl)amino]ethoxy}-phenyl)-1-(4-methoxyphen-
yl)-1H-pyrazol-3-yl]carbamate (478 mg) in CH2Cl2 (3 ml) The
reaction mixture was stirred at ambient temperature for 5 hours and
concentrated in vacuo. The residue was partitioned between CHCl3
and saturated aqueous sodium bicarbonate solution. The aq layer was
reextracted with CHCl3. The combined organic layer was dried over
magnesium sulfate, and concentrated in vacuo. The residue was
purified by silica gel column chromatography eluted with
CHCl3:MeOH:28% aqueous NH4OH=10:1:0.1 to give
N-(2-{4-[3-amino-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea
(244.6 mg) as an amorphous powder.
[2796] MS (ESI+): m/z 368 (M+H).
[2797] IR (neat): 3400, 3388, 3342, 3330, 1658, 1651, 1643, 1612,
1579, 1562, 1554, 1520 cm-1
[2798] 1H NMR (DMSO-d6) .delta. 3.27-3.37(2H, m), 3.73(3H, s),
3.89-3.95(2H, m), 4.83(2H, s), 5.52(2H, s), 5.73(1H, s), 6.15(1H,
t, J=5.5 Hz), 6.85-6.92(4H, m), 7.03-7.12(4H, m)
EXAMPLE 513
[2799] 37% aqueous solution of formaldehyde (0.23 ml) and sodium
cyanoborohydride (53 mg) were added to a solution of
N-(2-{4-[3-amino-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethyl)urea
(103.1 mg) in MeOH (2 ml). The reaction mixture was stirred at
ambient temperature for 3 hours. 37% aqueous solution of
formaldehyde (0.23 ml) and sodium cyanoborohydride (53 mg) were
added to the mixture and the reaction mixture was stirred at
ambient temperature for 4 days The mixture was concentrated in
vacuo, and the residue was partitioned between ethyl acetate and
H2O. The organic layer was washed with saturated aqueous sodium
chloride solution, dried over magnesium sulfate, and concentrated
in vacuo. The residue was purified by preparative thin layer silica
gel chromatography developed by CHCl3:MeOH:28% aqueous
NH4OH=100:10:1. The separated silica gel was extracted with same
solvent and the solvent was evaporated in vacuo to give
N-(2-{4-[3-(dimethylamino)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}et-
hyl)urea (59.9 mg) as an amorphous powder.
[2800] MS (ESI+): m/z 396 (M+H).
[2801] 1H NMR (DMSO-d6) .delta. 2.81(6H, s), 3.27-3.36(2H, m),
3.74(3H, s), 3.89-3.96(2H, m), 5.52(2H, s), 5.78(1H, s), 6.15(1H,
t, J=5.7 Hz), 6.87-6.92(4H, m), 7.05-7.15(4H, m)
EXAMPLE 514
[2802] To a solution of
4-[3-(dimethylamino)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol
(98.7 mg) in DMF (2 ml) was added sodium hydride 60% dispersion in
mineral oil (15.3 mg). The mixture was stirred at ambient
temperature for 1 hour. To the reaction mixture was added
(2-bromoethoxy)-tert-butyldimethylsilane (153 mg) in DMF (1 ml)
dropwise and the mixture was stirred at ambient temperature
overnight. The mixture was poured into ice water, extracted with
AcOEt, washed with H2O and saturated aqueous sodium chloride
solution. The aqueous layer was reextracted with AcOEt. The
combined organic layers were dried over magnesium sulfate, and
concentrated in vacuo. The residue was dissolved in EtOH (2 ml). To
this solution was added concentrated hydrochloric acid (100 .mu.l)
and the mixture was stirred at ambient temperature for 3 hours. The
mixture was concentrated in vacuo, and the residue was partitioned
between AcOEt and saturated aqueous sodium bicarbonate solution,
washed with saturated aqueous sodium chloride solution, dried over
magnesium sulfate, and concentrated in vacuo. The residue was
purified by preparative thin layer silica gel chromatography
developed by AcOEt/n-hexane=60%. The residual crystals were
collected and washed with IPE to give
2-{4-[3-(dimethylamino)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethan-
ol (97 mg) as a white powder.
[2803] mp. 120-122.degree. C.
[2804] IR (KBr): 3292, 2924, 1612, 1577, 1562, 1531, 1514 cm-1
[2805] Mass (ESI+): 354 (M+H)+
[2806] 200 MHz 1H NMR (DMSO-d6, d): 2.81(6H, s), 3.66-3.72(2H, m),
3.74(3H, s), 3.94-4.00(2H, m), 4.86(1H, br), 6.02(1H, s),
6.86-6.94(4H, m), 7.10(2H, d, J=8.9 Hz), 7.12(2H, d, J=8.7 Hz)
[2807] The following compound(s) was(were) obtained in a similar
manner to that of Example 514.
EXAMPLE 515
N-[5-[4-(2-hydroxyethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N'-
,N'-trimethylurea
[2808] oil
[2809] IR (neat): 3410, 2931, 1658, 1649, 1641, 1631, 1612, 1518,
1502 cm-1
[2810] Mass (ESI+): 411 (M+H)+
[2811] 200 MHz 1H NMR (CDCl3, d): 2.08(1H, t, J=5.9 Hz), 2.89(6H,
s), 3.33(3H, s), 3.81(3H, s), 3.92-4.00(2H, m), 4.05-4.10(2H, m),
6.15(1H, s), 6.84(4H, d, J=9.1 Hz), 7.14(2H, d, J=9.1 Hz), 7.19(2H,
d, J=9.1 Hz)
EXAMPLE 516
2-{4-[3-ethoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethanol
[2812] white powder: mp. 67.7-69.2.degree. C.
[2813] IR (ATR): 3363, 2993, 2956, 2925, 2837, 1610, 1577, 1552,
1508 cm-1
[2814] Mass (ESI+): 355 (M+H)+
[2815] 200 MHz 1H NMR (CDCl3, d): 1.42(3H, t, J=7.1 Hz), 2.01(1H,
t, J=6.0 Hz), 3.79(3H, s), 3.92-4.00(2H, m), 4.04-4.10(2H, m),
4.29(2H, q, J=7.1 Hz), 5.87(1H, s), 6.77-6.85(4H, m), 7.14(2H, d,
J=8.8 Hz), 7.17(2H, d, J=8.9 Hz)
EXAMPLE 517
2-{4-[3-isobutoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethanol
[2816] oil
[2817] Mass (ESI+): m/z 383 (M+H)+
[2818] 200 MHz 1H NMR (CDCl3, d): 1.03(6H, d, J=6.8 Hz), 2.02(1H,
t, J=6.1 Hz), 2.11(1H, m), 3.79(3H, s), 3.91-4.09(4H, m), 3.99(2H,
d, J=6.8 Hz), 5.88(1H, s), 6.77-6.86(4H, m), 7.09-7.21(4H, m)
EXAMPLE 518
2-{4-[3-(2-methoxyethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}etha-
nol
[2819] oil
[2820] Mass (ESI+): 385 (M+H)+
[2821] IR (neat): 3400, 3390, 3369, 2935, 1612, 1517 cm-1
[2822] 200 MHz 1H NMR (DMSO-d6, d): 3.31(3H, s), 3.62-3.73(4H, m),
3.75(3H, s), 3.94-3.99(2H, m), 4.22-4.27(2H, m), 4.85(1H, t, J=5.5
Hz), 6.04(1H, s), 6.89(2H, d, J=8.8 Hz), 6.92(2H, d, J=8.9 Hz),
7.08-7.15(4H, m)
EXAMPLE 519
2-{4-[3-(2-ethoxyethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethan-
ol
[2823] oil
[2824] IR(neat): 2972, 2933, 2873, 1612, 1554, 1518, 1510 cm-1
[2825] Mass (ESI+): 399 (M+H)+
[2826] 200 MHz 1H NMR (CDCl3, d): 1.25(3H, t, J=7.0 Hz), 2.04(1H,
t, J=6.1 Hz), 3.61(2H, q, J=7.0 Hz), 3.78-3.83(2H, m), 3.79(3H, s),
3.93-4.00(2H, m), 4.04-4.07(2H, m), 4.38-4.44(2H, m), 5.92(1H, s),
6.82(4H, d, J=8.8 Hz), 7.13(2H, d, J=8.8 Hz), 7.16(2H, d, J=8.8
Hz)
EXAMPLE 520
2-{[5-[4-(2-hydroxyethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]oxy}-
-N,N-dimethylacetamide
[2827] white powder: mp. 106.6-107.1.degree. C.
[2828] IR (KBr) 3321, 2939, 1658, 1643, 1608, 1518 cm-1
[2829] MS (ESI+): m/z 412 (M+H)+
[2830] 200 MHz 1H NMR (DMSO-d6, d): 2.84(3H, s), 2.97(3H, s),
3.65-3.73(2H, m), 3.75(3H, s), 3.94-4.00(2H, m), 4.87(1H, t, J=5.1
Hz), 4.87(2H, s), 6.07(1H, s), 6.90(2H, d, J=8.8 Hz), 6.92(2H, d,
J=9.0 Hz), 7.11(2H, d, J=9.0 Hz), 7.12(2H, d, J=8.8 Hz)
EXAMPLE 521
2-{4-[3-methoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethanol
[2831] white powder: mp. 92.2-92.5.degree. C.
[2832] IR (KBr): 3325, 1614, 1525, 1504 cm-1
[2833] MS (ESI+): m/z 342 (M+H)+
[2834] 200 MHz 1H NMR (CDCl3, d): 2.01(1H, t, J=6.1 Hz),
3.92-4.10(4H, m), 3.92(3H, s), 3.97(3H, s), 5.91(1H, s), 6.70(1H,
d, J=8.5 Hz), 6.85(2H, d, J=8.8 Hz), 7.15(2H, d, J=8.8 Hz),
7.52(1H, dd, J=2.5,8.5 Hz), 8.04(1H, d, J=2.5 Hz)
EXAMPLE 522
2-{4-[3-ethoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethanol
[2835] white powder: mp. 81-82.degree. C.
[2836] IR (KBr): 3303, 3298, 1612, 1516 cm-1
[2837] Mass (sample ID cox022145) (ESI+): 356 (M+H)+
[2838] 200 MHz 1H NMR (DMSO-d6, d): 1.33(3H, t, J=7.0 Hz),
3.65-3.74(2H, m), 3.84(3H, s), 3.95-4.01(2H, m), 4.19(2H, q, J=7.0
Hz), 4.87(1H, t, J=5.4 Hz), 6.09(1H, s), 6.85(1H, d, J=8.8 Hz),
6.93(2H, d, J=8.8 Hz), 7.16(2H, d, J=8.8 Hz), 7.58(1H, d, J=2.6,8.8
Hz), 7.99(1H, d, J=2.6 Hz)
EXAMPLE 523
[2839] To a solution of
5-(hydroxyl)phenyl-1-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1H-py-
razole (5.0 g) and 2-bromoethoxy-tert-butyldimethylsilane (6.87 g)
in DMF (100 ml) was added portionwise NaH (919 mg, 50% in oil) at
room temperature. The reaction mixture was stirred overnight. The
reaction mixture was quenched with water. Aqueous layer was
extracted twice with EtOAc. Combined organic layer was washed twice
with water, and brine. Dried, filtered and evaporated under reduced
pressure to give 5.29 g (73%) of
5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-ethoxy)phenyl]-1-(4-met-
hoxyphenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazole.
[2840] MASS (ESI+): m/z=507.1 (M+1), 529.0 (M+Na).
[2841] 1HNMR (400 MHz, CDCl3): 0.07 (3H, s), 0.09 (3H, s), 0.9 (9H,
s), 2.15 (3H, s), 3.78 (3H, s), 3.62-4.13 (4H, m), 6.79 (2H, d,
J=8.5 Hz), 6.88 (2H, d, J=8.7 Hz), 7.05 (2H, d, J=8.7 Hz), 7.13
(2H, d, J=8.5 Hz).
EXAMPLE 524
2-{4-[1-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]phenox-
y}ethanol
[2842] mp 50.7-51.7.degree. C.
[2843] Mass (ESI+): 409 (M+H)+
[2844] 1HNMR (200 MHz, CDCl3): 1.99 (1H, t, J=6.0 Hz), 3.80 (3H,
s), 3.92-4.00 (2H, m), 4.05-4.10 (2H, m), 4.62 (1H, d, J=8.5 Hz),
4.70 (1H, d, J=8.5 Hz), 5.95 (1H, s), 6.79-6.92 (4H, m), 7.07-7.18
(4H, m)
EXAMPLE 525
2-{4-[3-(2,2-difluoroethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}e-
thanol
[2845] oil
[2846] Mass (ESI+) 391 (M+H).
[2847] 1HNMR (200 MHz, CDCl3): 1.99 (1H, t, J=6.1 Hz), 3.80 (3H,
s), 3.92-4.00 (2H, m), 4.05-4.09 (2H, m), 4.47 (2H, dt, J=4.2, 13.5
Hz), 5.92 (1H, s), 6.17 (1H, tt, J=4.2,55.5 Hz), 6.79-6.87 (4H, m),
7.09-7.20 (4H, m)
EXAMPLE 526
2-{4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro-ethoxy)-1H-pyrazol-5-yl-
]phenoxy}ethanol
[2848] mp. 91.2-91.3.degree. C.
[2849] Mass (sample ID cox031168) (ESI+): 410 (M+H)+
[2850] 1HNMR (200 MHz, CDCl3): 1.99 (1H, t, J=6.1 Hz), 3.91 (3H,
s), 3.92-4.01 (2H, m), 4.06-4.11 (2H, m), 4.61 (1H, d, J=8.4 Hz),
4.70 (1H, d, J=8.4 Hz), 5.98 (1H, s), 6.71 (1H, d, J=8.8 Hz), 6.86
(2H, d, J=8.8 Hz), 7.14 (2H, d, J=8.8 Hz), 7.48 (1H, dd, J=2.7, 8.8
Hz), 8.02 (1H, d, J=2.7 Hz)
EXAMPLE 527
2-{4-[3-(2,2-difluoroethoxy)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phe-
noxy}ethanol
[2851] oil
[2852] Mass (ESI+): 392 (M+H).
[2853] 1HNMR (200 MHz, CDCl3): 3.92 (3H, s), 3.93-4.00 (2H, m),
4.06-4.11 (2H, m), 4.46 (2H, dt, J=4.2, 13.2 Hz), 5.94 (1H, s),
6.17 (1H, tt, J=4.2, 55.5 Hz), 6.71 (1H, d, J=9.0 Hz), 6.86 (2H, d,
J=8.9 Hz), 7.14 (2H, d, J=8.9 Hz), 7.48 (1H, dd, J=2.7, 9.0 Hz),
8.02 (1H, d, J=2.7 Hz
EXAMPLE 528
[2854] Carbonyldiimidazole (1.26 g) was added to a solution of
5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-3-amino-1H-pyrazole
(2.4 g) in 1-methyl-2-pyrrolidinone (22 ml). After stirring at
ambient temperature for 2 hour, 2M solution of dimethylamine in THF
(7.4 ml) was added and the mixture was stirred ambient temperature
for 2 hour. The reaction mixture was partitioned between ethyl
acetate and H2O. The organic layer was washed with saturated
aqueous sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo. The residue was purified by silica gel
column chromatography eluted with AcOEt/n-hexane=80% to give
N'-[5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N-dime-
thylurea (2.35 g) as amorphous powder.
[2855] Mass (ESI+): 443 (M+H)+
[2856] 200 MHz 1H NMR (DMSO-d6, d): 2.91(6H, s), 3.76(3H, s),
5.09(2H, s), 6.63(1H, s), 6.93(2H, d, J=9.0 Hz), 6.98(2H, d, J=9.0
Hz), 7.14(2H, d, j=9.0 Hz), 7.15(2H, d, J=9.0 Hz), 7.34-7.44(5H,
m), 9.02(1H, s)
EXAMPLE 529
[2857] A mixture of
N'-[5-[4-(hydroxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N-dimeth-
ylurea (121.9 mg), 2-(tert-butyldimethylsilyloxy)ethyl bromide (166
mg), and K2CO3 (95.6 mg) in DMF (1.5 ml) was stirred at 75.degree.
C. for 7 hours. 2-(tert-butyldimethylsilyloxy)ethyl bromide (83 mg)
and KI (57.4 mg) was added to the reaction mixture, and the mixture
was stirred at 75.degree. C. overnight. The mixture was allowed to
cool to ambient temperature, and was partitioned between ethyl
acetate and H2O. The aqueous layer was reextracted with ethyl
acetate. The combined organic layer was washed with saturated
aqueous sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo. The residue was purified by preparative thin
layer silica gel chromatography developed by 5% MeOH/CHCl3. The
separated silica gel was extracted with 10% MeOH/CHCl3 and the
solvent was evaporated in vacuo to give
N'-[5-[4-(2-hydroxyethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,-
N-dimethylurea (115 mg) as an amorphous powder. 84.3 mg of
amorphous powder was crystallized from AcOEt-IPE to give
N'-[5-[4-(2-hydroxyethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,-
N-dimethylurea (79.5 mg) as a white powder.
[2858] mp. 167.4-167.6.degree. C.
[2859] IR (KBr): 3317, 1670, 1612, 1587, 1572, 1510 cm-1
[2860] Mass (ESI+): 397 (M+H)+
[2861] 200 MHz 1H NMR (DMSO-d6, d): 2.91(6H, s), 3.65-3.74(2H, m),
3.76(3H, s), 3.94-4.00(2H, m), 4.87(1H, t, J=5.5 Hz), 6.62(1H, s),
6.90(2H, d, J=8.7 Hz), 6.93(2H, d, J=8.9 Hz), 7.12(2H, d, J=8.7
Hz), 7.15(2H, d, J=89 Hz), 9.02(1H, s)
EXAMPLE 530
[2862] Diethylazodicarboxylate 308 mg was added to a solution of
N'-[5-[4-(hydroxy)-phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N-dimet-
hylurea 415 mg, tert-butyl N-(2-hydroxyethyl)carbamate 380 mg, and
triphenylphosphine 463 mg in THF 5 ml. After stirring at ambient
temperature for overnight, the reaction mixture was concentrated in
vacuo. To a solution of the residue in CH2Cl2 5 ml, was added 4M
solution of HCl in dioxane 5 ml. After stirring at ambient
temperature for 1.5 hours, the reaction mixture was concentrated in
vacuo. The residue was partitioned between AcOEt and 1M HCl. The
aqueous layer was reextracted with AcOEt and concentrated in vacuo.
