U.S. patent application number 16/287871 was filed with the patent office on 2019-10-03 for saturated-ring-fused dihydropyrimidinone or dihydrotriazinone compounds and pharmaceutical use thereof.
The applicant listed for this patent is Japan Tobacco Inc.. Invention is credited to Shingo FUJIOKA, Noriyoshi SEKI, Eiichi WATANABE, Masahiro YOKOTA.
Application Number | 20190300490 16/287871 |
Document ID | / |
Family ID | 67805013 |
Filed Date | 2019-10-03 |
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United States Patent
Application |
20190300490 |
Kind Code |
A1 |
YOKOTA; Masahiro ; et
al. |
October 3, 2019 |
SATURATED-RING-FUSED DIHYDROPYRIMIDINONE OR DIHYDROTRIAZINONE
COMPOUNDS AND PHARMACEUTICAL USE THEREOF
Abstract
The present invention relates to saturated-ring-fused
dihydropyrimidinone or dihydrotriazinone compounds, or
pharmaceutically acceptable salts thereof, having ROR.gamma.
antagonist activity, pharmaceutical compositions comprising the
same, and pharmaceutical use thereof. A compound of Formula [I] or
a pharmaceutically acceptable salt thereof, a pharmaceutical
composition comprising the same, and pharmaceutical use thereof are
provided: ##STR00001## wherein each substituent is defined as
defined in the description.
Inventors: |
YOKOTA; Masahiro; (Osaka,
JP) ; SEKI; Noriyoshi; (Osaka, JP) ; WATANABE;
Eiichi; (Osaka, JP) ; FUJIOKA; Shingo; (Osaka,
JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Japan Tobacco Inc. |
Tokyo |
|
JP |
|
|
Family ID: |
67805013 |
Appl. No.: |
16/287871 |
Filed: |
February 27, 2019 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 239/82 20130101;
C07D 498/04 20130101; C07D 487/04 20130101; C07D 491/048 20130101;
C07D 239/80 20130101; C07D 491/052 20130101; C07D 239/70
20130101 |
International
Class: |
C07D 239/82 20060101
C07D239/82; C07D 498/04 20060101 C07D498/04; C07D 239/70 20060101
C07D239/70; C07D 491/048 20060101 C07D491/048; C07D 487/04 20060101
C07D487/04 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 28, 2018 |
JP |
2018-035601 |
Claims
1: A compound of Formula [I]: ##STR00329## wherein R.sup.1 is (1)
C.sub.1-8 alkyl, (2) halo-C.sub.1-8 alkyl, (3) C.sub.3-8 cycloalkyl
optionally substituted with the same or different 1 to 3
substituents selected from Group A.sup.1, or (4) C.sub.3-8
cycloalkyl-C-4 alkyl wherein the C.sub.3-8 cycloalkyl moiety may be
optionally substituted with the same or different 1 to 3
substituents selected from Group A.sup.1, Group A.sup.1 is (1)
halogen, (2) C.sub.1-4 alkyl, or (3) halo-C.sub.1-4 alkyl, X.sup.1
is (1) a bond, or (2) --O--, R.sup.2 is (1) hydrogen, or (2)
halogen, R.sup.3 is (1) hydrogen, or (2) --Y.sup.3--COO--R.sup.30,
Y.sup.3 is (1) C.sub.1-8 alkylene, (2) C.sub.5-8 cycloalkylene, (3)
bridged C.sub.5-8 cycloalkylene, or (4) C.sub.6-14 arylene,
R.sup.30 is (1) hydrogen, or (2) C.sub.1-4 alkyl, X.sup.2 is (1)
.dbd.C(R.sup.4)--, or (2) .dbd.N--, R.sup.4 is (1) hydrogen, or (2)
C.sub.1-4 alkyl, X.sup.3 is (1) --C(R.sup.5)(R.sup.6)--, X.sup.4 is
(1) a bond, or (2) --C(R.sup.7)(R.sup.8)--, X.sup.5 is (1)
--C(R.sup.9)(R.sup.10)-- (2) --N(R.sup.11)--, or (3) --O--, R.sup.5
and R.sup.6 are each independently (1) hydrogen, (2) C.sub.1-4
alkyl, (3) halo-C.sub.1-4 alkyl, (4) cyano-C.sub.1-4 alkyl, or (5)
C.sub.1-4 alkyl substituted with one substituent selected from the
group consisting of --O--R.sup.51, --CO--R.sup.61, --COO--R.sup.52,
--N(R.sup.71)(R.sup.72), --CO--N(R.sup.73)(R.sup.74),
--N(R.sup.75)--CO--R.sup.62, --N(R.sup.76)--COO--R.sup.53, and
--O--S(O).sub.2--R.sup.63, R.sup.7, R.sup.8, R.sup.9 and R.sup.10
are each independently (1) hydrogen, (2) halogen, (3) cyano, (4)
hydroxy, (5) C.sub.1-4 alkyl, (6) halo-C.sub.1-4 alkyl, (7)
cyano-C.sub.1-4 alkyl, (8) C.sub.1-4 alkoxy, or (9) C.sub.1-4 alkyl
substituted with one substituent selected from the group consisting
of --O--R.sup.51, --CO--R.sup.61, --COO--R.sup.52,
--N(R.sup.71)(R.sup.72), --CO--N(R.sup.73)(R.sup.74),
--N(R.sup.75)--CO--R.sup.62, --N(R.sup.76)--COO--R.sup.53, and
--O--S(O).sub.2--R.sup.3, R.sup.51, R.sup.52, and R.sup.53 are each
independently (1) hydrogen, (2) C.sub.1-4 alkyl, or (3) C.sub.6-14
aryl-C.sub.1-4 alkyl, R.sup.61, R.sup.62, and R.sup.63 are each
independently (1) C.sub.1-4 alkyl, R.sup.71, R.sup.72, R.sup.73,
R.sup.74, R.sup.75, and R.sup.76 are each independently (1)
hydrogen, or (2) C.sub.1-4 alkyl, R.sup.11 is (1) --CO--R.sup.111,
or (2) --COO--R.sup.112, R.sup.111 is (1) C.sub.1-4 alkyl, and
R.sup.112 is (1) C.sub.1-4 alkyl, or a pharmaceutically acceptable
salt thereof.
2: The compound according to claim 1, having a structure of Formula
[II]: ##STR00330## wherein each variable is defined as defined in
claim 1, or a pharmaceutically acceptable salt thereof.
3: The compound according to claim 1, wherein X.sup.2 is .dbd.N--,
or a pharmaceutically acceptable salt thereof.
4: The compound according to claim 1, wherein X.sup.2 is
--C(R.sup.4)-- and R.sup.4 is hydrogen, or a pharmaceutically
acceptable salt thereof.
5: The compound according to claim 1, wherein R.sup.3 is hydrogen,
or a pharmaceutically acceptable salt thereof.
6: The compound according to claim 1, wherein R.sup.3 is
--Y.sup.3--COO--R.sup.3, Y.sup.3 is (1) C.sub.1-8 alkylene, (2) Cm
cycloalkylene, or (3) bridged C.sub.5-8 cycloalkylene, and R.sup.30
is hydrogen or C.sub.1-4 alkyl, or a pharmaceutically acceptable
salt thereof.
7: The compound according to claim 1, wherein R.sup.2 is halogen,
or a pharmaceutically acceptable salt thereof.
8: The compound according to claim 1, wherein R.sup.1 is C.sub.1-8
alkyl and X.sup.1 is a bond, or a pharmaceutically acceptable salt
thereof.
9: The compound according to claim 1, wherein R.sup.5 and R.sup.6
are each independently hydrogen or C.sub.1-4 alkyl, or a
pharmaceutically acceptable salt thereof.
10: The compound according to claim 1, wherein X.sup.4 is a bond or
--C(R.sup.7)(R.sup.8)-- and both of R.sup.7 and R.sup.8 are
hydrogen, or a pharmaceutically acceptable salt thereof.
11: The compound according to claim 1, wherein X.sup.5 is
--C(R.sup.9)(R.sup.10)-- or --O-- and both of R.sup.9 and R.sup.10
are hydrogen, or a pharmaceutically acceptable salt thereof.
12. (canceled)
13: A pharmaceutical composition comprising a compound according to
claim 1 or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.
14: An ROR.gamma. antagonist comprising a compound according to
claim 1 or a pharmaceutically acceptable salt thereof.
15. (canceled)
16: A method of antagonizing ROR.gamma., comprising administering a
therapeutically effective amount of a compound according to claim 1
or a pharmaceutically acceptable salt thereof to a mammal.
17: A method of treating or preventing a disease selected from the
group consisting of autoimmune diseases, allergic diseases, dry
eye, fibrosis, cancers, metabolic disease, ischemia,
cardiomyopathy, hypertension, and periodontal disease, comprising
administering a therapeutically effective amount of a compound
according to claim 1 or a pharmaceutically acceptable salt thereof
to a mammal.
18-21. (canceled)
22: The compound according to claim 1, having a structure:
##STR00331## or a pharmaceutically acceptable salt thereof.
23: The compound according to claim 1, having a structure:
##STR00332## or a pharmaceutically acceptable salt thereof.
24: The compound according to claim 1, having a structure:
##STR00333## or a pharmaceutically acceptable salt thereof.
25: The compound according to claim 1, having a structure:
##STR00334## or a pharmaceutically acceptable salt thereof.
26: The compound according to claim 1, having a structure:
##STR00335## or a pharmaceutically acceptable salt thereof.
27: The compound according to claim 1, having a structure:
##STR00336## or a pharmaceutically acceptable salt thereof.
28: The compound according to claim 1, having a structure:
##STR00337## or a pharmaceutically acceptable salt thereof.
29: The compound according to claim 1, having a structure:
##STR00338## or a pharmaceutically acceptable salt thereof.
30: The compound according to claim 1, having a structure:
##STR00339## or a pharmaceutically acceptable salt thereof.
31: The compound according to claim 1, having a structure:
##STR00340## or a pharmaceutically acceptable salt thereof.
32: The compound according to claim 1, having a structure:
##STR00341## or a pharmaceutically acceptable salt thereof.
33: The compound according to claim 1, having a structure:
##STR00342## or a pharmaceutically acceptable salt thereof.
34: The compound according to claim 1, having a structure:
##STR00343## or a pharmaceutically acceptable salt thereof.
35: The compound according to claim 1, having a structure:
##STR00344## or a pharmaceutically acceptable salt thereof.
36: The compound according to claim 1, having a structure:
##STR00345## or a pharmaceutically acceptable salt thereof.
37: The compound according to claim 1, having a structure:
##STR00346## or a pharmaceutically acceptable salt thereof.
Description
TECHNICAL FIELD
[0001] The present invention relates to saturated-ring-fused
dihydropyrimidinone or dihydrotriazinone compounds, or
pharmaceutically acceptable salts thereof, having ROR.gamma.
antagonist activity, pharmaceutical compositions comprising the
same, and pharmaceutical use thereof.
BACKGROUND ART
[0002] ROR.gamma. (i.e., Retinoid-related Orphan Receptor gamma) is
a nuclear receptor which is important for the differentiation and
activation of Th17 cells. ROR.gamma.t is also known as a splicing
variant of ROR.gamma. (Non patent literature 1). ROR.gamma. and
ROR.gamma.t differ only in their N-terminal domains and share the
same ligand-binding domain and DNA-binding domain. It is reported
that ROR.gamma. is expressed in other tissues besides Th17 cells
(Non Patent Literature 1).
[0003] Inhibition of ROR.gamma. can inhibit the differentiation and
activation of Th17 cells. IL-17 produced in Th17 cells is involved
in the induction of a variety of chemokines, cytokines,
metalloproteases, and other inflammatory mediators and the
migration of neutrophil, and therefore, inhibition of IL-17 may
lead to inhibit such induction and migration (Non Patent
Literatures 2 and 3). It is known that Th17 cells are involved in
autoimmune diseases (such as rheumatoid arthritis, psoriasis,
inflammatory bowel disease (such as Crohn's disease and ulcerative
colitis), multiple sclerosis, systemic lupus erythematosus (SLE),
Behcet's disease, sarcoidosis, Harada disease, ankylosing
spondylitis, uveitis, polymyalgia rheumatica, type I diabetes,
graft-versus-host disease, alopecia areata, and vitiligo), allergic
diseases, dry eye, fibrosis (such as lung fibrosis and primary
biliary cirrhosis), and cancers (such as malignant melanoma and
prostate cancer).
[0004] ROR.gamma. in adipose tissues is related to the regulation
of adipogenesis and inhibition of ROR.gamma. can ameliorate insulin
resistance (Non Patent Literature 4). It is known that adipose
tissues are involved in metabolic diseases (such as hepatic
steatosis).
[0005] It is also known that IL-17 and Th17 cells are involved in
ischemia, cardiomyopathy, hypertension, and periodontitis.
[0006] For example, as for rheumatoid arthritis, it is reported
that administration of anti-IL-17 antibody can ameliorate swelling
and joint destruction associated with collagen-induced arthritis
(Non Patent Literature 5). It is also reported that swelling and
joint destruction associated with collagen-induced arthritis can be
ameliorated in experiments using IL-17-deficient mice (Non Patent
Literature 6).
[0007] As for psoriasis, it is reported that administration of
anti-IL-17 antibody is effective in treating psoriasis in clinical
trials (Non Patent Literature 7). Anti IL-17 antibodies have been
placed on the market for use in psoriasis (Non Patent Literature
8).
[0008] As for inflammatory bowel diseases such as Crohn's disease
and ulcerative colitis, adaptive transfer of T cells derived from
ROR.gamma.-KO mice does not increase IL-17 in the mucosa in a
colitis model induced by the adaptive transfer of T cells, thereby
the onset of colitis can be inhibited (Non Patent Literature 9). It
is also reported that an anti-IL-23 antibody, an antibody against
IL-23 which activates Th17 cells, was effective in treating Crohn's
disease in clinical trials (Non Patent Literature 20).
[0009] As for multiple sclerosis, the disease state of a mouse
experimental autoimmune encephalomyelitis model which is an animal
model of multiple sclerosis can be inhibited in ROR.gamma.-KO mice
(Non Patent Literature 10). It is also reported that an anti-IL-17A
antibody can ameliorate MRI observation in relapsing remitting
multiple sclerosis in clinical trials (Non Patent Literature
21).
[0010] As for systemic lupus erythematosus, it is reported that
administration of anti-IL-17 antibody can inhibit onset of GBM
nephritis model in ROR.gamma.t-KO mice which is an animal model of
glomerulonephritis (Non Patent Literature 11). Administration of
anti-IL-17 antibody potentially inhibits nephritis associated with
SLE as well (Non Patent Literature 12).
[0011] As for ankylosing spondylitis, it is reported that
administration of anti-IL-17 antibody is effective in treating
ankylosing spondylitis (Non Patent Literature 13).
[0012] As for uveitis, it is reported that administration of
anti-IL-17 antibody is effective in treating uveitis associated
with Behcet's disease, sarcoidosis, and Harada disease (Non Patent
Literature 7).
[0013] As for polymyalgia rheumatica, efficacy of anti-IL-17
antibody is currently assessed in clinical trials for polymyalgia
rheumatica.
[0014] As for type I diabetes, administration of anti-IL-17
antibody can inhibit progression of disease states in a NOD mouse
model which is a type I diabetes model (Non Patent Literature 14).
Efficacy of anti-IL-17A antibody is currently assessed in clinical
trials (Non Patent Literature 22).
[0015] As for graft-versus-host disease, it is reported that
transfection of ROR.gamma.-KO-mouse-derived cells can ameliorate
survival rates and rejections in a host in a mouse transplant model
(Non Patent Literature 19).
[0016] As for alopecia areata, efficacy of anti-IL-17A antibody is
currently assessed in clinical trials (Non Patent Literature
25).
[0017] As for vitiligo, increases of IL-17 and Th17 cells are
recognized in patient sera and pathological tissues, respectively
(Non Patent Literature 34).
[0018] As for allergic diseases such as asthma, attenuated
eosinophilic pulmonary inflammation, the reduced number of CD4+
lymphocytes, and the decrease of Th2 cytokines/chemokines levels
are exhibited in ROR.gamma.-KO mice in an OVA-sensitized model,
which then allergic reactions 21 can be inhibited (Non Patent
Literature 15). Efficacy of anti-IL-17A antibody is currently
assessed in clinical trials for atopic dermatitis (Non Patent
Literature 23). Efficacy of anti-IL-23 antibody is currently
assessed in clinical trials for asthma (Non Patent Literature
24).
[0019] As for dry eye, it is reported that Th17 cells increase in
an animal model of dry eye, and efficacy of anti-IL-17 antibody is
currently assessed in clinical trials for dry eye patients (Non
Patent Literature 16).
[0020] As for fibrosis, administration of anti-IL-17 antibody can
inhibit inflammation and fibrosis in lung and extend survival of
animals in a bleomycin-induced lung fibrosis model which is an
animal model of lung fibrosis (Non Patent Literature 17).
[0021] As for primary biliary cirrhosis, it is reported that Th17
cells increase in the lesion area of patients with primary biliary
cirrhosis, and efficacy of anti-IL-23 antibody is currently
assessed in clinical trials (Non Patent Literature 18).
[0022] As for malignant melanoma, efficacy of anti-TL-17 antibody
is currently assessed in clinical trials (Non Patent Literatures 26
and 27).
[0023] As for prostate cancer, it is recognized that anti-IL-17
antibody treatment decreased the formation of micro-invasive
prostate cancer in Pten-null mice (Non Patent Literature 28).
[0024] As for insulin resistance, the insulin resistance induced by
feeding high-fat diets can be inhibited in ROR.gamma. KO mice (Non
Patent Literature 4).
[0025] As for hepatic steatosis, it is recognized that anti-IL-17
antibody ameliorated steatosis on pathological tissues in an
alcoholic liver-disease model (Non Patent Literature 29).
[0026] As for non-alcoholic fatty liver disease, it is recognized
that anti-IL-17 antibody treatment improved liver function,
attenuated hepatic lipid accumulation, suppressed Kupffer cells
activation, and decreased pro-inflammatory cytokines levels in a
high fat diet-induced non-alcoholic fatty liver disease model (Non
Patent Literature 30).
[0027] As for ischemia and cardiomyopathy, it is reported that
IL-17A contributes to myocardial ischemia/reperfusion injury by
regulating cardiomyocyte apoptosis and neutrophil infiltration. It
is recognized that anti-IL-17A antibody treatment or IL-17A
knockout reduced infarct size, improved cardiac function, and thus,
ameliorated ischemia/reperfusion injury (Non Patent Literature
31).
[0028] As for hypertension, it is reported that treatment with
antibody against IL-17A or IL-17RA suppressed increased blood
pressure by administration of angiotensin II (Non Patent Literature
32).
[0029] As for periodontitis, increase of Th17 cells or IL-17 was
recognized in an experimental periodontitis model. It is reported
that treatment with ROR.gamma. antagonist, GSK805, or anti-IL-17A
antibody diminished bone loss in the model (Non Patent Literature
33).
[0030] On the basis of these findings, ROR.gamma. antagonists are
deemed to be beneficial for preventing or treating autoimmune
diseases, allergic diseases, dry eye, fibrosis, cancers (such as
malignant melanoma and prostate cancer), metabolic disease,
ischemia, cardiomyopathy, hypertension, and periodontal
disease.
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faces of interleukin-17 in inflammatory skin diseases", Br. J.
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SUMMARY OF INVENTION
[0065] The present invention provides saturated-ring-fused
dihydropyrimidinone or dihydrotriazinone compounds, or
pharmaceutically acceptable salts thereof, having ROR.gamma.
antagonist activity, pharmaceutical compositions comprising the
same, and their medical use. One aspect of the present invention
includes the following illustrative embodiments.
[Item 1]
[0066] A compound of Formula [I]:
##STR00002##
wherein R.sup.1 is (1) C.sub.1-8 alkyl, (2) halo-C.sub.1-8 alkyl,
(3) C.sub.3-8 cycloalkyl optionally substituted with the same or
different 1 to 3 substituents selected from Group A.sup.1, or (4)
C.sub.3-A cycloalkyl-C.sub.1-4 alkyl wherein the C.sub.3-8
cycloalkyl moiety may be optionally substituted with the same or
different 1 to 3 substituents selected from Group A, [0067] Group
A.sup.1 is (1) halogen, (2) C.sub.1-4 alkyl, and (3) halo-C.sub.1-4
alkyl, [0068] X.sup.1 is (1) a bond, or
(2) --O--,
[0068] [0069] R.sup.2 is (1) hydrogen, or (2) halogen, [0070]
R.sup.3 is (1) hydrogen, or (2) --Y.sup.3--COO--R.sup.30, [0071]
Y.sup.3 is (1) C.sub.1-8 alkylene, (2) C.sub.3-8 cycloalkylene, (3)
bridged C.sub.5-8 cycloalkylene, or (4) C.sub.6-14 arylene, [0072]
R.sup.30 is (1) hydrogen, or (2) C.sub.1-4 alkyl, [0073] X.sup.2
is
(1) .dbd.C(R.sup.4)--, or
(2) .dbd.N--,
[0073] [0074] R.sup.4 is (1) hydrogen, or (2) C.sub.1-4 alkyl,
[0075] X is (1) --C(R.sup.5) (R.sup.6)--, [0076] X.sup.4 is (1) a
bond, or (2) --C(R.sup.7) (R.sup.8)--, [0077] X.sup.5 is (1)
--C(R.sup.9) (R.sup.10)--,
(2) --N(R.sup.11)--, or
(3) --O--,
[0077] [0078] R.sup.5 and R.sup.6 are each independently (1)
hydrogen, (2) C.sub.1-4 alkyl, (3) halo-C.sub.1-4 alkyl, (4)
cyano-C.sub.1-4 alkyl, or (5) C.sub.1-4 alkyl substituted with one
substituent selected from the group consisting of --O--R.sup.51,
--CO--R.sup.61, --COO--R.sup.52, --N(R.sup.71) (R.sup.2),
--CO--N(R.sup.73) (R.sup.74), --N(R.sup.75) --CO--R.sup.62,
--N(R.sup.76) --COO--R.sup.53, and --O--S(O).sub.2--R.sup.63,
[0079] R.sup.7, R.sup.8, R.sup.9, and R.sup.13 are each
independently (1) hydrogen, (2) halogen, (3) cyano, (4) hydroxy,
(5) C.sub.1-4 alkyl, (6) halo-C.sub.1-4 alkyl, (7) cyano-C.sub.1-4
alkyl, (8) C.sub.1-4 alkoxy, or (9) C.sub.1-4 alkyl substituted
with one substituent selected from the group consisting of
--O--R.sup.51, --CO--R.sup.61, --COO--R.sup.52, --N(R.sup.71)
(R.sup.72), --CO--N(R.sup.73) (R.sup.74), --N(R.sup.75)
--CO--R.sup.62, --N(R.sup.76) --COO--R.sup.53, and
--O--S(O).sub.2--R.sup.63, [0080] R.sup.51, R.sup.52, and R.sup.53
are each independently (1) hydrogen, (2) C.sub.1-4 alkyl, or (3)
C.sub.6-14 aryl-C.sub.1-4 alkyl, [0081] R.sup.61, R.sup.62, and
R.sup.63 are each independently (1) C.sub.1-4 alkyl, [0082]
R.sup.71, R.sup.72, R.sup.73, R.sup.74, R.sup.75, and R.sup.76 are
each independently (1) hydrogen, or (2) C.sub.1-4 alkyl, [0083]
R.sup.11 is
(1) --CO--R.sup.111, or
(2) --COO--R.sup.112,
[0083] [0084] R.sup.111 is (1) C.sub.1-4 alkyl, [0085] R.sup.112 is
(1) C.sub.1-4 alkyl, or a pharmaceutically acceptable salt
thereof.
[Item 2]
[0086] The compound according to Item 1, having a structure of
Formula [II]:
##STR00003##
wherein each variable is defined as defined in Item 1, or a
pharmaceutically acceptable salt thereof.
[Item 3]
[0087] The compound according to Item 1 or 2, wherein X.sup.2 is
.dbd.N--, or a pharmaceutically acceptable salt thereof.
[Item 4]
[0088] The compound according to Item 1 or 2, wherein X.sup.2 is
.dbd.C(R.sup.4)-- and R.sup.4 is hydrogen, or a pharmaceutically
acceptable salt thereof.
[Item 5]
[0089] The compound according to any one of Items 1 to 4, wherein
R.sup.3 is hydrogen, or a pharmaceutically acceptable salt
thereof.
[Item 6]
[0090] The compound according to any one of Items 1 to 4, wherein
R.sup.3 is --Y.sup.3--COO--R.sup.30, [0091] Y.sup.3 is (1)
C.sub.1-8 alkylene, (2) C.sub.3-8 cycloalkylene, or (3) bridged
C.sub.5-8 cycloalkylene, [0092] R.sup.30 is hydrogen or C.sub.1-4
alkyl, or a pharmaceutically acceptable salt thereof.
[Item 7]
[0093] The compound according to any one of Items 1 to 6, wherein
R.sup.2 is halogen, or a pharmaceutically acceptable salt
thereof.
[Item 8]
[0094] The compound according to any one of Items 1 to 7, wherein
R.sup.1 is C.sub.1-6 alkyl and X.sup.1 is a bond, or a
pharmaceutically acceptable salt thereof.
[Item 9]
[0095] The compound according to any one of Items 1 to 8, wherein R
and R.sup.6 are each independently hydrogen or C.sub.1-4 alkyl, or
a pharmaceutically acceptable salt thereof.
[Item 10]
[0096] The compound according to any one of Items 1 to 9, wherein
X.sup.4 is a bond or --C(R.sup.7) (R.sup.8)-- and both of R.sup.7
and R.sup.8 are hydrogen, or a pharmaceutically acceptable salt
thereof.
[Item 11]
[0097] The compound according to any one of Items 1 to 10, wherein
X.sup.5 is --C(R') (R.sup.10)-- or --O-- and both of R.sup.9 and
R.sup.10 are hydrogen, or a pharmaceutically acceptable salt
thereof.
[Item 12]
[0098] The compound according to Item 1, selected from the
following compound group:
##STR00004## ##STR00005## ##STR00006## ##STR00007##
or a pharmaceutically acceptable salt thereof.
[Item 13]
[0099] A pharmaceutical composition comprising a compound according
to any one of Items 1 to 12 or a pharmaceutically acceptable salt
thereof and a pharmaceutically acceptable carrier.
[Item 14]
[0100] An ROR.gamma. antagonist comprising a compound according to
any one of Items 1 to 12 or a pharmaceutically acceptable salt
thereof.
[Item 15]
[0101] A therapeutic or preventive agent for a disease selected
from the group consisting of autoimmune diseases, allergic
diseases, dry eye, fibrosis, cancers, metabolic disease, ischemia,
cardiomyopathy, hypertension, and periodontal disease, comprising a
compound according to any one of Items 1 to 12 or a
pharmaceutically acceptable salt thereof.
[Item 16]A method of antagonizing ROR.gamma., comprising
administering a therapeutically effective amount of a compound
according to any one of Items 1 to 12 or a pharmaceutically
acceptable salt thereof to a mammal. [Item 17]A method of treating
or preventing a disease selected from the group consisting of
autoimmune diseases, allergic diseases, dry eye, fibrosis, cancers,
metabolic disease, ischemia, cardiomyopathy, hypertension, and
periodontal disease, comprising administering a therapeutically
effective amount of a compound according to any one of Items 1 to
12 or a pharmaceutically acceptable salt thereof to a mammal.
[Item 18]
[0102] Use of a compound according to any one of Items 1 to 12 or a
pharmaceutically acceptable salt thereof in the manufacture of an
ROR.gamma. antagonist.
[Item 19]
[0103] Use of a compound according to any one of Items 1 to 12 or a
pharmaceutically acceptable salt thereof in the manufacture of a
therapeutic or preventive agent for a disease selected from the
group consisting of autoimmune diseases, allergic diseases, dry
eye, fibrosis, cancers, metabolic disease, ischemia,
cardiomyopathy, hypertension, and periodontal disease.
[Item 20]A compound according to any one of Items 1 to 12 or a
pharmaceutically acceptable salt thereof for use in an ROR.gamma.
antagonist. [Item 21]A compound according to any one of Items 1 to
12 or a pharmaceutically acceptable salt thereof for use in 1C
treating or preventing a disease selected from the group consisting
of autoimmune diseases, allergic diseases, dry eye, fibrosis,
cancers, metabolic disease, ischemia, cardiomyopathy, hypertension,
and periodontal disease.
[0104] [Item 22]A commercial package comprising a pharmaceutical
composition according to Item 13 and a package insert concerning
the pharmaceutical composition describing that the pharmaceutical
composition can be used for treating or preventing a disease
selected from the group consisting of autoimmune diseases, allergic
diseases, dry eye, fibrosis, cancers, metabolic disease, ischemia,
cardiomyopathy, hypertension, and periodontal disease.
[Item 23]A kit comprising a pharmaceutical composition according to
Item 13 and a package insert concerning the pharmaceutical
composition describing that the pharmaceutical composition can be
used for treating or preventing a disease selected from the group
consisting of autoimmune diseases, allergic diseases, dry eye,
fibrosis, cancers, metabolic disease, ischemia, cardiomyopathy,
hypertension, and periodontal disease.
DESCRIPTION OF EMBODIMENTS
[0105] Definitions of terms used herein are shown as follows.
[0106] A wavy line as follows:
in a partial structure shows a binding site.
[0107] The term "halogen" includes fluoro, chloro, bromo, and iodo.
A preferable "halogen" is fluoro, chloro, or bromo.
[0108] The term "C.sub.1-4 alkyl" means a straight- or
branched-chain saturated hydrocarbon group with 1 to 4 carbon
atoms. The "C.sub.1-4 alkyl" group includes methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and
tert-butyl.
[0109] The term "C.sub.1-8 alkyl" means a straight- or
branched-chain saturated hydrocarbon group with 1 to 8 carbon
atoms. The "C.sub.1-8 alkyl" group includes, for example, methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, 1,1-dimethylpropyl,
1-ethylpropyl, n-hexyl, isohexyl, 3,3-dimethylbutyl,
2,2-dimethylbutyl, 1,1-dimethylbutyl, 2-ethylbutyl, n-heptyl,
5-methylhexyl, 4-methylhexyl, 4,4-dimethylpentyl,
3,3-dimethylpentyl, 3,4-dimethylpentyl, 2,3-dimethylpentyl,
3-ethylpentyl, 2-ethylpentyl, heptan-4-yl, n-octyl, 6-methylheptyl,
5,5-dimethylhexyl, 4,5-dimethylhexyl, 4-ethylhexyl, 3-ethylhexyl,
2-propylpentyl, and octan-4-yl.
[0110] The term "C.sub.1-8 alkylene" means a divalent group derived
from straight- or branched-chain saturated hydrocarbon with 1 to 8
carbon atoms. The "C.sub.1-8 alkylene" group includes, for example,
the following groups:
##STR00008## ##STR00009##
[0111] The term "halo-C.sub.1-4 alkyl" means the "C.sub.1-4 alkyl"
group substituted with 1 to 5 halogen atoms independently selected
from the group of the term "halogen". The "halo-C.sub.1-4 alkyl"
group includes, for example, monofluoromethyl, difluoromethyl,
trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl,
1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,
3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl,
3,3,3-trifluoropropyl, 4-fluorobutyl, and 4,4,4-trifluorobutyl.
[0112] The term "halo-C.sub.1-8 alkyl" means the "C.sub.1-9 alkyl"
group substituted with 1 to 9 halogen atoms independently selected
from the group of the term "halogen". The "halo-C.sub.1-8 alkyl"
group includes, for example, monofluoromethyl, difluoromethyl,
trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl,
1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,
3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl,
3,3,3-trifluoropropyl, 4-fluorobutyl, 4,4,4-trifluorobutyl,
5-fluoropentyl, 5,5,5-trifluoropentyl, 4,4,5,5,5-pentafluoropentyl,
3,3,4,4,5,5,5-heptafluoropentyl, 6-fluorohexyl,
6,6,6-trifluorohexyl, 7-fluoroheptyl, 7,7,7-trifluoroheptyl,
8-fluorooctyl, 8,8,8-trifluorooctyl, and
7,7,8,8,8-pentafluorooctyl.
[0113] The term "cyano-C.sub.1-4 alkyl" means the "C.sub.1-4 alkyl"
group substituted with one cyano group. The "cyano-C.sub.1-4 alkyl"
group includes, for example, cyanomethyl, 1-cyanoethyl,
2-cyanoethyl, 2-cyanopropyl, 3-cyanopropyl, 4-cyanobutyl, and
2-cyano-2-methylpropyl.
[0114] The term "C.sub.1-4 alkoxy" means those which the "C.sub.1-4
alkyl" group binds to an oxygen atom and the group binds to another
group via the oxygen atom. The "C.sub.1-4 alkoxy" group includes
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,
sec-butoxy, and tert-butoxy.
[0115] The term "C.sub.3-8 cycloalkyl" means a monocyclic saturated
hydrocarbon group with 3 to 8 carbon atoms. The "C.sub.3-8
cycloalkyl" group includes cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl.
[0116] The term "C.sub.3-8 cycloalkyl-C.sub.1-4 alkyl" means the
"C.sub.1-4 alkyl" group substituted with one cycloalkyl group
selected from the group of the "C.sub.3-8 cycloalkyl". The
"C.sub.3-8 cycloalkyl-C.sub.1-4 alkyl" group includes, for example,
cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl,
2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl,
2-cyclohexylethyl, 2-cycloheptylethyl, 2-cyclooctylethyl,
1-cyclopropylethyl, 1-cyclobutylethyl, 1-cyclopentylethyl,
1-cyclohexylethyl, 1-cycloheptylethyl, 1-cyclooctylethyl,
3-cyclopropylpropyl, 3-cyclobutylpropyl, 3-cyclopentylpropyl,
3-cyclohexylpropyl, 3-cycloheptylpropyl, and
3-cyclooctylpropyl.
[0117] The term "C.sub.3-8 cycloalkylene" means a divalent group
derived from a monocyclic saturated hydrocarbon group with 3 to 8
carbon atoms. The "C.sub.3-8 cycloalkylene" group includes, for
example, the following groups:
##STR00010##
[0118] The term "bridged C.sub.5-8 cycloalkylene" means a divalent
group derived from a bridged cyclic saturated hydrocarbon group
with 5 to 8 carbon atoms. The "bridged C.sub.5-s cycloalkylene"
group includes, for example, the following groups:
##STR00011##
[0119] The term "C.sub.6-14 aryl" means an aromatic hydrocarbon
group with 6 to 14 carbon atoms. The "C.sub.6-14 aryl" group
includes, for example, phenyl, naphthyl, anthryl, indenyl,
azulenyl, fluorenyl, phenanthryl, and pentalenyl.
[0120] The term "C.sub.6-14 aryl-C.sub.1-4 alkyl" means the
"C.sub.1-4 alkyl" group substituted with one aryl group selected
from the group of the "C.sub.6-14 aryl". The "C.sub.6-14
aryl-C.sub.1-4 alkyl" group includes, for example, benzyl,
phenethyl, 3-phenylpropyl, 4-phenylbutyl, naphthalen-1-ylmethyl,
naphthalen-2-ylmethyl, anthracen-1-ylmethyl, anthracen-2-ylmethyl,
and anthracen-9-ylmethyl.
[0121] The term "C.sub.6-14 arylene" means a divalent group derived
from an aromatic hydrocarbon group with 6 to 14 carbon atoms. The
"C.sub.6-14 arylene" group includes, for example, the following
groups:
##STR00012##
[0122] As for the term "substituted", for example, the phrase
"C.sub.3-8 cycloalkyl optionally substituted with the same or
different 1 to 3 substituents selected from Group A.sup.1" in
R.sup.1 means unsubstituted C.sub.3-8 cycloalkyl or a group where
any of replaceable hydrogen atoms in C.sub.3-8 cycloalkyl are
substituted with the same or different 1 to 3 substituents selected
from Group A.sup.1, i.e., the group consisting of (1) halogen, (2)
C.sub.1-4 alkyl, and (3) halo-C.sub.1-4 alkyl. Such a substituted
C.sub.3-8 cycloalkyl group includes, for example, the following
groups:
##STR00013##
[0123] The term "a compound of Formula [I]" herein may also be
referred to as "Compound [I]". In one embodiment, Compound [I] is a
compound of Formula [IT]:
##STR00014##
wherein each variable is defined as defined above. The term "a
compound of Formula [II]" herein may also be referred to as
"Compound [II]".
[0124] Embodiments of partial structures and substituents of
Compound [I] and Compound [II] are illustrated as below, but each
partial structure or substituent of Compound [I] and Compound [II]
is not limited to those embodiments; Compound [II] and Compound
[II] include any combinations of two or more embodiments optionally
selected from the embodiments in each partial structure or
substituent.
[0125] The following partial structure of Compound [I]:
##STR00015##
means either of the following partial structures:
##STR00016##
[0126] A preferable structure is any of the following partial
structures:
##STR00017##
[0127] A more preferable one is any of the following partial
structures:
##STR00018##
[0128] A further preferable one is any of the following partial
structures:
##STR00019##
[0129] The following partial structure of Compound [II]:
##STR00020##
means either of the following partial structures:
##STR00021##
[0130] A preferable structure is any of the following partial
structures:
##STR00022##
[0131] A more preferable one is any of the following partial
structures:
##STR00023##
[0132] A further preferable one is any of the following partial
structures:
##STR00024##
[0133] Another embodiment of the following partial structure of
Compound [I]:
##STR00025##
includes the following partial structure:
##STR00026##
Such a partial structure means either of the following partial
structures:
##STR00027##
a preferable one is any of the following partial structures:
##STR00028##
[0134] A more preferable one is any of the following partial
structures:
##STR00029##
[0135] A further preferable one is any of the following partial
structures:
##STR00030##
[0136] R.sup.1 is preferably C.sub.1-8 alkyl, or C.sub.3-8
cycloalkyl substituted with the same or different 1 to 3
substituents selected from Group A.sup.1, and is more preferably
C.sub.1-8 alkyl.
[0137] Group A.sup.1 is preferably halogen and C.sub.1-4 alkyl.
[0138] X.sup.1 is preferably a bond.
[0139] A partial structure of --X.sup.1--R.sup.1 is preferably any
one of the following structures:
##STR00031##
[0140] R.sup.2 is preferably halogen and more preferably
chloro.
[0141] R.sup.3 is preferably --Y.sup.3--COO--R.sup.30.
[0142] Y.sup.3 is preferably C.sub.1-8 alkylene, C.sub.1-8
cycloalkylene, or bridged C.sub.5-8 cycloalkylene, and more
preferably C.sub.3-8 cycloalkylene or bridged C.sub.5-8
cycloalkylene.
[0143] C.sub.1-8 alkylene in Y.sup.3 is preferably any one of the
following groups:
##STR00032##
[0144] C.sub.3-8 cycloalkylene in Y.sup.3 is preferably the
following group:
##STR00033##
[0145] Bridged C.sub.5-8 cycloalkylene in Y.sup.3 is preferably any
one of the following groups:
##STR00034##
[0146] C.sub.6-14 arylene in Y.sup.3 is preferably the following
group:
##STR00035##
[0147] R.sup.30 is preferably hydrogen or ethyl, and more
preferably hydrogen.
[0148] R.sup.4 is preferably hydrogen or methyl, and more
preferably hydrogen.
[0149] R.sup.5 and R.sup.6 are preferably each independently
hydrogen, C.sub.1-4 alkyl, cyano-C.sub.1-4 alkyl, or C.sub.1-4
alkyl substituted with one substituent selected from the group
consisting of --O--R.sup.51, --COO--R.sup.52, --N(R.sup.71)
(R.sup.72), --CO--N(R.sup.73) (R.sup.74), --N(R.sup.75)
--CO--R.sup.62, and --O--S(O).sub.2--R.sup.63 and are more
preferably each independently hydrogen or C.sub.1-4 alkyl.
[0150] In one embodiment, R.sup.5 and R.sup.6 are selected from the
following options:
(A) both are hydrogen; (B) one is hydrogen and the other is
C.sub.1-4 alkyl, preferably methyl; (C) both are C.sub.1-4 alkyl,
preferably methyl for both; (D) one is hydrogen and the other is
cyano-C.sub.4 alkyl, preferably cyanomethyl; or (E) one is hydrogen
and the other is C.sub.1-4 alkyl, preferably methyl or ethyl,
substituted with one substituent selected from the group consisting
of --O--R.sup.51, --COO--R.sup.52, --N(R.sup.71) (R.sup.72),
--CO--N(R.sup.73)(R.sup.74), --N(R.sup.75) --CO--R.sup.62, and
--O--S(O).sub.2--R.sup.63.
[0151] R.sup.7 and R.sup.8 are preferably each independently
hydrogen, halogen, cyano, C.sub.1-4 alkyl, halo-C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, or C.sub.1-4 alkyl substituted with
--O--R.sup.51, and more preferably, both of them are hydrogen.
[0152] In one embodiment, R.sup.7 and R.sup.8 are selected from the
following options:
(A) both are hydrogen; (B) both are halogen, preferably fluoro for
both; (C) both are C.sub.1-4 alkyl, preferably methyl for both; or
(D) one is hydrogen and the other is cyano, C.sub.1-4 alkyl
(preferably methyl, ethyl, or isopropyl), halo-C.sub.1-4 alkyl
(preferably trifluoromethyl), C.sub.1-4 alkoxy (preferably
methoxy), or C.sub.1-4 alkyl, preferably methyl, substituted with
one --O--R.sup.51.
[0153] R.sup.9 and R.sup.10 are preferably each independently
hydrogen or C.sub.1-4 alkyl, and more preferably, both of them are
hydrogen.
[0154] In one embodiment, R.sup.9 and R.sup.10 are selected from
the following options:
(A) both are hydrogen; or (B) both are methyl.
[0155] In one embodiment, X.sup.2 is .dbd.N-- and R.sup.3 is
hydrogen.
[0156] In another embodiment, X.sup.2 is .dbd.C(R.sup.4)-- and
R.sup.3 is --Y.sup.3--COO--R.sup.3.
[0157] The term "pharmaceutically acceptable salt" may be any salts
without excess toxicity known in the art. Specifically, it
includes, for example, salts with inorganic acids, salts with
organic acids, salts with inorganic bases, and salts with organic
bases. Various forms of pharmaceutically acceptable salts are well
known in the art and are listed, for example, in the following
references:
(a) Berge et al., J. Pharm. Sci., 66, p1-19 (1977);
(b) Stahl et al., "Handbook of Pharmaceutical Salts: Properties,
Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002);
[0158] (c) Paulekuhn et al., J. Med. Chem., 50, p6665-6672
(2007).
[0159] According to known methods, Compound [I] may be reacted with
an inorganic acid, organic acid, inorganic base, or organic base to
give each pharmaceutically acceptable salt thereof.
[0160] Such salts with inorganic acids include, for example, salts
with hydrofluoric acid, hydrochloric acid, hydrobromic acid,
hydroiodic acid, nitric acid, phosphoric acid, and sulfuric acid.
Preferable salts include salts with hydrochloric acid, nitric acid,
sulfuric acid, phosphoric acid, and hydrobromic acid.
[0161] Such salts with organic acids include, for example, salts
with acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid,
anhydromethylenecitric acid, benzoic acid, benzenesulfonic acid,
camphor acid, camphor-10-sulfonic acid, carbonic acid, citric acid,
edetic acid, ethane-1,2-disulfonic acid, dodecylsulfonic acid,
ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic
acid, glucuronic acid, glucoheptonic acid, glycollylarsanilic acid,
hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic
acid, lactobionic acid, malic acid, maleic acid, mandelic acid,
methanesulfonic acid, methylsulfuric acid, methylnitric acid,
methylenebis(salicylic acid), galactaric acid,
naphthalene-2-sulfonic acid, 2-naphthoic acid,
1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic
acid, pantothenic acid, pectic acid, picric acid, propionic acid,
polygalacturonic acid, salicylic acid, stearic acid, succinic acid,
tannic acid, tartaric acid, teoclic acid, thiocyanic acid,
trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid,
asparaginic acid, and glutamic acid. Preferable salts include salts
with oxalic acid, maleic acid, citric acid, fumaric acid, lactic
acid, malic acid, succinic acid, tartaric acid, acetic acid,
trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid,
pamoic acid, methanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid, and 2-hydroxy-1-ethanesulfonic acid.
[0162] Such salts with inorganic bases include, for example, salts
with lithium, sodium, potassium, magnesium, calcium, barium,
aluminum, zinc, bismuth, and ammonium. Preferable salts include
salts with sodium, potassium, calcium, magnesium, and zinc.
[0163] Such salts with organic bases include, for example, salts
with arecoline, betaine, choline, clemizole, ethylenediamine,
N-methylglucamine, N-benzylphenethylamine,
tris(hydroxymethyl)methylamine, arginine, and lysine. Preferable
salts include salts with tris(hydroxymethyl)methylamine,
N-methylglucamine, and lysine.
[0164] A preferable "pharmaceutically acceptable salt" includes
hydrochloride and sodium salt.
[0165] Compound [I] or a pharmaceutically acceptable salt thereof
may exist in a solvate form.
[0166] The term "solvate" means Compound [I] or a pharmaceutically
acceptable salt thereof coordinate with a solvent molecule and
includes a hydrate. Such a solvate is preferably a pharmaceutically
acceptable solvate and includes hydrates, ethanolates, and solvates
with dimethylsufoxide of Compound [I] or a pharmaceutically
acceptable salt thereof.
[0167] Specifically, such a solvate includes a hemihydrate,
monohydrate, dihydrate, or monoethanolate of Compound [I], or a
monohydrate of a hydrochloride salt of Compound [I] or a 2/3
ethanolate of a dihydrochloride salt thereof. Such a solvate may be
obtained according to known methods.
[0168] Compound [I] or a pharmaceutically acceptable salt thereof
may exist in its tautomeric form. Such Compound [I] or a
pharmaceutically acceptable salt thereof may exist in each
tautomeric form or in the form of a mixture of its tautomers.
[0169] Compound [I] or a pharmaceutically acceptable salt thereof
may have stereoisomers recognized as cis/trans isomers. Such
Compound [I] or a pharmaceutically acceptable salt thereof may
exist in its cis or trans form, or in the form of a mixture of its
cis and trans isomers.
[0170] Compound [I] or a pharmaceutically acceptable salt thereof
may have one or more asymmetric carbon atoms. Such Compound [I] or
a pharmaceutically acceptable salt thereof may exist in a single
enantiomeric form or a single diastereomeric form, or in the form
of a mixture of its enantiomers or diastereomers.
[0171] Compound [I] or a pharmaceutically acceptable salt thereof
may exist in its atropisomeric form. Such Compound [I] or a
pharmaceutically acceptable salt thereof may exist in each
atropisomeric form or in the form of a mixture of its
atropisomers.
[0172] Compound [I] or a pharmaceutically acceptable salt thereof
may simultaneously comprise multiple structural features
responsible for the above isomers. Compound [I] or a
pharmaceutically acceptable salt thereof may comprise the above
isomers in any ratios.
[0173] Formulae, chemical structures, or compound names herein
without stereochemistry specified include any of the above isomers
available, unless otherwise specified. For example, the following
structure:
##STR00036##
includes, unless otherwise specified, all of: (1) a racemate of the
following two (i.e., S-- and R--) enantiomers:
##STR00037##
(2) the S-enantiomer; and
(3) the R-enantiomer.
[0174] A diastereomeric mixture may be separated into each
diastereomer by conventional methods such as chromatography and
crystallization. Each diastereomer may also be prepared with a
stereochemically-single starting material or by synthetic methods
with stereoselective reactions.
[0175] An enantiomeric mixture may be separated into each single
enantiomer by methods well known in the art.
[0176] For example, an enantiomeric mixture may be reacted with a
substantially pure enantiomer that is known as a chiral auxiliary
to form a diastereomeric mixture, followed by separation from the
diastereomeric mixture by ordinary methods such as fractional
crystallization and chromatography to give a single diastereomer
with an enhanced isomeric ratio or a substantially pure single
diastereomer. Then, the separated diastereomer may be converted
into a desired enantiomer by removal of the added chiral auxiliary
in a cleavage reaction.
[0177] An enantiomeric mixture may also be directly separated into
each enantiomer by chromatography methods with a chiral stationary
phase well known in the art. Alternatively, either of enantiomers
may be obtained with a substantially-pure optically-active starting
material or by stereoselective synthesis, i.e., asymmetric
induction, for a prochiral intermediate with a chiral auxiliary or
asymmetric catalyst.
[0178] Absolute configurations may be determined by X-ray
crystallography for crystalline products or intermediates.
Crystalline products or intermediates derivatized with a reagent
with a known configuration and an asymmetric center may optionally
be used in the determination.
[0179] Compound [I] or a pharmaceutically acceptable salt thereof
may be labelled with an isotope atom such as .sup.1H, .sup.3H,
.sup.14C, and .sup.35S.
[0180] For example, any hydrogen atoms of Compound [I]include
protium .sup.1H (H), deuterium .sup.2H (D), and tritium .sup.3H (T)
For example, when C.sub.1-8 alkyl of R.sup.1 is ethyl, the ethyl
group includes --CD.sub.2CD.sub.3 and --CT.sub.2CT.sub.3 besides
--CH.sub.2CH.sub.3.
[0181] Compound [I], or a pharmaceutically acceptable salt thereof
is preferably Compound [I], or a pharmaceutically acceptable salt
thereof, substantially purified. More preferable one is Compound
[I], or a pharmaceutically acceptable salt thereof, having 80% or
more of purity.
[0182] According to known methods in the art of pharmaceutical
formulations, a pharmaceutical composition herein may be prepared
by, for example, mixing Compound [1] or a pharmaceutically
acceptable salt thereof with at least one or more pharmaceutically
acceptable carrier(s) in an appropriate amount. The content (also
referred to as "a therapeutically effective amount" herein) of
Compound [I] or a pharmaceutically acceptable salt thereof in the
pharmaceutical composition varies depending on dosage forms and
doses and is, for example, 0.1 to 100% by weight of the
composition.
[0183] A dosage form of Compound [I] or a pharmaceutically
acceptable salt thereof includes an oral preparation such as
tablets, capsules, granules, powders, lozenges, syrups, emulsions,
and suspensions and a parenteral preparation such as external
preparations, suppositories, injections, eye drops, nasal
preparations, and pulmonary preparations.
[0184] The term "pharmaceutically acceptable carrier" includes
various conventional organic or inorganic carrier substances for
formulation materials such as excipients, disintegrants, binders,
fluidizers, and lubricants in solid formulations; solvents,
solubilizing agents, suspending agents, tonicity agents, buffers,
and soothing agents in liquid formulations; and bases, emulsifying
agents, wetting agents, stabilizers, stabilizing agents,
dispersants, plasticizers, pH regulators, absorption promoters,
gelators, preservatives, fillers, solubilizers, solubilizing
agents, and suspending agents in semisolid formulations. A
preserving agent, an antioxidant agent, a colorant, or a sweetening
agent may also be optionally used as an additive.
[0185] Such an "excipient" includes, for example, lactose, white
soft sugar, D-mannitol, D-sorbitol, cornstarch, dextrin,
microcrystalline cellulose, crystalline cellulose, carmellose,
carmellose calcium, sodium carboxymethyl starch, low substituted
hydroxypropyl cellulose, and gum arabic.
[0186] Such a "disintegrant" includes, for example, carmellose,
carmellose calcium, carmellose sodium, sodium carboxymethyl starch,
croscarmellose sodium, crospovidone, low substituted hydroxypropyl
cellulose, hydroxypropyl methylcellulose, and crystalline
cellulose.
[0187] Such a "binder" includes, for example, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, povidone, crystalline
cellulose, white soft sugar, dextrin, starch, gelatin, carmellose
sodium, and gum arabic.
[0188] Such a "fluidizer" includes, for example, light anhydrous
silicic acid and magnesium stearate.
[0189] Such a "lubricant" includes, for example, magnesium
stearate, calcium stearate, and talc.
[0190] Such a "solvent" includes, for example, purified water,
ethanol, propyleneglycol, macrogol, sesame oil, corn oil, and olive
oil.
[0191] Such a "solubilizing agent" includes, for example,
propyleneglycol, D-mannitol, benzyl benzoate, ethanol,
triethanolamine, sodium carbonate, and sodium citrate.
[0192] Such a "suspending agent" includes, for example,
benzalkonium chloride, carmellose, hydroxypropyl cellulose,
propyleneglycol, povidone, methylcellulose, and glyceryl
monostearate.
[0193] Such a "tonicity agent" includes, for example, glucose,
D-sorbitol, sodium chloride, and D-mannitol.
