Note: Descriptions are shown in the official language in which they were submitted.
CA 02238723 1998-OS-27
S P E C I F I C A T I O N
ARYLETHENESULFONAMIDE DERIVATIVES AND DRUG
COMPOSITION'., CONTAINING THE SAME
(Technical Field)
The present invention relates to pharmaceuticals, more
particularly, novel arylethenesulfonamide derivatives having
a high affinity to endothelia receptor, pharmaceutically-
acceptable salts thereof and pharmaceutical compositions
containing the same, particuarly an antagonist to endothelia
receptor.
(Background Art)
Endothelia is an endogenous physiologically active
peptide consisting of 21 amino acids and it has been known that,
in endothelia, there are three isopeptides of ET-1, ET-2 anel
ET-3 wherein the amino acid sequences are somewhat different.
Endothelia expresses its physiological action by binding
to an endothelia receptor on a target cell membrane. For
endothelia receptor, it has been clarified until now that there
are at least two subtypes and those subtypes are named ETA and
ETB, respectively. Those receptors differ in their affinity
to endothelia. ETA receptor has a higher affinity to ET-1 and
1
CA 02238723 1998-OS-27
Et-2 than to ET-3 while ETH receptor has the affinity of a similar
degree to the three types of endothelin.
Endothelin and endothelin receptor are produced and
expressed, respectively, in various cells of various organs and
varieties of physiological actions which are caused by them have
been known. For example, in blood vessel, ET-1 which is
produced and secreted in vascular endothelial cells b~ur,~
ETA receptor on smooth muscle cells of blood vessel existing
near there and contracts the blood vessel strongly and
continuously. On the other hand, vascular endothelial cells
themselves express ETH receptor and, when ET-1 is bonded thereto,
nitrogen monoxide (NO) is produced and released. Nitrogen
monoxide has an action of relaxing the smooth muscle of blood
vessel. In fact, when ET-1 is intravenously injected to rat
experimentally, long-lasting hypertension is observed after a
transient hypotension.
As noted from the physiological action in blood vessel
as mentioned above, ET-1 has an aspect as a physiologically
active peptide having a very strong and continuous contraction
to blood vessel and, because of that, its relation to diseases,
particularly to cardiovascular diseases, has been discussed
since the time when it was found.
Today, it is pointed out that there is a possibility that
an excessive secretion of endothelin, particularly ET-1 (to be
more specific, an increase in ET-1 concentration either
2
CA 02238723 1998-OS-27
topically or in tissues and circulating blood), participates
not only in cardiovascular diseases but also in many other
diseases. Thus, it was reported to participate, for example,
in essential hypertension, pulmonary hypertension,
hypertension induced by erythropoietin, hypertension induced
by cyclosporin A, bronchial asthma, acute renal failure,
chronic renal failure, glomerular nephritis, renal failure
induced by cyclosporin, acute myocardial infarction, unstable
angina, congestive heart failure, cerebrovascular spasm mostly
after subarachnoid hemorrhage, cerebroischemic disturbance,
urinary incontinence, benign prostatic hypertrophy,
arteriosclerosis, Raynaud's syndrome, diabetic peripheral
circulatory disturbance, diabetic renal diseases,preeclampsia,
premature delivery, digestive ulcer, hepatic failure,
rheumatism, restenosisafter PTCA,chronic respiratory failure,
chronic obstructive pulmonary diseases, cor pulmonale, acute
respiratory failure, pulmonary edema, ischemic hepatic
disturbance, adult respiratory distresssyndrome, interstitia3
pneumonia, pulmonary fibrosis, glaucoma, osteoarthritis,
chronic articular rheumatism, hepatic cirrhosis, inflammatory
bowel diseases (IBD), cancer, etc. (G. M. Rubanyi, M. A. Plokoff,
Pharmacological Reviews, vol. 46, no. 3, 325 (1994); Saishin
Igaku, vol. 49, no.3, 335 (1994); Kidney International, 37,
1487-1491(1990); hancet, 339, 381-385(1992); Cell Mol.
Neurobiol. , 13, 15-23 ( 1993 ) ; J. Clin. Encocrino. Metab. , 76,
3
CA 02238723 1998-OS-27
378-383 ( 1993 ) ; J. Clin. Pathol. , 48 ( 6 ) , 519-524 ( 1995 ) ; Chest,
104(2), 476-480(1993); Am. J. Med., 99(3), 155-160 (1995);
Hepatology, 16, 95-99 (1992); etc.).