The remained H2O was evaporated azeotropically with toluene to give
N'-[5-[4-(2-aminoethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N--
dimethylurea hydrochloride 580 mg as an amorphous powder.
[2863] Mass (ESI+): 396 (M+H)+
[2864] 200 MHz 1H NMR (DMSO-d6, d): 2.91(6H, s), 3.15-3.24(2H, m),
3.76(3H, s), 4.14-4.21 (2H, m), 6.64 (1H, s), 6.94 (2H, d, J=8.9
Hz), 6.95(2H, d, J=8.7 Hz), 7.15(2H, d, J=8.9 Hz), 7.17(2H, d,
J=8.7 Hz), 8.20(2H, brs), 9.04(1H, s)
[2865] The following compound(s) was(were) obtained in a similar
manner to that of Example 530.
EXAMPLE 531
N-[5-[4-(2-aminoethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N',N-
'-trimethylurea hydrochloride
[2866] amorphous
[2867] Mass (ESI+): 410(M+H)+
[2868] 200 MHz 1H NMR (DMSO-d6, d): 2.79(6H, s), 3.13(3H, s),
3.14-3.24(2H, m), 3.80(3H, s), 4.15-4.20(2H, m), 6.27(1H, s), 6.94
(2H, d, J=8.6 Hz), 6.94 (2H, d, J=8.9 Hz), 7.16(2H, d, J=8.9 Hz),
7.19(2H, d, J=8.6 Hz), 8.24(2H, brs)
EXAMPLE 532
2-{[5-[4-(2-aminoethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]oxy}-N-
,N-dimethylacetamide hydrochloride
[2869] amorphous
[2870] MS (ESI+): m/z 411 (M+H)+
[2871] 200 MHz 1H NMR (DMSO-d6, d): 2.84(3H, s), 2.97(3H, s),
3.14-3.24(2H, m), 3.76(3H, s), 4.14-4.20(2H, m), 4.88(2H, s),
6.09(1H, s), 6.93(2H, d, J=9.0 Hz), 6.95(2H, d, J=8.8 Hz),
7.07-7.29(4H, m), 8.21(2H, brs)
EXAMPLE 533
[2872] A solution of potassium cyanate (64.9 mg) in H2O (0.5 ml)
was added to a solution of
N'-[5-[4-(2-aminoethoxy)phenyl]-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-N,N-
-dimethylurea hydrochloride (172.8 mg) and sodium acetate (65.6 mg)
in a mixture of DMF (1.5 ml) and H2O (0.5 ml). The reaction mixture
was stirred at ambient temperature overnight. The mixture was
diluted with H2O, partitioned between AcOEt and H2O. The aqueous
layer was reextracted with AcOEt. saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo.
The residue was purified by preparative thin layer silica gel
chromatography developed by 10% MeOH/CHCl3. The separated silica
gel was extracted with 10% MeOH/CHCl3 and the solvent was
evaporated in vacuo. The residue was crystallized from AcOEt-IPE to
give N'-[5-(4-{2-[(aminocarbonyl)-amino]
ethoxy}phenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N-dimethylurea
(87.0 mg) as a powder.
[2873] mp. 193-196.degree. C.
[2874] IR (KBr): 3437, 3421, 1660, 1649, 1620, 1612, 1581, 1562,
1554, 1529, 1512 cm-1
[2875] Mass (ESI+): 439 (M+H)+
[2876] 200 MHz 1H NMR (DMSO-d6, d): 2.91(6H, s), 3.27-3.34(2H, m),
3.76(3H, s), 3.93(2H, t, J=5.5 Hz), 5.53(2H, s), 6.16(1H, t, J=5.7
Hz), 6.62(1H, s), 6.91(2H, d, J=8.7 Hz), 6.93(2H, d, J=8.9 Hz),
7.13(2H, d, J=8.7 Hz), 7.15(2H, d, J=8.9 Hz), 9.02(1H, s)
[2877] The following compound(s) was(were) obtained in a similar
manner to that of Example 533.
EXAMPLE 534
N-[5-(4-{2-[(aminocarbonyl)amino]ethoxy}phenyl)-1-(4-methoxyphenyl)-1H-pyr-
azol-3-yl]-N,N',N'-trimethylurea
[2878] powder: mp. 158.6-159.0.degree. C.
[2879] IR (KBr): 3433, 3369, 1687, 1658, 1643, 1612, 1514, 1500
cm-1
[2880] Mass (ESI+): 453 (M+H)+
[2881] 200 MHz 1H NMR (DMSO-d6, d): 2.79(6H, s), 3.12(3H, s),
3.27-3.34(2H, m), 3.76(3H, s), 3.93(2H, t, J=5.5 Hz), 5.53(2H, s),
6.15(1H, t, J=5.6 Hz), 6.25(1H, s), 6.91(2H, d, J=8.7 Hz), 6.94(2H,
d, J=8.9 Hz), 7.15(2H, d, J=8.7 Hz), 7.15(2H, d, J=8.9 Hz)
EXAMPLE 535
N-(2-{4-[3-(2-methoxyethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}e-
thyl)urea
[2882] white powder: mp. 131-132.degree. C.
[2883] IR (KBr): 3435, 3429, 3388, 3350, 1658, 1612, 1562, 1554,
1518 cm-1
[2884] Mass (sample ID cox022116) (ESI+): 427 (M+H)+
[2885] 200 MHz 1H NMR (DMSO-d6, d): 3.28-3.38(2H, m), 3.30(3H, s),
3.62-3.68(2H, m), 3.75(3H, s), 3.89-3.96(2H, m), 4.21-4.27(2H, m),
5.53(2H, s), 6.05(1H, s), 6.15(1H, t, J=5.7 Hz), 6.91(2H, d, J=8.9
Hz), 6.92(2H, d, J=9.0 Hz), 7.10-7.15(4H, m)
EXAMPLE 536
N-(2-{4-[3-(2-ethoxyethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}et-
hyl)urea
[2886] white powder: mp. 124.1-124.2.degree. C.
[2887] IR (KBr): 3388, 3379, 3340, 1657, 1643, 1612, 1562, 1554,
1518 cm-1
[2888] Mass (ESI+): 441 (M+H)+
[2889] 200 MHz 1H NMR (DMSO-d6, d): 1.13(3H, t, J=7.0 Hz),
3.27-3.36(2H, m), 3.49(2H, q, J=7.0 Hz), 3.66-3.71(2H, m), 3.75(3H,
s), 3.89-3.96(2H, m), 4.21-4.26(2H, m), 5.53(2H, s), 6.06(1H, s),
6.15(1H, t, J=5.7 Hz), 6.91(2H, d, J=8.8 Hz), 6.92(2H, d, J=9.0
Hz), 7.10-7.15(4H, m)
EXAMPLE 537
2-{[5-(4-{2-[(aminocarbonyl)amino]ethoxy}phenyl)-1-(4-methoxyphenyl)-1H-py-
razol-3-yl]oxy}-N,N-dimethyl-acetamide
[2890] white powder: mp. 223-227.degree. C.
[2891] IR (KBr): 3402, 3332, 3201, 3194, 2925, 1664, 1612, 1518,
1502 cm-1
[2892] MS (ESI+): m/z 454 (M+H)+
[2893] 200 MHz 1H NMR (DMSO-d6, d): 2.84(3H, s), 2.97(3H, s),
3.27-3.35(2H, m), 3.75(3H, s), 3.89-3.96(2H, m), 4.87(2H, s),
5.53(2H, s), 6.07 (1H, s), 6.15(1H, t, J=5.5 Hz), 6.91(2H, d, J=8.9
Hz), 6.93(2H, d, j=9.0 Hz), 7.11 (2H, d, J=9.0 Hz), 7.13(2H, d,
J=8.9 Hz)
EXAMPLE 538
N-(2-{4-[3-methoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl-
)urea
[2894] white powder: mp. 192.6-192.7.degree. C.
[2895] IR (KBr): 3390, 3352, 3311, 3305, 1657, 1610, 1583, 1568,
1525, 1502 cm-1
[2896] MS (ESI+): m/z 384 (M+H)+
[2897] 200 MHz 1H NMR (DMSO-d6, d): 3.27-3.36(2H, m), 3.34(3H, s),
3.85(3H, s), 3.91-3.97(2H, m), 5.53(2H, s), 6.11(1H, s), 6.15(1H,
t, J=5.7 Hz), 6.85(1H, d, J=8.7 Hz), 6.94(2H, d, J=8.8 Hz),
7.17(2H, d, J=8.8 Hz), 7.59(1H, dd, J=2.6,8.7 Hz), 8.00(1H, d,
J=2.6 Hz)
EXAMPLE 539
N-(2-{4-[3-ethoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)-
urea
[2898] white powder: mp. 133-138.degree. C.
[2899] IR (KBr): 3350, 1657, 1643, 1612, 1579, 1562, 1554, 1518,
1500 cm-1; MS (ESI+): m/z 398 (M+H)+
[2900] 200 MHz 1H NMR (DMSO-d6, d): 1.33(3H, t, J=7.0 Hz),
3.28-3.35(2H, m), 3.84(3H, s), 3.91-3.97(2H, m), 4.19(2H, q, J=7.0
Hz), 5.53(2H, s), 6.09(1H, s), 6.16(1H, t, J=5.6 Hz), 6.85(1H, d,
J=8.8 Hz), 6.94(2H, d, J=8.8 Hz), 7.17(2H, d, J=8.8 Hz), 7.58(1H,
dd, J=2.7,8.8 Hz), 8.00(1H, d, J=2.7 Hz)
EXAMPLE 540
N-(2-{4-[3-cyclopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}e-
thyl)urea
[2901] mp. 94-96.degree. C.
[2902] MS (ESI+): m/z 394 (M+H)
[2903] 1HNMR (200 MHz, DMSOd6): 0.72-0.78 (2H, m), 0.87-0.95 (2H,
m), 1.87-2.01 (1H, m), 3.23-3.42 (2H, m), 3.85 (3H, s), 3.90-3.97
(2H, m), 5.52 (2H, s), 6.12 (1H, t, J=5.6 Hz), 6.30 (1H, s), 6.85
(1H, d, J=8.8 Hz), 6.92 (2H, d, J=8.7 Hz), 7.13 (2H, d, J=8.7 Hz),
7.58 (1H, dd, J=2.7, 8.8 Hz), 8.01 (1H, d, J=2.7 Hz)
EXAMPLE 541
N-(2-{4-[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl)-1H-pyrazol-5-yl]phe-
noxy}ethyl)urea
[2904] mp. 152.0-152.2.degree. C.
[2905] Mass (ESI+): 464 (M+H).
[2906] 1HNMR (200 MHz, DMSOd6): 1.42-1.73 (6H, m), 3.27-3.36 (2H,
m), 3.53-3.67 (2H, m), 3.73-3.96 (2H, m), 3.78 (3H, s), 3.90-3.97
(2H, m), 5.51 (2H, s), 6.14 (1H, t, J=5.7 Hz), 6.77 (1H, s), 6.92
(2H, d, J=8.8 Hz), 6.98 (2H, d, J=9.0 Hz), 7.17 (2H, d, J=8.8 Hz),
7.23 (2H, d, J=9.0 Hz
EXAMPLE 542
N-(2-{4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl-carbonyl)-1H-pyrazol-5-
-yl]phenoxy}ethyl)urea
[2907] mp. 164-167.degree. C.
[2908] Mass (ESI+): 465 (M+H).
[2909] 1HNMR (200 MHz, DMSOd6): 1.42-1.73 (6H, m), 3.22-3.40 (2H,
m), 3.52-3.70 (2H, m), 3.75-3.95 (2H, m), 3.87 (3H, s), 3.92-3.98
(2H, m), 5.52 (2H, s), 6.15 (1H, t, J=5.6 Hz), 6.81 (1H, s), 6.90
(1H, d, J=8.9 Hz), 6.95 (2H, d, J=8.8 Hz), 7.21 (2H, d, J=8.8 Hz),
7.67 (1H, dd, J=2.7, 8.9 Hz), 8.14 (1H, d, J=2.7 Hz)
EXAMPLE 543
5-(4-{2-[(aminocarbonyl)amino]ethoxy}phenyl)-N-ethyl-1-(6-methoxy-3-pyridi-
nyl)-N-methyl-1H-pyrazole-3-carboxamide
[2910] mp. 146.3-146.7.degree. C.
[2911] MS (ESI+): m/z 439 (M+H).
[2912] 1HNMR (200 MHz, DMSOd6) 1.09-1.23 (3H, m), 2.98, 3.28 (3H,
s), 3.28-3.37 (2H, m), 3.40-3.53, 3.63-3.77 (2H, m), 3.87 (3H, s),
3.92-3.98 (2H, m), 5.52 (2H, s), 6.15 (1H, t, J=5.5 Hz), 6.82, 6.85
(1H, s), 6.90 (1H, d, J=9.0 Hz), 6.95 (2H, d, J=8.7 Hz), 7.21 (2H,
d, J=8.7 Hz), 7.60-7.73 (1H, m), 8.14-8.16 (1H, m)
EXAMPLE 544
N-(2-{4-[1-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]phe-
noxy}ethyl)urea
[2913] mp. 130-132.degree. C.
[2914] MS (ESI+): m/z 451 (M+H).
[2915] 1HNMR (200 MHz, DMSOd6): 3.27-3.33 (2H, m), 3.76 (3H, s),
3.90-3.96 (2H, m), 4.81 (1H, d, J=9.0 Hz), 4.90 (1H, d, J=9.0 Hz),
5.52 (2H, s), 6.14 (1H, t, J=5.6 Hz), 6.21 (1H, s), 6.89-6.98 (4H,
m), 7.12-7.18 (4H, m)
EXAMPLE 545
N-(2-{4-[3-(2,2-difluoroethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenox-
y}ethyl)urea
[2916] mp. 138.6-139.1.degree. C.
[2917] MS (ESI+): m/z 432 (M+H).
[2918] 1HNMR (200 MHz, DMSOd6): 3.27-3.36 (2H, m), 3.76 (3H, s),
3.90-3.96 (2H, m), 4.44 (2H, dt, J=3.5, 14.9 Hz), 5.52 (2H, s),
6.11-6.17 (1H, m), 6.15 (1H, s), 6.41 (1H, tt, J=3.5, 54.6 Hz),
6.91 (2H, d, J=8.9 Hz), 6.93 (2H, d, J=8.9 Hz), 7.14 (2H, d, J=8.9
Hz), 7.15 (2H, d, J=8.9 Hz)
EXAMPLE 546
N-(2-{4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro-ethoxy)-1H-pyrazol-5-
-yl]phenoxy}ethyl)urea
[2919] mp. 134.8-134.9.degree. C.
[2920] MS (ESI+): m/z 452 (M+H).
[2921] 1HNMR (200 MHz,): 3.24-3.39 (2H, m), 3.85 (3H, s), 3.91-3.98
(2H, m), 4.83 (1H, d, J=9 Hz), 4.92 (1H, d, J=9 Hz), 5.52 (2H, s),
6.15 (1H, t, J=5.6 Hz), 6.27 (1H, s), 6.87 (1H, d, J=8.8 Hz), 6.95
(2H, d, J=8.8 Hz), 7.18 (2H, d, J=8.8 Hz), 7.61 (1H, dd, J=2.7, 8.8
Hz), 8.04 (1H, d, J=2.7 Hz)
EXAMPLE 547
N-(2-{4-[3-(2,2-difluoroethoxy)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]-
phenoxy}ethyl)urea
[2922] mp. 146.9-147.3.degree. C.
[2923] MS (ESI+): m/z 434 (M+H).
[2924] 1HNMR (200 MHz, DMSOd6): 3.23-3.40 (2H, m), 3.85 (3H, s),
3.91-3.97 (2H, m), 4.45 (2H, dt, J=3.5, 14.9 Hz), 5.52 (2H, s),
6.15 (1H, t, J=5.7 Hz), 6.21 (1H, s), 6.42 (1H, tt, J=3.5, 54.6
Hz), 6.86 (1H, d, J=8.8 Hz 6.94 (2H, d, J=8.8 Hz), 6.94 (2H, d,
J=8.8 Hz), 7.60 (1H, dd, J=2.8, 8.8 Hz), 8.03 (1H, d, J=2.8 Hz
EXAMPLE 548
5-(4-{[(aminocarbonyl)amino]methyl}phenyl)-N-ethyl-1-(4-methoxyphenyl)-N-m-
ethyl-1H-pyrazole-3-carboxamide
[2925] mp. 184.7-185.1.degree. C.
[2926] MS (ESI+): m/z 408 (M+H).
[2927] 1HNMR (200 MHz, DMSOd6): 1.09-1.22 (3H, m), 2.98, 3.29 (3H,
s), 3.41-3.78 (2H, m), 3.78 (3H, s), 4.16 (2H, d, J=6.0 Hz), 5.54
(2H, s), 6.44 (1H, t, J=6 Hz), 6.84, 6.86 (1H, s), 6.99 (2H, d,
J=8.9 Hz), 7.2-7.27 (6H, m)
EXAMPLE 549
N-{4-[3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}urea
[2928] amorphous powder
[2929] MS (ESI+): m/z 365 (M+H).
[2930] 1HNMR (200 MHz, DMSOd6): 1.27 (6H, d, J=7.0 Hz), 2.95 (1H,
m), 3.76 (3H, s), 4.15 (2H, d, J=6.0 Hz), 5.53 (2H, s), 6.42 (1H,
t, J=6.0 Hz), 6.44 (1H, s), 6.93 (2H, d, J=8.9 Hz), 7.11-7.22 (6H,
m)
EXAMPLE 550
N-{4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl-carbonyl)-1H-pyrazol-5-yl-
]benzyl}urea
[2931] mp. 178.9-178.9.degree. C.