[0194] Such a "buffer" includes, for example, sodium hydrogen
phosphate, sodium acetate, sodium carbonate, and sodium
citrate.
[0195] Such a "soothing agent" includes, for example, benzyl
alcohol.
[0196] Such a "base" includes, for example, water, animal or
vegetable oils such as olive oil, corn oil, arachis oil, sesame
oil, and castor oil, lower alcohols such as ethanol, propanol,
propylene glycol, 1,3-butylene glycol, and phenol, higher fatty
acids and esters thereof, waxes, higher alcohols, polyalcohols,
hydrocarbons such as white petrolatum, liquid paraffin, and
paraffin, hydrophilic petrolatum, purified lanolin, absorptive
ointment, hydrous lanolin, hydrophilic ointment, starch, pullulan,
gum arabic, tragacanth gum, gelatin, dextran, cellulose derivatives
such as methylcellulose, carboxymethylcellulose, hydroxyethyl
cellulose, and hydroxypropyl cellulose, synthetic polymers such as
carboxyvinyl polymers, sodium polyacrylate, polyvinyl alcohol, and
polyvinylpyrrolidone, propylene glycol, macrogol such as macrogol
200 to 600, and a combination of any two or more of them.
[0197] Such a "preserving agent" includes, for example, ethyl
parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium
dehydroacetate, and sorbic acid.
[0198] Such an "antioxidant agent" includes, for example, sodium
sulfite and ascorbic acid.
[0199] Such a "colorant" includes, for example, food dye such as
Food Red No. 2 and No. 3, and Food Yellow No. 4 and No. 5, and
.beta.-carotene.
[0200] Such a "sweetening agent" includes, for example saccharin
sodium, dipotassium glycyrrhizate, and aspartame.
[0201] A pharmaceutical composition herein may be administered
orally or parenterally such as locally, rectally, intravenously,
intramuscularly, and subcutaneously to human as well as mammals
other than human such as mice, rats, hamsters, guinea pigs,
rabbits, cats, dogs, pigs, cattle, horses, sheep, and monkeys. A
dose may vary depending on subjects to be administered, diseases,
symptoms, dosage forms, routes of administration, etc. For example,
in oral administration to an adult patient, the dose of Compound
[I], the active ingredient, ranges generally from about 0.01 mg to
about 1 g per day, which may be administered once or several times
in a divided amount.
[0202] A kit such as kits for administration, treatment, and/or
prevention, a package such as packaged goods, and a set and/or case
of medicine which comprises a pharmaceutical composition comprising
Compound [I] or a pharmaceutically acceptable salt thereof as the
active ingredient or active agent and a written matter concerning
the composition indicating that the composition may or should be
used for treatment and/or prevention are also useful. Such a kit,
package, and set of medicine may comprise one or more containers
filled with the pharmaceutical composition or one or more active
ingredients and other drugs or medicines (or ingredients) used for
the composition. Examples of such a kit, package, and set of
medicine include commercial kits, commercial packages, and
commercial medicine set for appropriate use in the treatment and/or
prevention of intended diseases. The written matter comprised in
such a kit, package, and set of medicine includes a cautionary note
or package insert in the form designated by the government
organization that regulates manufactures, use, or sales of
pharmaceutical or biological products which ensures an approval by
the government organization on manufactures, use, or sales of
products concerning administration to humans. The kit, package, and
set of medicine may include packaged products as well as structures
configured for appropriate administration steps and configured so
as to be able to achieve more preferable medical treatment and/or
prevention including treatment and/or prevention of intended
diseases.
[0203] Compound [I] or a pharmaceutically acceptable salt thereof
has ROR.gamma. antagonism and is useful for an ROR.gamma.
antagonist.
[0204] The term "having ROR.gamma. antagonist activity", "having
ROR.gamma. antagonism", or "antagonizing ROR.gamma." means that the
function of ROR.gamma. is antagonized, preferably specifically
antagonized, to disappear or reduce its activity, and includes, for
example, antagonizing, preferably specifically antagonizing, the
function of ROR.gamma. according to the conditions described in
Test Example 1 below.
[0205] The term "ROR.gamma. antagonist" means any substances that
antagonize the function of ROR.gamma., preferably any substances
that specifically antagonize the function of ROR.gamma..
[0206] The term "ROR.gamma." is preferably "human ROR.gamma.".
[0207] Compound [I] or a pharmaceutically acceptable salt thereof
has ROR.gamma. antagonism, and is expected to be effective against
diseases that involve the function of ROR.gamma..
[0208] Specifically, Compound [I] or a pharmaceutically acceptable
salt thereof is expected to be useful for treating or preventing a
disease selected from the group consisting of autoimmune diseases,
allergic diseases, dry eye, fibrosis, cancers, metabolic disease,
ischemia, cardiomyopathy, hypertension, and periodontal
disease.
[0209] The term "autoimmune diseases" means a generic name of
diseases where an immune system of a subject overreacts to and
attacks even normal cells and tissues thereof to cause symptoms,
and includes, specifically, rheumatoid arthritis, psoriasis,
inflammatory bowel diseases such as Crohn's disease and ulcerative
colitis, multiple sclerosis, systemic lupus erythematosus (SLE),
Behcet's disease, sarcoidosis, Harada disease, ankylosing
spondylitis, uveitis, polymyalgia rheumatica, type I diabetes,
graft-versus-host disease, alopecia areata, and vitiligo.
[0210] The term "allergic diseases" means diseases derived from the
condition where an immune reaction excessively occurs against a
certain antigen, and includes, specifically, atopic dermatitis,
allergic rhinitis such as pollen allergy, allergic conjunctivitis,
allergic gastroenteritis, asthma such as bronchial asthma and
infantile asthma, food allergy, medication allergy, and hives.
[0211] The term "fibrosis" means a condition with increased
fibroconnective tissues, and includes, specifically, lung fibrosis
and primary biliary cirrhosis.
[0212] The term "cancer" includes malignant melanoma and prostate
cancer.
[0213] The term "metabolic disease" means a disease caused by
abnormality of metabolic turnover or a disease which includes
metabolic abnormality as an element that constitutes pathogenesis,
and includes, for example, diabetes such as type I diabetes and
type II diabetes, hepatic steatosis, and non-alcoholic fatty liver
disease.
[0214] The term "treating" used herein also includes ameliorating
symptoms, preventing from becoming severe, maintaining remission,
preventing exacerbation, and preventing relapse.
[0215] The term "preventing" used herein means suppressing
pathogenesis of symptoms.
[0216] As long as an embodiment disclosed herein is compatible with
another embodiment disclosed in another portion of the description,
any two or more combinations of these embodiments are also intended
to be included in the invention.
[0217] A general method of preparing Compound [I] or a
pharmaceutically acceptable salt thereof is illustrated as below. A
method of preparing Compound [I] or a pharmaceutically acceptable
salt thereof, however, is not intended to be limited thereto. Salts
of each compound in the general method may be selected from the
above "pharmaceutically acceptable salt" unless otherwise
specified.
[0218] Each compound obtained in each step may be isolated and/or
purified by known methods such as distillation, recrystallization,
and column chromatography, if necessary, but each reaction may
optionally proceed to a sequential step without isolation and/or
purification.
[0219] The room temperature herein means a temperature under no
control, and includes 1.degree. C. to 40.degree. C. as one
embodiment.
[0220] Abbreviations used herein are defined as follows.
IPA: Isopropyl alcohol Hex.: n-Hexane DMSO: Dimethyl sulfoxide NOE:
Nuclear overhauser effect DsPhSO.sub.3N.sub.3:
p-Dodecylbenzenesulfonylazide DMEAD: Di-2-methoxyethyl
azodicarboxylate TBAI: Tetrabutylammonium iodide PPTS: Pyridinium
p-toluenesulfonate
THF: Tetrahydrofuran
[0221] WSC.HCl: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride
DMAP: Dimethylaminopyridine
[0222] LDA: Lithium diisopropylamide
DMF: N,N-Dimethylformamide
[0223] DIBAL-H: Diisobutylaluminum hydride TFA: Trifluoroacetic
acid NaHMDS: Sodium bis(trimethylsilyl)amide
HMDS: Bis(trimethylsilyl)amine
[0224] TEMPO: 2,2,6,6-Tetramethylpiperidin-1-oxyl TBAF:
Tetrabutylammonium fluoride
[Preparation Method 1]: Preparation of Compound [I-1] or a Salt
Thereof
[0225] Compound [I] wherein X.sup.2 is .dbd.C(R.sup.4)--, or a salt
thereof, may be obtained by, for example, the following Preparation
method 1.
##STR00038##
In the scheme, R.sup.1, R.sup.2, R.sup.3, R.sup.4, X.sup.1,
X.sup.3, X.sup.4, and X.sup.5 are defined as defined above, and
[0226] L.sup.1 is halogen, for example, selected from chloro,
bromo, and iodo.
(Step 1-1)
[0227] Compound [13] or a salt thereof may be prepared by reaction
of Compound [11] with Compound [12] or a salt thereof in a solvent
in the presence of an organometallic reagent and Lewis acid.
[0228] Such a solvent includes, for example, ether solvents such as
tetrahydrofuran; hydrocarbon solvents such as toluene; and a mixed
solvent of any of them. A preferable solvent herein is
tetrahydrofuran.
[0229] Such an organometallic reagent includes, for example,
n-butyllithium and tert-butyllithium. A preferable organometallic
reagent herein is n-butyllithium.
[0230] Such Lewis acid includes a boron trifluoride-diethyl ether
complex.
[0231] The reaction temperature herein ranges, for example, from
-102.degree. C. to -69.degree. C., preferably from -78.degree. C.
to -70.degree. C.
[0232] Compound [11] is commercially available or may be prepared
by known methods from commercially available products.
[0233] Compound [12] or a salt thereof may be prepared by, for
example, any of Preparation methods 1A to 1R below.
(Step 1-2)
[0234] Compound [14] or a salt thereof may be prepared by reduction
of Compound [13] or a salt thereof in a solvent in the presence of
a metal reagent and an acid.
[0235] Such a metal reagent includes, for example, zinc and iron. A
preferable metal reagent herein is zinc.
[0236] Such an acid includes, for example, acetic acid,
trifluoroacetic acid, hydrochloric acid, and sulfuric acid. A
preferable acid herein is acetic acid or hydrochloric acid.
[0237] Such a solvent includes, for example, ether solvents such as
tetrahydrofuran; alcohol solvents such as methanol; water; and a
mixed solvent of any of them. A preferable solvent herein is
tetrahydrofuran, methanol, or water.
[0238] The reaction temperature herein ranges, for example, from
0.degree. C. to 80.degree. C., preferably from room temperature to
80.degree. C.
[0239] Compound [14] or a salt thereof may also prepared by
hydrogenation of Compound [13] or a salt thereof in a solvent in
the presence of a catalytic amount of palladium. Such a solvent
includes, for example, ether solvents such as tetrahydrofuran;
alcohol solvents such as ethanol; ester solvents such as ethyl
acetate; and a mixed solvent of any of them. A preferable solvent
herein is tetrahydrofuran, ethanol, or ethyl acetate. The reaction
temperature herein is room temperature.
(Step 1-3)
[0240] Compound [16] or a salt thereof may be prepared by reaction
of Compound [14] or a salt thereof with Compound [15] or a salt
thereof in a solvent.
[0241] Such a solvent includes, for example, hydrocarbon solvents
such as toluene; ether solvents such as tetrahydrofuran;
halogenated solvents such as dichloromethane; and a mixed solvent
of any of them. A preferable solvent herein is toluene,
tetrahydrofuran, or dichloromethane.
[0242] The reaction temperature herein ranges, for example, from
0.degree. C. to 80.degree. C., preferably from 0.degree. C. to room
temperature.
[0243] The reaction may also be carried out with optional addition
of triethylamine.
(Step 1-4)
[0244] Compound [I-1] or a salt thereof may be prepared by
oxidation of Compound [16] or a salt thereof in a solvent in the
presence of an oxidizing agent, followed by cyclization.
[0245] Such a solvent includes, for example, halogenated solvents
such as chloroform; ester solvents such as ethyl acetate; nitrile
solvents such as acetonitrile; ether solvents such as cyclopentyl
methyl ether; carboxylic acid solvents such as acetic acid; and a
mixed solvent of any of them. A preferable solvent herein is
dichloromethane, chloroform, cyclopentyl methyl ether, or acetic
acid.
[0246] Such an oxidizing agent includes, for example,
2-azaadamantan-N-oxyl, 2,2,6,6-tetramethylpiperidin-1-oxyl radical,
and Dess-Martin reagent. The reaction may also be carried out with
optional addition of a co-oxidizing agent such as
(diacetoxyiodo)benzene and sodium hypochlorite. A preferable
oxidizing agent herein is a mixture of
2,2,6,6-tetramethylpiperidin-1-oxyl radical and
(diacetoxyiodo)benzene.
[0247] An acid in the cyclization includes hydrochloric acid,
trifluoroacetic acid, and p-toluenesulfonic acid. A preferable acid
herein is trifluoroacetic acid.
[0248] The reaction temperature herein ranges, for example, from
0.degree. C. to 80.degree. C., preferably from 0.degree. C. to room
temperature.
[Preparation Method 1A]: Preparation of Compound [I-1A] or a Salt
Thereof
[0249] Compound [I] wherein X.sup.2 is .dbd.C(R.sup.4)-- and
R.sup.4 is hydrogen (Compound [I-1A]):
##STR00039##
wherein R.sup.1, R.sup.2, R.sup.3, X.sup.1, X.sup.3, X.sup.4, and
X.sup.5 are defined as defined above, or a salt thereof, may be
obtained by, for example, using Compound [12a] or a salt thereof
obtained in Preparation method 1A as follows, instead of Compound
[12] or a salt thereof in Preparation method 1.
##STR00040##
In the scheme, X.sup.3, X.sup.4, and X.sup.5 are defined as defined
above.
(Step 1A-1)
[0250] Compound [A2] or a salt thereof may be prepared by oxidation
of Compound [A1] or a salt thereof in a solvent.
[0251] Such a solvent includes, for example, ester solvents such as
ethyl acetate; hydrocarbon solvents such as toluene; sulfoxide
solvents such as dimethyl sulfoxide; ether solvents such as
tetrahydrofuran; and halogenated solvents such as chloroform. A
preferable solvent herein is chloroform or dichloromethane.
[0252] The oxidizing agent herein includes, for example,
2,2,6,6-tetramethypiperidin-1-oxyl radical, dimethyl sulfoxide, a
sulfur trioxide-pyridine complex, iodoxybenzoic acid, pyridinium
chlorochromate, and Dess-Martin reagent. A preferable oxidizing
agent herein is 2,2,6,6-tetramethylpiperidin-1-oxyl radical.
[0253] The reaction temperature herein ranges, for example, from
-78.degree. C. to room temperature, preferably from 0.degree. C. to
room temperature.
[0254] The reaction may also be carried out with optional addition
of (diacetoxyiodo)benzene.
(Step 1A-2)
[0255] Compound [A3] or a salt thereof may be prepared by reaction
of Compound [A2] or a salt thereof with hydroxylamine hydrochloride
in a solvent.
[0256] Such a solvent includes, for example, alcohol solvents such
as ethanol; hydrocarbon solvents such as toluene; halogenated
solvents such as dichloromethane; ether solvents such as
tetrahydrofuran; amide solvents such as dimethylformamide; nitrile
solvents such as acetonitrile; water; and a mixed solvent of any of
them. A preferable solvent herein is ethanol, toluene,
tetrahydrofuran, or water.
[0257] The reaction temperature herein ranges from room temperature
to 120.degree. C.
[0258] The reaction may also be carried out with optional addition
of sodium acetate.
(Step 1A-3)
[0259] Compound [12a] or a salt thereof may be prepared by
cyclization of Compound [A3] or a salt thereof in a solvent in the
presence of an oxidizing agent.
[0260] Such an oxidizing agent includes, for example,
(diacetoxyiodo)benzene, sodium hypochlorite, chloramine T, and
N-chlorosuccinimide. A preferable oxidizing agent herein is
(diacetoxyiodo)benzene or sodium hypochlorite.
[0261] When (diacetoxyiodo)benzene is used for the oxidizing agent,
an acid is used for an additive. Such an acid includes
trifluoroacetic acid. A solvent used herein includes, for example,
alcohol solvents such as methanol; halogenated solvents such as
dichloromethane; and a mixed solvent of any of them. A preferable
solvent herein is methanol or dichloromethane. The reaction
temperature herein ranges from 0.degree. C. to room
temperature.
[0262] When aqueous sodium hypochlorite solution is used for the
oxidizing agent, a base is used for an additive. Such a base
includes, for example, triethylamine and pyridine. A preferable
base herein is triethylamine. A solvent used herein includes, for
example, halogenated solvents such as dichloromethane; alcohol
solvents such as ethanol; nitrile solvents such as acetonitrile;
ether solvents such as tert-butyl methyl ether; and a mixed solvent
of any of them. A preferable solvent herein is dichloromethane. The
reaction temperature herein ranges, for example, from 0.degree. C.
to room temperature and is preferably room temperature.
[Preparation Method 1B]: Preparation of Compound [1-13] or a Salt
Thereof
[0263] Compound [I] wherein X.sup.2 is .dbd.C(R.sup.4)--, R.sup.4
is hydrogen, X.sup.4 is a bond, and X.sup.5 is --O-- (Compound
[I-1B]):
##STR00041##
wherein R.sup.1, R.sup.2, R.sup.3, X.sup.1, and X.sup.3 are defined
as defined above, or a salt thereof, may be obtained by, for
example, using Compound [12b] or a salt thereof obtained in
Preparation method 1B as follows, instead of Compound [12] or a
salt thereof in the above Preparation method 1.
##STR00042##
In the scheme, X.sup.3 is defined as defined above, and
[0264] G.sup.1 is a protective group of carboxy, for example,
selected from methyl, ethyl, isopropyl, tert-butyl, or benzyl.
(Step 1B-1)
[0265] Compound [B3] or a salt thereof may be prepared by reaction
of Compound [B1] with Compound [B2] or a salt thereof in a solvent
or without any solvents in the presence of a catalyst.
[0266] Such a solvent includes, for example, halogenated solvents
such as dichloromethane; ester solvents such as ethyl acetate;
ether solvents such as diethyl ether; hydrocarbon solvents such as
benzene; and a mixed solvent of any of them. Herein, no solvent or
dichloromethane is preferable.
[0267] Such a catalyst includes, for example, rhodium (II) acetate
dimer dihydrate, indium (III) chloride, and iron (III) chloride. A
preferable catalyst herein is rhodium (II) acetate dimer
dihydrate.
[0268] The reaction temperature herein is room temperature.
(Step 1R-2)
[0269] Compound [B4] or a salt thereof may be prepared by reduction
of Compound [B3] or a salt thereof in a solvent.
[0270] Such a solvent includes, for example, ether solvents such as
tetrahydrofuran; halogenated solvents such as dichloromethane;
hydrocarbon solvents such as toluene; and a mixed solvent of any of
them. A preferable solvent herein is tetrahydrofuran,
dichloromethane, or toluene.
[0271] A reducing agent used herein includes, for example,
diisobutylaluminum hydride, and lithium aluminum hydride. A
preferable reducing agent herein is diisobutylaluminum hydride.
[0272] The reaction temperature herein ranges, for example, from
-78.degree. C. to room temperature, preferably from -78.degree. C.
to 0.degree. C.
(Step 1B-3)
[0273] Compound [B5] or a salt thereof may be prepared from
Compound [B4] or a salt thereof in a similar manner to Step
1A-2.
(Step 1B-4)
[0274] Compound [12b] or a salt thereof may be prepared from
Compound [B5] or a salt thereof in a similar manner to Step
1A-3.
[Preparation Method 1C]: Preparation of Compound [I-1C] or a Salt
Thereof
[0275] Compound [1] wherein X.sup.2 is .dbd.C(R.sup.4)--, R.sup.4
is hydrogen, X.sup.4 is a bond, X.sup.1 is --C(R.sup.9)
(R.sup.10)--, and both of R.sup.9 and R.sup.10 are hydrogen
(Compound [I-1C]):
##STR00043##
wherein R.sup.1, R.sup.2, R.sup.3, X.sup.1, and X.sup.3 are defined
as defined above, or a salt thereof, may be obtained by, for
example, using Compound [12c] or a salt thereof obtained in
Preparation method 1C as follows, instead of Compound [12] or a
salt thereof in the above Preparation method 1.
##STR00044##
In the scheme, X.sup.3 and G.sup.1 are defined as defined
above.
[Preparation Method 1D]: Preparation of Compound [I-1D] or a Salt
Thereof
[0276] Compound [I] wherein X.sup.2 is .dbd.C(R.sup.4)--, R.sup.4
is hydrogen, X.sup.3 is --C(R.sup.5) (R.sup.6)--, R.sup.5 is
hydrogen, R.sup.6 is C.sub.1-4 alkyl, X.sup.4 is --C(R.sup.7)
(R.sup.8)--, R.sup.7 and R.sup.8 are each independently hydrogen or
C.sub.1-4 alkyl, X.sup.5 is --C(R.sup.9) (R.sup.10)--, and both of
R.sup.9 and R.sup.10 are hydrogen (Compound [I-1D]):
##STR00045##
wherein R.sup.6D is C.sub.1-4 alkyl,
[0277] R.sup.7D and R.sup.OD are each independently hydrogen or
C.sub.1-4 alkyl, and
[0278] R.sup.1, R.sup.2, R.sup.3, and X.sup.1 are defined as
defined above, or a salt thereof, may be obtained by, for example,
using Compound [12d] or a salt thereof obtained in Preparation
method ID as follows, instead of Compound [12] or a salt thereof in
the above Preparation method 1.
##STR00046## ##STR00047##
In the scheme, G.sup.1, R.sup.6D, R.sup.7D, and R.sup.6D are
defined as defined above.
[Preparation Method 1E]: Preparation of Compound [I-1E] or a Salt
Thereof
[0279] Compound [I] wherein X.sup.2 is .dbd.C(R.sup.4)--, R.sup.4
is hydrogen, and X.sup.5 is --O-- (Compound [I-1E]):
##STR00048##
wherein R.sup.1, R.sup.2, R.sup.3, X.sup.1, X.sup.3, and X.sup.4
are defined as defined above, or a salt thereof, may be obtained
by, for example, using Compound [12e] or a salt thereof obtained in
Preparation method 1E as follows, instead of Compound [12] or a
salt thereof in the above Preparation method 1.
##STR00049##
In the scheme, X.sup.3 and X.sup.4 are defined as defined
above.
(Step 1E-1)
[0280] Compound [E3] may be prepared by reaction of Compound [E1]
with Compound [E2] in a solvent in the presence of a base.
[0281] Such a solvent includes, for example, ether solvents such as
tetrahydrofuran; hydrocarbon solvents such as toluene; alcoholic
solvents such as methanol; amide solvents such as
dimethylformamide; sulfoxide solvents such as dimethylsulfoxide;
and a mixed solvent of any of them. A preferable solvent herein is
tetrahydrofuran.
[0282] Such a base includes, for example, sodium hydride, sodium
hydroxide, sodium tert-butoxide, sodium bis(trimethylsilyl)amide,
lithium diisopropylamide, and n-butyllithium. A preferable base
herein is sodium hydride.
[0283] The reaction temperature herein ranges, for example, from
0.degree. C. to 14C.degree. C., preferably from 0.degree. C. to
room temperature.
(Step 1E-2)
[0284] Compound [E4] may be prepared by treatment of Compound [E3]
in a solvent in the presence of an acid.
[0285] Such a solvent includes, for example, ether solvents such as
tetrahydrofuran; halogen solvents such as dichloromethane;
alcoholic solvents such as methanol; water; and a mixed solvent of
any of them. A preferable solvent herein is tetrahydrofuran or
water.
[0286] Such an acid includes, for example, hydrochloric acid,
sulfuric acid, acetic acid, phosphoric acid, boron
trifluoride-diethyl ether complex, trimethylsilyl iodide, iodine,
and ion-exchange resin. A preferable acid herein is hydrochloric
acid.
[0287] The reaction temperature herein ranges, for example, from
0.degree. C. to 120.degree. C. and is preferably 60.degree. C.
(Step 1E-3)
[0288] Compound [E5] or a salt thereof may be prepared from
Compound [E4] in a similar manner to Step 1A-2.
(Step 1E-4)
[0289] Compound [12e] or a salt thereof may be prepared from
Compound [E5] or a salt thereof in a similar manner to Step
1A-3.
[Preparation Method 1F]: Preparation of Compound [I-1F] or a Salt
Thereof
[0290] Compound [I] wherein X.sup.2 is .dbd.C(R.sup.4)--, R.sup.4
is hydrogen, X.sup.3 is --C(R.sup.5) (R.sup.6)--, R.sup.5 is
hydrogen, R.sup.6 is C.sub.1-4 alkyl, X.sup.4 is a bond, X.sup.5 is
--C(R.sup.9) (R.sup.10)--, and R.sup.3 and R.sup.10 are each
independently hydrogen or C.sub.1-4 alkyl (Compound [I-1F]):
##STR00050##
wherein R.sup.9F and R.sup.10F are each independently hydrogen or
C.sub.1-4 alkyl, and
[0291] R.sup.1, R.sup.2, R.sup.3, R.sup.6D, and X.sup.1 are defined
as defined above, or a salt thereof, may be obtained by, for
example, using Compound [12f] or a salt thereof obtained in
Preparation method 1F as follows, instead of Compound [12] or a
salt thereof in the above Preparation method 1.
##STR00051## ##STR00052##
In the scheme, R.sup.6D, R.sup.9F, and R.sup.00F are defined as
defined above.
[Preparation Method 1G]: Alternative Preparation of Compound [I-1A]
or a Salt Thereof
[0292] Compound [I] wherein X.sup.2 is .dbd.C(R.sup.4)-- and
R.sup.4 is hydrogen (Compound [I-1A]):
##STR00053##
wherein R.sup.1, R.sup.2, R.sup.3, X.sup.1, X.sup.3, X.sup.4, and
X.sup.5 are defined as defined above, or a salt thereof, may be
obtained by, for example, using Compound [12a] or a salt thereof
obtained in Preparation method 1G as follows, instead of Compound
[12] or a salt thereof in the above Preparation method 1.
##STR00054##
In the scheme, R.sup.G1 and R.sup.G2 each independently C.sub.1-4
alkyl, and X.sup.3, X.sup.4, and X.sup.5 are defined as defined
above.
(Step 1G-1)
[0293] Compound [G3] or a salt thereof may be prepared by reaction
of Compound [G1] or a salt thereof with Compound [G2] in a solvent
in the presence of a base.
[0294] Such a solvent includes, for example, ether solvents such as
tetrahydrofuran; hydrocarbon solvents such as toluene; sulfoxide
solvents such as dimethyl sulfoxide; and a mixed solvent of any of
them. A preferable solvent herein is tetrahydrofuran.
[0295] Such a base includes sodium hydride and lithium
diisopropylamide.
[0296] The reaction temperature herein ranges, for example, from
-78.degree. C. to 110.degree. C., preferably from -78.degree. C. to
65.degree. C.
[0297] The reaction may also be carried out with optional addition
of 18-crown-6-ether.
(Step 1G-2)
[0298] Compound [G5] or a salt thereof may be prepared by
protection of a carbonyl group of Compound [G3] or a salt thereof
with Compound [G4] in a solvent in the presence of an acid.
[0299] Such a solvent includes, for example, hydrocarbon solvents
such as toluene; halogenated solvents such as dichloromethane;
nitrile solvents such as acetonitrile; and a mixed solvent of any
of them. A preferable solvent herein is toluene.
[0300] Such an acid includes, for example, p-toluenesulfonic acid
and pyridinium p-toluenesulfonate. A preferable acid herein is
p-toluenesulfonic acid.
[0301] The reaction temperature herein ranges, for example, from
room temperature to 120.degree. C., preferably from 100.degree. C.
to 120.degree. C.
(Step 1G-3)
[0302] Compound [G6] or a salt thereof may be prepared by reduction
of Compound [G5] or a salt thereof in a solvent.
[0303] Such a solvent includes, for example, ether solvents such as
tetrahydrofuran; hydrocarbon solvents such as toluene; halogenated
solvents such as dichloromethane; and a mixed solvent of any of
them. A preferable solvent herein is tetrahydrofuran or
toluene.
[0304] A reducing agent used herein includes, for example, lithium
aluminum hydride and diisobutylaluminum hydride. A preferable
reducing agent herein is diisobutylaluminum hydride.
[0305] The reaction temperature herein ranges, for example, from
-78.degree. C. to 65.degree. C., preferably from -78.degree. C. to
room temperature.
(Step 1G-4)
[0306] Compound [G8] or a salt thereof may be prepared by Mitsunobu
reaction of Compound [G6] or a salt thereof with Compound [G7] in a
solvent.
[0307] Such a solvent includes, for example, ether solvents such as
tetrahydrofuran; halogenated solvents such as dichloromethane;
hydrocarbon solvents such as toluene; and a mixed solvent of any of
them. A preferable solvent herein is tetrahydrofuran or
dichloromethane.
[0308] A reagent used in Mitsunobu reaction includes, for example,
a mixture of triphenylphosphine or tributylphosphine with diethyl
azodicarboxylate or dipiperidineamide azodicarboxylate. A
preferable reagent used in Mitsunobu reaction is a mixture of
triphenylphosphine with diethyl azodicarboxylate.
[0309] The reaction temperature herein ranges, for example, from
0.degree. C. to 80.degree. C., preferably from 0.degree. C. to room
temperature.
(Step 1G-5)
[0310] Compound [G9] or a salt thereof may be prepared by removal
of a phthaloyl group of Compound [G8] or a salt thereof in a
solvent.
[0311] Such a solvent includes, for example, alcohol solvents such
as ethanol; halogenated solvents such as dichloromethane; ether
solvents such as diethyl ether; and a mixed solvent of any of them.
A preferable solvent herein is ethanol or dichloromethane.
[0312] A reagent used for removal of the phthaloyl group includes,
for example, methylhydrazine, hydrazine, and ethanolamine. A
preferable reagent used for removal of the phthaloyl group is
methylhydrazine or hydrazine.
[0313] The reaction temperature herein ranges, for example, from
0.degree. C. to 100.degree. C., preferably from room temperature to
100.degree. C.
(Step 1G-6)
[0314] Compound [12a] or a salt thereof may be prepared by removal
of an acetal group of Compound [G9] or a salt thereof in a solvent
in the presence of an acid, followed by intramolecular cyclization
in the presence of a base.
[0315] Such a solvent includes, for example, alcohol solvents such
as methanol; ether solvents such as tetrahydrofuran; halogenated
solvents such as dichloromethane; and a mixed solvent of any of
them. A preferable solvent herein is methanol or
tetrahydrofuran.
[0316] Such an acid includes, for example, hydrochloric acid,
acetic acid, and p-toluenesulfonic acid. A preferable acid herein
is hydrochloric acid or p-toluenesulfonic acid.
[0317] Such a base includes, for example, potassium carbonate,
sodium acetate, and triethylamine. A preferable base herein is
potassium carbonate.
[0318] The reaction temperature herein ranges, for example, from
0.degree. C. to 120.degree. C., preferably from 0.degree. C. to
room temperature.
[Preparation Method 1H]: Preparation of Compound [I-1H] or a Salt
Thereof
[0319] Compound [I] wherein X.sup.2 is .dbd.C(R.sup.4)--, R.sup.4
is hydrogen, X.sup.3 is --C(R.sup.5)(R.sup.6)--, R.sup.5 is
hydrogen, R.sup.6 is C.sub.1-4 alkyl, X.sup.4 is --C(R.sup.7)
(R.sup.8)--, R.sup.7 is C.sub.1-4 alkyl, R.sup.8 is hydrogen,
X.sup.5 is --C(R.sup.9) (R.sup.10)--, and both of R.sup.9 and
R.sup.10 are hydrogen (Compound [I-1H]):
##STR00055##
wherein R.sup.7H is C.sub.1-4 alkyl, and
[0320] R.sup.1, R.sup.2, R.sup.3, R.sup.6D, and X.sup.1 are defined
as defined above, or a salt thereof, may be obtained by, for
example, using Compound [12h] or a salt thereof obtained in
Preparation method 1H as follows, instead of Compound [12] or a
salt thereof in the above Preparation method 1.
##STR00056## ##STR00057##
In the scheme, R.sup.6D, R.sup.7H, and G.sup.1 are defined as
defined above.
[Preparation Method 1I]: Preparation of Compound [1-1I] or a Salt
Thereof
[0321] Compound [I] wherein X.sup.2 is .dbd.C(R.sup.4)--, R.sup.4
is hydrogen, X.sup.3 is --C(R.sup.5) (R.sup.6)--, R.sup.5 is
hydrogen, R.sup.6 is C.sub.1-4 alkyl, X.sup.4 is --C(R.sup.7)
(R.sup.8)--, R.sup.7 is C.sub.1-4 alkyl, R.sup.8 is hydrogen,
X.sup.5 is --C(R.sup.9) (R.sup.10)--, and both of R.sup.9 and
R.sup.10 are hydrogen (Compound [I-1I]):
##STR00058##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.6D, R.sup.7H, and X.sup.1
are defined as defined above, or a salt thereof, may be obtained
by, for example, using Compound [12i] or a salt thereof obtained in
Preparation method 1I as follows, instead of Compound [12] or a
salt thereof in the above Preparation method 1.
##STR00059## ##STR00060##
In the scheme, R.sup.6D, R.sup.7H, and G.sup.1 are defined as
defined above.
[Preparation Method 1J]: Preparation of Compound [I-1J] or a Salt
Thereof
[0322] Compound [I] wherein X.sup.2 is .dbd.C(R.sup.4)-- and
R.sup.4 is C.sub.1-4 alkyl (Compound [I-1J]):
##STR00061##
wherein R.sup.41 is C.sub.1-4 alkyl, and
[0323] R.sup.1, R.sup.2, R.sup.3, X.sup.1, X.sup.3, X.sup.4, and
X.sup.5 are defined as defined above, or a salt thereof, may be
obtained by, for example, using Compound [12j] or a salt thereof
obtained in Preparation method 1J as follows, instead of Compound
[12] or a salt thereof in the above Preparation method 1.
##STR00062##
In the scheme, X.sup.3, X.sup.4, X.sup.5, and R.sup.4J are defined
as defined above.
[Preparation Method 1K]: Preparation of Compound [I-1K] or a Salt
Thereof
[0324] Compound [I] wherein X.sup.2 is .dbd.C(R.sup.4)--, R.sup.4
is hydrogen, X.sup.3 is --C(R.sup.5) (R.sup.6)--, R.sup.5 is
hydrogen, and R.sup.6 is:
(1) halo-C.sub.1-4 alkyl, (2) cyano-C.sub.1-4 alkyl, or (3)
C.sub.J-4 alkyl substituted with one substituent selected from the
group consisting of --O--R.sup.51, --O--R--R.sup.61,
--COO--R.sup.52, --N(R.sup.71) (R.sup.72), --CO--N(R.sup.73)
(R.sup.74), --N(R.sup.75) --CO--R.sup.62, --N(R.sup.76)
--COO--R.sup.53, and --O--S(O).sub.2--R.sup.63 (Compound
[I-1K]):
##STR00063##
wherein R.sup.6K is: (1) halo-C.sub.1-4 alkyl, (2) cyano-C.sub.1-4
alkyl, or (3) C.sub.1-4 alkyl substituted with one substituent
selected from the group consisting of --O--R.sup.51,
--CO--R.sup.61, --COO--R.sup.52, --N(R.sup.71) (R.sup.72),
--CO--N(R.sup.73) (R.sup.74), --N(R.sup.75) --CO--R.sup.62,
--N(R.sup.76) --COO--R.sup.53, and --O--S(O).sub.2--R.sup.63,
and
[0325] R.sup.1, R.sup.2, R.sup.3, X.sup.1, X.sup.4, and X.sup.5 are
defined as defined above, or a part of salts thereof, may be
obtained by, for example, using Compound [12k] or a salt thereof
obtained in Preparation method 1K as follows, instead of Compound
[12] or a salt thereof in the above Preparation method 1, or by
converting a benzyl ether moiety of the resulting compound into
various substituents.
##STR00064## ##STR00065##
In the scheme, X.sup.4, X.sup.5, and G.sup.1 are defined as defined
above.
[Preparation Method 1M]: Preparation of Compound [I-1M] or a Salt
Thereof
[0326] Compound [I] wherein X.sup.2 is .dbd.C(R.sup.4)--, R.sup.4
is hydrogen, X.sup.3 is --C(R.sup.5) (R.sup.6)--, both of R.sup.5
and R.sup.6 are hydrogen, X.sup.4 is a bond, and X.sup.5 is
--C(R.sup.9) (R.sup.10)-- (Compound [I-1M]):
##STR00066##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.9, R.sup.10, and X.sup.1
are defined as defined above, or a salt thereof, may be obtained
by, for example, using Compound [12m] or a salt thereof obtained in
Preparation method 1M as follows, instead of Compound [12] or a
salt thereof in the above Preparation method 1.
##STR00067## ##STR00068##
In the scheme, R.sup.9 and R.sup.10 are defined as defined
above.
[Preparation Method 1N]: Preparation of Compound [I-1N] or a Salt
Thereof
[0327] Compound [I] wherein X.sup.2 is .dbd.C(R.sup.4)--, R.sup.4
is hydrogen, X.sup.1 is --C(R.sup.5) (R.sup.6)--, R.sup.5 is
hydrogen, R.sup.6 is:
(1) halo-C.sub.1-4 alkyl, (2) cyano-C.sub.1-4 alkyl, or (3)
C.sub.1-4 alkyl substituted with one substituent selected from the
group consisting of --O--R.sup.51, --CO--R.sup.61, --COO--R.sup.52,
--N(R.sup.71) (R.sup.72), --CO--N(R.sup.73) (R.sup.74),
--N(R.sup.73) --CO--R.sup.62, --N(R.sup.76) --COO--R.sup.53, and
--O--S(O).sub.2--R.sup.63, and X.sup.4 is a bond (Compound
[I-1N]):
##STR00069##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.6, X.sup.1, and X.sup.5
are defined as defined above, or a part of salts thereof, may be
obtained by, for example, using Compound [12n] or a salt thereof
obtained in Preparation method 1N as follows, instead of Compound
[12] or a salt thereof in the above Preparation method 1, or by
converting a benzyl ether moiety of the resulting compound into
various substituents.
##STR00070## ##STR00071##
In the scheme, X.sup.5 and G.sup.1 are defined as defined
above.
[Preparation Method 1P]: Preparation of Compound [I-1P] or a Salt
Thereof
[0328] Compound [I] wherein X.sup.2 is .dbd.C(R.sup.4)--, R.sup.4
is hydrogen, X.sup.4 is a bond, and X.sup.5 is --N(R.sup.11)--
(Compound [I-1P]):
##STR00072##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.11, X.sup.1, and X.sup.3
are defined as defined above, or a salt thereof, may be obtained
by, for example, using Compound [12p] or a salt thereof obtained in
Preparation method 1P as follows, instead of Compound [12] or a
salt thereof in the above Preparation method 1.
##STR00073##
[0329] In the scheme, R.sup.11, X.sup.3, and G.sup.1 are defined as
defined above.
(Step 1P-1)
[0330] Compound [P2] or a salt thereof may be prepared from
Compound [P1] or a salt thereof in a similar manner to Step
1B-2.
(Step 1P-2)
[0331] Compound [P3] or a salt thereof may be prepared from
Compound [P2] or a salt thereof in a similar manner to Step
1A-2.
(Step 1P-3)
[0332] Compound [12p] or a salt thereof may be prepared from
Compound [P3] or a salt thereof in a similar manner to Step
1A-3.
[Preparation Method 1Q]: Preparation of Compound [I-1Q] or a Salt
Thereof
[0333] Compound [I] wherein X.sup.2 is .dbd.C(R.sup.4)--, R.sup.4
is hydrogen, X.sup.3 is --C(R.sup.5) (R.sup.6)--, R.sup.5 and
R.sup.6 are each independently C.sub.1-4 alkyl, X.sup.4 is a bond,
X.sup.5 is --C(R.sup.9) (R.sup.10)--, and both of R.sup.9 and
R.sup.10 are hydrogen (Compound [I-1Q]):
##STR00074##
wherein R.sup.50 is C.sub.1-4 alkyl, and
[0334] R.sup.1, R.sup.2, R.sup.3, R.sup.6D, and X.sup.1 are defined
as defined above, or a salt thereof, may be obtained by, for
example, using Compound [12q] or a salt thereof obtained in
Preparation method 1Q as follows, instead of Compound [12] or a
salt thereof in the above Preparation method 1.
##STR00075##
In the scheme, R.sup.5Q and R.sup.6D are defined as defined
above.
[Preparation Method 1R]: Preparation of Compound [I-1R] or a Salt
Thereof
[0335] Compound [I] wherein X.sup.2 is .dbd.C(R.sup.4)--, R.sup.4
is hydrogen, X.sup.4 is --C(R.sup.7) (R.sup.8)--, both of R.sup.7
and R.sup.8 are hydrogen, X.sup.5 is --C(R.sup.9) (R.sup.10)--, and
both of R.sup.9 and R.sup.10 are hydrogen (Compound [I-1R]):
##STR00076##
wherein R.sup.1, R.sup.2, R.sup.3, X.sup.1, and X.sup.1 are defined
as defined above, or a salt thereof, may be obtained by, for
example, using Compound [12r] or a salt thereof obtained in
Preparation method 1R as follows, instead of Compound [12] or a
salt thereof in the above Preparation method 1.
##STR00077## ##STR00078##
In the scheme, X.sup.3 and G.sup.1 are defined as defined
above.
[Preparation Method 1S]: Preparation of Compound [11] Used in
Preparation Method 1
[0336] Compound [11]:
##STR00079##
wherein R.sup.1, R.sup.2, X.sup.1, and L.sup.1 are defined as
defined above, may be prepared by, for example, cross-coupling
reaction of Compound [S1] shown as follows, when X.sup.1 is a bond,
R.sup.1 is C.sub.1-8 alkyl, optionally substituted C.sub.3-8
cycloalkyl, or optionally substituted C.sub.3-8
cycloalkyl-C.sub.1-4 alkyl (i.e., Compound [11s] or [11t]).
##STR00080##
In the scheme, R.sup.2 and L.sup.1 are defined as defined
above,
[0337] L.sup.2 is halogen (e.g., iodo) or
trifluoromethanesulfonyloxy,
[0338] R.sup.18 is C.sub.1-8 alkyl, optionally substituted
C.sub.3-8 cycloalky, or optionally substituted C.sub.3-8
cycloalkyl-C.sub.1-4 alkyl,
[0339] R.sup.W1 is boronic acid, boronic acid ester, or
trifluoroborate,
[0340] R.sup.W2 is zinc, or zinc halide,
[0341] R.sup.1T is C.sub.2-9 alkyl, or optionally substituted
C.sub.3-8 cycloalkyl-C.sub.2-4 alkyl, and
[0342] R.sup.100T is trimethylsilyl or a straight- or
branched-chain saturated hydrocarbon with 1 to 6 carbon atoms.
[0343] Such a cross-coupling reaction includes methods described in
literatures such as F. Diederich, P. J. Stang (1998).
Metal-catalyzed Cross-coupling Reactions, Weinheim, Germany,
Wiley-VCH, which includes Suzuki coupling, Negishi coupling, and
Sonogashira coupling.
[0344] Compound [S1] is preferably a compound wherein L.sup.1 is
bromo and L.sup.2 is iodo, more preferably a compound shown as
follows.
##STR00081##
[0345] As for Compound [S2], Compound [S3], and Compound [S4], for
example, commercially available products such as isobutylboronic
acid, 1-hexylboronic acid pinacol ester, potassium
(3,3-dimethylbutyl)trifluoroborate, butylzinc bromide, and
cyclohexylacetylene may be used, or these compounds may be prepared
from corresponding commercially available compounds with chloro,
bromo, or iodo, such as 1-chloro-3,3-dimethyl-butane and
bromomethyl-cyclohexane, according to known methods.
[0346] Compound [S2] wherein R.sup.W1 is boronic acid may be
prepared by preparation of a Grignard reagent from commercially
available compounds such as R.sup.1--Br and magnesium, followed by
reaction with, for example, trimethyl borate or triisopropyl
borate.
[0347] Compound [S2] wherein R.sup.W1 is boronic acid ester may be
prepared by, for example, reaction of a boronic acid compound with
pinacol.
[0348] Compound [S2] wherein R.sup.W1 is trifluoroborate may be
prepared by, for example, reaction of a boronic acid compound with
potassium hydrogen fluoride.
[0349] Compound [S3] may be prepared from, for example,
commercially available compounds such as R.sup.1--I and zinc.
[0350] An activating agent for zinc includes iodine, trimethylsilyl
chloride, and 1,2-dibromoethane, and these agents can be used alone
or in combination with any two or more of them. A preferable
activating agent is trimethylsilyl chloride or
1,2-dibromoethane.
[0351] As for Compound [S4], commercially available products such
as 3,3-dimethyl-1-butyne, cyclohexylacetylene, and phenylacetylene
may be used.
[0352] Compound [11t] may be obtained by catalytic hydrogenation of
an alkynylene compound obtained in Sonogashira reaction with a
catalyst such as palladium carbon, platinum carbon, and
rhodium-alumina to convert into an alkyl compound.
[0353] The solvent in each step includes tetrahydrofuran,
N,N-dimethylformamide, and N,N-dimethylacetamide. A preferable
solvent herein is tetrahydrofura or N,N-dimethylacetamide.
[0354] The reaction temperature in each step includes room
temperature to 80.degree. C. A preferable reaction temperature
herein is room temperature.
[Preparation Method 12]: Preparation of Compound [15] or a Salt
Thereof Used in Preparation Method 1
[0355] Compound [15] or a salt thereof may be a commercially
available product such as ethyl 6-isocyanato-hexanoate, methyl
2-isocyanato-2-methyl-propionate, methyl 3-isocyanato-propionate,
ethyl 3-isocyanato-propionate, methyl
4-isocyanato-cyclohexanecarboxylate, and ethyl
4-isocyanatobenzoate, or may also be obtained by, for example,
Preparation method 1Z shown as follows.
##STR00082##
In the scheme, R.sup.3 is defined as defined above.
[0356] Compound [15] or a salt thereof may be prepared by azidation
reaction of Compound [Z1] such as a commercially available product
such as 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid,
3-(methoxycarbonyl)bicyclo[2.1.1]pentane-1-carboxylic acid,
1-(2-methoxy-2-oxcethyl)-5-oxopyrrolidine-3-carboxylic acid, and
3-[1-(ethoxycarbonyl)cyclopropyl]propanoic acid, or a salt thereof,
in the presence of a base in a solvent, followed by Curtius
rearrangement.
[0357] Such a solvent includes, for example, benzene, toluene,
xylene, tetrahydrofuran, and a mixed solvent of any of them. A
preferable solvent herein is toluene.
[0358] The azidation agent herein includes, for example,
diphenylphosphoryl azide.
[0359] Such a base includes, for example, triethylamine and
diisopropylethylamine. A preferable base herein is
triethylamine.
[0360] The reaction temperature herein ranges, for example, from
0.degree. C. to 140.degree. C., preferably from 100.degree. C. to
120.degree. C.
[0361] When R.sup.3 is --Y.sup.3--COO--R.sup.30 and R.sup.30 is
C.sub.1-4_alkyl in Compound [15] or a salt thereof obtained from
Preparation method 1Z illustrated herein, Compound [I-1] wherein
R.sup.30 is hydrogen may be obtained by preparation of Compound
[I-1] wherein R.sup.30 is C.sub.1-4 alkyl from the aforementioned
Compound [15] or a salt thereof in Preparation method 1, followed
by hydrolysis under known methods.
[Preparation Method 2]: Preparation of Compound [I-2A] or a Salt
Thereof
[0362] Compound [I] wherein X.sup.2 is .dbd.N--, X.sup.3 is
--C(R.sup.5) (R.sup.6)--, R.sup.3 is hydrogen, and R.sup.5 is
hydrogen (Compound [I-2A]), or a salt thereof, may be obtained by,
for example, Preparation method 2 as follows.
##STR00083##
In the scheme, R.sup.1, R.sup.2, R.sup.6, X.sup.1, X.sup.4,
X.sup.5, and L.sup.1 are defined as defined above.
(Step 2-1)
[0363] Compound [22] or a salt thereof may be prepared by oxidation
of Compound [21] or a salt thereof in a solvent. Such a solvent
includes, for example, ether solvents such as tetrahydrofuran;
ester solvents such as ethyl acetate; hydrocarbon solvents such as
toluene; halogenated solvents such as dichloromethane; nitrile
solvents such as acetonitrile; and a mixed solvent of any of them.
A preferable solvent herein is dichloromethane.
[0364] An oxidizing agent used herein includes, for example, sulfur
trioxide-pyridine complex, dimethyl sulfoxide, pyridinium
chlorochromate, and Dess-Martin reagent. A preferable oxidizing
agent herein is sulfur trioxide-pyridine complex.
[0365] The reaction temperature herein ranges, for example, from
-60.degree. C. to 60.degree. C., preferably from 0.degree. C. to
room temperature.
(Step 2-2)
[0366] Compound [24] or a salt thereof may be prepared by reaction
of Compound [22] or a salt thereof with Compound [23] or a salt
thereof in a solvent in the presence of a base.
[0367] Such a solvent includes, for example, alcohol solvents such
as ethanol; halogenated solvents such as chloroform; hydrocarbon
solvents such as chlorobenzene; and a mixed solvent of any of them.
A preferable solvent herein is ethanol or water.
[0368] Such a base includes, for example, sodium hydrogen carbonate
and triethylamine. A preferable base herein is sodium hydrogen
carbonate.
[0369] The reaction temperature herein ranges, for example, from
-10.degree. C. to 100.degree. C., preferably from 0.degree. C. to
room temperature.
(Step 2-3)
[0370] Compound [26] or a salt thereof may be prepared by reaction
of Compound [24] or a salt thereof with Compound [11] or a salt
thereof in a solvent.
[0371] Such a solvent includes, for example, ether solvents such as
tetrahydrofuran. A preferable solvent herein is tetrahydrofuran or
diethyl ether.
[0372] A reagent used herein includes, for example, organometallic
reagents such as n-butyllithium and Grignard reagents such as
magnesium. A preferable reagent herein is n-butyllithium.
[0373] The reaction temperature herein ranges from -78.degree. C.
to room temperature.
(Step 2-4)
[0374] Compound [I-2A] or a salt thereof may be prepared by
oxidation of Compound [26] or a salt thereof in a solvent.
[0375] Such a solvent includes halogenated solvents such as
dichloromethane. A preferable solvent herein is
dichloromethane.
[0376] An oxidizing agent used herein includes
m-chloroperoxybenzoic acid.
[0377] The reaction temperature herein is room temperature.
EXAMPLES
[0378] The present invention is illustrated in more detail with
Examples and Test Examples, but is not intended to be limited
thereto.
[0379] 1H-NMR spectra were measured in CDCl.sub.3, DMSO-D.sub.6, or
MeOH-D.sub.4 with tetramethylsilane as an internal standard, and
all .delta. values are shown in ppm. Symbols in spectral data mean
as follows.
s: singlet d: doublet t: triplet q: quartet dd: double doublet ddd:
double double doublet brs: broad singlet m: multiplet J: coupling
constant
Example 1
Step 1
4-Bromo-2-chloro-1-(2,2-dimethyl-propoxy)benzene
##STR00084##
[0381] 4-Bromo-2-chloro-phenol (100 g) and cesium carbonate (126 g)
were mixed in N,N-dimethylformamide (800 mL) under nitrogen gas,
and thereto was added 1-iodo-2,2-dimethyl-propanol (100 mL) at room
temperature. The reaction solution was stirred under heating at
100.degree. C. for 2 days. The reaction solution was slowly cooled
to room temperature, and then, thereto were added water (500 mL)
and n-hexane (500 mL). The solution was separated. The organic
layer was washed with 20 w/w % aqueous sodium sulfite solution (100
mL), 2N aqueous sodium hydroxide solution (100 mL), water (100 mL),
and saturated aqueous sodium chloride solution (100 mL), and dried
over sodium sulfate. Sodium sulfate was removed with a filter, and
then the filtrate was concentrated under reduced pressure to give
the title compound (138 g).
