U.S. patent application number 10/629655 was filed with the patent office on 2004-03-18 for radicicol derivatives.
This patent application is currently assigned to KYOWA HAKKO KOGYO CO., LTD. Invention is credited to Akinaga, Shiro, Akiyama, Tadakazu, Amishiro, Nobuyoshi, Ino, Yoji, Miyata, Mayumi, Murakata, Chikara, Ogawa, Harumi, Shiotsu, Yukimasa, Soga, Shiro.
Application Number | 20040053990 10/629655 |
Document ID | / |
Family ID | 26337204 |
Filed Date | 2004-03-18 |
United States Patent
Application |
20040053990 |
Kind Code |
A1 |
Ino, Yoji ; et al. |
March 18, 2004 |
Radicicol derivatives
Abstract
Radicicol derivatives represented by the following formula (I)
having tyrosine kinase inhibition activity or pharmacologically
acceptable salts thereof: 1 wherein R.sup.1 and R.sup.2 are the
same or different, and each represents hydrogen, alkanoyl,
alkenoyl, tert-butyldiphenylsilyl or tert-butyldimethylsilyl;
R.sup.3 represents Y--R.sup.5 {wherein Y represents substituted or
unsubstituted alkylene; and R.sup.5 represents CONR.sup.6R.sup.7
(wherein R.sup.6 represents hydrogen, hydroxyl, substituted or
unsubstituted lower alkyl, substituted or unsubstituted higher
alkyl, and the like; R.sup.7 represents hydroxyl, substituted lower
alkyl, and the like), CO.sub.2R.sup.12 (wherein R.sup.12 represents
substituted lower alkyl, substituted or unsubstituted higher alkyl,
and the like), and the like} and the like; X represents halogen or
is combined together with R.sup.4 to represent a single bond; and
R.sup.4 is combined together with X to represent a single bond, or
represents hydrogen, alkanoyl, and the like.
Inventors: |
Ino, Yoji; (Sunto-gun,
JP) ; Amishiro, Nobuyoshi; (Sunto-gun, JP) ;
Miyata, Mayumi; (Sunto-gun, JP) ; Murakata,
Chikara; (Sunto-gun, JP) ; Ogawa, Harumi;
(Machida-shi, JP) ; Akiyama, Tadakazu; (Sunto-gun,
JP) ; Akinaga, Shiro; (Sunto-gun, JP) ; Soga,
Shiro; (Sunto-gun, JP) ; Shiotsu, Yukimasa;
(Sunto-gun, JP) |
Correspondence
Address: |
FITZPATRICK CELLA HARPER & SCINTO
30 ROCKEFELLER PLAZA
NEW YORK
NY
10112
US
|
Assignee: |
KYOWA HAKKO KOGYO CO., LTD
6-1, Ohtemachi 1-chome
Chiyoda-ku
JP
|
Family ID: |
26337204 |
Appl. No.: |
10/629655 |
Filed: |
July 30, 2003 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10629655 |
Jul 30, 2003 |
|
|
|
09791602 |
Feb 26, 2001 |
|
|
|
6635662 |
|
|
|
|
09791602 |
Feb 26, 2001 |
|
|
|
09513472 |
Feb 25, 2000 |
|
|
|
6239168 |
|
|
|
|
09513472 |
Feb 25, 2000 |
|
|
|
09091752 |
Jun 24, 1998 |
|
|
|
6316491 |
|
|
|
|
09091752 |
Jun 24, 1998 |
|
|
|
PCT/JP97/03874 |
Oct 24, 1997 |
|
|
|
Current U.S.
Class: |
514/450 ;
514/337; 514/422; 514/63; 546/281.7; 548/525; 549/269 |
Current CPC
Class: |
C07D 313/00 20130101;
C07D 493/04 20130101 |
Class at
Publication: |
514/450 ;
514/063; 514/337; 514/422; 549/269; 546/281.7; 548/525 |
International
Class: |
A61K 031/695; A61K
031/365; A61K 031/4433; A61K 031/4025; C07D 313/20; C07D 45/02 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 25, 1996 |
JP |
P.HEI.8-284439 |
Jan 13, 1997 |
JP |
P.HEI.9-003578 |
Claims
What is claimed is:
1. A radicicol derivative represented by the following formula (I)
or a pharmacologically acceptable salt thereof: 104wherein R.sup.1
and R.sup.2 are the same or different, and each represents
hydrogen, alkanoyl, alkenoyl, tert-butyldiphenylsilyl or
tert-butyldimethylsilyl; R.sup.3 represents: Y--R.sup.5 {wherein Y
represents substituted or unsubstituted alkylene; and R.sup.5
represents CONR.sup.6R.sup.7 (wherein R.sup.6 represents hydrogen,
hydroxyl, substituted or unsubstituted lower alkyl, substituted or
unsubstituted higher alkyl, substituted or unsubstituted lower
cycloalkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted lower alkoxy, substituted or unsubstituted aryl, a
substituted or unsubstituted heterocyclic group, or NR.sup.8R.sup.9
(wherein R.sup.8 and R.sup.9 are the same or different, and each
represents hydrogen, substituted or unsubstituted lower alkyl,
substituted or unsubstituted higher alkyl, substituted or
unsubstituted lower cycloalkyl, substituted or unsubstituted aryl,
a substituted or unsubstituted heterocyclic group, substituted or
unsubstituted alkanoyl, substituted or unsubstituted aroyl,
carbonyl bound to a substituted or unsubstituted heterocyclic ring,
or substituted or unsubstituted arylcarbamoyl), or is combined
together with R.sup.7 and adjoining N to represent a substituted or
unsubstituted heterocyclic group; and R.sup.7 is combined together
with R.sup.6 and adjoining N to represent a substituted or
unsubstituted heterocyclic group, or represents hydroxyl,
substituted lower alkyl, substituted or unsubstituted higher alkyl,
substituted or unsubstituted lower cycloalkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted lower alkoxy,
substituted or unsubstituted aryl, a substituted or unsubstituted
heterocyclic group, or NR.sup.10R.sup.11 (wherein R.sup.10 and
R.sup.11 have the same meaning as R.sup.8 and R.sup.9 defined
above, respectively)), CO.sub.2R.sup.12 (wherein R.sup.12
represents substituted lower alkyl, substituted or unsubstituted
higher alkyl, substituted or unsubstituted lower cycloalkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
aryl, or a substituted or unsubstituted heterocyclic group),
substituted or unsubstituted aryl, substituted or unsubstituted
pyridyl, substituted or unsubstituted pyridonyl, substituted or
unsubstituted pyrrolidonyl, substituted or unsubstituted uracilyl,
substituted or unsubstituted piperidyl, substituted or
unsubstituted piperidino, substituted or unsubstituted
pyrrolidinyl, substituted or unsubstituted morpholino, substituted
or unsubstituted morpholinyl, substituted or unsubstituted
piperazinyl, substituted or unsubstituted thiomorpholino, or
substituted or unsubstituted dioxolanyl}, COR.sup.13 (wherein
R.sup.13 represents hydrogen, substituted or unsubstituted lower
alkyl, substituted or unsubstituted higher alkyl, substituted or
unsubstituted aryl, substituted or unsubstituted lower alkoxy, or
NR.sup.14R.sup.15 (wherein R.sup.14 and R.sup.15 are the same or
different, and each represents hydrogen, substituted or
unsubstituted lower alkyl, substituted or unsubstituted higher
alkyl, substituted or unsubstituted aryl, or substituted or
unsubstituted pyridyl, or R.sup.14 and R.sup.15 are combined
together with adjoining N to represent a substituted or
unsubstituted heterocyclic group)), or substituted or unsubstituted
aryl; X represents halogen, or is combined together with R.sup.4 to
represent a single bond; and R.sup.4 is combined together with X to
represent a single bond, or represents hydrogen, alkanoyl,
alkenoyl, or --SO-Z {wherein Z represents formula (A): 105wherein
R.sup.1A and R.sup.2A have the same meaning as R.sup.1 and R.sup.2
defined above, respectively; X.sup.A represents halogen; and W
represents O or N--O--R.sup.3A (wherein R.sup.3A has the same
meaning as R.sup.3 defined above)}.
2. The compound according to claim 1 or a pharmacologically
acceptable salt thereof, wherein X is halogen.
3. The compound according to claim 1 or a pharmacologically
acceptable salt thereof, wherein X is combined together with
R.sup.4 to represent a single bond.
4. The compound according to claim 3 or a pharmacologically
acceptable salt thereof, wherein R.sup.1 and R.sup.2 each is
hydrogen.
5. The compound according to claim 4 or a pharmacologically
acceptable salt thereof, wherein R.sup.3 is Y--R.sup.5.
6. The compound according to claim 5 or a pharmacologically
acceptable salt thereof, wherein R.sup.5 is substituted or
unsubstituted aryl, substituted or unsubstituted pyridyl,
substituted or unsubstituted pyridonyl, substituted or
unsubstituted pyrrolidonyl, substituted or unsubstituted uracilyl,
substituted or unsubstituted piperidyl, substituted or
unsubstituted piperidino, substituted or unsubstituted
pyrrolidinyl, substituted or unsubstituted morpholino, substituted
or unsubstituted morpholinyl, substituted or unsubstituted
piperazinyl., substituted or unsubstituted thiomorpholino, or
substituted or unsubstituted dioxolanyl.
7. The compound according to claim 5 or a pharmacologically
acceptable salt thereof, wherein R.sup.5 is pyrrolidonyl.
8. A therapeutic agent of diseases caused by tyrosine kinase, which
comprises at least one of the compounds according to any one of
claims 1 to 6 or a pharmacologically acceptable salt thereof.
Description
TECHNICAL FIELD
[0001] The present invention relates to novel radicicol derivatives
or pharmacologically acceptable salts thereof which show tyrosine
kinase inhibition activity and have antitumor or immunosuppression
effects.
BACKGROUND ART
[0002] It is known that microbial metabolite radicicol represented
by the following formula (B) has an antifungal effect and an
anticancer effect [Nature, 171, 344 (1953); Neoplasma, 24, 21
(1977)], an immunosuppression effect (Japanese Published Unexamined
Patent Application No. 298764/94), or morphology normalization
effect of ras or mos canceration cells [Oncogene, 11, 161 (1995)].
2
[0003] Furthermore, it is known that radicicol derivatives in which
the phenolic hydroxyl group is modified with various acyl groups
have an antitumor effect (Japanese Published Unexamined Patent
Application No. 226991/92). In addition, it is disclosed that
radicicol derivatives in which the phenolic hydroxyl group is
modified with an acyl group or an alkyl group show an angiogenesis
inhibition effect (Japanese Published Unexamined Patent Application
No. 279279/94) or an interleukin 1 production inhibition effect
(Japanese Published Unexamined Patent Application No. 40893/96).
Recently, oxime derivatives of dienone of a radicicol derivative
showing antitumor action and immunosuppression action have been
published (WO 96/33989: published on Oct. 31, 1996), and antitumor
radicicol derivatives represented by the following formula (B')
have also been published (Japanese Published Unexamined Patent
Application 202781/97: published on Aug. 5, 1997). 3
[0004] (In the formula, R.sup.1p and R.sup.2p represent a hydrogen
atom or an acyl group; and X.sup.o represents a halogen atom, a
hydroxyl group or a lower alkoxy group.)
[0005] Additionally, it is known that ansamycins antibiotics,
geldanamycin, represented by formula (C) [The Journal of
Antibiotics, 23, 442 (1970)] has tyrosine kinase inhibition
activity and antitumor effects [for example, Cancer Research, 52,
1721 (1992) and Cancer Research, 54, 2724 (1994)]. It is shown that
these effects are expressed by the inhibition of the activation of
a tyrosine kinase, such as Src, ErbB-2, Lck or the like, and a
serine/threonine kinase Raf-1, through the formation of a complex
of geldanamycin with a molecular chaperone Hsp (heat shock/stress
protein) 90 by binding to Hsp90 [for example, Proceedings of the
National Academy of Sciences of the U.S.A, 91, 8324 (1994) and The
Journal of Biological Chemistry, 270, 24585 (1995)]. Consequently,
drugs capable of acting upon Hsp90 are also included in tyrosine
kinase inhibitors and useful not only as antitumor agents but also
for the prevention and treatment of various diseases such as
osteoporosis, immune diseases, and the like. 4
[0006] Tyrosine kinase is an enzyme which uses ATP as a phosphate
donor and catalyzes transfer of its .gamma.-phosphate group to the
hydroxyl group of a specified tyrosine residue of a substrate
protein, thereby taking an important role in the control mechanism
of intracellular signal transduction. Various tyrosine kinase
families are known. Tyrosine kinase activities, such as Src in
colon cancer, ErbB-2 in breast cancer and gastric cancer, Abl in
leukemia, and the like, increase. Disordered increase in the
tyrosine kinase activity causes abnormal differentiation and
proliferation of cells. Consequently, specific inhibitors of
tyrosine kinase are useful in preventing and treating various
diseases, including as antitumor agents.
[0007] Lck is a tyrosine kinase which is activated when T
lymphocytes are activated by antigen stimulation, and an inhibitor
of this enzyme is useful as an immunosuppressant. Also, it is known
that Src relates to bone resorption in osteoclast, and an inhibitor
of this tyrosine kinase is useful as a bone resorption inhibitor
for the treatment of osteoporosis. Additionally, inhibitors of
receptor type tyrosine kinases of various growth factors, such as
EGF-R (epidermal growth factor receptor), FGF-R (fibroblast growth
factor receptor), PDGF-R (platelet-derived growth factor receptor),
and the like, are useful as a solid cancer growth inhibitor, an
angiogenesis inhibitor, a vascular smooth muscle growth inhibitor,
and the like.
DISCLOSURE OF THE INVENTION
[0008] An object of the present invention is to provide novel
radicicol derivatives or pharmacologically acceptable salts thereof
which show tyrosine kinase inhibition activity and have antitumor
or immunosuppression effects.
[0009] The present invention can provide radicicol derivatives
represented by the following formula (I) or pharmacologically
acceptable salts thereof: 5
[0010] wherein R.sup.1 and R.sup.2 are the same or different, and
each represents hydrogen, alkanoyl, alkenoyl,
tert-butyldiphenylsilyl or tert-butyldimethylsilyl;
[0011] R.sup.3 represents:
[0012] Y--R.sup.5 {wherein Y represents substituted or
unsubstituted alkylene; and R.sup.5 represents CONR.sup.6R.sup.7
(wherein R.sup.6 represents hydrogen, hydroxyl, substituted or
unsubstituted lower alkyl, substituted or unsubstituted higher
alkyl, substituted or unsubstituted lower cycloalkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted lower
alkoxy, substituted or unsubstituted aryl, a substituted or
unsubstituted heterocyclic group, or NR.sup.8R.sup.9 (wherein
R.sup.8 and R.sup.9 are the same or different, and each represents
hydrogen, substituted or unsubstituted lower alkyl, substituted or
unsubstituted higher alkyl, substituted or unsubstituted lower
cycloalkyl, substituted or unsubstituted aryl, a substituted or
unsubstituted heterocyclic group, substituted or unsubstituted
alkanoyl, substituted or unsubstituted aroyl, carbonyl bound to a
substituted or unsubstituted heterocyclic ring, or substituted or
unsubstituted arylcarbamoyl), or is combined together with R.sup.7
and adjoining N to represent a substituted or unsubstituted
heterocyclic group; and R.sup.7 is combined together with R.sup.6
and adjoining N to represent a substituted or unsubstituted
heterocyclic group, or represents hydroxyl, substituted lower
alkyl, substituted or unsubstituted higher alkyl, substituted or
unsubstituted lower cycloalkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted lower alkoxy, substituted or
unsubstituted aryl, a substituted or unsubstituted heterocyclic
group, or NR.sup.10R.sup.11 (wherein R.sup.10 and R.sup.11 have the
same meaning as R.sup.8 and R.sup.9 defined above, respectively)),
CO.sub.2R.sup.12R (wherein R.sup.12 represents substituted lower
alkyl, substituted or unsubstituted higher alkyl, substituted or
unsubstituted lower cycloalkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted aryl, or a substituted or
unsubstituted heterocyclic group), substituted or unsubstituted
aryl, substituted or unsubstituted pyridyl, substituted or
unsubstituted pyridonyl, substituted or unsubstituted pyrrolidonyl,
substituted or unsubstituted uracilyl, substituted or unsubstituted
piperidyl, substituted or unsubstituted piperidino, substituted or
unsubstituted pyrrolidinyl, substituted or unsubstituted
morpholino, substituted or unsubstituted morpholinyl, substituted
or unsubstituted piperazinyl, substituted or unsubstituted
thiomorpholino, or substituted or unsubstituted dioxolanyl},
[0013] COR.sup.13 (wherein R.sup.13 represents hydrogen,
substituted or unsubstituted lower alkyl, substituted or
unsubstituted higher alkyl, substituted or unsubstituted aryl,
substituted or unsubstituted lower alkoxy, or NR.sup.14R.sup.15
(wherein R.sup.14 and R.sup.15 are the same or different, and each
represents hydrogen, substituted or unsubstituted lower alkyl,
substituted or unsubstituted higher alkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted pyridyl, or
R.sup.14 and R.sup.15 are combined together with adjoining N to
represent a substituted or unsubstituted heterocyclic group)),
or
[0014] substituted or unsubstituted aryl;
[0015] X represents halogen, or is combined together with R.sup.4
to represent a single bond; and
[0016] R.sup.4 is combined together with X to represent a single
bond, or represents hydrogen, alkanoyl, alkenoyl, or --SO-Z
{wherein Z represents formula (A): 6
[0017] wherein R.sup.1A and R.sup.2A have the same meaning as
R.sup.1 and R.sup.2 defined above, respectively; X.sup.A represents
halogen; and W represents O or N--O--R.sup.3A (wherein R.sup.3A has
the same meaning as R.sup.3 defined above)}.
[0018] Hereinafter, the compound represented by formula (I) will be
called compound (I). Compounds of other formula numbers with also
be called in the same manner.
[0019] (1) Explanation of Each Group
[0020] In the definition of each group of compound (I), the term
"lower" means 1 to 8 carbon atoms, and the term "higher" means 9 to
30 carbon atoms, unless otherwise indicated.
[0021] Examples of the alkanoyl include straight or branched groups
having 1 to 30 carbon atoms, such as formyl, acetyl, propanoyl,
isopropanoyl, butanoyl, caproyl, lauroyl, myristoyl, palmitoyl,
stearoyl, and the like. Examples of the alkenoyl include straight
or branched groups having 3 to 30 carbon atoms, such as acryloyl,
methacryloyl, crotonoyl, isocrotonoyl, palmitoleoyl, linoleoyl,
linolenoyl, and the like. Examples of the alkyl moiety of the lower
alkyl and the lower alkoxy include straight or branched groups,
such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl,
octyl, isooctyl, and the like, and one of the carbon atoms thereof
may be substituted with a silicon atom. Examples of the higher
alkyl include straight or branched groups, such as decanyl,
dodecyl, hexadecyl, and the like. Examples of the alkenyl include
straight or branched groups having 2 to 30 carbon atoms, such as
vinyl, allyl, 1-propenyl, 2-butenyl, 1-pentenyl, 2-hexenyl,
1,3-pentadienyl, 1,3-hexadienyl, dodecenyl, hexadecenyl, and the
like. Examples of the lower cycloalkyl include groups having 3 to 8
carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cyclooctyl, and the like. Examples of the aryl include
phenyl, naphthyl, and the like, and the aryl moiety of aroyl and
arylcarbamoyl has the same meaning. Examples of the heterocyclic
group include alicyclic heterocyclic groups, aromatic heterocyclic
groups, and the like, such as pyridonyl, pyrrolidonyl, uracilyl,
dioxolanyl, pyrrolyl, tetrazolyl, pyrrolidinyl, thienyl,
morpholino, thiomorpholino, piperazinyl, pyrazolidinyl, piperidino,
pyridyl, homopiperazinyl, pyrazolyl, pyrazinyl, indolyl,
isoindolyl, furyl, piperidyl, quinolyl, phthalazinyl,
imidazolidinyl, imidazolinyl, pyrimidinyl, and the like. The
heterocyclic group moiety in the carbonyl bound to a heterocyclic
ring has the same meaning as defined above, and examples of the
entire group containing carbonyl include furoyl, thenoyl,
nicotinoyl, isonicotinoyl, and the like. Examples of the nitrogen
containing heterocyclic group formed by R.sup.6 and R.sup.7 with
the adjoining N and the nitrogen containing heterocyclic group
formed by R.sup.14 and R.sup.15 with the adjoining N (said
heterocyclic group may further contain O, S or other N) include
pyrrolidyl, morpholino, thiomorpholino, piperazinyl, pyrazolidinyl,
pyrazolinyl, piperidino, homopiperazinyl, indolinyl, isoindolinyl,
perhydroazepinyl, perhydroazocinyl, indolyl, isoindolyl, and the
like. Examples of the alkylene include those groups in which one
hydrogen atom is removed from the group of alkyl moiety of the
above lower alkyl or higher alkyl. Examples of the halogen include
fluorine, chlorine, bromine and iodine atoms.