[2932] MS (ESI+): m/z 435 (M+H).
[2933] 1HNMR (400 MHz, DMSOd6): 1.47-1.70 (6H, m), 3.55-3.66 (2H,
m), 3.78-3.89 (2H, m), 3.87 (3H, s), 4.17 (2H, d, J=6.0 Hz), 5.55
(2H, s), 6.45 (1H, t, J=6.0 Hz), 6.86 (1H, s), 6.91 (1H, d, J=8.8
Hz), 7.24 (4H, s), 7.70 (1H, dd, J=2.7, 8.8 Hz), 8.14 (1H, d, J=2.7
Hz
EXAMPLE 551
5-(4-{[(aminocarbonyl)amino]methyl}phenyl)-N-ethyl-1-(6-methoxy-3-pyridiny-
l)-N-methyl-1H-pyrazole-3-carboxamide
[2934] mp. 172.6-172.8.degree. C.
[2935] MS (ESI+): m/z 409 (M+H).
[2936] 1HNMR (400 MHz, DMSOd6): 1.13, 1.19 (3H, t, J=7.0 Hz 2.98,
3.29 (3H, s), 3.48, 3.72 (2H, q, J=7.0 Hz), 3.87 (3H, s), 4.18 (2H,
d, J=6.0 Hz), 5.55 (2H, s), 4.45 (1H, t, J=6.0 Hz), 6.87-6.93 (2H,
m), 7.24 (4H, s), 7.67-7.73 (1H, m), 8.14-8.16 (1H, m)
EXAMPLE 552
N-{4-[3-isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]benzyl}urea
[2937] mp. 139-144.degree. C.
[2938] MS (ESI+): m/z 366 (M+H).
[2939] 1HNMR (200 MHz, DMSOd6): 1.27 (6H, d, J=7.0 Hz), 2.97 (1H,
m), 3.85 (3H, s), 4.17 (2H, d, J=6.0 Hz), 5.53 (2H, s), 6.43 (1H,
t, J=6.0 Hz), 6.50(1H, s), 6.86 (1H, d, J=8.8 Hz), 7.15-7.26 (4H,
m), 7.62 (1H, dd, J=2.8, 8.8 Hz), 8.02 (1H, d, J=2.7 Hz)
EXAMPLE 553
N-{4-[3-isobutyryl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]benzyl}urea
[2940] mp. 157.0-157.3.degree. C.
[2941] MS (ESI+): m/z 394 (M+H).
[2942] 1HNMR (200 MHz, DMSOd6): 1.16 (6H, d, J=6.8 Hz), 3.68 (1H,
m), 3.88 (3H, s), 4.17 (2H, d, J=6.0 Hz), 5.54 (2H, s), 6.45 (1H,
t, J=6.0 Hz), 6.93 (1H, d, J=8.8 Hz), 7.06 (1H, s), 7.25 (4H, s),
7.76 (1H, dd, J=2.7, 8.8 Hz), 8.18 (1H, d, J=2.7 Hz)
EXAMPLE 554
N-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}urea
[2943] mp. 206.0-260.9.degree. C.
[2944] MS (ESI+): m/z 353 (M+H).
[2945] 1HNMR (200 MHz, DMSOd6): 3.76 (3H, s), 3.84 (3H, s), 4.15
(2H, d, J=6.0 Hz), 5.53 (2H, s), 6.09 (1H, s), 6.42 (1H, t, J=6.0
Hz), 6.93 (2H, d, J=9 Hz), 7.12-7.23 (6H, m)
EXAMPLE 555
N-{4-[3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}urea
[2946] solid
[2947] MS (ESI+): m/z 381 (M+H).
[2948] 1HNMR (200 MHz, DMSOd6): 1.31 (6H, d, J=6.1 Hz), 3.76 (3H,
s), 4.15 (2H, d, J=6.0 Hz), 4.76 (1H, m), 5.53 (2H, s), 6.04 (1H,
s), 6.43 (1H, t, J=6.0 Hz), 6.92 (2H, d, J=8.9 Hz), 7.10-7.22 (6H,
m)
EXAMPLE 556
N-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-benzyl}urea
[2949] mp. 125.5-126.2.degree. C.
[2950] Mass (ESI+): 357 (M+H).
[2951] 1HNMR (200 MHz, DMSOd6): 3.78 (3H, s), 4.15 (2H, d, J=6.1
Hz), 5.54 (2H, s), 6.43 (1H, t, J=6.1 Hz), 6.73 (1H, s), 6.97 (2H,
d, J=8.9 Hz), 7.14-7.24 (6H, m)
EXAMPLE 557
N-{4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]benzyl}urea
[2952] mp. 111-115.degree. C.
[2953] Mass (ESI+): 358 (M+H)
[2954] 1HNMR (200 MHz, DMSOd6): 3.87 (3H, s), 4.17 (2H, d, J=6.0
Hz), 5.54 (2H, s), 6.44 (1H, t, J=6.0 Hz), 6.79 (1H, s), 6.89 (1H,
d, J=0.8 Hz), 7.23 (4H, s), 7.69 (1H, dd, J=2.7, 8.8 Hz), 8.11 (1H,
d, J=2.7 Hz)
EXAMPLE 558
N-(2-{4-[1-(4-methoxyphenyl)-4-methyl-1H-pyrazol-5-yl]-phenoxy}ethyl)urea
[2955] amorphous powder
[2956] MS (ESI+): m/z 367 (M+H).
[2957] 1HNMR (400 MHz, DMSOd6): 2.02 (3H, s), 3.32-3.36 (2H, m),
3.74 (3H, s), 3.92-3.96 (2H, m), 5.51 (2H, s), 6.15 (1H, t, J=5.6
Hz), 6.89 (2H, d, J=8.9 Hz), 6.94 (2H, d, J=8.8 Hz), 7.08 (2H, d,
J=8.8 Hz), 7.09 (2H, d, J=8.9 Hz), 7.55 (1H, s)
EXAMPLE 559
N-(2-{4-[1-(6-methoxy-3-pyridinyl)-4-methyl-1H-pyrazol-5-yl]phenoxy}ethyl)-
urea
[2958] powder
[2959] MS (ESI+): m/z 368 (M+H).
[2960] 1HNMR (400 MHz, DMSOd6): 2.03 (3H, s), 3.31-3.36 (2H, m),
3.83 (3H, s), 3.94-3.98 (2H, m), 5.51 (2H, s), 6.15 (1H, t, J=5.6
Hz), 6.82 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.13 (2H, d,
J=8.8 Hz), 7.53 (1H, dd, J=2.7, 8.8 Hz), 7.62 (1H, s), 7.98 (1H, d,
J=2.7 Hz
EXAMPLE 560
N-(2-{4-[1-(4-methoxyphenyl)-3-(methylthio)-1H-pyrazol-5-yl]phenoxy}ethyl)-
urea
[2961] mp. 141.2-142.2.degree. C.
[2962] MS (ESI+): m/z 399 (M+H)
[2963] 1HNMR (200 MHz, DMSOd6): 2.50 (3H, s), 3.27-3.36 (2H, m),
3.77 (3H, s), 3.90-3.96 (2H, m), 5.52 (2H, s), 6.14 (1H, t, J=5.6
Hz), 6.56 (1H, s), 6.91 (2H, d, J=8.8 Hz), 6.95 (2H, d, J=8.8 Hz),
7.14 (2H, d, J=8.8 Hz), 7.17 (2H, d, J=8.8 Hz)
EXAMPLE 561
N-(2-{4-[1-(6-methoxy-3-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phe-
nyl}ethyl)urea
[2964] mp. 205-206.degree. C.
[2965] MS (ESI+): m/z 406 (M+H).
[2966] 1HNMR (200 MHz, DMSOd6): 2.64-2.72 (2H, m), 3.13-3.24 (2H,
m), 3.88 (3H, s), 5.42 (2H, s), 5.95 (1H, t, J=5.6 Hz), 6.92 (1H,
d, J=8.9 Hz), 7.17 (1H, s), 7.24 (4H, s), 7.75 (1H, dd, J=2.8, 8.9
Hz), 8.19 (1H, d, J=2.8 Hz
EXAMPLE 562
5-(4-{2-[(aminocarbonyl)amino]ethyl}phenyl)-N-methoxy-1-(4-methoxyphenyl)--
N-methyl-1H-pyrazole-3-carboxamide
[2967] oil
[2968] MS (ESI+): m/z 243 (M+H).
[2969] 1HNMR (200 MHz, CDCl3): 2.75-2.82 (2H, m), 3.34-3.45 (2H,
m), 3.51 (3H, s), 3.82 (3H, s), 3.83 (3H, s), 4.46 (2H, s), 4.92
(1H, t, J=5.5 Hz), 6.84 (2H, d, J=9.0 Hz), 6.92 (1H, s), 7.11 (4H,
s), 7.15 (2H, d, J=9.0 Hz
EXAMPLE 563
5-(4-{2-[(aminocarbonyl)amino]ethyl}phenyl)-N-methoxy-1-(6-methoxy-3-pyrid-
inyl)-N-methyl-1H-pyrazole-3-carboxamide
[2970] oil
[2971] MS (ESI+): m/z 425 (M+H)
[2972] 1HNMR (200 MHz, CDCl3): 2.78-2.86 (2H, m), 3.39-3.49 (2H, m)
3.49 (3H, s), 3.85 (3H, s), 3.94 (3H, s), 4.39 (2H, s), 4.70 (1H,
t, J=5.8 Hz), 6.75 (1H, d, J=8.9 Hz), 6.80 (1H, s), 7.12-7.23 (4H,
m), 7.56 (1H, dd, J=2.7,8.9 Hz), 8.05 (1H, d, J=2.7 Hz
EXAMPLE 564
[2973] Sodium hydride 60% dispersion in mineral oil 93.1 mg was
added in one portion to a solution of
N-[5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N',N'-dim-
ethylurea 1.43 g in DMF 10 ml under ice bath cooling. The reaction
mixture was stirred at ambient temperature for 1 hour. MeI 688 mg
was added the reaction mixture was stirred at ambient temperature
overnight. The mixture was partitioned between ethylacetate and
H2O. The organic layer was washed with saturated aqueous sodium
chloride solution, dried over magnesium sulfate, and concentrated
in vacuo. The residue was purified by silica gel column
chromatography eluted with AcOEt-n-hexane=75% o, 80% to give
N-[5-[4-(benzyloxy)phenyl]-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-N,N-
',N'-trimethylurea 1.45 g as an oil.
[2974] Mass (ESI+): 457 (M+H)+
[2975] 200 MHz 1H NMR (DMSO-d6, d): 2.79(6H, s), 3.12(3H, s),
3.77(3H, s) 5.09(2H, s), 6.25(1H, s), 6.91-7.00(4H, m),
7.14-7.19(4H, m), 7.32-7.46(5H, m)
EXAMPLE 565
[2976] A mixture of
N-(2-{4-[3-amino-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea
111 mg, lithium chloride 64 mg, and copper(II) chloride 81.2 mg in
acetonitrile 2 ml was stirred at ambient temperature for 10
minutes. To this mixture was added isoamyl nitrite 62.3 mg, and the
mixture was stirred at ambient temperature for 3 hours The mixture
was partitioned between ethyl acetate and saturated aqueous
ammonium chloride solution. The organic layer was washed with
saturated aqueous ammonium chloride solution, H2O, and saturated
aqueous sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo. The residue was purified by preparative thin
layer silica gel chromatography developed by MeOH/CHCl3=10%. The
separated silica gel was extracted with 10% MeOH/CHCl3 and the
solvent was evaporated in vacuo. The residue was crystallized from
AcOEt/IPE to give
N-(2-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea
31.1 mg as a white powder.
[2977] mp. 140-142.degree. C.
[2978] Mass (ESI+): 386 (M+H)+
[2979] 200 MHz 1H NMR (DMSO-d6, d): 3.27-3.34 (2H, m), 3.77 (3H,
s), 3.93(2H, t, J=5.5 Hz), 5.52(2H, s), 6.15(1H, t, J=5.7 Hz),
6.68(1H, s), 6.92(2H, d, J=9.0 Hz), 6.97(2H, d, J=9.0 Hz), 7.15(2H,
d, J=9.0 Hz), 7.20(2H, d, J=9.0 Hz)
EXAMPLE 566
[2980] Diethyl azodicarboxylate (0.17 ml) was added dropwise to a
suspension of
3-methoxy-1-(4-methoxyphenyl)-5-(4-hydroxyphenyl)-1H-pyrazole
(215.6 mg), tert-butyl N-(2-hydroxyethyl)carbamate (352 mg), and
triphenylphosphine (286 mg) in THF (3 ml). The mixture was stirred
at ambient temperature for 7 hours. Triphenylphosphine (19.1 mg)
and diethyl azodicarboxylate (11.5 .mu.l) were added and the
mixture stirred at ambient temperature overnight. The mixture was
concentrated in vacuo. The residue was purified by silica gel
column chromatography eluted with AcOEt/n-hexane=30% to give
tert-butyl
(2-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)carbam-
ate
[2981] (319 mg) as an oil.
[2982] Mass (ESI+): 440 (M+H)+
[2983] 200 MHz 1H NMR (CDCl3, d): 1.45(9H, s), 3.47-3.56(2H, m),
3.80(3H, s), 3.96-4.03(2H, m), 3.97(3H, s), 4.96(1H, brs), 5.87(1H,
s), 6.79(2H, d, J=8.8 Hz), 6.82(2H, d, J=8.9 Hz), 7.09-7.20(4H,
m)
[2984] The following compound(s) was(were) obtained in a similar
manner to that of Example 566.
EXAMPLE 567
tert-butyl
(2-{4-[3-isobutoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}-
ethyl)carbamate
[2985] white powder
[2986] Mass (ESI+): 482 (M+H)+
[2987] 200 MHz 1H NMR (CDCl3, d): 1.03(6H, d, J=6.7 Hz), 1.45(9H,
s), 2.11(1H, m), 3.48-3.57(2H, m), 3.79(3H, s), 3.97-4.03(2H, m),
4.97(1H, br), 5.88(1H, s), 6.79(2H, d, J=8.7 Hz), 6.82(2H, d, J=8.9
Hz), 7.09-7.19(4H, m)
EXAMPLE 568
tert-butyl
(2-{4-[3-(2-methoxyethoxy)-1-(4-methoxy-phenyl)-1H-pyrazol-5-yl-
]phenoxy}ethyl)carbamate
[2988] solid
[2989] Mass (ESI+): 484 (M+H)+
[2990] 200 MHz 1H NMR (DMSO-d6, d): 1.37 (9H, s), 3.22-3.32 (2H,
m), 3.31(3H, s), 3.62-3.67(2H, m), 3.75(3H, s), 3.91-3.97(2H, m),
4.21-4.27(2H, m), 6.04(1H, s), 6.86-6.99(5H, m), 7.10-7.15(4H,
m)
EXAMPLE 569
tert-butyl
(2-{4-[3-(2-ethoxyethoxy)-1-(4-methoxy-phenyl)-1H-pyrazol-5-yl]-
phenoxy}ethyl)carbamate
[2991] oil
[2992] Mass (ESI+): 498 (M+H)+
[2993] 200 MHz 1H NMR (DMSO-d6, d): 1.09-1.21(3H, overlapping),
1.37(9H, s), 3.25-3.34(2H, m), 3.66-3.71(2H, m), 3.75(3H, s),
3.90-4.15(4H, m), 4.21-4.26(2H, m), 6.06(1H, s), 6.86-6.96(4H, m),
7.01(1H, m), 7.12(4H, d, J=8.9 Hz),
EXAMPLE 570
tert-butyl
(2-{4-[3-methoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phen-
oxy}ethyl)carbamate
[2994] powder
[2995] MS (ESI+): m/z 441 (M+H)+
[2996] 200 MHz 1H NMR (CDCl3, d): 1.45(9H, s), 3.48-3.57(2H, m),
3.92(3H, s), 3.97(3H, s), 3.98-4.03(2H, m), 4.99(1H, br), 5.90(1H,
s), 6.70(1H, d, J=8.5 Hz), 6.82(2H, d, J=8.9 Hz), 7.14(2H, d, J=8.9
Hz), 7.52(1H, dd, J=2.5,8.5 Hz), 8.03(1H, d, J=2.5 Hz)
EXAMPLE 571
tert-butyl
(2-{4-[3-ethoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]pheno-
xy}ethyl)carbamate
[2997] white powder
[2998] MS (ESI+): m/z 455 (M+H)+
[2999] 200 MHz 1H NMR (DMSO-d6, d): 1.33(3H, t, J=7.0 Hz), 1.37(9H,
s), 3.22-3.33(2H, m), 3.84(3H, s), 3.92-3.98(2H, m), 4.19(2H, q)
6.08(1H, s), 6.85(1H, d, J=8.8 Hz), 6.92(2H, d, J=8.8 Hz), 7.02(1H,
t, J=5.5 Hz), 7.16(2H, d, J=8.8 Hz), 7.58(1H, dd, J=2.7,8.8 Hz),
7.99(1H, d, J=2.7 Hz)
EXAMPLE 572
tert-butyl[2-(4-{3-(difluoromethyl)-1-[4-(methyl-thio)phenyl]-1H-pyrazol-5-
-yl}phenoxy)ethyl]carbamate
[3000] MASS (ESI+): m/z=498.2 (M+Na).
[3001] 1HNMR (400 MHz, CDCl3): 1.45 (9H, s), 2.49 (3H, s), 3.54
(2H, q, J=5.1 Hz), 4.02 (2H, t, J=5.1 Hz), 4.98 (1H, b.s), 6.66
(1H, s), 6.76 (1H, t, J=55.1 Hz), 6.84 (2H, d, J=8.8 Hz), 7.15 (2H,
d, J=8.8 Hz), 7.2 (4H, s).
EXAMPLE 573
tert-butyl
(2-{4-[3-cyclopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]-
phenoxy}ethyl)carbamate
[3002] oil
[3003] MS ESI+): m/z 451 (M+H).