[0382] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.07 (s, 9H), 3.61 (s,
2H), 6.76 (d, J=8.8 Hz, 1H), 7.29 (dd, J=8.8, 2.3 Hz, 1H), 7.49 (d,
J=2.5 Hz, 1H)
Step 2
3-Methylsulfanyl-6,7-dihydro-5H-cyclopenta[1,2,4]triazine
##STR00085##
[0384] Cyclopentane-1,2-dione (580 mg) was mixed in 1M aqueous
sodium hydrogen carbonate solution (6.0 mL) and ethanol (6.0 mL)
under nitrogen gas, and then, thereto was added S-methyl
isothiosemicarbazide hydroiodide (1.38 g) at room temperature. The
reaction solution was stirred at room temperature for 1 day. To the
reaction solution were added ethyl acetate and water, and the
reaction solution was separated. The organic layer was washed with
saturated aqueous sodium chloride solution and dried over sodium
sulfate. Sodium sulfate was removed with a filter, and then the
filtrate was concentrated under reduced pressure. The resulting
residue was purified by silica gel column chromatography (20 g,
ethyl acetate/chloroform=1/5) to give the title compound (520
mg).
[0385] .sup.1H-NMR (400 MHz, CDCl.sub.3) 2.17-2.24 (m, 2H), 2.66
(s, 3H), 3.00 (t, J=7.7 Hz, 2H), 3.17 (t, J=7.7 Hz, 2H)
Step 3
4a-[3-Chloro-4-(2,2-dihydro-propoxy)phenyl]-3-methylsulfanyl-4a,5,6,7-tetr-
ahydro-2H-cyclopenta[1,2,4]triazine
##STR00086##
[0387] Magnesium (30 mg) and diethyl ether (2.0 mL) were mixed
under nitrogen gas, and then thereto was added one drop of a mixed
solution of diethyl ether in iodine at room temperature. The
reaction solution was stirred at room temperature for 30 minutes.
To the reaction solution was added a mixed solution of
4-bromo-2-chloro-1-(2,2-dimethyl-propoxy)benzene (420 mg) in
diethyl ether (2.0 mL) at room temperature. The reaction solution
was stirred under heating at 60.degree. C. for 4 hours. The
reaction solution was slowly cooled to room temperature, and then,
to the reaction solution was added a mixed solution of
3-methylsulfanyl-6,7-dihydro-5H-cyclopenta[1,2,4]triazine (100 mg)
in tetrahydrofuran (2 mL). The reaction solution was stirred at
room temperature for 1 day. To the reaction solution were added
aqueous ammonium chloride solution and ethyl acetate under ice
cooling, and the reaction solution was separated. The organic layer
was washed with saturated aqueous sodium chloride solution and
dried over sodium sulfate. The resulting residue was purified by
thin-layer silica gel column chromatography (ethyl
acetate/chloroform=1/3) to give the title compound (17.4 mg).
[0388] 1H-NMR (400 MHz, CDCl.sub.3) 1.06 (s, 9H), 1.68-1.78 (m,
2H), 2.13-2.20 (m, 1H), 2.39-2.43 (m, 1H), 2.44 (d, J=5.5 Hz, 3H),
2.53-2.62 (m, 1H), 2.67-2.75 (m, 1H), 3.60 (s, 2H), 6.78 (d, J=8.6
Hz, 1H), 7.07 (dd, J=8.6, 2.3 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H), 7.74
(br s, 1H)
Step 4
4a-[3-Chloro-4-(2,2-dimethyl-propoxy)phenyl]-2,4,4a,5,6,7-hexahydro-cyclop-
enta[1,2,4]triazin-3-one
##STR00087##
[0390]
4a-[3-Chloro-4-(2,2-dihydro-propoxy)phenyl]-3-methylsulfanyl-4a,5,6-
,7-tetrahydro-2H-cyclopenta[1,2,4]triazine (17.4 mg) and
dichloromethane (0.5 mL) were mixed under nitrogen gas, and thereto
was added meta-chloroperoxybenzoic acid (75 wt % of water
inclusive, 26 mg) under ice cooling. The reaction solution was
stirred at room temperature for 1 hour. To the reaction solution
were added 20 w/w % aqueous sodium sulfite solution (5 mL) and
ethyl acetate (10 mL) under ice cooling. The organic layer was
washed with saturated aqueous sodium hydrogen carbonate solution (5
mL) and saturated aqueous sodium chloride solution (5 mL) and dried
over sodium sulfate. The resulting residue was purified by
thin-layer silica gel column chromatography
(methanol/chloroform=1/15) to give the title compound (4.2 mg).
Example 3
Step 1
Methyl 7,7-dimethyl-1,4-dioxa-spiro[4.4]nonane-6-carboxylate
##STR00088##
[0392] 2,2-Dimethyl-5-oxo-cyclopentanecarboxylic acid methyl ester
(3.58 g) was mixed in ethylene glycol (1.76 mL) and toluene (40 mL)
under nitrogen gas, and thereto was added para-toluenesulfonic acid
monohydrate (200 mg) at room temperature. The reaction solution was
stirred under heating at 140.degree. C. for 3 hours to remove
water. The resultant was slowly cooled to room temperature. Then,
to the reaction solution were added 1M aqueous sodium carbonate
solution (1.1 mL) and ethyl acetate, and the solution was
separated. The organic layer was washed with saturated aqueous
sodium chloride solution and dried over sodium sulfate. Sodium
sulfate was removed with a filter, and then the filtrate was
concentrated under reduced pressure to give a crude product of the
title compound (4.24 g).
Step 2
(7,7-Dimethyl-1,4-dioxa-spiro[4.4]non-6-yl)methanol
##STR00089##
[0394] Lithium aluminum hydride (1.6 g) and tetrahydrofuran (30 mL)
were mixed under nitrogen gas, and thereto was added a mixed
solution of 7,7-dimethyl-1,4-dioxa-spiro[4.4]none-6-carboxylic acid
methyl ester (4.24 g) in tetrahydrofuran (10 mL) under ice cooling.
The reaction solution was stirred at room temperature for 1 hour.
Then, thereto were added sequentially water (1.6 mL), 2N aqueous
sodium hydroxide solution (1.6 mL), and water (4.8 mL) under ice
cooling. Celite (20 g) and magnesium sulfate (20 g) were added
thereto, and the mixture was stirred at room temperature for 1
hour. The reaction solution was diluted with tetrahydrofuran (100
mL), and the resulting solid was removed through Celite. Then, the
filtrate was concentrated under reduced pressure to give a crude
product of the title compound.
Step 3
2-(7,7-Dimethyl-1,4-dioxa-spiro[4.4]
non-6-ylmethoxy)isoxazole-1,3-dione
##STR00090##
[0396] (7,7-Dimethyl-1,4-dioxa-spiro[4.4]non-6-yl)methanol,
N-hydroxyphthalimide (5.14 g) and triphenylphosphine (8.26 g) were
mixed in tetrahydrofuran (50 mL) under nitrogen gas, and thereto
was added di-2-methoxyethyl azodicarboxylate (7.37 g) under ice
cooling. The reaction solution was stirred at room temperature for
3 hours. The reaction solution was concentrated under reduced
pressure, and thereto were added ethyl acetate and water. The
solution was separated. The organic layer was washed with saturated
aqueous sodium chloride solution and dried over sodium sulfate.
Sodium sulfate was removed with a filter, and then the filtrate was
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (200 g, ethyl
acetate/n-hexane=1/3) to give the title compound (1.58 g).
[0397] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.02 (s, 3H), 1.22 (s,
3H), 1.49-1.60 (m, 2H), 1.86-1.91 (m, 2H), 2.29 (t, J=6.6 Hz, 1H),
3.81 (dd, J=5.0, 4.5 Hz, 1H), 3.91 (dt, J=6.9, 2.1 Hz, 1H), 4.03
(dq, J=16.9, 5.1 Hz, 2H), 4.22 (dd, J=8.3, 6.7 Hz, 1H), 4.35 (dd,
J=8.2, 6.6 Hz, 1H), 7.73 (d, J=3.0 Hz, 1H), 7.74 (d, J=3.0 Hz, 1H),
7.82 (d, J=3.0 Hz, 1H), 7.83 (d, J=3.0 Hz, 1H)
Step 4
O-(7,7-Dimethyl-1,4-dioxa-spiro[4.4]non-6-ylmethyl)-hydroxylamine
##STR00091##
[0399]
2-(7,7-dimethyl-1,4-dioxa-spiro[4.4]non-6-ylmethoxy)isoxazole-1,3-d-
ione (1.58 g) and chloroform (20 mL) were mixed under nitrogen gas,
and thereto was added N-methylhydrazine (0.3 mL) under ice cooling.
The reaction solution was stirred at room temperature for 1 hour.
The reaction solution was filtered through Celite, and then the
filtrate was concentrated under reduced pressure to give a crude
product of the title compound (1.61 g).
[0400] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.90 (s, 3H), 1.10 (s,
3H), 1.43-1.56 (m, 2H), 1.82-1.87 (m, 2H), 2.08 (dd, J=7.4, 6.5 Hz,
1H), 3.68-3.96 (m, 6H), 5.31 (br s, 2H)
Step 5
4,4-Dimethyl-3a,4,5,6-tetrahydro-3H-cyclopenta[c]isoxazole
##STR00092##
[0402] O-(7,7-Dimethyl-,
4-dioxa-spiro[4.4]non-6-ylmethyl)-hydroxylamine (1.61 g) and
tetrahydrofuran (10 mL) were mixed under nitrogen gas, and thereto
was added 3N hydrochloric acid (5 mL) at room temperature. The
reaction solution was stirred at room temperature for 2 hours. To
the reaction solution were added potassium carbonate (2.1 g) and
diethyl ether, and the solution was separated. The organic layer
was washed with saturated aqueous sodium chloride solution and
dried over sodium sulfate. Sodium sulfate was removed with a
filter, and then the filtrate was concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (20 g, diethyl ether/n-hexane=1/1) to give the title
compound (573 mg).
[0403] 1H-NMR (400 MHz, CDCl.sub.3) 0.91 (s, 3H), 1.12 (s, 3H),
1.96 (ddd, J=13.0, 7.2, 3.6 Hz, 1H), 2.05-2.13 (m, 1H), 2.43-2.49
(m, 2H), 3.53-3.59 (m, 1H), 3.89 (dd, J=11.9, 8.2 Hz, 1H), 4.33
(dd, J=10.5, 8.2 Hz, 1H)
Step 6
6a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-4,4-dimethyl-hexahydro-cyclopen-
ta[c]isoxazole
##STR00093##
[0405] 4-Bromo-2-chloro-1-(3,3-dimethyl-butyl)benzene mg) was mixed
in toluene (7.0 mL) and tetrahydrofuran (2.8 mL) under argon gas,
and thereto was added dropwise 1.6M n-butyllithium/n-hexane
solution (1.55 mL) under cooling at -78.degree. C. The reaction
solution was stirred under cooling at -78.degree. C. for 1 hour
(Reaction solution A).
4,4-Dimethyl-3a,4,5,6-tetrahydro-3H-cyclopenta[c]isoxazole (173 mg)
and toluene (10 mL) were mixed, and thereto were added boron
trifluoride-diethyl ether complex (0.314 mL) and Reaction solution
A under cooling at -78.degree. C. The reaction solution was stirred
for 1 hour, and then thereto were added aqueous ammonium chloride
solution (5 mL) and ethyl acetate at -78.degree. C. The solution
was separated. The organic layer was washed with saturated aqueous
sodium chloride solution and dried over sodium sulfate. The
resulting residue was purified by silica gel column chromatography
(10 g, diethyl ether/n-hexane=1/1) to give the title compound (364
mg).
[0406] .sup.1H-NMR (400 MHz, CDCl.sub.2) 0.98 (s, 9H), 1.10 (s,
6H), 1.12-1.30 (m, 2H), 1.42-1.47 (m, 2H), 1.74-1.82 (m, 1H),
2.15-2.24 (m, 1H), 2.64-2.68 (m, 2H), 2.79 (dd, J=6.7, 5.5 Hz,
111), 3.80-4.20 (m, 2H), 4.98 (s, 1H), 7.17 (d, J=7.9 Hz, 1H), 7.30
(d, J=7.9 Hz, 1H), 7.47 (s, 1H)
Step 7
{2-Amino-2-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5,5-dimethyl-cyclopenty-
l}methanol
##STR00094##
[0408]
6a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-4,4-dimethyl-hexahydro-c-
yclopenta[c]isoxazole (320 mg) was mixed in acetic acid (4.5 mL),
tetrahydrofuran (1.5 mL), and water (1.5 mL) under nitrogen gas,
and thereto was added zinc powder (640 mg) in two parts under
heating at 60.degree. C. The reaction solution was stirred under
heating at 60.degree. C. for 1.5 hours. The reaction solution was
filtered through Celite at room temperature, and then the filtrate
was concentrated under reduced pressure. The resulting residue was
mixed with chloroform (30 mL) and 28 w/w % ammonia water (7.5 mL)
and separated. The organic layer was washed with saturated aqueous
sodium chloride solution and dried over sodium sulfate. Sodium
sulfate was removed with a filter, and then the filtrate was
concentrated under reduced pressure to give a crude product of the
title compound (383 mg).
[0409] 1H-NMR (400 MHz, CDCl.sub.3) 0.98 (s, 9H), 1.11 (s, 3H),
1.16 (s, 3H), 1.41-1.47 (m, 2H), 1.70-1.88 (m, 3H), 2.25-2.34 (m,
4H), 2.63-2.68 (m, 2H), 3.77 (dd, J=7.3, 1.7 Hz, 2H), 7.17 (d,
J=8.1 Hz, 1H), 7.33 (dd, J=8.1, 2.1 Hz, 1H), 7.47 (d, J=2.1 Hz,
1H)
Step 8
Ethyl
3-(3-{1-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-2-hydroxymethyl-3,3--
dimethyl-cyclopentyl}ureido)propionate
##STR00095##
[0411]
{2-Amino-2-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5,5-dimethyl-cyc-
lopentyl}methanol (190 mg) and tetrahydrofuran (2.0 mL) were mixed
under nitrogen gas, and 23 thereto was added ethyl
3-isocyanato-propionate (0.076 mL). The reaction solution was
stirred at room temperature for 1 hour. The reaction solution was
concentrated under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (10 g, ethyl
acetate/chloroform=2/3) to give the title compound (163 mg).
[0412] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.98 (s, 9H), 1.12 (s,
3H), 1.13 (s, 3H), 1.27 (t, J=7.2 Hz, 3H), 1.43-1.48 (m, 2H),
1.65-1.78 (m, 2H), 1.98 (dd, J=6.7, 4.2 Hz, 1H), 2.26 (dq, J=27.3,
7.1 Hz, 2H), 2.47 (td, J=5.9, 1.7 Hz, 2H), 2.61-2.66 (m, 2H), 3.40
(ddd, J=12.0, 6.0, 1.2 Hz, 2H), 3.78 (ddd, J=9.9, 5.6, 3.3 Hz, 2H),
4.14 (q, J=7.2 Hz, 2H), 4.87 (t, J=6.1 Hz, 1H), 5.93 (s, 1H), 7.13
(d, J=8.1 Hz, 1H), 7.27 (dd, J=8.1, 2.1 Hz, 1H), 7.38 (d, J=2.1 Hz,
1H)
Step 9
Ethyl
3-{7a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5,5-dimethyl-2-oxo-1,2-
,5,6,7,7a-hexahydro-cyclopentapyrimidin-3-yl}propionate
##STR00096##
[0414] Ethyl
3-(3-{1-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-2-hydroxymethyl-3,3-dimet-
hyl-cyclopentyl}ureido)propionate and dichloromethane (1.5 mL) were
mixed under nitrogen gas, and thereto were added
(diacetoxyiodo)benzene (109 mg) and
2,2,6,6-tetramethylpiperidin-1-oxyl radical (2.7 mg) at room
temperature. The reaction solution was stirred at room temperature
for 16 hours, and then thereto was added trifluoroacetic acid (0.1
mL) at room temperature. The mixture was stirred at room
temperature for 4 hours. To the reaction solution were added
saturated aqueous sodium hydrogen carbonate solution (2 mL) and
ethyl acetate, and the solution was separated. Thereto was added
aqueous sodium carbonate solution (30 mL), and the mixture was
separated. The organic layer was dried over sodium sulfate. Sodium
sulfate was removed with a filter, and then the filtrate was
concentrated under reduced pressure. The resulting residue was
purified by thin-layer silica gel column chromatography (ethyl
acetate/chloroform=1/10) to give a racemate of the title compound.
Then, the racemate was purified by preparative chiral column
chromatography (IA, isopropanol/n-hexane=7/93, 15 ml/min) to give
the title compound (55.1 mg, 94.5% ee).
[0415] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.98 (s, 9H), 1.10 (s,
3H), 1.24 (s, 3H), 1.26 (t, J=6.2 Hz, 3H), 1.34-1.41 (m, 1H),
1.42-1.47 (m, 2H), 1.59 (ddd, J=9.6, 3.6, 2.8 Hz, 1H), 2.12 (td,
J=11.8, 7.2 Hz, 1H), 2.3B (ddd, J=12.3, 6.2, 3.1 Hz, 1H), 2.56 (t,
J=6.7 Hz, 2H), 2.62-2.67 (m, 2H), 3.47 (dt, J=14.1, 6.9 Hz, 1H),
3.95 (dt, J=14.0, 6.4 Hz, 1H), 4.15 (ddd, J=14.2, 7.1, 2.3 Hz, 2H),
5.09 (s, 1H), 6.14 (s, 1H), 7.11 (dd, J=7.9, 1.8 Hz, 1H), 7.15 (d,
J=7.9 Hz, 1H), 7.27 (s, 1H)
Step 10
3-{7a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-5,5-dimethyl-2-oxo-1,2,5,6,7-
,7a-hexahydro-cyclopentapyrimidin-3-yl}propionate
##STR00097##
[0417] Ethyl
3-{7a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5,5-dimethyl-2-oxo-1,2,5,6,-
7,7a-hexahydro-cyclopentapyrimidin-3-yl}propionate (55 mg) and
methanol (0.5 mL) were mixed under nitrogen gas, and thereto was
added 2N aqueous sodium hydroxide solution (0.24 mL) under ice
cooling. The reaction solution was stirred at room temperature for
4 hours. To the reaction solution was added 2N hydrochloric acid
(0.24 mL) under ice cooling, and the mixture was extracted with
ethyl acetate. The organic layer was dried over sodium sulfate.
Sodium sulfate was removed with a filter, and then the filtrate was
concentrated under reduced pressure to give the title compound
(44.0 mg).
Example 7
Step 1
Ethyl (1,1-dimethylallyloxy)acetate
##STR00098##
[0419] 2-Methyl-3-buten-2-ol (4.6 mL) and rhodium (II) acetate (97
mg) were mixed under nitrogen gas, and thereto was added dropwise
ethyl diazoacetate (4.6 mL) for 2 hours under water cooling. The
mixture was stirred for 1 hour and then concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (eluent: ethyl acetate/n-hexane (ethyl
acetate/n-hexane=1/5->1/2) to give the title compound (3.65
g).
[0420] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.27 (t, J=7.17 Hz, 3H),
1.32 (s, 6H), 3.95 (s, 2H), 4.20 (q, J=7.17 Hz, 2H), 5.20-5.15 (m,
2H), 5.83 (dd, J=17.34, 10.87 Hz, 1H)
Step 2
(1,1-Dimethylallyloxy)acetaldehyde oxime
##STR00099##
[0422] Ethyl (1,1-dimethylallyloxy)acetate (1.65 g) and toluene
(150 mL) were mixed under nitrogen gas, and thereto was added
dropwise 1M diisobutylaluminum hydride/toluene solution (14 mL)
under cooling at -78.degree. C. The mixture was stirred for 30
minutes, and then the reaction solution was added to 1N
hydrochloric acid (15 mL) under ice cooling. The mixture was
stirred for 1 hour and then separated. Hydroxylamine hydrochloride
(910 mg) was mixed in ethanol (10 mL) and water (2.5 mL), and
thereto was added dropwise 4N aqueous solution of sodium hydroxide
(3.35 mL) for 20 minutes under ice cooling. The resulting organic
layer was added thereto, and the mixture was stirred at room
temperature for 1 hour. The organic layer was washed sequentially
with water and saturated aqueous sodium chloride solution and then
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (eluent: ethyl
acetate/n-hexane (ethyl acetate/n-hexane=1/3->2/3) to give a
geometric isomer mixture (1:4) of the title compound (774 mg).
[0423] .sup.1H-NMR (400 MHz, CDCl.sub.1) 1.31 (s, 6H), 3.96 (d,
J=5.55 Hz, 1.6H), 4.23 (d, J=3.47 Hz, 0.4H), 5.15-5.19 (m, 2H),
5.77-5.86 (m, 1H), 6.87 (t, J=3.47 Hz, 0.2H), 7.42 (br s, 0.8H),
7.46 (t, J=5.55 Hz, 0.8E), 7.69 (br s, 0.2H)
Step 3
4,4-Dimethyl-3a,4-dihydro-3H,6H-furan[3,4-c]isoxazole
##STR00100##
[0425] (1,1-Dimethylallyloxy)acetaldehyde oxime (774 mg) and
dichloromethane (40 mL) were mixed, and thereto was added
triethylamine (65 mL) under ice cooling. Then, thereto was added
dropwise antiformin (10 mL) for 15 minutes, and then the mixture
was stirred for 30 minutes. Then, thereto was added chloroform. The
organic layer was washed sequentially with water and saturated
aqueous sodium chloride solution and then concentrated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (eluent: ethyl acetate/n-hexane (ethyl
acetate/n-hexane=1/2) to give the title compound (771 mg).
[0426] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.20 (s, 3H), 1.41 (s,
3H), 4.01-3.92 (m, 2H), 4.38 (dd, J=13.99, 1.27 Hz, 1H), 4.45-4.50
(m, 2H)
Step 4
6a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-4,4-dimethyl-tetrahydro-furan[3-
,4-c]isoxazole
##STR00101##
[0428] 4-Bromo-2-chloro-1-(3,3-dimethyl-butyl)-benzene (1.23 g) was
mixed in tetrahydrofuran (5 mL) and toluene (12 mL), and then
thereto was added dropwise 1.6M n-butyllithium/n-hexane solution
(2.66 mL) under cooling at -78.degree. C. The reaction solution was
stirred at -78.degree. C. for 1 hour (Reaction solution A).
4,4-Dimethyl-3a,4-dihydro-3H,6H-furan[3,4-c]isoxazole (300 mg) and
toluene (18 mL) were mixed, and thereto was added boron
trifluoride-diethyl ether complex (0.537 mL) under cooling at
-78.degree. C. The mixture was stirred for 10 minutes. Then,
thereto was added dropwise Reaction solution A under cooling at
-78.degree. C. The reaction solution was stirred for 1 hour, and
then thereto was added an aqueous solution of ammonium chloride (8
mL) under cooling at -78.degree. C. The mixture was extracted with
ethyl acetate, and the organic layer was concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (eluent: ethyl acetate/n-hexane (ethyl
acetate/n-hexane=1/5->1/3) to give the title compound (439
mg).
[0429] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.98 (s, 9H), 1.38 (s,
3H), 1.42 (s, 3H), 1.43-1.47 (m, 2H), 2.65-2.69 (m, 2H), 3.04 (dd,
J=6.94, 4.16 Hz, 1H), 3.86-4.22 (m, 4H), 5.20 (br s, 1H), 7.21 (d,
J=8.55 Hz, 1H), 7.33-7.28 (m, 1H), 7.52-7.46 (m, 1H)
Step 5
{4-Amino-4-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-2,2-dimethyl-tetrahydro-
-furan-3-yl}methanol
##STR00102##
[0431]
6a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-4,4-dimethyl-tetrahydro--
furan[3,4-c] isoxazole (411 mg) was mixed in acetic acid (6 mL),
tetrahydrofuran (2 mL), and water (2 mL), and thereto was added
zinc powder (800 mg) under heating at 60.degree. C. The mixture was
stirred with heating at 60.degree. C. for 3 hours, and then ammonia
water (10 mL) was added dropwise to the reaction solution at room
temperature. The reaction solution was extracted with chloroform
(15 mL, three times), and the organic layers were dried over sodium
sulfate. Sodium sulfate was removed with a filter, and then the
filtrate was concentrated under reduced pressure to give a crude
product of the title compound (229 mg).
[0432] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.98 (s, 9H), 1.36 (s,
311), 1.41 (s, 3H), 1.43-1.47 (m, 2H), 2.19 (t, J=6.10 Hz, 1H),
2.65-2.69 (m, 2H), 3.68 (d, J=9.25 Hz, 1H), 3.83 (d, J=6.01 Hz,
2H), 4.11 (d, J=9.25 Hz, 1H), 7.20 (d, J=8.09 Hz, 1H), 7.34 (dd,
J=8.09, 2.08 Hz, 1H), 7.49 (d, J=2.08 Hz, 1H)
Step 6
Ethyl
4-(3-{3-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-4-hydroxymethyl-5,5--
dimethyl-tetrahydro-furan-3-yl}ureido)benzoate
##STR00103##
[0434]
{4-Amino-4-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-2,2-dimethyl-tet-
rahydro-furan-3-yl}methanol (125 mg) and tetrahydrofuran (2.5 mL)
were mixed, and thereto was added 4-ethoxycarbonylphenyl isocyanate
(70 mg) under ice cooling. The mixture was stirred at room
temperature for 51 minutes, and then the reaction solution was
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (eluent: ethyl
acetate/n-hexane (ethyl
acetate/n-hexane=1/10->1/6->1/2->1/1) to give the title
compound (142 mg).
[0435] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.96 (s, 9H), 1.28 (s,
3H), 1.37 (t, J=7.00 Hz, 3H), 1.40 (s, 3H), 1.41-1.44 (m, 2H),
2.61-2.65 (m, 2H), 2.85 (dd, J=9.66, 4.35 Hz, 1H), 3.34 (br s, 1H),
3.75-3.87 (m, 2H), 3.90 (d, J=10.14 Hz, 1H), 4.00 (d, J=10.14 Hz,
1H), 4.34 (q, J=7.00 Hz, 2H), 6.34 (br s, 1H), 7.08 (br s, 1H),
7.16 (d, J=8.21 Hz, 1H), 7.32 (d, J=8.69 Hz, 2H), 7.37 (dd, J=8.21,
2.17 Hz, 1H), 7.52 (d, J=2.17 Hz, 1H), 7.94 (d, J=8.69 Hz, 2H)
Step 7
Ethyl
4-{(S)-7a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5,5-dimethyl-2-oxo-
-1,2,7,7a-tetrahydro-5H-furan[3,4-d]pyrimidin-3-yl}benzoate
##STR00104##
[0437] Ethyl
4-(3-{3-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-4-hydroxymethyl-5,5-dimet-
hyl-tetrahydro-furan-3-yl-}ureido)benzoate (124 mg) and chloroform
(3 mL) were mixed, and thereto were added (diacetoxyiodo)benzene
(75 mg) and 2,2,6,6-tetramethylpiperidin-1-oxyl radical (3.6 mg) at
room temperature. The mixture was stirred at room temperature for 7
hours, and then thereto was added an aqueous solution of sodium
thiosulfate under ice cooling. The mixture was extracted with
chloroform, and the organic layer was dried over magnesium sulfate.
Magnesium sulfate was removed with a filter, and then the filtrate
was concentrated under reduced pressure. The resulting residue was
mixed in cyclopentyl methyl ether (5 mL), and thereto was added 4N
hydrogen chloride/cyclopentyl methyl ether solution (0.137 mL)
under ice cooling. The mixture was stirred under ice cooling for 2
hours and then stirred at room temperature for 1 hour. The mixture
was stirred under heating at 40.degree. C. for 1 hour, and then the
reaction solution was concentrated under reduced pressure. The
resulting residue was purified by thin-layer silica gel column
chromatography (ethyl acetate/n-hexane=1/1) to give a racemate of
the title compound (73.2 mg). The racemate was purified with a
Recycling Preparative Liquid Chromatograph to give a single
enantiomer of the title compound (30.8 mg)
[0438] Purification conditions for the preparative chromatography
are shown as follows.
Preparative apparatus: Recycling preparative liquid chromatograph
LC-92XX NEXT SERIES, Japan Analytical Industry Co., Ltd. Column:
Daicel CHIRALPAK IA 2.0 cm.phi..times.25 cm Mobile phase:
n-hexane:2-propanol=80:20 Flow rate: 10.0 mL/min
Detection: UV (254 nm)
[0439] Measurement of the resulting compound with a chiral column
showed 6.5 minutes of the retention time for the resulting
enantiomer with >99% ee of optical purity. The retention time
for the opposite enantiomer on the phenyl group was 8.8
minutes.
[0440] Analytical conditions for the chiral column are shown as
follows.
Measurement apparatus: HPLC system, Shimadzu Corporation,
High-Performance Liquid Chromatograph Prominence Column: Daicel
CHIRALPAK IA-3 0.46 cm.phi..times.15 cm Column temperature:
30.degree. C. Mobile phase: hexane:2-propanol=80:20 Flow rate: 1.0
mL/min
Detection: UV (254 nm)
[0441] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.98 (s, 9H), 1.33 (s,
3H), 1.40 (t, J=7.12 Hz, 3H), 1.42-1.46 (m, 2H), 1.50 (s, 3H),
2.65-2.69 (m, 2H), 4.09 (d, J=8.69 Hz, 1H), 4.38 (q, J=7.12 Hz,
2H), 4.51 (d, J=8.69 Hz, 1H), 5.35 (s, 1H), 6.34 (s, 1H), 7.22 (d,
J=7.97 Hz, 1H), 7.30 (dd, J=7.97, 1.93 Hz, 1H), 7.45 (d, J=9.02 Hz,
2H), 7.49 (d, J=1.93 Hz, 1H), 8.07 (d, J=9.02 Hz, 2H)
Step 8
4-{(S)-7a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-5,5-dimethyl-2-oxo-1,2,7-
,7a-tetrahydro-5H-furan[3,4-d] pyrimidin-3-yl}benzoic acid
##STR00105##
[0443] Ethyl
4-{(S)-7a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5,5-dimethyl-2-oxo-1,2,-
7,7a-tetrahydro-5H-furan[3,4-d]pyrimidin-3-yl}benzoate (28.0 mg)
and ethanol (1 mL) were mixed, and thereto was added 2N aqueous
solution of sodium hydroxide (0.110 mL) at room temperature. The
reaction solution was stirred at room temperature for 4 hours 30
minutes, and then thereto was added 2N hydrochloric acid (0.136
mL). The precipitated solid was collected by filtration to give the
title compound (22.1 mg).
Example 10
Step 1
Ethyl
4-(3-{1-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-2-hydroxymethyl-3,3--
dimethyl-cyclopentyl}ureido)benzoate
##STR00106##
[0445]
{2-Amino-2-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5,5-dimethyl-cyc-
lopentyl}methanol (166 mg) was mixed with tetrahydrofuran (2 mL)
under nitrogen gas, and thereto was added ethyl
4-isocyanatobenzoate (94 mg) under ice cooling. The reaction
solution was stirred at room temperature for 1 hour. The reaction
solution was concentrated, and then purified by silica gel column
chromatography (eluent: ethyl acetate/n-hexane (ethyl
acetate/n-hexane=25/1->1/1) to give the title compound (144
mg).
[0446] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.97 (s, 9H), 1.13 (s,
3H), 1.21 (s, 3H), 1.33-1.39 (m, 3H), 1.40-1.46 (m, 2H), 1.69-1.88
(m, 3H), 1.91-1.99 (m, 1H), 2.38-2.48 (m, 1H), 2.53-2.66 (m, 3H),
3.80-3.95 (m, 2H), 4.30-4.37 (m, 2H), 6.45-6.49 (m, 1H), 6.88-6.96
(m, 1H), 7.13-7.17 (m, 1H), 7.26-7.29 (m, 1H), 7.32-7.42 (m, 3H),
7.90-7.96 (m, 2H)
Step 2
Ethyl
4-{7a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5,5-dimethyl-2-oxo-1,2-
,5,6,7,7a-hexahydro-cyclopentapyrimidin-3-yl}benzoate
##STR00107##
[0448] Ethyl
4-(3-{1-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-2-hydroxymethyl-3,3-dimet-
hyl-cyclopentyl}ureido)benzoate (135 mg) and dichloromethane (5 mL)
were mixed under nitrogen gas, and thereto were added
(diacetoxyiodo)benzene (82 mg) and
2,2,6,6-tetramethylpiperidin-1-oxyl radical (4 mg) at room
temperature. The reaction solution was stirred at room temperature
for 3.5 hours, and then thereto was added trifluoroacetic acid (78
.mu.L) at room temperature. The mixture was stirred at room
temperature overnight, and then thereto were added aqueous sodium
thiosulfate solution and chloroform under ice cooling. The mixture
was separated. The organic layer was dried over sodium sulfate. 2C
Sodium sulfate was removed with a filter, and then the filtrate was
concentrated under reduced pressure. The resulting residue was
purified by thin-layer silica gel column chromatography (eluent:
ethyl acetate/n-hexane=1/1, Rf=0.5) to give a racemate of the title
compound (91 mg). The racemate was purified with a Recycling
Preparative Liquid Chromatograph to give a single enantiomer of the
title compound (23 mg).
[0449] Purification conditions for the preparative chromatography
are shown as follows.
Preparative apparatus: Recycling preparative liquid chromatograph
LC-92XX NEXT SERIES, Japan Analytical Industry Co., Ltd. Column:
Daicel CHIRALPAK IA 2.0 cm.phi..times.25 cm Mobile phase:
n-hexane/2-propanol=80/20 Flow rate: 10.0 mL/min
Detection: UV (254 nm)
[0450] Measurement of the resulting compound with a chiral column
showed 12.8 minutes of the retention time for the resulting
enantiomer with >99% ee of optical purity. The retention time
for the opposite enantiomer was 10.6 minutes.
[0451] Analytical conditions for the chiral column are shown as
follows.
Measurement apparatus: HPLC system, Shimadzu Corporation,
High-Performance Liquid Chromatograph Prominence Column: Daicel
CHIRALPAK IA-3 0.46 cm.phi..times.15 cm Column temperature:
40.degree. C. Mobile phase: n-hexane/2-propanol=90/10 Flow rate:
1.0 mL/min
Detection: UV (254 nm)
[0452] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.98 (s, 9H), 1.17 (s,
3H), 1.30 (s, 3H), 1.36-1.41 (m, 3H), 1.41-1.47 (m, 2H), 1.64-1.71
(m, 1H), 2.18-2.27 (m, 1H), 2.43-2.51 (m, 1H), 2.62-2.69 (m, 2H),
4.33-4.40 (m, 2H), 5.36 (br s, 1H), 6.36 (s, 1H), 7.17-7.24 (m,
2H), 7.37-7.39 (m, 1H), 7.41-7.47 (m, 2H), 8.01-8.06 (m, 2H)
Step 3
4-{7a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-5,5-dimethyl-2-oxo-1,2,5,6,7-
,7a-hexahydro-cyclopentapyrimidin-3-yl}benzoic acid
##STR00108##
[0454] Ethyl
4-{7a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5,5-dimethyl-2-oxo-1,2,5,6,-
7,7a-hexahydro-cyclopentapyrimidin-3-yl}benzoate (21 mg) and
ethanol (1 mL) were mixed under nitrogen gas, and thereto was added
2N aqueous sodium hydroxide solution (82 .mu.L) at room
temperature. The reaction solution was stirred under heating at
60.degree. C. for 1 hour, and then concentrated under reduced
pressure. To The resulting residue were added 2N hydrochloric acid
and water at room temperature, and the resulting slurry was stirred
at room temperature. The precipitated solid was collected by
filtration to give the title compound (16 mg).
Example 27
Step 1
Ethyl 6-(tert-butyl-dimethyl-silanyloxy)-3-vinyl-hexanoate
##STR00109##
[0456] (E)-6-(tert-butyl-dimethyl-silanyloxy)hex-2-en-1-ol (10.1 g)
and triethyl orthoformate (102 mL) were mixed, and thereto was
added propionate (51 mL). The reaction solution was stirred under
heating at 150.degree. C. for 3.5 hours. The reaction solution was
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (Biotage flash
purification systems, eluent: ethyl acetate/n-hexane, Rf=0.33
(ethyl acetate/n-hexane=5/95)) to give the title compound (13.2
g).
[0457] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.04 (s, 6H), 0.89 (s,
9H), 1.24 (t, J=6.94 Hz, 3H), 1.29-1.38 (m, 1H), 1.42-1.60 (m, 3H),
2.28 (dd, J=14.57, 8.55 Hz, 1H), 2.36 (dd, J=14.57, 6.24 Hz, 1H),
2.48-2.57 (m, 1H), 3.59 (t, J=6.47 Hz, 2H), 4.11 (q, J=7.17 Hz,
2H), 4.99-5.06 (m, 2H), 5.62 (ddd, J=17.34, 10.40, 8.32 Hz, 1H)
Step 2
6-(tert-Butyl-dimethyl-silanyloxy)-3-vinyl-hexan-1-ol
##STR00110##
[0459] Ethyl 6-(tert-butyl-dimethyl-silanyloxy)-3-vinyl-hexanoate
(11.5 g) and tetrahydrofuran (231 mL) were mixed under argon gas,
and thereto was added dropwise 1M diisobutylaluminum
hydride/toluene solution (92.2 mL) under cooling at -78.degree. C.
The reaction solution was stirred under ice cooling for 1 hour. To
the reaction solution was added dropwise an aqueous solution of
Rochelle salt (231 mL) under ice cooling. The reaction solution was
stirred at room temperature for 16 hours. To the reaction solution
was added ethyl acetate, and the solution was separated. The
aqueous layer was extracted with ethyl acetate. Combined organic
layers were washed with brine, and then dried over magnesium
sulfate. Magnesium sulfate was removed with a filter, and then
concentrated under reduced pressure. The resulting residue was
azeotroped with toluene to give a crude product of the title
compound (11.3 g).
[0460] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.04 (s, 6H), 0.89 (s,
9H), 1.24-1.34 (m, 2H), 1.40-1.61 (m, 3H), 1.64-1.72 (m, 1H),
2.10-2.19 (m, 1H), 3.59 (t, J=6.47 Hz, 2H), 3.62-3.72 (m, 2H),
4.99-5.04 (m, 2H), 5.57 (ddd, J=18.73, 9.71, 9.02 Hz, 1H)
Step 3
[4-(2-Benzyloxy-ethyl)hex-5-enyloxy]-tert-butyl-dimethyl-silane
##STR00111##
[0462] Sodium hydride (2.73 g) and dimethylformamide (125 mL) were
mixed under argon gas, and thereto was added dropwise a mixed
solution of 6-(tert-butyl-dimethyl-silanyloxy)-3-vinyl-hexan-1-ol
(12.6 g) in dimethylformamide (60 mL) under ice cooling. The
reaction solution was stirred under ice cooling for 1 hour. To the
reaction solution was added dropwise a mixed solution of benzyl
bromide (8.41 mL) in dimethylformamide (60 mL) under ice cooling.
The reaction solution was stirred at room temperature overnight. To
the reaction solution were added aqueous ammonium chloride solution
(125 mL), water (60 mL), and ethyl acetate/n-hexane=1/3, and the
solution was separated. The aqueous layer was extracted with ethyl
acetate/n-hexane=1/3. Combined organic layers were washed with
water (three times) and brine, and then dried over magnesium
sulfate. Magnesium sulfate was removed with a filter, and then
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (Biotage flash
purification systems, eluent: ethyl acetate/n-hexane, Rf=0.36
(ethyl acetate/n-hexane=10/90)) to give the title compound (19.5
g).
[0463] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.04 (s, 6H), 0.89 (s,
9H), 1.21-1.31 (m, 2H), 1.38-1.60 (m, 3H), 1.70-1.78 (m, 1H),
2.10-2.20 (m, 1H), 3.41-3.51 (m, 2H), 3.58 (t, J=6.24 Hz, 2H), 4.46
(d, J=11.79 Hz, 1H), 4.49 (d, J=11.79 Hz, 1H), 4.93-4.99 (m, 2H),
5.52 (ddd, J=17.11, 10.40, 9.02 Hz, 1H), 7.27-7.37 (m, 5H)
Step 4
4-(2-Benzyloxy-ethyl)hex-5-en-1-ol
##STR00112##
[0465]
[4-(2-Benzyloxy-ethyl)hex-5-enyloxy]-tert-butyl-dimethyl-silane
(12.88 g) and tetrahydrofuran (130 mL) were mixed under argon gas,
and thereto was added dropwise 1M tetra-n-butylammonium
fluoride/tetrahydrofuran solution (55.4 mL) under ice cooling. The
reaction solution was stirred at room temperature for 19.5 hours.
To the reaction solution were added water (100 mL) and ethyl
acetate, and the solution was separated. The aqueous layer was
extracted with ethyl acetate (three times). Combined organic layers
were washed with brine, and then dried over magnesium sulfate.
Magnesium sulfate was removed with a filter, and then concentrated
under reduced pressure. The resulting residue was purified by
silica gel column chromatography (Biotage flash purification
systems, eluent: ethyl acetate/n-hexane) to give the title compound
(8.43 g). 1H-NMR (400 MHz, CDCl.sub.3) 1.35-1.21 (m, 2H), 1.42-1.67
(m, 3H), 1.70-1.79 (m, 1H), 2.13-2.22 (m, 1H), 3.42-3.52 (m, 2H),
3.60-3.64 (m, 2H), 4.46 (d, J=12.02 Hz, 1H), 4.49 (d, J=12.02 Hz,
1H), 4.94-5.01 (m, 2H), 5.52 (ddd, J=16.88, 10.17, 8.79 Hz, 1H),
7.27-7.38 (m, 5H)
Step 5
4-(2-Benzyloxy-ethyl)hex-5-enal
##STR00113##
[0467] 4-(2-Benzyloxy-ethyl)hex-5-en-1-ol (7.14 g) and
(diacetoxyiodo)benzene (10.7 g) were mixed in chloroform (72 mL)
under nitrogen gas, and thereto was added
2,2,6,6-tetramethylpiperidin-1-oxyl radical (0.477 g) at room
temperature. The reaction solution was stirred at room temperature
for 22 hours. To the reaction solution were added saturated aqueous
sodium hydrogen carbonate solution (20 mL), water (10 mL), sodium
thiosulfate (0.723 g), and ethyl acetate, and the solution was
separated. The aqueous layer was extracted with ethyl acetate.
Combined organic layers were washed with brine, and then dried over
magnesium sulfate. Magnesium sulfate was removed with a filter, and
then concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (Biotage flash
purification systems, eluent: ethyl acetate/n-hexane, Rf=0.50
(ethyl acetate/n-hexane=20/80)) to give the title compound (7.24
g).
[0468] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.50-1.60 (m, 2H),
1.71-1.81 (m, 2H), 2.13-2.23 (m, 1H), 2.35-2.51 (m, 2H), 3.42-3.52
(m, 2H), 4.46 (d, J=11.79 Hz, 1H), 4.49 (d, J=11.79 Hz, 1H),
4.96-5.05 (m, 2H), 5.47 (ddd, J=17.11, 10.17, 9.02 Hz, 1H),
7.27-7.36 (m, 5H), 9.75 (t, J=1.39 Hz, 1H)
Step 6
4-(2-Benzyloxy-ethyl)hex-5-enal oxime
##STR00114##
[0470] 4-(2-Benzyloxy-ethyl)hex-5-enal (5.94 g), ethanol (51.2 mL),
and water (25.6 mL) were mixed under nitrogen gas, and thereto were
added sodium acetate (15.4 g) and hydroxylamine hydrochloride (7.78
g) at room temperature. The reaction solution was stirred under
heating at 60.degree. C. for 21.5 hours. The reaction solution was
concentrated under reduced pressure, and thereto was added toluene.
The solution was separated. The aqueous layer was extracted with
toluene (twice). Combined organic layers were washed with brine
(twice), and then dried over sodium sulfate. Sodium sulfate was
removed with a filter, and then concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (Biotage flash purification systems, eluent: ethyl
acetate/n-hexane, Rf=0.27 (ethyl acetate/n-hexane=20/80)) to give
the title compound (7.38 g).
[0471] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.38-1.48 (m, 1H),
1.50-1.64 (m, 2H), 1.70-1.80 (m, 1H), 2.09-2.28 (m, 2H), 2.30-2.44
(m, 1H), 3.41-3.52 (m, 2H), 4.46 (d, J=12.95 Hz, 1H), 4.49 (d,
J=12.95 Hz, 1H), 4.97-5.05 (m, 2H), 5.56-5.45 (m, 1H), 6.70 (t,
J=5.55 Hz, 0.5H), 7.27-7.36 (m, 5H), 7.41 (t, J=6.01 Hz, 0.5H)
Step 7
4-(2-Benzyloxy-ethyl)-3a,4,5,6-tetrahydro-3H-cyclopenta[c]isoxazole
##STR00115##
[0473] 4-(2-Benzyloxy-ethyl)hex-5-enal oxime (5.90 g) and
triethylamine (2.04 mL) were mixed in dichloromethane (118 mL), and
then thereto was added a mixed aqueous solution of sodium
hypochlorite 5-hydrate (3.61 g) in water (53.1 mL) under water
cooling. The reaction solution was stirred at room temperature for
3.5 hours. To the reaction solution was added a mixed solution of
sodium hypochlorite 5-hydrate (4.95 g) in water (53.1 mL) under
water cooling. The reaction solution was stirred at room
temperature for 17 hours. To the reaction solution was added ethyl
acetate, and the solution was separated. The aqueous layer was
extracted with ethyl acetate. Combined organic layers were washed
with water (twice) and brine, and then dried over sodium sulfate.
Sodium sulfate was removed with a filter, and then concentrated
under reduced pressure. The resulting residue was purified by
silica gel column chromatography (Biotage flash purification
systems, eluent: ethyl acetate/n-hexane, Rf=0.27 (ethyl
acetate/n-hexane=30/70)) and (Biotage flash purification systems,
eluent: acetone/chloroform) to give the title compound (2.34
g).
[0474] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.66-1.57 (m, 1H),
1.77-2.06 (m, 3H), 2.33-2.56 (m, 3H), 3.35-3.50 (m, 3H), 3.79 (dd,
J=12.26, 8.07 Hz, 1H), 4.41 (dd, J=9.57, 8.07 Hz, 1H), 4.44 (d,
J=11.66 Hz, 1H), 4.48 (d, J=11.66 Hz, 1H), 7.28-7.37 (m, 5H)
Step 8
4-(2-Benzyloxy-ethyl)-6a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]hexahydro--
cyclopenta[c]isoxazole
##STR00116##
[0476] This step was performed according to Example 3 Step 6.
Step 9
{2-Amino-5-(2-benzyloxy-ethyl)-2-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]cy-
clopentyl}methanol
##STR00117##
[0478] This step was performed according to Example 3 Step 7.
.sup.1H-NMR (400 MHz, CDCl.sub.3) 0.98 (s, 9H), 1.42-1.77 (m, 6H),
1.88-1.96 (m, 1H), 2.02-2.12 (m, 1H), 2.25-2.37 (m, 2H), 2.64-2.69
(m, 2H), 3.53-3.59 (m, 2H), 3.64 (dd, J=11.91, 4.97 Hz, 1H), 3.72
(dd, J=11.91, 3.12 Hz, 1H), 3.77-3.82 (m, 2H), 4.49 (d, J=11.79 Hz,
1H), 4.53 (d, J=11.79 Hz, 1H), 7.18 (d, J=8.09 Hz, 1H), 7.28-7.35
(m, 6H), 7.44 (d, J=2.08 Hz, 1H)
Step 10
Ethyl
3-(3-{3-(2-benzyloxy-ethyl)-1-[3-chloro-4-(3,3-dimethyl-butyl)phenyl-
]-2-hydroxymethyl-cyclopentyl}ureido)propionate
##STR00118##
[0480] This step was performed according to Example 3 Step 8.
.sup.1H-NMR (400 MHz, CDCl.sub.3) 0.97 (s, 9H), 1.25 (t, J=7.17 Hz,
3H), 1.42-1.68 (m, 6H), 1.77-1.85 (m, 1H), 2.08-2.15 (m, 1H),
2.27-2.41 (m, 2H), 2.45-2.50 (m, 2H), 2.60-2.65 (m, 28), 3.34-3.42
(m, 2H), 3.52-3.68 (m, 4H), 4.12 (q, J=7.17 Hz, 2H), 4.52 (s, 2H),
4.69 (t, J=5.53 Hz, 1H), 6.52 (s, 1H), 7.13 (d, J=7.92 Hz, 1H),
7.19 (dd, J=7.92, 1.94 Hz, 1H), 7.29-7.38 (m, 6H)
Step 11
Ethyl
3-{5-(2-benzyloxy-ethyl)-7a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]--
2-oxo-1,2,5,6,7,7a-hexahydro-cyclopentapyrimidin-3-yl}propionate
##STR00119##
[0482] This step was performed according to Example 3 Step 9.
Step 12
Ethyl
3-{7a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5-(2-hydroxy-ethyl)-2--
oxo-1,2,5,6,7,7a-hexahydro-cyclopentapyrimidin-3-yl}propionate
##STR00120##
[0484] Ethyl
3-{5-(2-benzyloxy-ethyl)-7a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-2-oxo-
-1,2,5,6,7,7a-hexahydro-cyclopentapyrimidin-3-yl}propionate (0.100
g) and dichloromethane (2 mL) were mixed under nitrogen gas, and
thereto was added dropwise 1.01M boron tribromide/dichloromethane
solution (0.42 mL) under cooling at -78.degree. C. The reaction
solution was stirred under cooling at -78.degree. C. for 1 hour. To
the reaction solution was added a mixed solution of triethylamine
(0.42 mL) in methanol (0.42 mL) under cooling at -78.degree. C. The
reaction solution was stirred at room temperature for 10 minutes.
To the reaction solution was added dropwise water (0.5 mL). To the
reaction solution was added ethyl acetate, and the solution was
separated. The aqueous layer was extracted with ethyl acetate.
Combined organic layers were washed with brine, and then dried over
sodium sulfate. Sodium sulfate was removed with a filter, and then
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (Biotage flash
purification systems, eluent: ethyl acetate/n-hexane, Rf=0.07
(ethyl acetate/n-hexane=2/3)) and (Biotage flash purification
systems, eluent: acetone/chloroform, Rf=0.43
(acetone/chloroform=3/7), followed by purification by thin-layer
silica gel column chromatography (acetone/chloroform=1/4) to give
the title compound (18.8 mg).
[0485] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.98 (s, 9H), 1.14-1.08
(m, 1H), 1.18-1.33 (m, 5H), 1.42-1.46 (m, 2H), 1.65-1.73 (m, 1H),
1.97-2.06 (m, 2H), 2.45-2.49 (m, 1H), 2.53-2.61 (m, 2H), 2.62-2.67
(m, 2H), 2.91-2.99 (m, 1H), 3.45-3.53 (m, 1H), 3.64-3.73 (m, 2H),
3.89-3.96 (m, 1H), 4.08-4.19 (m, 2H), 5.11 (s, 1H), 6.25 (d, J=1.85
Hz, 1H), 7.06-7.27 (m, 3H)
Step 13
Ethyl
3-{7a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5-(2-methoxy-ethyl)-2--
oxo-1,2,5,6,7,7a-hexahydro-cyclopentapyrimidin-3-yl}propionate
##STR00121##
[0487] Ethyl
3-{7a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5-(2-hydroxy-ethyl)-2-oxo-1-
,2,5,6,7,7a-hexahydro-cyclopentapyrimidin-3-yl}propionate (52 mg)
and acetonitrile (0.75 mL) were mixed under nitrogen gas, and
thereto were added methyl iodide (0.75 mL) and silver (I) oxide (38
mg) at room temperature. The reaction solution was stirred under
heating at 80.degree. C. The resulting solid was removed with
Celite, and then the filtrate was concentrated under reduced
pressure. The resulting residue was purified by thin-layer silica
gel column chromatography (ethyl acetate/n-hexane=1/1) and
thin-layer silica gel column chromatography
(acetone/chloroform=7/93) to give the title compound (15.5 mg).
[0488] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.98 (s, 9H), 1.04-1.14
(m, 1H), 1.25 (t, J=7.17 Hz, 3H), 1.41-1.46 (m, 2H), 1.50-1.59 (m,
2H), 1.66-1.74 (m, 1H), 1.94-2.06 (m, 2H), 2.42-2.47 (m, 1H),
2.55-2.59 (m, 2H), 2.62-2.66 (m, 2H), 2.88-2.95 (m, 1H), 3.34 (s,
3H), 3.35-3.53 (m, 3H), 3.89-3.95 (m, 1H), 4.12-4.19 (m, 2H), 5.20
(s, 1H), 6.21 (d, J=1.85 Hz, 1H), 7.06-7.24 (m, 3H)
Step 14
3-{7a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-5-(2-methoxy-ethyl)-2-oxo-1,-
2,5,6,7,7a-hexahydro-cyclopentapyrimidin-3-yl}propionate
##STR00122##
[0490] This step was performed according to Example 3 Step 10.