[0022] (2) Explanation of Substituent in Each Group
[0023] Examples of the substituent in the substituted lower alkyl,
the substituted higher alkyl, the substituted alkenyl, the
substituted lower alkoxy and the substituted alkanoyl include 1 to
3 substituents, which are the same or different, such as hydroxyl,
lower cycloalkyl, lower cycloalkenyl, lower alkoxy, lower
alkanoyloxy, azido, amino, mono- or di-lower alkylamino, mono- or
di-lower alkanoylamino, lower alkoxycarbonylamino, lower
alkenyloxycarbonylamino, halogen, lower alkanoyl, substituted or
unsubstituted aryl, a substituted or unsubstituted heterocyclic
group, cyclic imido (a group formed by removing hydrogen bound to
an imido N atom), CONR.sup.16R.sup.17 (wherein R.sup.16 and
R.sup.17 are the same or different, and each represents hydrogen,
hydroxyl, lower alkyl, lower cycloalkyl, higher alkyl, alkenyl,
lower alkoxy, aryl, a heterocyclic group, or NR.sup.18R.sup.19
(wherein R.sup.18 and R.sup.19 are the same or different, and each
represents hydrogen, lower alkyl, lower cycloalkyl, aryl, a
heterocyclic group, lower alkanoyl, aroyl, carbonyl bound to a
heterocyclic ring, or arylcarbamoyl)), CO.sub.2R.sup.20 (wherein
R.sup.20 represents hydrogen, lower alkyl, higher alkyl, lower
cycloalkyl, alkenyl, substituted or unsubstituted aryl, or a
substituted or unsubstituted heterocyclic group), or
--(OCH.sub.2CH.sub.2).sub.nOCH.sub.3 (wherein n is an integer of 1
to 10).
[0024] Examples of the substituent in the substituted alkylene
include 1 to 3 substituents, which are the same or different, such
as hydroxyl, lower alkoxy, lower alkanoyloxy, azido, amino, mono-
or di-lower alkylamino, mono- or di-lower alkanoylamino, lower
alkoxycarbonylamino, lower alkenyloxycarbonylamino, halogen, lower
alkanoyl, substituted or unsubstituted aryl, substituted or
unsubstituted pyridyl, substituted or unsubstituted pyridonyl,
substituted or unsubstituted pyrrolidonyl, substituted or
unsubstituted uracilyl, substituted or unsubstituted piperidyl,
substituted or unsubstituted piperidino, substituted or
unsubstituted pyrrolidinyl, substituted or unsubstituted
morpholino, substituted or unsubstituted morpholinyl, substituted
or unsubstituted piperazinyl, substituted or unsubstituted
thiomorpholino, substituted or unsubstituted dioxolanyl, cyclic
imido (a group formed by removing hydrogen bound to an imido N
atom), CONR.sup.16R.sup.17 (wherein R.sup.16 and R.sup.17 have the
same meaning as defined above), or CO.sub.2R.sup.20 (wherein
R.sup.20 has the same meaning as defined above).
[0025] Examples of the substituent in the substituted lower
cycloalkyl, the substituted aryl, the substituted heterocyclic
group, the substituted aroyl, the carbonyl bound to a substituted
heterocyclic ring, the substituted arylcarbamoyl, the substituted
pyridyl, the substituted pyridonyl, the substituted pyrrolidonyl,
the substituted uracilyl, the substituted piperidyl, the
substituted piperidino, the substituted pyrrolidinyl, the
substituted morpholino, the substituted morpholinyl, the
substituted piperazino, the substituted piperazinyl, the
substituted thiomorpholino, the substituted dioxolanyl and the
substituted nitrogen containing heterocyclic group formed with the
adjoining N include 1 to 3 substituents, which are the same or
different, such as hydroxyl, lower alkyl, lower alkyl substituted
with a heterocyclic ring (said heterocyclic ring may be substituted
with lower alkyl), higher alkyl, alkenyl, lower cycloalkyl, lower
cycloalkenyl, lower alkoxy, lower alkoxy-lower alkoxy, lower
alkanoyloxy, azido, amino, mono- or di-lower alkylamino, mono- or
di-lower alkanoylamino, lower alkoxycarbonylamino, lower
alkenyloxycarbonylamino, halogen, lower alkanoyl, aryl, a
heterocyclic group, cyclic imido (a group formed by removing
hydrogen bound to an imido N atom), CONR.sup.16R.sup.17 (wherein
R.sup.16 and R.sup.17 have the same meaning as defined above),
CO.sub.2R.sup.20 (wherein R.sup.20 has the same meaning as defined
above), or SO.sub.2NR.sup.21R.sup.22 (wherein R.sup.21 and R.sup.22
are the same or different, and each represents hydrogen or lower
alkyl). The lower alkyl, the higher alkyl, the alkenyl, the lower
cycloalkyl, the lower alkoxy, the halogen, the aryl, the aroyl, the
arylcarbamoyl, the heterocyclic group, and the carbonyl bound to a
heterocyclic ring used herein have the same meaning as defined
above. The lower alkyl moieties of the mono- or di-lower
alkylamino, the lower alkoxycarbonyl, the lower
alkoxycarbonylamino, and the lower alkoxy-lower alkoxy have the
same meaning as defined above. The lower alkenyl moiety of the
lower alkenyloxycarbonylamino means the above alkenyl group having
2 to 8 carbon atoms, such as vinyl, allyl, 1-propenyl, 2-butenyl,
1-pentenyl, 2-hexenyl, 1,3-pentadienyl, 1,3-hexadienyl, and the
like. Examples of the lower cycloalkenyl include those having 4 to
8 carbon atoms, such as 2-cyclopentenyl, 2-cyclohexenyl,
1,3-cyclopentadienyl, and the like. Examples of the lower alkanoyl
moiety of the lower alkanoyl, the lower alkanoyloxy and the mono-
or di-lower alkanoylamino include straight or branched groups
having 1 to 8 carbon atoms, such as formyl, acetyl, propanoyl,
isopropanoyl, butanoyl, caproyl, and the like. Examples of the
cyclic imido include phthalimido, succinimido, glutarimido, and the
like.
[0026] As compound (I), compounds in which X is a halogen are
preferred, and compounds in which X is combined together with
R.sup.4 to represent a single bond are also preferred. Among the
compounds in which X is combined together with R.sup.4 to represent
a single bond, compounds in which R.sup.1 and R.sup.2 are hydrogen
are preferred. Among these, compounds in which R.sup.3 (wherein
R.sup.3 has the same meaning as defined above) is Y--R.sup.5
(wherein R.sup.5 has the same meaning as defined above) are more
preferred. Among the compounds in which X is combined together with
R.sup.4 to represent a single bond, compounds in which R.sup.1 and
R.sup.2 are hydrogen, R.sup.3 is Y--R.sup.5 (wherein R.sup.5 has
the same meaning as defined above) and R.sup.5 is substituted or
unsubstituted aryl, and the like, are most preferred, and among
these, compounds in which R.sup.5 is pyrrolidonyl are particularly
preferred.
[0027] The pharmacologically acceptable salts of compound (I)
include acid addition salts, metal salts, ammonium salts, organic
amine addition salts, amino acid addition salts, and the like.
Examples of the acid addition salts include inorganic acid salts
(for example, hydrochloride, hydrobromide, sulfate, phosphate, and
the like), and organic acid salts (for example, formate, acetate,
oxalate, benzoate, methanesulfonate, p-toluenesulfonate, maleate,
fumarate, tartrate, citrate, succinate, lactate, and the like).
Examples of the metal salts include alkali metal salts (for
example, lithium salt, sodium salt, potassium salt, and the like),
alkaline earth metal salts (for example, magnesium salt, calcium
salt, and the like), aluminum salts, zinc salts, and the like.
Examples of the ammonium salts include salts with ammonium,
tetramethylammonium, and the like. Examples of the organic amine
addition salts include addition salts with morpholine,.piperidine,
and the like. Examples of the amino acid addition salts include
addition salts with glycine, phenylalanine, aspartic acid, glutamic
acid, lysine, and the like.
[0028] The compound of the present invention is generally prepared
using radicicol as a starting material. Compound (I) may contain
various stereoisomers, geometric isomers, tautomeric isomers, and
the like. All of possible isomers and their mixtures are included
in the present invention, and the mixing ratio is not particularly
limited.
[0029] A production method of compound (I) is described below.
[0030] The production method of compound (I) mainly comprises oxime
formation (production method 1),
acylation/carbamoylation/alkoxycarbonyla- tion (production method
2), alkylation (production method 3), amidation/esterification
(production method 4), desilylation (production method 5),
halohydrination (production method 6), silylation (production
method 7), and acylation (production method 8), and each compound
of interest is produced by combining these reaction steps depending
on the object.
[0031] In the production methods shown below, when a defined group
changes under conditions of the employed method or is not fit for
carrying out the method, the compound of interest can be prepared
using an introduction-elimination method of protecting groups
usually used in synthetic organic chemistry [for example, see
Protective Groups in Organic Synthesis, T. W. Greene, John Wiley
& Sons Inc. (1981)]. As occasion demands, the sequence of
reaction steps, such as introduction of substituent groups and the
like, may be changed.
[0032] Production Method 1
[0033] Compound (Ia) can be prepared according to following
reaction step, by oxime formation of the dienone carbonyl of
radicicol, compound (D) which is prepared from radicicol by a known
method (Japanese Published Unexamined Patent Application No.
226991/92) or compound (E) which is prepared from radicicol or a
radicicol derivative in which one of the phenolic hydroxyl groups
is substituted with alkanoyl or alkenoyl in accordance with a known
method [for example, Journal of the American Chemical Society, 94,
6190 (1972)). 7
[0034] [In the above reaction formula, R.sup.1a and R.sup.2a
represent groups in which tert-butyldimethylsilyl and
tert-butyldiphenylsilyl are removed from R.sup.1 and R.sup.2
described above; R.sup.1b and R.sup.2b represent groups in which at
least one of R.sup.1 and R.sup.2 described above is substituted
with tert-butyldimethylsilyl or tert-butyldiphenylsilyl; R.sup.3a
is a group in which COR.sup.13 (wherein R.sup.13 has the same
meaning as described above) is removed from R.sup.3 described
above; and R.sup.1 and R.sup.2 have the same meaning as defined
above.]
[0035] Step 1
[0036] Compound (Ia) can be prepared by allowing compound (D) or
compound (E) to react with compound (II) represented by the
following formula H.sub.2N--O--R.sup.3a (II) (wherein R.sup.3a has
the same meaning as defined above) or an acid addition salt
thereof.
[0037] Examples of the reaction solvent include pyridine,
chloroform, dichloromethane, ethyl acetate, ether, tetrahydrofuran
(THF), dimethylformamide (DMF), acetonitrile, and the like, which
may be used either alone or as a mixture thereof, and pyridine is
preferred. Examples of the acid include hydrochloric acid, acetic
acid, trifluoroacetic acid, sulfuric acid, p-toluenesulfonic acid,
camphorsulfonic acid, and the like, and they are preferably used in
an amount of 0.1 to 10 equivalents based on compound (D) or (E).
When an acid addition salt of compound (II) is used, the reaction
can be carried out in the presence of a base, for example, amines
(e.g., pyridine, triethylamine, diisopropylethylamine,
N,N-dimethylaniline, N,N-diethylaniline, or the like) or alkali
metal carbonate or bicarbonate (e.g., sodium carbonate, potassium
carbonate, or the like), in an amount of 1 equivalent or more based
on the acid addition salt of compound (II), preferably using
pyridine which also serves as the solvent. The compound (II) or an
acid addition salt thereof is used in an amount of 1 equivalent or
more, preferably 1 to 5 equivalents, based on compound (D) or (E).
The reaction is carried out at a temperature of -20 to 100.degree.
C., preferably 20 to 60.degree. C., and the reaction completes
after 1 to 80 hours.
[0038] Production Method 2
[0039] Compound (Ib) can be prepared by the steps in which compound
(F) is converted into oxime compound (G), and then the resulting
hydroxyl group is subjected to acylation, carbamoylation or
alkoxycarbonylation. 8
[0040] [In the above reaction formula, R.sup.1c and R.sup.2c are
the same or different, and each represents alkanoyl, alkenoyl,
tert-butyldimethylsilyl or tert-butyldiphenylsilyl, and R.sup.3b
represents COR.sup.13 (wherein R.sup.13 has the same meaning as
defined above).]
[0041] Step 2-1
[0042] Compound (G) can be prepared by allowing compound (F) to
react with hydroxylamine or an acid addition salt thereof according
to method of the above step 1.
[0043] Step 2-2
[0044] Compound (Ib) can be prepared by allowing compound (G) to
react with compound (III) represented by the following formula
R.sup.13COCl (III) (wherein R.sup.13 has the same meaning as
defined above), or with compound (IV) represented by the following
formula R.sup.23NCO (IV) (wherein R.sup.23 represents substituted
or unsubstituted lower alkyl, substituted or unsubstituted higher
alkyl, substituted or unsubstituted aryl, or substituted or
unsubstituted pyridyl), in the presence of a base.
[0045] As the reaction solvent, dichloromethane, ether, THF, DMF,
and the like, may be used alone or as a mixture thereof. As the
base, amines (for example, pyridine, triethylamine,
diisopropylethylamine, or the like) are used in an amount of 0.1
equivalent or more, preferably 1 to 10 equivalents, based on
compound (III) or (IV). Compound (III) or (IV) is used in an amount
of 1 equivalent or more, preferably 1 to 5 equivalents, based on
compound (G). The reaction is carried out at a temperature of -80
to 100.degree. C., preferably -80 to 0.degree. C., when compound
(III) is used, or at a temperature of 0 to 80.degree. C. when
compound (IV) is used, and each reaction completes after 10 minutes
to 48 hours.
[0046] Production Method 3
[0047] Compound (Ic) can be prepared by a step in which the
hydroxyl group of the above compound (G) is alkylated. 9
[0048] [In the above reaction formula, R.sup.3c represents
Y--R.sup.5 (wherein Y and R.sup.5 have the same meaning as defined
above), and R.sup.1c and R.sup.2c have the same meaning as defined
above.]
[0049] Step 3
[0050] Compound (Ic) can be prepared by allowing compound (G) to
react with compound (V) represented by the following formula
HOR.sup.24 (V) (wherein R.sup.24 has the same meaning as R.sup.3c
defined above) in the presence of a condensing agent.
[0051] As the reaction solvent, toluene, THF, dichloromethane, and
the like, are used alone or as a mixture thereof. As the condensing
agent, trivalent phosphorous compounds (for example,
triphenylphosphine, tributylphosphine, or the like) and azo
compounds (for example, diethyl azodicarboxylate (DEAD),
1,1-(azodicarbonyl) dipiperidine, and the like) are used as a
mixture thereof. Each of compound (V) and the condensing agent is
used in an amount of 1 equivalent or more, preferably 1 to 5
equivalents, based on compound (G). The reaction is carried out at
a temperature of -20 to 80.degree. C., preferably 0 to 30.degree.
C., and the reaction completes after 5 minutes to 48 hours.
[0052] Production Method 4
[0053] Compound (Id) can be prepared by steps in which compound (H)
is converted into oxime compound (J) in which a carboxyl group is
introduced, and then the carboxyl group is subjected to amidation
or esterification. 10
[0054] {In the above reaction formula, R.sup.3d represents
Y--R.sup.5a [wherein R.sup.5a represents CONR.sup.6R.sup.7 (wherein
R.sup.6 and R.sup.7 have the same meaning as defined above) or
CO.sub.2R.sup.12 (wherein R.sup.12 has the same meaning as defined
above), and Y has the same meaning as defined above], and Y,
R.sup.1 and R.sup.2 have the same meaning as defined above.}
[0055] Step 4-1
[0056] Compound (J) can be prepared by allowing compound (H) to
react with compound (VI) represented by the following formula
H.sub.2N--O--Y--CO.sub.2H (VI) (wherein Y has the same meaning as
defined above) or an acid addition salt thereof according to the
method of the above step 1.
[0057] Step 4-2
[0058] Compound (Id) can be prepared by allowing compound (J) to
react with compound (VII) represented by the following formula
HNR.sup.6R.sup.7 (VII) (wherein R.sup.6 and R.sup.7 have the same
meaning as defined above) or an acid addition salt thereof, or with
a compound (VIII) represented by the following formula HOR.sup.12
(VIII) (wherein R.sup.12 has the same meaning as defined above), in
the presence of a condensing agent.
[0059] As the condensing agent,
1-(3-dimethylaminopropyl)3-ethylcarbodiimi- de hydrochloride
(EDCI), N,N'-dicyclohexylcarbodiimide (DCC),
1,1'-carbonyldiimidazole, or the like, is used. Additionally, the
reaction can be accelerated by adding an additive agent, such as
N-hydroxysucciniimide (HONSu), 4-(dimethylamino)pyridine (DMAP),
1-hydroxybenzotriazole hydrate (HOBt), or the like, in an amount of
0.1 to 5 equivalents based on compound (J). As the reaction
solvent, dichloromethane, ether, THF, DMF, and the like, may be
used alone or as a mixture thereof. When an acid addition salt of
compound (VII) is used, the reaction can be carried out in the
presence of a base, such as amines (for example, pyridine,
triethylamine, diisopropylethylamine, or the like), preferably
triethylamine, in an amount of 1 equivalent or more, preferably 1
to 10 equivalents, based on the acid addition salt of compound
(VII). Each of compound (VII) or an acid addition salt thereof or
compound (VIII) and the condensing agent is used in an amount of 1
equivalent or more, preferably 1 to 5 equivalents, based on
compound (J). The reaction is carried out at a temperature of -20
to 80.degree. C., preferably 0 to 40.degree. C., and each reaction
completes after 10 minutes to 48 hours.
[0060] Production Method 5
[0061] Compound (If) can be prepared by carrying out desilylation
of compound (Ie) which is a derivative compound of (I) in which at
least one of R.sup.1 and R.sup.2 is substituted with
tert-butyldimethylsilyl or tert-butyldiphenylsilyl. 11
[0062] (In the above reaction formula, R.sup.1b, R.sup.2b and
R.sup.3 have the same meaning as defined above, and R.sup.1d and
R.sup.2d are groups in which at least one of
tert-butyldimethylsilyl or tert-butyldiphenylsilyl of the above
R.sup.1b and R.sup.2b is substituted with hydrogen.)
[0063] Step 5
[0064] Compound (If) can be prepared by allowing compound (Ie) to
react with a desilylation agent.
[0065] As the reaction solvent, THF, chloroform, dichloromethane,
toluene, water, methanol, and the like may be used alone or as a
mixture thereof. Examples of the desilylation agent include
tetrabutylammonium fluoride (TBAF), sodium fluoride, hydrofluoric
acid, and the like. The reaction may be carried out by increasing
the reaction pH by adding an acid, such as acetic acid,
hydrochloric acid or the like. The desilylation agent is used in an
amount of 0.1 equivalent or more, preferably 1 to 10 equivalents,
based on compound (Ie). The reaction is carried out at a
temperature of -20 to 50.degree. C., and the reaction completes
after 5 minutes to 24 hours.
[0066] Production method 6
[0067] Compound (Ih) can be prepared by ring-opening the epoxide of
compound (Ig) into a halohydrin or the like. 12
[0068] [In the above reaction formula, R.sup.1a, R.sup.2a and
R.sup.3 have the same meaning as defined above; X.sup.a represets
halogen; and R.sup.4a represents hydrogen, formyl, or --SO-Z
(wherein Z has the same meaning as defined above).]
[0069] Step 6-1
[0070] A member of compound (Ih) in which R.sup.4a is hydrogen can
be prepared by allowing compound (Ig) to react with an acid (for
example, hydrogen chloride, hydrogen bromide, or the like) or a
Lewis acid (for example, titanium tetrachloride, or the like).
[0071] As the solvent, dioxane, THF, ether, chloroform,
dichloromethane, DMF, acetonitrile, methanol, ethyl acetate, and
the like may be used either alone or as a mixture thereof. The acid
or Lewis acid is used in an amount of 1 equivalent or more,
preferably 1 to 10 equivalents, based on compound (Ig). The
reaction is carried out at a temperature of -20 to 40.degree. C.,
preferably 0 to 40.degree. C., and the reaction completes after 10
minutes to 48 hours.
[0072] Step 6-2
[0073] A member of compound (Ih) in which R.sup.4a is formyl can be
prepared by allowing compound (Ig) to react with phosphorous
oxychloride or phosphorous oxybromide in DMF. Phosphorous
oxychloride or phosphorous oxybromide is used in an amount of 1
equivalent or more, preferably 2 to 5 equivalents, based on
compound (Ig). The reaction is carried out at a temperature of -10
to 40.degree. C., preferably 0 to 40.degree. C., and the reaction
completes after 1 to 48 hours.
[0074] Step 6-3
[0075] A dimer compound as a member of compound (Ih) in which
R.sup.4a is --SO-Z (wherein Z has the same meaning as defined
above) can be prepared by allowing compound (Ig) to react with
thionyl chloride or thionyl bromide. As the solvent, DMF,
chloroform, dichloromethane, dimethyl sulfoxide (DMSO),
acetonitrile, and the like may be used either alone or as a mixture
thereof. Thionyl chloride or thionyl bromide is used in an amount
of 1 equivalent or more, preferably 2 to 10 equivalents, based on
compound (Ig). The reaction is carried out at a temperature of -10
to 40.degree. C., preferably 0 to 40.degree. C., and the reaction
completes after 1 to 48 hours.