[3004] 1HNMR (200 MHz, CDCl3): 0.77-0.86 (2H, m), 0.93-1.04 (2H,
m), 1.45 (9H, s), 1.96-2.09 (1H, m), 3.48-3.57 (2H, m), 3.92 (3H,
s), 3.97-4.03 (2H, m), 4.97 (1H, brs), 6.10 (1H, s), 6.71 (1H, d,
J=8.8 Hz), 6.81 (2H, d, J=8.8 Hz), 7.11 (2H, d, J=8.8 Hz), 7.53
(1H, dd, J=2.7, 8.8 Hz), 8.03 (1H, d, J=2.7 Hz)
EXAMPLE 574
tert-butyl
(2-{4-[3-(cyclopentyloxy)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol--
5-yl]phenoxy}ethyl)carbamate
[3005] oil
[3006] MS (ESI+): m/z 494 (M+H).
[3007] 1HNMR (200 MHz, CDCl3): 1.45 (9H, s), 1.5-1.99 (8H, m),
3.48-3.57 (2H, m), 3.91 (3H, s), 3.98-4.04 (2H, m), 4.92-5.05 (2H,
m), 5.88 (1H, s), 6.69 (1H, d, J=8.9 Hz), 6.82 (2H, d, J=8.8 Hz),
7.14 (2H, d, J=8.8 Hz), 7.52 (1H, dd, J=2.7, 8.9 Hz), 8.02 (1H, d,
J=2.7 Hz)
EXAMPLE 575
tert-butyl
(2-{4-[1-(4-methoxyphenyl)-3-(2,2,2-tri-fluoroethoxy)-1H-pyrazo-
l-5-yl]phenoxy}ethyl)carbamate
[3008] oil
[3009] MS (ESI+): m/z 508 (M+H).
[3010] 1HNMR (200 MHz, CDCl3): 1.45 (9H, s), 3.48-3.57 (2H, m),
3.81 (3H, s), 3.97-4.03 (2H, m), 4.62 (1H, d, J=8.5 Hz), 4.70 (1H,
d, J=8.5 Hz), 4.95 (1H, brs), 5.95 (1H, s), 6.77-6.86 (4H, m),
7.08-7.18 (4H, m)
EXAMPLE 576
tert-butyl
(2-{4-[3-(2,2-difluoroethoxy)-1-(4-methoxy-phenyl)-1H-pyrazol-5-
-yl]phenoxy}ethyl)carbamate
[3011] oil
[3012] MS (ESI+): m/z 490 (M+H).
[3013] 1HNMR (200 MHz, CDCl3): 1.45 (9H, s), 3.48-3.57 (2H, m),
3.80 (3H, s), 3.97-4.03 (2H, m), 4.46 (2H, dt, J=4.3, 13.4 Hz),
4.96 (1H, brs), 5.91 (1H, s), 6.17 (1H, tt, J=4.3, 55.5 Hz),
6.77-6.88 (4H, m), 7.09-7.18 (4H, m)
EXAMPLE 577
tert-butyl
(2-{4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-p-
yrazol-5-yl]phenoxy}ethyl)-carbamate
[3014] oil
[3015] MS (ESI+): m/z 509 (M+H).
[3016] 1HNMR (200 MHz, CDCl3): 1.45 (9H, s), 3.48-3.57 (2H, m),
3.92 (3H, s), 3.98-4.04 (2H, m), 4.61 (1H, d, J=8.4 Hz), 4.70 (1H,
d, J=8.4 Hz), 4.96 (1H, brs), 5.97 (1H, s), 6.71 (1H, d, J=8.8 Hz),
6.83 (2H, d, J=8.8 Hz), 7.13 (2H, d, J=8.8 Hz), 7.48 (1H, dd,
J=2.7, 8.8 Hz) 8.02 (1H, d, J=2.7 Hz)
EXAMPLE 578
tert-butyl
(2-{4-[3-(2,2-difluoroethoxy)-1-(6-methoxy-3-pyridinyl)-1H-pyra-
zol-5-yl]phenoxy}ethyl)-carbamate
[3017] solid
[3018] MS (ESI+): m/z 513 (M+Na).
[3019] 1HNMR (200 MHz, CDCl3): 1.45 (9H, s), 3.48-3.57 (2H, m),
3.92 (3H, s), 3.98-4.04 (2H, m), 4.46 (2H, dt, J=4.2, 13.4 Hz),
4.96 (1H, brs), 5.94 (1H, s), 6.16 (1H, tt, J=4.2, 55.5 Hz), 6.71
(1H, d, J=8.8 Hz), 6.83 (2H, d, J=8.9 Hz), 7.13 (2H, d, J=8.9 Hz),
7.48 (1H, dd, J=2.7, 8.8 Hz), 8.02 (1H, d, J=2.7 Hz
EXAMPLE 579
tert-butyl
(2-{4-[1-(4-methoxyphenyl)-4-methyl-1H-pyrazol-5-yl]phenoxy}eth-
yl)carbamate
[3020] oil
[3021] MS (ESI+): m/z 424 (M+H)
[3022] 200 MHz 1H NMR (DMSO-d6, d): 1.37(9H, s), 2.01(3H, s),
3.23-3.33(2H, m), 3.74(3H, s), 3.92-3.98(2H, m), 6.86-6.95(4H, m),
7.05-7.12(4H, m), 7.55(1H, s)
EXAMPLE 580
tert-butyl
(2-{4-[1-(6-methoxy-3-pyridinyl)-4-methyl-1H-pyrazol-5-yl]pheno-
xy}ethyl)carbamate
[3023] oil
[3024] MS (ESI+): m/z 425 (M+H).
[3025] 1HNMR (400 MHz, CDCl3): 1.42 (9H, s), 2.09 (3H, s),
3.52-3.57 (2H, m), 3.91 (3H, s), 4.01-4.04 (2H, m), 4.98 (1H, brs),
6.68 (1H, d, J=8.8 Hz), 6.87 (2H, d, J=8.8 Hz) 7.08 (2H, d, J=8.8
Hz), 7.48 (1H, dd, J=2.7, 8.8 Hz), 7.58 (1H, s), 8.00 (1H, d, J=2.7
Hz)
EXAMPLE 581
tert-butyl
(2-{4-[1-(4-methoxyphenyl)-3-(methylthio)-1H-pyrazol-5-yl]pheno-
xy}ethyl)carbamate
[3026] oil
[3027] Mass (ESI+): m/z 456 (M+H).
[3028] 1HNMR (200 MHz, CDCl3): 1.45 (9H, s), 2.58 (3H, s),
3.48-3.57 (2H, m), 3.81 (3H, s), 3.97-4.03 (2H, m), 4.96 (1H, m),
6.36 (1H, s), 6.77-6.86 (4H, m), 7.12 (2H, d, J=8.9 Hz), 7.2 (2H,
d, J=9.0 Hz)
EXAMPLE 582
[3029] To a solution of
(2-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)amine
hydrochloride (150 mg) and triethylamine (121 mg) in CH2Cl2 (3 ml)
was added trifluoromethanesulfonic anhydride (113 mg). The mixture
was stirred at ambient temperature for 2 hours. Additional
triethylamine (92 mg) was added and stirring at ambient temperature
was continued for 4 hours. The mixture was concentrated in vacuo.
The residue was partitioned between AcOEt and 1M HCl. The organic
layer was washed with saturated aqueous sodium bicarbonate solution
and saturated aqueous sodium chloride solution, dried over
magnesium sulfate, and concentrated in vacuo. The residue was
purified by silica gel column chromatography eluted with
AcOEt/n-hexane 50% to give
1,1,1-trifluoro-N-(2-{4-[3-methoxy-1-(4-methoxy-phenyl)-1H-pyrazol-5-yl]p-
henoxy}ethyl)methane-sulfonamide (109 mg) as an oil.
[3030] IR (neat): 2960, 1612, 1522 cm-1
[3031] Mass (ESI+): 472 (M+H)+
[3032] 200 MHz 1H NMR (CDCl3, d): 3.60-3.73(2H, m), 3.80(3H, s),
3.97(3H, s), 4.06-4.12(2H, m), 5.45(1H, brs), 5.89(1H, s),
6.70-6.87(4H, m), 7.15(2H, d, J=8.9 Hz), 7.17(2H, d, J=9.0 Hz)
EXAMPLE 583
[3033] To a suspension of
5-[4-(benzyloxy)phenyl]-3-hydroxy-1-(4-methoxyphenyl)-1H-pyrazole
2.0 g and K2CO3 2.23 g in DMSO 20 ml was added diethylsulfate 1.24
g. After stirring at ambient temperature for 2 hours, the reaction
was quenched by adding 28% aqueous ammonium hydroxide solution and
ice. The mixture was partitioned between AcOEt and H2O. The organic
layer was washed with H2O and saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo.
The residue was purified by silica gel column chromatography eluted
with AcOEt/n-hexane=40% and the solvent was evaporated in vacuo.
The reisual solid was recrystallized from IPE to give
5-[4-(benzyloxy)phenyl]-3-ethoxy-1-(4-methoxy-phenyl)-1H-pyrazole
1.44 g as a powder.
[3034] Mass (ESI+): 401(M+H)+
[3035] 200 MHz 1H NMR (DMSO-d6, d): 1.32(3H, t, J=7.0 Hz), 3.76(3H,
s), 4.17(2H, q, J=7.0 Hz), 5.08(2H, s), 6.03(1H, s), 6.92(2H, d,
J=9.0 Hz), 6.97(2H, d, J=8.8 Hz), 7.09-7.16(4H, m), 7.32-7.46(5H,
m)
[3036] The following compound(s) was(were) obtained in a similar
manner to that of Example 583.
EXAMPLE 584
5-{5-[4-(benzyloxy)phenyl]-3-ethoxy-1H-pyrazol-1-yl}-2-methoxypyridine
[3037] oil; MS (ESI+): m/z 402 (M+H)+
[3038] 200 MHz 1H NMR (CDCl3, d): 1.43(3H, t, J=7.1 Hz), 3.92(3H,
s), 4.28(2H, q, J=7.1 Hz), 5.05(2H, s), 5.90(1H, s), 6.70(1H, d,
J=8.7 Hz), 6.91 (2H, d, J=8.8 Hz), 7.14 (2H, d, J=8.8 Hz),
7.35-7.43(5H, m), 7.51(1H, dd, J=2.6,8.7 Hz), 8.04(1H, d, J=2.6
Hz)
EXAMPLE 585
[3039] To a solution of
4-[3-ethoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol (515.5 mg)
in DMF (5 ml) was added sodium hydride 60% dispersion in mineral
oil (79.7 mg) at 3.degree. C. The mixture was stirred at ambient
temperature for 40 minutes. To the reaction mixture was added a
solution of tert-butyl (2-bromoethyl)carbamate (558 mg) in DMF (2
ml). The mixture was stirred at 60.degree. C. for 24 hours. The
reaction mixture was poured into ice water and was extracted with
AcOEt. The organic layer was washed with saturated aqueous sodium
chloride solution, dried over magnesium sulfate, and concentrated
in vacuo. The residue was crystallized from AcOEt, collected and
washed with IPE to give 1st crop of tert-butyl
(2-{4-[3-ethoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)carbama-
te (344 mg) as a white powder. The mother liqour was concentrated
in vacuo and purified by silica gel column chromatography eluted
with AcOEt/CHCl3=10% to give 2nd crop of tert-butyl
(2-{4-[3-ethoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)carbama-
te (218 mg) as a powder.
[3040] Mass (ESI+): 454 (M+H)+
[3041] 200 MHz 1H NMR (CDCl3, d): 1.42(3H, t, J=7.1 Hz), 1.45(9H,
s), 3.48-3.57(2H, m), 3.80(3H, s), 3.97-4.03(2H, m), 4.29(2H, q,
J=7.1 Hz), 5.87(1H, s), 6.79(2H, d, J=9.0 Hz), 6.82(2H, d, J=8.9
Hz), 7.00-7.19(4H, m)
EXAMPLE 586
[3042] A suspension of
5-[4-(benzyloxy)phenyl]-3-hydroxy-1-(4-methoxyphenyl)-1H-pyrazole
(1.5 g), 1-bromo-2-methylpropane (2.76 g) and anhydrous potassium
carbonate (1.67 g) in DMF (10 ml) was added stirred at 100.degree.
C. for 1 hour. The mixture was poured into ice water and extracted
with AcOEt. The organic layer was washed with H2O, saturated
aqueous sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo. The residue was purified by silica gel
column chromatography eluted with AcOEt/n-hexane=30% to give
5-[4-(benzyloxy)phenyl]-3-isobutoxy-1-(4-methoxyphenyl)-1H-pyrazole
(1.64 g) as a solid.
[3043] powder
[3044] Mass (ESI+): 429 (M+H)+
[3045] 200 MHz 1H NMR (CDCl3, d): 1.03(6H, d, J=6.6 Hz), 2.11(1H,
m), 3.80(3H, s), 3.99(2H, d, J=6.6 Hz), 5.04(2H, s), 5.88(1H, s),
6.82(2H, d, J=9.0 Hz), 6.88(2H, d, J=8.8 Hz), 7.11-7.20(4H, m),
7.35-7.43(5H, m)
[3046] The following compound(s) was(were) obtained in a similar
manner to that of Example 586.
EXAMPLE 587
5-[4-(benzyloxy)phenyl]-3-(2-methoxyethoxy)-[(4-methoxyphenyl)-1H-pyrazole
[3047] powder
[3048] Mass (ESI+): 431 (M+H)+
[3049] 200 MHz 1H NMR (CDCl3, d): 3.46(3H, s), 3.73-3.80(2H, m),
3.79(3H, s), 4.39-4.44(2H, m), 5.04(2H, s), 5.91(1H, s), 6.83(2H,
d, J=8.9 Hz), 6.87 (2H, d, J=9.0 Hz), 7.10-7.20(4H, m),
7.34-7.42(5H, m)
EXAMPLE 588
5-[4-(benzyloxy)phenyl]-3-(2-ethoxyethoxy)-1-(4-methoxyphenyl)-1H-pyrazole
[3050] oil
[3051] Mass (ESI+): 445 (M+H)+
[3052] 400 MHz 1H NMR (CDCl3, d): 1.25(3H, t, J=7.0 Hz), 3.61(2H,
q, j=7.0 Hz), 3.79-3.82(2H, m), 3.80(3H, s), 4.39-4.42(2H, m),
5.04(2H, s), 5.91(1H, s), 6.82(2H, d, J=8.9 Hz), 6.88(2H, d, J=8.7
Hz), 7.12(2H, d, J=8.7 Hz), 7.17(2H, d, J=8.9 Hz), 7.36-7.41(5H,
m)
EXAMPLE 589
2-{[5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]oxy}-N,N-d-
imethylacetamide
[3053] powder
[3054] Mass (ESI+): 458 (M+H)+
[3055] 200 MHz 1H NMR (DMSO-d6, d): 2.84(3H, s), 2.97(3H, s),
3.76(3H, s), 4.87(2H, s), 5.09(2H, s), 6.08(1H, s), 6.92(2H, d,
J=9.0 Hz), 6.98(2H, d, J=8.8 Hz), 7.09-7.17 (4H, m), 7.34-7.43(5H,
m)
EXAMPLE 590
5-[5-[4-(benzyloxy)phenyl]-3-(cyclopentyloxy)-1H-pyrazol-1-yl]-2-methoxypy-
ridine
[3056] solid
[3057] MS (ESI+): m/z 442 (M+H).
[3058] 1HNMR (200 MHz, CDCl3): 1.52-1.98 (8H, m), 3.92 (3H, s),
4.98-5.05 (1H, m), 5.05 (2H, s), 5.88 (1H, s), 6.69 (1H, d, J=8.7
Hz), 6.91 (2H, d, J=8.8 Hz), 7.15 (2H, d, J=8.8 Hz), 7.35-7.43 (5H,
m), 7.52 (1H, dd, J=2.7, 8.7 HZ), 8.04 (1H, d, J=2.7 Hz
EXAMPLE 591
5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H-p-
yrazole
[3059] oil
[3060] MS (ESI+): m/z 455 (M+H).
[3061] 1HNMR (200 MHz, DMSOd6): 3.76 (3H, s), 4.81 (1H, d, J=9.0
Hz), 4.90 (1H, d, J=9.0 Hz), 5.09 (2H, s), 6.21 (1H, s), 6.91-7.01
(4H, m), 7.13-7.19 (4H, m), 7.34-7.46 (5H, m)
EXAMPLE 592
5-[4-(benzyloxy)phenyl]-3-(2,2-difluoroethoxy)-1-(4-methoxyphenyl)-1H-pyra-
zole
[3062] oil
[3063] MS (ESI+): m/z 437 (M+H).
[3064] 1HNMR (200 MHz, CDCl3): 3.80 (3H, s), 4.46 (2H, dt, J=4.2,
13.5 Hz), 5.04 (2H, s), 5.91 (1H, s), 6.17 (1H, tt, J=4.2, 55.5
Hz), 6.81-6.91 (4H, m), 7.10-7.19 (4H, m), 7.34-7.43 (5H, m)
EXAMPLE 593
5-[5-[4-(benzyloxy)phenyl]-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-1-yl]-2-me-
thoxypyridine
[3065] oil
[3066] Mass (ESI+): 456 (M+H).
[3067] 1HNMR (200 MHz, CDCl3): 3.93 (3H, s), 4.61 (1H, d, J=8.4
Hz), 4.69 (1H, d, J=8.4 Hz), 5.05 (2H, s), 5.97 (1H, s), 6.71 (1H,
d, J=9 Hz), 6.91 (2H, d, J=8.9 Hz), 7.14 (2H, d, J=8.9 Hz),
7.36-7.43 (5H, m), 7.48 (1H, dd, J=2.7, 9 Hz), 8.04 (1H, d, J=2.7
Hz)
EXAMPLE 594
5-[5-[4-(benzyloxy)phenyl]-3-(2,2-difluoroethoxy)-1H-pyrazol-1-yl]-2-metho-
xypyridine
[3068] oil
[3069] MS (ESI+): m/z 438 (M+H).