Example 34
Step 1
2,2,3-Trimethylpent-4-en-1-ol
##STR00123##
[0492] Lithium aluminum hydride (4.0 g) and tetrahydrofuran (210
mL) were mixed under argon gas, and thereto was added a mixed
solution of 2,2,3-trimethylpent-4-enoic acid (5.0 g) in
tetrahydrofuran (70 mL) under ice cooling. The mixture was stirred
under ice cooling for 20 minutes, and then the reaction solution
was stirred with being heated to reflux for 2 hours 30 minutes.
Then, thereto were added dropwise sequentially water (4 mL), 2N
sodium hydroxide (4 mL), and water (12 mL) under ice cooling. The
reaction solution was stirred at room temperature for 1 hour. To
the reaction solution were added Celite (4 g) and magnesium sulfate
(4 g), and Celite was removed with a filter, and then the filtrate
was concentrated under reduced pressure to give the title compound
(4.2 g).
[0493] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.84 (s, 3H), 0.87 (s,
3H), 0.97 (d, J=6.94 Hz, 3H), 1.37 (br s, 1H), 2.13-2.21 (m, 1H),
3.37 (s, 2H), 4.97-5.05 (m, 2H), 5.82 (ddd, J=18.15, 9.25, 7.86 Hz,
1H)
Step 2
2,2,3-Trimethyl-pent-4-en-1-ol methanesulfonic acid ester
##STR00124##
[0495] 2,2,3-Trimethylpent-4-en-1-ol (4.2 g) and triethylamine (7.2
mL) were mixed in chloroform (50 mL) under argon gas, and thereto
was added dropwise a mixed solution of methanesulfonyl chloride
(3.8 mL) in chloroform (15 mL) under ice cooling. The reaction
solution was stirred under ice cooling for 5 minutes, and then
warmed to room temperature. The reaction solution was stirred at
room temperature for 3 hours, and then thereto was added water (13
mL). The solution was stirred at room temperature, and then thereto
was added ethyl acetate (20 mL). The solution was separated. The
aqueous layer was extracted with ethyl acetate (20 mL) once. The
organic layer was washed with 1N hydrochloric acid (12 mL),
saturated sodium hydrogen carbonate (12 mL), and saturated aqueous
sodium chloride solution (12 mL) and dried over magnesium sulfate.
Magnesium sulfate was removed with a filter, and then the filtrate
was concentrated under reduced pressure to give the title compound
(7.1 q).
[0496] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.92 (s, 3H), 0.96 (s,
3H), 0.99 (d, J=6.88 Hz, 3H), 2.16-2.24 (m, 1H), 3.00 (s, 3H), 3.94
(s, 2H), 5.01-5.08 (m, 2H), 5.67-5.78 (m, 1H)
Step 3
5-Iodo-3,4,4-trimethylpent-1-ene
##STR00125##
[0498] 2,2,3-Trimethyl-pent-4-en-1-ol methanesulfonic acid ester
(7.1 g) and N-methylpyridone (65 mL) were mixed under nitrogen gas,
and thereto was added sodium iodide (24 g) at room temperature. The
reaction solution was heated at 140.degree. C. for 4 hours 20
minutes. Then, thereto was added 20 w/w % aqueous sodium
thiosulfate solution (31 mL) at room temperature, and the mixture
was stirred for 1 hour. The reaction solution was extracted with
ethyl acetate/n-hexane=1/2 (50 mL) twice. The organic layer was
washed with water (21 mL) twice, 20 w/w % aqueous sodium
thiosulfate solution (21 mL), and saturated aqueous sodium chloride
solution (21 mL) and dried over magnesium sulfate. Magnesium
sulfate was removed with a filter, and then the filtrate was
concentrated under reduced pressure to give the title compound (5.4
g).
[0499] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.95-0.99 (m, 9H),
2.20-2.28 (m, 1H), 3.16-3.24 (m, 2H), 5.00-5.11 (m, 2H), 5.70 (ddd,
J=18.03, 9.25, 7.86 Hz, 1H)
Step 4
4-Trimethyhex-5-enenitrile
##STR00126##
[0501] 5-Iodo-3,4,4-trimethylpent-1-ene (3.8 g) and dimethyl
sulfoxide (42 mL) were mixed under argon gas, and thereto was added
tetraethylammonium cyanide (6.8 g) at room temperature. The
reaction solution was stirred under heating at 80.degree. C. for 7
hours. To the reaction solution was added water (21 mL) at room
temperature, and the aqueous layer was extracted with a mixed
solvent of ethyl acetate/n-hexane=1/2 (21 mL, twice). The organic
layer was washed with water (12 mL, three times) and saturated
aqueous sodium chloride solution (12 mL) and dried over magnesium
sulfate. Magnesium sulfate was removed with a filter, and then the
filtrate was concentrated under reduced pressure. The resulting
residue was combined with a crude product (0.5 g) synthesized
separately according to Example 34 Step 4 and purified by silica
gel column chromatography (Biotage flash purification systems,
eluent: ethyl acetate/n-hexane, 5/95 to 30/70) and then azeotroped
with n-hexane to give the title compound (2.0 g).
[0502] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.97-1.02 (m, 6H), 1.06
(s, 3H), 2.13-2.22 (m, 1H), 2.24 (s, 2H), 5.04-5.12 (m, 2H), 5.69
(ddd, J=18.15, 9.13, 7.98 Hz, 1H)
Step 5
3,3,4-Trimethylhex-5-enal
##STR00127##
[0504] 3,3,4-Trimethylhex-5-enenitrile (2.0 g) and dichloromethane
(150 mL) were mixed under argon gas, and thereto was added dropwise
1.02M diisobutylaluminum hydride/n-hexane solution (22 mL) under
cooling at -78.degree. C. The reaction solution was stirred under
cooling at -78.degree. C. for 15 minutes. The reaction solution was
gradually warmed to 0.degree. C. and stirred under ice cooling for
2 hours. Then, thereto was added dropwise a saturated aqueous
solution of Rochelle salt (150 mL) under ice cooling. The reaction
solution was stirred at room temperature for 2 hours. The aqueous
layer was extracted with ethyl acetate/n-hexane=1/2 (20 mL, twice).
The organic layer was washed with saturated aqueous sodium chloride
solution (6 mL) and dried over magnesium sulfate. Magnesium sulfate
was removed with a filter, and then the filtrate was concentrated
under reduced pressure to give the title compound (1.8 g).
[0505] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.99 (d, J=5.78 Hz, 3H),
1.03 (s, 3H), 1.05 (s, 3H), 2.06-2.15 (m, 1H), 2.27-2.30 (m, 2H),
4.98-5.05 (m, 2H), 5.74 (ddd, J=18.09, 9.19, 7.69 Hz, 1H), 9.86 (t,
J=3.12 Hz, 1H)
Step 6
3,3,4-Trimethylhex-5-enal oxime
##STR00128##
[0507] 3,3,4-Trimethylhex-5-enal (1.8 g) was mixed in ethanol (30
mL) and water (15 mL) under argon gas, and thereto were added
sodium acetate (7.4 g) and hydroxylamine hydrochloride (3.1 g) at
room temperature. The reaction solution was stirred under heating
at 60.degree. C. for 1 day. The reaction solution was concentrated
under reduced pressure, and thereto were added ethyl acetate and
water. The solution was separated. The aqueous layer was extracted
with ethyl acetate. The organic layer was washed with saturated
aqueous sodium chloride solution (twice) and dried over sodium
sulfate. Sodium sulfate was removed with a filter, and then the
filtrate was concentrated under reduced pressure. The resulting
residue was mixed with ethyl acetate, and the resulting solid was
filtered with Celite. Then, the filtrate was concentrated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (Biotage flash purification systems, eluent:
ethyl acetate/n-hexane, 5/95 to 20/80) to give the title compound
(1.7 g).
[0508] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.90 (s, 1.5H), 0.91 (s,
1.5H), 0.93 (s, 1.5H), 0.94 (s, 1.5H), 0.97 (d, J=4.39 Hz, 1.5H),
0.99 (d, J=4.39 Hz, 1.5H), 1.98-2.09 (m, 1H), 2.12 (dd, J=6.82,
2.89 Hz, 1H), 2.29 (dd, J=15.67, 5.55 Hz, 0.5H), 2.38 (dd, J=15.67,
5.90 Hz, 0.5H), 4.96-5.03 (m, 2H), 5.72-5.82 (m, 1H), 6.83 (t,
J=5.90 Hz, 0.5H), 6.91 (br s, 1H), 7.48 (t, J=6.82 Hz, 0.5H)
Step 7
4,5,5-Trimethyl-3a,4,5,6-tetrahydro-3H-cyclopenta[c]isoxazole
##STR00129##
[0510] Heptan-6-al oxime (1.7 g) and methanol (34 mL) were mixed
under nitrogen gas, and thereto was added trifluoroacetic acid
(0.25 mL) under sodium chloride-ice cooling, followed by addition
of (diacetoxyiodo)benzene (5.1 g) over 40 minutes. The reaction
solution was stirred under ice cooling for 20 minutes and at room
temperature for 35 minutes. Then, thereto were added saturated
aqueous sodium hydrogen carbonate solution (17 mL) and sodium
sulfite (0.75 g) under ice cooling, and the mixture was stirred at
room temperature for 30 minutes. The reaction solution was
concentrated under reduced pressure. The aqueous layer was
extracted with ethyl acetate (10 mL, twice). The organic layer was
washed with saturated aqueous sodium chloride solution (5 mL,
twice) and dried over sodium sulfate. Sodium sulfate was removed
with a filter, and then the filtrate was concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (Biotage flash purification systems, eluent: ethyl
acetate/n-hexane=5/95 to 30/70), followed by further purification
by silica gel column chromatography (Biotage flash purification
systems, eluent: acetone/n-hexane=5/95 to 20/80), and then
azeotroped with n-hexane to give the title compound (0.87 g).
[0511] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.96 (d, J=6.94 Hz, 3H),
1.02 (s, 3H), 1.12 (s, 3H), 1.55-1.64 (m, 1H), 2.35-2.37 (m, 2H),
3.51-3.62 (m, 1H), 3.78 (dd, J=12.02, 7.86 Hz, 1H), 4.48 (dd,
J=9.48, 7.86 Hz, 1H)
Step 8
6a-(3-Chloro-4-(3,3-dimethylbutyl)phenyl)-4,5,5-trimethylhexahydro-1H-cycl-
openta[c]isoxazole
##STR00130##
[0513] This step was performed according to Example 3 Step 6.
.sup.1H-NMR (400 MHz, CDCl.sub.3) 0.57-0.69 (m, 3H), 0.94-1.01 (m,
15H), 1.42-1.49 (m, 2H), 1.59-1.68 (m, 1H), 1.93-1.99 (m, 1H),
2.33-2.41 (m, 1H), 2.64-2.68 (m, 2H), 2.85-2.91 (m, 1H), 3.73-3.79
(m, 1H), 4.00-4.04 (m, 1H), 7.18 (d, J=8.09 Hz, 1H), 7.26-7.30 (m,
1H), 7.42-7.44 (m, 1H)
Step 9
(2-Amino-2-(3-chloro-4-(3,3-dimethylbutyl)phenyl)-4,4,5-trimethylcyclopent-
yl)methanol
##STR00131##
[0515] This step was performed according to Example 3 Step 7.
.sup.1H-NMR (400 MHz, CDCl.sub.3) 0.85 (s, 3H), 0.94 (d, J=6.70 Hz,
3H), 0.97 (s, 9H), 1.14 (s, 3H), 1.42-1.48 (m, 2H), 1.50-1.57 (m,
1H), 1.79-1.85 (m, 1H), 2.07-2.16 (m, 1H), 2.30 (d, J=14.10 Hz,
1H), 2.63-2.69 (m, 2H), 3.28 (s, 3H), 3.66 (dd, J=12.02, 4.62 Hz,
1H), 3.77-3.83 (m, 2H), 7.17 (d, J=7.86 Hz, 11), 7.25-7.28 (m, 1H),
7.42 (d, J=2.08 Hz, 1H)
Step 10
Methyl
3-(3-{1-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-2-(hydroxymethyl)-3-
,4,4-trimethylcyclopentyl}ureido)bicyclo[1.1.1]pentane-1-carboxylate
##STR00132##
[0517] This step was performed according to Example 54 Step 8.
H-NMR (400 MHz, CDCl.sub.3) 0.85 (s, 3H), 0.92 (d, J=6.70 Hz, 3H),
0.97 (s, 10H), 0.99 (s, 3H), 1.14 (s, 3H), 1.41-1.46 (m, 3H),
1.57-1.63 (m, 1H), 2.13-2.18 (m, 1H), 2.22-2.26 (m, 1H), 2.33 (s,
6H), 2.57-2.65 (m, 3H), 3.66-3.69 (m, 5H), 4.63-4.67 (m, 1H),
6.67-6.70 (m, 1H), 7.10-7.18 (m, 2H)
Step 11
Methyl
3-{(S)-7a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5,6,6-trimethyl-2-
-oxo-1,2,5,6,7,7a-hexahydro-3H-cyclopenta[d]pyrimidin-3-yl}bicyclo[1.1.1]p-
entane-1-carboxylate
##STR00133##
[0519] This step was performed according to Example 54 Step 9.
[0520] Purification was perfomed with a chiral preparative column.
Purification conditions for the preparative column are shown as
follows.
Preparative apparatus: Recycling Preparative Liquid Chromatograph
LC-92XX NEXT SERIES, Japan Analytical Industry Co., Ltd. Column:
Daicel CHIRALPAK IA 2.0 cm.phi..times.25 cmL Mobile phase:
n-hexane/2-propanol=92/8 Flow rate: 10.0 mL/min
Detection: UV (254 nm)
[0521] Measurement with a chiral column showed 6.0 minutes of the
retention time for the resulting title compound (8.5 minutes of the
retention time for the enantiomer of the title compound) with
>99% ee purity. Analytical conditions for the chiral column are
shown as follows.
Measurement apparatus: HPLC system, Shimadzu Corporation,
High-Performance Liquid Chromatograph Prominence Column: Daicel
CHIRALPAK IA-3 0.46 cm.phi..times.15 cmL Column temperature:
30.degree. C. Mobile phase: n-hexane/2-propanol=90/10 Flow rate:
1.0 mL/min
Detection: UV (254 nm)
[0522] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.76 (s, 3H), 0.90 (d,
J=7.34 Hz, 3H), 0.97 (s, 9H), 1.13 (s, 3H), 1.41-1.47 (m, 2H), 2.01
(d, J=13.33 Hz, 1H), 2.30 (d, J=13.33 Hz, 1H), 2.37-2.46 (m, 7H),
2.60-2.67 (m, 2H), 3.69 (s, 3H), 4.91 (s, 1H), 6.23 (d, J=0.73 Hz,
1H), 7.05 (dd, J=7.83, 1.96 Hz, 1H), 7.14 (d, J=7.83 Hz, 1H), 7.20
(d, J=1.96 Hz, 1H)
Step 12
3-{(S)-7a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-5,6,6-trimethyl-2-oxo-1,-
2,5,6,7,7a-hexahydro-3H-cyclopenta[d]pyrimidin-3-yl}bicyclo[1.1.1]pentane--
1-carboxylic acid
##STR00134##
[0524] This step was performed according to Example 54 Step 10.
Example 54
Step 1
##STR00135##
[0526] Hept-6-en-1-ol (150 g) and (diacetoxyiodo)benzene (508 1C g)
were mixed in chloroform (1500 mL) under nitrogen gas, and thereto
was added a mixed solution of 2,2,6,6-tetramethylpiperidin-1-oxyl
radical (20.5 g) in chloroform (20.0 mL) at room temperature. The
reaction solution was stirred at room temperature for 3 days. Then,
thereto was added an aqueous solution (1500 mL) of sodium carbonate
(278 g) and sodium thiosulfale (208 g) under water cooling, and the
mixture was stirred at room temperature for 1 hour, and then
separated. The aqueous layer was extracted with chloroform (1000
mL). Combined organic layers were washed with saturated aqueous
sodium chloride solution and dried over sodium sulfate. Sodium
sulfate was removed with a filter, and then the filtrate was
concentrated under reduced pressure. The resulting residue was
distilled under reduced pressure (85.degree. C., 70 mmHg) to give a
crude product of the title compound (214 g, 46.4 w % of iodobenzene
inclusive).
[0527] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.40-1.47 (m, 2H),
1.62-1.69 (m, 2H), 2.03-2.11 (m, 2H), 2.44 (td, J=7.40, 1.62 Hz,
2H), 4.95-5.04 (m, 2H), 5.74-5.84 (m, 1H), 9.77 (t, J=1.62 Hz,
1H)
Step 2
Hept-6-enal oxime
##STR00136##
[0529] Hept-6-enal (214 g, 46.4 w % of iodobenzene inclusive) was
mixed in water (1149 mL) and ethanol (2298 mL) under nitrogen gas,
and then thereto were added sodium acetate (151 g) and
hydroxylamine hydrochloride (107 g) at room 2C temperature. The
reaction solution was stirred at room temperature for 2 days. The
reaction solution was concentrated under reduced pressure, and
thereto were added ethyl acetate and water. The solution was
separated. The aqueous layer was extracted with ethyl acetate
(twice). The organic layer was washed with saturated aqueous sodium
chloride solution and concentrated under reduced pressure. The
resulting residue was mixed with ethyl acetate, and the resulting
solid was filtered with Celite. The filtrate was concentrated under
reduced pressure to give a crude product of the title compound (203
g, 24.5 w % of ethyl acetate, 2.5 w % of ethanol, and 9.2 w % of
iodobenzene inclusive) (geometric isomer mixture).
[0530] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.40-1.56 (m, 4H),
2.05-2.10 (m, 2H), 2.18-2.24 (m, 1H), 2.38-2.43 (m, 1H), 4.94-5.04
(m, 2H), 5.74-5.85 (m, 1E), 6.72 (t, J=5.32 Hz, 0.55H), 7.43 (t,
J=6.01 Hz, 0.45H)
Step 3
3,3a,4,5,6,7-Hexahydro-benzo[c]isoxazole
##STR00137##
[0532] Hept-6-enal oxime (203 g, 24.5 w % of ethyl acetate, 2.5 w %
of ethanol, and 9.2 w % of iodobenzene inclusive) and methanol
(2333 mL) were mixed under nitrogen gas, and thereto was added
trifluoroacetic acid (17.5 mL) under salt-ice cooling, followed by
addition of (diacetoxyiodo)benzene (384 g) over 1 hour. The
reaction solution was stirred at room temperature for 3 hours.
Then, thereto was added an aqueous solution (1000 mL) of sodium
carbonate (194 g) and sodium sulfite (57.8 g) under ice cooling,
and the solution was stirred at room temperature for 1 hour. The
reaction solution was concentrated under reduced pressure, and
thereto was added water (2500 mL). The aqueous layer was extracted
with ethyl acetate (1200 mL, twice). The organic layer was washed
with saturated aqueous sodium chloride solution (twice) and
concentrated under reduced pressure. The resulting residue was
combined with a crude product (45.0 g) synthesized separately
according to Example 54 Steps 1 to 2 and purified by silica gel
column chromatography (Yamazen Corporation, automated refining
apparatus, eluent: ethyl acetate/n-hexane, Rf=0.25 (ethyl
acetate/n-hexane=1/4)), and then azectroped with n-hexane to give
the title compound (92.2 g, 2.5 w % of n-hexane inclusive).
[0533] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.24-1.45 (m, 3H),
1.84-1.90 (m, 1H), 1.96-2.20 (m, 3H), 2.77-2.82 (m, 1H), 3.10-3.20
(m, 1H), 3.77 (dd, J=9.48, 7.86 Hz, 1H), 4.49 (dd, J=9.48, 7.86 Hz,
1H)
Step 4
7a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]
octahydro-benzo[c]isoxazole
##STR00138##
[0535] 4-Bromo-2-chloro-1-(3,3-dimethyl-butyl)benzene (119 g) and
tetrahydrofuran (210 mL) were mixed under argon gas, and thereto
was added 2.69M n-butyllithium/n-hexane solution (100 mL) under
cooling at -78.degree. C. The reaction solution was stirred under
cooling at -78.degree. C. for 2.5 hours (Reaction solution A).
3,3a,4,5,6,7-Hexahydro-benzo[c]isoxazole (33.4 g) was mixed in
toluene (900 mL) and tetrahydrofuran (180 mL), and thereto were
added boron trifluoride-diethyl ether complex (37.7 mL) and
Reaction solution A under cooling at -78.degree. C. The reaction
solution was stirred for 2 hours, and then thereto was added 2N
aqueous sodium hydroxide solution (240 mL) under cooling at
-78.degree. C. The mixture was stirred at room temperature, and
then thereto were added toluene (300 mL) and water (240 mL). The
mixture was separated. The organic layer was washed with 13 w/w %
aqueous sodium chloride solution (400 mL) and saturated aqueous
sodium chloride solution and dried over sodium sulfate. Sodium
sulfate was removed with a filter, and then the filtrate was
concentrated under reduced pressure to give a crude product of the
title compound (107 g).
[0536] .sup.1H-NMR (400 MHz, CDCCl.sub.3) 0.98 (s, 9H), 1.43-1.86
(m, 7H), 1.86-1.98 (m, 3H), 2.64-2.77 (m, 3H), 3.37-4.20 (brm, 2H),
5.82 (brs, 1H), 7.18 (d, J=7.83 Hz, 1H), 7.37 (d, J=6.60 Hz, 1H),
7.52 (s, 1H)
Step 5
{2-Amino-2-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]
cyclohexyl}methanol
##STR00139##
[0538]
7a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]octahydro-benzo[c]isoxazo-
le (107 g) was mixed in acetic acid (600 mL), tetrahydrofuran (180
mL), and water (180 mL) under nitrogen gas, and thereto was added
zinc powder (24.4 g) in 5 parts under heating at 80.degree. C. The
reaction solution was stirred under heating at 80.degree. C. for 30
minutes. The reaction solution was filtered with Celite at room
temperature, and then the filtrate was concentrated under reduced
pressure. The resulting residue was mixed in ethyl acetate (1000
mL) and 28 w/w % ammonia water (140 mL), and the mixture was
separated. The organic layer was washed with 20 w/w % aqueous
sodium carbonate solution (200 mL) and saturated aqueous sodium
chloride solution and dried over sodium sulfate. Sodium sulfate was
removed with a filter, and then the filtrate was concentrated under
reduced pressure to give a crude product of the title compound
(99.6 g).
[0539] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.98 (s, 9H), 1.39-1.50
(m, 4H), 1.53-1.66 (m, 2H), 1.70-1.93 (m, 4H), 2.02 (td, J=13.20,
2.93 Hz, 1H), 2.65-2.69 (m, 2H), 3.26 (dd, J=11.25, 2.93 Hz, 1H),
3.44 (dd, J=11.25, 2.93 Hz, 1H), 7.19 (d, J=8.07 Hz, 1H), 7.33 (dd,
J=8.07, 1.96 Hz, 1H), 7.48 (d, J=1.96 Hz, 1H)
Step 6
{(R)-2-Amino-2-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]
cyclohexyl}methanol (2S,3S)-2,3-bis-benzoyloxy-succinate
##STR00140##
[0541]
{2-Amino-2-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]cyclohexyl}methan-
ol (99.6 g) and tetrahydrofuran (245 mL) were mixed under nitrogen
gas, and thereto was added a mixed solution of
(2S,3S)-2,3-bis-benzoyloxy-succinic acid (94.0 g) in
tetrahydrofuran (345 mL) under heating at 85.degree. C. The
reaction solution was stirred under heating at 85.degree. C. for
5.5 hours. The solution was stirred for 13.5 hours with being
slowly cooled to room temperature, and then the precipitated solid
was collected by filtration to give the title compound (62.2
g).
[0542] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) 0.96 (s, 9H), 1.38-1.65
(m, 4H), 1.78-1.70 (m, 8H), 1.86-1.94 (m, 1H), 1.99-2.06 (m, 1H),
2.62-2.67 (m, 2H), 3.09 (dd, J=10.76, 5.62 Hz, 1H), 3.19 (dd,
J=10.76, 2.45 Hz, 1H), 5.64 (s, 2H), 7.36-7.42 (m, 2H), 7.45-7.49
(m, 4H), 7.58-7.63 (m, 3H), 7.89-7.91 (m, 4H)
Step 7
{(R)-2-Amino-2-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]
cyclohexyl}methanol
##STR00141##
[0544]
{(R)-2-Amino-2-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]cyclohexyl}me-
thanol (2S,3S)-2,3-bis-benzoyloxy-succinate (62.2 g) and
tetrahydrofuran (290 mL) were mixed under nitrogen gas. The
reaction solution was stirred under heating at 85'C for 6 hours.
The solution was stirred for 13.5 hours with being slowly cooled to
room temperature, and then the precipitated solid was collected by
filtration to give
{2-amino-2-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]cyclohexyl}methanol
(2S,3S)-2,3-bis-benzoyloxy-succinate (59.5 g). The resulting
{2-amino-2-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]cyclohexyl}methanol
(2S,3S)-2,3-bis-benzoyloxy-succinate was mixed in ethyl acetate
(600 mL) and methanol (60 mL), and thereto was added 1N aqueous
sodium hydroxide solution (150 mL) under ice cooling. The mixture
was separated at room temperature. The organic layer was washed
with 20 w/w % aqueous sodium carbonate solution (135 mL for the
first round and 50 mL for the second round), 13 w/w % aqueous
sodium chloride solution (130 mL), and saturated aqueous sodium
chloride solution and dried over sodium sulfate. Sodium sulfate was
removed with a filter, and then the filtrate was concentrated under
reduced pressure to give the title compound (25.5 g).
[0545] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.98 (s, 9H), 1.39-1.50
(m, 4H), 1.53-1.66 (m, 2H), 1.70-1.93 (m, 4H), 2.02 (td, J=13.20,
2.93 Hz, 1H), 2.65-2.69 (m, 2H), 3.26 (dd, J=11.25, 2.93 Hz, 1H),
3.44 (dd, J=11.25, 2.93 Hz, 1H), 7.19 (d, J=8.07 Hz, 1H), 7.33 (dd,
J=8.07, 1.96 Hz, 1H), 7.48 (d, J=1.96 Hz, 1H)
Step 8
Methyl
3-(3-{(R)-1-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-2-hydroxymethyl-
-cyclohexyl}ureido)bicyclo[1.1.1]pentane-1-carboxylate
##STR00142##
[0547] 3-(Methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid
(14.7 g) and toluene (135 mL) were mixed under nitrogen gas, and
thereto were added diphenylphosphoryl azide (20.3 mL) and
triethylamine (13.1 mL) at room temperature. The reaction solution
was stirred under heating at 100.degree. C. for 1 hour. The
reaction solution was added dropwise to a mixed solution of
{(R)-2-amino-2-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]cyclohexyl}methanol
(25.5 g) in tetrahydrofuran (135 mL) over 35 minutes under ice
cooling. The reaction solution was stirred at room temperature for
26 hours, and then the precipitated solid was collected by
filtration to give the title compound (21.3 g). To the filtrate
were added ethyl acetate (400 mL) and saturated aqueous sodium
hydrogen carbonate solution (150 mL), and the mixture was
separated. The organic layer was washed with saturated aqueous
sodium hydrogen carbonate solution (150 mL), water (100 mL), and
saturated aqueous sodium chloride solution and dried over sodium
sulfate. Sodium sulfate was removed with a filter, and then the
filtrate was concentrated under reduced pressure. The resulting
residue was mixed with ethyl acetate (50 mL) and stirred under
heating at 70.degree. C. for 1.5 hours. The reaction solution was
stirred at room temperature for 2 hours, and then the precipitated
solid was collected by filtration to give the title compound (13.9
g).
[0548] Measurement with a chiral column showed 9.4 minutes of the
retention time for the resulting title compound (12.3 minutes of
the retention time for the enantiomer of the title compound) with
>99% ee purity. Conditions for the chiral column are shown as
follows.
Measurement apparatus: HPLC system, Shimadzu Corporation,
High-Performance Liquid Chromatograph Prominence Column: Daicel
CHIRALPAK OZ-3R 0.46 cm.phi..times.15 cmL Column temperature:
40.degree. C. Mobile phase: 0.1 v/v % aqueous formic acid
solution/0.1 v/v % formic acid-acetonitrile solution=45/55 Flow
rate: 1.0 mL/min
Detection: UV (254 nm)
[0549] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.97 (s, 9H), 1.42-1.48
(m, 3H), 1.70-1.52 (m, 4H), 1.72-1.79 (m, 1H), 1.88-1.98 (m, 2H),
2.37 (s, 6H), 2.61-2.66 (m, 2H), 2.98-3.04 (m, 1H), 3.37-3.41 (m,
1H), 3.45-3.49 (m, 1H), 3.69 (s, 3H), 4.71 (s, 1H), 6.27 (s, 1H),
7.15-7.18 (m, 1H), 7.26-7.27 (m, 2H)
Step 9
Methyl
3-{(S)-8a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-2-oxo-1,5,6,7,8,8-
a-hexahydro-2H-quinazolin-3-yl}bicyclo[1.1.1]pentane-1-carboxylate
##STR00143##
[0551] Methyl
3-(3-{(R)-1-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-2-hydroxymethyl-cyclo-
hexyl}ureido)bicyclo[1.1.1]pentane-carboxylate (16.7 g) and
chloroform (495 mL) were mixed under nitrogen gas, and thereto were
added at room temperature (diacetoxyiodo)benzene (11.9 g) and
2,2,6,6-tetramethylpiperidin-1-oxyl radical (0.527 g). The reaction
solution was stirred at room temperature for 21.5 2C hours, and
then thereto was added 2,2,6,6-tetramethylpiperidin-1-oxyl radical
(0.527 g) at room temperature. The mixture was stirred at room
temperature for 4 hours, and then thereto were added
(diacetoxyiodo)benzene (1.20 g) and
2,2,6,6-tetramethylpiperidin-1-oxyl radical (0.527 g) at room
temperature. The mixture was stirred at room temperature for 17
hours, and then thereto were added 20 w/w % aqueous sodium sulfite
solution (200 mL) and 20 w/w % aqueous sodium carbonate solution
(30 mL) at room temperature. The mixture was separated. The organic
layer was dried over sodium sulfate. Sodium sulfate was removed
with a filter, and then the filtrated was concentrated under
reduced pressure. The resulting residue was mixed with toluene (300
mL), and thereto was added pentafluoroaniline
trifluoromethanesulfonate (0.561 g) at room temperature. The
reaction solution was stirred for 2 hours with being heated to
100.degree. C., and then thereto was added trifluoroacetic acid (10
mL) at room temperature. The reaction solution was stirred at room
temperature for 15 hours, and then concentrated under reduced
pressure. The resulting residue was combined with a crude product
(48.3 g) synthesized separately according to Example 54 Steps 1 to
8 and purified by silica gel column chromatography (ethyl
acetate/n-hexane=1/4->1/2->1/1) to give the title compound
(35.3 g).
[0552] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.98 (s, 9H), 1.26-1.42
(m, 2H), 1.43-1.47 (m, 2H), 1.68-1.73 (m, 2H), 1.88-1.97 (m, 2H),
2.13-2.17 (m, 1H), 2.44 (s, 6H), 2.48-2.53 (m, 1H), 2.64-2.69 (m,
2H), 3.70 (s, 3H), 4.54 (s, 1H), 5.96 (d, J=1.47 Hz, 1H), 7.15 (dd,
J=8.07, 1.96 Hz, 1H), 7.21 (d, J=8.07 Hz, 1H), 7.28 (d, J=1.96 Hz,
1H)
Step 10
3-{(S)-8a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-2-oxo-1,5,6,7,8,8a-hexah-
ydro-2H-quinazolin-3-yl}bicyclo[1.1.1]pentane-1-carboxylic acid
##STR00144##
[0554] Methyl
3-{(S)-8a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-2-oxo-1,5,6,7,8,8a-hexa-
hydro-2H-quinazolin-3-yl}bicyclo[(1.1.1]pentane-1-carboxylate (35.3
g) was mixed in tetrahydrofuran (150 mL) and methanol (600 mL)
under nitrogen gas, and thereto was added 2N aqueous sodium
hydroxide solution (72 mL) under ice cooling. The reaction solution
was stirred at room temperature for 17.5 hours, and then thereto
was added water (300 mL). The reaction solution was concentrated
under reduced pressure. To The resulting residue was added 2N
hydrochloric acid (90 mL) under ice cooling, and the mixture was
extracted with ethyl acetate/methanol=100/1 (1010 mL). The organic
layer was washed with 13 w/w % aqueous sodium chloride solution
(200 mL, twice) and saturated aqueous sodium chloride solution
(twice) and dried over sodium sulfate. Sodium sulfate was removed
with a filter, and then the filtrate was concentrated under reduced
pressure. The resulting residue was mixed in ethyl acetate (55 mL)
and n-hexane (220 mL) and stirred under heating at 55.degree. C.
for 9 hours. The reaction solution was stirred for 9 hours with
being slowly cooled to room temperature, and then the precipitated
solid 0.5 was collected by filtration to give the title compound
(22.8 g).
[0555] Absolute configuration of the asymmetric carbon of the title
compound was determined by single-crystal X-ray structural
analysis.
Intermediate Step 1
4-Bromo-2-chloro-1-(3,3-dimethyl-but-1-ynyl)benzene
##STR00145##
[0557] 4-Bromo-2-chloro-1-iodo-benzene (325 g),
3,3-dimethyl-but-1-yne (97 g), bis(triphenylphosphino)palladium
(II) dichloride (14.3 g), copper (I) iodide (7.80 g),
triphenylphosphine (10.7 g), and diisopropylamine (2.17 L) were
mixed under argon gas and stirred under heating at 100.degree. C.
for 15 hours. Then, thereto was added n-hexane (2.20 L) at room
temperature, and the precipitated solid was filtered with Celite.
Then, the filtrate was concentrated under reduced pressure. The
resulting residue was mixed with n-hexane (2.00 L) and silica gel
(327 g) and stirred at room temperature for 17 hours. The resulting
solid was removed with a filter, and then the filtrate was
concentrated under reduced pressure to give a crude product of the
title compound (316 g).
[0558] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.33 (s, 9H), 7.26 (d,
J=8.31 Hz, 1H), 7.30 (dd, J=8.31, 1.71 Hz, 1H), 7.54 (d, J=1.96 Hz,
1H)
Intermediate Step 2
4-Bromo-2-chloro-1-(3,3-dimethyl-butyl)benzene
##STR00146##
[0560] 4-Bromo-2-chloro-1-(3,3-dimethyl-but-1-ynyl)benzene (66.0 g)
was mixed with ethanol (330 mL), and thereto was added 5 w/w %
platinum/activated carbon (13.2 g). The reaction solution was
stirred under ordinary pressure and hydrogen gas for 6 hours, and
then the gas in the reaction vessel was replaced with nitrogen gas.
Celite was added to the reaction solution and removed with a
filter, and then the filtrate was concentrated under reduced
pressure. The resulting residue was mixed with ethanol (330 mL),
and thereto was added 5 w/w % platinum/activated carbon (13.6 g).
The reaction solution was stirred under 0.1 MPa hydrogen gas for 55
hours, and then the gas in the reaction vessel was replaced with
nitrogen gas. Celite was added to the reaction solution and removed
with a filter, and then the filtrate was concentrated under reduced
pressure. The resulting residue was mixed with n-hexane (200 mL),
and the mixture was separated. The organic layer was washed with
water. All aqueous layers were extracted with n-hexane (20 mL). The
organic layer was washed with water and saturated aqueous sodium
chloride solution and dried over magnesium sulfate. Magnesium
sulfate was removed with a filter, and then the filtrate was
concentrated under reduced pressure to give Crude product A (61.0
g).
[0561] 4-Bromo-2-chloro-1-(3,3-dimethyl-but-1-ynyl)benzene (10.0 g)
was mixed with ethanol (50.0 mL), and thereto was added 5 w/w %
platinum/activated carbon (2.03 g). The reaction solution was
stirred under ordinary pressure and hydrogen gas for 18 hours, and
then the gas in the reaction vessel was replaced with nitrogen gas.
Celite was added to the reaction solution and removed with a
filter, and then the filtrate was concentrated under reduced
pressure to give Crude product B (9.81 g).
[0562] 4-Bromo-2-chloro-1-(3,3-dimethyl-but-1-ynyl)benzene (82.1 g)
was mixed with ethanol (411 mL), and thereto was added 5 w/w %
platinum/activated carbon (16.7 g). The reaction solution was
stirred under ordinary pressure and hydrogen gas for 26 hours, and
then the gas in the reaction vessel was replaced with nitrogen gas.
Celite was added to the reaction solution and removed with a
filter, and then the filtrate was concentrated under reduced
pressure. The resulting residue was mixed with n-hexane (250 mL)
and water (20 mL.) and separated. The organic layer was washed with
water. All aqueous layers were extracted with n-hexane (50 mL). The
organic layer was washed with water and saturated aqueous sodium
chloride solution and dried over magnesium sulfate. Magnesium
sulfate was removed with a filter, and then the filtrate was
concentrated under reduced pressure to give Crude product C (78.4
q).
[0563] 4-Bromo-2-chloro-1-(3,3-dimethyl-but-1-ynyl)benzene (82.1 g)
was mixed with ethanol (411 mL), and thereto was added 5 w/w %
platinum/activated carbon (16.7 g). The reaction solution was
stirred under ordinary pressure and hydrogen gas for 26 hours, and
then the gas in the reaction vessel was replaced with nitrogen gas.
Celite was added to the reaction solution and removed with a
filter, and then the filtrate was concentrated under reduced
pressure. The resulting residue was mixed with n-hexane (250 mL)
and water (20 mL), and the mixture was separated. The organic layer
was washed with water. All aqueous layers were extracted with
n-hexane (50 mL). The organic layer was washed with water and
saturated aqueous sodium chloride solution and dried over magnesium
sulfate. Magnesium sulfate was removed with a filter, and then the
filtrate was concentrated under reduced pressure to give Crude
product D (74.9 g).
[0564] 4-Bromo-2-chloro-1-(3,3-dimethyl-but-1-ynyl)benzene (82.1 g)
was mixed with ethanol (410 mL), and thereto was added 5 w/w %
platinum/activated carbon (16.4 g). The reaction solution was
stirred under ordinary pressure and hydrogen gas for 27 hours, and
then the gas in the reaction vessel was replaced with nitrogen gas.
Celite was added to the reaction solution and removed with a
filter, and then the filtrate was concentrated under reduced
pressure. The resulting residue was mixed with n-hexane (250 mL)
and water (20 mL), and the mixture was separated. The organic layer
was washed with water. All aqueous layers were extracted with
n-hexane (50 mL). The organic layers were washed with water and
saturated aqueous sodium chloride solution and dried over magnesium
sulfate. Magnesium sulfate was removed with a filter, and then the
filtrate was concentrated under reduced pressure to give Crude
product E (74.4 g).
[0565] The title compound (298.51 g) of Crude products A, B, C, D,
and E was mixed with n-hexane (2.00 L) and silica gel (150 g) and
stirred at room temperature for 3 hours. The resulting solid was
removed with a filter, and then the filtrate was concentrated under
reduced pressure. The resulting residue was azeotroped with toluene
(300 mL) to give a crude product of the title compound (304 g).
[0566] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.97 (s, 9H), 1.40-1.45
(m, 2H), 2.61-2.66 (m, 2H), 7.08 (d, J=8.07 Hz, 1H), 7.29 (dd,
J=8.07, 1.96 Hz, 1H), 7.48 (d, J=1.96 Hz, 1H)
Example 63
Step 1
Ethyl 8,8-difluoro-1,4-dioxa-spiro[4.5]decane-6-carboxylate
##STR00147##
[0568] Ethyl 5,5-difluoro-2-oxo-cyclohexanecarboxylate (4.45 g) and
toluene (53 mL) were mixed under nitrogen gas, and thereto were
added ethylene glycol (1.45 mL) and p-toluenesulfonic acid
monohydrate (205 mg) at room temperature. The reaction solution was
stirred under heating at 140.degree. C. with dehydration for 1 day.
Then, thereto was added a mixed aqueous solution of sodium
carbonate (114 mg) in water (18 mL) under ice cooling, and the
mixture was separated. The aqueous layer was extracted with ethyl
acetate (twice). The organic layer was washed with water (three
times) and saturated aqueous sodium chloride solution and dried
over magnesium sulfate. Magnesium sulfate was removed with a
filter, and then the filtrate was concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (Biotage flash purification systems, eluent: ethyl
acetate/n-hexane, Rf=0.38 (ethyl acetate/n-hexane=1/4)) to give a
crude product of the title compound (3.46 g, 15 w % 23 of ethyl
acetate inclusive).
[0569] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.28 (t, J=7.1 Hz, 3H),
1.78-1.91 (m, 2H), 2.06-2.16 (m, 2H), 2.23-2.31 (m, 1H), 2.38-2.53
(m, 1H), 2.99 (ddd, J=12.4, 4.6, 1.6 Hz, 1H), 3.90-4.01 (m, 4H),
4.17 (q, J=7.1 Hz, 2H)
Step 2
(8,8-Difluoro-1,4-dioxa-spiro[4.5]dec-6-yl)methanol
##STR00148##
[0571] Lithium aluminum hydride (886 mg) and tetrahydrofuran (12
mL) were mixed under argon gas, and thereto was added dropwise a
mixed solution in tetrahydrofuran (18 mL) of ethyl
8,8-difluoro-1,4-dioxa-spiro[4.5]decane-6-carboxylate (2.92 g)
azeotroped with toluene over 1 hour under ice cooling. The reaction
solution was stirred under ice cooling for 20 minutes and stirred
at room temperature for 4 hours. To the reaction solution were
added slowly water (0.886 mL), 2N aqueous solution of sodium
hydroxide (0.886 mL), and water (2.66 mL) under ice cooling. The
reaction solution was stirred at room temperature for 30 minutes.
To the reaction solution were added Celite (1 g), magnesium sulfate
(1 g), and ethyl acetate (30 mL), and the mixture was stirred for
30 minutes. Solids were removed with Celite, and then the filtrate
was concentrated under reduced pressure to give a crude product of
the title compound (3.06 g, 22 w % of ethyl acetate inclusive).
[0572] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.67-1.75 (m, 1H),
1.83-1.90 (m, 1H), 1.91-2.18 (m, 4H), 2.18-2.26 (m, 1H), 2.56 (dd,
J=6.5, 5.3 Hz, 1H), 3.62-3.76 (m, 2H), 3.98-4.08 (m, 4H)
Step 3
2-(8,8-Difluoro-1,4-dioxa-spiro[4.5]dec-6-ylmethoxy)-isoindole-1,3-dione
##STR00149##
[0574] (8,8-Difluoro-1,4-dioxa-spiro[4.5]dec-6-yl)methanol (2.38 g)
and tezrahydrofuran (36 mL) were mixed, and thereto were added
N-hydroxyphthalimide (2.79 g) and triphenylphosphine (4.49 g) under
ice cooling. To the mixed solution was added
bis(2-methoxyethyl)azodicaroxylate (4.01 g) in 8 parts over 40
minutes under ice cooling. The reaction solution was stirred at
room temperature for 15 hours. The reaction solution was
concentrated under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (Biotage flash
purification systems, eluent: ethyl acetate/n-hexane, Rf=0.46
(ethyl acetate/n-hexane=2/3)) to give a crude product of the title
compound (3.44 g).
[0575] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.71-1.85 (m, 2H),
1.96-2.20 (m, 3H), 2.51-2.59 (m, 1H), 2.65-2.75 (m, 1H), 3.93-4.10
(m, 5H), 4.41 (ddd, J=9.1, 4.0, 2.0 Hz, 1H), 7.74 (d, J=3.0 Hz,
1H), 7.76 (d, J=3.0 Hz, 1H), 7.83 (d, J=3.0 Hz, 1H), 7.84 (d, J=3.0
Hz, 1H)
Step 4
O-((8,8-Difluoro-1,4-dioxaspiro[4.5]decan-6-yl)methyl)hydroxylamine
##STR00150##
[0577]
2-(8,8-Difluoro-1,4-dioxa-spiro[4.5]dec-6-ylmethoxy)-isoindole-1,3--
dione (3.44 g) and chloroform (34 mL) were mixed, and thereto was
added a mixed solution of methylhydrazine (0.619 mL) in chloroform
(2 mL) over 5 minutes under ice cooling. The reaction solution was
stirred at room temperature for 2 hours. Solids were removed with
Celite, and then the filtrate was concentrated under reduced
pressure to give a crude product of the title compound (3.49 g, 38
w % of chloroform inclusive).
[0578] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.71-2.10 (m, 5H),
2.23-2.32 (m, 1H), 2.39-2.47 (m, 1H), 3.52 (dd, J=9.9, 8.3 Hz, 1H),
3.88 (ddd, J=10.1, 4.3, 2.2 Hz, 1H), 3.91-4.02 (m, 4H), 5.40 (s,
2H)
Step 5
5,5-Difluoro-3,3a,4,5,6,7-hexahydrobenzo[c]isoxazole
##STR00151##
[0580]
O-(8,8-Difluoro-1,4-dioxa-spiro[4.5]dec-6-ylmethyl)-hydroxylamine
(2.17 g, 38 w % of chloroform inclusive) and tetrahydrofuran (19.5
mL) were mixed, and then thereto was added slowly 6N hydrochloric
acid (4.87 mL) under ice cooling. The reaction solution was stirred
at room temperature for 1 hour, and then thereto was added
tetrahydrofuran (20 mL). The mixture was stirred further for 4
hours. To the reaction solution was added water (5 mL), and the
mixture was stirred under heating at 60.degree. C. for 6 hours.
Then, thereto was added potassium carbonate (4.04 g) under ice
cooling, and the mixture was concentrated under reduced pressure
and then extracted with ethyl acetate (twice). The organic layers
were washed with saturated aqueous sodium chloride solution (twice)
and dried over sodium sulfate. Sodium sulfate was removed with a
filter, and then the filtrate was concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (Biotage flash purification systems, eluent: ethyl
acetate/n-hexane, Rf=0.19 (ethyl acetate/n-hexane=2/3)) to give the
title compound (1.11 g).
[0581] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.76-2.02 (m, 2H),
2.33-2.42 (m, 1H), 2.44-2.60 (m, 2H), 2.89 (ddt, J=14.6, 5.8, 2.1
Hz, 1H), 3.49-3.59 (m, 1H), 3.91 (dd, J=9.8, 8.4 Hz, 1H), 4.57
(ddd, J=10.4, 8.3, 1.5 Hz, 1H)
Step 6
7a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-5,5-difluoro-octahydro-benzo[c]-
isoxazole
##STR00152##
[0583] 4-Bromo-2-chloro-1-(3,3-dimethyl-butyl)-benzene (1.26 g) and
tetrahydrofuran (5 mL) were mixed under argon gas, and thereto was
added dropwise 1.54M n-butyllithium/n-hexane solution (2.42 mL)
under cooling at -78.degree. C. The reaction solution was stirred
for 1 hour under cooling at -78.degree. C. (Reaction solution A).
5,5-Difluoro-3,3a,4,5,6,7-hexahydro-benzo[c]isoxazole (500 mg) and
toluene (12.5 mL) were mixed, and thereto were added boron
trifluoride-diethyl ether complex (0.464 mL) and Reaction solution
A under cooling at -78.degree. C. The reaction solution was stirred
at -78.degree. C. for 3 hours, and then thereto was added saturated
aqueous sodium chloride solution (16 mL). The aqueous layer was
extracted with ethyl acetate (twice) at room temperature. The
organic layers were washed with saturated aqueous sodium chloride
solution (twice) and dried over sodium sulfate. Sodium sulfate was
removed with a filter, and then the filtrate was concentrated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (Biotage flash purification systems, eluent:
ethyl acetate/n-hexane, Rf=0.43 (ethyl acetate/n-hexane=1/4)) to
give a crude product of the title compound (1.09 g, 8 w % of ethyl
acetate inclusive).
[0584] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.98 (s, 9H), 1.43-1.47
(m, 2H), 1.88-2.32 (m, 6H), 2.65-2.70 (m, 2H), 3.02 (qd, J=7.0, 3.8
Hz, 1H), 3.79-3.88 (m, 2H), 5.67 (s, 1H), 7.21 (d, J=7.9 Hz, 1H),
7.34 (dd, J=8.0, 2.0 Hz, 1H), 7.52 (d, J=1.4 Hz, 1H)
Step 7
{2-Amino-2-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5,5-difluoro-cyclohexyl-
}methanol
##STR00153##
[0586]
7a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-5,5-difluoro-octahydro-b-
enzo[c]isoxazole (1.00 g), acetic acid (15 mL), tetrahydrofuran (10
mL), and water (5 mL) were mixed under nitrogen gas, and thereto
was added zinc powder (1.83 g) in 5 parts under heating at
60.degree. C. The reaction solution was stirred under heating at
60.degree. C. for 4 hours. Then, thereto was added 28 w/w % ammonia
water (25 mL) under ice cooling, and the mixture was extracted with
cyclopentyl methyl ether (three times). The organic layers were
washed with saturated aqueous sodium chloride solution and dried
over sodium sulfate. Sodium sulfate was removed with a filter, and
then the filtrate was concentrated under reduced pressure to give a
crude product of the title compound (1.41 g, 31 w % of cyclopentyl
methyl ether inclusive).
[0587] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.99 (s, 9H), 1.43-1.48
(m, 2H), 1.50-1.75 (m, 7H), 2.04-2.44 (m, 3H), 2.66-2.70 (m, 2H),
3.30 (dd, J=11.7, 3.4 Hz, 1H), 3.44 (dt, J=11.6, 2.9 Hz, 1H), 7.22
(d, J=8.1 Hz, 1H), 7.29 (dd, J=8.1, 2.1 Hz, 1H), 7.47 (d, J=2.1 Hz,
1H)
Step 8
Ethyl
3-(3-{1-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-4,4-difluoro-2-hydro-
xymethyl-cyclohexyl}ureido)propionate
##STR00154##
[0589]
{2-Amino-2-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5,5-difluoro-cyc-
lohexyl}methanol (300 mg, 31 w % of cyclopentyl methyl ether
inclusive) and tetrahydrofuran (3 mL) were mixed under argon gas,
and thereto was added ethyl 3-isocyanato-propionate (0.122 mL)
under ice cooling. The reaction solution was stirred at room
temperature for 24 hours. Then, thereto was added
N,N,N'-trimethylethylenediamine, and the mixture was stirred at
room temperature for 10 minutes. The organic layer was concentrated
under reduced pressure. Then, thereto was added ethyl acetate, and
the mixture was washed with 10 w/w % aqueous citric acid solution,
10 w/w % aqueous sodium chloride solution, and saturated aqueous
sodium chloride solution. The organic layer was dried over
magnesium sulfate. Magnesium sulfate was removed with a filter, and
then the filtrate was concentrated under reduced pressure. The
resulting residue was purified by silica gel column chromatography
(Biotage flash purification systems, eluent: ethyl
acetate/n-hexane, Rf=0.41 (ethyl acetate/n-hexane=1/2)) to give a
crude product of the title compound (496 mg, 21 w % of ethyl
acetate inclusive).
[0590] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.97 (s, 9H), 1.29 (t,
J=7.2 Hz, 3H), 1.41-1.46 (m, 2H), 1.81-1.89 (m, 2H), 1.96-2.11 (m,
5H), 2.54 (dd, J=6.7, 5.2 Hz, 2H), 2.61-2.67 (m, 2H), 3.20 (d,
J=9.3 Hz, 1H), 3.38-3.52 (m, 4H), 4.18 (q, J=7.2 Hz, 2H), 4.91 (t,
J=6.1 Hz, 1H), 6.44 (s, 1H), 7.12 (dd, J=8.1, 1.8 Hz, 1H), 7.17 (d,
J=7.8 Hz, 1H), 7.26 (d, J=1.8 Hz, 1H)
Step 9
Ethyl
3-{8a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-6,6-difluoro-2-oxo-1,5-
,6,7,8,8a-hexahydro-2H-quinazolin-3-yl}propionate
##STR00155##
[0592] Ethyl
3-(3-{1-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-4,4-difluoro-2-hydroxymet-
hyl-cyclohexyl}ureido)propionate (366 mg) and chloroform (3.7 mL)
were mixed, and thereto were added (diacetoxyiodo)benzene (266 mg)
and 2,2,6,6-tetramethylpiperidin-1-oxyl radical (11 mg) at room
temperature. The reaction solution was stirred at room temperature
for 24 hours, and then thereto were added 20 w/w % aqueous sodium
sulfite solution and saturated aqueous sodium hydrogen carbonate
solution at room temperature. The mixture was stirred at room
temperature for 30 minutes. The aqueous layer was extracted with
ethyl acetate (twice) and washed with saturated aqueous sodium
chloride solution. The organic layers were dried over magnesium
sulfate. Magnesium sulfate was removed with a filter, and then the
filtrate was concentrated under reduced pressure. The resulting
residue and toluene (7.3 mL) were mixed, and thereto was added
pentafluoroaniline trifluoromethanesulfonate (12.1 mg) at room
temperature. The reaction solution was stirred under heating at
120.degree. C. for 6 hours, and then the reaction solution was
concentrated under reduced pressure. To the resulting residue was
added saturated aqueous sodium hydrogen carbonate solution at room
temperature, and the aqueous layer was extracted with ethyl acetate
(twice). The organic layers were washed with saturated aqueous
sodium chloride solution and dried over magnesium sulfate.