[0076] Production Method 7
[0077] Compound (Ij) which is a derivative of compound (I) in which
at least one of R.sup.1 and R.sup.2 is substituted with
tert-butyldimethylsilyl or tert-butyldiphenylsilyl can be prepared
from compound (Ii) by the following step. 13
[0078] (In the above reaction formula, R.sup.3, R.sup.4, and X have
the same meaning as defined above; R.sup.1e and R.sup.2e represent
both hydrogen, or one represents hydrogen and the other represents
alkanoyl or alkenoyl; and R.sup.1f and R.sup.2f represent groups in
which at least one hydrogen of either of the above R.sup.1e and
R.sup.2e is substituted with tert-butyldimethylsilyl or
tert-butyldiphenylsilyl.)
[0079] Step 7
[0080] Compound (Ij) can be prepared by allowing compound (Ii) to
react with tert-butyl(chloro)dimethylsilane or
tert-butylchlorodiphenylsilane in the presence of a base.
[0081] As the solvent, chloroform, dichloromethane, ether, THF,
acetone, DMF, acetonitrile, and the like are used either alone or a
mixture thereof. As the base, amines (for example, pyridine,
imidazole, triethylamine, diisopropylethylamine, or the like) are
used. Tert-butyl(chloro)dimethylsilane or
tert-butylchlorodiphenylsilane is used in an amount of 1 equivalent
or more, preferably 1 to 10 equivalents, based on compound (Ii).
The base is used in an amount of 1 equivalent or more, preferably 1
to 10 equivalent, based on tert-butyl(chloro)dimethylsilane or
tert-butylchlorodiphenylsilane. The reaction is carried out at a
temperature of -20 to 50.degree. C., preferably 10 to 40.degree.
C., and the reaction completes after 10 minutes to 24 hours.
[0082] Production Method 8
[0083] Compound (Im) in which at least one hydrogen of any one of
R.sup.1, R.sup.2 and R.sup.4 in compound (I) is substituted with
alkanoyl or alkenoyl can be prepared by carrying out acylation of
the following compound (Ik). 14
[0084] (In the above reaction formula, R.sup.3 and X have the same
meaning as defined above; at least one of R.sup.1g, R.sup.2g and
R.sup.4b represents hydrogen; and R.sup.1h, R.sup.2h and R.sup.4c
represent groups in which at least one hydrogen of the above
R.sup.1g, R.sup.2g and R.sup.4b is substituted with alkanoyl or
alkenoyl.)
[0085] Step 8
[0086] Compound (Im) can be prepared by allowing compound (Ik) to
react with 1 equivalent or more, preferably 1 to 100 equivalents,
of an acid halide, an acid anhydride, a mixed acid anhydride
containing the alkanoyl or alkenoyl of interest, or the like, in
the presence of a base.
[0087] As the solvent, DMF, DMSO, chloroform, dichloromethane,
toluene, and the like may be used either alone or as a mixture
thereof. An optional hydroxyl group can be modified by optionally
carrying out introduction and elimination of a protecting group of
the hydroxyl group, and it is possible to modify a plurality of
hydroxyl groups at the same time. As the base, pyridine,
triethylamine, N,N-dimethylaniline, N,N-diethylaniline, or the like
is used in an amount of 1 equivalent or more, preferably 1 to 200
equivalents, based on compound (Ik). It is possible to use a base
(for example, pyridine, or the like) also as the solvent.
Additionally, the reaction can be accelerated by adding DMAP or the
like in an amount of 0.1 to 4 equivalents based on compound (Ik).
The reaction is carried out at a temperature of -20 to 50.degree.
C., and the reaction completes after 5 minutes to 24 hours.
[0088] In the production of compound (I), conversion of the
functional group of R.sup.1, R.sup.2, R.sup.3, R.sup.4 or X can be
carried out not only by the above steps but also by known methods
[for example, Comprehensive Organic Transformations, R. C. Larock
(1989)].
[0089] Isolation and purification of the products of the above
methods can be carried out by carrying out optional combinations of
techniques generally used in organic syntheses (e.g., filtration,
extraction, washing, drying, concentration, crystallization,
various types of chromatography, and the like). The intermediates
may be used in the subsequent reactions without purification.
[0090] If a salt of compound (I) is prepared, the salt of compound
(I) can be purified as such when it can be prepared; or, when the
compound is prepared in its free form, its salt can be formed by
dissolving or suspending it in an appropriate solvent and adding an
acid or base thereto.
[0091] Also, compound (I) or pharmacologically acceptable salts
thereof may exist in the form of addition products with water or
various solvents, and these addition products are also included in
the present invention. Examples of compound (I) are shown in Table
1.
1TABLE 1 Specific examples of compound (I) 15 Compound R.sup.3 1 16
2 17 3 18 4 19 5
CH.sub.2CONH(CH.sub.2).sub.2N(CH.sub.2CH.sub.3).sub.2 6
CH.sub.2CONH(CH.sub.2).sub.2OH 7 CH.sub.2CON[(CH.sub.2).sub.2OH].s-
ub.2 8 CH.sub.2CONHCH.sub.2CO.sub.2CH.sub.3 9 CH.sub.2CONHNH.sub.2
10 CH.sub.2CONHNHCONHC.sub.6H.sub.5 11 20 12 21 13 22 14 23 15 24
16 CH.sub.2CONH(CH.sub.2).sub- .9CH.sub.3 17 25 18 26 19 27 20 28
21 29 22 30 23 31 24 32 25 33 26 34 27 35 28
CH.sub.2CONHC.sub.6H.su- b.5 29 36 30 37 31 38 32 39 33
CH.sub.2CONHN(CH.sub.3).sub.2 34 40 35 CH.sub.2CONHNHC.sub.5H.sub.6
36 41 37 42 38 43 39 44 40 45 41 CH.sub.2CO.sub.2(CH.sub.2CH.s-
ub.2O).sub.5CH.sub.3 42
CH.sub.2CO.sub.2(CH.sub.2CH.sub.2O).sub.3CH- .sub.3 43 46 44 47 45
48 46 49 47 50 48 51 49 52 50 53 51 54 52 55 53 56 54 57 55 58 56
59 57 60 58 61 59 62 60 63 61 64 62 65 63 66 64 67 65 68 66 69 67
70 68 71 69 72 70 73 71 74 72 75 73 CO.sub.2CH.sub.2CH.sub.3 74
CONHCH.sub.3 75 COCH.sub.3 76 C.sub.6H.sub.5
[0092] Next, pharmacological activities of typical examples of
compound (I) are described by the following test examples.
TEST EXAMPLE 1
[0093] Inhibition Test of Intracellular Tyrosine Kinase:
[0094] SR-3Y1 cells were cultured at 37.degree. C. for 15 hours in
an atmosphere of 5% carbon dioxide, using Dulbecco's modified
Eagle's medium (DMEM) containing 10% fetal calf serum (FCS), to
which each radicicol derivative to be tested had been added in
varied concentration. The thus cultured cells were lysed at
4.degree. C. for 20 minutes in a cooled buffer for lysis use (50 mM
Tris HCl, pH 7.5, 150 mM sodium chloride (NaCl), 1% Triton X-100,
0.1% sodium dodecyl sulfate (SDS), 1% sodium deoxycholate, 2 mM
ethylenediaminetetraacetic acid (EDTA), 1 mM phenylmethanesulfonyl
fluoride (PMSF), 20 .mu.M leupeptin, 0.15 unit/ml aprotinin, 1 mM
sodium orthovanadate (Na.sub.3VO.sub.4) and then centrifuged at
20,000 G for 30 minutes. After measuring protein concentration in
the resulting supernatant fluid, samples were adjusted to the same
protein quantity per lane to carry out separation of protein by
SDS-PAGE. The thus separated protein samples were transferred onto
a nitrocellulose membrane to which were subsequently added a mouse
polyclonal phosphotyrosine antibody MX-pTYR (Kyowa Medex Co., Ltd.)
as a first antibody and a horseradish peroxidase-conjugated mouse
IgG antibody (BIO-RAD Co.) as a second antibody, thereby reacting
them with the protein samples on the membrane. Detection was
carried out using ECL reagent (Amersham Co.), and the amount of
tyrosine-phosphorylated protein was determined by scanning the
density of bands prepared on an X-ray film. The activity of
radicicol derivatives to inhibit tyrosine phosphorylation can be
shown as a concentration (IC.sub.50) of each derivative by which
the ratio of tyrosine-phosphorylated protein is reduced to half in
comparison with a control to which the drug is not added.
[0095] The results are shown in Table 2.
2TABLE 2 Inhibitory activity of intracellular tyrosine kinase
Compound IC.sub.50 (.mu.M) Radicicol 0.37 1 0.02 3 0.21 73 0.13
[0096] According to Table 2, the test compounds show clearly
stronger action to inhibit intracellular tyrosine kinase activity
than radicicol, and therefore, compound (I) is useful as a tyrosine
kinase inhibitor.
TEST EXAMPLE 2
[0097] Inhibition Test on the Growth of Rat Normal Fibroblast Cell
Line 3Y1-B and its v-src Oncogene Transformed Cell Line SR-3Y1:
[0098] The cells were inoculated into a 96 well microplate (#
167008, manufactured by Nunc) in an amount of 1,000 cells per well
and pre-cultured at 37.degree. C. for 24 hours in a 5% carbon
dioxide gas incubator using Dulbecco's modified Eagle's medium
(DMEM) which had been supplemented with 10% fetal calf serum (FCS).
Next, a DMSO solution of each test compound which had been adjusted
to 10 mM was serially diluted with the culturing medium and added
to the wells in 50 ml portions. Thereafter, the culturing was
continued at 37.degree. C. for 72 hours in the 5% carbon dioxide
gas incubator. Five hours before completion of the culturing,
3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyltetrazolium bromide
(manufactured by Sigma, hereinafter referred to as "MTT") which had
been dissolved in the culturing medium to a final concentration of
1 mg/ml was dispensed into the wells in 50 ml portions. After
completion of the culturing, DMSO was dispensed into the wells in
150 ml portions, and the plate was vigorously stirred using a plate
mixer to dissolve MTT-formazan crystals completely. Thereafter,
absorbance at 550 nM was measured using a microplate reader MTP-32
(manufactured by Corona Denki). The cell growth inhibition activity
was expressed by 50% inhibition concentration (IC.sub.50).
[0099] The results are shown in Table 3.
3TABLE 3 Growth inhibition activity upon rat normal fibroblast cell
line 3Y1-B and its v-src oncogene transformed cell line SR-3Y1
Growth inhibition activity IC.sub.50 (.mu.M) Compond 3Y1-B SR-3Y1
Radicicol 0.780 0.042 1 0.008 <0.004 21 0.032 0.018 27 0.041
0.010 44 0.069 0.012 50 0.120 0.021 53 0.008 <0.004 55 0.009
<0.004 67 0.140 0.018 69 0.008 0.004 72 0.055 0.010 74 0.072
0.027 76 0.110 0.026
[0100] According to Table 3, the test compounds showed stronger
cell growth inhibition activity upon SR-3Y1 than that upon 3Y1-B
and stronger cell growth inhibition activity than that of radicicol
upon SR-3Y1. Because of these results, compound (I) is useful as an
antitumor agent.
TEST EXAMPLE 3
[0101] Antitumor Test on Nude Mouse-Transplanted Human Breast
Cancer MX-1 Solid Tumor:
[0102] From a tumor lump of a-human breast cancer cell line MX-1
subcultured in nude mice (BALB/c nu/nu mice: CLEA Japan), a portion
showing good growth was selected and cut into a 2 mm square
fragment which was then transplanted under the abdominal side skin
of each male nude mouse of 7 to 9 weeks of age using a trocar. The
tumor size was measured on the 13th day after the tumor
transplantation to select properly growing tumors having a tumor
volume of 100 to 300 mm.sup.3 (calculated by a calculation formula
of "major axis.times.minor axis.sup.2.times.{fraction (1/2)}"), the
mice were optionally grouped into 5 animals per group, and then
each test compound which had been dissolved in a 7.5% cremohor EL
(manufactured by Sigma)/5% dimethylacetamide (DMA)/87.5%
physiological saline solution was administered to the mice by
intravenous injection at a dosage of 0.05 ml (100 mg/kg) per day,
once a day for 5 days. The antitumor activity of each test compound
was expressed by a ratio (T/C) of the tumor volume (T) in the test
drug-administered group to the tumor volume (C) in the control
group on the 12th or 14th day after administration of the test
compound.
[0103] The results are shown in Table 4.
4TABLE 4 Antitumor activity against human breast cancer MX-1 solid
tumor inoculated in nude mouse Day measured (after Compound T/C (%)
administration of test compound) 1 3 14 51 33 14 53 46 12 69 4
12
[0104] According to Table 4, the test compounds show excellent
antitumor activity, and therefore, compound (I) is useful as an
antitumor agent.
TEST EXAMPLE 4
[0105] Effect of Decreasing Intracellular Raf-1 Protein Quantity
and Erk2 Phosphorylation Inhibition Activity:
[0106] Activated K-ras gene-introduced rat kidney epithelial cell
line KNRK 5.2 was cultured at 37.degree. C. for 40 hours in an
atmosphere of 5% carbon dioxide gas using Dulbecco's modified
Eagle's medium (DMEM) which was supplemented with 10% fetal calf
serum (FCS) and to which was added each radicicol derivative at
respective test concentration. The resulting cells were lysed for
30 minutes at 4.degree. C. in a cooled buffer for lysis use [50 mM
HEPES NaOH, pH 7.4, 250 mM sodium chloride (NaCl), 1 mM
ethylenediaminetetraacetic acid (EDTA), 1% Nonidet P-40 (NP40), 1
mM dithiothreitol (DTT), 1 mM phenylmethylsulfonyl fluoride (PMSF),
5 .mu.g/ml leupeptin, 2 mM sodium orthovanadate (Na.sub.3VO.sub.4),
1 mM sodium fluoride (NaF), 10 mM .beta.-glycerophosphatel and then
centrifuged at 30,000 G for 10 minutes. The protein content of the
thus prepared supernatant fluids was measured to prepare samples
having the same protein quantity for each lane, and then separation
of proteins was carried out by SDS-PAGE. The thus separated protein
samples were transferred on a polyvinylidene difluoride (PVDF)
membrane, and then anti-phosphorylation MAPK antibody (anti-phospho
MAPK, manufactured by New England Biolabs), anti-Erk2 antibody
(anti-Erk2, manufactured by Upstate Biotechnology) and anti-Raf-1
antibody (anti-Raf-1(C-12), manufactured by Santa Cruz
Biotechnology) were added thereto as primary antibodies and allowed
to react with the proteins on the membrane. Thereafter, a
horseradish peroxidase-labeled secondary antibody (anti-rabbit Ig
antibody or anti-mouse Ig antibody, manufactured by Amersham)
capable of reacting with respective primary antibodies was added
thereto as the secondary antibody to carry out the reaction.
Detection was carried out using ECL reagent (manufactured by
Amersham), and the amount of phosphorylated Erk2 protein, total
Erk2 protein and Raf-1 protein was determined by carrying out
density scanning of the bands generated on the X-ray film. The Erk2
phosphorylation inhibition activity of radicicol derivatives is
determined by calculating the ratio of phosphorylated Erk2 protein
(phosphorylated Erk2 protein/total Erk2 protein) based on the
results prepared from the samples of respective drug
concentrations, which is expressed as the concentration of each
derivative (IC.sub.50) by which the ratio becomes half in
comparison with the case in which the drug is not added. Also, the
Raf-1 protein decreasing action is examined by calculating the
ratio of Raf protein to the amount of Erk2 protein which does not
cause changes in the protein quantity by the drug-treatment (Raf-1
protein/total Erk2 protein) based on the results prepared from the
samples having respective drug concentrations, which is expressed
as the concentration of each derivative (IC.sub.50) by which the
ratio becomes half in comparison with the case in which the drug is
not added.
[0107] The results are shown in Table 5.
5TABLE 5 Effect of decreasing intracellular Raf-1 protein quantity
and Erk2 phosphorylation inhibition activity Raf-1 protein quantity
Erk2 phosphorylation Compound decrease: IC.sub.50 (.mu.M)
inhibition: IC.sub.50 (.mu.M) 50 0.34 0.35 53 0.38 0.07 64 0.19
0.11 69 0.12 0.06
[0108] According to Table 5, the test compounds showed effect of
decreasing intracellular Raf-1 protein quantity and Erk2
phosphorylation inhibition activity.
[0109] Compound (I) or a pharmacologically acceptable salt thereof
is administered orally or parenterally as it is or in the form of a
pharmaceutical composition. Examples of the dosage form of such a
pharmaceutical composition include tablets, pills, powders,
granules, capsules, suppositories, injections, drip infusions, and
the like.
[0110] These dosage forms can be prepared by employing generally
known methods and may contain various fillers, lubricants, binders,
disintegrators, suspending agents, tonicity agents, emulsifying
agents, absorption enhancers, and the like.
[0111] Examples of carriers to be used in the pharmaceutical
composition include water, distilled water for injection use,
physiological saline, glucose, fructose, sucrose, mannitol,
lactose, starch, corn starch, cellulose, methyl cellulose,
carboxymethyl cellulose, hydroxypropyl cellulose, alginic acid,
talc, sodium citrate, calcium carbonate, calcium hydrogenphosphate,
magnesium stearate, urea, silicone resin, sorbitan fatty acid
ester, glycerol fatty acid ester and the like, which may be
optionally selected according to the kind of the pharmaceutical
preparation.
[0112] Although the dosage and the number of administration times
for the purposes may vary depending on the intended therapeutic
effect, administration method, treating period, age, body weight,
and the like, it may be administered generally in a dose of 0.01 to
5 mg/kg per day per adult.
BEST MODE OF CARRYING OUT THE INVENTION
[0113] Examples and Reference Examples are shown below. The NMR
data shown in Examples and Reference Examples are values obtained
by measuring at 270 MHz, and the number of protons observed,
multiplicity and coupling constant (unit, Hz) are shown in that
order in parentheses after the 8 value of each signal.
[0114] TBS and Boc shown in the following structural formulae and
Tables mean tert-butyldimethylsilyl and tert-butoxycarbonyl,
respectively.
EXAMPLE 1
[0115] Compound 1:
[0116] (1-1):
[0117] A 1.50 g (4.11 mmol) portion of radicicol was dissolved in 5
ml of pyridine, and the solution was mixed with 1.00 g (9.15 mmol)
of aminooxyacetic acid hemihydrochloride and stirred at room
temperature for 20 hours and then at 60.degree. C. for 1.5 hours.
The solvent was evaporated under reduced pressure, and the
resulting residue was purified by silica gel column chromatography
(chloroform/methanol=49/1) to obtain 692 mg (yield, 38%) of a
compound (K). The thus prepared compound (K) was found to be a
mixture of oxime-based isomers (about 3:1) according to
.sup.1H-NMR.
[0118] FAB-MS m/z: 438 [M+H].sup.+
[0119] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.27 (1H, dd, 16.1, 11.2 Hz), 6.82 (1H, d, 16.1 Hz), 6.42 (1H, s),
6.17 (1H, dd, 11.2, 10.5 Hz), 5.61 (1H, dd, 10.5, 3.4 Hz), 5.31
(1H, m), 4.64 (2H, m), 3.91 (1H, d, 16.4 Hz), 3.82 (1H, d, 16.4
Hz), 3.34 (1H, m), 3.02 (1H, m), 2.42 (1H, m), 1.60 (1H, ddd, 14.4,
9.0, 4.2 Hz), 1.53 (3H, d, 6.6 Hz). 76
[0120] (1-2):
[0121] A 230 mg (0.525 mmol) portion of compound (K) was dissolved
in 3 ml of DMF, and the solution was mixed with 121 mg (0.788 mmol)
of HOBt, 151 mg (0.788 mmol) of EDCI and 0.078 ml (0.788 mmol) of
piperidine and stirred at room temperature for 23 hours and 40
minutes. The reaction solution was mixed with a 0.01 M phosphate
buffer of pH 7 and then extracted with ethyl acetate. The ethyl
acetate layer was washed with saturated brine and dried with
anhydrous sodium sulfate, and then the solvent was evaporated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (chloroform/methanol=50/1) to obtain 63.6 mg
(yield, 24%) of compound 1. The thus prepared compound 1 was found
to be a mixture of oxime-based isomers (about 4:1) according to
.sup.1H-NMR.
[0122] FAB-MS m/z: 505 [M+H].sup.+
[0123] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.27 (1H, dd, 15.8, 10.9 Hz), 6.80 (1H, d, 16.3 Hz), 6.44 (1H, s),
6.17 (1H, dd, 11.9, 10.9 Hz), 5.61 (1H, dd, 10.9, 3.5 Hz), 5.31
(1H, m), 4.80 (2H, s), 3.93 (1H, d, 15.9 Hz), 3.82 (1H, d, 16.3
Hz), 3.40-3.60 (4H, m), 3.34 (1H, m), 3.02 (1H, m), 2.49 (1H, ddd,
14.4, 3.5, 3.5 Hz), 1.60-1.80 (7H, m), 1.52 (3H, d, 6.4 Hz).
EXAMPLE 2
[0124] Compound 2:
[0125] According to (1-2) described in Example 1, 109 mg (yield,
49%) of compound 2 was prepared from 200 mg (0.457 mmol) of
compound (K), 77 mg (0.503 mmol) of HOBt, 96 mg (0.503 mmol) of
EDCI and 0.042 ml (0.503 mmol) of pyrroridine. The thus prepared
compound 2 was found to be a mixture of oxime-based isomers (about
3:1) according to .sup.1H-NMR.