Accordingly, pharmaceuticals which inhibit the binding
of ET-1 to endothelin receptor by bonding to endothelin receptor,
i.e. endothelin receptor antagonists, can be effective
preventive and therapeutic agents to the diseases as mentioned
hereinabove.
With regard to such endothelin receptor antagonists, a
series of benzenesulfonamide derivatives is disclosed in the
Japanese Zaid-Open Patent Publications Hei-05/155,864, Hei-
05/222,003,Hei-06/211,810and Hei-07/017,972. In particular,
a compound which is represented by the following formula
t10
~0
N \ 0
0 Me
I
~N~N~ NIIS z
~N I _
0_-~~ l-t3u
which is disclosed in Example 67 of the Japanese Laid-Open Patent
Publication Hei-05/222,003 (generic name: Bosentan) has been
reported for its effectiveness and absorption by oral
administration in pathogenic animal models (J. Pharmacol. Exp.
Ther., 270(1), 228-2345, 1994; Hypertension, 224, 183-188,
1994; Clin. Pharmacol. Ther., 60, 124-137, 1996).
4
CA 02238723 1998-OS-27
(Disclosure of the Invention)
An object of the present invention is to offer novel
compounds having far better antagonizing action to endothelin
receptor.
The present inventors have proceeded a screening for the
compounds having a high affinity to endothelin receptor and,
as a result, they have found that novel arylethenesulfonamide
derivatives which are different from conventional compounds in
such a respect that arylethene group is substituted at
sulfonamide of a pyrimidine ring exhibit a high affinity to
endothelin receptor, particularly to ET" receptor, and strongly
antagonize whereupon the present invention has been achieved.
Thus, the present invention relates to a novel
arylethenesulfonamide derivative represented by the following
formula (I) or a pharmaceutically acceptable salt thereof.
RZ' X
Y~Rs
N ~ CI)
i
R,~N~ NHSOZ CRS CRs-~~
(In the formula,
CA 02238723 1998-OS-27
Ar: optionally substituted aryl group or optionally
substituted five- to six-membered heteroaryl group;
X: oxygen atom, sulfur atom or a group represented by a
formula
-NH-;
Y: oxygen atom or sulfur atom;
R1: hydrogen atom, optionally halogen-substituted lower
alkyl group, cycloalkyl group, optionally substituted aryl
group or optionally substituted five- to six-membered
heteroaryl group;
RZ : lower alkyl group, lower alkenyl group or lower alkynyl
group where each of which may be substituted with one to three
substituent(s) selected from a group consisting of hydroxyl
group, lower alkoxy group, cycloalkyl group, halogen atom,
carboxyl group and lower alkoxycarbonyl group;
R,: phenyl group which may be substituted with one to four
substituent(s) selected from a group consisting of optionally
halogen-substituted lower alkyl group, lower alkoxy group;
halogen atom,lower alkylthio group, lower alkylsulfinyl group,
lower alkanesulfonyl group, carboxyl group, lower
alkoxycarbonyl group and carbamoyl group; and
RQ and R5: they may be same or different and each is hydrogen
atom or lower alkyl group)
6
CA 02238723 1998-OS-27
Preferred compounds which are preferred in the present
invention are arylethenesulfonamide derivatives represented by
the above-mentioned formula (I) in which:
Ar is an aryl group which may be substituted with one to
five substituent ( s ) selected from a group consisting of lower
alkyl group ( said lower alkyl group may be substituted with one
to four substituent(s) selected from a group consisting of
halogen atom, lower alkoxy group, carboxyl group, amino group
and mono- or di-lower alkylamino group), lower alkoxy group,
lower alkoxycarbonyl group,carboxyl group, halogen atom, nitro
group, cyano group, amino group, mono- or di-lower alkylamino
group, hydroxyl group and C1_3 alkylenedioxy group; or five- to
six-membered heteroaryl group which may be substituted with one
to four substituent ( s ) selected from a group consisting of lower
alkyl group ( said lower alkyl group may be substituted with one
to four substituent(s) selected from a group consisting of
halogen atom, lower alkoxy group, carboxyl group, amino group
and mono- or di-lower alkylamino group), lower alkoxy group;
lower alkoxycarbonyl group,carboxyl group, halogen atom, nitro
group, cyano group, amino group, and mono- or di-lower
alkylamino group; and