[3070] 1HNMR (200 MHz, CDCl3): 3.93 (3H, s), 4.46 (2H, dt, J=4.2,
13.3 Hz), 5.05 (2H, s), 5.94 (1H, s), 6.16 (1H, tt, J=4.2, 55.4
Hz), 6.71 (1H, d, J=8.8 Hz), 6.91 (2H, d, J=8.8 Hz), 7.14 (2H, d,
J=8.8 Hz), 7.35-7.43 (5H, m) 7.48 (1H, dd, J=2.8, 8.8 Hz), 8.04
(1H, d, J=2.8 Hz
EXAMPLE 595
[3071] A suspension of
5-{5-[4-(benzyloxy)phenyl]-3-hydroxy-1H-pyrazol-1-yl}-2-methoxypyridine
(800 mg), dimethyl carbonate (0.9 ml) and potassium carbonate (888
mg) in DMF (8 ml) was stirred at 120.degree. C. for 5 hours. The
mixture was poured into ice water and extracted with AcOEt. The
organic layer was washed with H2O, saturated aqueous sodium
chloride solution, dried over magnesium sulfate, and concentrated
in vacuo. The residue was purified by silica gel column
chromatography eluted with AcOEt/n-hexane=30% to give
5-{5-[4-(benzyloxy)phenyl]-3-methoxy-1H-pyrazol-1-yl}-2-methoxy-pyridine
(1.069 g) as a solid.
[3072] powder
[3073] MS (ESI+): m/z 388 (M+H)+
[3074] 200 MHz 1H NMR (CDCl3, d): 3.92(3H, s), 3.97(3H, s),
5.05(2H, s), 5.90(1H, s), 6.71(1H, d, J=8.7 Hz), 6.91(2H, d, J=8.9
Hz), 7.14(2H, d, J=8.9 Hz), 7.35-7.43(5H, m), 7.52(1H, dd,
J=2.6,8.7 Hz), 8.05(1H, d, J=2.6 Hz)
EXAMPLE 596
[3075] A solution of
4,4,4-trifluoro-1-[4-(2-hydroxy-ethyl)phenyl]-1,3-butanedione (670
mg) and (4-nitrophenyl)hydrazine hydrochloride (439 mg) in AcOH (5
ml) and H2O (0.5 ml) was stirred at ambient temperature overnight.
The mixture was concentrated in vacuo, and the residue was
partitioned between AcOEt and 1M HCl. The organic layer was washed
with 1M HCl for two times, saturated aqueous sodium bicarbonate
solution for three times, and saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo.
The residue was purified by silica gel column chromatography eluted
with AcOEt/n-hexane=10% and 15% to give
2-{4-[1-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethyl
acetate (501 mg) as an oil.
[3076] MS (ESI+): m/z 420(M+H)+, 442(M+Na)+
[3077] 200 MHz 1H NMR (DMSO-d6, d): 1.96(3H, s), 2.91(2H, t, J=6.8
Hz), 4.22(2H, t, J=6.8 Hz), 7.22-7.37(5H, m), 7.61(2H, d, J=9.0
Hz), 8.30(2H, d, J=9.0 Hz)
[3078] The following compound(s) was(were) obtained in a similar
manner to that of Example 596.
EXAMPLE 597
5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1-
H-pyrazole
[3079] MASS (ESI+): m/z=439.1 (M+1), 461.2 (M+Na).
[3080] 1HNMR (400 MHz, CDCl3): 2.15 (3H, s), 3.79 (3H, s), 5.06
(2H, s), 6.8 (2H, d, J=8.9 Hz), 6.95 (2H, d, J=8.7 Hz), 7.07 (2H,
d, J=8.7 Hz), 7.14 (2H, d, J=8.9 Hz), 7.342-7.44 (5H, m).
EXAMPLE 598
2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenyl}-
ethyl acetate
[3081] MASS (ESI+): m/z=346.1 (M-Ac+2), 388.1 (M+1).
[3082] 1HNMR (400 MHz, CDCl3): 2.04 (3H, s), 2.94 (2H, t, J=7 Hz),
3.94 (3H, s), 4.28 (2H, t, J=7 Hz), 6.72 (1H, s), 6.77 (1H, t, J=55
Hz), 6.75 (1H, d, J=8.8 Hz), 7.17 (2H, d, J=8.5 Hz), 7.22 (2H, d,
J=8.5 Hz), 7.54 (1H, dd, J=3.9, 8.8 Hz), 8.08 (1H, d, J=3.9
Hz).
EXAMPLE 599
[3083] To a solution of ammonium chloride 58.8 mg in H2O 0.5 ml was
added iron powder 368 mg and EtOH 2 ml. The reaction mixture was
warmed in oil bath, and a solution of
2-{4-[1-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethyl
acetate 460.7 mg in EtOH 3 ml was added. After being refluxed for 3
hours, the reaction mixture was cooled to ambient temperature and
unsoluble matter was removed by filtration. The filtrate was
concentrated in vacuo. The residue was dissolved in AcOEt, and
washed with saturated aqueous sodium bicarbonate solution and
saturated aqueous sodium chloride solution, dried over magnesium
sulfate, and concentrated in vacuo. The residue was recrystallized
from IPE to give
2-{4-[1-(4-aminophenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]phenyl}ethyl
acetate 182.3 mg as a powder.
[3084] MS (ESI+) m/z 390 (M+H)+
[3085] 200 MHz 1H NMR (DMSO-d6, d): 1.96(3H, s), 2.87(2H, t, J=6.8
Hz), 4.20(2H, t, J=6.8 Hz), 5.46(2H, s), 6.54(2H, d, J=8.7 Hz),
6.95(2H, d, J=8.7 Hz), 7.07(1H, s), 7.18-7.28(4H, m)
EXAMPLE 600
[3086] A mixture of
2-{4-[1-(4-aminophenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]phenyl}ethyl
acetate 165.6 mg and 2,5-dimethoxytetrahydrofuran 112 mg in AcOH 3
ml was stirred at 50.degree. C. for 3 hours.
2,5-Dimethoxytetrahydrofuran 0.22 ml was added and the mixture was
stirred at 50.degree. C. for 2 hours. The mixture was partitioned
between ethyl acetate and H2O. The organic layer was washed with
saturated aqueous sodium bicarbonate solution and saturated aqueous
sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo. The residue was purified by preparative thin
layer silica gel chromatography developed by AcOEt/n-hexane=20%.
The separated silica gel was extracted with 10% MeOH/CHCl3 and the
solvent was evaporated in vacuo to give
2-{4-[1-[4-(1H-pyrrol-1-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]ph-
enyl}ethyl acetate 136.1 mg as an oil.
[3087] MS (ESI+): m/z 440 (M+H)+
[3088] 200 MHz 1H NMR (DMSO-d6, d): 1.95(3H, s), 2.88(2H, t, J=6.8
Hz), 4.20(2H, t, J=6.8 Hz), 6.29(2H, t, J=2.0 Hz), 7.18(1H, s),
7.23-7.32(4H, m), 7.39-7.47(4H, m), 7.69(2H, d, J=8.8 Hz)
EXAMPLE 601
[3089] 1M NaOH (436 .mu.l) was added to a solution of
2-{4-[1-[4-(1H-pyrrol-1-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]ph-
enyl}ethyl acetate (128 mg) in THF (1.5 ml) and MeOH (0.3 ml) under
ice bath cooling. The mixture was stirred at 0.degree.
C..about.ambient temperature for 2 hours. The mixture was
neutralized with 1M HCl (436 .mu.l), and was partitioned between
AcOEt and H2O. The organic layer was washed with saturated aqueous
sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo. The residue was purified by preparative thin
layer silica gel chromatography developed by AcOEt/n-hexane=50%.
The separated silica gel was extracted with 10% MeOH/CHCl3 and the
solvent was evaporated in vacuo to give
2-{4-[1-[4-(1H-pyrrol-1-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]ph-
enyl}ethanol (96.5 mg) as an amorphous powder.
[3090] IR (KBr): 3404, 2924, 2883, 1612, 1522 cm-1
[3091] MS (ESI+): m/z 398 (M+H)+
[3092] 200 MHz 1H NMR (DMSO-d6, d): 2.67-2.75(2H, m), 3.55-3.65(2H,
m), 4.64(1H, t, J=5.1 Hz), 6.30(2H, t, J=2.0 Hz), 7.16(1H, s),
7.19-7.28(4H, m), 7.40-7.48(4H, m), 7.70(2H, d, J=8.9 Hz)
EXAMPLE 602
[3093] A mixture of 10% Pd--C 50% wet (100 mg) and ethyl
5-(4-cyanophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate (1
g) in THF (10 ml), MeOH (5 ml), and 1M HCl (2.9 ml) was
hydrogenated under H2 1 atm at ambient temperature for 6.5 hours.
The catalyst was filtered off through a celite pad and the pad was
washed with MeOH. The filtrate and combined washings were
concentrated in vacuo. The residue was dissolved in EtOH and
concentrated in vacuo. The residue was crystallized from AcOEt to
give ethyl
5-[4-(aminomethyl)phenyl]-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate
hydrochloride (984 mg) as a powder.
[3094] MS (ESI+): m/z 352 (M+H)+
[3095] 1H NMR (DMSO-d6) .delta. 1.32(3H, t, J=7.1 Hz), 3.80(3H, s),
4.01(2H, s), 4.33(2H, q, J=7.1 Hz), 7.00(2H, d, J=9.0 Hz), 7.14(1H,
s), 7.28(2H, d, J=9.0 Hz), 7.31(2H, d, J=8.3 Hz), 7.47(2H, d, J=8.3
Hz), 8.30(2H, brs)
[3096] The following compound(s) was(were) obtained in a similar
manner to that of Example 602.
EXAMPLE 603
ethyl
5-[4-(aminomethyl)phenyl]-1-(6-methoxy-3-pyridinyl)-1H-pyrazole-3-ca-
rboxylate dihydrochloride
[3097] powder
[3098] MS (ESI+): m/z 353 (M+H).
[3099] 1HNMR (200 MHz, DMSOd6): 1.32 (3H, t, J=7.1 Hz), 3.88 (3H,
s), 3.97-4.06 (2H, m), 4.34 (2H, q, J=7.1 Hz), 6.94 (1H, d, J=8.7
Hz), 7.17 (1H, s), 7.35 (2H, d, J=8.2 Hz), 7.51 (2H, d, J=8.2 Hz),
7.78 (1H, dd, J=2.7, 8.7 Hz), 8.15 (1H, d, J=2.7 Hz), 8.47 (2H,
brs)
EXAMPLE 604
{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-benzyl}amine
hydrochloride
[3100] oil
[3101] MS (ESI+): m/z 310 (M+H).
[3102] 1HNMR (200 MHz, DMSOd6): 3.76 (3H, s), 3.85 (3H, s),
3.91-4.26 (2H, m), 6.16 (1H, s), 6.93 (2H, d, J=8.9 Hz), 7.16 (2H,
d, J=8.9 Hz), 7.26 (2H, d, J=8.2 Hz), 7.45 (2H, d, J=8.2 Hz), 8.41
(2H, brs)
EXAMPLE 605
{4-[3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}amine
hydrochloride
[3103] powder
[3104] MS (ESI+): m/z 338 (M+H).
[3105] 1HNMR (200 MHz, DMSOd6): 1.32 (6H, d, J=6.2 Hz), 3.76 (3H,
s), 4.00 (2H, s), 4.77 (1H, m), 6.11 (1H, s), 6.93 (2H, d, J=8.9
Hz), 7.15 (2H, d, J=8.9 Hz), 7.25 (2H, d, J=8.2 Hz), 7.44 (2H, d,
J=8.2 Hz), 8.31 (2H, brs)
EXAMPLE 606
[3106] Et3N (326 mg) and then a solution of
di-tert-butyldicarbonate (594 mg) in CH2Cl2 (3 ml) was added
successively to a suspension of ethyl
5-[4-(aminomethyl)phenyl]-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate
hydrochloride (960 mg) in CH2Cl2 (9 ml). After stirring at ambient
temperature for 1 hour, the reaction mixture was concentrated in
vacuo. The residue was partitioned between ethyl acetate and 1M
HCl. The organic layer was washed with saturated aqueous sodium
bicarbonate solution and saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo.
The residue was recrystallized from AcOEt/n-hexane to give ethyl
5-(4-{[(tert-butoxy-carbonyl)amino]methyl}phenyl)-1-(4-methoxyphenyl)-1H--
pyrazole-3-carboxylate (1.045 g) as a powder.
[3107] MS (ESI+): m/z 452 (M+H)+
[3108] 1H NMR (DMSO-d6) .delta. 1.31(3H, t, J=7.1 Hz), 1.38(9H, s),
3.79(3H, s), 4.11(2H, d, J=6.2 Hz), 4.32(2H, q, J=7.1 Hz), 6.99(2H,
d, J=8.9 Hz), 7.07(1H, s), 7.20(4H, s), 7.26(2H, d, J=8.9 Hz),
7.40(1H, t, J=6.2 Hz)
[3109] The following compound(s) was(were) obtained in a similar
manner to that of Example 606.
EXAMPLE 607
ethyl
5-(4-{[(tert-butoxycarbonyl)amino]methyl}phenyl)-1-(6-methoxy-3-pyri-
dinyl)-1H-pyrazole-3-carboxylate
[3110] powder
[3111] Mass (ESI+): m/z 453 (M+H).
[3112] 1HNMR (200 MHz, DMSOd6): 1.32 (3H, t, J=7.1 Hz), 1.38 (9H,
s), 3.88 (3H, s), 4.12 (2H, d, J=6.1 Hz), 4.33 (2H, q, J=7.1 Hz),
6.92 (1H, d, J=8.9 Hz), 7.10 (1H, s), 7.19-7.28 (4H, m), 7.41 (1H,
t, J=6.0 Hz), 7.74 (1H, dd, J=2.7, 8.9 Hz), 8.14 (1H, d, J=2.7
Hz)
EXAMPLE 608
[3113] A mixture of ethyl
5-(4-{(tert-butoxycarbonyl)amino]-methyl}phenyl)-1-(4-methoxyphenyl)-1H-p-
yrazole-3-carboxylate (500 mg) and sodium methoxide (239 mg) in
formamide 5 ml was stirred at 70.degree. C. for 2 hours. The
mixture was cooled to ambient temperature and partitioned between
AcOEt and brine. The organic layer was washed with saturated
aqueous sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo to give tert-butyl
{4-[3-(aminocarbonyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}carbamat-
e (512 mg) as an oil.
[3114] MS (ESI+): m/z 423 (M+H)+
[3115] 1H NMR (DMSO-d6) .delta. 1.38(9H, s), 3.78(3H, s), 4.11(2H,
d, J=6.1 Hz), 6.93(1H, s), 6.98(2H, d, J=8.9 Hz), 7.19-7.43(8H, m),
7.64 (1H, brs)
EXAMPLE 609
[3116] Phosphorous oxychloride (0.22 ml) was added to DMF (2 ml)
under ice bath cooling. To this solution was added a solution of
tert-butyl
{4-[3-(aminocarbonyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}carbamat-
e (499 mg) in DMF (3 ml) dropwise. The reaction mixture was stirred
at 4.degree. C. for 1 hour. Phosphorous oxychloride (0.15 ml) was
added and the reaction mixture was stirred at 4.degree. C. for 1
hour. The reaction was quenched by adding saturated aqueous sodium
bicarbonate solution. The mixture was extracted with ethyl acetate.
The organic layer was washed with saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo.
The residue was purified by preparative thin layer silica gel
chromatography developed by AcOEt/n-hexane=40%. The separated
silica gel was extracted with 10% MeOH/CHCl3 and the solvent was
evaporated in vacuo to give
tert-butyl{4-[3-cyano-1-(4-methoxy-phenyl)-1H-pyrazol-5-yl]benzylcarbamat-
e (136 mg) as an oil.
[3117] MS (ESI+): m/z 427 (M+Na)+, (ESI-): m/z 403 (M-H)+
[3118] 200 MHz 1H NMR (CDCl3, d): 1.46(9H, s), 3.83(3H, s),
4.32(2H, d, J=5.9 Hz), 4.75(1H, br), 6.83(1H, s), 6.87(2H, d, J=9.0
Hz), 7.11-7.26(6H, m)
EXAMPLE 610
[3119] To a solution of
5-[4-(2-{[tert-butyl(dimethyl)-silyl]oxy}ethoxy)phenyl]-1-(4-methoxypheny-
l)-4-methyl-3-(trifluoromethyl)-1H-pyrazole (5.2 g) in EtOH (200
ml) was added conc.HCl (20 ml) at room temperature. After stirring
for 2 hrs, the reaction mixture was partitioned between EtOAc and
water. Organic layer was separated and washed with water, dried
over MgSO4, filtered and evaporated. The residue was
chromatographed on silica gel (Hex/EtOAc=2:1-1:1) to give 2.05 g
(51%) of
2-{4-[1-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]ph-
enoxy}ethanol as a crystal.
[3120] MASS (ESI+): e/z=415.1 (M+Na).
[3121] 1HNMR (400 MHz, CDCl3): 2.15 (3H, s), 1.99 (1H, t, J=6.2
Hz), 2.15 (3H, s), 3.95-4.00 (2H, m), 4.08-4.10 (2H, m), 6.80 (2H,
d, J=9 Hz), 6.90 (2H, d, J=8.8 Hz) 7.08 (2H, d, J=8.8 Hz), 7.13
(2H, d, J=9 Hz)
EXAMPLE 611
[3122] To solution of
4-[1-[4-(methylthio)phenyl]-3-(tri-fluoromethyl)-1H-pyrazol-5yl]phenol
(5.0 g) in DMF (20 ml) was added NaH (0.75 g) over 25 min under ice
cooling (5.about.20.degree. C.) (gas), stir at 3.degree. C. for 10
min. tert-Butyl N-(2-bromoethyl)carbamate (4.48 g) in DMF (5 ml)
was added to the mixture over 10 min stir at 60.degree. C. (bath
70.degree. C.) for 6 h and allowed to stand for overnight.
[3123] The mixture was poured into water (50 ml) and EtOAc (30 ml)
separation and extracted with EtOAc (10 ml). The organic layer was
washed with water (25.times.3) and brine (25 ml), dried MgSO4,
evaporated. The residue was column chromatographed on silica gel
(75 ml, 15v/w, AcOEt/Hex(2:1-1:1) and evaporated to give 7.0 g of
tert-butyl
(2-{4-[1-[4-(methyl-thio)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-phe-
noxy}ethyl)carbamate as an oil.