[0126] FAB-MS m/z: 491 [M+H].sup.+
[0127] Major component: .sup.1H-NMR (DMSO-d.sub.6) .delta. (ppm):
10.34 (1H, br s), 10.00 (1H, br s), 7. 14 (1H, dd, 16.0, 11.4 Hz),
6,74 (1H, d, 15.8 Hz), 6.51 (1H, s), 6.23 (1H, dd, 11.2, 10.9 Hz),
5.63 (1H, dd, 10.4, 3.5 Hz), 5.14 (1H, m), 4.68 (2H, s), 3.80 (1H,
d, 15.8 Hz), 3.51 (1H, d, 15.2 Hz), 3.27-3.54 (4H, m), 3.05 (1H,
m), 2.44 (1H, m), 1.70-1.91 (5H, m), 1.43 (3H, d, 6.3 Hz).
EXAMPLE 3
[0128] Compound 3:
[0129] According to (1-2) described in Example 1, 42 mg (yield,
12%) of compound 3 was prepared from 300 mg (0.685 mmol) of
compound (K), 155 mg (0.753 mmol) of DCC, 87 mg (0.753 mmol) of
HONSu and 0.090 ml (0.753 mmol) of morpholine. The thus prepared
compound 3 was found to be a mixture of oxime-based isomers (about
4:1) according to .sup.1H-NMR.
[0130] FAB-MS m/z: 507 [M+H].sup.+
[0131] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.28 (1H, dd, 15.8, 11.4 Hz), 6.78 (1H, d, 16.3 Hz), 6.42 (1H, s),
6.17 (1H, dd, 11.4, 10.4 Hz), 5.62 (1H, dd, 10.4, 3.0 Hz), 5.30
(1H, m), 4.82 (2H, s), 3.87 (1H, d, 15.8 Hz), 3.82 (1H, d, 16.3
Hz), 3.57-3.71 (8H, m), 3.34 (1H, m), 3.05 (1H, m), 2.42 (1H, ddd,
14.4, 4.0, 3.5 Hz), 1.94 (1H, m), 1.52 (3H, d, 6.9 Hz).
EXAMPLE 4
[0132] Compound 4:
[0133] According to (1-2) described in Example 1, 24 mg (yield,
20%) of compound 4 was prepared from 100 mg (0.288 mmol) of
compound (K), 52 mg (0.251 mmol) of DCC, 29 mg (0.251 mmol) of
HONSu and 0.028 ml (0.251 mmol) of 1-methylpiperazine. The thus
prepared compound 4 was found to be a mixture of oxime-based
isomers (about 4:1) according to .sup.1H-NMR.
[0134] FAB-MS m/z: 520 [M+H].sup.+
[0135] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.01 (1H, dd, 15.8, 11.4 Hz), 6.69 (1H, d, 15.8 Hz), 6.33 (1H, s),
6.07 (1H, t, 10.9 Hz), 5.52 (1H, dd, 10.4, 4.0 Hz), 5.20 (1H, m),
4.72 (2H, s), 3.84 (1H, d, 16.3 Hz), 3.72 (1H, d, 16.3 Hz),
3.41-3.55 (4H, m), 3.25 (1H, m), 2.92 (1H, m), 2.28-2.41 (5H, m),
2.22 (3H, s), 1.50 (1H, m), 1.42 (3H, d, 6.4 Hz).
EXAMPLE 5
[0136] Compound 5:
[0137] According to (1-2) described in Example 1, 46 mg (yield,
37%) of compound 5 was prepared from 100 mg (0.288 mmol) of
compound (K), 52 mg (0.251 mmol) of DCC, 29 mg (0.251 mmol) of
HONSu and 0.035 ml (0.251 mmol) of N,N-diethylethylenediamine. The
thus prepared compound 5 was found to be a mixture of oxime-based
isomers (about 3:1) according to .sup.1H-NMR.
[0138] FAB-MS m/z: 537 [M+H].sup.+
[0139] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.30 (1H, dd, 15.8, 11.4 Hz), 6.84 (1H, d, 16.3 Hz), 6.39 (1H, s),
6.18 (1H, t, 10.9 Hz), 5.63 (1H, dd, 10.9, 3.5 Hz), 5.30 (1H, m),
3.96 (2H, br), 3.44-3.52 (2H, m), 3.36 (1H, m), 3.00 (1H, m),
2.77-2.82 (6H, m), 2.60 (1H, m), 1.67 (1H, m), 1.51 (3H, d, 6.4
Hz), 1.07-1.19 (6H, m).
EXAMPLE 6
[0140] Compound 6:
[0141] According to (1-2) described in Example 1, 87 mg (yield,
40%) of compound 6 was prepared from 200 mg (0.456 mmol) of
compound (K), 88 mg (0.457 mmol) of EDCI, 56 mg (0.457 mmol) of
DMAP and 25 mg (0.457 mmol) of 2-aminoethanol. The thus prepared
compound 6 was found to be a mixture of oxime-based isomers (about
5:1) according to .sup.1H-NMR.
[0142] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.30 (1H, dd, 15.8, 11.4 Hz), 6.85 (1H, d, 16.3 Hz), 6.44 (1H, s),
6.19 (1H, t, 10.9 Hz), 5.63 (1H, dd, 10.9, 3.0 Hz), 5.31 (1H, m),
4.58 (2H, s), 3.96 (1H, d, 16.3 Hz), 3.85 (1H, d, 16.3 Hz),
3.54-3.70 (2H, m), 3.31-3.40 (2H, m), 3.31 (1H, m), 3.02 (1H, m),
2.43 (1H, m), 1.61 (1H, m), 1.52 (3H, d, 6.4 Hz).
EXAMPLE 7
[0143] Compound 7:
[0144] According to (1-2) described in Example 1, 45 mg (yield,
13%) of compound 7 was prepared from 300 mg (0.685 mmol) of
compound (K), 132 mg (0.685 mmol) of EDCI, 84 mg (0.685 mmol) of
DMAP and 97 mg (0.685 mmol) of 2,2'-iminodiethanol hydrochloride.
The thus prepared compound 7 was found to be a mixture of
oxime-based isomers (about 5:1) according to .sup.1H-NMR.
[0145] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.26 (1H, dd, 15.8, 10.9 Hz), 6.83 (1H, d, 15.8 Hz), 6.42 (1H, s),
6.17 (1H, dd, 11.4, 10.4 Hz), 5.60 (1H, dd, 10.4, 3.5 Hz), 5.29
(1H, m), 4.91 (2H, s), 3.91 (1H, d, 15.8 Hz), 3.80 (1H, d, 15.8
Hz), 3.71-3.90 (4H, m), 3.52-3.59 (4H, m), 3.34 (1H, m), 3.00 (1H,
m), 2.42 (1H, ddd, 14.8, 3.5, 3.5 Hz), 1.60 (1H, m), 1.52 (3H, d,
6.4 Hz).
EXAMPLE 8
[0146] Compound 8:
[0147] According to (1-2) described in Example 1, 89 mg (yield,
38%) of compound 8 was prepared from 200 mg (0.456 mmol) of
compound (K), 87 mg (0.456 mmol) of EDCI, 56 mg (0.457 mmol) of
DMAP and 63 mg (0.502 mmol) of glycine methyl ester hydrochloride.
The thus prepared compound 8 was found to be a mixture of
oxime-based isomers (about 4:1) according to .sup.1H-NMR.
[0148] FAB-MS m/z: 509 [M+H].sup.+
[0149] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.30 (1H, dd, 16.3, 11.9 Hz), 6.87 (1H, d, 15.8 Hz), 6.44 (1H, s),
6.20 (1H, dd, 10.4, 9.4 Hz), 5.63 (1H, dd, 10.4, 4.0 Hz), 5.31 (1H,
m), 4.85 (2H, s), 4.02 (1H, d, 2.0 Hz), 3.96 (1H, d, 15.8 Hz), 3.83
(1H, d, 15.8 Hz), 3.73 (3H, s), 3.36 (1H, m), 3.03 (1H, m), 2.44
(1H, ddd, 14.3, 3.5, 3.5 Hz), 1.65 (1H, m), 1.53 (3H, d, 6.4
Hz).
EXAMPLE 9
[0150] Compound 9:
[0151] A 46 mg (0.150 mmol) portion of compound (K) was dissolved
in 1.5 ml of tetrahydrofuran, and the solution was mixed with 23 mg
(0.200 mmol) of HOBt, 2.7 mg (0.022 mmol) of DMAP and 44 mg (0.228
mmol) of EDCI and stirred at room temperature for 16 hours. The
resulting precipitate was separated by filtration, and the solvent
was evaporated under reduced pressure. The thus prepared residue
was dissolved in 1.5 ml of tetrahydrofuran, and the solution was
mixed with 0.100 ml (0.720 mmol) of triethylamine and 0.050 ml
(1.030 mmol) of hydrazine hydrate and stirred at room temperature
for 12 hours. The reaction solution was mixed with ethyl acetate,
washed with a saturated ammonium chloride aqueous solution and
dried with anhydrous sodium sulfate, and then the solvent was
evaporated under reduced pressure. The resulting residue was
purified by silica gel column chromatography
(chloroform/methanol=24/1) to obtain 33 mg (yield, 48%) of compound
9. The thus prepared compound 9 was found to be a mixture of
oxime-based isomers (about 3:1) according to .sup.1H-NMR.
[0152] FAB-MS m/z: 452 [M+H].sup.+
[0153] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.28 (1H, dd, 16.1, 11.3 Hz), 6.83 (1H, d, 16.1 Hz), 6.43 (1H, s),
6.19 (1H, dd, 11.3, 10.7 Hz), 5.62 (1H, dd, 10.7, 3.7 Hz), 5.30
(1H, m), 3.94 (1H, d, 16.1 Hz), 3.79 (1H, d, 16.1 Hz), 3.31 (1H,
m), 3.02 (1H, m), 2.43 (1H, m), 1.59 (1H, m), 1.52 (3H, d, 6.5
Hz).
EXAMPLE 10
[0154] Compound 10:
[0155] According to (1-2) described in Example 1, 35 mg (yield,
27%) of compound 10 was prepared from 100 mg (0.228 mmol) of
compound (K), 44 mg (0.228 mmol) of EDCI and 35 mg (0.228 mmol) of
4-phenylsemicarbazide. The thus prepared compound 10 was found to
be a mixture of oxime-based isomers (about 5:1) according to
.sup.1H-NMR.
[0156] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.23-7.42 (5H, m), 7.02 (1H, t, 7.4 Hz), 6.88 (1H, d, 15.8 Hz),
6.45 (1H, s), 6.18 (1H, t, 10.9 Hz), 5.62 (1H, dd, 10.9, 3.5 Hz),
5.31 (1H, m), 4.73 (2H, s), 3.97 (1H, d, 16.3 Hz), 3.86 (1H, d,
16.3 Hz), 3.36 (1H, m), 3.01 (1H, m), 2.42 (1H, ddd, 14.3, 3.5, 3.5
Hz), 1.61 (1H, m), 1.51 (3H, d, 6.4 Hz).
EXAMPLES 11-37
[0157] Compounds 11 to 38 were prepared from compound (K) according
to (1-2) described in Example 1.
EXAMPLE 11
[0158] Compound 11:
[0159] Isomer ratio: about 10:1
[0160] FAB-MS m/z: 519 [M+H].sup.+
[0161] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
10.78 (1H, br), 7.86 (1H, br s), 7.14 (1H, dd, 15.8, 11.6 Hz), 6.75
(1H, d, 15.8 Hz), 6.60 (1H, s), 6.09 (1H, dd, 11.6, 10.2 Hz), 5.60
(1H, dd, 10.6, 3.0 Hz), 5.47 (1H, m), 4.85 (1H, d, 13.9 Hz), 4.79
(1H, d, 13.9 Hz), 4.69 (1H, br), 3.98 (1H, br), 3.37-3.56 (4H, m),
3.16 (1H, br), 2.94 (2H, dd, 8.6, 2.6, 2.3 Hz), 2.31 (1H, ddd,
15.2, 3.6, 3.6 Hz), 1.95 (1H, ddd, 15.2, 4.0, 4.0 Hz), 1.74 (2H,
br), 1.53 (3H, d, 6.9 Hz), 1.49-1.58 (2H, br), 1.20-1.29 (4H,
br).
EXAMPLE 12
[0162] Compound 12:
[0163] Isomer ratio: about 3:1
[0164] FAB-MS m/z: 519 [M+H].sup.+
[0165] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
10.99 (1H, br), 8.00 (1H, br), 7.16 (1H, m), 6.73 (1H, d, 16.2 Hz),
6.59 (1H, s), 6.11 (1H, dd, 10.6, 10.2 Hz), 5.62 (1H, br d, 9.6
Hz), 5.48 (1H, m), 4.80 (2H, s), 4.67 (1H, d, 12.2 Hz), 4.54 (2H,
br), 4.00 (1H, br), 3.73-3.89 (2H, br), 3.17 (1H, br), 3.04 (1H,
m), 2.50-2.65 (2H, m), 2.32 (1H, ddd, 15.2, 3.6, 3.3 Hz), 1.93 (1H,
ddd, 18.8, 4.6, 4.6 Hz), 1.58-1.70 (2H, m), 1.54 (3H, d, 6.9 Hz),
1.04-1.19 (2H, m), 0.94 (3H, d, 6.3 Hz).
EXAMPLE 13
[0166] Compound 13:
[0167] Isomer ratio: about 3:1
[0168] FAB-MS m/z: 521 [M+H].sup.+
[0169] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
7.16 (1H, m), 6.70 (1H, d, 16.2 Hz), 6.57 (1H, s), 6.11 (1H, dd,
10.6, 10.2 Hz), 5.63 (1H, br d, 11.2 Hz), 5.48 (1H, m), 4.80 (2H,
s), 4.63 (1H, br), 3.95 (3H, br), 3.76 (1H, br), 3.19-3.47 (3H, m),
2.96 (1H, br), 2.33 (1H, m), 1.90 (1H, m), 1.54 (3H, d, 6.6 Hz),
1.20-1.28 (4H, m).
EXAMPLE 14
[0170] Compound 14:
[0171] Isomer ratio: about 8:1
[0172] FAB-MS m/z: 588 [M+H].sup.+
[0173] Major component: .sup.1H-NMR (CDCl.sub.3+CD.sub.3OD) .delta.
(ppm): 7.01 (1H, dd, 16.0, 11.0 Hz), 6.62 (1H, d, 15.8 Hz), 6.34
(1H, s), 6.06 (1H, dd, 11.6, 9.9 Hz), 5.46 (1H, br d, 10.6 Hz),
5.34 (1H, br), 4.68 (2H, s), 4.55 (1H, d, 17.8 Hz), 3.96 (1H, br),
3.20 (1H, br), 2.82-2.99 (2H, m), 2.60 (8H, br), 2.25 (1H, br d,
11.6 Hz), 1.89 (2H, br), 1.70-1.80 (4H, br), 1.61 (4H, br), 1.44
(3H, d, 6.6 Hz).
EXAMPLE 15
[0174] Compound 15:
[0175] Isomer ratio: about 3:1
[0176] FAB-MS m/z: 548 [M+H].sup.+
[0177] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
7.13 (1H, dd, 16.0, 11.4 Hz), 6.64 (1H, d, 16.2 Hz), 6.41 (1H, s),
6.06 (1H, dd, 11.9, 10.2 Hz), 5.57 (1H, dd, 10.2, 3.0 Hz), 5.37
(1H, m), 4.70 (2H, s), 4.33-4.52 (2H, m), 3.91-4.01 (2H, m), 3.17
(1H, br), 2.80-3.08 (2H, m), 2.66 (1H, m), 2.24-2.40 (2H, m),
1.54-1.84 (5H, br), 1.47 (3H, d, 6.6 Hz).
EXAMPLE 16
[0178] Compound 16:
[0179] Isomer ratio: about 4:1
[0180] FAB-MS m/z: 577 [M+H].sup.+
[0181] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
10.71 (1H, br), 8.83 (1H, br), 7.23 (1H, dd, 16.0, 11.4 Hz), 6.66
(1H, d, 16.2 Hz), 6.60 (1H, s), 6.41 (1H, t, 5.8 Hz), 6.13 (1H, dd,
11.2, 10.9 Hz), 5.67 (1H, dd, 10.2, 3.0 Hz), 5.47 (1H, m), 4.66
(1H, br), 4.59 (2H, s), 4.02 (1H, d, 15.2 Hz), 3.25-3.35 (2H, m),
3.20 (1H, br), 2.95 (1H, m), 2.33 (1H, m), 1.95 (1H, m), 1.54 (3H,
d, 6.6 Hz), 1.51 (2H, br), 1.21 (14H, br), 0.83 (3H, t, 5.6
Hz).
EXAMPLE 17
[0182] Compound 17:
[0183] Isomer ratio: about 13:1
[0184] FB-MS m/z: 513 [M+H].sup.+
[0185] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
10.77 (1H, br), 7.25 (1H, dd, 16.2, 11.2 Hz), 7.02 (1H, br), 6.68
(1H, d, 16.2 Hz), 6.61 (1H, s), 6.51 (1H, t, 5.9 Hz), 6.17 (1H, dd.
11.2, 10.6 Hz), 5.71 (1H, dd, 10.2, 3.3 Hz), 5.51 (1H, m), 4.73
(1H, d, 15.8 Hz), 4.62 (2H, s), 4.06 (1H, d, 15.2 Hz), 3.61 (2H, t,
6.3 Hz), 3.45-3.54 (2H, m), 3.22 (1H, br), 2.99 (1H, ddd, 8.3, 2.6,
2.6 Hz), 2.36 (1H, ddd, 15.2, 3.6, 3.6 Hz), 1.95-2.10 (3H, m), 1.58
(3H, d, 6.6 Hz).
EXAMPLE 18
[0186] Compound 18:
[0187] Isomer ratio: about 10:1
[0188] FAB-MS m/z: 509 [M+H].sup.+
[0189] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
10.76 (1B, br), 7.23 (1H, dd, 15.5, 10.9 Hz), 6.84 (1H, br), 6.69
(1H, d, 16.2 Hz), 6.67 (1H, br), 6.16 (1H, dd, 11.2, 10.6 Hz), 5.70
(1H, dd, 10.4, 3.1 Hz), 5.51 (1H, m), 4.75 (1H, br), 4.64 (2H, s),
4.10 (1H, br), 3.45-3.57 (6H, m), 3.22 (1H, br), 2.99 (1H, ddd,
8.3, 2.6, 2.3 Hz), 2.36 (1H, ddd, 15.2, 3.6, 3.3 Hz), 2.00 (1H,
ddd, 15.2, 4.3, 4.0 Hz), 1.58 (3H, d, 6.6 Hz), 1.14 (3H, t, 7.1
Hz).
EXAMPLE 19
[0190] Compound 19:
[0191] Isomer ratio: about 3:1
[0192] FAB-MS m/z: 477 [M+H].sup.+
[0193] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
10.77 (1H, br), 7.47 (1H, br), 7.24 (1H, dd, 16.1, 11.2 Hz), 6.68
(1H, d, 16.2 Hz), 6.61 (1H, s), 6.40 (1H, br), 6.16 (1H, dd, 11.6,
11.5 Hz), 5.86 (1H, m), 5.70 (1H, dd, 10.2, 3.3 Hz), 5.51 (1H, m),
5.23 (1H, dd, 17.2, 1.3 Hz), 5.16 (1H, dd, 10.2, 1.3 Hz), 4.71 (1H,
br), 4.64 (2H, s), 3.96-3.98 (3H, m), 3.21 (1H, br), 2.99 (1H, m),
2.35 (1H, ddd, 15.2, 3.6, 3.3 Hz), 1.98 (1H, ddd, 15.2, 4.0, 4.0
Hz), 1.56 (3H, d, 6.9 Hz).
EXAMPLE 20
[0194] Compound 20:
[0195] Isomer ratio: about 4:1
[0196] FAB-MS m/z: 533 [M+H].sup.+
[0197] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
10.75 (1H, br), 8.17 (1H, br), 7.24 (1H, dd, 16.2, 11.2 Hz), 6.68
(1H, d, 15.8 Hz), 6.42 (1H, t, 6.1 Hz), 6.16 (1H, dd. 11.2, 10.6
Hz), 5.69 (1H, dd, 10.4, 3.1 Hz), 5.50 (1H, m), 4.61 (2H, s), 4.04
(1H, d, 14.2 Hz), 3.09-3.27 (4H, m), 2.99 (1H, m), 2.35 (1H, ddd,
15.2, 3.3, 3.3 Hz), 1.98 (1H, m), 1.68-1.73 (6H, br), 1.56 (3H, d,
6.6 Hz), 1.49 (1H, br), 1.10-1.24 (4H, br).
EXAMPLE 21
[0198] Compound 21:
[0199] Isomer ratio: about 7:1
[0200] FAB-MS m/z: 617 [M+H].sup.+
[0201] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
10.71 (1H, br), 7.75 (1H, br), 7.20 (1H, dd, 16.0, 11.4 Hz), 6.64
(1H, d, 15.8 Hz), 6.54 (1H, s), 6.52-6.64 (3H, m), 6.11 (1H, dd,
11.5, 10.2 Hz), 5.67 (1H, dd, 10.2, 3.3 Hz), 5.46 (1H, m), 4.69
(1H, d, 13.5 Hz), 4.63 (1H, d, 16.2 Hz), 4.62 (1H, br), 4.45 (1H,
d, 5.9 Hz), 3.99 (1H, d, 15.8 Hz), 3.83 (3H, s), 3.82 (3H, s), 3.81
(3H, s), 3.18 (1H, br), 2.96 (1H, m), 2.33 (1H, ddd, 15.2, 3.6, 3.6
Hz), 1.95 (1H, ddd, 15.2, 3.9, 3.9 Hz), 1.52 (3H, d, 6.6 Hz).