Magnesium sulfate was removed with a filter, and then the filtrate
was concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (Biotage flash
purification systems, eluent: ethyl acetate/n-hexane, Rf=0.37
(ethyl acetate/n-hexane=2/3)) to give a crude product of the title
compound (330 mg, 18 w % of ethyl acetate inclusive).
[0593] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.98 (d, J=4.9 Hz, 9H),
1.28 (t, J=7.1 Hz, 3H), 1.42-1.47 (m, 2H), 1.61-1.77 (m, 1H), 2.13
(s, 1H), 2.21-2.38 (m, 2H), 2.53-2.73 (m, 6H), 3.58-3.65 (m, 1H),
3.83 (dt, J=14.1, 6.1 Hz, 1H), 4.19 (q, J=7.2 Hz, 2H), 4.78 (s,
1H), 6.22 (d, J=1.8 Hz, 1H), 7.16 (dd, J=8.0, 2.0 Hz, 1H), 7.24 (d,
J=8.1 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H)
Step 10
3-{8a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-6,6-difluoro-2-oxo-1,5,6,7,8-
,8a-hexahydro-2H-quinazolin-3-yl}propionic acid
##STR00156##
[0595] Ethyl
3-{8a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-6,6-difluoro-2-oxo-1,5,6,7,-
8,8a-hexahydro-2H-quinazolin-3-yl}propionate (25 mg) was mixed in
tetrahydrofuran (0.25 mL) and methanol (0.25 mL), and thereto was
added 2N aqueous solution of sodium hydroxide (0.518 mL) at room
temperature. The reaction solution was stirred at room temperature
for 16 hours, and then the reaction solution was concentrated under
reduced pressure. To the resulting residue were added water and 2N
hydrochloric acid (0.518 mL) under ice cooling, and the
precipitated solid was collected by filtration to give the title
compound (23.6 mg).
Example 68
Step 1
7a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-5-methoxy-octahydro-benzo[c]iso-
xazole
##STR00157##
[0597] 4-Bromo-2-chloro-1-(3,3-dimethyl-butyl)-benzene (1.3 g) was
mixed in toluene (11 mL) and tetrahydrofuran (4.4 mL) under argon
gas, and thereto was added dropwise 2.66M n-butyllithium/n-hexane
solution (1.45 mL) under cooling at -78.degree. C. The reaction
solution was stirred under cooling at -78.degree. C. for 1 hour
(Reaction solution A).
5-methoxy-3,3a,4,5,6,7-hexahydrobenzo[c]isoxazole (0.5 g) and
toluene (32 mL) were mixed, and thereto were added boron
trifluoride-diethyl ether complex (0.49 mL) and Reaction solution A
under cooling at -78.degree. C. The reaction solution was stirred
under cooling at -78.degree. C. for 2 hours, and then thereto was
added a saturated aqueous solution of ammonium chloride. The
mixture was stirred at room temperature, and then thereto were
added ethyl acetate and water. The mixture was separated. The
aqueous layer was extracted with chloroform. The organic layer was
concentrated under reduced pressure, and the crude product was
purified by silica gel column chromatography (ethyl
acetate/n-hexane=1/9->2/3) to give the title compound (0.68
g).
[0598] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.97 (s, 9H), 1.40-1.48
(m, 2H), 1.49-1.61 (m, 4H), 1.79-2.19 (m, 4H), 2.63-2.69 (m, 2H),
2.86-2.98 (m, 1H), 3.39 (s, 3H), 3.49-3.61 (m, 1H), 3.65-3.81 (m,
1H), 7.13-7.2C (m, 1H), 7.34-7.42 (m, 1H), 7.52-7.58 (m, 1H)
Step 2
{2-Amino-2-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5-methoxy-cyclohexyl}me-
thanol
##STR00158##
[0600]
7a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-5-methoxy-octahydro-benz-
o[c]isoxazole (0.66 g) was mixed in acetic acid (10 mL),
tetrahydrofuran (3.3 mL), and water (3.3 mL) under nitrogen gas,
and thereto was added zinc powder (1.24 g) in parts at room
temperature. The reaction solution was stirred under heating at
60.degree. C. for 1 hour 30 minutes. Then, thereto was added 28 w/w
% ammonia water (15 mL) under ice cooling, and the mixture was
stirred at room temperature. To the reaction solution were added
chloroform, methanol, and water, and the mixture was separated. The
organic layer was dried over magnesium sulfate. Magnesium sulfate
was removed with a filter, and then the filtrate was concentrated
under reduced pressure. The crude product was purified by silica
gel column chromatography (methanol/ethyl acetate=0/1->1/99) to
give the title compound (0.75 g).
[0601] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.96 (s, 9H), 1.11-1.28
(m, 1H), 1.40-1.48 (m, 2H), 1.48-1.65 (m, 3H), 1.67-1.78 (m, 1H),
1.89-2.05 (m, 5E), 2.29-2.43 (m, 1H), 2.62-2.69 (m, 2H), 3.18-3.25
(m, 1H), 3.36 (s, 3H), 3.43-3.48 (m, 1H), 3.64-3.69 (m, 1H),
7.15-7.19 (m, 1H), 7.31-7.35 (m, 1H), 7.47-1.50 (m, 1H)
Step 3
Ethyl
3-(3-{1-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-2-hydroxymethyl-4-me-
thoxy-cyclohexyl}ureido)propionate
##STR00159##
[0603]
{2-Amino-2-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5-methoxy-cycloh-
exyl}methanol (0.18 g) and tetrahydrofuran (3 mL) were mixed, and
thereto was added ethyl 3-isocyanato-propionate (74 .mu.L) under
ice cooling. The reaction solution was stirred at room temperature
for 40 minutes and then concentrated under reduced pressure. The
resulting residue was purified by silica gel column chromatography
(methanol/ethyl acetate=0/1->1/99) to give the title compound
(0.26 g).
[0604] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.97 (s, 9H), 1.22-1.33
(m, 3H), 1.40-1.49 (m, 2H), 1.64-1.72 (m, 2H), 1.72-1.86 (m, 2H),
1.86-2.00 (m, 2H), 2.05-2.21 (m, 2H), 2.49-2.57 (m, 2H), 2.59-2.68
(m, 2H), 2.68-2.81 (m, 1H), 3.29-3.40 (m, 3H), 3.40-3.53 (m, 3H),
3.62-3.66 (m, 1H), 4.09-4.22 (m, 2H), 4.80 (br s, 1H), 6.35 (br s,
1H), 7.12-7.21 (m, 2H), 7.29-7.34 (m, 1H)
Step 4
Ethyl
3-{8a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-6-methoxy-2-oxo-1,5,6,-
7,8,8a-hexahydro-21-quinazolin-3-yl}propionate
##STR00160##
[0606] Ethyl
3-(3-{1-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-2-hydroxymethyl-4-methoxy-
-cyclohexyl}ureido)propionate (0.257 g) and dichloromethane (3 mL)
were mixed under nitrogen gas, and thereto were added
(diacetoxyiodo)benzene (0.18 g) and
2,2,6,6-tetramethylpiperidin-1-oxyl radical (8 mg) under ice
cooling. The reaction solution was stirred at room temperature for
3 hours, and then thereto were added ethyl acetate, an aqueous
solution of sodium thiosulfate, and an aqueous solution of sodium
hydrogen carbonate at room temperature. The mixture was separated.
The organic layer was washed with water and then dried over sodium
sulfate. Sodium sulfate was removed with a filter, and then the
filtrate was concentrated under reduced pressure. The resulting
residue and toluene (4 mL) were mixed, and thereto was added
pentafluoroaniline trifluoromethanesulfonate (8 mg) at room
temperature. The reaction solution was stirred under heating at
120.degree. C. for 1 hour 30 minutes and then concentrated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (ethyl acetate/n-hexane=1/4->1/2->1/1)
to give a diastereomeric mixture of the title compound (0.19 g).
The diastereomeric mixture was purified with a Recycling
Preparative Liquid Chromatograph to give a single enantiomer of the
title compound (40 mg).
[0607] Purification conditions for the preparative chromatography
are shown as follows.
Preparative apparatus: Recycling preparative liquid chromatograph
LC-92XX NEXT SERIES, Japan Analytical Industry Co., Ltd. Column:
Daicel CHIRALPAK IA 2.0 cm.phi..times.25 cm Mobile phase:
n-hexane:2-propanol=85:15 Flow rate: 10.0 mL/min
Detection: UV (254 nm)
[0608] Measurement of the resulting compound with a chiral column
showed 7.8 minutes of the retention time for the resulting
enantiomer with >99% ee of optical purity. The retention time
for the opposite enantiomer was 5.2 minutes.
[0609] Analytical conditions for the chiral column are shown as
follows.
Measurement apparatus: HPLC system, Shimadzu Corporation,
High-Performance Liquid Chromatograph Prominence Column: Daicel
CHIRALPAK IA-3 0.46 cm.phi..times.15 cm Column temperature:
40.degree. C. Mobile phase: n-hexane:2-propanol=85:15 Flow rate:
1.0 mL/min
Detection: UV (254 nm)
[0610] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.96 (s, 9H), 1.15-1.23
(m, 1H), 1.23-1.29 (m, 3H), 1.37-1.45 (m, 2H), 1.74-1.84 (m, 1H),
1.87-1.98 (m, 1H), 1.98-2.06 (m, 1H), 2.47-2.56 (m, 2H), 2.57-2.70
(m, 4H), 3.17-3.27 (m, 1H), 3.29 (s, 3H), 3.53-3.63 (m, 1H),
3.75-3.85 (m, 1H), 4.13-4.21 (m, 2H), 4.65 (br s, 1H), 6.09-6.13
(m, 1H), 7.09-7.15 (m, 1H), 7.15-7.21 (m, 1H), 7.25-7.28 (m,
1H)
Step 5
3-{(S)-8a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-6-methoxy-2-oxo-1,5,6,7,-
8,8a-hexahydro-2H-quinazolin-3-yl}propionic acid
##STR00161##
[0612] Ethyl
3-{8a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-6-methoxy-2-oxo-1,5,6,7,8,8-
a-hexahydro-2H-quinazolin-3-yl}propionate (36 mg) and ethanol (1
mL) were mixed, and thereto was added 2N aqueous solution of sodium
hydroxide (0.11 mL) at room temperature. The reaction solution was
stirred at room temperature for 1 hour 30 minutes and then
concentrated under reduced pressure. To the resulting residue were
added at room temperature 1N hydrochloric acid (0.23 mL) and water,
and then the precipitated solid was collected by filtration to give
the title compound (27.4 mg).
Example 77
Step 1
Methyl
3-(3-{1-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-2-hydroxymethyl-4-m-
ethoxy-cyclohexyl}ureido)bicyclo[1.1.1]pentane-1-carboxylate
##STR00162##
[0614] 3-(Methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid
(96 mg) and toluene (2 mL) were mixed under argon gas, and thereto
were added diphenylphosphoryl azide (0.13 mL) and triethylamine
(0.087 mL) at room temperature. The reaction solution was stirred
under heating at 120.degree. C. for 1 hour. The reaction solution
was added dropwise to a mixed solution of
{2-amino-2-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5-methoxy-cyclohexyl}m-
ethanol (200 mg) in tetrahydrofuran (3 mL) under ice cooling. The
reaction solution was stirred at room temperature for 2 hours and
then concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (methanol/ethyl
acetate=0/1->1/99) to give the title compound (0.29 g).
[0615] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.97 (s, 9H), 1.40-1.47
(m, 2H), 1.61-1.72 (m, 1H), 1.75-1.84 (m, 1H), 1.88-1.99 (m, 2H),
2.05-2.17 (m, 2H), 2.36 (s, 6H), 2.60-2.67 (m, 2H), 2.76-2.88 (m,
1H), 3.31-3.37 (m, 1H), 3.38 (s, 3H), 3.45-3.53 (m, 1H), 3.61-3.67
(m, 1H), 3.69 (s, 4H), 4.80-4.87 (m, 1H), 6.41 (br s, 1H),
7.13-7.16 (br m, 2H), 7.29 (br s, 1H)
Step 2
Methyl
3-{8a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-6-methoxy-2-oxo-1,5,6-
,7,8,8a-hexahydro-2H-quinazolin-3-yl}bicyclo[1.1.1]pentane-1-carboxylate
##STR00163##
[0617] Methyl
3-(3-{1-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-2-hydroxymethyl-4-methoxy-
-cyclohexyl}ureido)bicyclo[1.1.1]pentane-1-carboxylate (0.287 g)
and dichloromethane (7 mL) were mixed, and thereto were added
(diacetoxyiodo)benzene (0.195 g) and
2,2,6,6-tetramethylpiperidin-1-oxyl radical (9 mg) under ice
cooling. The reaction solution was stirred at room temperature for
14 hours 30 minutes, and then thereto were added ethyl acetate, an
aqueous solution of sodium thiosulfate, and saturated aqueous
sodium hydrogen carbonate solution at room temperature. The mixture
was separated and dried over magnesium sulfate. Magnesium sulfate
was removed with a filter, and then the filtrate was concentrated
under reduced pressure. The resulting residue and toluene (3 mL)
were mixed, and then thereto was added pentafluoroaniline
trifluoromethanesulfonate (9 mg) at room temperature. The reaction
solution was stirred under heating at 120.degree. C. for 1 hour and
then concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (ethyl
acetate/n-hexane=1/4->1/2->1/1) to give a diastereomeric
mixture of the title compound (0.20 g). The diastereomeric mixture
was purified with a Recycling Preparative Liquid Chromatograph to
give a single enantiomer of the title compound (78 mg).
[0618] Purification conditions for the preparative chromatography
are shown as follows.
Preparative apparatus: Recycling preparative liquid chromatograph
LC-92XX NEXT SERIES, Japan Analytical Industry Co., Ltd. Column:
Daicel CHIRALPAK IA 2.0 cm.phi..times.25 cm Mobile phase:
n-hexane:2-propanol=85:15 Flow rate: 10.0 mL/min
Detection: UV (254 nm)
[0619] Measurement of the resulting compound with a chiral column
showed 6.5 minutes of the retention time for the resulting
enantiomer with >99% ee of optical purity. The retention time
for the opposite enantiomer was 4.0 minutes.
[0620] Analytical conditions for the chiral column are shown as
follows.
Measurement apparatus: HPLC system, Shimadzu Corporation,
High-Performance Liquid Chromatograph Prominence Column: Daicel
CHIRALPAK IA-3 0.46 cm.phi..times.15 cm Column temperature:
40.degree. C. Mobile phase: n-hexane:2-propanol=85:15 Flow rate:
1.0 mL/min
Detection: UV (254 nm)
[0621] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.98 (s, 9H), 1.16-1.28
(m, 1H), 1.39-1.47 (m, 2H), 1.80-1.89 (m, 1H), 1.89-2.00 (m, 1H),
2.00-2.08 (m, 1H), 2.45 (s, 6H), 2.51-2.59 (m, 2H), 2.62-2.69 (m,
2H), 3.20-3.29 (m, 1H), 3.31 (s, 3H), 3.70 (s, 3H), 4.67-4.70 (m,
1H), 6.01-6.04 (m, 1H), 7.10-7.16 (m, 1H), 7.16-7.23 (m, 1H),
7.24-7.29 (m, 1H)
Step 3
3-{(S)-8a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-6-methoxy-2-oxo-1,5,6,7,-
8,8a-hexahydro-2H-quinazolin-3-yl}bicyclo[1.1.1]pentane-1-carboxylic
acid
##STR00164##
[0623] Methyl
3-{(S)-8a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-6-methoxy-2-oxo-1,5,6,7-
,8,8a-hexahydro-2H-quinazolin-3-yl}bicyclo[1.1.1]pentane-1-carboxylate
(69 mg) and methanol (2 mL) were mixed, and thereto was added 2N
aqueous solution of sodium hydroxide (0.21 mL) at room temperature.
The reaction solution was stirred at room temperature for 2 hours
and then concentrated under reduced pressure. To the resulting
residue were added 2N hydrochloric acid (0.3 mL), chloroform, and
methanol at room temperature, and the mixture was separated. The
organic layer was dried over sodium sulfate. Sodium sulfate was
removed with a filter, and then the filtrate was concentrated under
reduced pressure to give the title compound (60 mg).
Example 87
Step 1
Methyl
3-(3-{1-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-4,4-difluoro-2-hydr-
oxymethyl-cyclohexyl}ureido)bicyclo[1.1.1]pentane-1-carboxylate
##STR00165##
[0625] 3-(Methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid
(319 mg) and toluene (4 mL) were mixed under argon gas, and thereto
were added diphenylphosphoryl azide (0.445 mL) and triethylamine
(0.288 mL) at room temperature. The reaction solution was stirred
under heating at 120.degree. C. for 1 hour 30 minutes. To the
reaction solution was added tetrahydrofuran (2 mL), and the mixture
was added dropwise to a mixed solution of
{2-amino-2-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5,5-difluoro-cyclohexy-
l}methanol (979 mg, 31 w % of cyclopentyl methyl ether inclusive)
in tetrahydrofuran (6.5 mL) over 10 minutes under ice cooling. The
reaction solution was stirred at room temperature for 1 hour 30
minutes and then concentrated under reduced pressure. The resulting
residue was purified by silica gel column chromatography (Biotage
flash purification systems, eluent: ethyl acetate/n-hexane, Rf=0.62
(ethyl acetate/n-hexane=1/2)) to give the title compound (493
mg).
[0626] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.97 (s, 9H), 1.42-1.46
(m, 2H), 1.88-1.93 (m, 1H), 2.06-2.51 (m, 121H), 2.62-2.67 (m, 2H),
3.21-3.25 (m, 1H), 3.42 (d, J=10.4 Hz, 1H), 3.50 (d, J=10.9 Hz,
1H), 3.69 (s, 3H), 4.84 (d, J=2.8 Hz, 1H), 6.45 (s, 1H), 7.11 (dd,
J=8.2, 2.0 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.25 (d, J=2.0 Hz,
1H)
Step 2
Methyl
3-{8a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-6,6-difluoro-2-oxo-1,-
5,6,7,8,8a-hexahydro-2H-quinazolin-3-yl}bicyclo[1.1.1]pentane-1-carboxylat-
e
##STR00166##
[0628] Methyl
3-(3-{1-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-4,4-difluoro-2-hydroxymet-
hyl-cyclohexyl)ureido}bicyclo[1.1.1]pentane-1-carboxylate (493 mg)
and chloroform (16 mL) were mixed, and thereto were added
(diacetoxyiodo)benzene (332 mg) and
2,2,6,6-tetramethylpiperidin-1-oxyl radical (15 mg) at room
temperature. The reaction solution was stirred at room temperature
for 16 hours, and then thereto were added an aqueous solution of
sodium thiosulfate and saturated aqueous sodium hydrogen carbonate
solution at room temperature. The aqueous layer was extracted with
chloroform (twice). The organic layers were dried over magnesium
sulfate. Magnesium sulfate was removed with a filter, and then the
filtrate was concentrated under reduced pressure. The resulting
residue and toluene (20 mL) were mixed, and thereto was added
pentafluoroaniline trifluoromethanesulfonate (16 mg) at room
temperature. The reaction solution was stirred under heating at
120.degree. C. for 2 hours and then concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (Biotage flash purification systems, eluent: ethyl
acetate/n-hexane, Rf=0.46 (ethyl acetate/n-hexane=1/2)) to give a
crude product of a racemate of the title compound (316 mg). The
racemate was purified with a Recycling Preparative Liquid
Chromatograph to give a single enantiomer of the title compound
(112 mg).
[0629] Purification conditions for the preparative chromatography
are shown as follows.
Preparative apparatus: Recycling preparative liquid chromatograph
LC-92XX NEXT SERIES, Japan Analytical Industry Co., Ltd. Column:
Daicel CHIRALPAK TA 2.0 cm.phi..times.25 cm Mobile phase:
n-hexane:2-propanol=85:15 Flow rate: 10.0 mL/min
Detection: UV (254 nm)
[0630] Measurement of the resulting compound with a chiral column
showed 5.2 minutes of the retention time for the resulting
enantiomer with >99% ee of optical purity. The retention time
for the opposite enantiomer was 3.1 minutes.
[0631] Analytical conditions for the chiral column are shown as
follows.
Measurement apparatus: HPLC system, Shimadzu Corporation,
High-Performance Liquid Chromatograph Prominence Column: Daicel
CHIRALPAK IA-3 0.46 cm.phi..times.15 cm Column temperature:
40.degree. C. Mobile phase: n-hexane:2-propanol=80:20 Flow rate:
1.0 mL/min
Detection: UV (254 nm)
[0632] .sup.1H-NMR (400 MHz, CDCl.sub.3) (s, 9H), 1.43-1.47 (m,
2H), 1.61-1.77 (m, 1H), 2.09-2.15 (m, 1H), 2.21-2.42 (m, 2H), 2.45
(s, 6H), 2.53-2.64 (m, 2H), 2.66-2.70 (m, 2H), 3.71 (s, 3H), 4.84
(s, 1H), 6.10 (d, J=1.8 Hz, 1H), 7.15 (dd, J=7.9, 1.9 Hz, 1H), 7.25
(d, J=8.1 Hz, 1H), 7.29 (d, J=2.1 Hz, 1H)
Step 3
3-{(S)-8a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-6,6-difluoro-2-oxo-1,5,6-
,7,8,8a-hexahydro-2H-quinazolin-3-yl}bicyclo[1.1.1]pentane-1-carboxylic
acid
##STR00167##
[0634] Methyl
3-{(S)-8a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-6,6-difluoro-2-oxo-1,5,-
6,7,8,8a-hexahydro-2H-quinazolin-3-yl}bicyclo[1.1.1]pentane-1-carboxylate
(94 mg) and methanol (2 mL) were mixed, and thereto was added 2N
aqueous solution of sodium hydroxide (0.28 mL) at room temperature.
The reaction solution was stirred at room temperature for 26 hours
and then concentrated under reduced pressure. To the resulting
residue were added 2N hydrochloric acid (0.28 mL) and water under
ice cooling, and the mixture was extracted with a mixed solution of
chloroform and methanol. The organic layer was dried over sodium
sulfate. Sodium sulfate was removed with a filter, and then the
filtrate was concentrated under reduced pressure to give the title
compound (73.0 mg).
Example 109
Step 1
4-(2,2-Diethoxy-ethoxy)-3,4-dimethyl-pent-1-ene
##STR00168##
[0636] 60 w % Sodium hydride (5.17 g) and tetrahydrofuran (66 mL)
were mixed under argon gas, and thereto was added slowly a mixed
solution of 2,3-dimethyl-pent-4-en-2-ol (5.0 g) in tetrahydrofuran
(11 mL) under ice cooling. The reaction solution was stirred under
ice cooling for 1 hour, and then thereto was added
bromoacetaldehyde diethyl acetal (20.4 mL) under ice cooling. The
reaction solution was stirred under heating at 80.degree. C. for 18
hours. To the reaction solution was added water (20 mL) under ice
cooling, and the mixture was stirred at room temperature for 1
hour. Then, the aqueous layer was extracted with ethyl acetate
(twice). The organic layers were washed with saturated aqueous
sodium chloride solution and dried over sodium sulfate. Sodium
sulfate was removed with a filter, and then the filtrate was
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (Diotage flash
purification systems, eluent: ethyl acetate/nhexane, Rf=0.24 (ethyl
acetate/n-hexane=1/19)). Evaporation of bromoacetaldehyde diethyl
acetal included in the resulting crude product under reduced
pressure gave a crude product of the title compound (2.80 g, 50 w %
of bromoacetaldehyde diethyl acetal inclusive).
[0637] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.00 (d, J=6.9 Hz, 3H),
1.09 (s, 3H), 1.11 (s, 3H), 1.22 (t, J=7.1 Hz, 6H), 2.33 (dt,
J=14.6, 6.9 Hz, 1H), 3.40 (dd, J=5.2, 2.7 Hz, 2H), 3.54-3.62 (m,
2H), 3.67-3.75 (m, 2H), 4.54 (t, J=5.3 Hz, 1H), 4.97-5.03 (m, 2H),
5.83 (ddd, J=17.7, 9.8, 7.3 Hz, 1H)
Step 2
(1,1,2-Trimethyl-but-3-enyloxy)acetaldehyde
##STR00169##
[0639] 4-(2,2-Diethoxy-ethoxy)-3,4-dimethyl-pent-1-ene (2.80 g, 50
w % of bromoacetaldehyde diethyl acetal inclusive) and
tetrahydrofuran (12.2 mL) were mixed, and thereto was added 2N
hydrochloric acid (6.1 mL) under ice cooling. The reaction solution
was stirred under heating at 60.degree. C. for 4 hours. To the
reaction solution was added potassium carbonate (0.84 g) under ice
cooling. The reaction solution was concentrated under reduced
pressure, and thereto was added saturated aqueous sodium chloride
solution (10 mL). The aqueous layer was extracted with diethyl
ether (twice). The organic layer was washed with saturated aqueous
sodium chloride solution and dried over magnesium sulfate.
Magnesium sulfate was removed with a filter, and then the filtrate
was concentrated under reduced pressure to give a crude product of
the title compound (2.03 q, 44 w % of tetrahydrofuran
inclusive).
[0640] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.04 (d, J=6.9 Hz, 3H),
1.14 (s, 3H), 1.15 (s, 3H), 2.36 (t, J=7.4 Hz, 1H), 3.96 (t, J=1.3
Hz, 2H), 2) 5.02-5.08 (m, 2H), 5.84 (ddd, J=17.9, 9.9, 7.4 Hz, 1H),
9.72 (t, J=1.3 Hz, 1E)
Step 3
(1,1,2-Trimethyl-but-3-enyloxy)acetaldehyde oxime
##STR00170##
[0642] (1,1,2-Trimethyl-but-3-enyloxy)acetaldehyde (2.03 g, 44 w %
of tetrahydrofuran inclusive) was mixed in ethanol (16.1 mL) and
water (8.1 mL) under argon gas, and thereto were added sodium
acetate (4.62 g) and hydroxylamine hydrochloride (2.24 g) at room
temperature. The reaction solution was stirred under heating at
60.degree. C. for 20 hours. The reaction solution was concentrated
under reduced pressure, and thereto was added saturated aqueous
sodium chloride solution (10 mL). The aqueous layer was extracted
with ethyl acetate (twice). The organic layers were washed with
saturated aqueous sodium chloride solution (twice) and dried over
sodium sulfate. Sodium sulfate was removed with a filter, and then
the filtrate was concentrated under reduced pressure. The resulting
residue was purified by silica gel column chromatography (Biotage
flash purification systems, eluent: ethyl acetate/n-hexane, Rf=0.38
(ethyl acetate/n-hexane=1/4)) to give a crude product of the title
compound (1.00 g, 32 w % of ethyl acetate inclusive).
[0643] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.00 (d, J=6.7 Hz, 1.38H),
1.01 (d, J=6.7 Hz, 1.62H), 1.12 (s, 3H), 1.15 (s, 1.62H), 1.16 (s,
1.38H), 2.33-2.40 (m, 1H), 2.95 (s, 1H), 4.03 (dd, J=5.5, 2.1 Hz,
0.92H), 4.29 (d, J=3.2 Hz, 1.08H), 5.00-5.06 (m, 2H), 5.77-5.86 (m,
1H), 6.87 (t, J=3.6 Hz, 0.54H), 7.47 (t, J=5.4 Hz, 0.46H)
Step 4
4,5,5-Trimethyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazole
##STR00171##
[0645] (1,1,2-Trimethyl-but-3-enyloxy)acetaldehyde oxime (1.00 g,
32 w % of ethyl acetate inclusive) and methanol (13.5 mL) were
mixed, and thereto was added slowly trifluoroacetic acid (0.101 mL)
under ice cooling. To the reaction solution was added
(diacetoxyiodo)benzene (1.70 g) over 1 hour under ice cooling. The
reaction solution was stirred under ice cooling for 20 minutes and
stirred at room temperature for 1 hour. To the reaction solution
were added saturated aqueous sodium hydrogen carbonate solution (7
mL) and sodium sulfite (248 mg), and then the mixture was stirred
at room temperature for 30 minutes. The reaction solution was
concentrated under reduced pressure, and the residue was extracted
with ethyl acetate (twice). The organic layers were washed with
saturated aqueous sodium chloride solution (twice) and dried over
sodium sulfate. Sodium sulfate was removed with a filter, and then
the filtrate was concentrated under reduced pressure. The resulting
residue was purified by silica gel column chromatography (Biotage
flash purification systems, eluent: ethyl acetate/n-hexane, Rf=0.24
(ethyl acetate/n-hexane=1/4)) to give the title compound (495
mg).
[0646] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.94 (d, J=6.9 Hz, 1.95H),
0.94 (d, J=7.2 Hz, 1.05H), 1.22 (s, 1.95H), 1.23 (s, 1.05H), 1.26
(s, 1.95H), 1.42 (s, 1.05H), 1.64-1.72 (m, 0.65H), 1.84 (dt,
J=13.7, 6.1 Hz, 0.35H), 3.16 (q, J=11.0 Hz, 0.65H), 3.77 (dd,
J=11.5, 7.9 Hz, 0.65H), 3.86-3.93 (m, 0.35H), 4.14 (t, J=8.5 Hz,
0.35H), 4.34 (ddd, J=15.3, 13.8, 1.1 Hz, 1H), 4.38 (dd, J=7.6, 4.0
Hz, 0.3511), 4.49 (d, J=9.6 Hz, 0.65H), 4.53 (d, J=9.3 Hz, 0.35H),
4.60 (dd, J=10.2, 7.8 Hz, 0.65H)
Step 5
7a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-4,5,5-trimethyl-hexahydro-pyran-
o[3,4-c]isoxazole
##STR00172##
[0648] 4-Bromo-2-chloro-1-(3,3-dimethyl-butyl)-benzene (0.553 g)
was mixed in tetrahydrofuran (2.2 mL) and toluene (5.53 mL) under
argon gas, and then thereto was added dropwise 1.54M
n-butyllithium/n-hexane solution (1.25 mL) under cooling at
-78.degree. C. The reaction solution was stirred under cooling at
-78.degree. C. for 1 hour (Reaction solution A).
4,5,5-Trimethyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazole (250
mg) and toluene (15 mL) were mixed, and thereto was added boron
trifluoride-diethyl ether complex (0.241 mL) under cooling at
-78.degree. C. The mixture was stirred for 10 minutes. Then,
thereto was added dropwise slowly Reaction solution A over 25
minutes under cooling at -78.degree. C. The reaction solution was
stirred for 3 hours, and then thereto was added a saturated aqueous
solution of ammonium chloride (8 mL) under cooling at -78.degree.
C. The mixture was stirred at room temperature for 30 minutes. The
aqueous layer was extracted with ethyl acetate (twice). The organic
layers were washed with saturated aqueous sodium chloride solution
(twice) and dried over sodium sulfate. Sodium sulfate was removed
with a filter, and then the filtrate was concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (Biotage flash purification systems, eluent: ethyl
acetate/n-hexane, Rf=0.48 (ethyl acetate/n-hexane=1/4)) to give a
crude product of the title compound (511 mg, 23 w % of ethyl
acetate inclusive).
[0649] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.96 (d, J=6.7 Hz, 1.95H),
0.98 (s, 9H), 1.05 (d, J=7.4 Hz, 1.05H), 1.28 (s, 1.05H), 1.29 (s,
1.95H), 1.30 (s, 1.05H), 1.32 (s, 1.95H), 1.41-1.47 (m, 2H), 1.63
(dt, J=18.0, 6.9 Hz, 0.65H), 2.19 (t, J=7.1 Hz, 0.35H), 2.43 (dd,
J=11.0, 5.0 Hz, 0.65H), 2.64-2.68 (m, 2H), 2.91 (td, J=9.2, 5.6 Hz,
0.35H), 3.55 (dd, J=7.4, 5.1 Hz, 0.65H), 3.64 (d, J=13.2 Hz,
0.65H), 3.74 (d, J=13.2 Hz, 0.35H), 3.82 (d, J=7.6 Hz, 0.35H), 3.85
(d, J=13.2 Hz, 1H), 3.89-4.20 (m, 1H), 5.73 (s, 0.35H), 6.24 (s,
0.65H), 7.18 (d, J=8.3 Hz, 0.35H), 7.19 (d, J=8.1 Hz, 0.65H), 7.36
(dd, J=8.2, 2.0 Hz, 0.35H), 7.42 (dd, J=8.0, 2.2 Hz, 0.65H), 7.52
(d, J=1.8 Hz, 0.35H), 7.57 (d, J=1.8 Hz, 0.65H)
Step 6
{5-Amino-5-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-2,2,3-trimethyl-tetrahy-
dro-pyran-4-yl}methanol
##STR00173##
[0651]
7a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-4,5,5-trimethyl-hexahydr-
o-pyrano[3,4-c] isoxazole (392 mg) was mixed in acetic acid (5.9
mL), tetrahydrofuran (2 mL), and water (2 mL), and thereto was
added zinc powder (70C mg) in 5 parts over 25 minutes under heating
at 60.degree. C. The reaction solution was stirred under heating at
60.degree. C. for 3 hours. To the reaction solution was added 28
w/w % ammonia water (10 mL) under ice cooling, and the aqueous
layer was extracted with cyclopentyl methyl ether (three times).
The organic layers were washed with saturated aqueous sodium
chloride solution and dried over sodium sulfate. Sodium sulfate was
removed with a filter, and then the filtrate was concentrated under
reduced pressure to give a crude product of the title compound (467
mg, 21 w % of cyclopentyl methyl ether inclusive).
[0652] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.97 (d, J=6.7 Hz, 1.95H),
0.99 (s, 9H), 1.14 (d, J=8.6 Hz, 1.05H), 1.20 (s, 1.05H), 1.28 (s,
1.95H), 1.32 (s, 1.05H), 1.38 (s, 1.95H), 1.44-1.49 (m, 2H),
1.50-1.76 (m, 4H), 2.13-2.21 (m, 0.65H), 2.26-2.30 (m, 0.35H),
2.66-2.71 (m, 2H), 3.08 (d, J=12.5 Hz, 0.65H), 3.41 (dd, J=12.5,
1.4 Hz, 0.35H), 3.42 (dd, J=12.0, 1.4 Hz, 0.65H), 3.53 (dd, J=11.9,
3.1 Hz, 0.65H), 3.72 (d, J=5.1 Hz, 0.70H), 4.04 (d, J=12.0 Hz,
0.35H), 4.10 (d, J=12.0 Hz, 0.65H), 7.21 (d, J=7.9 Hz, 0.35H), 7.23
(d, J=7.6 Hz, 0.65H), 7.27 (dd, J=8.0, 2.2 Hz, 0.65H), 7.40 (d,
J=2.1 Hz, 0.65H), 7.42 (dd, J=7.7, 2.0 Hz, 0.35H), 7.57 (d, J=1.8
Hz, 0.35H)
Step 7
Methyl
3-(3-{3-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-4-hydroxymethyl-5,6-
,6-trimethyl-tetrahydro-pyran-3-yl}ureido)bicyclo[1.1.1]pentane-1-carboxyl-
ate
##STR00174##
[0654] 3-(Methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid
(197 mg) and toluene (4 mL) were mixed under argon gas, and thereto
were added diphenylphosphoryl azide (0.270 mL) and triethylamine
(0.174 mL) at room temperature. The reaction solution was stirred
under heating at 120.degree. C. for 1 hour. To the reaction
solution was added tetrahydrofuran (4 mL), and the mixture was
added dropwise to a mixed solution of
{5-amino-5-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-2,2,3-trimethyl-tetrah-
ydro-pyran-4-yl}methanol (467 mg, 21 w % of cyclopentyl methyl
ether inclusive) in tetrahydrofuran (4 mL) over 10 minutes under
ice cooling. The reaction solution was stirred at room temperature
for 13 hours, and then thereto was added
N,N,N'-trimethylethylenediamine (0.0195 mL). The reaction solution
was concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (Biotage flash
purification systems, eluent: acetone/n-hexane, Rf=0.50
(acetone/n-hexane=2/3)) to give a crude product of the title
compound (511 mg, 5 w % of ethyl acetate inclusive).
[0655] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.90-0.99 (m, 3H), 0.97
(s, 9H), 1.10 (s, 1.05H), 1.21 (s, 1.95H), 1.32 (s, 1.95H),
1.42-1.49 (m, 2H), 1.43 (s, 1.05H), 1.50-1.73 (m, 1H), 1.98-2.41
(m, 2H), 2.29 (s, 2.1H), 2.38 (s, 3.9H), 2.61-2.67 (m, 2H),
3.58-3.76 (m, 2H), 3.67 (s, 1.05H), 3.69 (s, 1.95H), 3.79-3.87 (m,
1.30H), 4.01-4.09 (m, 0.70H), 4.68 (s, 0.35H), 4.97 (s, 0.65H),
5.94 (s, 0.65H), 6.21 (s, 0.35H), 7.12-7.17 (m, 1.65H), 7.25-7.27
(m, 0.65H), 7.45 (d, J=8.1 Hz, 0.35H), 7.51 (d, J=1.8 Hz,
0.35H)
Step 8
Methyl
3-{8a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5,6,6-trimethyl-2-oxo-
-1,2,5,6,8,8a-hexahydro-pyrano[3,4-d]pyrimidin-3-yl}bicyclo[1.1.1]pentane--
1-carboxylate
##STR00175##
[0657] Methyl
3-(3-(3-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-4-hydroxymethyl-5,6,6-tri-
methyl-tetrahydro-pyran-3-yl)ureido)bicyclo[1.1.1]pentane-1-carboxylate
(511 mg, 5 w % of ethyl acetate inclusive) and chloroform (4.8 mL)
were mixed, and thereto were added (diacetoxyiodo)benzene (330 mg)
and 2,2,6,6-tetramethylpiperidin-1-oxyl radical (14.1 mg) at room
temperature. The reaction solution was stirred at room temperature
for 19 hours, and then thereto were added 20 w/w % aqueous sodium
sulfite solution and saturated aqueous sodium hydrogen carbonate
solution at room temperature. The mixture was stirred at room
temperature for 30 minutes. The aqueous layer was extracted with
ethyl acetate (twice). The organic layers were washed with
saturated aqueous sodium chloride solution and dried over magnesium
sulfate. Magnesium sulfate was removed with a filter, and then the
filtrate was concentrated under reduced pressure. The resulting
residue and toluene (9.7 mL) were mixed, and thereto was added
pentafluoroaniline trifluoromethanesulfonate (15 mg) at room
temperature. The reaction solution was stirred under heating at
120.degree. C. for 1 hour 30 minutes and then concentrated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (Biotage flash purification systems, eluent:
ethyl acetate/n-hexane, Rf=0.40 (ethyl acetate/n-hexane=2/3)) to
give a diastereomeric mixture of the title compound (434 mg). The
diastereomeric mixture was purified with a Recycling Preparative
Liquid Chromatograph to give a single enantiomer of the title
compound (39.8 mg).
[0658] Purification conditions for the preparative chromatography
are shown as follows.
Preparative apparatus: Recycling preparative liquid chromatograph
LC-92XX NEXT SERIES, Japan Analytical Industry Co., Ltd. Column:
Daicel CHIRALPAK IA 2.0 cm.phi..times.25 cm Mobile phase:
n-hexane:2-propanol=85:15 Flow rate: 10.0 mL/min
Detection: UV (254 nm)
[0659] Measurement of the resulting compound with a chiral column
showed 7.6 minutes of the retention time for the resulting
enantiomer with >99% ee of optical purity. The retention time
for a diastereomer on the methyl group was 9.8 minutes, and the
retention time for a diastereomer on the phenyl group as well as
the opposite enantiomer was 3.9 minutes.
[0660] Analytical conditions for the chiral column are shown as
follows.
Measurement apparatus: HPLC system, Shimadzu Corporation,
High-Performance Liquid Chromatograph Prominence Column: Daicel
CHIRALPAK IA-3 0.46 cm.phi..times.15 cm Column temperature:
30.degree. C. Mobile phase: n-hexane:2-propanol=85:15 Flow rate:
1.0 mL/min
Detection: UV (254 nm)
[0661] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.88 (d, J=6.9 Hz, 3H),
0.98 (s, 9H), 1.14 (s, 3H), 1.21 (s, 3H), 1.42-1.47 (m, 2H), 2.09
(ddd, J=13.8, 7.1, 2.4 Hz, 1H), 2.49 (s, 6H), 2.64-2.69 (m, 2H),
3.71 (s, 3H), 3.90 (d, J=11.6 Hz, 1H), 4.08 (d, J=11.6 Hz, 1H),
4.45 (s, 1H), 5.74 (d, J=1.8 Hz, 1H), 7.19 (d, J=8.1 Hz, 1H), 7.33
(dd, J=8.0, 2.0 Hz, 1H), 7.50 (d, J=2.1 Hz, 1H)
Step 9
3-((S)-8a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-5,6,6-trimethyl-2-oxo-1,-
2,5,6,8,8a-hexahydro-pyrano[3,4-d]pyrimidin-3-yl)bicyclo[1.1.1]pentane-1-c-
arboxylic acid
##STR00176##
[0663] Methyl
3-{(S)-8a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5,6,6-trimethyl-2-oxo-1-
,2,5,6,8,8a-hexahydro-pyrano[3,4-d]pyrimidin-3-yl}bicyclo[1.1.1]pentane-1--
carboxylate (39.8 mg) was mixed in tetrahydrofuran (0.398 mL) and
methanol (0.398 mL) under nitrogen gas, and thereto was added 2N
aqueous solution of sodium hydroxide (0.0791 mL) at room
temperature. The reaction solution was stirred at room temperature
for 16 hours and then concentrated under reduced pressure. To the
resulting residue was added water (1 mL), and then thereto was
added 2N hydrochloric acid (0.0791 mL) under ice cooling. The
precipitated solid was collected by filtration to give the title
compound (19.7 mg).
Example 114
Step 1
Methyl
3-(3-{(3R,4S)-1-[4-(3-tert-butyl-2,2-difluoro-cyclopropyl)-3-chloro-
-phenyl]-2-hydroxymethyl-3,4-dimethyl-cyclohexyl}ureido)bicyclo[1.1.1]pent-
ane-1-carboxylate
##STR00177##
[0665] 3-(Methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid
(97.9 mg) was mixed in toluene (2 mL) and tetrahydrofuran (2 mL)
under argon gas, and thereto were added triethylamine (0.866 mL)
and diphenylphosphoryl azide (0.134 mL) at room temperature. The
reaction solution was stirred under heating at 120.degree. C. for 1
hour. The reaction solution was added dropwise to a mixed solution
of
{(5S,6R)-2-amino-2-[4-(3-tert-butyl-2,2-difluoro-cyclopropyl)-3-chloro-ph-
enyl]-5,6-dimethyl-cyclohexyl}methanol (200 mg) in tetrahydrofuran
(4 mL) under ice cooling. The reaction solution was stirred at room
temperature for 13 hours, and then thereto was added
trimethylethylenediamine (0.129 mL). The reaction solution was
concentrated under reduced pressure, and then the resulting residue
was purified by silica gel column chromatography (Biotage flash
purification systems, eluent: acetone/n-hexane) to give the title
compound (328 mg).
[0666] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.02-1.05 (m, 6H),
1.11-1.11 (m, 9H), 1.30-1.34 (m, 1H), 1.37-1.42 (m, 1H), 1.46-1.48
(m, 1H), 1.61-1.73 (m, 2H), 1.78-1.85 (m, 1H), 2.39-2.35 (m, 7H),
2.73-2.80 (m, 1H), 3.04 (d, J=13.64 Hz, 1H), 3.32 (d, J=11.79 Hz,
1H), 3.69 (s, 3H), 3.74 (d, J=11.33 Hz, 1H), 4.73 (s, 1H), 6.37 (s,
1H), 7.13-7.15 (m, 2H), 7.32 (d, J=14.57 Hz, 1H)
Step 2
Methyl
3-{(5R,6S)-8a-[4-(3-tert-butyl-2,2-difluoro-cyclopropyl)-3-chloro-p-
henyl]-5,6-dimethyl-2-oxo-1,5,6,7,8,8a-hexahydro-2H-quinazolin-3-yl}bicycl-
o[1.1.1]pentane-1-carboxylate
##STR00178##
[0668] Methyl
3-(3-{(3R,4S)-1-[4-(3-tert-butyl-2,2-difluoro-cyclopropyl)-3-chloro-pheny-
l]-2-hydroxymethyl-3,4-dimethyl-cyclohexyl)ureido}bicyclo[1.1.1]pentane-1--
carboxylate (21' mg) and chloroform (2.2 mL) were mixed, and
thereto were added (diacetoxyiodo)benzene (139 mg) and
2,2,6,6-tetramethylpiperidin-1-oxyl radical (6.0 mg) at room
temperature. The reaction solution was stirred at room temperature
for 14 hours, and then thereto were added 20 w/w % aqueous sodium
sulfite solution and 5 w/w % aqueous solution of sodium hydrogen
carbonate at room temperature. The mixture was stirred at room
temperature for 30 minutes and then extracted with ethyl acetate
(twice). The organic layer was washed with saturated aqueous sodium
chloride solution and dried over magnesium sulfate. Magnesium
sulfate was removed with a filter, and then the filtrate was
concentrated under reduced pressure. The resulting residue and
toluene (4.3 mL) were mixed, and then thereto was added
pentafluoroaniline trifluoromethanesulfonate (6.3 mg) at room
temperature. The reaction solution was stirred under heating at
120.degree. C. for 3 hours 30 minutes, and then stirred under
microwave radiation (100W, 120.degree. C.) for 30 minutes. The
reaction solution was concentrated under reduced pressure, and then
the resulting residue was purified by silica gel column
chromatography (Biotage flash purification systems, eluent: ethyl
acetate/n-hexane) to give a diastereomeric mixture of the title
compound (61.2 mg). The diastereomeric mixture was purified with a
Recycling Preparative Liquid Chromatograph to give a single
enantiomer of the title compound (18.0 mg).
[0669] Purification conditions for the preparative chromatography
are shown as follows.
Preparative apparatus: Recycling preparative liquid chromatograph
LC-92XX NEXT SERIES, Japan Analytical Industry Co., Ltd. Column:
Daicel CHIRALPAK IA 2.0 cm.phi..times.25 cm Mobile phase:
n-hexane:2-propanol=88:12 Flow rate: 10.0 mL/min
Detection: UV (254 nm)
[0670] Measurement of the resulting compound with a chiral column
showed 8.0 minutes of the retention time for the resulting
enantiomer with >99% ee of optical purity. The retention time
for the opposite enantiomer on the phenyl group was 4.8
minutes.
[0671] Analytical conditions for the chiral column are shown as
follows.
Measurement apparatus: HPLC system, Shimadzu Corporation,
High-Performance Liquid Chromatograph Prominence Column: Daicel
CHIRALPAK IA-3 0.46 cm.phi..times.15 cm Column temperature:
30.degree. C. Mobile phase: n-hexane:2-propanol=85:15 Flow rate:
1.0 mL/min
Detection: UV (254 nm)
[0672] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.65 (d, J=7.40 Hz, 3H),
1.03 (d, J=6.94 Hz, 3H), 1.12 (s, 9H), 1.36-1.42 (m, 1H), 1.62-1.74
(m, 2H), 1.77-1.86 (m, 1H), 2.05-2.09 (m, 1H), 2.11-2.16 (m, 1H),
2.31-2.25 (m, 1H), 2.48 (s, 6H), 2.79 (dd, J=14.33, 9.48 Hz, 1H),
3.71 (s, 3H), 4.44 (s, 1H), 6.01 (s, 1H), 7.17 (d, J=8.09 Hz, 1H),
7.24 (dd, J=8.32, 2.08 Hz, 1H), 7.39 (d, J=2.08 Hz, 1H)
Step 3
3-{(5R,6S)-8a-[4-(3-tert-Butyl-2,2-difluoro-cyclopropyl)-3-chloro-phenyl]--
5,6-dimethyl-2-oxo-1,5,6,7,8,8a-hexahydro-2H-quinazolin-3-yl}bicyclo[1.1.1-
]pentane-1-carboxylic acid
##STR00179##
[0674] Methyl
3-{(5R,6S)-8a-[4-(3-tert-butyl-2,2-difluoro-cyclopropyl)-3-chloro-phenyl]-
-5,6-dimethyl-2-oxo-1,5,6,7,8,8a-hexahydro-2H-quinazolin-3-yl}bicyclo[1.1.-
1]pentane-1-carboxylate (18.0 mg) was mixed in tetrahydrofuran
(0.18 mL) and methanol (0.18 mL), and then thereto was added 2N
aqueous solution of sodium hydroxide (0.0329 mL) at room
temperature. The reaction solution was stirred a: room temperature
for 7 hours 30 minutes and then concentrated under reduced
pressure. To the resulting residue was added water (1 mL), and then
thereto was added 2N hydrochloric acid (0.0329 mL) under ice
cooling. The precipitated solid was collected by filtration to give
the title compound (14.7 mg).
Example 115
Step 1
(2R,3S)-2,3-Dimethyl-pent-4-enoic acid methoxy-methyl-amide
##STR00180##
[0676] (2R,3S)-2,3-Dimethyl-pent-4-enoic acid (3.5 g),
N,O-dimethylhydroxylamine hydrochloride (4.0 g) and
1-hydroxybenzotriazole monohydrate (6.3 g) were mixed in
dimethylformamide (20 mL) under nitrogen gas, and thereto were
added triethylamine (7.6 mL) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.9 g)
under ice cooling. The reaction solution was stirred at room
temperature overnight. Then, thereto was added water (175 mL), and
the aqueous layer was extracted with ethyl acetate/n-hexane=1/1.
The organic layer was washed with saturated aqueous sodium hydrogen
carbonate solution, 1N hydrochloric acid, and saturated aqueous
sodium chloride solution and dried over magnesium sulfate.
Magnesium sulfate was removed with a filter, and then the filtrate
was concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (Biotage flash
purification systems, eluent: ethyl acetate/n-hexane, Rf=0.25
(ethyl acetate/n-hexane=1/4)) to give the title compound (4.4
g).
[0677] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.99-1.03 (m, 3H),
1.06-1.11 (m, 3H), 2.40-2.49 (m, 1H), 2.74-2.87 (m, 1H), 3.15 (s,
3H), 3.66 (s, 3H), 4.89-5.03 (m, 2H), 5.69-5.83 (m, 1H)
Step 2
(2R,3S)-2,3-Dimethyl-pent-4-enal
##STR00181##
[0679] (2R,3S)-2,3-Dimethyl-pent-4-enoic acid methoxy-methyl-amide
(4.4 g) and tetrahydrofuran (44 mL) were mixed under nitrogen gas,
and thereto was added dropwise 1.02M diisobutylaluminum
hydride/n-hexane solution (30 mL) under cooling at -78.degree. C.
The mixture was stirred under cooling at -78.degree. C. for 2.5
hours, and then thereto was added dropwise 1.5M aqueous sulfuric
acid solution (41 mL). The mixture was stirred for 2 hours under
ice cooling, and then the aqueous layer was extracted with methyl
tort-butyl ether. The organic layer was washed with 1.0 M sulfuric
acid and saturated aqueous sodium chloride solution and dried over
magnesium sulfate. Magnesium sulfate was removed with a filter, and
then the filtrate was concentrated under reduced pressure to give a
crude product of the title compound (3.7 g, 39 w % of
tetrahydrofuran inclusive).