[3124] MASS (ESI+): m/z=516.1 (M+Na).
[3125] 1HNMR (400 MHz, CDCl3): 1.45 (9H, s), 2.49 (3H, s),
3.49-3.58 (2H, m), 4.02 (2H, t, J=10.2 Hz), 4.97 (1H, b.s), 6.68
(1H, s), 6.84 (2H, d, J=17.5 Hz), 7.14 (2H, d, J=17.5 Hz), 7.21
(4H, s).
[3126] The following compound(s) was(were) obtained in a similar
manner to that of Example 611.
EXAMPLE 612
tert-butyl
(2-{4-[1-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1H-pyra-
zol-5-yl]phenoxy}ethyl)-carbamate
[3127] MASS (ESI+): m/z=514.2 (M+Na).
[3128] 1HNMR (400 MHz, CDCl3): 1.45 (9H, s), 2.15 (3H, s),
3.52-3.56 (2H, m), 3.79 (3H, s), 4.02 (2H, t, J=5.1 Hz), 4.99 (1H,
b.s), 6.80 (2H, d, J=9.0 Hz), 6.87 (2H, d, J=8.8 Hz), 7.07 (2H, d,
J=8.8 Hz), 7.13 (H, d, J=9.0 Hz)
EXAMPLE 613
[3129] To a suspension of
(2-{4-[1-[4-(methylthio)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]pheno-
xy}ethyl)amine hydrochloride (7.5 g) in H2O (150 ml) and EtOH (75
ml) was added NaOCN (2.27 g) at room temperature. pH was adjusted
to 6.3 with 1NHCl. The mixture was stirred for 5 hours under the
condition of pH 6.0-7.0. The reaction mixture was extracted with
EtOAc and washed with dil. NaCl (twice), dried over MgSO4, filtered
and evaporated. The residue was column chromatographed on silica
gel (CH2Cl2/MeOH) and evaporated. The residue was crystallized from
IPE/EtOH. Recrystallized from EtOH/H2O (50 ml-50 ml Final) and
dried to give 4.10 g (54%) of
N-(2-{4-[1-[4-(methylthio)phenyl]-3-(trifluoro-methyl)-1H-pyrazol-5-yl]ph-
enoxy}ethyl)urea.
[3130] MASS (ESI+): m/z=459.1 (m+Na).
[3131] 1HNMR (400 MHz, DMSOd6): 2.05 (3H, s), 3.33 (2H, q, J=5.6
Hz), 3.95 (2H, t, J=5.6 Hz), 5.54 (2H, b.s), 6.16 (1H, t, J=5.6
Hz), 6.96 (2H, d, J=8.8 Hz), 7.09 (1H, s), 7.22 (2H, d, J=8.6 Hz),
7.27 (2H, d, J=8.7 Hz), 7.32 (2H, d, J=8.7 Hz).
[3132] HORIBA FT-IR for Windows Ver. 4.08 (cm-1): 3399.89, 3197.40,
1650.77, 1614.13, 1554.34, 1475.28, 1459.85, 1442.49, 1232.29,
1160.94, 1126.22, 1087.66, 1049.09, 970.019, 827.312.
[3133] The following compound(s) was(were) obtained in a similar
manner to that of Example 613.
EXAMPLE 614
N-(2-{4-[1-(4-methoxyphenyl)-4-methyl-3-(trifluoro-methyl)-1H-pyrazol-5-yl-
]phenoxy}ethyl)urea
[3134] mp: 150.5-151.1.degree. C.
[3135] MASS (ESI+): m/z=457.2 (m+Na).
[3136] 1HNMR (400 MHz, CDCl3): 2.15 (3H, s), 3.6 (2H, dt, J=5, 5.4
Hz), 3.78 (3H, s), 4.04 (2H, t, J=5 Hz), 4.5 (2H, b.s), 5.08 (1H,
t, J=5.4 Hz), 6.8 (2H, d, J=9 Hz), 6.86 (2H, d, J=8.8 Hz) 7.07 (2H,
d, J=8.8 Hz) 7.13 (2H, d, J=9 Hz
EXAMPLE 615
N-[2-(4-{3-(difluoromethyl)-1-[4-(methylthio)phenyl]-1H-pyrazol-5-yl}pheno-
xy)ethyl]urea
[3137] mp: 184.3-184.7.degree. C.
[3138] MASS (ESI+): m/z=441.1 (M+Na).
[3139] 1HNMR (400 MHz, DMSOd6): 2.5 (3H, s), 3.33 (2H, dt, J=5.6,
6.3 Hz), 3.95 (2H, t, J=5.6 Hz), 5.53 (2H, b.s), 6.15 (1H, t, J=6.3
Hz), 6.85 (1H, s), 6.95 (2H, d, J=8.7 Hz), 7.09(1H, t, J=54.1 Hz),
7.2 (2H, d, J=8.7 Hz), 7.23 (2H, d, J=8.7 Hz), 7.3 (2H, d, J=8.7
Hz).
EXAMPLE 616
N-(2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phen-
yl}ethyl)urea
[3140] mp: 194-196.degree. C.
[3141] MASS (ESI+): m/z=410.2 (M+Na).
[3142] 1HNMR (400 MHz, DMSOd6): 2.68 (2H, t, J=7.3 Hz), 3.19 (2H,
dt, J=5.6, 7.3 Hz), 3.88 (3H, s), 5.42 (2H, b.s), 5.95 (1H, t,
J=5.6 Hz), 6.91 (1H, d, J=8.8 Hz), 6.93 (1H, s), 7.11 (1H, t,
J=54.4 Hz), 7.23 (4H, s), 7.7 (1H, dd, J=2.8, 8.8 Hz), 8.15 (1H, d,
J=2.8 Hz).
EXAMPLE 617
N-{4-[1-(6-methoxy-3-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzyl-
}urea
[3143] Crystal. mp: 147-149.degree. C.
[3144] MASS (ESI+): m/z=414.1 (M+Na).
[3145] 1HNMR 400 MHz, CDCl3): 3.93 (3H, s), 4.37 (2H, d, J=6 Hz),
4.52 (2H, b.s), 5.08 (1H, t, J=6 Hz), 6.73 (1H, s), 6.77 (1H, d,
J=8.8 Hz), 7.18 (2H, d, J=8.3 Hz), 7.27 (2H, d, J=8.3 Hz), 7.59
(1H, dd, J=2.7, 8.8 Hz), 8.03 (1H, d, J=2.7 Hz).
EXAMPLE 618
N-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]benzyl}-
urea
[3146] MASS (ESI+): m/z=396.1 (m+Na).
[3147] 1HNMR (400 MHz, DMSOd6): 3.87 (3H, s) 4.17 (2H, d, J=6 Hz),
5.55 (2H, b.s), 6.45 (1H, t, J=6 Hz), 6.91 (1H, d, J=8.8 Hz), 6.94
(1H, s), 7.11 (1H, t, J=53.2 Hz), 7.27 (4H, s), 7.71 (1H, dd,
J=2.7, 8.8 Hz), 8.14 (1H, d, J=2.7 Hz).
EXAMPLE 619
[3148] A mixture of
N-(2-{4-[1-[4-(methylthio)phenyl]-3-(tri-fluoromethyl)-1H-pyrazol-5-yl]ph-
enoxy}ethyl)urea (250 mg) and mCPBA (326 mg) in CH2Cl2 (10 ml) was
stirred for 18 hrs. sat. NaHCO3 and CH2Cl2 was added. Aqueous layer
was separated and extracted. The combined organic layer was washed
with sat. NaHCO3 (twice), dried and evaporated to give 207 mg
(79.9%) of crude product. The crude product was column
chromatographed by preparative TLC to give 207 mg (80%) of
N-(2-{4-[1-[4-(methylsulfinyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl-
]phenoxy}ethyl)urea as an amorphous.
[3149] MASS (ESI+): 475.1 (m+Na).
[3150] 1HNMR (400 MHz, DMSOd6): 2.79 (3H, s), 3.3-3.34 (2H, m),
3.95 (2H, t, J=5.6 Hz), 5.53 (2H, b.s), 6.15 (1H, t, J=5.6 Hz),
6.97 (2H, d, J=8.8 Hz), 7.16 (1H, s), 7.23 (2H, d, J=8.8 Hz), 7.55
(2H, d, J=8.6 Hz), 7.77 (2H, d, J=8.6 Hz).
EXAMPLE 620
[3151] A mixture of
N-(2-{4-[1-[4-(methylthio)phenyl]-3-(tri-fluoromethyl)-1H-pyrazol-5-yl]ph-
enoxy}ethyl)urea (250 mg) and mCPBA (326 mg) in CH2Cl2 (10 ml) was
stirred for 18 hrs. sat. NaHCO3 and CH2Cl2 was added. Aqueous layer
was separated and extracted. The combined organic layer was washed
with sat. NaHCO3 (twice), dried and evaporated to give 207 mg
(79.9%) of crude product. The crude product was column
chromatographed by preparative TLC to give 116 mg (43%) of
N-(2-{4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl-
]phenoxy}ethyl)urea as a amorphous.
[3152] MASS (ESI+): m/z=491.0 (m+Na).
[3153] 1HNMR (400 MHz, DMSOd6): 3.28 (3H, s), 3.28-3.34 (2H, m),
3.96 (2H, t, J=5.4 Hz), 5.54 (2H, b.s), 6.16 (1H, t, J=5.4 Hz),
6.99 (2H, d, J=8.4 Hz), 7.18 (1H, s), 7.25 (2H, d, J=8.4 Hz), 7.61
(2H, d, J=8.4 Hz), 8.01 (2H, d, J=8.4 Hz).
EXAMPLE 621
[3154] To a solution of
2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenyl-
}ethyl acetate (10 g) in THF (120 ml) and MeOH (30 ml) was added
1NNaOH (60 ml) at room temperature. The reaction mixture was
stirred at the same temperature for 4 hrs, and then neutralized
with 1N HCl (60 ml), evaporated, and extracted twice with EtOAc.
The organic layer was washed with water and brine, dried over
MgSO4, filtered and evaporated to give crude product.
[3155] The residue was column chromatographed on silica gel and
crystallized from IPE and filtered to give 3.0 g of
2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenyl-
}ethanol. The filtrate was evaporated and filtered to give 4.65 g
of second crystal.
[3156] MASS (ESI+): m/z=368.2 (M+Na).
[3157] 1HNMR (400 MHz, CDCl3): 1.49 (1H, t, J=5.8 Hz), 2.87 (2H, t,
J=6.5 Hz), 3.88 (2H, dt, J=5.8, 6.5 Hz), 6.71 (1H, s), 6.76 (1H, t,
J=55 Hz), 6.75 (1H, d, J=8.8 Hz), 7.17 (2H, d, J=8.4 Hz), 7.21 (2H,
d, J=8.4 Hz), 7.55 (1H, dd, J=2.8, 8.8 Hz), 8.08 (1H, d, J=2.8
Hz).
EXAMPLE 622
[3158] To a solution of
2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenyl-
}ethanol (7.4 g) and Et3N (4.5 ml) in CH2Cl2 (75 ml) was added MsCl
(2.5 ml) under ice-cooling. After stirring for 1 hour, the reaction
mixture was quenched with water, separated. The aqueous layer was
extracted with CH2Cl2 and combined organic layer was washed with
water and brine, dried over MgSO4, filtered and evaporated under
reduced pressure to give 10.5 g (quant) of
2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenyl-
}ethyl methanesulfonate as an oil.
[3159] MASS (ESI+): m/z=446.1 (M+Na).
[3160] 1HNMR (400 MHz, CDCl3): 2.9 (3H, s), 3.06 (2H, t, J=6.8 Hz),
3.94 (3H, s), 4.42 (2H, t, J=6.8 Hz), 6.73 (1H, s), 6.76 (1H, d,
J=8.8 Hz), 6.77 (1H, t, J=55 Hz), 7.19 (2H, d, J=8.6 Hz), 7.23 (2H,
d, J=8.6 Hz), 7.55 (1H, dd, J=2.6, 8.8 Hz), 8.04 (1H, d, J=2.6
Hz).
EXAMPLE 623
[3161] A mixture of
2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenyl-
}ethyl methanesulfonate (7.4 g) and Ph(CO)2NK (3.88 g) in DMF (50
ml) was stirred at 60.degree. C. for 8 hours. Added water. The
organic layer was extracted twice with EtOAc. Aqueous layer was
washed with water (twice) and brine, dried over MgSO4, filtered,
and evaporated under reduced pressure. The residue was triturated
with IPE, filtered and dried to give 7.65 g of
2-(2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazo-
l-5-yl]phenyl}ethyl)-1H-isoindole-1,3(2H)-dione as a solid.
[3162] MASS (ESI+): 475.2 (M+1), 497.2 (M+Na).
[3163] 1HNMR (400 MHz, CDCl3): 3 (2H, t, J=7.6 Hz), 3.92 (2H, t,
J=7.6 Hz), 3.95 (3H, s), 6.7 (1H, s), 6.73 (1H, d, J=8.8 Hz), 6.76
(1H, t, J=55 Hz), 7.14 (2H, d, J=8.1 Hz), 7.22 (2H, d, J=8.1 Hz),
7.46 (1H, dd, J=2.7, 8.8 Hz), 7.71-7.73 (2H, m), 7.83-7.85 (2H, m),
8.1 (1H, d, J=2.7 Hz).
EXAMPLE 624
[3164] A mixture of
2-(2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phe-
nyl}ethyl)-1H-isoindole-1,3(2H)-dion (5.0 g) and NH2NH2 (2.8 ml) in
CH3CN (50 ml) was stirred at 60.degree. C. for 8 hours. The
reaction mixture was filtered. Filtrate was evaporated under
reduced pressure. 4N HCl/Dioxane and then IPE was added. The
product was triturated, filtered and died under reduced pressure to
give 3.94 g (90%) of
(2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]pheny-
l}ethyl)amine dihydrochloride as a solid.
[3165] MASS (ESI+): m/z=345.2 (M(free)+1).
[3166] 1HNMR (400 MHz, DMSOd6): 2.9-2.95 (2H, m), 3.01-3.06 (2H,
m), 3.88 (3H, s), 6.92 (1H, d, J=8.8 Hz), 6.95 (1H, s), 7.13 (1H,
t, J=56.1 Hz), 7.27 (2H, d, J=8.4 Hz), 7.3 (2H, d, J=8.4 Hz), 7.72
(1H, dd, J=2.8, 8.8 Hz), 8.15 (1H, d, J=2.8 Hz).
[3167] The following compound(s) was(were) obtained in a similar
manner to that of Example 602.
EXAMPLE 625
{4-[1-(6-methoxy-3-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzyl}a-
mine dihydrochloride
[3168] MASS (ESI+): m/z=332.2 (M-NH2), 349.1 (M+H).
[3169] 1HNMR (400 MHz, DMSOd6): 3.88 (3H, s), 6.94 (1H, d, J=9.6
Hz), 7.25 (1H, s), 7.37 (2H, d, J=8 Hz), 7.53 (2H, d, J=8 Hz), 7.8
(1H, dd, J=2.9, 9.6 Hz), 8.45 (1H, d, J=2.8 Hz).
EXAMPLE 626
{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]-benzyl}a-
mine hydrochloride
[3170] MASS (ESI+): m/z=314.2 (M-NH2), 331.1 (M+1).
[3171] 1HNMR (400 MHz, DMSOd6): 3.88 (3H, s), 6.93 (1H, d, J=8.8
Hz), 7.00 (1H, s), 7.14 (1H, t, J=54 Hz), 7.35 (2H, d, J=8.2 Hz),
7.53 (2H, d, J=8.2 Hz), 7.75 (1H, dd, J=2.7, 8.8 Hz), 8.15 (1H, d,
J=2.7 Hz).
EXAMPLE 627
[3172] To a solution of 5-hydrazino-2-methoxypyridine
dihydrochloride (4.78 g) and Et3N (7.01 g) in EtOH (50 ml) was
added
{(2R,3S)-3-[4-(benzyloxy)phenyl]-2-oxiranyl}-(cyclopropyl)methanone
(5.10 g) and refluxed for 9 hours. THs mixture was concentrated in
vacuo. To the residue were added AcOEt and 1MHCl, and unsoluble
matter was filtered off through a celit pad. The filtrate was
partitioned, and the organic lauer was washed with saturated
aqueous sodium bicarbonate solution, dried over magnesium sulfate,
and concentrated in vacuo. The residue was dissolved in CH2Cl2 (50
ml). To this solution were added Et3N (5.26 g) and methanesulfonyl
chloride (2.98 g) successively under ice-bath cooling. The mixture
was stirred at ambient temperature for 2 hours. The mixture was
washed with 1M HCl, saturated aqueous sodium bicarbonate solution,
and saturated aqueous sodium chloride solution, dried over
magnesium sulfate, and concentrated in vacuo. The residue was
purified by silica gel column chromatography eluted with
AcOEt/n-hexane=20% to give
5-{5-[4-(benzyloxy)phenyl]-3-cyclopropyl-1H-pyrazol-1-yl}-2-methoxypyridi-
ne (4.20 g) as a solid.
[3173] MS (ESI+): m/z 398 (M+H).
[3174] 1HNMR (200 MHz, DMSOd6): 0.69-0.78 (2H, m), 0.87-0.97 (2H,
m), 1.89-1.99 (1H, m), 3.85 (3H, s), 5.09 (2H, s), 6.30 (1H, s),
6.85 (1H, d, J=8.8 Hz), 6.99 (2H, d, J=8.8 Hz), 7.15 (2H, d, J=8.8
Hz), 7.34-7.46 (5H, m), 7.60 (1H, dd, J=2.7, 8.8 Hz), 8.01 (1H, d,
J=2.7 Hz
EXAMPLE 628
[3175] To a mixture of tert-butyl
(2-{4-[1-(4-methoxyphenyl)-3-carboxy-1H-pyrazol-5-yl]phenoxy}ethyl)carbam-
ate (313.9 mg), piperidine (88.4 mg), and 1-hydroxybenzotriazole
(140 mg) in DMF 3 ml was added water soluble carbodiimide
hydrochloride (199 mg) under ice-bath cooling. The mixture was
stirred at ambient temperature overnight, then was partitioned
between AcOEt and H2O. The organic layer was separated, washed with
1M HCl, saturated aqueous sodium bicarbonate solution and saturated
aqueous sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo. The residue was purified by silica gel
column chromatography eluted with AcOEt/n-hexane=70%. The residue
was crystallized from IPE to give tert-butyl
2-{4-[1-(4-methoxyphenyl)-3-(1-piperidinyl-carbonyl)-1H-pyrazol-5-yl]phen-
oxy}ethyl)carbamate (332.5 mg) as a white powder.