EXAMPLE 22
[0202] Compound 22:
[0203] Isomer ratio: about 3:1
[0204] FAB-MS m/z: 528 [M+H].sup.+
[0205] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
8.57 (1H, br s), 8.47 (1H, br d, 4.3 Hz), 7.81 (1H, ddd, 8.2, 2.0,
1.7 Hz), 7.36 (1H, dd, 7.9, 4.6 Hz), 7.20 (1H, dd, 15.8, 11.2 Hz),
6.93 (1H, t, 6.3 Hz), 6.65 (1H, d, 16.2 Hz), 6.46 (1H, s), 6.10
(1H, dd, 10.6, 9.9 Hz), 5.67 (1H, dd, 10.2, 3.0 Hz), 5.45 (1H, m),
4.48-4.64 (5H, m), 3.90 (1H, d, 15.2 Hz), 3.15 (1H, br), 2.94 (1H,
br d, 8.9 Hz), 2.31 (1H, ddd, 15.2, 3.3, 3.3 Hz), 1.92 (1H, m),
1.52 (3H, d, 6.9 Hz).
EXAMPLE 23
[0206] Compound 23:
[0207] Isomer ratio: about 3:1
[0208] FAB-MS m/z: 544 [M+H].sup.+
[0209] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
10.70 (1H, br), 9.02 (1H, br), 7.22 (1H, dd, 15.8, 11.2 Hz),
6.61-6.65 (2H, m), 6.60 (1H, s), 6.53 (1H, m), 6.15 (1H, dd, 10.9,
10.6 Hz), 5.89-5.98 (2H, m), 5.68 (1H, dd, 10.2, 3.0 Hz), 5.47 (1H,
m), 4.64 (1H, d, 15.5 Hz), 4.61 (1H, br), 4.58 (1H, d, 16.2 Hz),
4.06 (1H, br), 3.41-3.60 (2H, m), 3.54 (3H, s), 3.23 (1H, br), 3.00
(1H, m), 2.81 (2H, m), 2.34 (1H, ddd, 15.2, 3.3, 3.3 Hz), 1.96 (1H,
ddd, 16.2, 4.0, 4.0 Hz), 1.55 (3H, d, 6.6 Hz).
EXAMPLE 24
[0210] Compounds 24 and 25:
[0211] Compound 24:
[0212] FAB-MS m/z: 548 [M+H].sup.+
[0213] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 7.61 (1H, br), 7.16
(1H, dd, 16.0, 11.4 Hz), 6.85 (2H, br), 6.60 (1H, d, 16.2 Hz), 6.45
(1H, s), 5.79 (1H, dd, 11.2, 10.9 Hz), 5.57 (1H, dd, 10.2, 3.0 Hz),
5.43 (1H, m), 4.70 (1H, br), 4.67 (1H, d, 15.8 Hz), 4.59 (1H, d,
15.8 Hz), 3.95 (1H, br), 3.51-3.72 (2H, m), 3.15 (1H, br), 2.93
(1H, br d, 8.6 Hz), 2.80 (2H, t, 5.6 Hz), 2.72 (4H, br), 2.30 (1H,
ddd, 14.9, 3.3, 3.3 Hz), 1.98 (1H, ddd, 14.9, 4.3, 4.0 Hz), 1.52
(3H, d, 6.6 Hz), 1.45-1.63 (6H, br).
[0214] Compound 25:
[0215] FAB-MS m/z: 548 [M+H].sup.+
[0216] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 8.58 (1H, br), 7.05
(1H, dd, 16.2, 11.2 Hz), 6.29 (1H, s), 5.98 (1H, d, 16.2 Hz), 5.98
(1H, dd, 10.9, 9.2 Hz), 5.55 (1H, br d, 10.2 Hz), 5.45 (1H, m),
4.78 (1H, d, 15.8 Hz), 4.68 (1H, d, 15.5 Hz), 4.07 (2H, br), 3.98
(1H, br), 3.69 (1H, br), 2.84-3.04 (8H, m), 2.22 (1H, br d, 14.9
Hz), 2.04 (1H, ddd, 14.5, 4.6, 4.3 Hz), 1.54 (3H, d, 6.9 Hz),
1.20-1.48 (6H, br), 1.57 (3H, d, 6.9 Hz).
EXAMPLE 25
[0217] Compound 26:
[0218] Isomer ratio: about 3:1
[0219] FAB-MS m/z: 562 [M+H].sup.+
[0220] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
10.92 (1H, br), 9.00 (1H, br), 7.17 (1H, m), 7.05 (1H, m), 6.81
(1H, d, 15.8 Hz), 6.56 (1H, s), 6.16 (1H, t, 10.6 Hz), 5.63 (1H,
dd, 10.4, 3.1 Hz), 5.44 (1H, m), 4.64 (1H, d, 19.5 Hz), 4.60 (1H,
br), 4.57 (1H, d, 17.8 Hz), 4.06 (1H, br), 3.40 (2H, t, 6.9 Hz),
3.25-3.36 (4H, m), 3.21 (1H, br), 2.96 (1H, br d, 8.2 Hz),
2.30-2.42 (3H, m), 2.03 (2H, t, 7.6 Hz), 2.00 (1H, m), 1.77 (2H,
m), 1.54 (3H, d, 6.6 Hz).
EXAMPLE 26
[0221] Compound 27:
[0222] Isomer ratio: about 3:1
[0223] FAB-MS m/z: 505 [M+H].sup.+
[0224] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
10.75 (1H, br), 8.50 (1H, br), 7.23 (1H, dd, 16.0, 11.4 Hz), 6.67
(1H, d, 16.2 Hz), 6.61 (1H, s), 6.32 (1H, d, 7.6 Hz), 6.14 (1H, dd,
11.9, 10.2 Hz), 5.68 (1H, dd, 10.4, 3.1 Hz), 5.49 (1H, m), 4.67
(1H, d, 15.8 Hz), 4.58 (2H, s), 4.26 (1H, m), 3.99 (1H, d, 15.8
Hz), 3.19 (1H, br), 2.96 (1H, m), 2.33 (1H, ddd, 15.2, 3.3, 3.3
Hz), 1.89-2.04 (3H, m), 1.58-1.66 (4H, m), 1.55 (3H, d, 6.6 Hz),
1.38-1.43 (2H, m).
EXAMPLE 27
[0225] Compound 28:
[0226] Isomer ratio: about 3:1
[0227] FAB-MS m/z: 513 [M+H].sup.+
[0228] Major component: 1H-NMR (CDCl.sub.3) .delta. (ppm): 10.76
(1H, br), 7.48-7.56 (2H, m), 7.25-7.37 (3H, m), 7.07-7.16 (2H, m),
6.77 (1H, d, 16.2 Hz), 6.61 (1H, s), 6.21 (1H, dd, 11.6, 10.6 Hz),
5.74 (1H, dd, 10.2, 3.6 Hz), 5.52 (1H, m), 4.80 (1H, br), 4.73 (2H,
s), 4.12 (1H, br), 3.23 (1H, br), 2.99 (1H, ddd, 8.3, 3.3, 2.6 Hz),
2.36 (1H, ddd, 15.2, 3.6, 3.3 Hz), 1.99 (1H, ddd, 15.2, 4.0, 4.0
Hz), 1.57 (3H, d, 6.9 Hz).
EXAMPLE 28
[0229] Compound 29:
[0230] Isomer ratio: about 4:1
[0231] FAB-MS m/z: 555 [M+H].sup.+
[0232] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
8.00 (1H, br s), 7.43 (2H, d, 8.6 Hz), 7.19 (2H, d, 8.3 Hz), 7.20
(1H, m), 6.77 (1H, d, 16.2 Hz), 6.59 (1H, s), 6.19 (1H, dd, 10.6,
9.9 Hz), 5.73 (1H, dd, 10.2, 3.3 Hz), 5.49 (1H, m), 4.72 (2H, s),
4.72 (1H, br), 4.09 (1H, br), 3.22 (1H, br), 2.82-3.01 (2H, m),
2.35 (1H, dd, 15.2, 3.3, 3.3 Hz), 1.98 (1H, ddd, 15.2, 4.0, 4.0
Hz), 1.55 (3H, d, 6.6 Hz), 1.22 (6H, d, 6.9 Hz).
EXAMPLE 29
[0233] Compound 30:
[0234] Isomer ratio: about 3:1
[0235] FAB-MS m/z: 543 [M+H].sup.+
[0236] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
7.97 (1H, d, 9.2 Hz), 7.38-7.44 (2H, m), 7.26 (1H, dd, 15.8, 11.5
Hz), 6.81-6.86 (2H, m), 6.75 (1H, d, 16.2 Hz), 6.56 (1H, s), 6.16
(1H, dd, 11.6, 10.2 Hz), 5.69 (1H, dd, 10.6, 3.3 Hz), 5.47 (1H, m),
4.73 (1H, d, 16.5 Hz), 4.67 (1H, d, 14.9 Hz), 4.64 (1H, br), 4.04
(1H, d, 14.5 Hz), 3.75 (3H, s), 3.20 (1H, br), 2.96 (1H, ddd, 9.9,
3.6, 2.3 Hz), 2.33 (1H, ddd, 15.2, 3.6, 3.3 Hz), 1.94 (1H, ddd,
15.2, 4.0, 4.0 Hz), 1.53 (3H, d, 6.9 Hz).
EXAMPLE 30
[0237] Compound 31:
[0238] Isomer ratio: about 3:1
[0239] FAB-MS m/z: 584 [M+H].sup.+
[0240] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
7.98 (1H, br s), 7.32 (2H, d, 8.9 Hz), 7.29 (1H, m), 6.75 (1H, d,
16.2 Hz), 6.64 (2H, d, 8.9 Hz), 6.58 (1H, s), 6.18 (1H, dd, 11.9,
9.9 Hz), 5.71 (1H, dd, 10.2, 3.0 Hz), 5.48 (1H, m), 4.72 (1H, d,
16.8 Hz), 4.71 (2H, s), 4.04 (1H, d, 15.8 Hz), 3.31 (4H, q, 7.1
Hz), 3.21 (1H, br), 2.99 (1H, ddd, 8.6, 2.6, 2.3 Hz), 2.34 (1H,
ddd, 15.2, 3.6, 3.3 Hz), 1.96 (1H, ddd, 15.2, 4.0, 4.0 Hz), 1.55
(3H, d, 6.6 Hz), 1.12 (6H, t, 7.1 Hz).
EXAMPLE 31
[0241] Compound 32:
[0242] Isomer ratio: about 3:1
[0243] FAB-MS m/z: 514 [M+H].sup.+
[0244] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
8.56 (1H, br d, 7.9 Hz), 8.46 (1H, m), 8.30-8.34 (2H, m), 7.31-7.42
(2H, m), 6.76 (1H, d, 16.2 Hz), 6.52 (1H, s), 6.17 (1H, dd, 10.9,
9.9 Hz), 5.72 (1H, dd, 10.2, 3.0 Hz), 5.48 (1H, m), 4.80 (1H, br),
4.77 (1H, d, 16.5 Hz), 4.70 (1H, d, 16.5 Hz), 4.03 (1H, d, 16.5
Hz), 3.20 (1H, br), 2.95 (1H, m), 2.34 (1H, ddd, 15.2, 3.3, 3.3
Hz), 1.97 (1H, ddd, 15.2, 4.3, 4.0 Hz), 1.56 (3H, d, 6.9 Hz).
EXAMPLE 32
[0245] Compound 33:
[0246] Isomer ratio: about 3:1
[0247] FAB-MS m/z: 480 [M+H].sup.+
[0248] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
10.77 (1H, br s), 7.24 (1H, dd, 16.2, 11.2 Hz), 7.00 (1H, br s),
6.67 (1H, d, 16.5 Hz), 6.64 (1H, s), 6.17 (1H, dd, 11.2, 10.6 Hz),
5.71 (1H, dd, 10.2, 3.0 Hz), 5.53 (1H, m), 4.75 (1H, br), 4.62 (2H,
s), 4.08 (1H, br), 3.22 (1H, br), 2.99 (1H, br d, 8.3 Hz), 2.63
(6H, s), 2.36 (1H, ddd, 14.8, 3.6, 3.6 Hz), 1.99 (1H, ddd, 15.5,
8.6, 4.1 Hz), 1.57 (3H, d, 6.6 Hz).
EXAMPLE 33
[0249] Compound 34:
[0250] Isomer ratio: about 3:1
[0251] FAB-MS m/z: 496 [M+H].sup.+
[0252] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
10.70 (1H, br), 7.72 (1H, br), 7.24 (1H, dd, 15.2, 11.5 Hz), 6.66
(1H, d, 16.2 Hz), 6.60 (1H, s), 6.17 (1H, dd, 11.9, 10.2 Hz), 5.72
(1H, dd, 10.4, 3.5 Hz), 5.51 (1H, m), 4.70 (1H, br), 4.70 (2H, s),
4.10 (1H, br), 3.62 (2H, t, 4.6 Hz), 2.96-2.98 (3H, m), 2.36 (1H,
ddd, 15.5, 3.8, 3.3 Hz), 2.00 (1H, ddd, 15.5, 8.6, 4.0 Hz), 1.58
(3H, d, 6.9 Hz).
EXAMPLE 34
[0253] Compound 35:
[0254] Isomer ratio: about 3:1
[0255] FAB-MS m/z: 528 [M+H].sup.+
[0256] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
10.75 (1H, br), 8.01 (1H, br s), 7.19-7.25 (2H, m), 7.00 (1H, dd,
15.2, 10.9 Hz), 6.86-6.93 (4H, m), 6.71 (1H, d, 16.2 Hz), 6.58 (1H,
s), 6.18 (1H, dd, 10.6, 9.9 Hz), 5.72 (1H, dd, 10.4, 3.1 Hz), 5.50
(1H, m), 4.82 (1H, br), 4.76 (2H, s), 4.12 (1H, d, 14.2 Hz), 3.22
(1H, br), 2.97 (1H, m), 2.35 (1H, ddd, 15.2, 3.6, 3.3 Hz), 1.99
(1H, ddd, 15.2, 8.6, 4.3 Hz), 1.55 (3H, d, 6.6 Hz).
EXAMPLE 35
[0257] Compound 36:
[0258] Isomer ratio: about 4:1
[0259] FAB-MS m/z: 529 [M+H].sup.+
[0260] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
8.30 (1H, br), 8.10 (1H, br d, 4.6 Hz), 8.07 (1H, br), 7.52 (1H,
dd, 7.6, 6.6 Hz), 7.22 (1H, m), 6.67-6.87 (3H, m), 6.54 (1H, s),
6.15 (1H, dd, 11.2, 10.9 Hz), 5.70 (1H, dd, 10.2, 3.0 Hz), 5.48
(1H, m), 4.74 (2H, s), 4.67 (1H, d, 15.5 Hz), 4.08 (1H, br), 3.23
(1H, br), 2.98 (1H, br d, 8.3 Hz), 2.35 (1H, br d, 15.5 Hz), 1.98
(1H, m), 1.55 (3H, d, 6.6 Hz).
EXAMPLE 36
[0261] Compound 37:
[0262] Isomer ratio: about 2:1
[0263] FAB-MS m/z: 520 [M+H].sup.+
[0264] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
10.80 (1H, br), 8.50 (1H, br), 7.25 (1H, dd, 15.8, 11.2 Hz), 7.06
(1H, s), 6.67 (1H, d, 13.5 Hz), 6.64 (1H, s), 6.16 (1H, dd, 11.2,
10.9 Hz), 5.70 (1H, dd, 10.2, 3.0 Hz), 5.50 (1H, m), 4.69 (1H, d,
15.8 Hz), 4.62 (2H, s), 4.01 (1H, d, 14.9 Hz), 3.19 (1H, br), 2.96
(1H, m), 2.73 (4H, br), 2.34 (1H, ddd, 15.2, 3.6, 3.0 Hz), 1.96
(1H, ddd, 15.2, 8.4, 4.1 Hz), 1.66 (6H, br), 1.56 (3H, d, 6.9
Hz).
EXAMPLE 37
[0265] Compound 38:
[0266] Isomer ratio: about 2:1
[0267] FAB-MS m/z: 535 [M+H].sup.+
[0268] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
7.25 (1H, m), 7.14 (1H, s), 6.68 (1H, 16.2 Hz), 6.44 (1H, s), 6.16
(1H, dd, 11.2, 10.9 Hz), 5.72 (1H, dd, 10.1, 2.8 Hz), 5.49 (1H, m),
4.74 (1H, br), 4.64 (1H, 16.5 Hz), 4.57 (1H, 16.5 Hz), 4.01 (1H,
br), 3.20 (1H, br), 2.93-2.99 (5H, br), 2.76 (4H, br), 2.45 (1H,
m), 2.37 (6H, s), 1.97 (1H, m), 1.56 (3H, d, 6.6 Hz).
EXAMPLE 38
[0269] Compound 39:
[0270] According to (1-1) described in Example 1, an oxime
derivative was prepared from radicicol and trifluoroacetate of
compound a, and then compound 39 was prepared according to (1-2)
described in Example 1.
[0271] Isomer ratio: about 5:1
[0272] FAB-MS m/z: 589 [M+H].sup.+
[0273] Major component: .sup.1H-NMR (CDCl.sub.3+CD.sub.3OD) .delta.
(ppm): 10.85 (1H, br), 7.90 (1H, br), 7.16 (1H, m), 6.67 (1H, d,
15.8 Hz), 6.58 (1H, s), 6.15 (1H, dd, 11.6, 10.6 Hz), 5.64 (1H, br
d, 9.9 Hz), 5.50 (1H, m), 4.75 (1H, br), 4.19 (2H, m), 4.02 (1H,
br), 3.55 (2H, br), 3.40 (2H, br), 3.19 (1H, br), 2.97 (1H, ddd,
7.9, 2.4, 2.4 Hz), 2.29-2.36 (3H, m), 1.99 (1H, ddd, 15.2, 8.9, 4.0
Hz), 1.59-1.64 (10H, br), 1.56 (3H, d, 6.6 Hz), 1.37 (6H, br).
EXAMPLE 39
[0274] Compound 40:
[0275] According to Example 38, compound 40 was prepared from a
trifluoroacetate of compound b.
[0276] Isomer ratio: about 2:1
[0277] FAB-MS m/z: 631 [M+H].sup.+
[0278] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
11.03 (1H, br), 8.72 (1H, br), 7.16 (1H, dd, 15.8, 12.9 Hz), 6.67
(1H, d, 16.2 Hz), 6.58 (1H, s), 6.14 (1H, dd, 11.2, 9.9 Hz), 5.62
(1H, br d, 9.6 Hz), 5.49 (1H, m), 4.72 (1H, br), 4.05-4.21 (3H, m),
3.56 (2H, br), 3.40 (2H, br), 3.21 (1H, br), 2.97 (1H, ddd, 8.3,
2.3, 2.3 Hz), 2.29-2.37 (3H, m), 2.01 (1H, ddd, 15.2, 8.6, 4.3 Hz),
1.60-1.76 (10H, br), 1.55 (3H, d, 6.6 Hz), 1.28 (12H, br).
EXAMPLE 40
[0279] Compound 41
[0280] According to (1-2) described in Example 1, 14 mg (yield,
10%) of compound 41 was prepared from 100 mg (0.228 mmol) of
compound (K), 52 mg (0.342 mmol) of HOBt, 65 mg (0.342 mmol) of
EDCI and 69 mg (0.274 mmol) of pentaethylene glycol monomethyl
ether. The thus prepared compound 41 was found to be a mixture of
oxime-based isomers (about 3:1) according to .sup.1H-NMR.
[0281] FAB-MS m/z: 672 [M+H].sup.+
[0282] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm) :
7.20 (1H, m), 6.77 (1H, d, 16.2 Hz), 6.58 (1H, s), 6.16 (1H, dd,
11.6, 10.6 Hz), 5.66 (1H, br d, 9.6 Hz), 5.53 (1H, m), 4.77 (1H,
br), 4.76 (1H, d, 16.5 Hz), 4.69 (1H, 16.2 Hz), 4.33 (2H, m), 4.00
(1H, br), 3.72 (2H, m), 3.64-3.65 (14H, m), 3.53-3.56 (2H, m), 3.37
(3H, s), 3.20 (1H, br), 2.98 (1H, br d, 8.6 Hz), 2.34 (1H, ddd,
15.2, 3.6, 3.3 Hz), 2.00 (1H, ddd, 15.5, 4.3, 4.0 Hz), 1.56 (3H, d,
6.6 Hz).
EXAMPLE 41
[0283] Compound 42:
[0284] According to Example 40, compound 42 was prepared from
compound (K).
[0285] Isomer ratio: about 3:1
[0286] FAB-MS m/z: 584 [M+H].sup.+
[0287] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
10.80 (1H, br), 7.20 (1H, m), 6.77 (1H, d, 16.2 Hz), 6.58 (1H, br),
6.58 (1H, s), 6.16 (1H, t, 10.9 Hz), 5.67 (1H, br d, 9.9 Hz), 5.51
(1H, m), 4.78 (1H, br), 4.76 (1H, d, 16.5 Hz), 4.69 (1H, d, 16.5
Hz), 4.31-4.35 (2H, m), 4.02 (1H, br), 3.73 (2H, t, 4.8 Hz),
3.63-3.67 (6H, m), 3.54-3.57 (2H, m), 3.38 (3H, s), 3.19 (1H, br),
2.98 (1H, ddd, 9.2, 3.3, 3.3 Hz), 2.34 (1H, ddd, 15.2, 3.6, 3.3
Hz), 1.98 (1H, ddd, 18.8, 4.0, 4.0 Hz), 1.57 (3H, d, 6.9 Hz).