[0680] 1H-NMR (400 MHz, CDCl.sub.3) 0.99-1.05 (m, 6H), 2.30-2.41
(m, 1H), 2.55-2.66 (m, 1H), 4.97-5.09 (m, 2H), 5.72-5.85 (m, 1H),
9.63-9.68 (m, 1H)
Step 3
Ethyl (E)-(4S,5S)-4,5-dimethyl-hepta-2,6-dienoate
##STR00182##
[0682] Sodium hydride (960 mg) and tetrahydrofuran (34 mL) were
mixed under nitrogen gas, and thereto was added dropwise ethyl
diphenylphosphonoacetate (5.2 mL) under ice cooling. The mixture
was stirred at room temperature for 30 minutes, and then thereto
was added dropwise a mixed solution of
(2R,3S)-2,3-dimethyl-pent-4-enal (2.24 g) in tetrahydrofuran (22
mL) under ice cooling. The reaction solution was stirred at room
temperature overnight. Then, thereto were added saturated aqueous
ammonium chloride solution and water at room temperature, and the
organic solvent was evaporated under reduced pressure. The aqueous
layer was extracted with ethyl acetate, and the organic layer was
washed with saturated aqueous sodium chloride solution and dried
over magnesium sulfate. Magnesium sulfate was removed with a
filter, and then the filtrate was concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (Biotage flash purification systems, eluent: ethyl
acetate/n-hexane) to give the title compound (3.2 g).
Step 4
Ethyl (4S,5S)-4,5-dimethyl-hept-6-enoate
##STR00183##
[0684] (E)-(4S,5S)-4,5-Dimethyl-hepta-2,6-dienoic acidethyl ester
(3.2 q) was mixed in tetrahydrofuran (45 mL) and methanol (26 mL)
under nitrogen gas, and thereto was added copper (I) chloride.
Then, thereto was added sodium borohydride (4.7 g) under ice
cooling. The reaction solution was stirred for 5 hours under ice
cooling. To the reaction solution was added 1N hydrochloric acid
(33 mL). Insoluble substances were removed with a filter, and the
filtrate was concentrated under reduced pressure. To the resulting
residue was added ethyl acetate, and the mixture was separated. The
organic layer was washed with 1N hydrochloric acid and saturated
aqueous sodium chloride solution. The resultant was dried over
magnesium sulfate, and then magnesium sulfate was removed with a
filter. The filtrate was concentrated under reduced pressure. The
resulting residue was purified by silica gel column chromatography
(eluent: ethyl acetate/n-hexane=1/1), and then azeotroped with
n-hexane to give the title compound (2.8 g, 6 w % of ethyl
(E)-(4S,5S)-4,5-dimethyl-hepta-2,6-dienoate inclusive).
[0685] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.79-0.84 (m, 3H),
0.92-0.96 (m, 3H), 1.21-1.28 (m, 3H), 1.34-1.47 (m, 2H), 1.70-1.80
(m, 1H), 2.02-2.12 (m, 1H), 2.15-2.39 (m, 2H), 4.05-4.15 (m, 2H),
4.90-4.98 (m, 2H), 5.64-5.79 (m, 1H)
Step 5
(4S,5S)-4,5-Dimethyl-hept-6-enal
##STR00184##
[0687] Ethyl (4S,5S)-4,5-dimethyl-hept-6-enoate (2.8 g) and
dichloromethane (150 mL) were mixed under nitrogen gas, and thereto
was added dropwise 1.02M diisobutylaluminum hydride/n-hexane
solution (19 mL) under cooling at -78.degree. C. The mixture was
stirred under cooling at -78.degree. C. for 30 minutes, and then
thereto was added dropwise methanol (7.6 mL). Then, thereto was
added a saturated aqueous solution of Rochelle salt (76 mL) under
ice cooling. Then, the mixture was stirred at room temperature for
2 hours, and thereto was added diethyl ether. The mixture was
separated, and the organic layer was washed with saturated aqueous
sodium chloride solution. The solution was dried over magnesium
sulfate, and then magnesium sulfate was removed with a filter. The
filtrate was concentrated under reduced pressure to give a crude
product of the title compound (2.6 g).
[0688] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.81-0.85 (m, 3H),
0.93-0.97 (m, 3H), 1.34-1.45 (m, 2H), 1.70-1.80 (m, 1H), 2.04-2.11
(m, 1H), 2.30-2.50 (m, 2H), 4.90-4.97 (m, 2H), 5.66-5.77 (m, 1H),
9.74-9.76 (m, 1H)
Step 6
(4S,5S)-4,5-Dimethyl-hept-6-enal-oxime
##STR00185##
[0690] (4S,5S)-4,5-Dimethyl-hept-6-enal (2.1 g) was mixed in water
(15 mL) and ethanol (30 mL) under nitrogen gas, and thereto were
added sodium acetate (8.7 g) and hydroxylamine hydrochloride (4.2
g) at room temperature. The reaction solution was stirred under
heating at 60.degree. C. overnight. The reaction solution was
concentrated under reduced pressure, and thereto were added ethyl
acetate and water. The solution was separated. The aqueous layer
was extracted with ethyl acetate (twice). The organic layer was
washed with saturated aqueous sodium chloride solution and
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (eluent: ethyl
acetate/n-hexane, Rf=0.1 (ethyl acetate/n-hexane=1/10)) to give the
title compound (2.0 g).
[0691] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.83-0.90 (m, 3H),
0.92-0.97 (m, 3H), 1.21-1.67 (m, 3H), 2.04-2.44 (m, 3H), 4.93-5.01
(m, 2H), 5.66-5.80 (m, 1H), 6.67-6.72 (m, 0.5H), 7.38-7.46 (m,
0.5H)
Step 7
(4R,5S)-4,5-Dimethyl-3,3a,4,5,6,7-hexahydro-benzo[c]isoxazole
##STR00186##
[0693] (4S,5S)-4,5-Dimethyl-hept-6-enal-oxime (2.0 g) and methanol
(40 mL) were mixed under nitrogen gas, and thereto were added
trifluoroacetic acid (0.3 mL) and (diacetoxyiodo)benzene (5.5 g)
under sodium chloride-ice cooling. The reaction solution was
stirred under ice cooling for 20 minutes and stirred at room
temperature for 1 hour. Then, thereto were added saturated aqueous
sodium hydrogen carbonate solution (20 ml) and sodium sulfite (0.8
g) under ice cooling, and the mixture was stirred at room
temperature for 30 minutes. The reaction solution was concentrated
under reduced pressure, and the aqueous layer was extracted with
ethyl acetate (twice). The organic layer was washed with saturated
aqueous sodium chloride solution (twice) and dried over sodium
sulfate. Then, sodium sulfate was removed with a filter, and the
filtrate was concentrated under reduced pressure. The resulting
residue was purified by silica gel column chromatography (Biotage
flash purification systems, eluent: ethyl acetate/n-hexane, Rf=0.1
(ethyl acetate/n-hexane=1/20)) to give the title compound (1.4
g).
[0694] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.93-0.98 (m, 6H),
1.08-1.34 (m, 2H), 1.77-1.99 (m, 2H), 2.09-2.21 (m, 1H), 2.69-2.78
(m, 2H), 2.78-2.89 (m, 1H), 3.76-3.85 (m, 1H), 4.45-4.52 (m,
1H)
Step 8
(4R,5S)-7a-[4-(3-tert-Butyl-2,2-difluoro-cyclopropyl)-3-chloro-phenyl]-4,5-
-dimethyl-octahydro-benzo[c]isoxazole
##STR00187##
[0696]
4-Bromo-1-(3-tert-butyl-2,2-difluoro-cyclopropyl)-2-chloro-benzene
(648 mg) and tetrahydrofuran (2.6 mL) were mixed under argon gas,
and thereto was added dropwise 1.5M n-butyllithium/n-hexane
solution (13 mL) under cooling at -78.degree. C. The reaction
solution was stirred under cooling at -78.degree. C. for 1 hour
(Reaction solution A). To a mixed solution of
(4R,5S)-4,5-dimethyl-3,3a,4,5,6,7-hexahydro-benzo[c]isoxazole (245
mg) in toluene (6.5 mL) were added boron trifluoride-diethyl ether
complex and Reaction solution A under cooling at -78.degree. C. The
reaction solution was stirred for 2 hours, and then thereto was
added saturated aqueous ammonium chloride solution (8 mL) under
cooling at -78.degree. C. The mixture was stirred at room
temperature, and then thereto was added ethyl acetate. The mixture
was separated. The organic layer was washed with saturated aqueous
sodium chloride solution and dried over sodium sulfate. Sodium
sulfate was removed with a filter, and then the filtrate was
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (Biotage flash
purification systems, eluent: ethyl acetate/n-hexane, Rf=0.30
(ethyl acetate/n-hexane=1/10)) to give the title compound (357 mg,
13 w % of ethyl acetate inclusive).
[0697] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.97-1.01 (m, 6H),
1.05-1.20 (m, 11H), 1.27-1.37 (m, 1H), 1.59-1.78 (m, 2H), 1.83-1.99
(m, 2H), 2.16-2.28 (m, 1H), 2.71-2.83 (m, 1H), 3.43-3.51 (m, 1H),
3.76-3.82 (m, 1H), 5.83 (br s, 1H), 7.11-7.17 (m, 1H), 7.42-7.49
(m, 1H), 7.58-7.67 (m, 1H)
Step 9
{(5S,6R)-2-Amino-2-[4-(3-tert-butyl-2,2-difluoro-cyclopropyl)-3-chloro-phe-
nyl]-5,6-dimethyl-cyclohexyl}methanol
##STR00188##
[0699]
(4R,5S)-7a-[4-(3-tert-Butyl-2,2-difluoro-cyclopropyl)-3-chloro-phen-
yl]-4,5-dimethyl-octahydro-benzo[c] isoxazole (311 mg) was mixed in
acetic acid (4.7 mL), tetrahydrofuran (1.6 mL), and water (1.6 mL)
under nitrogen gas, and thereto was added zinc powder (510 mg) in
several parts under heating at 60.degree. C. The reaction solution
was stirred under heating at 60.degree. C. for 2 hours 20 minutes.
To the reaction solution was added dropwise ammonia water (8 ml)
under ice cooling. The aqueous layer was extracted with cyclopentyl
methyl ether (three times), and then washed with saturated aqueous
sodium chloride solution and dried over sodium sulfate. Sodium
sulfate was removed with a filter, and then the filtrate was
concentrated under reduced pressure to give a crude product of the
title compound (492 mg).
[0700] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.03-1.06 (m, 6H), 1.11
(s, 9H), 1.18-1.33 (m, 2H), 1.34-1.42 (m, 1H), 1.44-1.77 (m, 5H),
2.01-2.14 (m, 1H), 2.73-2.83 (m, 1H), 3.21-3.25 (m, 1H), 3.50-3.58
(m, 1H), 3.75-3.82 (m, 2H), 7.13-7.21 (m, 1H), 7.30-7.39 (m, 1H),
7.44-7.56 (m, 1H)
Step 10
Methyl
4-(3-{(3R,4S)-1-[4-(3-tert-butyl-2,2-difluoro-cyclopropyl)-3-chloro-
-phenyl]-2-hydroxymethyl-3,4-dimethyl-cyclohexyl}ureido)bicyclo[2.1.1]hexa-
ne-1-carboxylate
##STR00189##
[0702] 3-(Methoxycarbonyl)bicyclo[2.1.1]pentane-1-carboxylic acid
(59 mg) and toluene (1.2 mL) were mixed under nitrogen gas, and
thereto were added diphenylphosphoryl azide (75 .mu.L) and
triethylamine (49 .mu.L) at room temperature. The reaction solution
was stirred under heating at 120.degree. C. for 1 hour. The
reaction solution was added dropwise to a mixed solution of
{(5S,6R)-2-amino-2-[4-(3-tert-butyl-2,2-difluoro-cyclopropyl)-3-chloro-ph-
enyl]-5,6-dimethyl-cyclohexyl}methanol (112 mg) in tetrahydrofuran
(2.3 mL) under ice cooling. The reaction solution was stirred at
room temperature for 13 hours, and then thereto was added
N,N,N'-trimethyl-ethane-1,2-diamine (7.2 .mu.L). The mixture was
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (Biotage flash
purification systems, eluent: acetone/n-hexane, Rf=0.40
(acetone/n-hexane=1/4)) to give the title compound (201 mg, 31 w %
of ethyl acetate inclusive).
[0703] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.93-1.06 (m, 8H), 1.10
(s, 9H), 1.54-1.83 (m, 5H), 1.89-1.93 (m, 5H), 1.98-2.02 (m, 1H),
2.12-2.29 (m, 4H), 2.70-2.81 (m, 1H), 2.99-3.09 (m, 1H), 3.29-3.35
(m, 1H), 3.67 (s, 3H), 3.70-3.75 (m, 1H), 4.81 (br s, 1H), 6.28 (br
s, 1H), 7.09-7.23 (m, 2H), 7.26-7.36 (m, 1H)
Step 11
Methyl
4-{(5R,6S)-8a-[4-(3-tert-butyl-2,2-difluoro-cyclopropyl)-3-chloro-p-
henyl]-5,6-dimethyl-2-oxo-1,5,6,7,8,8a-hexahydro-2H-quinazolin-3-yl}bicycl-
o[2.1.1]hexane-1-carboxylate
##STR00190##
[0705] Methyl
4-(3-{(3R,4S)-1-[4-(3-tert-butyl-2,2-difluoro-cyclopropyl)-3-chloro-pheny-
l]-2-hydroxymethyl-3,4-dimethyl-cyclohexyl}ureido)bicyclo[2.1.1]hexane-1-c-
arboxylate (140 mg) and chloroform (1.4 mL) were mixed under
nitrogen gas, and thereto were added (diacetoxyiodo)benzene (88 mg)
and 2,2,6,6-tetramethylpiperidin-1-oxyl radical (3.8 mg) at room
temperature. The reaction solution was stirred at room temperature
for 14 hours, and then thereto were added saturated aqueous sodium
hydrogen carbonate solution and sodium sulfite at room temperature.
The mixture was stirred at room temperature for 30 minutes, and
then extracted with ethyl acetate. The organic layer was washed
with saturated aqueous sodium chloride solution, and then dried
over magnesium sulfate. Magnesium sulfate was removed with a
filter, and then the filtrate was concentrated under reduced
pressure. The resulting residue was mixed with toluene (2.8 mL),
and thereto was added pentafluoroaniline trifluoromethanesulfonate
(4 mg) at room temperature. The reaction solution was stirred for 7
hours under heating at 120'C, and then the reaction solution was
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (Biotage flash
purification systems, eluent: ethyl acetate/n-hexane, Rf=0.25
(ethyl acetate/n-hexane=3/7)) to give the title compound (36
mg).
[0706] This racemate was purified with Recycling Preparative Liquid
Chromatograph to give a single enantiomer of the title compound (9
mg).
[0707] Purification conditions for the preparative chromatography
are shown as follows.
Preparative apparatus: Recycling Preparative Liquid Chromatograph
LC-92XX NEXT SERIES, Japan Analytical Industry Co., Ltd. Column:
Daicel CHIRALPAK IA 2.0 cm.phi..times.25 cm Mobile phase:
n-hexane/2-propanol=85/15 Flow rate: 10.0 mL/min
Detection: UV (254 nm)
[0708] Measurement of the resulting compound with a chiral column
showed 6.9 minutes of the retention time for the resulting
enantiomer with >99% ee of optical purity. The retention time
for the opposite enantiomer was 10.3 minutes.
[0709] Analytical conditions for the chiral column are shown as
follows.
Measurement apparatus: HPLC system, Shimadzu Corporation,
High-Performance Liquid Chromatograph Prominence Column: Daicel
CHIRALPAK IA-3 0.46 cm.phi..times.15 cm Column temperature:
40.degree. C. Mobile phase: n-hexane/2-propanol=85/15 Flow rate:
1.0 mL/min
Detection: UV (254 nm)
[0710] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.62-0.67 (m, 3H),
0.99-1.05 (m, 5H), 1.12 (s, 9H), 1.33-1.47 (m, 2H), 1.56-1.84 (m,
3H), 1.93-2.13 (m, 9H), 2.22-2.31 (m, 1H), 2.70-2.83 (m, 1H), 3.70
(s, 3H), 4.44 (br s, 1H), 5.96 (br s, 1H), 7.13-7.20 (m, 1H),
7.21-7.23 (m, 1H), 7.38-7.40 (m, 1H)
Step 12
4-{(5R,6S)-8a-[4-(3-tert-Butyl-2,2-difluoro-cyclopropyl)-3-chloro-phenyl]--
5,6-dimethyl-2-oxo-1,5,6,7,8,8a-hexahydro-2H-quinazolin-3-yl}bicyclo[2.1.1-
]hexane-1-carboxylic acid
##STR00191##
[0712] Methyl
3-{8a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-2-oxo-1,5,6,7,8,8a-hexahydr-
o-2H-quinazolin-3-yl}bicyclo[1.1.1]pentane-1-carboxylate (8.7 mg)
was mixed in tetrahydrofuran (87 .mu.L) and methanol (136 .mu.L)
under nitrogen gas, and thereto was added 2N aqueous sodium
hydroxide solution (16 .mu.L) at room temperature. The reaction
solution was stirred at room temperature for 8 hours, and then
thereto was added water (1 mL), followed by addition of 2N
hydrochloric acid under ice cooling. Then, the mixture was stirred
under ice cooling, and the precipitated solid was collected by
filtration to give the title compound (7 mg).
Intermediate Step 1
1-(4-Bromo-2-chloro-phenyl)-3,3-dimethyl-butan-1-ol
##STR00192##
[0714] 4-Bromo-2-chloro-1-iodo-benzene (10 g) and tetrahydrofuran
(100 mL) were mixed under argon gas, and thereto was added dropwise
2.0M isopropylmagnesium chloride/tetrahydrofuran solution (17 mL)
under cooling at -40.degree. C. The mixture was stirred under
cooling at -40.degree. C. for 1.5 hours, and then thereto was added
dropwise 3,3-dimethylbutyraldehyde (4.8 mL). The mixture was
stirred under cooling at -40.degree. C. for 1 hour 20 minutes, and
then thereto was added 2N hydrochloric acid (17 mL) under ice
cooling. Then, thereto was added ethyl acetate, and the mixture was
separated. The organic layer was washed with saturated aqueous
sodium chloride solution and dried over magnesium sulfate. Then,
magnesium sulfate was removed with a filter, and the filtrate was
concentrated under reduced pressure and azeotroped with toluene to
give the title compound (9.8 g, 9.0 w % of toluene inclusive).
[0715] .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.03 (s, 9H), 1.53-1.55
(m, 2H), 1.75-1.77 (m, 1H), 5.19-5.24 (m, 1H), 7.37-7.48 (m,
3H)
Intermediate Step 2
4-Bromo-2-chloro-1-((E)-3,3-dimethyl-but-1-enyl)benzene
##STR00193##
[0717] 1-(4-Bromo-2-chloro-phenyl)-3,3-dimethyl-butan-1-ol (800 mg)
and toluene (12 mL) were mixed, and thereto was added
pentafluoroanilinium trifluoromethanesulfonate (494 mg) at room
temperature. The mixture was stirred under heating at 120.degree.
C. for 3 hours, and then the reaction solution was concentrated
under reduced pressure. The resulting residue was purified by
silica gel column chromatography (eluent: ethyl acetate/n-hexane,
Rf=0.8 (ethyl acetate/n-hexane=5/95)) to give the title compound
(9.5 g, 16 w % of ethyl acetate inclusive).
[0718] .sup.1H-NMR (400 MHz, CDCl.sub.4) 1.12 (s, 9H), 6.16-6.24
(m, 1H), 6.53-6.62 (m, 1H), 7.27-7.38 (m, 2H), 7.47-7.50 (m,
1H)
Intermediate Step 3
4-Bromo-1-(3-tert-butyl-2,2-difluoro-cyclopropyl)-2-chloro-benzene
##STR00194##
[0720] To 4-bromo-2-chloro-1-((E)-3,3-dimethyl-but-1-enyl)benzene
(800 mg) were added tetra-n-butylammonium bromide (48 mg) and
(bromodifluoromethyl)trimethylsilane (0.69 mL) at room temperature
under argon gas. The mixture was stirred under heating at
110.degree. C. overnight, and then thereto were added
tetra-n-butylammonium bromide (48 mg) and
(bromodifluoromethyl)trimethylsilane (0.69 mL). The mixture was
stirred under heating at 120.degree. C. for 8 hours. Then, thereto
was added water (12 mL) and ethyl acetate at room temperature, and
the mixture was separated. The organic layer was washed with
saturated aqueous sodium chloride solution and dried over magnesium
sulfate. Then, magnesium sulfate was removed with a filter, and The
resulting residue was purified by silica gel column chromatography
(eluent: ethyl acetate/n-hexane, Rf=0.75 (ethyl
acetate/n-hexane=5/95)) to give the title compound (697 mg, 7 w %
of toluene inclusive).
[0721] .sup.1H-NMR (400 MHz, CDCl.sub.7) 1.10 (s, 9H), 1.60-1.73
(m, 1H), 2.66-2.78 (m, 1H), 7.01-7.08 (m, 1H), 7.31-7.37 (m, 1H),
7.54-7.58 (m, 1H)
Example 118
Step 1
Ethyl (E)-4,4,5-trimethylhepta-2,6-dienoate
##STR00195##
[0723] 60 wt % Sodium hydride (1.1 g) and tetrahydrofuran (28 mL)
were mixed under ice cooling and argon gas, and thereto was added
dropwise triethyl phosphonoacetate (6.4 g). The reaction solution
was stirred at room temperature for 30 minutes. Then, thereto was
added dropwise a mixed solution of 2,2,3-trimethylpent-4-enal in
tetrahydrofuran (28 mL) under ice cooling. The reaction solution
was stirred under ice cooling for 10 minutes, and then stirred at
room temperature for 12.5 hours. To the reaction solution were
added saturated aqueous ammonium chloride solution (22 mL) and
water (6 mL), and the mixture was concentrated under reduced
pressure. The resultant aqueous layer was extracted with ethyl
acetate (20 mL, twice). The organic layer was washed with saturated
aqueous sodium chloride solution (10 mL, twice) and dried over
magnesium sulfate. Magnesium sulfate was removed with a filter, and
then the filtrate was concentrated under reduced pressure to give a
crude product of the title compound (3.2 g).
[0724] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.94 (d, J=6.94 Hz, 3H),
1.01 (s, 3H), 1.02 (s, 3H), 1.30 (t, J=7.17 Hz, 3H), 2.05-2.14 (m,
1H), 4.19 (q, J=7.17 Hz, 2H), 4.97-5.03 (m, 2H), 5.65-5.75 (m, 2H),
6.95 (d, J=15.95 Hz, 1H)
Step 2
Ethyl 4,4,5-trimethylhept-6-enoate
##STR00196##
[0726] Ethyl (E)-4,4,5-trimethylhepta-2,6-dienoate (3.2 g) and
copper (I) chloride (1.6 g) were mixed in tetrahydrofuran (44 mL)
and methanol (25 mL) under argon gas, and thereto was added sodium
borohydride over 1 hour under ice cooling. The reaction solution
was stirred under ice cooling for 2 hours, and then thereto was
added 1N hydrochloric acid (32 mL). Solid substances were removed
with a filter, and then the resultant was washed with ethyl acetate
and water. The filtrate was concentrated under reduced pressure.
The resulting aqueous layer was extracted with ethyl acetate (10
mL) twice. The organic layer was washed with 1N hydrochloric acid
(9 mL) and saturated aqueous sodium chloride solution (9 mL) and
dried over magnesium sulfate. Magnesium sulfate was removed with a
filter, and then the filtrate was concentrated under reduced
pressure. To The resulting residue were added silica gel (15 g),
ethyl acetate (16 mL), and n-hexane (16 mL), and the mixture was
stirred for 30 minutes. Silica gel was removed with a filter, and
then the filtrate was washed with a mixed solvent of ethyl
acetate/n-hexane=1/1 (64 mL). The filtrate was concentrated under
reduced pressure to give a crude product of the title compound (3.4
g).
[0727] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.83 (s, 3H), 0.83 (s,
3H), 0.95 (d, J=6.94 Hz, 3H), 1.25 (t, J=7.13 Hz, 3H), 1.54-1.61
(m, 2H), 1.94-2.02 (m, 1H), 2.22-2.29 (m, 2H), 4.12 (q, J=7.13 Hz,
2H), 4.94-5.02 (m, 3H), 5.68-5.82 (m, 2H)
Step 3
4,4,5-Trimethylhept-6-enal
##STR00197##
[0729] Ethyl 4,4,5-trimethylhept-6-enoate (3.4 g) and
dichloromethane (170 mL) were mixed under argon gas, and thereto
was added dropwise 1.02M diisobutylaluminum hydride/n-hexane
solution (25 mL) under cooling at -78.degree. C. The reaction
solution was stirred under cooling at -78.degree. C. for 2 hours.
To the reaction solution was added methanol (10 mL) under cooling
at -78.degree. C. The reaction solution was warmed to 0.degree. C.,
and thereto was added a saturated aqueous solution of Rochelle salt
(85 mL). The reaction solution was stirred at room temperature for
3 hours. The aqueous layer was extracted with diethyl ether (40 mL,
twice). The organic layer was washed with saturated aqueous sodium
chloride solution (10 mL, twice) and dried over magnesium sulfate.
Magnesium sulfate was removed with a filter, and then the filtrate
was concentrated under reduced pressure to give a crude product of
the title compound (2.5 g).
[0730] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.82-0.84 (m, 6H),
0.95-0.97 (m, 3H), 1.54-1.58 (m, 2H), 1.96-2.04 (m, 1H), 2.35-2.43
(m, 2H), 4.93-4.99 (m, 3H), 5.71-5.81 (m, 1H), 9.77 (t, J=1.97 Hz,
1H)
Step 4
4,4,5-Trimethylhept-6-enal oxime
##STR00198##
[0732] 4,4,5-Trimethylhept-6-enal (1.9 g) was mixed in ethanol (25
mL) and water (12 mL) under argon gas, and thereto were added
sodium acetate (7.0 g) and hydroxylamine hydrochloride (3.4 g) at
room temperature. The reaction solution was stirred under heating
at 60.degree. C. for 14.5 hours. The reaction solution was
concentrated under reduced pressure, and thereto were added ethyl
acetate and water. The mixture was separated. The aqueous layer was
extracted with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution (twice) and dried over
sodium sulfate. Sodium sulfate was removed with a filter, and then
the filtrate was concentrated under reduced pressure. The resulting
residue was purified by silica gel column chromatography (Biotage
flash purification systems, eluent: ethyl acetate/n-hexane, 5/95 to
20/80) to give the title compound (1.8 g).
[0733] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.83-0.98 (m, 9H),
1.37-1.43 (m, 2H), 1.97-2.08 (m, 1H), 2.13-2.20 (m, 1H), 2.31-2.37
(m, 1H), 4.93-5.00 (m, 3H), 5.51-5.81 (m, 2H), 6.67-6.73 (m, 1H),
7.00 (t, J=1.27 Hz, 0.5H), 7.41 (t, J=6.13 Hz, 0.5H)
Step 5
4,5,5-Trimethyl-3,3a,4,5,6,7-hexahydrobenzo[c]isoxazole
##STR00199##
[0735] 4,4,5-Trimethylhept-6-enal oxine (1.8 g) and methanol (36
mL) were mixed under nitrogen gas, and thereto was added
trifluoroacetic acid (0.27 mL) under sodium chloride-ice cooling,
followed by addition of (diacetoxyiodo)benzene (4.5 g) over 1 hour.
The reaction solution was stirred under ice cooling for 20 minutes
and at room temperature for 1.5 hours. Then, thereto were added
saturated aqueous sodium hydrogen carbonate solution (18 mL) and
sodium sulfite (0.66 g) under ice cooling, and the mixture was
stirred at room temperature for 30 minutes. The reaction solution
was concentrated under reduced pressure. The aqueous layer was
extracted with ethyl acetate (10 mL, twice). The organic layer was
washed with saturated aqueous sodium chloride solution (5 mL,
twice) and dried over sodium sulfate. Sodium sulfate was removed
with a filter, and then the filtrate was concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (Biotage flash purification systems, eluent: ethyl
acetate/n-hexane=5/95 to 30/70), and then purified further by
silica gel column chromatography (Biotage flash purification
systems, eluent: acetone/n-hexane=5/95 to 20/80) and azeotroped
with n-hexane to give the title compound (0.42 g).
[0736] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.80-0.98 (m, 9H),
1.25-1.45 (m, 2H), 1.63-1.70 (m, 1H), 3.76 (dd, J=10.87, 7.86 Hz,
1H), 4.10-4.15 (m, 1H), 4.51 (dd, J=10.40, 7.86 Hz, 1H)
Step 6
7a-(3-Chloro-4-(3,3-dimethylbutyl)phenyl)-4,5,5-trimethyloctahydrobenzo[c]-
isoxazole
##STR00200##
[0738] This step was performed according to Example 3 Step 6.
.sup.1H-NMR (400 MHz, CDCl.sub.3) 0.93 (d, J=6.70 Hz, 3H), 0.98 (s,
9H), 0.99 (s, 3H), 1.01 (s, 3H), 1.27-1.34 (m, 1H), 1.36-1.41 (m,
2H), 1.42-1.48 (m, 2H), 1.79-1.86 (m, 1H), 1.93-2.00 (m, 1H),
2.28-2.35 (m, 1H), 2.62-2.69 (m, 2H), 3.52 (dd, J=7.40, 5.55 Hz,
1H), 3.81 (d, J=7.40 Hz, 1H), 5.88 (s, 1H), 7.16 (d, J=8.04 Hz,
1H), 7.41 (dd, J=8.04, 1.91 Hz, 1H), 7.56 (d, J=1.91 Hz, 1H)
Step 7
(2-Amino-2-(3-chloro-4-(3,3-dimethylbutyl)phenyl)-5,5,6-trimethylcyclohexy-
l)methanol
##STR00201##
[0740] This step was performed according to Example 3 Step 7.
[0741] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.94 (s, 3H), 0.95-0.99
(m, 12H), 1.05 (s, 3H), 1.18-1.23 (m, 1H), 1.36-1.87 (m, 4H),
2.22-2.31 (m, 1H), 2.65-2.70 (m, 2H), 3.28-3.32 (m, 1H), 3.45-3.49
(m, 1H), 3.77-3.83 (m, 1H), 7.19 (d, J=8.09 Hz, 1H), 7.30 (dd,
J=8.09, 2.08 Hz, 1H), 7.45 (d, J=2.08 Hz, 1H)
Step 8
Methyl
3-(3-{1-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-2-(hydroxymethyl)-3-
,4,4-trimethylcyclohexyl)ureido}bicyclo[1.1.1]pentane-1-carboxylate
##STR00202##
[0743] This step was performed according to Example 54 Step 8.
[0744] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.94 (s, 6H), 0.97 (s,
9H), 1.03 (s, 3H), 1.29-1.68 (m, 5H), 1.86-2.00 (m, 2H), 2.36 (s,
6H), 2.59-2.67 (m, 2H), 2.86-2.92 (m, 1H), 3.34-3.40 (m, 1H),
3.62-3.69 (m, 4H), 4.71 (br s, 1H), 6.42 (s, 1H), 7.10-7.17 (m,
2H), 7.22-7.27 (m, 3H)
Step 9
Methyl
3-{8a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5,6,6-trimethyl-2-oxo-
-1,5,6,7,8,8a-hexahydroquinazolin-3
(2H)-yl}bicyclo[1.1.1]pentane-1-carboxylate
##STR00203##
[0746] This step was performed according to Example 54 Step 9. The
product was purified with a chiral preparative column. Purification
conditions for the preparative column are shown as follows.
Preparative apparatus: Recycling Preparative Liquid Chromatograph
LC-92XX NEXT SERIES, Japan Analytical Industry Co., Ltd. Column:
Daicel CHIRALPAK IA 2.0 cm.phi..times.25 cmL Mobile phase:
n-hexane/2-propanol=90/10 Flow rate: 10.0 mL/min
Detection: UV (254 nm)
[0747] Measurement with a chiral column showed 11.2 minutes of the
retention time for the resulting title compound (4.2 minutes of the
retention time for the enantiomer of the title compound) with
>99% ee purity. Analytical conditions for the chiral column are
shown as follows.
Measurement apparatus: HPLC system, Shimadzu Corporation,
High-Performance Liquid Chromatograph Prominence Column: Daicel
CHIRALPAK IA-3 0.46 cm.phi..times.15 cmL Column temperature:
30.degree. C. Mobile phase: n-hexane/2-propanol=90/10 Flow rate:
1.0 mL/min
Detection: UV (254 nm)
[0748] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.47 (d, J=7.40 Hz, 3H),
0.82 (s, 3H), 0.98 (s, 9H), 1.04 (s, 3H), 1.18-1.32 (m, 2H),
1.40-1.48 (m, 2H), 1.96-2.11 (m, 2H), 2.35-2.41 (m, 1H), 2.48 (s,
6H), 2.63-2.68 (m, 2H), 3.71 (s, 3H), 4.46 (br s, 1H), 5.96-5.98
(m, 1H), 7.16-7.18 (m, 2H), 7.30-7.32 (m, 1H)
Step 10
3-{7a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-5,6,6-trimethyl-2-oxo-1,2,5,-
6,7,7a-hexahydro-3H-cyclopenta[d]pyrimidin-3-yl}bicyclo[1.1.1]pentane-1-ca-
rboxylic acid
##STR00204##
[0750] This step was performed according to Example 54 Step 10.
Example 120
Step 1
Methyl
4-(3-{3-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-4-hydroxymethyl-5,6-
,6-trimethyl-tetrahydro-pyran-3-yl}ureido)bicyclo[2.1.1]hexane-1-carboxyla-
te
##STR00205##
[0752] Methyl bicyclo[2.1.1]hexane-1,4-dicarboxylate (144 mg) and
toluene (2.89 mL) were mixed under argon gas, and thereto were
added diphenylphosphoryl azide (0.183 mL) and triethylamine (0.118
mL) at room temperature. The reaction solution was stirred under
heating at 120.degree. C. for 1 hour. To the reaction solution was
added tetrahydrofuran (2.89 mL), and the mixture was added dropwise
to a mixed solution of
{5-amino-5-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-2,2,3-trimethyl-tetrah-
ydro-pyran-4-yl}methanol (251 mg, 21 w % of cyclopentyl methyl
ether inclusive) in tetrahydrofuran (5.02 mL) over 10 minutes under
ice cooling. The reaction solution was stirred at room temperature
for 13 hours, and then thereto was added
N,N,N'-trimethylethylenediamine (0.0176 mL). The reaction solution
was concentrated under reduced pressure, and the resulting residue
was purified by silica gel column chromatography (Biotage flash
purification systems, eluent: acetone/n-hexane, Rf=0.29
(acetone/n-hexane=1/2)) to give a crude product of the title
compound (906 mg, 67 w % of ethyl acetate inclusive).
[0753] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.94 (d, J=7.2 Hz, 3H),
0.96 (s, 9H), 1.08 (s, 1.05H), 1.20 (s, 1.95H), 1.31 (s, 1.95H),
1.40-1.48 (m, 2H), 1.42 (s, 1.05H), 1.66-2.34 (m, 7H), 1.91 (s,
1.40H), 2.03 (s, 2.60H), 2.60-2.66 (m, 2H), 3.55-3.69 (m, 2H), 3.66
(s, 1.95H), 3.69 (s, 1.05H), 3.81-3.87 (m, 1.30H), 4.02-4.08 (m,
0.70H), 4.69 (s, 0.35H), 5.03 (s, 0.65H), 5.80 (s, 0.65H), 6.19 (s,
0.35H), 7.12-7.17 (m, 1.65H), 7.25 (d, J=1.8 Hz, 0.65H), 7.46 (d,
J=8.3 Hz, 0.35H), 7.53 (d, J=1.8 Hz, 0.35H)
Step 2
Methyl
4-{8a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5,6,6-trimethyl-2-oxo-
-1,2,5,6,8,8a-hexahydro-pyrano[3,4-d]pyrimidin-3-yl}bicyclo[2.1.1]hexane-1-
-carboxylate
##STR00206##
[0755] Methyl
4-(3-{3-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-4-hydroxymethyl-5,6,6-tri-
methyl-tetrahydro-pyran-3-yl}ureido)bicyclo[2.1.1]hexane-1-carboxylate
(906 mg, 67 w % of ethyl acetate inclusive) and chloroform (3.0 mL)
were mixed, and then thereto were added (diacetoxyiodo)benzene (202
mg) and 2,2,6,6-tetramethylpiperidin-1-oxyl radical (8.6 mg) at
room temperature. The reaction solution was stirred at room
temperature for 14 hours, and then thereto were added 20 w/w %
aqueous sodium sulfite solution (2 mL) and saturated aqueous sodium
hydrogen carbonate solution (2 mL) at room temperature. The mixture
was stirred at room temperature for 30 minutes. The aqueous layer
was extracted with ethyl acetate (twice). The organic layers were
washed with saturated aqueous sodium chloride solution and dried
over magnesium sulfate. Magnesium sulfate was removed with a
filter, and then the filtrate was concentrated under reduced
pressure. The resulting residue and toluene (6.1 mL) were mixed,
and then thereto was added pentafluoroaniline
trifluoromethanesulfonate (9.1 mg) at room temperature. The
reaction solution was stirred under heating at 120.degree. C. for 2
hours and then concentrated under reduced pressure. The resulting
residue was purified by silica gel column chromatography (Biotage
flash purification systems, eluent: ethyl acetate/n-hexane, Rf=0.42
(ethyl acetate/n-hexane=2/3)) to give a diastereomeric mixture of
the title compound (245 mg). The diastereomeric mixture was
purified with a Recycling Preparative Liquid Chromatograph to give
a single enantiomer of the title compound (50.3 mg).
[0756] Purification conditions for the preparative chromatography
are shown as follows.
Preparative apparatus: Recycling preparative liquid chromatograph
LC-92XX NEXT SERIES, Japan Analytical Industry Co., Ltd. Column:
Daicel CHIRALPAK IA 2.0 cm.phi..times.25 cm Mobile phase:
n-hexane:2-propanol=85:15 Flow rate: 10.0 mL/min
Detection: UV (254 nm)
[0757] Measurement of the resulting compound with a chiral column
showed 12.9 minutes of the retention time for the resulting
enantiomer with >99% ee of optical purity. The retention time
for a diastereomer on the methyl group was 10.6 minutes, and the
retention time for a diastereomer on the phenyl group as well as
the opposite enantiomer was 6.6 or 7.5 minutes.
[0758] Analytical conditions for the chiral column are shown as
follows.
Measurement apparatus: HPLC system, Shimadzu Corporation,
High-Performance Liquid Chromatograph Prominence Column: Daicel
CHIRALPAK IA-3 0.46 cm.phi..times.15 cm Column temperature:
30.degree. C. Mobile phase: n-hexane:2-propanol=85:15 Flow rate:
1.0 mL/min
Detection: UV (254 nm)
[0759] .sup.1H-NMR (400 MHz, CDCl.sub.3) 0.54 (d, J=7.2 Hz, 3H),
0.98 (s, 9H), 1.12 (s, 3H), 1.34 (s, 3H), 1.41-1.46 (m, 2H),
2.00-2.10 (m, 9H), 2.64-2.69 (m, 2H), 3.73 (s, 3H), 3.90 (d, J=12.0
Hz, 1H), 4.22 (d, J=1l 0.8 Hz, 1H), 4.38 (s, 1H), 5.91 (s, 1H),
7.17 (d, J=8.1 Hz, 1H), 7.31 (dd, J=8.0, 2.0 Hz, 1H), 7.47 (d,
J=2.1 Hz, 1H)
Step 3
4-{(S)-8a-[3-Chloro-4-(3,3-dimethyl-butyl)phenyl]-5,6,6-trimethyl-2-oxo-1,-
2,5,6,8,8a-hexahydro-pyrano[3,4-d]pyrimidin-3-yl)}bicyclo[2.1.1]hexane-1-c-
arboxylic acid
##STR00207##
[0761] Methyl
4-{(S)-8a-[3-chloro-4-(3,3-dimethyl-butyl)phenyl]-5,6,6-trimethyl-2-oxo-1-
,2,5,6,8,8a-hexahydro-pyrano[3,4-d]pyrimidin-3-yl}bicyclo[2.1.1]hexane-1-c-
arboxylate (50.3 mg) was mixed in tetrahydrofuran (0.553 mL) and
methanol (0.553 mL), and then thereto was added 2N aqueous solution
of sodium hydroxide (0.0951 mL) at room temperature. The reaction
solution was stirred at room temperature for 16 hours and then
concentrated under reduced pressure. To the resulting residue was
added water (1 mL), and thereto was added 2N hydrochloric acid
(0.0951 mL) under ice cooling. The precipitated solid was collected
by filtration to give the title compound (42.4 mg).
[0762] The following tables show structures, structural
information, and physical property data for the above Example
compounds and Example compounds prepared according to any of the
above methods of Examples.
[0763] In the tables, "chiral column IA-3" means CHIRALPAK IA-3
analytical column (Product code: 80524; internal diameter: 4.6 mm,
length: 150 mm, particle size: 3 .mu.m; Daicel Corporation).
[0764] "Chiral column AS-3R" means CHIRALPAK AS-3R analytical
column (Product code: 20824; internal diameter: 4.6 mm, length: 150
mm, particle size: 3 .mu.m; Daicel Corporation).
[0765] Each absolute configuration of the enantiomer shown in the
structure of each example compound was estimated according to the
following regularities:
1) a certain regularity in the retention time of chiral column for
a methyl or ethyl ester derivative of example compound; and 2) a
certain regularity in the degree of inhibitory activity against
ROR.gamma. transcription of each enantiomer of example compound
(see Test Example 1);
[0766] provided that the absolute configuration of Example 54
compound was determined by single-crystal X-ray structural
analysis.
[0767] In the following table, the term "methyl ester derivative"
or "ethyl ester derivative" described in the structural information
means a methyl-ester derivative or ethyl-ester derivative
corresponding to each example compound, respectively.
TABLE-US-00001 Example Structure Structural Information 1
##STR00208## Racemate 2 ##STR00209## Racemate 3 ##STR00210##
Enantiomer of Example 4 (Absolute configuration was not
determined.) Analytical conditions for corresponding ethyl ester
derivative: chiral column IA-3, Hexane/IPA = 93/7, flow 1 ml/min
Retention time: 7.4 min 4 ##STR00211## Enantiomer of Example 3
(Absolute configuration was not determined.) Analytical conditions
for corresponding ethyl ester derivative: chiral column IA-3,
Hexane/IPA = 93/7, flow 1 ml/min Retention time: 8.7 min 5
##STR00212## Enantiomer of Example 6 (Absolute configuration was
not determined.) Analytical conditions for corresponding ethyl
ester derivative: chiral column IA-3, Hexane/IPA = 90/10, flow 1
ml/min Retention time: 6.6 min 6 ##STR00213## Enantiomer of Example
5 (Absolute configuration was not determined.) Analytical
conditions for corresponding ethyl ester derivative: chiral column
IA-3, Hexane/IPA = 90/10, flow 1 ml/min Retention time: 6.9 min 7
##STR00214## Enantiomer of Example 8 (Absolute configuration was
not determined.) Analytical conditions for corresponding ethyl
ester derivative: chiral column IA-3, Hexane/IPA = 80/20, flow 1
ml/min Retention time: 6.5 min 8 ##STR00215## Enantiomer of Example
7 (Absolute configuration was not determined.) Analytical
conditions for corresponding ethyl ester derivative: chiral column
IA-3, Hexane/IPA = 80/20, flow 1 ml/min Retention time: 8.8 min 9
##STR00216## Enantiomer of Example 10 (Absolute configuration was
not determined.) Analytical conditions for corresponding ethyl
ester derivative: chiral column IA-3, Hexane/IPA = 90/10, flow 1
ml/min Retention time: 10.6 min 10 ##STR00217## Enantiomer of
Example 9 (Absolute configuration was not determined.) Analytical
conditions for corresponding ethyl ester derivative: chiral column
IA-3, Hexane/IPA = 90/10, flow 1 ml/min Retention time: 12.8 min 11
##STR00218## Optically active. Optical purity was not determined.
(Absolute configuration was not determined.) Single diastereomer.
Configuration of methyl group on the cyclopentane ring was
estimated to be R derived from a starting material. Analytical
conditions for corresponding methyl ester derivative: chiral column
IA-3, Hexane/IPA = 90/10, flow 1 ml/min Retention time: 5.3 min 12
##STR00219## Optically active. Optical purity was not determined.
(Absolute configuration was not determined.) Single diastereomer.
Configuration of methyl group on the cyclopentane ring was
estimated to be R derived from a starting material. Analytical
conditions for corresponding methyl ester derivative: chiral column
IA-3, Hexane/IPA = 90/10, flow 1 ml/min Retention time: 6.2 min 13
##STR00220## Racemate. Estimated Structure. 14 ##STR00221##
Racemate. Estimated Structure. 15 ##STR00222## Enantiomer of
Example 16 (Absolute configuration was not determined.) Analytical
conditions for corresponding ethyl ester derivative: chiral column
IA-3, Hex./IPA = 85/15, flow rate = 1.0 ml/min, Retention time: 6.4
min Relative configuration of 3-chloro-4-(3,3- dimethylbutyl)phenyl
and benzyloxymethyl was estimated to be trans 16 ##STR00223##
Enantiomer of Example 15 (Absolute configuration was not
determined.) Analytical conditions for corresponding ethyl ester
derivative: chiral column IA-3, Hex./IPA = 85/15, flow rate = 1.0
ml/min, Retention time: 8.8 min Relative configuration of
3-chloro-4-(3,3- dimethylbutyl)phenyl and benzyloxymethyl was
estimated to be trans 17 ##STR00224## Enantiomer of Example 18
(Absolute configuration was not determined.) Analytical conditions
for corresponding ethyl ester derivative: chiral column IA-3,
Hex./IPA = 80/20, flow rate = 1.0 ml/min, Retention time: 6.3 min
Relative configuration of 3-chloro-4-(3,3- dimethylbutyl)phenyl and
hydroxymethyl was estimated to be trans 18 ##STR00225## Enantiomer
of Example 17 (Absolute configuration was not determined.)
Analytical conditions for corresponding ethyl ester derivative:
chiral column IA-3, Hex./IPA = 80/20, flow rate = 1.0 ml/min,
Retention time: 7.6 min Relative configuration of 3-chloro-4-(3,3-
dimethylbutyl)phenyl and hydroxymethyl was estimated to be trans 19
##STR00226## Enantiomer of Example 20 (Absolute configuration was
not determined.) Analytical conditions for corresponding ethyl
ester derivative: chiral column IA-3, Hex./IPA = 90/10, flow rate =
1.0 ml/min, Retention time: 8.7 min Relative configuration of
3-chloro-4-(3,3- dimethylbutyl)phenyl and methoxymethyl was
estimated to be trans 20 ##STR00227## Enantiomer of Example 19
(Absolute configuration was not determined, >98% ee) Analytical
conditions for corresponding ethyl ester derivative: chiral column
IA-3, Hex./IPA = 90/10, flow rate = 1.0 ml/min, Retention time: 9.8
min Relative configuration of 3-chloro-4-(3,3- dimethylbutyl)phenyl
and methoxymethyl was estimated to be trans 21 ##STR00228##
Enantiomer of Example 22 (Absolute configuration was not
determined.) Analytical conditions for corresponding ethyl ester
derivative: chiral column IA-3, Hex./IPA = 90/10, flow rate = 1.0
ml/min, Retention time: 7.5 min, Optical purity was not determined
Relative configuration of 3-chloro-4-(3,3- dimethylbutyl)phenyl and
butoxymethyl was estimated to be trans 22 ##STR00229## Enantiomer
of Example 21 (Absolute configuration was not determined.)
Analytical conditions for corresponding ethyl ester derivative:
chiral column IA-3, Hex./IPA = 90/10, flow rate = 1.0 ml/min,
Retention time: 8.3 min, Optical purity was not determined Relative
configuration of 3-chloro-4-(3,3- dimethylbutyl)phenyl and
butoxymethyl was estimated to be trans 23 ##STR00230## Racemate 24
##STR00231## Racemate 25 ##STR00232## Racemate Configuration of
hydroxyethyl and 3- chloro-4-(3,3- dimethylbutyl)phenyl was
estimated to be trans Single diastereomer 26 ##STR00233## Racemate
Configuration of benzyloxyethyl and 3- chloro-4-(3,3-
dimethylbutyl)phenyl was estimated to be trans Single diastereomer
27 ##STR00234## Racemate Configuration of methoxyethyl and 3-
chloro-4-(3,3- dimethylbutyl)phenyl was estimated to be trans
Single diastereomer 28 ##STR00235## Racemate The number of sodium
salt was estimated. Configuration of dimethylaminoethyl and 3-
chloro-4-(3,3- dimethylbutyl)phenyl was estimated to be trans
Single diastereomer 29 ##STR00236## Racemate Configuration of
hydroxymethyl and 3- chloro-4-(3,3- dimethylbutyl)phenyl was
estimated to be trans Single diastereomer 30 ##STR00237## Racemate
Configuration of methylacetamide and 3- chloro-4-(3,3-
dimethylbutyl)phenyl was estimated to be trans from the synthetic
method Single diastereomer 31 ##STR00238## Racemate Configuration
of nitrilemethyl and 3- chloro-4-(3,3- dimethylbutyl)phenyl was
estimated to be trans 32 ##STR00239## Enantiomer of Example 33
(Absolute configuration was not determined.) Analytical conditions
for corresponding ethyl ester derivative: chiral column IA-3,
Hexane/IPA = 90/10, flow 1 ml/min Retention time: 5.9 min 33
##STR00240## Enantiomer of Example 32 (Absolute configuration was
not determined.) Analytical conditions for corresponding ethyl
ester derivative: chiral column IA-3, Hexane/IPA = 90/10, flow 1
ml/min Retention time: 6.9 min 34 ##STR00241## Enantiomer of
Example 35 (Absolute configuration was not determined.) (>99% ee
for corresponding methyl ester derivative chiral column IA-3,
Hexane/IPA = 90/10, flow 1 ml/min Retention time: 6.0 min) Single
stereoisomer, Relative configuration of methyl and 3-chloro-
4-(3,3- dimethylbutyl)phenyl was uncertain 35 ##STR00242##
Enantiomer of Example 34 (Absolute configuration was not
determined.) (>99% ee for corresponding methyl ester derivative
chiral column IA-3, Hexane/IPA = 90/10, flow 1 ml/min Retention
time: 8.5 min) Single stereoisomer, Relative configuration of three
methyl groups on the cyclopentane ring methyl and 3-chloro- 4-(3,3-
dimethylbutyl)phenyl was uncertain 36 ##STR00243## Racemate 37
##STR00244## Enantiomer of Example 38 (Absolute configuration was
not determined.) Analytical conditions for corresponding ethyl
ester derivative: chiral column IA-3, Hexane/IPA = 90/10, flow 1
ml/min Retention time: 4.9 min 38 ##STR00245## Enantiomer of
Example 37 (Absolute configuration was not determined.) Analytical
conditions for corresponding ethyl ester derivative: chiral column
IA-3, Hexane/IPA = 90/10, flow 1 ml/min Retention time: 8.5 min 39
##STR00246## Racemate 40 ##STR00247## Optically active (Absolute
configuration was not determined.) (>99% ee, IA-3 IPA/Hex. = 7%,
flow rate = 1 ml/min, R.T. = 7.3 min) Enantiomer of Example 41 41
##STR00248## Optically active (Absolute configuration was not
determined.) (>99% ee, IA-3 IPA/Hex. = 7%, flow rate = 1 ml/min,
R.T. = 12.4 min) Enantiomer of Example 40 42 ##STR00249## Estimated
structure Racemate 43 ##STR00250## Racemate Configuration of
benzyloxyethyl and 3- chloro-4-(3,3- dimethylbutyl)phenyl was
estimated to be trans 44 ##STR00251## Racemate Configuration of
hydroxyethyl and 3- chloro-4-(3,3- dimethylbutyl)phenyl was
estimated to be trans 45 ##STR00252## Racemate Configuration of
carboxymethyl and 3- chloro-4-(3,3- dimethylbutyl)phenyl was
estimated to be trans 46 ##STR00253## Racemate Configuration of
methoxyethyl and 3- chloro-4-(3,3- dimethylbutyl)phenyl was
estimated to be trans 47 ##STR00254## Racemate Configuration of
aminomethyl and 3- chloro-4-(3,3- dimethylbutyl)phenyl was
estimated to be trans 48 ##STR00255## Racemate Configuration of
mesyloxyethyl and 3- chloro-4-(3,3- dimethylbutyl)phenyl was
estimated to be trans 49 ##STR00256## Racemate Configuration of
methylaminoethyl and 3- chloro-4-(3,3- dimethylbutyl)phenyl was
estimated to be trans The number of hydrochloride salt was
estimated 50 ##STR00257## Racemate Configuration of
dimethylaminoethyl and 3- chloro-4-(3,3- dimethylbutyl)phenyl was
estimated to be trans The number of hydrochloride salt was
estimated 51 ##STR00258## Racemate Configuration of
carboxamidemethyl and 3- chloro-4-(3,3- dimethylbutyl)phenyl was
estimated to be trans 52 ##STR00259## Racemate Configuration of
nitrilemethyl and 3- chloro-4-(3,3- dimethylbutyl)phenyl was
estimated to be trans 53 ##STR00260## Optically active Enantiomer
of Example 54 (>99% ee for corresponding methyl ester derivative
chiral column IA-3, Hexane/IPA = 90/10, flow 1 ml/min Retention
time: 5.3 min) 54 ##STR00261## Optically active Enantiomer of
Example 53 (>99% ee for corresponding methyl ester derivative,
the product of Example 54 Step 9) chiral column IA-3, Hexane/IPA =
90/10, flow 1 ml/min Retention time: 8.5 min) 55 ##STR00262##
Racemate Configuration of hydroxymethyl and 3- chloro-4-(3,3-
dimethylbutyl)phenyl was estimated to be trans 56 ##STR00263##
Racemate Configuration of methoxymethyl and 3- chloro-4-(3,3-
dimethylbutyl)phenyl was estimated to be trans 57 ##STR00264##
Racemate Configuration of 3- chloro-4-(3,3- dimethylbutyl)phenyl
and methyl group on the cyclohexane ring was estimated to be cis
from NOE 58 ##STR00265## Racemate 59 ##STR00266## Racemate
60 ##STR00267## Racemate 61 ##STR00268## Racemate 62 ##STR00269##
Racemate 63 ##STR00270## Racemate 64 ##STR00271## Racemate.