[3176] MS (ESI+): m/z 521 (M+H).
[3177] 1HNMR (200 MHz, CDCl3): 1.45 (9H, s), 1.53-1.79 (6H, m),
3.48-3.57 (2H, m), 3.67-3.81 (2H, m), 3.82 (3H, s), 3.88-4.02 (2H,
m), 3.98-4.04 (2H, m), 4.96 (1H, brs), 6.77 (1H, s), 6.81 (2H, d,
J=8.8 Hz), 6.86 (2H, d, J=9.0 Hz), 7.15 (2H, d, J=8.8 Hz), 7.21
(2H, d, J=9.0 Hz)
[3178] The following compound(s) was(were) obtained in a similar
manner to that of Example 628.
EXAMPLE 629
tert-butyl
(2-{4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinylcarbonyl)-1H-p-
yrazol-5-yl]phenoxy}ethyl)-carbamate
[3179] powder
[3180] MS (ESI+): m/z 522 (M+H).
[3181] 1HNMR (200 MHz, CDCl3): 1.45 (9H, s), 1.54-1.78 (6H, m),
3.49-3.57 (2H, m), 3.69-3.82 (2H, m), 3.86-3.99 (2H, m), 3.94 (3H,
s), 3.99-4.05 (2H, m), 4.96 (1H, s), 6.73 (1H, d, J=8.8 Hz), 6.79
(1H, s), 6.84 (2H, d, J=8.8 Hz), 7.16 (2H, d, J=8.8 Hz), 7.50 (1H,
dd, J=2.7, 8.8 Hz), 8.12 (1H, d, J=2.7 Hz)
EXAMPLE 630
tert-butyl
(2-{4-[3-{[ethyl(methyl)amino]carbonyl}-1-(6-methoxy-3-pyridiny-
l)-1H-pyrazol-5-yl]phenoxy}-ethyl)carbamate
[3182] powder
[3183] Mass (ESI+): m/z 496 (M+H).
[3184] 1HNMR (200 MHz, DMSOd6): 1.08-1.22 (3H, m), 1.37 (9H, s),
2.98, 3.29 (3H, s), 3.23-3.32 (2H, m), 3.42-3.53, 3.63-3.75 (2H,
m), 3.87 (3H, s), 3.93-4.00 (2H, m), 6.82, 6.84 (1H, s), 6.87-7.00
(4H, m), 7.21 (2H, d, J=8.6 Hz), 7.61-7.72 (1H, m), 8.13-8.15 (1H,
m)
EXAMPLE 631
2-{4-[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl)-1H-pyrazol-5-yl]phenox-
y}ethanol
[3185] mp. 121.9-123.8.degree. C.
[3186] Mass (ESI+): m/z 422 (M+H).
[3187] 1HNMR (200 MHz, DMSOd6): 1.42-1.74 (6H, m), 3.53-3.70 (2H,
m), 3.65-3.73 (2H, m), 3.70-3.92 (2H, m), 3.78 (3H, s), 3.95-4.00
(2H, m), 4.86 (1H, t, J=5.4 Hz), 6.77 (1H, s), 6.91 (2H, d, J=8.8
Hz), 6.98 (2H, d, J=8.9 Hz), 7.16 (2H, d, J=8.8 Hz), 7.23 (2H, d,
J=8.9 Hz
EXAMPLE 632
2-{4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl-carbonyl)-1H-pyrazol-5-yl-
]phenoxy}ethanol
[3188] mp. 123.4-124.0.degree. C.
[3189] Mass (ESI+): m/z 423 (M+H).
[3190] 1HNMR (200 MHz, DMSOd6): 1.45-1.74 (6H, m), 3.50-3.69 (2H,
m), 3.65-3.74 (2H, m), 3.71-3.90 (2H, m), 3.87 (3H, s), 3.96-4.02
(2H, m), 4.86 (1H, t, J=5.4 Hz), 6.81 (1H, s), 6.90 (1H, d, J=8.7
Hz), 6.94 (2H, d, J=8.6 Hz), 7.20 (2H, d, J=8.6 Hz), 7.68 (1H, dd,
J=2.7, 8.7 Hz), 8.14 (1H, d, J=2.7 Hz)
EXAMPLE 633
tert-butyl
{4-[1-(4-methoxyphenyl)-3-(1-piperidinyl-carbonyl)-1H-pyrazol-5-
-yl]benzyl}carbamate
[3191] amorphous powder
[3192] MS (ESI+): m/z 491 (M+H).
[3193] 1HNMR (200 MHz, CDCl3): 1.46 (9H, s), 1.55-1.8 (6H, m),
3.68-3.82 (2H, m), 3.82 (3H, s), 3.97-4.00 (2H, m), 4.31 (2H, d,
J=6.0 Hz), 4.84 (1H, brs), 6.82 (1H, s), 6.86 (2H, d, J=9 Hz),
7.15-7.25 (6H, m)
EXAMPLE 634
tert-butyl
{4-[3-{[ethyl(methyl)amino]carbonyl}-1-(4-methoxyphenyl)-1H-pyr-
azol-5-yl]benzyl}carbamate amorphous powder
[3194] MS (ESI+): m/z 465 (M+H).
[3195] 1HNMR (200 MHz, CDCl3): 1.20-1.31 (3H, m), 1.46 (9H, s),
3.11, 3.40 (3H, s), 3.61, 3.85 (2H, q, J=7.1 Hz), 3.82 (3H, s),
4.31 (2H, d, J=5.8 Hz), 4.86 (1H, brs), 6.81-6.90 (3H, m),
7.16-7.25 (6H, m)
EXAMPLE 635
tert-butyl
{4-[3-{[methoxy(methyl)amino]carbonyl}-1-(4-methoxyphenyl)-1H-p-
yrazol-5-yl]benzyl}carbamate solid
[3196] MS (ESI+): m/z 467 (M+H).
[3197] 1HNMR (200 MHz, CDCl3): 1.46 (9H, s), 3.51 (3H, s), 3.82
(3H, s), 3.85 (3H, s), 4.31 (2H, d, J=5.9 Hz), 4.87 (1H, brs), 6.86
(2H, d, J=9.0 Hz), 6.96 (1H, s), 7.15-7.26 (6H, m)
EXAMPLE 636
tert-butyl{4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl-carbonyl)-1H-pyra-
zol-5-yl]benzyl}carbamate
[3198] oil
[3199] MS (ESI+): m/z 492 (M+H).
[3200] 1HNMR (200 MHz, DMSOd6): 1.39 (9H, s), 1.46-1.75 (6H, m),
3.52-3.69 (2H, m), 3.75-3.93 (2H, m), 3.87 (3H, s), 4.13 (2H, d,
J=6.1 Hz), 6.86 (1H, s), 6.90 (1H, d, J=8.9 Hz), 7.19-7.28 (4H, m),
7.41 (1H, t, J=6.1 Hz 7.70 (1H, dd, J=2.7, 8.9 Hz), 8.13 (1H, d,
J=2.7 Hz)
EXAMPLE 637
tert-butyl
{4-[3-{[ethyl(methyl)amino]carbonyl}-1-(6-methoxy-3-pyridinyl)--
1H-pyrazol-5-yl]benzyl}-carbamate
[3201] oil
[3202] MS (ESI+): m/z 466 (M+H).
[3203] 1HNMR (200 MHz, DMSOd6): 1.09-1.22 (3H, m), 1.39 (9H, s),
2.98, 3.28 (3H, s), 3.73-3.77 (2H, m), 3.87 (3H, s), 4.13 (2H, d,
J=6.0 Hz), 6.87-6.93 (2H, m), 7.18-7.30 (4H, m), 7.41 (1H, t, J=6.0
Hz), 7.65-7.74 (1H, m), 8.14 (1H, d, J=2.6 Hz)
EXAMPLE 638
tert-butyl
{4-[3-{[methoxy(methyl)amino]carbonyl}-1-(6-methoxy-3-pyridinyl-
)-1H-pyrazol-5-yl]benzyl}carbamate
[3204] powder
[3205] MS (ESI+): m/z 468 (M+H).
[3206] 1HNMR (200 MHz, DMSOd6): 1.39 (9H, s), 3.37 (3H, s), 3.77
(3H, s), 3.87 (3H, s), 4.13 (2H, d, J=6.1 Hz), 6.91 (1H, d, J=8.8
Hz), 6.97 (1H, s), 7.25 (4H, s), 7.42 (1H, t, J=6.1 Hz) 7.71 (1H,
dd, J=2.7, 8.8 Hz), 8.15 (1H, d, J=2.7 Hz)
EXAMPLE 639
5-[4-(2-hydroxyethyl)phenyl]-N-methoxy-1-(4-methoxy-phenyl)-N-methyl-1H-py-
razole-3-carboxamide
[3207] oil
[3208] MS (ESI+): m/z 382 (M+H).
[3209] 1HNMR (200 MHz, CDCl3): 1.44 (1H, t, J=5.8 Hz) 2.83-2.90
(2H, m), 3.51 (3H, s), 3.82 (3H, s), 3.85 (3H, s), 3.84-3.89 (2H,
m), 6.86 (2H, d, J=9.0 Hz) 6.96 (1H, s), 7.13-7.26 (6H, m)
EXAMPLE 640
5-[4-(2-hydroxyethyl)phenyl]-N-methoxy-1-(6-methoxy-3-pyridinyl)-N-methyl--
1H-pyrazole-3-carboxamide
[3210] oil
[3211] Mass (ESI+): m/z 383 (M+H).
[3212] 1HNMR (200 MHz, CDCl3): 2.84-2.91 (2H, m), 3.51 (3H, s),
3.85 (3H, s), 3.81-3.92 (2H, m), 3.95 (3H, s), 6.74 (1H, d, J=8.6
Hz), 6.97 (1H, s), 7.20 (4H, s), 7.55 (1H, dd, J=2.8, 8.6 Hz), 8.13
(1H, d, J=2.8 Hz)
EXAMPLE 641
[3213] To a solution of
tert-butyl{4-[3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxyphenyl)-1H-pyrazol-
-5-yl]benzyl}-carbamate (1.1 g) and Et3N (1.02 g) was added
methanesulfonyl chloride (576 mg). The mixture was stirred at
ambient temperature overnight. The mixture was concentrated in
vacuo. The residue was partitioned between AcOEt and 1M HCl. The
organic layer was separated, washed with saturated aqueous sodium
bicarbonate solution and saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo.
The residue was purified by silica gel column chromatography eluted
with AcOEt/n-hexane=25%. The pure fraction was collected and
concentrated in vacuo to give tert-butyl
{4-[3-isopropenyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}carbamate
(857 mg) as a solid.
[3214] MS (ESI+): m/z 420 (M+H).
[3215] 1HNMR (200 MHz,): 1.46 (9H, s), 2.21(3H, s), 3.81 (3H, s),
4.30 (2H, d, J=5.9 Hz), 4.84 (1H, brs), 5.13 (1H, brs), 5.60 (1H,
brs), 6.60 (1H, s), 6.84 (2H, d, J=8.9 Hz), 7.18-7.26 (6H, m)
[3216] The following compound(s) was(were) obtained in a similar
manner to that of Example 641.
EXAMPLE 642
tert-butyl
{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]ben-
zyl}carbamate
[3217] oil
[3218] MS (ESI+): m/z 421 (M+H).
[3219] 1HNMR (200 MHz, DMSOd6): 1.39 (9H, s), 2.10 (3H, s), 3.86
(3H, s), 4.12 (2H, d, J=6.2 Hz), 5.15 (1H, brs), 5.63 (1H, brs),
6.88 (1H, s), 6.88 (1H, d, J=8.8 Hz), 7.22 (4H, s), 7.40 (1H, t,
J=6.2 Hz), 7.67 (1H, dd, J=2.7, 8.8 Hz), 8.06 (1H, d, J=2.7 Hz)
EXAMPLE 643
[3220] A 0.76 M solution of isopropyl magnesium bromide in THF (8.5
ml) was added dropwise to a solution of tert-butyl
{4-[3-{[methoxy(methyl)amino]carbonyl}-1-(4-methoxy-phenyl)-1H-pyrazol-5--
yl]benzyl}carbamate (1 g) in THF (10 ml) at 10-15.degree. C. The
mixture was stirred at ambient temperature for 4 hours. The
reaction mixture was poured into a mixture of 1M HCl and ice. The
mixture was extracted with AcOEt. The organic layer was washed with
saturated aqueous sodium bicarbonate solution and saturated aqueous
sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo. The residue was purified by silica gel
column chromatography eluted with AcOEt/n-hexane=20%, 25%, then 10%
MeOH/CHCl3. The combined pure fraction was concentrated in vacuo to
give tert-butyl
{4-[3-isobutyryl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}carbamate
(318 mg) as an amorphous powder.
[3221] MS (ESI+): m/z 450 (M+H).
[3222] 1HNMR (200 MHz, CDCl3): 1.25 (6H, d, J=6.8 Hz), 1.46 (9H,
s), 3.72-3.87 (1H, m), 3.83 (3H, s), 4.31 (2H, d, J=5.9 Hz),
4.75-4.93 (1H, m), 6.88 (2H, d, J=9 Hz), 6.98 (1H, s), 7.14-7.27
(6H, m)
[3223] The following compound(s) was (were) obtained in a similar
manner to that of Example 643.
EXAMPLE 644
tert-butyl
{4-[3-isobutyryl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]benz-
yl}carbamate
[3224] oil
[3225] MS (ESI+): m/z 451 (M+H).
[3226] 1HNMR (200 MHz, DMSOd6): 1.16 (6H, d, J=6.8 Hz), 1.38 (9H,
s), 3.68 (1H, m), 3.88 (3H, s), 4.13 (2H, d, J=6.1 Hz), 6.92 (1H,
d, J=8.8 Hz), 7.07 (1H, s), 7.19-7.29 (4H, m), 7.41 (1H, t, J=6.1
Hz), 7.75 (1H, dd, J=2.7, 8.8 Hz), 8.17 (1H, d, J=2.7 Hz)
EXAMPLE 645
[3227] To a solution of
4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]be-
nzonitrile (197 mg) in THF (2 ml) was added lithium aluminum
hydride (30 mg) under ice-bath cooling. The mixture was stirred at
same temperature for 1 hour and then at ambient temperature for 2
hours. The reaction was quenched by adding 5% aqueous solution of
potassium sodium tartaric acid (ca. 0.5 ml). The mixture was
diluted with AcOEt, dried over MgSO4, and filtered through a celite
pad. The filtrate was concentrated in vacuo to give
{4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro-ethoxy)-1H-pyrazol--
5-yl]benzyl}amine (200 mg) as an oil.
[3228] MS ((ESI+): m/z 379 (M+H).
[3229] 1HNMR (200 MHz, DMSOd6): 3.75 (2H, s), 3.85 (3H, s), 4.84
(1H, d, J=9 Hz), 4.93 (1H, d, J=9 Hz), 6.32 (1H, s), 6.87 (1H, d,
J=8.9 Hz), 7.19 (2H, d, J=8.2 Hz), 7.33 (2H, d, J=8.2 Hz), 7.64
(1H, dd, J=2.7, 8.9 Hz), 8.03 (1H, d, J=2.7 Hz)
[3230] The following compound(s) was(were) obtained in a similar
manner to that of Example 645.
EXAMPLE 646
1-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenyl}methanamine
[3231] oil
[3232] MS: (ESI+): m/z 314 (M+H).
[3233] 1HNMR (200 MHz, DMSOd6): 3.69 (2H, s), 3.78 (3H, s), 6.72
(1H, s), 6.96 (2H, d, J=9 Hz), 7.16 (2H, d, J=8.2 Hz), 7.22 (2H, d,
J=9 Hz), 7.3 (2H, d, J=8.2 Hz)
EXAMPLE 647
1-{4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenyl}methanamin-
e
[3234] powder
[3235] MS (ESI+): m/z 315 (M+H).
[3236] 1HNMR (200 MHz, DMSOd6): 3.70 (2H, s), 3.86 (3H, s), 6.78
(1H, s), 6.89 (1H, d, J=8.7 Hz), 7.20 (2H, d, J=8.3 Hz), 7.33 (2H,
d, J=8.3 Hz), 7.69 (1H, dd, J=2.7, 8.7 Hz), 8.10 (1H, d, J=2.7
Hz)
EXAMPLE 648
[3237] A mixture of
5-[4-(benzyloxy)phenyl]-3-amino-1-(4-methoxyphenyl)-1H-pyrazole
(4.0 g), lithium chloride (2.28 g), and copper(II) chloride (2.90
g) in acetonitrile (50 ml) was stirred at ambient temperature for
10 minutes. To this mixture was added isoamyl nitrite (2.52 g), and
the mixture was stirred at ambient temperature for 1.5 hours. To
the reaction mixture was added a mixture of ethyl acetate and
saturated aqueous ammonium chloride solution. The mixture was
stirred at ambient temperature for a while, and partitioned. The
aqueous layer was reextracted with ethyl acetate. The combined
organic layers were washed with saturated aqueous ammonium chloride
solution and saturated aqueous sodium chloride solution, dried over
magnesium sulfate, and concentrated in vacuo. The residue was
purified by silica gel column chromatography eluted with 20%
AcOEt/n-hexane. The pure fractions were collected and concentrated
in vacuo to give
5-[4-(benzyloxy)phenyl]-3-chloro-1-(4-methoxyphenyl)-1H-pyrazole
(2.81 g) as a solid.