EXAMPLE 42
[0288] Compound 43:
[0289] According to (1-1) described in Example 1, 338 mg (yield,
53%) of compound 43 was prepared from 500 mg (1.37 mmol) of
radicicol and 438 mg (2.74 mmol) of o-benzylhydroxylamine
hydrochloride. The thus prepared compound 43 was found to be a
mixture of oxime-based isomers (about 2:1) according to
.sup.1H-NMR.
[0290] FAB-MS m/z: 470 [M+H].sup.+
[0291] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.10-7.50 (6H, m), 6.78 (1H, d, 15.8 Hz), 6.42 (1H, s), 6.18 (1H,
t, 10.9 Hz), 5.59 (1H, dd, 10.9, 3.3 Hz), 5.30 (1H, m), 5.16 (2H,
s), 3.91 (1H, d, 16.3 Hz), 3.81 (1H, d, 16.3 Hz), 3.32 (1H, m),
3.01 (1H, dt, 7.9, 3.3 Hz), 2.41 (1H, dd, 14.3, 3.5 Hz), 1.55 (1H,
m), 1.52 (3H, d, 6.4 Hz).
EXAMPLE 43
[0292] Compound 44:
[0293] A 205 mg (1.12 mmol) portion of compound c was dissolved in
3 ml of methanol, and the solution was mixed with 0.467 ml of 12 N
hydrochloric acid and stirred at room temperature for 2.5 hours.
The solvent was evaporated under reduced pressure, the thus
prepared residue was dissolved in 2 ml of pyridine and mixed with
136 mg (0.37 mmol) of radicicol which had been dissolved in 2 ml of
pyridine, and then the mixture was stirred at room temperature for
138 hours. The reaction solution was mixed with 0.5 N hydrochloric
acid and extracted with ethyl acetate. The ethyl acetate layer was
washed with saturated brine and dried with anhydrous sodium
sulfate, and then the solvent was evaporated under reduced
pressure. The resulting residue was purified by thin layer
chromatography (chloroform/methanol=5/1, then
chloroform/acetone=4/1) to obtain 119 mg (yield, 65%) of compound
44. The thus prepared compound 44 was found to be a mixture of
oxime-based isomers (about 2.5:1) according to .sup.1H-NMR.
[0294] FAB-MS m/z: 486 [M+H].sup.+
[0295] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
11.00 (1H, br), 9.09 (1H, br), 7.22-7.32 (3H, m), 7.00 (1H, d, 8.2
Hz), 6.91 (1H, ddd, 7.6, 7.3, 1.1 Hz), 6.64 (1H, d, 15.8 Hz), 6.57
(1H, s), 6.14 (1H, dd, 9.9, 9.6 Hz), 5.69 (1H, br d, 10.2 Hz), 5.47
(1H, m), 5.15 (1H, d, 13.5 Hz), 5.08 (1H, d, 12.9 Hz), 4.80 (1H,
br), 3.99 (1H, br), 3.20 (1H, br), 2.96 (1H, ddd, 8.3, 2.6, 2.5
Hz), 2.31 (1H, ddd, 15.2, 3.6, 3.3 Hz), 1.97 (1H, ddd, 14.9, 8.6,
4.0 Hz), 1.55 (3H, d, 6.6 Hz).
EXAMPLES 44-49
[0296] According to Example 43, compounds 45 to 50 were prepared
from radicicol and compounds d to i, respectively.
EXAMPLE 44
[0297] Compound 45:
[0298] Isomer ratio: about 1.7:1
[0299] FAB-MS m/z: 502 [M+H].sup.+
[0300] Major component: .sup.1H-NMR (CDCl.sub.3+CD.sub.3OD) .delta.
(ppm): 7.11 (1H, dd, 16.2, 11.2 Hz), 6.67 (1H, d, 16.2 Hz), 6.37
(1H, s), 6.35 (1H, d, 2.0 Hz), 6.32 (1H, d, 2.0 Hz), 6.18 (1H, d,
2.0 Hz), 6.05 (1H, t, 10.6 Hz), 5.54 (1H, dd, 10.1, 2.8 Hz), 5.36
(1H, m), 4.97 (2H, s), 4.36 (1H, d, 16.2 Hz), 3.86 (1H, d, 18.1
Hz), 3.16 (1H, br), 2.91 (1H, br d, 8.9 Hz), 2.26 (1H, ddd, 14.9,
3.3, 3.0 Hz), 1.77 (1H, ddd, 14.9, 4.3, 4.0 Hz), 1.47 (3H, d, 6.6
Hz).
EXAMPLE 45
[0301] Compound 46:
[0302] Isomer ratio: about 1.8:1
[0303] FAB-MS m/z: 560 [M+H].sup.+
[0304] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
7.17 (1H, dd, 15.8, 11.5 Hz), 6.73 (1H, d, 16.2 Hz), 6.63 (2H, s),
6.54 (1H, s), 6.13 (1H, dd, 12.5, 10.6 Hz), 5.60 (1H, br d, 11.2
Hz), 5.49 (1H, m), 5.11 (2H, s), 4.69 (1H, br), 4.04 (1H, br), 3.85
(3H, s), 3.84 (6H, s), 3.18 (1H, br), 2.96 (1H, br d, 8.9 Hz), 2.32
(1H, ddd, 14.9, 3.6, 3.3 Hz), 1.95 (1H, ddd, 14.5, 9.4, 4.1 Hz),
1.54 (3H, d, 6.6 Hz).
EXAMPLE 46
[0305] Compound 47:
[0306] Isomer ratio: about 1.8:1
[0307] FAB-MS m/z: 500 [M+H].sup.+
[0308] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
7.16 (1H, dd, 16.5, 11.2 Hz), 6.74 (1H, d, 16.2 Hz), 6.52 (1H, s),
6.21 (1H, d, 2.0 Hz), 6.18 (1H, d, 2.0 Hz), 6.14 (1H, dd, 10.9,
10.6 Hz), 5.98 (1H, dd, 3.6, 2.0 Hz), 5.65 (1H, br d, 10.2 Hz),
5.49 (1H, m), 5.02 (1H, s), 4.70 (1H, br), 3.99 (1H, br), 3.18 (1H,
br), 2.96 (1H, ddd, 8.9, 3.3, 2.6 Hz), 2.32 (1H, ddd, 15.2, 3.6,
3.3 Hz), 1.96 (1H, ddd, 15.0, 9.4, 4.5 Hz), 1.55 (3H, d, 6.9
Hz).
EXAMPLE 47
[0309] Compound 48:
[0310] Isomer ratio: about 3:1
[0311] FAB-MS m/z: 527 [M+H].sup.+
[0312] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
7.15 (1H, m), 7.14 (2H, d, 8.6 Hz), 6.72 (2H, d, 8.6 Hz), 6.69 (1H,
d, 15.8 Hz), 6.56 (1H, s), 6.14 (1H, dd, 11.2, 10.6 Hz), 5.64 (1H,
dd, 10.2, 3.3 Hz), 5.50 (1H, m), 4.73 (1H, br), 4.25-4.38 (2H, m),
4.06 (1H, br), 3.21 (1H, br), 2.95-3.00 (3H, m), 2.92 (6H, s), 2.34
(1H, ddd, 15.2, 3.5, 3.3 Hz), 1.99 (1H, ddd, 14.8, 8.9, 4.0 Hz),
1.57 (3H, d, 6.9 Hz).
EXAMPLE 48
[0313] Compound 49:
[0314] Isomer ratio: about 2.4:1
[0315] FAB-MS m/z: 582 [M+H].sup.+
[0316] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
7.38 (2H, d, 7.9 Hz), 7.14-7.32 (1H, m), 7.23 (2H, d, 7.6 Hz), 6.71
(1H, d, 15.8 Hz), 6.38 (1H, s), 6.15 (1H, dd, 11.9, 10.6 Hz), 5.64
(1H, dd, 10.2, 2.0 Hz), 5.47 (1H, m), 5.17 (2H, s), 4.70 (1H, br),
3.68 (1H, br), 3.66 (2H, s), 3.21 (1H, br), 2.97 (1H, br d, 8.3
Hz), 2.61 (8H, br), 2.37 (3H, s), 2.33 (1H, ddd, 14.2, 3.6, 3.3
Hz), 1.99 (1H, m), 1.54 (3H, d, 6.6 Hz).
EXAMPLE 49
[0317] Compound 50:
[0318] Isomer ratio: about 1.4:1
[0319] FAB-MS m/z: 577 [M+H].sup.+
[0320] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
7.88 (1H, d, 7.9 Hz), 7.71 (1H, m), 7.57 (1H, dd, 7.9, 7.3 Hz),
7.42 (1H, d, 8.3, 7.3 Hz), 7.19 (1H, m), 6.79 (1H, d, 16.2 Hz),
6.56 (1H, s), 6.17 (1H, dd, 10.9, 9.6 Hz), 5.59-5.72 (3H, m), 5.51
(1H, m), 4.66 (1H, br), 3.96 (1H, br), 3.20 (1H, br), 2.99 (1H,
ddd, 8.6, 2.6, 2.6 Hz), 2.80 (6H, s), 2.34 (1H, ddd, 15.2, 3.6, 3.3
Hz), 1.97 (1H, m), 1.56 (3H, d, 6.6 Hz).
EXAMPLE 50
[0321] Compound 51:
[0322] A 565 mg (4.55 mmol) portion of compound j was dissolved in
10 ml of pyridine, and the solution was mixed with 0.4 ml of
concentrated hydrochloric acid and 664 mg (1.82 mmol) of radicicol
and stirred at room temperature for 21 hours. The reaction solution
was mixed with a saturated ammonium chloride aqueous solution and
extracted with ethyl acetate, the ethyl acetate layer was washed
with saturated brine and dried with anhydrous sodium sulfate, and
then the solvent was evaporated under reduced pressure. The
resulting residue was purified by silica gel column chromatography
(chloroform/methanol=40/1) to obtain 694 mg (yield, 81%) of
compound 51.
[0323] Isomer ratio: about 2:1
[0324] FAB-MS m/z: 471 [M+H].sup.+
[0325] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
8.48 (1H, d, 4.0 Hz), 7.84 (1H, dt, 7.6, 1.8 Hz), 7.53 (1H, m),
7.33 (1H, m), 7.26 (1H, dd, 16.2, 11.2 Hz), 6.87 (1H, d, 15.8 Hz),
6.40 (1H, s), 6.17 (1H, t, 10.9 Hz), 5.60 (1H, dd, 10.9, 3.0 Hz),
5.28 (1H, m), 5.23 (2H, s), 3.92 (1H, d, 16.2 Hz), 3.77 (1H, d,
16.2 Hz), 3.33 (1H, m), 3.01 (1H, m), 2.40 (1H, ddd, 14.2, 3.6, 3.3
Hz), 1.58 (1H, ddd, 13.8, 8.9, 4.4 Hz), 1.51 (3H, d, 6.3 Hz).
EXAMPLE 51
[0326] Compounds 52 and 53:
[0327] A mixture of compounds 52 and 53 (about 4:1) was prepared
from radicicol and compound k according to Example 50, 380 mg of
the thus prepared mixture of compounds 52 and 53 (about 4:1) was
separated by high performance liquid chromatography (column:
YMC-Pack ODS AM, SH-365-10AM, 500.times.30 mm I.D., eluent: 50 mM4
phosphate buffer (pH 7.3)/methanol=47/53, flow rate: 40 ml/min,
detection: UV 276 nm), the eluate was extracted with ethyl acetate,
washed with saturated brine and dried with anhydrous sodium
sulfate, and then the solvent was evaporated under reduced
pressure. Each of the resulting residues was powdered from a mixed
solvent of ethanol and water to obtain 219 mg of compound 52 and
133 mg of compound 53.
[0328] Compound 52:
[0329] FAB-MS m/z: 471 [M+H].sup.+
[0330] .sup.1H-NMR (CD.sub.3OD) .delta. (ppm): 8.58 (1H, d, 2.0
Hz), 8.47 (1H, dd, 5.0, 2.0 Hz), 7.89 (1H, dd, 7.9, 2.0 Hz), 7.43
(1H, ddd, 7.9, 5.0, 2.0 Hz), 7.26 (1H, dd, 15.8, 10.9 Hz), 6.76
(1H, d, 15.8 Hz), 6.41 (1H, s), 6.16 (1H, t, 10.9 Hz), 5.61 (1H,
dd, 10.9, 3.0 Hz), 5.31 (1H, m), 5.22 (2H, s), 3.91 (1H, d, 15.8
Hz), 3.81 (1H, d, 16.3 Hz), 3.35 (1H, m), 3.02 (1H, m), 2.42 (1H,
dt, 15.3, 4.0 Hz), 1.58 (1H, ddd, 13.8, 8.9, 4.4 Hz), 1.52 (3H, d,
6.4 Hz).
[0331] Compound 53:
[0332] FAB-MS m/z: 471 [M+H].sup.+
[0333] .sup.1H-NMR (CD.sub.3OD) .delta. (ppm): 8.61 (1H, d, 2.0
Hz), 8.49 (1H, dd, 5.0, 2.0 Hz), 7.93 (1H, dd, 7.9, 2.0 Hz), 7.45
(1H, ddd, 7.9, 5.0, 2.0 Hz), 7.15 (1H, dd, 16.2, 10.9 Hz), 6.41
(1H, s), 6.12 (1H, d, 15.8 Hz), 6.09 (1H, t, 10.9 Hz), 5.48 (1H,
dd, 10.9, 3.0 Hz), 5.31 (1H, m), 5.26 (2H, s), 4.64 (1H, d, 16.4
Hz), 3.40 (1H, d, 16.2 Hz), 3.35 (1H, m), 2.96 (1H, dt, 8.9, 2.6
Hz), 2.42 (1H, dt, 14.5, 3.0 Hz), 1.60 (1H, m), 1.50 (3H, d, 6.4
Hz).
EXAMPLE 52
[0334] Compound 54:
[0335] According to Example 50, compound 54 was prepared from
radicicol and compound m.
[0336] Isomer ratio: about 2:1
[0337] FAB-MS m/z: 471 [M+H].sup.+
[0338] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
8.60 (2H, m), 7.50 (1H, m), 7.29 (1H, dd, 16.2, 11.2 Hz), 6.85 (1H,
d, 11.2 Hz), 6.43 (1H, s), 6.18 (1H, t, 10.9 Hz), 5.62 (1H, dd,
10.6, 3.3 Hz), 5.30 (1H, m), 5.23 (2H, s), 3.91 (1H, d, 16.2 Hz),
3.81 (1H, d, 16.2 Hz), 3.35 (1H, m), 3.02 (1H, dt, 7.9, 3.3 Hz),
2.42 (1H, dd, 14.5, 4.0 Hz), 1.59 (1H, ddd, 13.8, 8.9, 4.4 Hz),
1.52 (3H, d, 6.3 Hz).
EXAMPLE 53
[0339] Compound 55:
[0340] According to Example 43, compound 55 was prepared from
radicicol and compound n.
[0341] Isomer ratio: about 1.5:1
[0342] FAB-MS m/z: 499 [M+H].sup.+
[0343] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
8.47 (1H, s), 8.42 (1H, d, 5.0 Hz), 7.62 (1H, d, 7.9 Hz), 7.28 (1H,
dd, 7.6, 4.9 Hz), 7.17 (1H, dd, 15.5, 11.5 Hz), 6.63 (1H, d, 16.2
Hz), 6.52 (1H, s), 6.15 (1H, dd, 11.6, 11.2 Hz), 5.65 (1H, br d,
9.9 Hz), 5.50 (1H, m), 4.71 (1H, d, 15.5 Hz), 4.20 (2H, t, 6.8 Hz),
4.01 (1H, br), 3.19 (1H, br), 2.97 (1H, br d, 8.6 Hz), 2.77 (2H, t,
7.3 Hz), 2.33 (2H, ddd, 15.2, 3.3, 3.0 Hz), 2.07 (2H, m), 1.94 (1H,
ddd, 16.8, 8.3, 4.0 Hz), 1.56 (3H, d, 6.9 Hz).
EXAMPLE 54
[0344] Compound 56:
[0345] According to Example 43, compound 56 was prepared from
radicicol and compound o.
[0346] Isomer ratio: about 3:1
[0347] FAB-MS m/z: 487 [M+H].sup.+
[0348] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
10.95 (1H, br), 9.36 (1H, br), 8.15 (1H, d, 4.3 Hz), 7.34 (1H, d,
8.3 Hz), 7.20-7.30 (2H, m), 6.69 (1H, d, 16.2 Hz), 6.57 (1H, s),
6.15 (1H, dd, 10.9, 10.6 Hz), 5.70 (1H, br d, 11.2 Hz), 5.48 (1H,
m), 5.32 (1H, d, 12.5 Hz), 5.24 (1H, d, 12.5 Hz), 4.77 (1H, br),
4.03 (1H, br), 3.19 (1H, br), 2.96 (1H, br d, 8.2 Hz), 2.32 (1H,
ddd, 15.2, 3.3, 3.0 Hz), 1.97 (1H, ddd, 14.7, 8.7, 4.3 Hz), 1.55
(3H, d, 6.6 Hz).
EXAMPLE 55
[0349] Compound 57:
[0350] (55-1):
[0351] A 5.00 g (13.7 mmol) portion of radicicol was dissolved in
10 ml of DMF to which, while cooling in an ice bath, were
subsequently added 2.80 g (41.1 mmol) of imidazole and 4.54 g (30.1
mmol) of tert-butyl(chloro)dimethylsilane, and the resulting
mixture was stirred at room temperature for 3 hours. The reaction
solution was mixed with a saturated ammonium chloride aqueous
solution and extracted with ethyl acetate, the ethyl acetate layer
was washed with saturated brine and dried with anhydrous sodium
sulfate, and then the solvent was evaporated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (chloroform/methanol=100/1) to obtain 6.96 g (yield,
86%) of a di-tert-butyldimethylsilyl derivative of radicicol.
[0352] FAB-MS m/z: 593 [M+H].sup.+
[0353] (55-2):
[0354] According to (1-1) described in Example 1, 18 mg (yield,
5.5%) of compound (L) was prepared from 319 mg (0.54 mmol) of
di-tert-butyldimethylsilyl derivative of radicicol and 240 mg (3.45
mmol) of hydroxylamine hydrochloride. The thus prepared compound
(L) was found to be a mixture of oxime-based isomers (about 1:1)
according to .sup.1H-NMR.
[0355] FAB-MS m/z: 608 [M+N].sup.+ 77
[0356] (55-3):
[0357] A 120 mg (0.20 mmol) portion of compound (L) was dissolved
in 1.7 ml of THF, the resulting solution was mixed with 167 mg
(0.99 mmol) of 2-hydroxymethyl-3-methoxymethoxypyridine dissolved
in 0.5 ml of THF, which had been prepared by dimethoxymethylation
of 3-hydroxy-2-pyridinecarboxylic acid and subsequent reduction
with lithium aluminum hydride, 103 mg (0.39 mmol) of
triphenylphosphine and 0.06 ml (0.39 mmol) of DEAD, and the mixture
was stirred at room temperature for 23 hours. The reaction solution
was mixed with a phosphate buffer (pH 7) and extracted with ethyl
acetate. The ethyl acetate layer was washed with saturated brine
and dried with anhydrous sodium sulfate, and then the solvent was
evaporated under reduced pressure. The resulting residue was
purified by thin layer chromatography (chloroform/methanol=100/1)
to obtain 39 mg (yield, 26%) of a di-tert-butyldimethylsilyl
derivative of compound 57.
[0358] FAB-MS m/z: 761 [M+H].sup.+
[0359] (55-4):
[0360] A 39 mg (0.05 mmol) portion of the
di-tert-butyldimethylsilyl derivative of compound 57 was dissolved
in 1.8 ml of THF, 0.13 ml (0.13 mmol) of a 1 M TBAF/THF solution
was added to the thus prepared solution which was cooled at
-10.degree. C., and the resulting mixture was stirred for 50
minutes at the same temperature. The reaction solution was mixed
with a phosphate buffer (pH 7) and extracted with chloroform. The
chloroform layer was washed with saturated brine and dried with
anhydrous sodium sulfate, and then the solvent was evaporated under
reduced pressure. The resulting residue was purified by thin layer
chromatography (chloroform/methanol=12/1) to obtain 26 mg (yield,
95%) of compound 57. The thus prepared compound 57 was found to be
a mixture of oxime-based isomers (about 1:1.7) according to
.sup.1H-NMR.
[0361] FAB-MS m/z: 531 [M+H].sup.+
[0362] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
11.15 (1H, br), 8.28 (1H, dd, 4.6, 1.3 Hz), 7.49 (1H, d, 8.3 Hz),
7.25 (1H, dd, 8.3, 5.0 Hz), 7.02 (1H, dd, 16.2, 10.9 Hz), 6.72 (1H,
s), 6.13 (1H, d, 15.8 Hz), 6.09 (1H, dd, 10.2, 9.6 Hz), 5.55 (1H,
dd, 10.6, 2.3 Hz), 5.49 (1H, m), 5.30 (2H, s), 5.23 (2H, s), 4.58
(1H, d, 16.5 Hz), 4.21 (1H, d, 16.5 Hz), 3.45 (3H, s), 3.08 (1H,
br), 2.90 (1H, br d, 9.9 Hz), 2.31 (1H, ddd, 15.2, 3.0, 2.6 Hz),
1.90 (1H, ddd, 15.2, 10.2, 4.3 Hz), 1.53 (3H, d, 6.9 Hz).