Estimated structure. 65 ##STR00272## Racemate 66 ##STR00273##
Racemate Single diastereomer Relative configuration of
3-chloro-4-(3,3- dimethylbutyl)phenyl and methyl group on the
cyclohexane ring was uncertain 67 ##STR00274## Enantiomer of
Example 68 (Absolute and relative configurations were not
determined.) Analytical conditions for corresponding ethyl ester
derivative: chiral column IA-3, Hexane/IPA = 85/15, flow 1 ml/min
Retention time: 5.2 min 68 ##STR00275## Enantiomer of Example 67
(Absolute and relative configurations were not determined.)
Analytical conditions for corresponding ethyl ester derivative:
chiral column IA-3, Hexane/IPA = 85/15, flow 1 ml/min Retention
time: 7.8 min 69 ##STR00276## Racemate Single diastereomer Relative
configuration of 3-chloro-4-(3,3- dimethylbutyl)phenyl and methyl
group on the cyclohexane ring was uncertain Diastereomer of Example
66 70 ##STR00277## Optically active (Absolute configuration was not
determined.) (Optical purity was not determined) Single
diastereomer Relative configuration of 3-chloro-4-(3,3-
dimethylbutyl)phenyl and methyl group on the tetrahydropyrane ring
was uncertain Enantiomer of Example 71 71 ##STR00278## Optically
active (Absolute configuration was not determined.) (Optical purity
was not determined) Single diastereomer Relative configuration of
3-chloro-4-(3,3- dimethylbutyl)phenyl and methyl group on the
tetrahydropyrane ring was uncertain Enantiomer of Example 70 72
##STR00279## Optically active (Absolute configuration was not
determined.) (Optical purity was not determined) Single
diastereomer Relative configuration of 3-chloro-4-(3,3-
dimethylbutyl)phenyl and methyl group on the tetrahydropyrane was
uncertain 73 ##STR00280## Racemate Configuration of 3-
chloro-4-(3,3- dimethylbutyl)phenyl and methyl group on the
cyclohexane ring was estimated to be cis 74 ##STR00281## Racemate
75 ##STR00282## Estimated to be optically active. (Absolute and
relative configurations were not determined.) Estimated structure.
76 ##STR00283## Enantiomer of Example 77 (Absolute and relative
configurations were not determined.) Analytical conditions for
corresponding methyl ester derivative: chiral column IA-3,
Hexane/IPA = 85/15, flow 1 ml/min Retention time: 4.0 min 77
##STR00284## Enantiomer of Example 76 (Absolute and relative
configurations were not determined.) Analytical conditions for
corresponding methyl ester derivative: chiral column IA-3,
Hexane/IPA = 85/15, flow 1 ml/min Retention time: 6.5 min 78
##STR00285## Optically active compound of Example 73 (Absolute and
relative configurations were not determined.) Enantiomer of Example
79 (>99% ee for corresponding methyl ester derivative chiral
column IA-3, Hexane/IPA = 85/15, flow 1 ml/min Retention time: 4.2
min) 79 ##STR00286## Optically active compound of Example 73
(Absolute and relative configurations were not determined.)
Enantiomer of Example 78 (>99% ee for corresponding methyl ester
derivative chiral column IA-3, Hexane/IPA = 85/15, flow 1 ml/min
Retention time: 7.2 min) 80 ##STR00287## Optically active compound
of Example 69 (Absolute configuration was not determined.)
Enantiomer of Example 81 (>99% ee for corresponding ethyl ester
derivative chiral column IA-3, Hexane/IPA = 90/10, flow 1 ml/min
Retention time: 5.8 min) Relative configuration of 3-chloro-4-(3,3-
dimethylbutyl)phenyl and methyl group on the cyclohexane ring was
uncertain 81 ##STR00288## Optically active compound of Example 69
(Absolute configuration was not determined.) Enantiomer of Example
80 (>99% ee for corresponding ethyl ester derivative chiral
column IA-3, Hexane/IPA = 90/10, flow 1 ml/min Retention time: 8.6
min) Relative configuration of 3-chloro-4-(3,3-
dimethylbutyl)phenyl and methyl group on the cyclohexane ring was
uncertain 82 ##STR00289## Optically active compound of Example 74
(Absolute configuration was not determined.) Enantiomer of Example
83 (>99% ee for corresponding ethyl ester derivative chiral
column IA-3, Hexane/IPA = 90/10, flow 1 ml/min Retention time: 5.2
min) 83 ##STR00290## Optically active compound of Example 74
(Absolute configuration was not determined.) Enantiomer of Example
82 (>99% ee for corresponding ethyl ester derivative chiral
column IA-3, Hexane/IPA = 90/10, flow 1 ml/min Retention time: 8.9
min) 84 ##STR00291## Enantiomer of Example 85 (Absolute and
relative configurations were not determined.) Analytical conditions
for corresponding methyl ester derivative: chiral column IA-3,
Hexane/IPA = 85/15, flow 1 ml/min Retention time: 3.9 min 85
##STR00292## Enantiomer of Example 84 (Absolute and relative
configurations were not determined.) Analytical conditions for
corresponding methyl ester derivative: chiral column IA-3,
Hexane/IPA = 85/15, flow 1 ml/min Retention time: 6.3 min 86
##STR00293## Enantiomer of Example 87 (Absolute configuration was
not determined.) Analytical conditions for corresponding methyl
ester derivative: chiral column IA-3, Hexane/IPA = 80/20, flow 1
ml/min Retention time: 3.1 min 87 ##STR00294## Enantiomer of
Example 86 (Absolute configuration was not determined.) Analytical
conditions for corresponding methyl ester derivative: chiral column
IA-3, Hexane/IPA = 80/20, flow 1 ml/min Retention time: 5.2 min 88
##STR00295## Racemate 1:1 diastereomeric mixture regarding the
substituents on cyclopropyl 89 ##STR00296## Enantiomer of Example
90 (Absolute and relative configurations were not determined.)
Analytical conditions for corresponding methyl ester derivative:
chiral column IA-3, Hexane/IPA = 90/10, flow 1 ml/min Retention
time: 4.6 min 90 ##STR00297## Enantiomer of Example 89 (Absolute
and relative configurations were not determined.) Analytical
conditions for corresponding methyl ester derivative: chiral column
IA-3, Hexane/IPA = 90/10, flow 1 ml/min Retention time: 8.4 min 91
##STR00298## Enantiomer of Example 92 (Absolute and relative
configurations were not determined.) Analytical conditions for
corresponding methyl ester derivative: chiral column IA-3,
Hexane/IPA = 90/10, flow 1 ml/min Retention time: 4.1 min 92
##STR00299## Enantiomer of Example 91 (Absolute and relative
configurations were not determined.) Analytical conditions for
corresponding methyl ester derivative: chiral column IA-3,
Hexane/IPA = 90/10, flow 1 ml/min Retention time: 7.8 min 93
##STR00300## Enantiomer of Example 94 (Absolute and relative
configurations were not determined.) Analytical conditions for
corresponding methyl ester derivative: chiral column IA-3,
Hexane/IPA = 90/10, flow 1 ml/min Retention time: 4.1 min 94
##STR00301## Enantiomer of Example 93 (Absolute and relative
configurations were not determined.) Analytical conditions for
corresponding methyl ester derivative: chiral column IA-3,
Hexane/IPA = 90/10, flow 1 ml/min Retention time: 7.3 min 95
##STR00302## Racemate 96 ##STR00303## Racemate 97 ##STR00304##
Single diastereomer. Estimated structure. Estimated to be
reacemate. 98 ##STR00305## Optically active (Absolute and relative
configurations were not determined.) Analytical conditions for
corresponding ethyl ester derivative: chiral column IA-3, IPA/Hex.
= 10/90, flow 1 ml/min Retention time: 3.7 min 99 ##STR00306##
Optically active (Absolute and relative configurations were not
determined.) Analytical conditions for corresponding ethyl ester
derivative: chiral column IA-3, IPA/Hex. = 10/90, flow 1 ml/min
Retention time: 6.5 min 100 ##STR00307## Racemate 101 ##STR00308##
Racemate 102 ##STR00309## Enantiomer of Example 103 (Absolute
configuration was not determined.) Analytical conditions for
corresponding methyl ester derivative: chiral column IA-3,
Hexane/IPA = 90/10, flow 1 ml/min Retention time: 4.3 min 103
##STR00310## Enantiomer of Example 102 (Absolute configuration was
not determined.) Analytical conditions for corresponding methyl
ester derivative: chiral column IA-3, Hexane/IPA = 90/10, flow 1
ml/min Retention time: 9.7 min 104 ##STR00311## Optically active
(Absolute and relative configurations were not determined.)
Analytical conditions for corresponding methyl ester derivative:
chiral column AS-3R, MeCN/H.sub.2O = 80/20, flow 1 ml/min Retention
time: 6.8 min Cyclopentane ring moiety was induced from methyl
(1R,3S)-3- aminocyclopentanecarboxylate hydrochloride. 105
##STR00312## Optically active (Absolute and relative configurations
were not determined.) Analytical conditions for corresponding
methyl ester derivative: chiral column AS-3R, MeCN/H.sub.2O =
80/20, flow 1 ml/min Retention time: 7.5 min Cyclopentane ring
moiety was induced from methyl (1R,3S)-3-
aminocyclopentanecarboxylate hydrochloride. 106 ##STR00313##
Optically active. (Absolute configuration was not determined.)
Optical purity was not determined. Single stereoisomer.
Configuration of two methyl groups on the cyclohexane ring was
estimated to be cis. Configuration of the two methyl groups and
3-chloro-4-(3,3- dimethylbutyl)phenyl was estimated to be trans
from NOE. 107 ##STR00314## Optically active. (Absolute
configuration was not determined.) Optical purity was not
determined. Single stereoisomer. Estimated structure. Configuration
of two methyl groups on the cyclohexane ring was estimated to be
trans. Analytical conditions for corresponding methyl ester
derivative: chiral column IA-3, Hexane/IPA = 90/10, flow 1 ml/min
Retention time: 9.7 min 108 ##STR00315## Diastereomeric mixture
(Absolute configuration was not determined.) Enantiomeric mixture
of Example 109 and Example 110 (>99% ee for corresponding methyl
ester derivative chiral column IA-3, Hexane/IPA = 85/15, flow 1
ml/min Retention time: 3.9 min) 109 ##STR00316## Optically active
(Absolute and relative configurations were not determined.)
Enantiomer of Example 108 Diastereomer of Example 110 (>99% ee
for corresponding methyl ester derivative chiral column IA-3,
Hexane/IPA = 85/15, flow 1 ml/min Retention time: 7.6 min) 110
##STR00317## Optically active (Absolute and relative configurations
were not determined.) Enantiomer of Example 108 Diastereomer of
Example 109 (>99% ee for corresponding methyl ester derivative
chiral column IA-3, Hexane/IPA = 85/15, flow 1 ml/min Retention
time: 9.8 min) 111 ##STR00318## Optically active (Absolute and
relative configurations were not determined.) Analytical conditions
for corresponding ethyl ester derivative: chiral column IA-3,
IPA/Hex. = 10/90, flow 1 ml/min Retention time: 6.4 min 112
##STR00319## Optically active (Absolute and relative configurations
were not determined.) Analytical conditions for corresponding ethyl
ester derivative: chiral column IA-3, IPA/Hex. = 10/90, flow 1
ml/min Retention time: 13.3 min 113 ##STR00320## Optically active
(Absolute and relative configurations were not determined.) Optical
purity was not determined Enantiomer of Example 114 114
##STR00321## Optically active (Absolute and relative configurations
were not determined.) Optical purity was not determined Enantiomer
of Example 113 115 ##STR00322## Optically active (Absolute and
relative configurations were not determined.) Optical purity was
not determined Enantiomer of Example 116 116 ##STR00323## Optically
active (Absolute and relative configurations were not determined.)
Optical purity was not determined Enantiomer of Example 115 117
##STR00324## Optically active (Absolute and relative
configurations
were not determined.) Single stereoisomer Enantiomer of Example 118
(>99% ee for corresponding ethyl ester derivative chiral column
IA-3, Hexane/IPA = 90/10, flow 1 ml/min Retention time: 4.2 min)
118 ##STR00325## Optically active (Absolute and relative
configurations were not determined.) Single stereoisomer Enantiomer
of Example 117 (>99% ee for corresponding ethyl ester derivative
chiral column IA-3, Hexane/IPA = 90/10, flow 1 ml/min Retention
time: 11.2 min) 119 ##STR00326## Diastereomeric mixture (Absolute
configuration was not determined.) Enantiomeric mixture of Example
120 and Example 121 (>99% ee for corresponding ethyl ester
derivative chiral column IA-3, Hexane/IPA = 85/15, flow 1 ml/min
Retention time: 6.6, 7.5 min) 120 ##STR00327## Optically active
(Absolute and relative configurations were not determined.) Single
stereoisomer Enantiomer of Example 119 Diastereomer of Example 121
(>99% ee for corresponding ethyl ester derivative chiral column
IA-3, Hexane/IPA = 85/15, flow 1 ml/min Retention time: 12.9 min)
121 ##STR00328## Optically active (Absolute and relative
configurations were not determined.) Single stereoisomer Enantiomer
of Example 119 Diastereomer of Example 120 (>99% ee for
corresponding ethyl ester derivative chiral column IA-3, Hexane/IPA
= 85/15, flow 1 ml/min Retention time: 10.5 min)
TABLE-US-00002 Exam- MS ple .sup.1H-NMR M + H M - H 1 .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta.: 1.02 336 334 (s, 9H), 1.47-1.60
(m, 1H), 1.78- 1.88 (m, 1H), 1.99-2.07 (m, 1H), 2.13-2.19 (m, 1H),
2.53-2.64 (m, 2H), 3.69 (s, 2H), 7.09 (d, J = 8.6 Hz, 1H), 7.12
(dd, J = 8.6, 2.1 Hz, 1H), 7.36 (d, J = 2.1 Hz, 1H), 8.09 (d, J =
1.8 Hz, 1H), 9.63 (d, J = 1.8 Hz, 1H). 2 .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 0.93 413 411 (s, 9H), 1.08 (s, 3H), 1.20 (s,
3H), 1.21-1.26 (m, 2H), 1.43 (ddd, J = 12.0, 7.5, 3.0 Hz, 2H),
1.46-1.51 (m, 1H), 1.53-1.63 (m, 2H), 2.00 (t, J = 8.1 Hz, 2H),
2.06 (td, J = 11.2, 5.7 Hz, 1H), 2.23 (dq, J = 12.8, 3.2 Hz, 1H),
2.45-2.49 (m, 1H), 2.99-3.06 (m, 1H), 3.55 (dt, J = 14.0, 6.6 Hz,
1H), 6.27 (s, 1H), 7.12 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz,
2H), 7.42 (s, 1H), 12.14 (br s, 1H). 3 .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 0.95 433 431 (s, 9H), 1.06 (s, 3H), 1.19 (s,
3H), 1.20-1.24 (m, 1H), 1.37-1.41 (m, 2H), 1.45-1.53 (m, 1H), 2.05
(dt, J = 18.3, 5.9 Hz, 1H), 2.19- 2.25 (m, 1H), 2.33 (t, J = 6.8
Hz, 2H), 2.59-2.63 (m, 2H), 3.28-3.35 (m, 1H), 3.67 (dt, J = 14.2,
6.8 Hz, 1H), 6.38 (s, 1H), 7.23 (dd, J = 8.0, 1.7 Hz, 1H), 7.27 (d,
J = 7.9 Hz, 1H), 7.42 (dr J = 1.6 Hz, 1H), 7.57 (s, 1H), 12.23 (br
s, 1H). 4 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.95 433 431
(s, 9H), 1.06 (s, 3H), 1.19 (s, 3H), 1.20-1.24 (m, 1H), 1.37-1.41
(m, 2H), 1.45-1.53 (m, 1H), 2.05 (dt, J = 18.3, 5.9 Hz, 1H), 2.19-
2.25 (m, 1H), 2.33 (t, J = 6.8 Hz, 2H), 2.59-2.63 (m, 2H),
3.28-3.35 (m, 1H), 3.67 (dt, J = 14.2, 6.8 Hz, 1H), 6.38 (s, 1H),
7.23 (dd, J = 8.0, 1.7 Hz, 1H), 7.27 (d, J = 7.9 Hz, 1H), 7.42 (d,
J = 1.6 Hz, 1H), 7.57 (s, 1H), 12.23 (br s, 1H). 5 .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta.: 0.95 435 433 (s, 9H), 1.18 (s, 3H),
1.36 (s, 3H), 1.37-1.41 (m, 2H), 2.40 (dt, J = 10.5, 3.5 Hz, 2H),
2.62 (ddd, J = 9.3, 4.2, 3.3 Hz, 2H), 3.37 (dt, J = 14.3, 6.8 Hz,
1H), 3.69- 3.76 (m, 1H), 3.83 (d, J = 8.6 Hz, 1H), 4.25 (d, J = 8.6
Hz, 1H), 6.52 (s, 1H), 7.27 (dd, J = 8.0, 1.7 Hz, 1H), 7.30 (d, J =
7.9 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.59 (s, 1H), 12.28 (br s,
1H). 6 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.95 435 433
(s, 9H), 1.18 (s, 3H), 1.36 (s, 3H), 1.37-1.41 (m, 2H), 2.40 (dt, J
= 10.5, 3.5 Hz, 2H), 2.62 (ddd, J = 9.3, 4.2, 3.3 Hz, 2H), 3.37
(dt, j = 14.3, 6.8 Hz, 1H), 3.69- 3.76 (m, 1H), 3.83 (d, J = 8.6
Hz, 1H), 4.25 (d, J = 8.6 Hz, 1H), 6.52 (s, 1H), 7.27 (dd, J = 8.0,
1.7 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H),
7.59 (s, 1H), 12.28 (br s, 1H), 7 .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 0.93 483 481 (s, 9H), 1.27 (s, 3H),
1.33-1.41 (m, 2H), 1.44 (s, 3H), 2.57-2.66 (m, 2H), 3.90-3.97 (m,
2H), 4.28- 4.35 (m, 2H), 6.86 (br s, 1H), 7.32-7.42 (m, 2H),
7.43-7.56 (m, 3H), 7.89-7.96 (m, 2H), 8.11 (br s, 1H), 12.90 (br s,
1H). 8 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.93 483 481
(s, 9H), 1.28 (s, 3H), 1.33-1.41 (m, 2H), 2.63 (s, 3H), 3.90-3.98
(m, 2H), 4.28-4.36 (m, 2H), 7.30- 7.44 (m, 2H), 7.44-7.56 (m, 3H),
7.87-7.96 (m, 2H), 8.11 (br s, 1H), 12.91 (br s, 1H). 9 .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta.: 0.92 481 479 (s, 9H), 1.15 (s,
3H), 1.22-1.33 (m, 4H), 1.33-1.41 (m, 2H), 1.51- 1.60 (m, 1H),
2.09-2.21 (m, 1H), 2.21-2.30 (m, 1H), 2.57-2.63 (m, 2H), 6.67 (s,
1H), 7.29-7.37 (m, 2H), 7.42-7.47 (m, 2H), 7.50-7.53 (m, 1H),
7.86-7.91 (m, 2H), 8.12, (br s, 1H), 12.85 (br s, 1H) 10
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.93 481 479 (s, 9H),
1.15 (s, 3H), 1.20-1.34 (m, 4H), 1.33-1.42 (m, 2H), 1.50- 1.63 (m,
1H), 2.10-2.22 (m, 1H), 2.22-2.33 (m, 1H), 2.55-2.64 (m, 2H), 6.87
(s, 1H), 7.28-7.37 (m, 2H), 7.41-7.48 (m, 2H), 7.50-7.55 (m, 1H),
7.85-7.93 (m, 2H), 8.12 (s, 1H), 12.85 (br s, 1H). 11 .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta.: 0.97 419 417 (s, 9H), 1.11 (d, J =
19.08 Hz, 3H), 1.40-1.48 (m, 2H), 1.86-2.07 (m, 2H), 2.33-2.41 (m,
1H), 2.51- 2.59 (m, 2H), 2.60-2.68 (m, 2H), 2.80-2.92 (m, 1H),
3.49-3.59 (m, 1H), 3.76-3.87 (m, 1H), 6.17-6.20 (m, 1H), 6.51 (br
s, 1H), 7.14- 7.16 (m, 2H), 7.30 (br s, 1H). 12 .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta.: 0.97 419 417 (s, 9H), 1.11 (d, J = 19.08
Hz, 3H), 1.40-1.48 (m, 2H), 1.86-2.07 (m, 2H), 2.33-2.41 (m, 1H),
2.51- 2.59 (m, 2H), 2.60-2.68 (m, 2H), 2.80-2.92 (m, 1H), 3.49-3.59
(m, 1H), 3.76-3.87 (m, 1H), 6.17-6.20 (m, 1H), 6.51 (br s, 1H),
7.14- 7.16 (m, 2H), 7.30 (br s, 1H). 13 .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta.: 0.96 534 532 (s, 9H), 1.19-1.29 (m, 5H), 1.37-
1.50 (m, 11H), 2.59-2.69 (m, 2H), 3.52-3.61 (m, 2H), 3.86-4.22 (m,
6H), 5.39 (br s, 1H), 6.25 (br s, 1H), 7.07-7.14 (m, 1H), 7.17-7.22
(m, 1H), 7.23-7.25 (m, 1H). 14 .sup.1H-NMR (400 MHz, MeOH-d.sub.4)
.delta.: 1.01 448 446 (s, 9H), 1.41-1.49 (m, 2H), 2.05 (s, 3H),
2.55-2.62 (m, 2H), 2.68- 2.786 (m, 2H), 3.48-3.64 (m, 2H),
3.80-3.95 (m, 2H), 4.05-4.55 (m, 3H), 6.55 (br s, 1H), 7.21-7.33
(m, 2H), 7.37-7.41 (m, 1H). 15 .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta.: 0.94 527 525 (s, 9H), 1.33-1.38 (m, 2H), 2.35- 2.40 (m,
2H), 2.57-2.61 (m, 2H), 3.35-3.41 (m, 3H), 3.65-3.72 (m, 1H), 3.77
(d, J = 8.55 Hz, 1H), 4.33 (d, J = 8.55 Hz, 1H), 4.42 (d, J = 12.95
Hz, 1H), 4.47 (d, J = 12.95 Hz, 1H), 4.74-4.78 (m, 1H), 6.56 (d, J
= 1.62 Hz, 1H), 7.20-7.35 (m, 7H), 7.41 (s, 1H), 7.65 (s, 1H),
12.18 (br s, 1H). 16 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.:
0.94 527 525 (s, 9H), 1.33-1.38 (m, 2H), 2.35- 2.40 (m, 2H),
2.57-2.61 (m, 2H), 3.35-3.41 (m, 3H), 3.65-3.72 (m, 1H), 3.77 (d, J
= 8.55 Hz, 1H), 4.33 (d, J = 8.55 Hz, 1H), 4.42 (d, J = 12.95 Hz,
1H), 4.47 (d, J = 12.95 Hz, 1H), 4.74-4.78 (m, 1H), 6.56 (d, J =
1.62 Hz, 1H), 7.20-7.35 (m, 7H), 7.41 (s, 1H), 7.65 (s, 1H), 12.18
(br s, 1H). 17 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.94
437 435 (s, 9H), 1.35-1.39 (m, 2H), 2.39 (dd, J = 7.17, 2.77 Hz,
2H), 2.58- 2.63 (m, 2H), 3.25-3.33 (m, 1H), 3.35-3.42 (m, 1H),
3.64-3.71 (m, 1H), 3.76 (d, J = 8.32 Hz, 1H), 4.29 (d, J = 8.55 Hz,
1H), 4.55 (dd, J = 7.17, 6.94 Hz, 1H), 4.87 (dd, J = 6.94, 5.78 Hz,
1H), 6.50 (d, J = 1.62 Hz, 1H), 7.26 (d, J = 8.09 Hz, 1H), 7.28 (d,
J = 8.09 Hz, 1H), 7.43 (s, 1H), 7.64 (s, 1H), 12.21 (s, 1H). 18
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.94 437 435 (s, 9H),
1.35-1.39 (m, 2H), 2.39 (dd, J = 7.17, 2.77 Hz, 2H), 2.58- 2.63 (m,
2H), 3.25-3.33 (m, 1H), 3.35-3.42 (m, 1H), 3.64-3.71 (m, 1H), 3.76
(d, J = 8.32 Hz, 1H), 4.29 (d, J = 8.55 Hz, 1H), 4.55 (dd, J =
7.17, 6.94 Hz, 1H), 4.87 (dd, J = 6.94, 5.78 Hz, 1H), 6.50 (d, J =
1.62 Hz, 1H), 7.26 (d, J = 8.09 Hz, 1H), 7.28 (d, J = 8.09 Hz, 1H),
7.43 (s, 1H), 7.64 (s, 1H), 12.21 (s, 1H). 19 .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 0.94 451 449 (s, 9H), 1.36-1.40 (m, 2H),
2.31- 2.45 (m, 2H), 2.59-2.63 (m, 2H), 3.18-3.25 (m, 1H), 3.21 (s,
3H), 3.27-3.33 (m, 1H), 3.35-3.42 (m, 1H), 3.64-3.71 (m, 1H), 3.76
(d, J = 8.55 Hz, 1H), 4.31 (d, J = 8.55 Hz, 1H), 4.71 (dd, J =
7.17, 4.16 Hz, 1H), 6.55 (d, J = 1.62 Hz, 1H), 7.24 (dd, J = 7.86,
1.62 Hz, 1H), 7.29 (d, J = 7.86 Hz, 1H), 7.42 (d, J = 1.62 Hz, 1H),
7.67 (s, 1H), 12.22 (s, 1H). 20 .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta.: 0.94 451 449 (s, 9H), 1.36-1.40 (m, 2H), 2.31- 2.45 (m,
2H), 2.59-2.63 (m, 2H), 3.18-3.25 (m, 1H), 3.21 (s, 3H), 3.27-3.33
(m, 1H), 3.35-3.42 (m, 1H), 3.64-3.71 (m, 1H), 3.76 (d, J = 8.55
Hz, 1H), 4.31 (d, J = 8.55 Hz, 1H), 4.71 (dd, J = 7.17, 4.16 Hz,
1H), 6.55 (d, J = 1.62 Hz, 1H), 7.24 (dd, J = 7.86, 1.62 Hz, 1H),
7.29 (d, J = 7.86 Hz, 1H), 7.42 (d, J = 1.62 Hz, 1H), 7.67 (s, 1H),
12.22 (s, 1H). 21 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.95
493 491 (s, 9H), 1.09 (s, 9H), 1.36-1.41 (m, 2H), 2.35-2.44 (m,
2H), 2.60- 2.64 (m, 2H), 3.20 (dd, J = 8.32, 5.78 Hz, 1H),
3.25-3.29 (m, 1H), 3.36-3.43 (m, 1H), 3.67-3.74 (m, 1H), 3.76 (t, J
= 6.36 Hz, 1H), 4.31 (d, J = 8.32 Hz, 1H), 4.58 (dd, J = 6.24, 5.78
Hz, 1H), 6.52 (d, J = 1.85 Hz, 1H), 7.28 (d, J = 7.17 Hz, 1H), 7.30
(d, J = 7.17 Hz, 1H), 7.44 (s, 1H), 7.67 (s, 1H). 22 .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta.: 0.95 493 491 (s, 9H), 1.09 (s,
9H), 1.36-1.41 (m, 2H), 2.35-2.44 (m, 2H), 2.60- 2.64 (m, 2H), 3.20
(dd, J = 8.32, 5.78 Hz, 1H), 3.25-3.29 (m, 1H), 3.36-3.43 (m, 1H),
3.67-3.74 (m, 1H), 3.76 (t, J = 6.36 Hz, 1H), 4.31 (d, J = 8.32 Hz,
1H), 4.58 (dd, J = 6.24, 5.78 Hz, 1H), 6.52 (d, J = 1.85 Hz, 1H),
7.28 (d, J = 7.17 Hz, 1H), 7.30 (d, J = 7.17 Hz, 1H), 7.44 (s, 1H),
7.67 (s, 1H). 23 .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.79-
333 -- 0.90 (m, 1H), 0.97 (s, 9H), 1.42- 1.46 (m, 2H), 1.78-1.88
(m, 1H), 2.03-2.11 (m, 1H), 2.32-2.42 (m, 2H), 2.46-2.54 (m, 1H),
2.63-2.67 (m, 2H), 5.42 (s, 1H), 6.03 (s, 1H), 6.10 (s, 1H), 7.15
(dd, J = 8.06, 1.61 Hz, 1H), 7.18 (d, J =
8.06 Hz, 1H), 7.27 (d, J = 1.61 Hz, 1H). 24 .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 0.93 405 403 (s, 9H), 1.35-1.39 (m, 3H),
1.65- 1.73 (m, 1H), 1.89-1.97 (m, 1H), 2.12-2.17 (m, 1H), 2.22-2.34
(m, 3H), 2.40-2.45 (m, 1H), 2.57-2.61 (m, 2H), 3.36-3.42 (m, 1H),
3.52- 3.59 (m, 1H), 6.29 (s, 1H), 7.19 (dd, J = 7.86, 1.85 Hz, 1H),
7.25 (d, J = 7.86 Hz, 1H), 7.37 (d, J = 1.85 Hz, 1H), 7.61 (br s,
1H). 25 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.91- 449 447
0.82 (m, 1H), 0.93 (s, 9H), 1.32- 1.40 (m, 3H), 1.56-1.64 (m, 1H),
1.82-1.90 (m, 2H), 2.25-2.35 (m, 3H), 2.57-2.61 (m, 2H), 2.75-2.83
(m, 1H), 3.39-3.46 (m, 3H), 3.60- 3.67 (m, 1H), 4.39 (t, J = 5.09
Hz, 1H), 6.34 (d, J = 1.85 Hz, 1H), 7.22 (dd, J = 8.09, 1.39 Hz,
1H), 7.25 (d, J = 8.09 Hz, 1H), 7.41 (d, J = 1.39 Hz, 1H), 7.56 (s,
1H), 12.20 (br s, 1H). 26 .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta.: 0.95 539 537 (s, 9H), 1.01-1.09 (m, 1H), 1.39- 1.43 (m,
2H), 1.54-1.63 (m, 1H), 1.64-1.73 (m, 1H), 1.88-2.03 (m, 2H), 2.42
(dd, J = 11.21, 6.13 Hz, 1H), 2.49-2.53 (m, 2H), 2.59-2.63 (m, 2H),
2.89-2.97 (m, 1H), 3.39- 3.54 (m, 3H), 3.75-3.82 (m, 1H), 4.46 (d,
J = 11.79 Hz, 1H), 4.50 (d, J = 11.79 Hz, 1H), 6.04 (d, J = 1.62
Hz, 1H), 6.14 (s, 1H), 7.10 (dd, J = 8.32, 1.39 Hz, 1H), 7.12 (d, J
= 8.32 Hz, 1H), 7.26-7.34 (m, 6H). 27 .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 0.91- 463 461 0.84 (m, 1H), 0.93 (s, 9H),
1.34- 1.47 (m, 3H), 1.60-1.68 (m, 1H), 1.81-1.90 (m, 2H), 2.26-2.35
(m, 3H), 2.57-2.61 (m, 2H), 2.73-2.80 (m, 1H), 3.21 (s, 3H),
3.31-3.38 (m, 3H), 3.61-3.68 (m, 1H), 6.34 (d, J = 1.62 Hz, 1H),
7.22 (dd, J = 7.86, 1.39 Hz, 1H), 7.25 (d, J = 7.86 Hz, 1H), 7.41
(d, J = 1.39 Hz, 1H), 7.56 (s, 1H), 12.20 (s, 1H). 28 .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta.: 0.91- 476 474 0.84 (m, 1H), 0.95
(s, 9H), 1.29- 1.42 (m, 4H), 1.54-1.61 (m, 1H), 1.83-1.94 (m, 4H),
2.10 (s, 6H), 2.17-2.28 (m, 3H), 2.59-2.63 (m, 2H), 3.20-3.27 (m,
1H), 3.48-3.55 (m, 1H), 6.41 (d, J = 1.49 Hz, 1H), 7.26 (d, J =
8.07 Hz, 1H), 7.28 (d, J = 8.07 Hz, 1H), 7.35 (s, 1H), 7.42 (s,
1H). 29 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.92- 435 433
0.86 (m, 1H), 0.93 (s, 9H), 1.35- 1.40 (m, 2H), 1.77-1.92 (m, 2H),
2.27-2.35 (m, 3H), 2.57-2.61 (m, 2H), 2.79-2.87 (m, 1H), 3.17-3.37
(m, 3H), 3.57-3.64 (m, 1H), 4.65 (br s, 1H), 6.39 (d, J = 1.85 Hz,
1H), 7.24-7.26 (m, 2H), 7.42 (s, 1H), 7.57 (s, 1H). 30 .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta.: 0.92- 476 474 0.85 (m, 1H), 0.94
(s, 9H), 1.36- 1.40 (m, 2H), 1.79 (s, 3H), 1.81- 1.90 (m, 2H),
2.26-2.38 (m, 3H), 2.58-2.62 (m, 2H), 2.83-2.92 (m, 2H), 3.03-3.11
(m, 1H), 3.31-3.37 (m, 1H), 3.59-3.66 (m, 1H), 6.39 (s, 1H),
7.24-7.28 (m, 2H), 7.44 (s, 1H), 7.57 (s, 1H), 7.85-7.88 (m, 1H),
12.23 (br s, 1H). 31 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.:
0.93 444 442 (s, 9H), 0.97-1.06 (m, 1H), 1.36- 1.40 (m, 2H),
1.88-2.00 (m, 2H), 2.30-2.36 (m, 3H), 2.51-2.62 (m, 4H), 3.01-3.08
(m, 1H), 3.32-3.38 (m, 1H), 3.60-3.67 (m, 1H), 6.58 (d, J = 1.85
Hz, 1H), 7.21 (dd, J = 7.86, 1.85 Hz, 1H), 7.26 (d, J = 7.86 Hz,
1H), 7.43 (d, J = 1.85 Hz, 1H), 7.69 (s, 1H), 12.21 (br s, 1H). 32
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.95 433 431 (s, 9H),
0.99 (s, 3H), 1.10 (s, 3H), 1.38-1.45 (m, 2H), 1.96-2.02 (m, 1H),
2.13-2.23 (m, 2H), 2.26- 2.33 (m, 1H), 2.54-2.66 (m, 4H), 3.45-3.56
(m, 1H), 3.79-3.92 (m, 1H), 5.70-5.76 (m, 1H), 6.14 (br s, 1H),
7.04-7.09 (m, 1H), 7.11- 7.16 (m, 1H), 7.18-7.21 (m, 1H). 33
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.95 433 431 (s, 9H),
0.99 (s, 3H), 1.10 (s, 3H), 1.38-1.45 (m, 2H), 1.96-2.02 (m, 1H),
2.13-2.23 (m, 2H), 2.26- 2.33 (m, 1H), 2.54-2.66 (m, 4H), 3.45-3.56
(m, 1H), 3.79-3.92 (m, 1H), 5.70-5.76 (m, 1H), 6.14 (br s, 1H),
7.04-7.09 (m, 1H), 7.11- 7.16 (m, 1H), 7.18-7.21 (m, 1H). 34
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.65 485 483 (s, 3H),
0.84 (d, J = 6.47 Hz, 3H), 0.93 (s, 9H), 1.02 (s, 3H), 1.36-1.40
(m, 2H), 2.05 (s, 2H), 2.19 (s, 6H), 2.40 (q, J = 6.47 Hz, 1H),
2.57-2.61 (m, 2H), 6.45 (d, J = 0.92 Hz, 1H), 7.17 (dd, J = 8.09,
1.85 Hz, 1H), 7.25 (d, J = 8.09 Hz, 1H), 7.34 (d, J = 1.85 Hz, 1H),
7.52 (s, 1H), 12.43 (s, 1H). 35 .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta.: 0.65 485 483 (s, 3H), 0.84 (d, J = 6.47 Hz, 3H), 0.93 (s,
9H), 1.02 (s, 3H), 1.36-1.40 (m, 2H), 2.05 (s, 2H), 2.19 (s, 6H),
2.40 (q, J = 6.47 Hz, 1H), 2.57-2.61 (m, 2H), 6.45 (d, J = 0.92 Hz,
1H), 7.17 (dd, J = 8.09, 1.85 Hz, 1H), 7.25 (d, J = 8.09 Hz, 1H),
7.34 (d, J = 1.85 Hz, 1H), 7.52 (s, 1H), 12.43 (s, 1H). 36
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 1.02 350 348 (s, 9H),
1.15-1.08 (m, 1H), 1.40- 1.48 (m, 1H), 1.61-1.65 (m, 1H), 1.73-1.81
(m, 2H), 2.08-2.18 (m, 1H), 2.41-2.55 (m, 2H), 3.71 (s, 2H), 7.11
(dd, J = 8.60, 1.76 Hz, 1H), 7.14 (d, J = 8.60 Hz, 1H), 7.30 (d, J
= 1.76 Hz, 1H), 7.58 (d, J = 1.98 Hz, 1H), 9.64 (d, J = 1.98 Hz,
1H). 37 .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.58 447 445 (s,
3H), 0.97 (s, 9H), 1.14 (s, 3H), 1.34-1.49 (m, 4H), 1.51-1.73 (m,
3H), 1.82-1.93 (m, 1H), 2.54- 2.76 (m, 4H), 3.60-3.72 (m, 1H),
3.79-3.92 (m, 1H), 5.08-5.17 (br 1H), 6.12 (br s, 1H), 7.14-7.22
(m, 2H), 7.30-7.36 (m, 1H). 38 .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta.: 0.58 447 445 (s, 3H), 0.97 (s, 9H), 1.14 (s, 3H),
1.34-1.49 (m, 4H), 1.51-1.73 (m, 3H), 1.82-1.93 (m, 1H), 2.54- 2.7
(m, 4H), 3.60-3.72 (m, 1H), 3.79-3.92 (m, 1H), 5.08-5.17 (br m,
1H), 6.12 (br s, 1H), 7.14-7.22 (m, 2H), 7.30-7.36 (m, 1H). 39
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.95 419 417 (s, 9H),
0.98-1.06 (m, 1H), 1.23- 1.30 (m, 1H), 1.38-1.42 (m, 2H), 1.59-1.81
(m, 4H), 2.16-2.22 (m, 1H), 2.42 (t, J = 7.05 Hz, 2H), 2.52-2.57
(m, 1H), 2.61-2.65 (m, 2H), 3.35-3.42 (m, 1H), 3.58-3.65 (m, 1H),
6.23 (d, J = 1.62 Hz, 1H), 7.07 (s, 1H), 7.24 (dd, J = 8.09, 1.85
Hz, 1H), 7.33 (d, J = 8.09 Hz, 1H), 7.35 (d, J = 1.85 Hz, 1H),
12.24 (s, 1H). 40 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.95
419 417 (s, 9H), 0.98-1.06 (m, 1H), 1.23- 1.30 (m, 1H), 1.38-1.42
(m, 2H), 1.59-1.81 (m, 4H), 2.16-2.22 (m, 1H), 2.42 (t, J = 7.05
Hz, 2H), 2.52-2.57 (m, 1H), 2.61-2.65 (m, 2H), 3.35-3.42 (m, 1H),
3.58-3.65 (m, 1H), 6.23 (d, J = 1.62 Hz, 1H), 7.07 (s, 1H), 7.24
(dd, J = 8.09, 1.85 Hz, 1H), 7.33 (d, J = 8.09 Hz, 1H), 7.35 (d, J
= 1.85 Hz, 1H), 12.24 (s, 1H). 41 .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 0.95 419 417 (s, 9H), 0.98-1.06 (m, 1H),
1.23- 1.30 (m, 1H), 1.38-1.42 (m, 2H), 1.59-1.81 (m, 4H), 2.16-2.22
(m, 1H), 2.42 (t, J = 7.05 Hz, 2H), 2.52-2.57 (m, 1H), 2.61-2.65
(m, 2H), 3.35-3.42 (m, 1H), 3.58-3.65 (m, 1H), 6.23 (d, J = 1.62
Hz, 1H), 7.07 (s, 1H), 7.24 (dd, J = 8.09, 1.85 Hz, 1H), 7.33 (d, J
= 8.09 Hz, 1H), 7.35 (d, J = 1.85 Hz, 1H), 12.24 (s, 1H). 42
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.95 433 431 (s, 9H),
1.00-1.06 (m, 1H), 1.23- 1.31 (m, 1H), 1.37-1.42 (m, 2H), 1.55-1.74
(m, 4H), 2.00 (s, 3H), 2.15-2.23 (m, 1H), 2.32-2.44 (m, 3H),
2.59-2.64 (m, 2H), 3.52-3.59 (m, 1H), 3.77-3.84 (m, 1H), 7.15- 7.18
(m, 2H), 7.28-7.31 (m, 2H), 12.19 (s, 1H). 43 .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 0.92 553 551 (s, 9H), 0.94-1.09 (m, 2H),
1.32- 1.42 (m, 3H), 1.53-1.66 (m, 5H), 2.40-2.48 (m, 3H), 2.58-2.68
(m, 3H), 3.16-3.22 (m, 1H), 3.33-3.40 (m, 1H), 3.67-3.74 (m, 1H),
4.30, (d, J = 11.79 Hz, 1H), 4.34 (d, J = 11.79 Hz, 1H), 6.14 (s,
1H), 7.00 (s, 1H), 7.25-7.28 (m, 5H), 7.31-7.35 (m, 3H), 12.31 (s,
1H). 44 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.94- 463 461
0.88 (m, 2H), 0.95 (s, 9H), 1.33- 1.41 (m, 3H), 1.52-1.66 (m, 4H),
2.46-2.50 (m, 3H), 2.60-2.67 (m, 3H), 3.12-3.17 (m, 1H), 3.23-3.29
(m, 1H), 3.36-3.43 (m, 1H), 3.68- 3.75 (m, 1H), 4.19 (s, 1H), 6.23
(s, 1H), 6.97 (s, 1H), 7.24-7.31 (m, 3H), 12.30 (s, 1H). 45
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.95 505 503 (s, 9H),
1.20 (t, J = 7.09 Hz, 3H), 1.26-1.34 (m, 1H), 1.38-1.42 (m, 2H),
1.50-1.81 (m, 6H), 2.53 (t, J = 6.94 Hz, 2H), 2.62-2.67 (m, 3H),
2.80-2.85 (m, 1H), 3.39- 3.46 (m, 1H), 3.70-3.77 (m, 1H), 4.10 (q,
J = 7.09 Hz, 2H), 6.34 (s, 1H), 7.05 (s, 1H), 7.23 (dd, J = 8.09,
2.08 Hz, 1H), 7.30 (d, J = 8.09 Hz, 1H), 7.31 (d, J = 2.08 Hz, 1H),
11.97 (s, 1H). 46 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.:
0.90- 477 475 1.02 (m, 2H), 0.95 (s, 9H), 1.35- 1.40 (m, 3H),
1.53-1.67 (m, 4H), 2.37-2.42 (m, 1H) 2.46-2.52 (m, 2H), 2.60-2.67
(m, 3H), 3.02-3.07 (m, 1H), 3.11 (s, 3H), 3.14-3.21 (m, 1H),
3.35-3.42 (m, 1H), 3.70- 3.77 (m, 1H), 6.18 (s, 1H), 7.00 (s, 1H),
7.25-7.32 (m, 3H), 12.29 (s, 1H). 47 .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 0.93- 476 -- 0.98 (m, 1H), 0.96 (s, 9H),
1.21 (t, J = 7.09 Hz, 3H), 1.37-1.41 (m, 2H), 1.45-1.74 (m, 4H),
2.09- 2.14 (m, 1H), 2.18-2.26 (m, 1H), 2.57-2.69 (m, 6H), 3.45-3.52
(m, 1H), 3.70-3.76 (m, 1H), 4.11 (q, J = 7.09 Hz, 2H), 6.36 (s,
1H), 7.16 1H), 7.25-7.34 (m, 3H), 7.51
(s, 3H). 48 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.95 541
539 (s, 9H), 1.03-1.10 (m, 1H), 1.18- 1.26 (m, 1H), 1.32-1.41 (m,
3H), 1.57-1.69 (m, 4H), 2.44-2.51 (m, 3H), 2.61-2.68 (m, 3H), 3.14
(s, 3H), 3.35-3.42 (m, 1H), 3.69-3.76 (m, 1H), 3.90-3.95 (m, 1H),
4.02- 4.08 (m, 1H), 6.28 (s, 1H), 7.05 (s, 1H), 7.26-7.32 (m, 3H),
12.30 (s, 1H). 49 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.96
504 -- (s, 9H), 1.03-1.12 (m, 2H), 1.22 (t, J = 7.17 Hz, 3H),
1.33-1.40 (m, 3H), 1.54-1.68 (m, 5H), 2.36- 2.42 (m, 1H), 2.37 (s,
3H), 2.56- 2.65 (m, 5H), 2.75-2.82 (m, 1H), 3.38-3.45 (m, 1H),
3.74-3.81 (m, 1H), 4.12 (q, J = 7.17 Hz, 2H), 6.33 (s, 1H), 7.10
(s, 1H), 7.24 (dd, J = 8.09, 1.85 Hz, 1H), 7.30 (d, J = 1.85 Hz,
1H), 7.31 (d, J = 8.09 Hz, 1H), 8.09 (s, 2H). 50 .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta.: 0.95 518 -- (s, 9H), 1.00-1.20 (m, 3H),
1.22 ( t, J = 7.17 Hz, 3H), 1.30-1.70 (m, 8H), 2.33-2.68 (m, 80H),
3.40- 3.47 (m, 1H), 3.72-3.80 (m, 1H), 4.12 (q, J = 7.17 Hz, 2H),
6.29 (s, 1H), 7.12 (s, 1H), 7.25-7.35 (m, 3H), 9.24 (br s, 1H). 51
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.95 476 474 (s, 9H),
1.31-1.70 (m, 6H), 2.41- 2.52 (m, 5H), 2.61-2.67 (m, 3H), 2.84-2.91
(m, 1H), 3.35-3.44 (m, 1H), 3.65-3.71 (m, 1H), 6.36 (s, 1H), 6.64
(s, 1H), 7.00 (s, 1H), 7.21-7.38 (m, 3H), 12.29 (br s, 1H). 52
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.95 458 456 (s, 9H),
1.21-1.32 (m, 1H), 1.37- 1.44 (m, 2H), 1.52-1.70 (m, 4H), 1.83 (dd,
J = 16.76, 9.13 Hz, 1H), 2.13 (dd, J = 16.76, 6.82 Hz, 1H),
2.45-2.53 (m, 2H), 2.62-2.67 (m, 3H), 2.70-2.78 (m, 1H), 3.41-3.48
(m, 1H), 3.67-3.74 (m, 1H), 6.48 (s, 1H), 7.15 (s, 1H), 7.27-7.38
(m, 3H), 12.31 (br s, 1H). 53 .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta.: 0.95 457 455 (s, 9H), 0.96-1.05 (m, 1H), 1.21- 1.33 (m,
1H), 1.37-1.42 (m, 2H), 1.56-1.73 (m, 3H), 1.76-1.85 (m, 1H),
2.25-2.29 (m, 1H), 2.25 (s, 6H), 2.40-2.57 (m, 1H), 2.61-2.65 (m,
2H), 6.20 (d, J = 1.47 Hz, 1H), 7.16 (s, 1H), 7.22 (dd, J = 8.07,
1.96 Hz, 1H), 7.34-7.36 (m, 2H), 12.48 (s, 1H). 54 .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta.: 0.95 457 455 (s, 9H), 0.96-1.05 (m,
1H), 1.21- 1.33 (s, 1H), 1.37-1.42 (m, 2H), 1.56-1.73 (m, 3H),
1.76-1.85 (m, 1H), 2.25-2.29 (s, 1H), 2.25 (s, 6H), 2.48-2.57 (m,
1H), 2.61-2.65 (m, 2H), 6.20 (d, J = 1.47 Hz, 1H), 7.16 (s, 1H),
7.22 (dd, J = 8.07, 1.96 Hz, (H), 7.34-7.36 (m, 2H), 12.48 (s, 1H).
55 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.95 449 447 (s,
9H), 1.17-1.26 (s, 1H), 1.30- 1.42 (m, 3H), 1.44-1.52 (m, 1H),
1.58-1.68 (m, 1H), 1.76-1.83 (m, 1H), 2.41-2.50 (m, 2H), 2.57-2.69
(m, 4H), 2.80-2.87 (m, 1H), 3.35- 3.44 (m, 1H), 3.62-3.73 (m, 1H),
4.35-4.40 (m, 1H), 6.31 (s, 1H), 7.02 (s, 1H), 7.22-7.34 (m, 3H),
12.30 (br s, 1H). 56 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.:
0.95 463 461 (s, 9H), 1.11-1.23 (m, 1H), 1.36- 1.69 (m, 6H),
2.41-2.47 (m, 2H), 2.50-2.73 (m, 8H), 3.01 (s, 3H), 3.39-3.47 (m,
1H), 3.61-3.67 (m, 1H), 6.31 (s, 1H), 7.05 (s, 1H), 7.24-7.40 (m,
3H), 12.29 (br s, 1H). 57 .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta.: 0.60 433 431 (d, J = 7.63 Hz, 3H), 0.95 (s, 9H), 1.30-1.43
(m, 1H), 1.48-1.67 (m, 3H), 2.43-2.68 (m, 6H), 3.33- 3.43 (m, 1H),
3.64-3.73 (m, 1H), 6.31 (s, 1H), 7.00 (s, 1H), 7.24- 7.36 (m, 3H),
12.31 (br s, 1H). 58 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.:
0.96 421 419 (s, 9H), 1.35-1.42 (m, 2H), 1.97- 2.08 (m, 2H),
2.43-2.50 (m, 2H), 2.58-2.67 (m, 2H), 3.34-3.46 (m, 3H), 3.65-3.72
(m, 1H), 3.88-3.95 (m, 1H), 4.32 (d, J = 11.10 Hz, 1H), 6.24 (s,
1H), 7.09 (s, 1H), 7.30-7.46 (m, 3H), 12.24 (br s, 1H). 59
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.94 421 419 (d, J =
5.50 Hz, 6H), 0.98-1.07 (m, 1H), 1.23-1.29 (m, 1H), 1.57- 1.85 (m,
7H), 2.13-2.20 (m, 1H), 2.40 (t, J = 7.05 Hz, 2H), 2.49- 2.56 (m,
1H), 3.34-3.42 (m, 1H), 3.57-3.64 (m, 1H), 4.07 (t, J = 6.47 Hz,
2H), 6.22 (s, 1H), 7.04 (s, 1H), 7.11-7.38 (m, 3H), 12.28 (s, 1H).