[3238] MS ESI+): m/z 391 (M+H)
[3239] 1HNMR (200 MHz, CDCl3): 3.81 (3H, s), 5.05 (2H, s), 6.35
(1H, s), 6.84 (2H, d, J=9 Hz), 6.89 (2H, d, J=8.9 Hz), 7.12 (2H, d,
J=8.9 Hz), 7.19 (2H, d, J=9 Hz), 7.34-7.43 (5H, m)
EXAMPLE 649
[3240] A solution of 4-benzyloxypropiophenone (5 g) in
N,N-dimethylformamide dimethyl acetal (20 ml) was refluxed for 24
hours. The mixture was concentrated in vacuo. The residue was
dissolved in toluene and concentrated in vacuo. This was repeated
one more time. The residue was dissolved in EtOH. To this solution
was added 4-methoxyphenylhydrazine hydrochloride (3.63 g), and the
mixture was refluxed for 3 hours. The reaction mixture was cooled
to ambient temperature and partitioned between AcOEt and 1MHCl. The
organic layer was washed with saturated aqueous sodium bicarbonate
solution and saturated aqueous sodium chloride solution, dried over
magnesium sulfate, and concentrated in vacuo. The residue was
purified by silica gel column chromatography eluted with
AcOEt/n-hexane=30% to give
5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-4-methyl-1H-pyrazole
(5.31 g) as a powder.
[3241] MS (ESI+): m/z 371(M+H)
[3242] 200 MHz 1H NMR (CDCl3, d): 2.10(3H, s), 3.79(3H, s),
5.06(2H, s), 6.80(2H, d, J=8.9 Hz), 6.94(2H, d, J=8.8 Hz), 7.09(2H,
d, J=8.8 Hz), 7.14(2H, d, J=8.9 Hz), 7.31-7.48(5H, m), 7.55(2H,
s)
[3243] The following compound(s) was(were) obtained in a similar
manner to that of Example 649.
EXAMPLE 650
5-{5-[4-(benzyloxy)phenyl]-4-methyl-1H-pyrazol-1-yl}-2-methoxypyridine
[3244] powder
[3245] MS (ESI+): m/z 372 (M+H)
[3246] 200 MHz 1H NMR (CDCl3, d): 2.10(3H, s), 3.91(3H, s),
5.06(2H, s), 6.68(1H, d, J=8.8 Hz), 6.96(2H, d, J=8.7 Hz), 7.09(2H,
d, J=8.7 Hz), 7.36-7.52(6H, m), 7.59(1H, s), 8.02(1H, c, J=2.7
Hz)
EXAMPLE 651
[3247] A solution of t-butyl nitrite (1.14 ml) in CHCl3 (3 ml) was
added dropwise to a solution of
5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-3-amino-1H-pyrazole
(1.5 g) and dimethyldisulfide (1.15 ml) in CHCl3 (10 ml). After all
of t-butyl nitrite solution was added, the temperature of reaction
mixture began to rise and reached to reflux. After the reflux
ceased, the mixture was stirred at ambient temperature for 1 hour.
The mixture was concentrated in vacuo and the residue was purified
by silica gel column chromatography eluted with AcOEt/n-hexane=25%
to give
5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-3-(methylthio)-1H-pyrazole
(635.2 mg) as an oil.
[3248] Mass (ESI+): m/z 403 (M+H).
[3249] 1HNMR (200 MHz, CDCl3): 2.58 (3H, s), 3.81 (3H, s), 5.04
(2H, s), 6.36 (1H, s), 6.81-6.91 (4H, m), 7.13 (2H, d, J=8.7 Hz),
7.20(2H, d, J=9 Hz), 7.34-7.43 (5H, m)
EXAMPLE 652
[3250] A mixture of
3-cyano-1-(4-methoxyphenyl)-5-[4-(aminometyl)phenyl]-1H-pyrazole
(90 mg), trimethylsilylisocyanate (152 mg) and Et3N (0.18 ml) in
CH2Cl2 (5 ml) was stirred at room temperature. After stirring for 5
hours (checked by TLC), water and CHCl3 was added. The organic
layer was separated. Aqueous layer was extracted with EtOAc. The
combined organic layer was washed with water and brine. Dried over
MgSO4, filtered and evaporated under reduced pressure to give 48 mg
(52%) of
N-{4-[3-cyano-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}urea.
[3251] MASS (ESI+): m/z=370.1 (M+Na).
[3252] 1HNMR (200 MHz, CDCl3): 3.83 (H, s), 4.38 (2H, d, J=6 Hz
4.42 (2H, b.s), 4.902-(1H, m), 6.82 (1H, s), 6.87 (2H, d, J=9 Hz),
7.15 (2H, d, J=8.3 Hz), 7.19 (2H, d, J=9 Hz), 7.26 (2H, d, J=8.3
Hz).
EXAMPLE 653
[3253] To a mixture of
(2-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)amine
hydrochloride (150 mg) in CHCl3 (2 ml) and saturated aqueous sodium
bicarbonate solution (1 ml) was added thiophosgene (68.8 mg) under
ice-bath cooling. The mixture was stirred at ambient temperature
for 5 hours. To the mixture was added 28% aqueous ammonium
hydroxide (1 ml) and the mixture was stirred at ambient temperature
overnight. To the mixture were added 28% aqueous ammonium hydroxide
(1 ml) and MeOH (1 ml) and the mixture was stirred at r.t. for 7
hours. The reaction mixture was partitioned between AcOEt and H2O.
The organic layer was washed with saturated aqueous sodium
bicarbonate solution and saturated aqueous sodium chloride
solution, dried over magnesium sulfate, and concentrated in vacuo.
The residue was crystallized from ACOEt-IPE. The obtained powder
was recrystallized from AcOEt-n-hexane to give
N-(2-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)thio-
urea (116 mg) as a powder.
[3254] mp. 141.6-142.3.degree. C.
[3255] MS (ESI+): m/z 399 (M+H).
[3256] 1HNMR (200 MHz, DMSOd6): 3.61-3.89 (2H, m), 3.75 (3H, s),
3.83 (3H, s), 3.98-4.12 (2H, m), 6.04 (1H, s), 6.92 (4H, d, J=8.9
Hz), 7.09 (2H, brs), 7.13 (4H, d, J=8.9 Hz), 7.77 (1H, t, J=5.2
Hz)
EXAMPLE 654
[3257] A solution of methanesulfonyl chloride (328 mg) in CH2Cl2 (2
ml) was added to a solution of
5-[4-(2-hydroxyethyl)-phenyl]-N-methoxy-1-(4-methoxyphenyl)-N-methyl-1H-p-
yrazole-3-carboxamide (840 mg) and Et3N (334 mg) in CH2Cl2 (10 ml)
under ice bath cooling. The mixture was stirred at same temperature
for 1 hour. The mixture was diluted with CHCl3 and washed with 1
MHCl, saturated aqueous sodium bicarbonate solution and saturated
aqueous sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo. The residue was purified by silica gel
column chromatography eluted with AcOEt/n-hexane=80%, 90%. The pure
fractions were collected and concentrated in vacuo to give
2-{4-[3-{[methoxy(methyl)amino]carbonyl}-1-(4-methoxyphenyl)-1H-pyrazol-5-
-yl]phenyl}ethyl methanesulfonate (1.01 g) as an oil.
[3258] Mass (ESI+): m/z 460 (M+H).
[3259] 1HNMR (200 MHz, CDCl3): 2.89 (3H, s), 3.05 (2H, t, J=6.8
Hz), 3.51 (3H, s), 3.83 (3H, s), 3.85 (3H, s), 4.41 (2H, t, J=6.8
Hz), 6.86 (2H, d, J=9.0 Hz), 6.97 (1H, s), 7.18-7.26 (6H, m)
[3260] The following compound(s) was (were) obtained in a similar
manner to that of Example 654.
EXAMPLE 655
2-{4-[3-{[methoxy(methyl)amino]carbonyl}-1-(6-methoxy-3-pyridinyl)-1H-pyra-
zol-5-yl]phenyl}ethyl methanesulfonate
[3261] oil
[3262] Mass (ESI+): m/z 461 (M+H).
[3263] 1HNMR (200 MHz, CDCl3): 2.91 (3H, s), 3.06 (2H, t, J=6.8
Hz), 3.50 (3H, s), 3.85 (3H, s), 3.94 (3H, s), 4.43 (2H, t, J=6.8
Hz), 6.74 (1H, d, J=8.8 Hz), 6.99 (1H, s), 7.32 (4H, s), 7.55 (1H,
dd, J=2.7, 8.8 Hz), 8.09 (1H, d, J=2.7 Hz
EXAMPLE 656
[3264] A mixture of
2-{4-[3-{[methoxy(methyl)amino]-carbonyl}-1-(4-methoxyphenyl)-1H-pyrazol--
5-yl]phenyl}ethyl methanesulfonate (1.02 g), 15-crown-5 (489 mg),
sodium azide (722 mg) in hexamethylphosphoric triamide (6 ml) was
stirred at 55.degree. C. for 1 hour. The mixture was poured into
ice water, and the mixture was extracted with AcOEt. The organic
layer was washed with saturated aqueous sodium chloride solution,
dried over magnesium sulfate, and concentrated in vacuo. The
residue was dissolved in MeOH (6 ml). To this solution was added a
solution of 6M HCl (0.37 ml) in MeOH (2 ml) and 10% palladium on
carbon (50% wet) (200 mg). The mixture was hydrogenated under H2 1
atm at ambient temperature for 2 hours. The catalyst was removed by
filtration. The filtrate was concentrated in vacuo to give
5-[4-(2-aminoethyl)phenyl]-N-methoxy-1-(4-methoxy-phenyl)-N-methyl-1H-pyr-
azole-3-carboxamide hydrochloride (0.93 g) as an oil.
[3265] Mass (ESI+): m/z 381 (M+H)
[3266] 1HNMR (200 MHz, DMSOd6): 2.79-3.16 (4H, m), 3.38 (3H, s),
3.77 (3H, s), 3.79 (3H, s), 6.95 (1H, s), 6.99 (2H, d, J=9.0 Hz),
7.15-7.36 (6H, m), 8.00 (2H, brs)
[3267] The following compound(s) was (were) obtained in a similar
manner to that of Example 656.
EXAMPLE 657
5-[4-(2-aminoethyl)phenyl]-N-methoxy-1-(6-methoxy-3-pyridinyl)-N-methyl-1H-
-pyrazole-3-carboxamide hydrochloride
[3268] oil
[3269] Mass (ESI+): m/z 382 (M+H).
[3270] 1HNMR (200 MHz, DMSOd6): 2.80-3.15 (4H, m), 3.38 (3H, s),
3.77 (3H, s), 3.88 (3H, s), 6.92 (1H, d, J=8.8 Hz), 6.98 (1H, s),
7.22-7.36 (4H, m), 7.72 (1H, dd, J=2.7, 8.8 Hz), 8.02 (2H, brs),
8.17 (1H, d, J=2.7 Hz)
EXAMPLE 658
[3271] To a 0.76M solution of isopropylmagnesium bromide in THF
(2.0 ml) was added a solution of
5-(4-{2-[(aminocarbonyl)-amino]ethyl}phenyl)-N-methoxy-1-(4-methoxyphenyl-
)-N-methyl-1H-pyrazole-3-carboxamide (130 mg) in THF (2 ml)
dropwise at 4.degree. C. The mixture was stirred at ambient
temperature overnight. Additional 0.76M solution of
isopropylmagnesium bromide in THF (2.0 ml) was added and the
mixture was stirred at 50.degree. C. for 5 hours. The reaction
mixture was cooled to ambient temperature and was quenched by
adding saturated aqueous ammonium chloride solution. The mixture
was extracted with AcOEt. The organic layer was washed with 1M HCl,
saturated aqueous sodium bicarbonate solution, saturated aqueous
sodium chloride solution, dried over magnesium sulfate, and
concentrated in vacuo. The residue was purified by preparative thin
layer silica gel chromatography developed by MeOH/CHC3 10%. The
separated silica gel was extracted with 10% MeOH/CHCl3 and the
solvent was evaporated in vacuo to give
N-(2-{4-[3-isobutyryl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenyl}ethyl)ur-
ea (30 mg) as amorphous powder.
[3272] MS (ESI+): m/z 407 (M+H).
[3273] 1HNMR (200 MHz, CDCl3): 1.25 (6H, d, J=6.8 Hz), 2.77-2.85
(2H, m), 3.37-3.48 (2H, m), 3.72-3.87 (1H, m), 3.83 (3H, s), 4.32
(2H, s), 4.57 (1H, t, J=4.9 Hz), 6.89 (2H, d, J=8.9 Hz), 6.96 (1H,
s), 7.14 (4H, s), 7.24 (2H, d, J=8.9 Hz)
[3274] The following compound(s) was(were) obtained in a similar
manner to that of Example 658.
EXAMPLE 659
N-(2-{4-[3-isobutyryl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenyl}ethyl)met-
hanesulfonamide
[3275] oil
[3276] MS (ESI+): m/z 442
[3277] 1HNMR (200 MHz, CDCl3): 1.26 (6H, d, J=6.9 Hz), 2.84-2.91
(2H, m), 2.87 (3H, s), 3.35-3.46 (2H, m), 3.73-3.87 (1H, m), 3.84
(3H, s), 4.21 (1H, t, J=6.1 Hz), 6.89 (2H, d, J=9.0 Hz), 6.99 (1H,
s), 7.13-7.29 (6H, m)
EXAMPLE 660
N-(2-{4-[3-isobutyryl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenyl}eth-
yl)urea
[3278] oil
[3279] MS (ESI+): m/z 408 (M+H).
[3280] 1HNMR (200 MHz, CDCl3): 1.26 (6H, d, J=6.9 Hz), 2.79-2.87
(2H, m), 3.39-3.50 (2H, m), 3.77-(1H, m), 3.95 (3H, s), 4.35 (2H,
s), 4.57 (1H, t, J=5.4 Hz), 6.78 (1H, d, J=8.9 Hz), 6.98 (1H, s),
7.17 (4H, s), 7.60 (1H, dd, J=2.7, 8.9 Hz), 8.07 (1H, d, J=2.7
Hz
EXAMPLE 661
N-(2-{4-[3-isobutyryl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenyl}eth-
yl)methanesulfonamide
[3281] oil
[3282] MS (ESI+): m/z 443 (M+H).
[3283] 1HNMR (200 MHz, CDCl3): 1.26 (6H, d, J=6.8 Hz), 2.85-2.93
(2H, m), 2.88 (3H, s), 3.36-3.47 (2H, m), 3.77 (3H, m), 3.95 (3H,
s), 4.24 (1H, t, J=6.2 Hz), 6.78 (1H, d, J=8.8 Hz), 7.00 (1H, s),
7.19 (4H, s), 7.57 (1H, dd, J=2.7, 8.8 Hz), 8.11 (1H, d, J=2.7
Hz)
EXAMPLE 662
[3284] To a solution of cyclopropylmagnesium bromide, which was
prepared from cyclopropyl bromide (257 mg) and magnesium (57 mg) in
THF (1 ml) as usual method, was added a solution of
5-(4-{2-[(aminocarbonyl)-amino]ethyl}phenyl)-N-methoxy-1-(4-methoxyphenyl-
)-N-methyl-1H-pyrazole-3-carboxamide (90 mg) in THF (3 ml) dropwise
at ambient temperature. The mixture was stirred at 50.degree. C.
for 5 hours. The reaction mixture was cooled to ambient temperature
and was quenched by adding saturated aqueous ammonium chloride
solution. The mixture was extracted with AcOEt. The organic layer
was washed with 1M HCl, saturated aqueous sodium bicarbonate
solution, saturated aqueous sodium chloride solution, dried over
magnesium sulfate, and concentrated in vacuo. The residue was
purified by preparative thin layer silica gel chromatography
developed by MeOH/CHC3 10%. The separated silica gel was extracted
with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to give
N-(2-{4-[3-(cyclopropylcarbonyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl-
]phenyl}ethyl)urea (23 mg) as a powder.
[3285] Mass (ESI+): m/z 405 (M+H).
[3286] 1HNMR (200 MHz, CDCl3): 0.99-1.09 (2H, m), 1.22-1.30 (2H,
m), 2.77-2.84 (2H, m), 3.13 (1H, m), 3.37-3.48 (2H, m), 3.84 (3H,
s), 4.33 (2H, s), 4.59 (1H, t, J=5.4 Hz), 6.89 (2H, d, J=8.9 Hz),
6.96 (1H, s), 7.14 (4H, s), 7.26 (2H, d, J=8.9 Hz)
[3287] The following compound(s) was(were) obtained in a similar
manner to that of Example 662.
EXAMPLE 663
N-(2-{4-[3-(cyclopropylcarbonyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]pheny-
l}ethyl)methanesulfonamide
[3288] oil
[3289] MS (ESI+): m/z 440 (M+H
[3290] 1HNMR (200 MHz, CDCl3): 0.99-1.09 (2H, m), 1.22-1.31 (2H,
m), 2.80-2.91 (2H, m), 2.87 (3H, s), 3.14 (1H, m), 3.35-3.46 (2H,
m), 3.84 (1H, s), 4.22 (1H, t, J=5.7 Hz), 6.90 (2H, d, J=9.0 Hz),
6.99 (1H, s), 7.12 (4H, s), 7.27 (2H, d, J=9.0 Hz)
EXAMPLE 664
N-(2-{4-[3-(cyclopropylcarbonyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl-
]phenyl}ethyl)methane-sulfonamide
[3291] oil
[3292] Mass (ESI+): m/z 441 (M+H).
[3293] 1HNMR (200 MHz, CDCl3): 1.03-1.11 (2H, m), 1.24-1.32 (2H,
m), 2.85-2.93 (2H, m), 2.88 (3H, s), 3.11 (1H, m), 3.36-3.47 (2H,
m), 3.96 (3H, s), 4.22 (1H, t, J=6.0 Hz), 6.78 (1H, d, J=8.9 Hz),
7.00(1H, s), 7.20 (4H, s), 7.60 (1H, dd, J=2.7, 8.9 Hz), 8.13 (1H,
d, J=2.7 Hz)
* * * * *