EXAMPLE 56
[0363] Compound 58:
[0364] According to Example 43, compound 58 was prepared from
radicicol and compound p.
[0365] Isomer ratio: about 1.4:1
[0366] FAB-MS m/z: 487 [M+H].sup.+
[0367] Major component: .sup.1H-NMR (CDCl.sub.3+CD.sub.3OD) .delta.
(ppm): 8.15 (0.25H, dd, 5.9, 3.3 Hz), 7.76 (0.25H, dd, 5.9, 3.3
Hz), 7.64 (1H, m), 7.33 (1H, dd, 3.3, 2.6 Hz), 7.11 (1H, dd, 16.0,
11.4 Hz), 6.56 (1H, d, 16.2 Hz), 6.50 (0.5H, d, 1.7 Hz), 6.38 (1H,
s), 6.05 (1H, dd, 10.9, 9.6 Hz), 5.56 (1H, dd, 10.2, 3.0 Hz), 5.37
(1H, m), 4.86 (2H, s), 4.46 (1H, d, 16.5 Hz), 3.88 (1H, d, 16.5
Hz), 3.18 (1H, br), 2.90 (1H, ddd, 8.6, 2.6, 2.3 Hz), 2.27 (1H,
ddd, 14.9, 4.3, 3.6 Hz), 1.79 (1H, ddd, 14.5, 8.9, 4.0 Hz), 1.47
(3H, d, 6.3 Hz).
EXAMPLE 57
[0368] Compound 59:
[0369] According to (1-1) described in Example 1, compound 59 was
prepared from radicicol and a trifluoroacetate of compound q.
[0370] Isomer ratio: about 2:1
[0371] FAB-MS m/z: 504 [M+H].sup.+
[0372] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.29 (1H, dd, 15.8, 11.2 Hz), 6.82 (1H, d, 16.2 Hz), 6.43 (1H, s),
6.18 (1H, dd, 9 Hz), 5.67 (1H, s), 5.66 (1H, dd, 10.6, 3.6 Hz),
5.31 4.87 (2H, s), 3.95 (1H, d, 16.2 Hz), 3.84 (1H, d, 3.30 (1H,
m), 3.02 (1H, dd, 5.6, 2.3 Hz), 2.43 (1H, 3.5 Hz), 1.62 (1H, m),
1.52 (3H, d, 6.6 Hz).
EXAMPLE 58 60: according to Example 43, compound 60 was prepared
cicol and compound r. ratio: about 2:1 z: 491 [M+H].sup.+component:
.sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 8.88 (2H, br), 7.19 6.66
(1H, d, 12.9 Hz), 6.38 (1H, s), 6.16 (1H, dd, Hz), 5.62 (1H, br d,
10.2 Hz), 5.42 (1H, m), 4.59 (1H, -4.00 (3H, m), 3.11-3.31 (3H, m),
2.95 (1H, br d, .53 (3H, s), 2.11-2.33 (3H, m), 1.95 (1H, m), 1.78
1.53 (3H, d, 6.6 Hz).
EXAMPLE 59 61: according to (1-1) described in Example 1, compound
prepared from radicicol and a hydrochloride of s. ratio: about
1.8:1 z: 477 [M+H].sup.+
[0373] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.27 (1H, dd, 16.5, 11.6 Hz), 6.75 (1H, d, 16.5 Hz), 6.39 (1H, s),
6.15 (1H, dd, 11.6, 10.6 Hz), 5.61 (1H, dd, 10.6, 3.6 Hz), 5.32
(1H, m), 4.38 (2H, m), 3.95 (2H, m), 3.28 (1H, m), 3.20 (2H, m),
3.03 (4H, m), 2.95 (1H, m), 2.41 (1H, m), 1.95 (4H, m), 1.66 (1H,
m), 1.52 (3H, d, 6.3 Hz).
EXAMPLE 60
[0374] Compound 62:
[0375] According to (1-1) described in Example 1, compound 62 was
prepared from radicicol and a hydrochloride of compound t.
[0376] Isomer ratio: about 5:1
[0377] FAB-MS m/z: 505 [M+H].sup.+
[0378] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.26 (1H, dd, 15.8, 10.9 Hz), 6.72 (1H, d, 16.2 Hz), 6.42 (1H, s),
6.16 (1H, dd, 11.9, 10.6 Hz), 5.62 (1H, dd, 10.6, 3.6 Hz), 5.30
(1H, m), 4.23 (2H, dd, 12.5, 6.3 Hz), 3.96 (1H, d, 16.2 Hz), 3.81
(1H, d, 16.2 Hz), 3.35 (1H, m), 3.15 (6H, m), 3.03 (1H, m), 2.44
(1H, dt, 14.5, 3.6 Hz), 2.15 (2H, m), 1.80-1.86 (4H, m), 1.66 (1H,
m), 1.52 (3H, d, 6.3 Hz).
EXAMPLE 61
[0379] Compound 63:
[0380] According to (1-1) described in Example 1, compound 63 was
prepared from radicicol and a hydrochloride of compound u.
[0381] Isomer ratio: about 2:1
[0382] FAB-MS m/z: 521 [M+H].sup.+
[0383] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.25 (1H, dd, 16.2, 11.9 Hz), 6.72 (1H, d, 16.2 Hz), 6.44 (1H, s),
6.16 (1H, dd, 11.9, 10.6 Hz), 5.61 (1H, dd, 10.6, 3.6 Hz), 5.31
(1H, m), 4.24 (2H, m), 3.96 (1H, d, 16.2 Hz), 3.89 (1H, m), 3.83
(1H, d, 16.2 Hz), 3.43 (1H, m), 3.35 (1H, m), 2.96-3.10 (5H, m),
2.43 (1H, dt, 10.9, 3.6 Hz), 1.95-2.20 (4H, m), 1.75-1.80 (4H, m),
1.62 (1H, m), 1.52 (3H, d, 6.6 Hz).
EXAMPLE 62
[0384] Compound 64:
[0385] According to (1-1) described in Example 1, compound 64 was
prepared from radicicol and a hydrochloride of compound v.
[0386] Isomer ratio: about 3:1
[0387] FAB-MS m/z: 521 [M+H].sup.+
[0388] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.24 (1H, dd, 16.2, 11.9 Hz), 6.73 (1H, d, 16.2 Hz), 6.42 (1H, s),
6.15 (1H, m), 5.60 (1H, dd, 10.8, 4.0 Hz), 5.30 (1H, m), 4.17 (2H,
m), 3.92 (1H, d, 16.2 Hz), 3.80 (1H, d, 16.2 Hz), 3.70 (2H, m),
3.35 (1H, m), 3.27 (4H, m), 3.02 (1H, ddd, 8.9, 3.3, 2.0 Hz),
2.41-2.56 (7H, m), 1.70 (5H, m), 1.53 (3H, d, 6.6 Hz).
EXAMPLE 63
[0389] Compound 65:
[0390] According to (1-1) in Example 1, compound 65 was prepared
from radicicol and a hydrochloride of compound w.
[0391] Isomer ratio: about 4:1
[0392] FAB-MS m/z: 520 [M+H].sup.+
[0393] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.24 (1H, dd, 16.2, 11.2 Hz), 6.71 (1H, d, 16.2 Hz), 6.42 (1H, s),
6.15 (1H, dd, 10.9, 9.6 Hz), 5.60 (1H, dd, 10.9, 3.3 Hz), 5.31 (1H,
m), 4.18 (2H, dt, 4.3, 2.0 Hz), 3.93 (1H, d, 15.8 Hz), 3.83 (1H, d,
15.8 Hz), 3.35 (1H, m), 3.02 (1H, dd, 8.9, 2.3 Hz), 2.45-2.60 (10H,
m), 2.45 (1H, dt, 14.5, 3.6 Hz), 2.36 (3H, s), 1.92 (2H, m), 1.62
(1H, m), 1.53 (3H, d, 6.6 Hz).
EXAMPLE 64
[0394] Compound 66:
[0395] According to (1-1) described in Example 1, compound 66 was
prepared from radicicol and a hydrochloride of compound x.
[0396] Isomer ratio: about 1.5:1
[0397] FAB-MS m/z: 596 [M+H].sup.+
[0398] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.20-7.30 (3H, m), 6.95 (2H, d, 7.9 Hz), 6.84 (1H, t, 7.4 Hz), 6.74
(1H, d, 16.2 Hz), 6.43 (1H, s), 6.11 (1H, m), 5.59 (1H, dd, 10.6,
3.3 Hz), 5.30 (1H, m), 4.20 (2H, m), 3.95 (1H, d, 15.8 Hz), 3.84
(1H, d, 15.8 Hz), 3.34 (1H, m), 3.19 (4H, m), 3.01 (1H, dd, 5.6,
3.3 Hz), 2.71 (4H, m), 2.52 (2H, m), 2.40 (1H, dd, 14.5, 3.6 Hz),
1.74 (4H, m), 1.61 (1H, m), 1.51 (3H, d, 6.6 Hz)
EXAMPLE 65
[0399] Compound 67:
[0400] According to (1-1) described in Example 1, compound 67 was
prepared from radicicol and a hydrochloride of compound y.
[0401] Isomer ratio: about 2:1
[0402] FAB-MS m/z: 537 [M+H].sup.+
[0403] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.24 (1H, dd, 16.2, 11.2 Hz), 6.73 (1H, d, 16.2 Hz), 6.42 (1H, s),
6.15 (1H, dd, 10.9, 9.6 Hz), 5.59 (1H, dd, 10.9, 3.3 Hz), 5.30 (1H,
m), 4.11-4.19 (2H, m), 3.94 (1H, d, 16.2 Hz), 3.84 (1H, d, 16.2
Hz), 3.34 (1H, m), 3.00 (1H, m), 2.78 (4H, m), 2.67 (4H, m), 2.47
(3H, m), 1.67 (5H, m), 1.53 (3H, d, 6.6 Hz).
EXAMPLE 66
[0404] Compounds 68 and 69:
[0405] According to (1-1) described in Example 1, a mixture of
compounds 68 and 69 was prepared from radicicol and a hydrochloride
of compound z, and then compounds 68 and 69 were prepared by
purifying the mixture using high performance liquid chromatography
(eluent: 50 mM phosphate buffer (pH 5.9)/acetonitrile=68/32)
according to Example 51.
[0406] Compound 68: FAB-MS m/z: 491 [M+H].sup.+
[0407] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 10.08 (1H, br s),
7.18 (1H, dd, 15.5, 11.5 Hz), 6.85 (1H, br s), 6.63 (1H, d, 15.5
Hz), 6.60 (1B, s), 6.15 (1H, t, 11.5 Hz), 5.67 (1H, d, 11.5 Hz),
5.51 (1H, m), 4.73 (1H, br), 4.29 (2H, t, 5.3 Hz), 4.03 (1H, br),
3.64 (2H, m), 3.51 (3H, m), 3.20 (1H, s), 2.98 (1H, m), 2.40 (2H,
m), 2.33 (1H, m), 2.01 (2H, m), 1.57 (3H, d, 6.9 Hz).
[0408] Compound 69: FAB-MS m/z: 491 [M+H].sup.+
[0409] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 11.25 (1H, br s),
7.02 (1H, dd, 16.0, 11.2 Hz), 6.58 (1H, br s), 6.11 (1H, d, 16.0
Hz), 6.09 (1H, m), 5.57 (1H, d, 10.9 Hz), 5.51 (1H, m), 4.45 (1H,
d, 16.5 Hz), 4.34 (2H, d, 5.2 Hz), 4.25 (1H, d, 16.5 Hz), 3.80 (1H,
m), 3.58 (3H, m), 3.08 (1H, s), 2.91 (1H, d, 9.9 Hz), 2.45 (2H, m),
2.32 (1H, m), 2.06 (2H, m), 1.95 (1H, m), 1.56 (3H, d, 6.9 Hz).
EXAMPLE 67
[0410] Compound 70:
[0411] According to Example 50, compound 70 was prepared from
radicicol and compound aa.
[0412] Isomer ratio: about 2:1
[0413] FAB-MS m/z: 505 [M+H].sup.+
[0414] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.25 (1H, dd, 16.2, 11.8 Hz), 6.75 (1H, d, 16.2 Hz) 6.43 (1H, s),
6.17 (1H, t, 11.2 Hz), 5.60 (1H, dd, 10.6, 3.6 Hz), 5.30 (1H, m),
4.18 (2H, m), 3.92 (1H, d, 16.2 Hz), 3.79 (1H, d, 16.2 Hz), 3.49
(2H, m), 3.41 (2H, q, 6.9 Hz), 3.34 (1H, m), 3.02 (1H, m), 2.43
(1H, m), 2.37 (2H, m), 2.04 (2H, m), 1.98 (2H, m), 1.62 (1H, m),
1.53 (3H, d, 6.6 Hz).
EXAMPLE 68
[0415] Compound 71:
[0416] According to (1-1) described in Example 1, compound 71 was
prepared from radicicol and a trifluoroacetate of compound bb.
[0417] Isomer ratio: about 3:1
[0418] FAB-MS m/z: 507 [M+H].sup.+
[0419] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.24 (1H, dd, 16.5, 11.2 Hz), 6.77 (1H, d, 16.2 Hz), 6.45 (1H, s),
6.17 (1H, dd, 10.9, 9.6 Hz), 5.61 (1H, m), 5.29 (1H, m), 4.11-4.90
(3H, m), 3.99 (1H, d, 16.2 Hz), 3.81 (1H, d, 16.2 Hz), 3.39 (4H,
m), 3.31 (1H, m), 3.01 (1H, m), 2.43 (1H, dt, 14.5, 3.6 Hz), 2.07
(4H, m), 1.60 (1H, m), 1.51 (3H, d, 6.6 Hz).
EXAMPLE 69
[0420] Compound 72:
[0421] According to Example 50, compound 72 was prepared from
radicicol and compound cc.
[0422] Isomer ratio: about 2:1
[0423] FAB-MS m/z: 580 [M+H].sup.+
[0424] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.24 (1H, dd, 16.2, 11.2 Hz), 6.72 (1H, d, 16.2 Hz), 6.43 (1H, s),
6.11 (1H, dd, 11.9, 10.6 Hz), 5.59 (1H, dd, 10.6, 3.3 Hz), 5.31
(1H, m), 4.99 (1H, t, 5.0 Hz), 3.81-3.99 (6H, m), 3.35 (1H, m),
2.99 (1H, m), 2.42 (1H, dt, 14.5, 3.5 Hz), 2.03 (2H, m), 1.61 (1H,
ddd, 14.2, 4.6, 4.6 Hz), 1.53 (3H, d, 6.3 Hz).
EXAMPLE 70
[0425] Compound 73:
[0426] (70-1):
[0427] A 300 mg (0.493 mmol) portion of compound (L) was dissolved
in 5 ml of dichloromethane to which were subsequently added 0.05 ml
(0.493 mmol) of ethyl chloroformate and 0.07 ml (0.493 mmol) of
triethylamine at -78.degree. C., and the mixture was stirred at
0.degree. C. for 2 hours. The reaction solution was mixed with a
saturated ammonium chloride aqueous solution and extracted with
ethyl acetate. The ethyl acetate layer was washed with saturated
brine and dried with anhydrous sodium sulfate, and then the solvent
was evaporated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (n-hexane/ethyl
acetate=6/1) to obtain 188 mg (yield, 56%) of a
di-tert-butyldimethylsilyl derivative of compound 73.
[0428] (70-2):
[0429] According to (55-4) described in Example 55, compound 73 was
prepared from the di-tert-butyldimethylsilyl derivative of compound
73.
[0430] Isomer ratio: about 1.3:1
[0431] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.45 (1H, dd, 16.3, 11.4 Hz), 6.71 (1H, d, 15.8 Hz), 6.46 (1H, s),
6.22 (1H, m), 5.73 (1H, dd, 10.4, 3.0 Hz), 5.33 (1H, m), 4.34 (1H,
d, 6.9 Hz), 4.11 (1H, d, 16.3 Hz), 4.00 (1H, d, 16.3 Hz), 3.35 (1H,
m), 3.04 (1H, m), 2.43 (1H, dt, 14.3, 3.5 Hz), 1.61 (1H, m), 1.53
(3H, d, 6.4 Hz), 1.35 (3H, t, 6.9 Hz).
EXAMPLE 71
[0432] Compound 74:
[0433] According to (70-1) and (70-2) described in Example 70,
compound 74 was prepared from compound (L), triethylamine and
methyl isocyanate.
[0434] Isomer ratio: about 1.2:1
[0435] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.42 (1H, dd, 16.3, 11.9 Hz), 6.76 (1H, d, 16.3 Hz), 6.46 (1H, s),
6.26 (1H, dd, 11.9, 10.6 Hz), 5.71 (1H, dd, 10.9, 3.5 Hz), 5.34
(1H, m), 4.10 (1H, d, 16.3 Hz), 3.85 (1H, d, 16.3 Hz), 3.36 (1H,
m), 3.04 (1H, m), 2.85 (3H, s), 2.43 (1H, dt, 14.3, 3.5 Hz), 1.65
(1H, m), 1.53 (3H, d, 6.4 Hz).
EXAMPLE 72
[0436] Compound 75:
[0437] According to (70-1) and (70-2) described in Example 70,
compound 75 was prepared from compound (L), triethylamine and
acetyl chloride.
[0438] Isomer ratio: about 1.2:1
[0439] Major component: .sup.1H-NMR (CD.sub.3OD) .delta. (ppm):
7.43 (1H, dd, 15.8, 11.9 Hz), 6.75 (1H, d, 15.8 Hz), 6.47 (1H, s),
6.15 (1H, dd, 11.9, 10.6 Hz), 5.72 (1H, dd, 10.4, 3.5 Hz), 5.34
(1H, m), 4.13 (1H, d, 16.3 Hz), 4.04 (1H, d, 16.3 Hz), 3.35 (1H,
m), 3.04 (1H, m), 2.40 (1H, dt, 14.3, 3.5 Hz), 2.23 (3H, s), 1.65
(1H, m), 1.53 (3H, d, 6.9 Hz).
EXAMPLE 73
[0440] Compound 76:
[0441] According to (1-1) described in Example 1, compound 76 was
prepared from radicicol and O-phenylhydroxylamine
hydrochloride.
[0442] Isomer ratio: about 3:1
[0443] FAB-MS m/z: 456 [M+H].sup.+
[0444] Major component: .sup.1H-NMR (CDCl.sub.3) .delta. (ppm):
10.95 (1H, br), 7.24-7.38 (5H, m), 7.05 (1H, m), 6.89 (1H, d, 16.2
Hz), 6.61 (1H, s), 6.23 (1H, ddd, 10.2, 10.2, 1.1 Hz), 5.73 (1H, br
d, 10.2 Hz), 5.53 (1H, m), 4.85 (1H, br), 4.21 (1H, br), 3.23 (1H,
br), 3.01 (1H, ddd, 8.3, 2.6, 2.3 Hz), 2.37 (1H, ddd, 15.2, 3.6,
3.3 Hz), 2.01 (1H, ddd, 15.5, 9.1, 3.8 Hz), 1.58 (3H, d, 6.6
Hz).
REFERENCE EXAMPLE 1
[0445] Compound a:
[0446] (1-1):
[0447] A 5.00 g (22.4 mmol) portion of 8-bromooctanoic acid was
dissolved in a mixed solvent of 2 ml dichloromethane and 10 ml
hexane, and the solution was mixed with 8.00 ml (44.8 mmol) of
tert-butyl 2,2,2-trichloroacetoimidate and 0.45 ml (3.66 mmol) of
boron trifluoride-ether complex and stirred at room temperature for
1 hour. The reaction solution was mixed with 10 ml of hexane and
0.031 g (3.66 mmol) of sodium bicarbonate, the resulting
precipitate was separated by filtration, and then the solvent was
evaporated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (n-hexane/ethyl
acetate=5/1) to obtain 2.34 g (yield, 38%) of tert-butyl
8-bromooctanoate.
[0448] (1-2):
[0449] A 2.70 g (8.29 mmol) portion of tert-butyl 8-bromooctanoate
was dissolved in 20 ml of DMF, and the solution was mixed with 1.35
g (8.28 mmol) N-hydroxyphthalimide and 1.86 ml (12.4 mmol) of
1,8-diazabicyclo[5,4,0]-7-undecene and stirred at room temperature
for 20.5 hours. The reaction solution was mixed with water and
extracted with ethyl acetate, the ethyl acetate layer was washed
with 0.5 N hydrochloric acid and then with saturated brine and
dried with anhydrous sodium sulfate, subsequently evaporating the
solvent under reduced pressure. The resulting residue was purified
by silica gel column chromatography (n-hexane/ethyl acetate=5/1) to
obtain 0.83 g (yield, 28%) of tert-butyl
8-(phthalimidoxy)-octanoate.
[0450] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 7.83 (2H, m), 7.75
(2H, m), 4.20 (2H, t, 6.8 Hz), 2.21 (2H, t, 7.6 Hz), 1.79 (2H, m),
1.60 (2H, m), 1.44 (9H, s), 1.45-1.29 (6H, m).