60 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.99- 421 419 1.06
(m, 1H), 1.03 (s, 9H), 1.20- 1.29 (m, 1H), 1.56-1.83 (m, 4H),
2.14-2.20 (m, 1H), 2.40 (t, J = 6.94 Hz, 2H), 2.47-2.56 (m, 1H),
3.34-3.41 (m, 1H), 3.57-3.65 (m, 1H), 3.70 (s, 2H), 6.22 (s, 1H),
7.04 (s, 1H), 7.09 (d, J = 8.55 Hz, 1H), 7.23 (dd, J = 8.55, 2.31
Hz, 1H), 7.37 (d, J = 2.31 Hz, 1H), 12.26 (br s, 1H). 61
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.95- 435 433 1.08 (m,
1H), 0.97 (s, 2H), 1.20- 1.35 (m, 2H), 1.56-1.82 (m, 6H), 2.13-2.21
(m, 1H), 2.42 (t, J = 6.90 Hz, 2H), 2.48-2.56 (m, 1H), 3.33-3.12
(m, 1H), 3.58-3.66 (m, 1H), 4.10 (t, J = 6.90 Hz, 2H), 6.22 (d, J =
1.39 Hz, 1H), 7.05 (s, 1H), 7.15 (d, J = 8.73 Hz, 1H), 7.24 (dd, J
= 8.73, 2.14 Hz, 1H), 7.36 (d, J = 2.14 Hz, 1H), 12.20 (br s, 1H).
62 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.96- 433 431 1.07
(m, 1H), 1.20-1.31 (m, 1H), 1.55-1.87 (m, 1H), 2.01-2.09 (m, 2H),
2.13-2.20 (m, 1H), 2.39 (t, J = 7.05 Hz, 2H), 2.42-2.47 (m, 1H),
2.19-2.55 (m, 1H), 3.34-3.41 (m, 1H), 3.56-3.65 (m, 1H), 3.98 (t, J
= 6.36 Hz, 2H), 6.22 (d, J = 1.62 Hz, 1H), 7.03 (s, 1H), 7.10 (d, J
= 8.55 Hz, 1H), 7.23 (dd, J = 8.55, 2.31 Hz, 1H), 7.36 (d, J = 2.31
Hz, 1H), 12.29 (br s, 1H). 63 .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta.: 0.95 455 493 (s, 9H), 1.38-1.59 (m, 3H), 1.88- 1.97 (m,
1H), 2.00-2.34 (m, 2H), 2.41-2.46 (m, 2H), 2.59-2.74 (m, 4H),
3.37-3.45 (m, 1H), 3.62-3.70 (m, 1H), 6.46 (d, J = 1.35 Hz, 1H),
7.25-7.41 (m, 4H), 12.28 (br s, 1H). 64 .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta.: 0.38 447 445 (s, 3H), 0.91 (s, 3H), 0.96 (s,
9H), 1.23-1.40 (m, 2H), 1.40-1.47 (m, 2H), 1.80-1.89 (m, 1H), 2.15-
2.23 (m, 2H), 2.32-2.40 (m, 1H), 2.55-2.69 (m, 4H), 3.53-3.65 (m,
1H), 3.65-3.76 (m, 1H), 5.57 (br s, 1H), 6.12 (br s, 1H), 7.10-7.19
(m, 2H), 7.24-7.26 (m, 1H). 65 .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta.: 0.97- 473 471 1.13 (m, 5H), 1.21-1.29 (m, 1H), 1.56-1.82
(m, 4H), 2.14-2.20 (m, 1H), 2.39-2.43 (m, 2H), 2.49-2.59 (m, 1H),
3.34-3.42 (m, 1H), 3.58- 3.65 (m, 1H), 4.19 (s, 2H), 6.22 (d, J =
1.62 Hz, 1H), 7.06 (br s, 1H), 7.12 (d, J = 8.79 Hz, 1H), 7.24 (dd,
J = 8.67, 2.20 Hz, 1H), 7.38 (d, J = 2.31 Hz, 1H), 12.25 (br s,
1H). 66 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.90- 433 431
10.99 (m, 12H), 1.28-1.43 (m, 4H), 1.81-2.05 (m, 4H), 2.22-2.34 (m,
1H), 2.39-2.45 (m, 2H), 2.58-2.67 (m, 2H), 3.34-3.43 (m, 1H), 3.59-
3.67 (m, 1H), 6.19 (s, 1H), 7.07 (br s, 1H), 7.22-7.37 (m, 3H),
12.21 (br s, 1H). 67 .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.:
0.95 449 447 (s, 9H), 1.07-1.27 (m, 1H), 1.38- 1.47 (m, 2H),
1.75-2.06 (m, 2H), 2.45-2.61 (m, 2H), 2.60-2.69 (m, 4H), 3.18-3.27
(m, 1H), 3.30 (s, 3H), 3.57-3.68 (m, 1H), 3.71-3.82 (m, 1H), 5.40
(br s, 1H), 6.07 (br s, 1H), 7.08-7.21 (m, 2H), 7.27- 7.31 (m, 1H).
68 .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.95 449 447 (s, 9H),
1.07-1.27 (m, 1H), 1.38- 1.47 (m, 2H), 1.75-2.06 (m, 2H), 2.45-2.61
(m, 2H), 2.60-2.69 (m, 4H), 3.18-3.27 (m, 1H), 3.30 (s, 3H),
3.57-3.68 (m, 1H), 3.71-3.82 (m, 1H), 5.40 (br s, 1H), 6.07 (br s,
1H), 7.08-7.21 (m, 2H), 7.27- 7.31 (m, 1H). 69 .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta.: 0.65- 433 431 0.78 (m, 4H), 0.77 (d, J
= 7.51 Hz, 3H), 0.96 (s, 9H), 1.36-1.60 (m, 5H), 1.70-1.80 (m, 1H),
2.14- 2.23 (m, 1H), 2.38-2.44 (m, 2H), 2.52-2.59 (m, 1H), 2.59-2.67
(m, 2H), 3.35-3.43 (m, 1H), 3.57-3.64 (m, 1H), 6.24 (s, 1H), 7.11
(s, 1H), 7.20-7.36 (m, 3H), 12.27 (br s, 1H). 70 .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta.: 0.95 435 433 (s, 9H), 1.18 (d, J = 6.80
Hz, 3H), 1.36-1.42 (m, 2H), 1.83 (d, J = 13.64 Hz, 1H), 2.15-2.22
(m, 1H), 2.46 (t, J = 6.94 Hz, 2H), 2.60-2.66 (m, 2H), 3.39-3.47
(m, 1H), 3.65-3.73 (m, 2H), 3.96 (d, J = 11.79 Hz, 1H), 4.03-4.12
(m, 1H), 6.20 (d, J = 1.62 Hz, 1H), 7.10 (s, 1H), 7.31-7.33 (m,
2H), 7.41-7.43 (m, 1H), 12.27 (br s, 1H). 71 .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 0.95 435 433 (s, 9H), 1.18 (d, J = 6.80 Hz,
3H), 1.36-1.42 (m, 2H), 1.83 (d, J = 13.64 Hz, 1H), 2.15-2.22 (m,
1H), 2.46 (t, J = 6.94 Hz, 2H), 2.60-2.66 (m, 2H), 3.39-3.47 (m,
1H), 3.65-3.78 (m, 2H), 3.96 (d, J = 11.79 Hz, 1H), 4.03-4.12 (m,
1H), 6.20 (d, J = 1.62 Hz, 1H), 7.10 (s, 1H), 7.31-7.33 (m, 2H),
7.41-7.43 (m, 1H), 12.27 (br s, 1H). 72 .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 0.95 473 471 (s, 9H), 1.18 (d, J = 6.47 Hz,
3H), 1.36-1.41 (m, 2H), 1.92 (d, J = 13.18 Hz, 1H), 2.18-2.27 (m,
1H), 2.28 (s, 6H), 2.60-2.66 (m, 2H), 3.73 (d, J = 11.79 Hz, 1H),
3.96 (d, J = 11.79 Hz, 1H), 4.05- 4.14 (m, 1H), 6.19 (d, J = 1.85
Hz, 1H), 7.17 (s, 1H), 7.26-7.42 (m, 3H), 12.46 (br s, 1H). 73
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.58 471 469 (d, J =
7.40 Hz, 3H), 0.95 (s, 9H), 1.34-1.41 (m, 5H), 1.49-1.66 (m, 3H),
2.23 (s, 6H), 2.59-2.68 (m, 3H), 6.25 (s, 1H), 7.02 (s,
1H), 7.21-7.34 (m, 3H). 74 .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta.: 0.79 447 445 (s, 3H), 0.90 (s, 3H), 0.95 (s, 9H),
1.25-1.32 (m, 1H), 1.36-1.43 (m, 2H), 1.63 (d, J = 13.76 Hz, 1H),
1.78 (dd, J = 13.76, 1.50 Hz, 1H), 1.83-1.93 (m, 1H), 2.37-2.51 (m,
2H), 2.40-2.44 (m, 2H), 2.59- 2.66 (m, 2H), 3.36-3.44 (m, 1H),
3.59-3.67 (m, 1H), 6.19 (d, J = 1.39 Hz, 1H), 7.10 (s, 1H), 7.21-
7.36 (m, 3H), 12.21 (br s, 1H). 75 .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta.: 0.97 525 523 (s, 9H), 1.39-1.48 (m, 2H), 1.53-
1.65 (m, 1H), 1.90-2.00 (m, 1H), 2.15-2.35 (m, 5H), 2.41 (br s,
6H), 2.61-2.69 (m, 2H), 5.60-5.76 (br m, 1H), 6.03 (br s, 1H),
7.11- 7.16 (m, 1H), 7.19-7.26 (m, 2H). 76 .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 0.94 487 485 (s, 9H), 1.34-1.41 (m, 2H),
1.53- 1.64 (m, 1H), 1.65-1.77 (m, 1H), 1.84-1.94 (m, 1H), 2.24 (br
s, 6H), 2.51-2.73 (m, 5H), 3.11-3.22 (m, 4H), 6.27-6.31 (m, 1H),
7.17- 7.27 (m, 2H), 7.30-7.37 (m, 2H), 12.45 (br s, 1H). 77
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.94 487 485 (s, 9H),
1.34-1.41 (m, 2H), 1.53- 1.64 (m, 1H), 1.65-1.77 (m, 1H), 1.84-1-94
(m, 1H), 2.24 (br s, 6H), 2.51-2.73 (m, 5H), 3.11-3.22 (m, 4H),
6.27-6.31 (m, 1H), 7.17- 7.27 (m, 2H), 7.30-7.37 (m, 2H), 12.45 (br
s, 1H). 78 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.58 471
469 (d, J = 7.40 Hz, 3H), 0.95 (s, 9H), 1.34-1.41 (m, 5H),
1.49-1.66 (m, 3H), 2.23 (s, 6H), 2.59-2.68 (m, 3H), 6.25 (s, 1H),
7.02 (s, 1H), 7.21-7.34 (m, 3H). 79 .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 0.58 471 469 (d, J = 7.40 Hz, 3H), 0.95 (s,
9H), 1.34-1.41 (m, 5H), 1.49-1.66 (m, 3H), 2.23 (s, 6H), 2.59-2.68
(m, 3H), 6.25 (s, 1H), 7.02 (s, 1H), 7.21-7.34 (m, 3H). 80
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.65- 433 431 0.78 (m,
4H), 0.77 (d, J = 7.51 Hz, 3H), 0.96 (s, 9H), 1.36-1.60 (m, 5H),
1.70-1.80 (m, 1H), 2.14- 2.23 (m, 1H), 2.38-2.44 (m, 2H), 2.52-2.59
(m, 1H), 2.59-2.67 (m, 2H), 3.35-3.43 (m, 1H), 3.57-3.64 (m, 1H),
6.24 (s, 1H), 7.11 (s, 1H), 7.20-7.36 (m, 3H), 12.27 (br s, 1H). 81
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.65- 433 431 0.78 (m,
4H), 0.77 (d, J = 7.51 Hz, 3H), 0.96 (s, 9H), 1.36-1.60 (m, 5H),
1.70-1.80 (m, 1H), 2.14- 2.23 (m, 1H), 2.38-2.44 (m, 2H), 2.52-2.59
(m, 1H), 2.59-2.67 (m, 2H), 3.35-3.43 (m, 1H), 3.57-3.64 (m, 1H),
6.24 (s, 1H), 7.11 (s, 1H), 7.20-7.36 (m, 3H), 12.27 (br, s, 1H).
82 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.79 447 445 (s,
3H), 0.90 (s, 3H), 0.95 (s, 9H), 1.25-1.32 (m, 1H), 1.36-1.43 (m,
2H), 1.63 (d, J = 13.76 Hz, 1H), 1.78 (dd, J = 13.76, 1.50 Hz, 1H),
1.83-1.93 (m, 1H), 2.37-2.51 (m, 2H), 2.40-2.44 (m, 2H), 2.59- 2.66
(m, 2H), 3.36-3.44 (m, 1H), 3.59-3.67 (m, 1H), 6.19 (d, J = 1.39
Hz, 1H), 7.10 (s, 1H), 7.21- 7.36 (m, 3H), 12.21 (br s, 1H). 83
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.79 447 445 (s, 3H),
0.90 (s, 3H), 0.95 (s, 9H), 1.25-1.32 (m, 1H), 1.36-1.43 (m, 2H),
1.63 (d, J = 13.76 Hz, 1H), 1.78 (dd, J = 13.76, 1.50 Hz, 1H),
1.83-1.93 (m, 1H), 2.37-2.51 (m, 2H), 2.40-2.44 (m, 2H), 2.59- 2.66
(m, 2H), 3.36-3.44 (m, 1H), 3.59-3.67 (m, 1H), 6.19 (d, J = 1.39
Hz, 1H), 7.10 (s, 1H), 7.21 = 7.36 (m, 3H), 12.21 (br s, 1H). 84
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.66- 501 499 0.80 (m,
1H), 0.94 (s, 9H), 1.33- 1.43 (m, 2H), 1.44-1.80 (m, 4H), 2.24 (s,
6H), 2.29-2.37 (m, 1H), 2.53-2.69 (m, 3H), 2.97-3.10 (m, 2H), 3.15
(s, 3H), 6.23 (s, 1H), 7.14-1.23 (m, 2H), 7.29-7.37 (m, 2H), 12.41
(br s, 1H). 85 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.66-
501 499 0.80 (m, 1H), 0.94 (s, 9H), 1.33- 1.43 (m, 2H), 1.44-1.80
(m, 4H), 2.24 (s, 6H), 2.29-2.37 (m, 1H), 2.53-2.69 (m, 3H),
2.97-3.10 (m, 2H), 3.15 (s, 3H), 6.23 (s, 1H), 7.14-7.23 (m, 2H),
7.29-7.37 (m, 2H), 12.41 (br s, 1H). 86 .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 0.93 493 491 (s, 9H), 1.34-1.43 (m, 2H),
1.43- 1.56 (m, 1H), 1.84-1.95 (m, 1H), 1.98-2.09 (m, 1H), 2.15-2.30
(m, 7H), 2.59-2.68 (m, 3H), 2.74-2.86 (m, 1H), 6.42-6.45 (m, 1H),
7.22- 7.27 (m, 1H) 7.34-7.43 (m, 3H). 87 .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 0.93 493 491 (s, 9H), 1.34-1.43 (m, 2H),
1.43- 1.56 (m, 1H), 1.84-1.95 (m, 1H), 1.98-2.09 (m, 1H), 2.15-2.30
(m, 7H), 2.59-2.68 (m, 3H), 2.74-2.86 (m, 1H), 6.42-6.45 (m, 1H),
7.22- 7.27 (m, 1H), 7.34-7.43 (m, 3H). 88 .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 0.31 433 431 (t, J = 4.74 Hz, 1H), 0.56 (dd,
J = 8.67, 4.28 Hz, 1H), 0.99-1.09 (m, 2H), 1.07 (s, 3H), 1.09 (s,
3H), 1.23-1.31 (m, 1H), 1.57-1.83 (m, 4H), 2.14-2.19 (m, 1H), 2.41
(t, J = 7.05 Hz, 2H), 2.49-2.55 (m, 1H), 3.35-3.42 (m, 1H), 3.57-
3.65 (m, 1H), 3.88-3.95 (m, 1H), 4.17-4.24 (m, 1H), 6.22 (d, J =
1.62 Hz, 1H), 7.04 (s, 1H), 7.13 (d, J = 8.55 Hz, 1H), 7.21-7.25
(m, 1H), 7.35-7.37 (m, 1H), 12.25 (br s, 1H). 89 .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta.: 0.61- 471 469 0.74 (m, 1H), 0.74-0.79
(m, 2H), 0.04 (s, 9H), 1.35-1.41 (m, 2H), 1.42-1.51 (m, 2H),
1.50-1.59 (m, 1H), 1.66-1.78 (m, 1H), 2.19-2.28 (m, 7H), 2.51-2.53
(m, 1H), 2.58- 2.64 (m, 2H), 6.19 (br s, 1H), 7.16 (br s, 1H),
7.18-7.22 (m, 1H), 7.30-7.35 (m, 2H), 12.46 (br s, 1H). 90
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.61- 471 469 0.74 (m,
1H), 0.74-0.79 (m, 2H), 0.94 (s, 9H), 11.35-1.41 (m, 2H), 1.42-1.51
(m, 2H), 1.50-1.59 (m, 1H), 1.66-1.78 (m, 1H), 2.19-2.28 (m, 7H),
2.51-2.58 (m, 1H), 2.58- 2.64 (m, 2H), 6.19 (br s, 1H), 7.16 (br s,
1H), 7.18-7.22 (m, 1H), 7.30-7.35 (m, 2H), 12.46 (br s, 1H). 91
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.89- 471 469 0.97 (m,
12H), 1.24-1.34 (m, 2H), 1.34-1.42 (m, 2H), 1.81-1.97 (m, 3H),
1.98-2.09 (m, 1H), 2.19-2.33 (m, 7H), 2.56-2.64 (m, 2H), 6.12- 6.16
(m, 1H), 7.11 (s, 1H), 7.18- 7.24 (m, 1H), 7.30-7.35 (m, 2H), 12.44
(br s, 1H). 92 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.89-
471 469 0.97 (m, 12H), 1.24-1.34 (m, 2H), 1.34-1.42 (m, 2H),
1.81-1.97 (m, 3H), 1.98-2.09 (m, 1H), 2.19-2.33 (m, 7H), 2.56-2.64
(m, 2H), 6.12- 6.16 (m, 1H), 7.11 (s, 1H), 7.18- 7.24 (m, 1H),
7.30-7.35 (m, 2H), 12.44 (br s, 1H). 93 .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 0.58- 485 483 0.71 (m, 1H), 0.75-0.81 (m,
3H), 0.94 (s, 9H), 1.02-1.12 (m, 2H), 1.18-1.32 (m, 1H), 1.34-1.42
(m, 2H), 1.56-1.65 (m, 1H), 1.65-1.77 (m, 1H), 2.23 (s, 6H),
2.27-2.36 (m, 1H), 2.52-2.65 (m, 3H), 6.21 (br s, 1H), 7.16 (br s,
1H), 7.18- 7.22 (m, 1H), 7.23-7.35 (m, 2H), 12.45 (br s, 1H). 94
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.58- 485 483 0.71 (m,
1H), 0.75-0.81 (m, 3H), 0.94 (s, 9H), 1.02-1.12 (m, 2H), 1.18-1.32
(m, 1H), 1.34-1.42 (m, 2H), 1.56-1.65 (m, 1H), 1.65-1.77 (m, 1H),
2.23 (s, 6H), 2.27-2.36 (m, 1H), 2.52-2.65 (m, 3H), 6.21 (br s,
1H), 7.16 (br s, 1H), 7.18- 7.22 (m, 1H), 7.28-7.35 (m, 2H), 12.45
(br s, 1H). 95 .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.80- 433
431 0.87 (m, 1H), 1.24-1.30 (m, 1H), 1.33-1.42 (m, 2H), 1.53-1.97
(m, 12H), 2.11-2.16 (m, 1H), 2.47-2.51 (m, 1H), 2.59-2.72 (m, 2H),
3.59- 3.66 (m, 1H), 3.70-3.78 (m, 1H), 4.26-4.32 (m, 1H), 5.10 (s,
1H), 6.00 (d, J = 1.47 Hz, 1H), 6.93 (d, J = 8.80 Hz, 1H), 7.17
(dd, J = 8.80, 2.45 Hz, 1H), 7.33 (d, J = 2.45 Hz 1H). 96
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.43- 393 391 1.21 (m,
2H), 1.38 (d, J = 6.11 Hz, 6H), 1.63-1.74 (m, 2H), 1.87- 1.97 (m,
2H), 2.11-2.15 (m, 1H), 2.47-2.53 (m, 1H), 2.56-2.67 (m, 2H), 3.61
(dt, J = 14.43, 6.36 Hz, 1H), 3.73 (dt, J = 13.94, 6.36 Hz, 1H),
4.50-4.59 (m, 1H), 5.81 (s, 1H), 6.01 (d, J = 1.47 Hz, 1H), 6.92
(d, J = 8.56 Hz, 1H), 7.19 (dd, J = 8.56, 2.45 Hz, 1H), 7.34 (d, J
= 2.45 Hz, 1H). 97 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.:
0.96 482 480 (s, 9H), 1.13-1.29 (m, 1H), 1.37- 1.45 (m, 2H),
1.71-1.81 (m, 1H), 1.94-2.05 (m, 2H), 2.22 (s, 6H), 2.55-2.74 (m,
4H), 2.78-2.89 (m, 1H), 6.35-6.38 (m, 1H), 7.19-7.23 (m, 1H), 7.30
(s, 1H), 7.33-7.40 (m, 2H). 98 .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta.: 0.81 499 497 (dd, J = 6.60, 2.45 Hz, 6H), 0.97- 0.93 (m,
1H), 0.98 (s, 9H), 1.19- 1.34 (m, 2H), 1.44-1.48 (m, 2H), 1.58-1.65
(m, 1H), 1.71-1.76 (m, 1H), 1.90-1.98 (m, 1H), 2.18-2.23 (m, 1H),
2.47 (s, 6H), 2.54-2.59 (m, 1H), 2.64-2.69 (m, 2H), 5.15 (s, 1H),
5.97 (d, J = 1.47 Hz, 1H), 7.14 (dd, J = 7.83, 2.20 Hz, 1H), 7.20
(d, J = 7.83 Hz, 1H), 7.27 (d, J = 2.20 Hz, 1H). 99 .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta.: 0.81 499 497 (dd, J = 6.60, 2.45 Hz,
6H), 0.97- 0.93 (m, 1H), 0.98 (s, 9H), 1.19- 1.34 (m, 2H),
1.44-1.48 (m, 2H), 1.58-1.65 (m, 1H), 1.71-1.76 (m, 1H), 1.90-1.98
(m, 1H), 2.18-2.23 (m, 1H), 2.47 (s, 6H), 2.54-2.59 (m, 1H),
2.64-2.69 (m, 2H), 5.15 (s, 1H), 5.97 (d, J = 1.47 Hz, 1H), 7.14
(dd, J = 7.83, 2.20 Hz, 1H), 7.20 (d, J = 7.83 Hz, 1H), 7.27 (d, J
= 2.20 Hz, 1H). 100 .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 1.10
447 445 (s, 3H), 1.18 (s, 3H), 1.24-1.39 (m, 2H), 1.78-1.68 (m,
4H), 1.87- 1.98 (m, 4H), 2.10-2.16 (m, 1H), 2.48-2.54 (m, 1H),
2.58-2.76 (m, 3H), 3.63 (dt, J = 14.35, 7.34 Hz, 1H), 3.75 (dt, J =
14.35, 6.24 Hz,
1H), 3.95 (d, J = 6.11 Hz, 2H), 5.48 (s, 1H), 6.01 (d, J = 1.71 Hz,
1H), 6.88 (d, J = 8.56 Hz, 1H), 7.19 (dd, J = 8.56, 2.20 Hz, 1H),
7.35 (d, J = 2.20 Hz, 1H). 101 .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta.: 0.99 407 405 (t, J = 7.34 Hz, 3H), 1.24-1.30 (m, 1H),
1.32-1.37 (m, 1H), 1.48- 1.58 (m, 2H), 1.67-1.73 (m, 2H), 1.78-1.85
(m, 2H), 1.89-1.99 (m, 2H), 2.12-2.16 (m, 1H), 2.47-2.53 (m, 1H),
2.64-2.73 (m, 2H), 3.61- 3.68 (m, 1H), 3.73-3.80 (m, 1H), 4.03 (t,
J = 6.48 Hz, 2H), 4.95 (s, 1H), 6.01 (d, J = 1.71 Hz, 1H), 6.90 (d,
J = 8.56 Hz, 1H), 7.19 (dd, J = 8.56, 2.45 Hz, 1H), 7.34 (d, J =
2.45 Hz, 1H). 102 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.78
485 483 (s, 3H), 0.88 (s, 3H), 0.90-1.06 (m, 10H), 1.20-1.32 (m,
1H), 1.35- 1.43 (m, 2H), 1.61-1.70 (m, 1H), 1.79-1.92 (m, 2H), 2.24
(s, 6H), 2.33-2.42 (m, 1H), 2.58-2.65 (m, 2H), 6.15 (br s, 1H),
7.15 (s, 1H), 7.17-7.22 (m, 1H), 7.30-7.35 (m, 2H), 12.41 (br s,
1H). 103 .sup.1H-NMR. (400 MHz, DMSO-d.sub.6) .delta.: 0.78 485 483
(s, 3H), 0.88. (s, 3H), 0.90-1.06 (m, 10H), 1.20-1.32 (m, 1H),
1.35- 1.43 (m, 2H), 1.61-1.70 (m, 1H), 1.79-1.92 (m, 2H), 2.24 (s,
6H), 2.33-2.42 (m, 1H), 2.58-2.65 (m, 2H), 6.15 (br s, 1H), 7.15
(s, 1H), 7.17-7.22 (m, 1H), 7.30-7.35 (m, 2H), 12.41 (br s, 1H).
104 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.67- 501 499 0.76
(m, 1H), 0.78 (dd, J = 6.60, 1.71 Hz, 6H), 0.95 (s, 9H), 1.13- 1.30
(m, 2H), 1.37-1.42 (m, 2H), 1.48-1.55 (m, 1H), 1.59-1.99 (m, 8H),
2.35-2.39 (m, 1H), 2.53-2.64 (m, 3H), 2.68-2.76 (m, 1H), 4.37- 4.66
(m, 1H), 6.35 (d, J = 1.22 Hz, 1H), 7.11 (s, 1H), 7.21 (dd, J =
7.95, 1.83 Hz, 1H), 7.32-7.34 (m, 2H), 12.18 (br s, 1H). 105
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.67- 501 499 0.76 (m,
1H), 0.78 (dd, J = 6.60, 1.71 Hz, 6H), 0.95 (s, 9H), 1.13- 1.30 (m,
2H), 1.37-1.42 (m, 2H), 1.48-1.55 (m, 1H), 1.59-1.99 (m, 8H),
2.35-2.39 (m, 1H), 2.58-2.64 (m, 3H), 2.68-2.76 (m, 1H), 4.57- 4.66
(m, 1H), 6.35 (d, J = 1.22 Hz, 1H), 7.11 (s, 1H), 7.21 (dd, J =
7.95, 1.83 Hz, 1H), 7.32-7.34 (m, 2H), 12.18 (br s, 1H). 106
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.79 485 483 (d, J =
6.80 Hz, 3H), 0.95-0.98 (m, 3H), 0.95 (s, 9H), 1.36-1.45 (m, 4H),
1.70-1.74 (m, 1H), 1.85- 1.93 (m, 1H), 2.09-2.15 (m, 1H), 2.28 (s,
6H), 2.30-2.37 (m, 1H), 2.59-2.65 (m, 2H), 5.89 (d, J = 1.62 Hz,
1H), 7.12 (s, 1H), 7.20 (dd, J = 8.09, 1.85 Hz, 1H), 7.31- 7.35 (m,
2H), 12.14 (br s, 1H). 107 .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta.: 0.57- 185 483 0.62 (m, 3H), 0.91-0.97 (m, 12H), 1.21-1.30
(m, 1H), 1.34-1.41 (m, 2H), 1.46-1.66 (m, 2H), 1.79-1.91 (m, 1H),
2.12-2.20 (m, 1H), 2.27 (s, 6H), 2.29-2.37 (m, 1H), 2.58- 2.64 (m,
2H), 6.21 (s, 1H), 7.01 (s, 1H), 7.18-7.25 (m, 1H), 7.28- 7.32 (m,
2H), 12.41 (br s, 1H). 108 .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta.: 0.44 501 499 (d, J = 7.29 Hz, 1.89H), 0.88 (d, J = 6.94
Hz, 1.11H), 0.95 (s, 9H), 1.02 (s, 1.89H), 1.04 (s, 1.11H), 1.11
(s, 1.11H), 1.25 (s, 1.89H), 1.34-1.41 (m, 2H), 1.94-1.99 (m,
0.37H), 2.13 (q, J = 7.29 Hz, 0.63H), 2.30 (s, 2.22H), 2.31 (s,
3.88H), 2.59-2.66 (m, 2H), 3.66 (d, J = 12.02 Hz, 0.63H), 3.69 (d,
J = 11.90 Hz, 0.37H), 4.06 (d, J = 11.90 Hz, 0.37H), 4.23 (d, J =
12.25 Hz, 0.63H), 5.88 (d, J = 1.85 Hz, 0.37H), 6.21 (s, 0.63H),
7.06 (s, 0.63H), 7.16 (s, 0.37H), 7.26-7.42 (m, 3H), 12.50 (br s,
1H). 109 .sup.1H-NMR (400 MHz, DMSO-d) .delta.: 0.88 501 499 (d, J
= 6.94 Hz, 3H), 0.95 (s, 9H), 1.04 (s, 3H), 1.11 (s, 3H), 1.37-1.41
(m, 2H), 1.94-1.99 (m, 1H), 2.30 (s, 6H), 2.60-2.65 (m, 2H), 3.69
(d, J = 11.90 Hz, 1H), 4.06 (d, J = 11.90 Hz, 1H), 5.88 (d, J =
1.35 Hz, 1H), 7.16 (s, 1H), 7.28-7.42 (m, 3H), 12.50 (br s, 1H).
110 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.44 501 499 (d, J
= 7.29 Hz, 3H), 0.95 (s, 9H), 1.02 (s, 3H), 1.25 (s, 3H), 1.34-1.41
(m, 2H), 2.13 (q, J = 7.29 Hz, 1H), 2.31 (s, 6H), 2.59- 2.66 (m,
2H), 3.66 (d, J = 12.02 Hz, 1H), 4.23 (d, J = 12.25 Hz, 1H), 6.21
(s, 1H), 7.06 (s, 1H), 7.26-7.38 (m, 3H), 12.49 (br s, 1H). 111
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.83 485 483 (d, J =
5.38 Hz, 3H), 0.98-0.92 (m, 1H), 0.99 (s, 9H) 1.45-1.49 (m, 2H),
1.54-1.67 (m, 3H), 1.95- 2.07 (m, 9H), 2.11-2.14 (m, 1H), 2.52-2.56
(m, 1H), 2.65-2.69 (m, 2H), 5.38 (s, 1H), 5.92 (s, 1H), 7.15 (dd, J
= 8.07, 1.96 Hz, 1H), 7.20 (d, J = 8.07 Hz, 1H), 7.29 (d, J = 1.96
Hz, 1H), 112 .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.83 485
483 (d, J = 5.38 Hz, 3H), 0.98-0.92 (m, 1H), 0.99 (s, 9H),
1.45-1.19 (m, 2H), 1.54-1.67 (m, 3H), 1.95- 2.07 (m, 9H), 2.11-2.14
(m, 1H), 2.52-2.56 (m, 1H), 2.65-2.69 (m, 2H), 5.38 (s, 1H), 5.92
(s, 1H), 7.15 (dd, J = 8.07, 1.96 Hz, 1H), 7.20 (d, J = 8.07 Hz,
1H), 7.29 (d, J = 1.96 Hz, 1H). 113 .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 0.62 533 531 (d, J = 7.40 Hz, 3H), 0.96 (d,
J = 6.80 Hz, 3H), 1.09 (s, 9H), 1.24- 1.31 (m, 1H), 1.49-1.65 (m,
2H), 1.84-1.92 (m, 1H), 2.06-2.22 (m, 2H), 2.26-2.37 (m, 1H), 2.29
(s, 6H), 2.89 (dd, J = 14.33, 9.25 Hz, 1H), 6.25 (s, 1H), 7.10 (s,
1H), 7.29-7.35 (m, 2H), 7.40-7.43 (m, 1H), 12.44 (br s, 1H). 114
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.62 533 531 (d, J =
7.40 Hz, 3H), 0.96 (d, J = 6.80 Hz, 3H), 1.09 (s, 9H), 1.24- 1.31
(m, 1H), 1.49-1.65 (m, 2H), 1.81-1.92 (m, 1H), 2.06-2.22 (m, 2H),
2.26-2.37 (m, 1H), 2.29 (s, 6H), 2.89 (dd, J = 14.33, 9.25 Hz, 1H),
6.25 (s, 1H), 7.10 (s, 1H), 7.29-7.35 (n, 2H), 7.40-7.43 (m, 1H),
12.44 (br s, 1H). 115 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.:
0.63 547 545 (d, J = 7.60 Hz, 3H), 0.96 (d, J = 7.20 Hz, 3H), 1.10
(s, 9H), 1.24- 1.31 (m, 1H), 1.48-1.64 (m, 2H), 1.80-1.96 (m, 9H),
2.06-2.22 (m, 2H), 2.87-2.93 (m, 1H), 6.19 (s, 1H), 6.98 (s, 1H),
7.32-7.35 (m, 2H), 7.43-7.46 (m, 1H), 12.25 (br s, 1H). 116
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.63 547 545 (d, J =
7.60 Hz, 3H), 0.96 (d, J = 7.20 Hz, 3H), 1.10 (s, 9H), 1.24- 1.31
(m, 1H), 1.48-1.64 (m, 2H), 1.80-1.96 (m, 9H), 2.06-2.22 (m, 2H),
2.87-2.93 (m, 1H), 6.19 (s, 1H), 6.98 (s, 1H), 7.32-7.35 (m, 2H),
7.43-7.46 (m, 1H), 12.25 (br s, 1H). 117 .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta.: 0.39 499 497 (d, J = 7.28 Hz, 3H), 0.75 (s,
3H), 0.95 (s, 9H), 0.97 (s, 3H), 1.10-1.26 (m, 2H), 1.35-1.46 (m,
3H), 1.77-1.85 (m, 1H), 1.99-2.05 (m, 1H), 2.29 (s, 6H), 2.59-2.66
(m, 2H), 6.18 (s, 1H), 7.04 (s, 1H), 7.20-7.35 (m, 3H). 118
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.39 499 497 (d, J =
7.28 Hz, 3H), 0.75 (s, 3H), 0.95 (s, 9H), 0.97 (s, 3H), 1.10-1.26
(m, 2H), 1.35-1.46 (m, 3H), 1.77-1.85 (m, 1H), 1.99-2.05 (m, 1H),
2.29 (s, 6H), 2.59-2.66 (m, 2H), 6.18 (s, 1H), 7.04 (s, 1H),
7.20-7.35 (m, 3H). 119 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.:
0.45 545 513 (d, J = 7.40 Hz, 1.77H), 0.87 (d, J = 6.70 Hz, 1.23H),
0.95 (s, 9H), 1.01 (s, 1.77H), 1.05 (s, 1.23H), 1.11 (s, 1.23H),
1.25 (s, 1.77H), 1.36-1.41 (m, 2H), 1.80-1.98 (m, 8.41H), 2.09-2.14
(m, 0.59H), 2.59-2.66 (m, 2H), 3.67 (d, J = 12.25 Hz, 0.59H), 3.70
(d, J = 12.02 Hz, 0.41H), 4.06 (d, J = 11.79 Hz, 0.41H), 4.24 (d, J
= 12.25 Hz, 0.59H), 5.82 (d, J = 1.85 Hz, 0.41H), 6.15 (s, 0.59H),
6.95 (s, 0.59H), 7.05 (s, 0.41H), 7.31-7.44 (m, 3H), 12.30 (br s,
1H). 120 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.45 545 513
(d, J = 7.40 Hz, 3H), 0.95 (s, 9H), 1.01 (s, 3H), 1.25 (s, 3H),
1.36-1.41 (m, 2H), 1.80-1.97 (m, 8H), 2.09-2.14 (m, 1H), 2.59-2.66
(m, 2H), 3.67 (d, J = 12.25 Hz, 1H), 4.24 (d, J = 12.25 Hz, 1H),
6.15 (s, 1H), 6.95 (s, 1H), 7.31- 7.41 (m, 3H), 12.31 (s, 1H). 121
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 0.87 545 513 (d, J =
6.70 Hz, 3H), 0.95 (s, 9H), 1.05 (s, 3H), 1.11 (s, 3H), 1.37-1.41
(m, 2H), 1.80-1.98 (m, 9H), 2.59-2.66 (m, 2H), 3.70 (d, J = 12.02
Hz, 1H), 4.06 (d, J = 11.79 Hz, 1H), 5.82 (d, J = 1.85 Hz, 1H),
7.05 (s, 1H), 7.31-7.35 (m, 2H), 7.41-7.44 (m, 1H), 12.30 (br s,
1H).
Test Example 1
[0768] In-vitro assay for inhibitory activity against ROR.gamma.
transcription
[0769] Inhibitory activity against ROR.gamma. transcription was
assessed for test compounds by either of the following Test Method
A or B of reporter gene assay.
(Test Method A)
[0770] cDNAs encoding human and mouse ROR.gamma. ligand binding
domains (LBD) were obtained based on the sequences of human
ROR.gamma. (Genbank registered number NM_005060.3) and mouse
ROR.gamma. (Genbank registered number NM_011281.2) (LBD sequences:
from Ser253 to Lys518 for human ROR.gamma.; from Ile251 to Lys516
for mouse ROR.gamma.).
[0771] LBD cDNAs of human and mouse ROR.gamma. were inserted into
pFA-CMV vector (Stratagene), which expresses GAL4-DNA binding
domain fusion protein. The resulting plasmids are hereinafter
referred to as GAL4-hROR.gamma. plasmid and GAL4-mROR.gamma.
plasmid, respectively.
[0772] GAL4-hROR.gamma. plasmid or GAL4-mROR.gamma. plasmid was
transiently co-transfected into Chinese hamster ovary cells (CHO
cells) with pG5-Luc (Promega), reporter plasmid expressing firefly
luciferase in a GAL4-dependent manner.
[0773] TransIT (Registered trademark) CHO Transfection Kit (Mirus)
was used to co-transfect CHO cells with the plasmids. One day prior
to the assay, CHO cells were suspended in HAM F-12 Nutrient medium
containing 10% (v/v) fetal bovine serum and seeded at
6.times.10.sup.6 cells per 175 cm.sup.2 cell culture flask each. 54
.mu.L of TransIT (Registered trademark) CHO reagent was added into
a 15 mL tube containing 1.16 mL of HAM F-12 Nutrient medium without
fetal bovine serum, and then mixed and incubated at room
temperature for 10 minutes. 36 .mu.L of a plasmid solution
containing 400 ng of GAL4-hROR.gamma. plasmid, 9000 ng of pG5-Luc
plasmid, and 8600 ng of pcDNA3 plasmid were added into the tube and
mixed gently. In the case of mouse assay, a plasmid solution
containing 250 ng of GAL4-mROR.gamma. plasmid, 9000 ng of pG5-Luc
plasmid, and 8750 ng of pcDNA3 plasmid was added, instead. The
mixture was incubated at room temperature for 10 minutes. 9 .mu.L
each of CHO Mojo Reagent 23 were then added into each tube and
mixed gently. The mixture was incubated at room temperature for 10
minutes. The resulting transfection reagent was applied to the cell
culture. After incubation at 37.degree. C., 5% CO.sub.2 for 4
hours, the plasmid-transfected CHO cells were harvested by trypsin
treatment. The collected cells were resuspended in culture medium
and plated into a 384-well-white plate at 8,000 cells/50
.mu.L/well. The plate was let stand at room temperature for 1 hour
and then further incubated at 37.degree. C., 5% CO; for 3 hours. A
test compound was dissolved in DMSO to obtain a concentration of 10
mM. Each solution was serially diluted with DMSO and further
diluted with culture medium just before use. The test compound
solutions were added to the cells in the plate at 8 different
concentrations. The final concentration of DMSO was 0.2% (v/v).
After the addition of test compound, the cells were incubated at
37.degree. C., 5% CO.sub.2 for 2 days.
[0774] Cell viability was tested by fluorescence method with
Resazurin (Invitrogen). Two days after the addition of test
compound, Resazurin was diluted to 20 .mu.M with a medium. 10 .mu.L
each of the diluted solution of Resazurin was added into the
384-well-plate. Just after the addition, fluorescence at 615 nm was
measured with a 570-nm excitation wavelength (0-hour value). After
incubation at 37.degree. C., 5% CO.sub.2 for 2 hours, fluorescence
at 615 nm was measured with the 570-nm excitation wavelength
(2-hour value). A fluorescence count (2h-0h) was calculated by
deducting the 0-hour value from the 2-hour value. The fluorescence
count (2h-0h) in the cells treated with 0.2% DMSO alone was defined
as 100%, and the cell viability after treatment with the test
compound was calculated as a percentage, %-of-control, based on the
value of 0.2% DMSO alone. When the cell viability was 70% or less,
a test compound was assessed to have cytotoxicity.
[0775] ROR.gamma. transcriptional activity was detected as the
intracellular luciferase activity using SteadyLite HTS Reporter
Gene Assay System (Perkin Elmer). StedyLite Reagent was diluted
five-fold with Extension buffer (10 mM Tricine, 0.2% (w/v) bovine
serum albumin, 0.02% (v/v) Tween-20) to obtain a luciferase
substrate solution. After the measurement of the cell viability
with Resazurin, the medium was removed in the plate and the
luciferase substrate solution was added thereto. After the
incubation at room temperature for 10 minutes, luminescence of each
well was measured with a microplate reader. The luciferase activity
derived from the luminescence count in a vehicle-control well
treated with 0.2% DMSO alone was defined as 100%, and the
luciferase activity after treatment with the test compound was
calculated as a percentage, %-of-control, based on the value of the
vehicle-control. An EC.sub.50 value of the test compound was
calculated by curve fitting with GraphPad Prism. The luminescence
counts at the concentration of test compound where cytotoxicity was
observed were excluded from data analysis.
(Test Method B)
[0776] cDNAs encoding human and mouse ROR.gamma. ligand binding
domains (LBD) were obtained based on the sequences of human
ROR.gamma. (Genbank registered number NM_005060.3) and mouse
ROR.gamma. (Genbank registered number NM_011281.2) (LBD sequences:
from Ser253 to Lys518 for human ROR.gamma.; from Ile251 to Lys516
for mouse ROR.gamma.).
[0777] LBD cDNAs of human and mouse ROR.gamma. were inserted into
pFA-CMV vector (Agilent Technologies, Inc.), which expresses
GAL4-DNA binding domain fusion protein. The resulting plasmids are
hereinafter referred to as pFA/hROR.gamma. plasmid and
pFA/mROR.gamma. plasmid, respectively.
[0778] pFA/hROR.gamma. plasmid or pFA/mROR.gamma. plasmid was
transiently co-transfected into Chinese hamster ovary cells (CHO
cells) with pG5-Luc (Promega), reporter plasmid expressing firefly
luciferase in a GAL4-dependent manner.
[0779] TransIT (Registered trademark) CHO Transfection Kit (Mirus)
was used to co-transfect CHO cells with the plasmids. One day prior
to the assay, CHO cells were suspended in HAM F-12 Nutrient medium
containing 10% (v/v) fetal bovine serum and seeded at
5.5.times.10.sup.6 cells per 225 cm.sup.2 cell culture flask each.
72 .mu.L of TransIT (Registered trademark) CHO reagent was added
into a 2 mL tube containing 1.55 mL of Opti-MEM, and then mixed and
incubated at room temperature for 10 minutes. 50.4 .mu.L of a
plasmid solution containing 300 ng of pFA/hROR.gamma. plasmid,
12000 ng of pG5-Luc plasmid, and 11700 ng of pcDNA3.1 plasmid were
added into the tube and mixed gently. In the case of mouse assay, a
plasmid solution containing 300 ng of pFA/mROR.gamma. plasmid,
12000 ng of pG5-Luc plasmid, and 11700 ng of pcDNA3.1 plasmid was
added, instead. The mixture was incubated at room temperature for
10 minutes. 12 .mu.L each of CHO Mojo Reagent were then added into
each tube and mixed gently. The mixture was incubated at room
temperature for 10 minutes. The resulting transfection reagent was
applied to the cell culture. After incubation at 37.degree. C., 5%
CO.sub.2 for 4 hours, the plasmid-transfected CHO cells were
harvested by trypsin treatment. The collected cells were
resuspended in culture medium and plated into a 384-well-white
plate at 8,000 cells/35 .mu.L/well. The plate was let stand at room
temperature for 1 hour and then further incubated at 37.degree. C.,
5% CO.sub.2 for 3 hours. A test compound was dissolved in dimethyl
sulfoxide (DMSO) to obtain a concentration of 10 mM. Each solution
was serially diluted with DMSO and further diluted with culture
medium just before use. The test compound solutions were added to
the cells in the plate at 6 different concentrations. The final
concentration of DMSO was 0.2% (v/v). After the addition of test
compound, the cells were incubated at 37.degree. C., 5% CO.sub.2
for 2 days.
[0780] Cell viability was tested by luminescence method with
CellTiter-Glo (Promega). Two days after the addition of test
compound, 40 .mu.L each of CellTiter-Glo was added into the
384-well-plate. Ten minutes after the addition, luminescence was
measured for each well with a microplate reader. The luminescence
count in the cells treated with 0.2% DMSO alone was defined as
100%, and the cell viability after treatment with the test compound
was calculated as a percentage, %-of-control, based on the value of
0.2% DMSO alone. When the cell viability was 70% or less, a test
compound was assessed to have cytotoxicity.
[0781] ROR.gamma. transcriptional activity was detected as the
intracellular luciferase activity using SteadyLite HTS Reporter
Gene Assay System (Perkin Elmer). StedyLite Reagent was diluted
2.5-fold with Extension buffer (10 mM Tricine, 0.2% (w/v) bovine
serum albumin, 0.02% (v/v) Tween-20) to obtain a luciferase
substrate solution. Two days after the addition of test compound,
40 .mu.L each of the luciferase substrate solution was added into
the 384-well-plate. After the incubation at room temperature for 10
minutes, luminescence of each well was measured with a microplate
reader. The luciferase activity derived from the luminescence count
in a vehicle-control well treated with 0.2% DMSO alone was defined
as 100%, and the luciferase activity after treatment of the test
compound was calculated as a percentage, %-of-control, based on the
value of the vehicle-control. An EC.sub.50 value of the test
compound was calculated by curve fitting. The luminescence counts
at the concentration of test compound where cytotoxicity was
observed were excluded from data analysis.
[0782] The results are shown in the table below.
[0783] The value with (%) is the activity after treatment with a
test compound which was calculated as a %-of-control value based on
100% of the vehicle-control treated with 0.2% DMSO alone.
TABLE-US-00003 Exam- LUC EC.sub.50 (.mu.M) Test ple hRORy mRORy
Method 1 1.693 0.536 A 2 0.030 0.022 A 3 0.008 0.013 A 4 1.022
1.014 A 5 0.007 0.009 A 6 0.554 0.714 A 7 0.009 0.011 A 8 0.427
0.381 A 9 0.819 1.466 A 10 0.016 0.030 A 11 0.021 0.022 A 12 2.584
3.429 A 13 5.701 5.374 A 14 2.878 3.805 A 15 >8 (71%) >8
(69%) A 16 0.755 0.174 A 17 >20 (65%) >20 (78%) A 18 0.773
0.452 A 19 17.130 15.590 A 20 0.025 0.025 A 21 2.263 1.270 A 22
16.170 >8 (74%) A 23 0.224 0.106 A 24 0.332 0.126 A 25 0.092
0.105 A 26 0.351 0.243 A 27 0.027 0.039 A 28 >20 (64%) >20
(73%) A 29 0.173 0.103 A 30 >20 (60%) >20 (54%) A 31 0.048
0.048 A 32 0.021 0.018 A 33 2.964 >3.2 (52%) A 34 0.087 0.169 B
35 4.193 4.974 B 36 0.435 0.071 A 37 3.870 5.508 A 38 0.011 0.021 A
39 0.032 0.021 A 40 4.638 5.328 A 41 0.017 0.013 A 42 0.290 0.139 A
43 0.043 0.159 A 44 1.274 0.482 A 45 1.627 0.840 A 46 0.302 0.211 A
47 >8 (51%) 8.828 A 48 1.990 1.867 A 49 3.2 (85%) >3.2 (87%)
A 50 >8 (51%) 7.479 A 51 4.971 1.796 A 52 0.018 0.029 A 53 >3
(69%) 2.732 A 54 0.064 0.035 A 55 0.093 0.058 A 56 0.020 0.029 A 57
0.034 0.021 A 58 0.033 0.020 A 59 0.279 0.149 A 60 0.118 0.072 A 61
0.106 0.068 A 62 0.151 0.099 A 63 0.022 0.022 A 64 0.034 0.052 A 65
1.159 0.160 A 66 0.024 0.030 A 67 4.719 8.341 A 68 0.015 0.016 A 69
0.015 0.027 A 70 0.541 0.516 A 71 0.010 0.007 A 72 0.028 0.015 A 73
0.014 0.027 A 74 0.016 0.024 A 75 0.061 0.038 A 76 2.406 5.031 A 77
0.024 0.031 A 78 2.203 >3.2 (51%) A 79 0.018 0.022 A 80 >10
(64%) >10 (61%) A 81 0.013 0.019 A 82 9.866 9.792 A 83 0.014
0.018 A 84 >10 (61%) >10 (74%) A 85 0.033 0.073 A 86 4.942
4.366 B 87 0.038 0.029 B 88 0.751 0.169 B 89 3.707 4.191 B 90 0.022
0.023 B 91 0.111 0.185 B 92 0.042 0.019 B 93 3.968 4.231 B 94 0.046
0.082 B 95 2.344 0.455 B 96 >10 (84%) >10 (84%) B 97 0.110
0.156 B 98 4.359 5.107 B 99 0.053 0.146 B 100 0.206 0.055 B 101
7.284 1.390 B 102 3.954 4.572 B 103 0.026 0.046 B 104 5.261 5.278 B
105 0.102 0.113 B 106 4.398 4.778 B 107 0.027 0.032 B 108 4.689
5.053 B 109 0.033 0.036 B 110 0.010 0.012 B 111 3.449 3.660 B 112
0.035 0.038 B 113 0.033 0.037 B 114 0.027 0.050 B 115 0.031 0.049 B
116 0.044 0.101 B 117 4.679 5.296 B 118 0.003 0.082 B 119 >10
>10 B 120 0.013 0.020 B 121 0.035 0.040 B
Formulation Examples
[0784] Formulation Examples in the present invention include, for
example, the following formulations. The present invention,
however, is not intended to be limited to these Formulation
Examples.
TABLE-US-00004 Formulation Example 1 (Preparation of a capsule) 1)
Example 1 Compound 30 mg 2) Microcrystalline cellulose 10 mg 3)
Lactose 19 mg 4) Magnesium stearate 1 mg
[0785] Ingredients 1), 2), 3), and 4) are mixed to be filled in a
gelatin capsule.
TABLE-US-00005 Formulation Example 2 (Preparation of a tablet) 1)
Example 1 Compound 10 g 2) Lactose 50 g 3) Cornstarch 15 g 4)
Carmellose calcium 44 g 5) Magnesium stearate 1 g
[0786] The total amount of Ingredients 1), 2), and 3) and 30 g of
Ingredient 4) are combined with water, dried in vacuo, and then
granulated. The resulted granules are mixed with 14 g of Ingredient
4) and 1 g of Ingredient 5), and tableted with a tableting machine.
In this manner, 1000 tablets comprising 10 mg of Example 1 Compound
per each are obtained.
INDUSTRIAL APPLICABILITY
[0787] A compound of Formula [I] or a pharmaceutically acceptable
salt thereof is expected to be useful for treating or preventing
autoimmune diseases, allergic diseases, dry eye, fibrosis, cancers,
metabolic disease, ischemia, cardiomyopathy, hypertension, and
periodontal disease.
* * * * *