[0451] (1-3):
[0452] A 1.00 g (2.77 mmol) portion of tert-butyl
8-(phthalimidoxy)-octano- ate was dissolved in 9 ml of chloroform,
and the solution was mixed with 4.1 ml (4.16 mmol) of a 1 M
hydrazine monohydrate/methanol solution and stirred at room
temperature for 0.5 hour. After separation of the resulting
precipitate by filtration, the resulting filtrate was mixed with
water and extracted with chloroform, the chloroform layer was
washed with saturated brine and dried with anhydrous sodium
sulfate, and then the solvent was evaporated under reduced
pressure. The thus prepared residue was dissolved in 14 ml of
dichloromethane, and the solution was mixed with 6.4 ml of
trifluoroacetic acid and stirred at room temperature for 2 hours.
By evaporating the solvent under reduced pressure, a
trifluoroacetate of the compound a was prepared.
REFERENCE EXAMPLE 2
[0453] Compound b:
[0454] According to (1-1) to (1-3) described in Reference Example
1, a trifluoroacetate of compound b was prepared from
11-bromoundecanoic acid.
REFERENCE EXAMPLE 3
[0455] Compound c:
[0456] (3-1):
[0457] According to (1-2) described in Reference Example 1, 1.29 g
(quantitative) of methyl 2-methoxymethoxybenzoate was prepared from
1.00 g (6.57 mmol) of methyl salicylate, 0.75 ml (9.86 mmol) of
chloromethyl methyl ether and 1.72 ml (9.86 mmol) of
diisopropylethylamine.
[0458] (3-2):
[0459] A 792 mg (4.04 mmol) portion of methyl
2-methoxymethoxybenzoate dissolved in 12 ml of THF was added to 337
mg (8.89 mmol) of lithium aluminum hydride dissolved in 5 ml of
THF, and the mixture was stirred at room temperature for 2.5 hours.
The reaction solution was mixed with water and extracted with ethyl
acetate, and the ethyl acetate layer was washed with saturated
brine and dried with anhydrous sodium sulfate. By evaporation of
the solvent under reduced pressure, 640 mg (yield, 94%) of
2-methoxymethoxybenzyl alcohol was prepared.
[0460] (3-3):
[0461] According to (55-3) described in Example 55, 486 mg (yield,
57%) of N-(2-methoxymethoxybenzyloxy)phthalimide was prepared from
454 mg (2.70 mmol) of 2-methoxymethoxybenzyl alcohol, 484 mg (2.97
mmol) of N-hydroxyphthalimide, 744 mg (2.84 mmol) of
triphenylphosphine and 0.446 ml (2.84 mmol) of DEAD.
[0462] (3-4):
[0463] According to (1-3) described in Reference Example 1, a
reaction solution prepared by treating 427 mg (1.36 mmol) of
N-(2-methoxymethoxybenzyloxy)phthalimide with 0.099 ml (2.04 mmol)
of hydrazine monohydrate was separated by filtration, and then the
solvent was evaporated under reduced pressure to obtain 244 mg
(yield, 98%) of compound c.
[0464] FAB-MS m/z: 184 [M+H].sup.+
[0465] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 7.37 (1H, dd, 7.4,
1.8 Hz), 7.27 (1H, ddd, 7.4, 7.3, 1.8 Hz), 7.11 (1H, dd, 7.3, 1.3
Hz), 7.02 (1H, ddd, 7.6, 7.6, 1.3 Hz), 5.42 (2H, br s), 5.22 (2H,
s), 4.79 (2H, s), 3.49 (3H, s).
REFERENCE EXAMPLE 4
[0466] Compound d:
[0467] According to (55-1) described in Example 55, methyl
3,5-di-(tert-butyldimethylsiloxy)benzoate was prepared from methyl
3,5-dihydroxybenzoate, and compound d was prepared from methyl
3,5-di-(tert-butyldimethylsiloxy) benzoate according to (3-2) to
(3-4) described in Reference Example 3.
[0468] FAB-MS m/z: 384 [M+H].sup.+
[0469] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 6.46 (2H, d, 2.3
Hz), 6.28 (1H, t, 2.3 Hz), 5.37 (2H, br), 4.57 (2H, s), 0.97 (18H,
s), 0.19 (12H, s).
REFERENCE EXAMPLE 5
[0470] Compound e:
[0471] According to (3-2) to (3-4) described in Reference Example
3, compound e was prepared from methyl
3,4,5-trimethoxybenzoate.
[0472] FAB-MS m/z: 214 [M+H].sup.+
[0473] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 6.60 (2H, s), 5.43
(2H, br), 4.64 (2H, s), 3.88 (6H, s), 3.85 (3H, s).
REFERENCE EXAMPLE 6
[0474] Compound f:
[0475] (6-1):
[0476] A 2.00 g (13.1 mmol) portion of 3,5-diaminobenzoic acid was
dissolved in a mixed solvent of 20 ml THF and 20 ml water, and the
solution was mixed with 6.88 g (31.5 mmol) of di-tert-butyl
dicarbonate, adjusted to pH 7 to 8 with a saturated sodium
bicarbonate aqueous solution and then stirred at room temperature
for 4 hours. The reaction solution was mixed with a 10% citric acid
aqueous solution and extracted with ethyl acetate. The ethyl
acetate layer was washed with saturated brine and dried with
anhydrous sodium sulfate, and then the solvent was evaporated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (chloroform/methanol=10/1) to obtain 3.93 g
(yield, 85%) of 3,5-di-(tert-butoxycarbonylamino)benzoic acid.
[0477] (6-2):
[0478] A 2.00 g (5.68 mmol) portion of
3,5-di-(tert-butoxycarbonylamino)be- nzoic acid was dissolved in 15
ml of THF, 3.77 ml (39.7 mmol) of borane-methyl sulfide complex
dissolved in 10 ml of THF was added dropwise to the thus prepared
solution, and the mixture was stirred at room temperature for 5
hours. The reaction solution was cooled to 0.degree. C., mixed with
water and extracted with ethyl acetate. The ethyl acetate layer was
washed with saturated brine and dried with anhydrous sodium
sulfate, and then the solvent was evaporated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (chloroform/methanol=20/1) to obtain 1.08 g (yield,
56%) of 1,3-di-tert-butoxycarbonylamino-5-hydroxymethylbenzene.
[0479] (6-3):
[0480] According to (3-3) and (3-4) described in Reference Example
3, compound f was prepared from
1,3-di-tert-butoxycarbonylamino-5-hydroxymet- hylbenzene.
[0481] FAB-MS m/z: 354 [M+H].sup.+
[0482] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 7.41 (1H, t, 1.7
Hz), 7.07 (2H, d, 1.7 Hz), 6.50 (2H, br s), 5.39 (2H, br), 4.62
(2H, s), 1.50 (18H, s).
REFERENCE EXAMPLE 7
[0483] Compound g:
[0484] According to (3-3) and (3-4) described in Reference Example
3, compound g was prepared from 4-(dimethylamino)phenetyl
alcohol.
[0485] FAB-MS m/z: 181 [M+H].sup.+
[0486] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 7.10 (2H, d, 8.6
Hz), 6.70 (2H, d, 8.6 Hz), 5.38 (2H, br s), 3.84 (2H, t, 7.1 Hz),
2.91 (6H, s), 2.81 (2H, t, 7.1 Hz).
REFERENCE EXAMPLE 8
[0487] Compound h:
[0488] According to (6-2) and (6-3) described in Reference Example
6, compound h was prepared from 4-(N-methylpiperazinomethyl)benzoic
acid.
[0489] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 7.29 (2H, m), 7.15
(2H, m), 5.20 (2H, br), 4.56 (2H, s), 3.93 (2H, s), 3.44-3.41 (4H,
br), 2.68-2.58 (4H, m), 2.55 (3H, s).
REFERENCE EXAMPLE 9
[0490] Compound i:
[0491] According to (1-2) described in Reference Example 1, methyl
2-(dimethylaminosulfonyl)benzoate was prepared from methyl
2-(aminosulfonyl)benzoate, methyl iodide and potassium carbonate,
and then compound i was prepared according to (3-2) to (3-4)
described in Reference Example 3.
[0492] FAB-MS m/z: 231 [M+H].sup.+
[0493] .sup.1H-NMR (CDCl.sub.3+CD.sub.3OD) .delta. (ppm): 7.87 (1H,
d, 7.9 Hz), 7.71 (1H, d, 7.6 Hz), 7.62 (1H, dd, 7.9, 7.3 Hz), 7.46
(1H, dd, 7.6, 7.3 Hz), 5.10 (2H, s), 2.81 (6H, s).
REFERENCE EXAMPLE 10
[0494] Compound j:
[0495] According to (3-3) and (3-4) described in Reference Example
3, compound j was prepared from 2-pyridylcarbinol.
[0496] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 7.21-7.30 (5H, m),
5.40 (2H, br), 3.90 (2H, t, 6.9 Hz), 2.91 (2H, t, 6.9 Hz).
REFERENCE EXAMPLE 11
[0497] Compound k:
[0498] According to (3-3) and (3-4) described in Reference Example
3, compound k was prepared from 3-pyridylcarbinol. .sup.1H-NMR
(CDCl.sub.3) .delta. (ppm): 8.63 (1H, d, 2.0 Hz), 8.57 (1H, dd,
5.0, 1.5 Hz), 7.73 (1H, dt, 7.9, 2.0 Hz), 7.33 (1H, dd, 7.9, 4.9
Hz), 4.92 (2H, br), 4.71 (2H, s).
REFERENCE EXAMPLE 12
[0499] Compound m:
[0500] According to (3-3) and (3-4) described in Reference Example
3, compound m was prepared from 4-pyridylcarbinol. .sup.1H-NMR
(CDCl.sub.3) .delta. (ppm): 8.59 (2H, d, 5.9 Hz), 7.26 (2H, d, 5.9
Hz), 5.55 (2H, br), 4.71 (2H, s).
REFERENCE EXAMPLE 13
[0501] Compound n:
[0502] According to (3-3) and (3-4) described in Reference Example
3, compound n was prepared from 3-pyridinepropanol. .sup.1H-NMR
(CDCl.sub.3) .delta. (ppm): 8.45 (1H, br s), 8.43 (1H, dd, 4.9, 1.3
Hz), 7.50 (1H, ddd, 7.6, 1.6, 1.3 Hz), 7.20 (1H, dd, 7.6, 4.9 Hz),
5.36 (2H, br), 3.67 (2H, t, 6.3 Hz), 2.67 (2H, t, 7.8 Hz), 1.90
(2H, m).
REFERENCE EXAMPLE 14
[0503] Compound o:
[0504] According to (3-1) to (3-4) described in Reference Example
3, compound o was prepared from 3-hydroxypicolinic acid.
[0505] FAB-MS m/z: 185 [M+H].sup.+
[0506] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 8.27 (1H, dd, 4.6,
1.3 Hz), 7.42 (1H, dd, 8.3, 1.3 Hz), 7.18 (1H, dd, 8.3, 4.6 Hz),
5.75 (2H, br), 5.22 (2H, d, 0.7 Hz), 4.92 (2H, s), 3.47 (3H, d, 1.0
Hz).
REFERENCE EXAMPLE 15
[0507] Compound p:
[0508] According to (3-1) to (3-4) described in Reference Example
3, compound p was prepared from 6-hydroxynicotinic acid.
[0509] .sup.1H-NMR (CDCl.sub.3+CD.sub.3OD) .delta. (ppm): 7.98 (1H,
d, 2.3 Hz), 7.52 (1H, dd, 8.6, 2.3 Hz), 6.68 (1H, d, 8.2 Hz), 5.32
(2H, s), 4.46 (2H, s), 3.35 (3H, s).
REFERENCE EXAMPLE 16
[0510] Compound q:
[0511] (16-1):
[0512] According to (1-2) described in Reference Example 1,
tert-butyl N-(6-uracilmethoxy)carbamate was prepared from
tert-butyl N-hydroxycarbamate, sodium hydride, and
6-(chloromethyl)uracil.
[0513] FAB-MS m/z: 258 [M+H].sup.+
[0514] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 10.34 (1H, br), 8.02
(1H, br), 5.54 (1H, s), 4.67 (2H, s), 1.48 (9H, s).
[0515] (16-2):
[0516] A 385 mg (1.50 mmol) portion of tert-butyl
N-(6-uracilmethoxy)carba- mate was dissolved in 0.5 ml of
dichloromethane, and the solution was mixed with 0.5 ml of
trifluoroacetic acid and stirred at room temperature for 1 hour. By
evaporating the solvent under reduced pressure, a trifluoroacetate
of compound q was prepared.
REFERENCE EXAMPLE 17
[0517] Compound r:
[0518] According to (3-3) and (3-4) described in Reference Example
3, compound r was prepared from 1-methyl-3-piperidinemethanol.
[0519] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 5.47 (2H, br), 3.55
(1H, dd, 9.9, 5.6 Hz), 3.48 (1H, dd, 9.9, 7.6 Hz), 2.92 (1H, br d,
10.9 Hz), 2.81 (1H, br d, 11.2 Hz), 2.28 (3H, s), 2.03 (1H, m),
1.89-1.97 (2H, m), 1.59-1.71 (4H, m).
REFERENCE EXAMPLE 18
[0520] Compound s:
[0521] According to (3-3) described in Reference Example 3,
1-(2-phthalimidoxyethyl)pyrrolidine was prepared from
pyrrolidineethanol and treated with a 4 N hydrochloric acid/ethyl
acetate solution to make it into a hydrochloride, and then compound
s was prepared from the hydrochloride according to (3-4) described
in Reference Example 3. By treating compound s with a 4 N
hydrochloric acid/ethyl acetate solution, a hydrochloride of
compound s was prepared.
[0522] FAB-MS m/z: 145 [M+H].sup.+
REFERENCE EXAMPLE 19
[0523] Compound t:
[0524] (19-1):
[0525] According to (1-2) described in Reference Example 1, 4.20 g
(yield, 39%) of ethyl N-(3-bromopropoxy)acetoimidate was prepared
from 5.00 g (48.5 mmol) of ethyl acetohydroxamate, 1.90 g (48.5
mmol) of sodium hydride and 7.4 ml (72.7 mmol) of
1,3-dibromopropane.
[0526] (19-2):
[0527] A 500 mg (2.23 mmol) portion of ethyl
N-(3-bromopropoxy)acetoimidat- e was dissolved in 6 ml of
dichloromethane, and the solution was mixed with 0.22 ml (2.23
mmol) of piperidine and 0.33 ml (2.23 mmol) of
1,8-diazabicyclo(5.4,0]-7-undecene and stirred at room temperature
for 36 hours. The reaction solution was mixed with a saturated
ammonium chloride aqueous solution and extracted with chloroform.
The chloroform layer was washed with saturated brine and dried with
anhydrous sodium sulfate, and then the solvent was evaporated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (chloroform/methanol=10- /1) to obtain 166 mg
(yield, 32%) of ethyl N-(3-piperidinopropoxy)acetoimi- date.
[0528] FAB-MS m/z: 229 [M+H].sup.+
[0529] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 4.00 (2H, q, 6.9
Hz), 3.93 (2H, t, 6.3 Hz), 2.53 (6H, m), 1.93 (2H, m), 1.92 (3H,
s), 1.70 (4H, m), 1.49 (2H, m), 1.27 (3H, t, 6.9 Hz).
[0530] (19-3):
[0531] A 166 mg (0.71 mmol) portion of ethyl
N-(3-piperidinopropoxy)acetoi- midate was dissolved in 0.5 ml of
THF, and the solution was mixed with 0.1 ml of concentrated
hydrochloric acid and stirred at room temperature for 1 hour. By
evaporating the solvent under reduced pressure, a hydrochloride of
compound t was prepared.
REFERENCE EXAMPLE 20
[0532] Compound u:
[0533] According to (19-2) and (19-3) described in Reference
Example 19, a hydrochloride of compound u was prepared from ethyl
N-(3-bromopropoxy)acetoimidate.
REFERENCE EXAMPLE 21
[0534] Compound v:
[0535] According to (19-1) described in Reference Example 19, ethyl
N-(4-bromobutoxy)acetoimidate was prepared from ethyl
acetohydroxamate, sodium hydride and 1,4-dibromobutane, and then a
hydrochloride of compound v was prepared according to (19-2) and
(19-3) described in Reference Example 19.
REFERENCE EXAMPLE 22
[0536] Compound w:
[0537] According to (19-2) and (19-3) described in Reference
Example 19, a hydrochloride of compound w was prepared from ethyl
N-(3-bromopropoxy)acetoimidate.
REFERENCE EXAMPLE 23
[0538] Compound x:
[0539] According to (19-2) and (19-3) described in Reference
Example 19, a hydrochloride of compound x was prepared from ethyl
N-(4-bromobutoxy)acetoimidate.
REFERENCE EXAMPLE 24
[0540] Compound y:
[0541] According to (19-2) and (19-3) described in Reference
Example 19, a hydrochloride of compound y was prepared from ethyl
N-(4-bromobutoxy)acetoimidate.
REFERENCE EXAMPLE 25
[0542] Compound z:
[0543] According to (3-3) and (3-4) described in Reference Example
3, compound z was prepared from 1-(2-hydroxyethyl)-2pyrrolidinone,
and then compound z was treated with a 4 N hydrochloric acid/ethyl
acetate solution to obtain a hydrochloride of compound z.
[0544] FAB-MS m/z: 145 [M+H].sup.+
REFERENCE EXAMPLE 26
[0545] Compound aa:
[0546] According to (3-3) and (3-4) described in Reference Example
3, compound aa was prepared from
1-(3-hydroxypropyl)-2-pyrrolidinone.
[0547] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 5.40 (2H, br), 3.68
(2H, t, 6.3 Hz), 3.39 (2H, dd, 11.5, 6.9 Hz), 3.37 (2H, m), 2.39 (
2H, dd, 8.6, 7.6 Hz), 2.02 (2H, ddd, 6.9, 6.3, 1.0 Hz), 1.81 (2H,
ddd, 11.5, 6.3, 1.0 Hz), 1.81 (2H, m).
REFERENCE EXAMPLE 27
[0548] Compound bb:
[0549] (27-1):
[0550] According to (16-1) described in Reference Example 16, 659
mg (3.80 mmol) of tert-butyl N-(allyloxy)carbamate prepared from
tert-butyl N-hydroxycarbamate, sodium hydride and allyl bromide was
dissolved in 10 ml of dichloromethane, and the thus prepared
solution was mixed with 886 mg (4.67 mmol) of m-chloroperbenzoic
acid and stirred at room temperature for 24 hours. The reaction
solution was filtered, mixed with a 1 N sodium hydroxide aqueous
solution and extracted with chloroform. The chloroform layer was
washed with saturated brine and dried with anhydrous sodium
sulfate, and then the solvent was evaporated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (n-hexane/ethyl acetate=4/1) to obtain 447 mg
(yield, 62%) of tert-butyl N-(2,3-epoxypropoxy)carbamate.
[0551] (27-2):
[0552] A 150 mg (0.79 mmol) portion of tert-butyl
N-(2,3-epoxypropoxy)carb- amate was dissolved in 1 ml of methanol,
and the solution was mixed with 0.08 ml (0.95 mmol) of pyrrolidine
and stirred at room temperature for 14 hours. The reaction solution
was mixed with a saturated ammonium chloride aqueous solution and
extracted with chloroform. The chloroform layer was washed with
saturated brine and dried with anhydrous sodium sulfate, and then
the solvent was evaporated under reduced pressure to obtain 181 mg
(yield, 88%) of tert-butyl
N-(2-hydroxy-3-pyrrolidinylpropoxy)-carbamate.
[0553] FAB-MS m/z: 261 [M+H].sup.+
[0554] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 4.02 (1H, m), 3.92
(1H, dd, 11.2, 3.3 Hz), 3.77 (1H, dd, 11.2, 7.3 Hz), 2.68 (4H, m),
2.65 (1H, m), 2.50 (1H, m), 1.89 (9H, s), 1.80 (4H, m).
[0555] (27-3):
[0556] According to (16-2) described in Reference Example 16, a
trifluoroacetate of compound bb was prepared from tertbutyl
N-(2-hydroxy-3-pyrrolidinylpropoxy)carbamate.
REFERENCE EXAMPLE 28
[0557] Compound cc:
[0558] According to (1-2) described in Reference Example 1,
2-(2-phthalimidoxyethyl)-1,3-dioxolan was prepared from
2-(2-bromoethyl)-1,3-dioxolan, N-hydroxyphthalimide and potassium
carbonate, and then compound cc was prepared from
2-(2-phthalimidoxyethyl- )-1,3-dioxolan according to (3-4)
described in Reference Example 3.
[0559] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 5.40 (2H, br), 4.97
(1H, t, 5.0 Hz), 3.80-4.00 (6H, m), 1.98 (2H, dt, 6.3, 5.0 Hz).
6TABLE 6 Reference Example H.sub.2NO--R.sup.3e Compound R.sup.3e a
(CH.sub.2).sub.7CO.sub.2H b (CH.sub.2).sub.10CO.sub.2H c 78 d 79 e
80 f 81 g 82 h 83 i 84 j 85 k 86 m 87 n 88 o 89 p 90 q 91 r 92 s 93
t 94 u 95 v 96 w 97 x 98 y 99 z 100 aa 101 bb 102 cc 103
[0560] Industrial Applicability
[0561] According to the present invention, novel radicicol
derivatives or pharmacologically acceptable salts thereof which
show tyrosine kinase inhibition activity and have antitumor or
immunosuppression effects are provided.
* * * * *