R1 is hydrogen; lower alkyl group which may be substituted
with halogen atom(s); cycloalkyl group; aryl group which may
be substituted with one to five substituent ( s ) selected from
a group consisting of lower alkyl group (said lower alkyl group
7
CA 02238723 1998-OS-27
may be substituted with one to four substituent ( s ) selected from
a group consisting of halogen atom, lower alkoxy group, carboxyl
group, amino group and mono- or di-lower alkylamino group),
lower alkoxy group, lower alkoxycarbonyl group,carboxyl group,
halogen atom, vitro group, cyano group, amino group, mono- or
di-lower alkylamino group, hydroxyl group and C1_3 alkylenedioxy
group; or five- to six-membered heteroaryl group which may be
substituted with one to four substituent(s) selected from a
group consisting of lower alkyl group ( said lower alkyl group
may be substituted with one to four substituent ( s ) selected from
a group consisting of halogen atom, lower alkoxy group, carboxyl
group, amino group and mono- or di-lower alkylamino group),
lower alkoxy group, lower alkoxycarbonyl group,carboxyl group,
halogen atom, vitro group, cyano group, amino group, and mono-
or di-lower alkylamino group;
or pharmaceutically aceptable salts thereof.
More preferred compounds are:
(1) arylethenesulfonamide derivatives represented by the
above-mentioned formula (I) or salts thereof in which
Ar is aryl group which may be substituted with one to five
substituent(s) selected from a group consisting of optionally
halogen-substituted lower alkyl group, lower alkoxy group,
lower alkoxycarbonyl group,carboxyl group, halogen atom, vitro
group and cyano group; or f ive- to s ix-membered heteroaryl group
which may be substituted with one to four substituent(s)
8
CA 02238723 1998-OS-27
selected from a group consisting of lower alkyl group and lower
alkoxy group;
X is oxygen atom or a group represented by a formula -
NH-;
Y is oxygen atom;
R1 is optionally halogen-substituted lower alkyl group;
cycloalkyl group; aryl group which may be substituted with one
to five substituent(s) selected from a group consisting of
optionally halogen-substituted lower alkyl group, lower alkoxy
group,lower alkoxycarbonyl group,carboxyl group,halogen atom,
nitro group, cyano group and C1_, alkylenedioxy group; or five-
to six-membered heteroaryl group which may be substituted with
one to four substituent ( s ) selected from a group consisting of
optionally halogen-substituted lower alkyl group, lower alkoxy
group,lower alkoxycarbonyl group,carboxyl group,halogen atom,
nitro group and cyano group; and
R3 is phenyl group which may be substituted with one to
four substituent(s) selected from a group consisting o-f
optionally halogen-substituted lower alkyl group, lower alkoxy
group, halogen atom, carboxyl group and lower alkoxycarbonyl
group;
(2) arylethenesulfonamide derivatives represented by the
formula (I) or pharmaceutically acceptable salts thereof in
which
9
CA 02238723 1998-OS-27
Ar is five- to six-membered heteroaryl group, naphthyl
group or phenyl group which may be substituted with one to five
substituent(s) selected from a group consisting of optionally
halogen-substituted lower alkyl group, lower alkoxy group and
halogen atom;
R1 is optionally halogen-substituted lower alkyl group;
cycloalkyl group; phenyl group which may be substituted with
one to five substituent ( s ) selected from a group consisting of
optionally halogen-substituted lower alkyl group, lower alkoxy
group, nitro group and C1_3 alkylenedioxy group; or five- to
six-membered heteroaryl group which may be substituted with one
to four substituent(s) selected from a group consisting of
optionally halogen-substituted lower alkyl group and lower
alkoxy group;
Rz is lower alkynyl group or lower alkyl group which may
be substituted with one to three substituent ( s ) selected from
a group consisting of hydroxyl group, lower alkoxy group,
cycloalkyl group and halogen atom; and
R3 is phenyl group which may be substituted with one to
four substituent ( s ) selected from a group consisting of lower
alkyl group, lower alkoxy group and lower alkoxycarbonyl group;
(3)arylethenesulfonamide derivativesrepresented by the
formula (I) or pharmaceutically acceptable salts thereof in
which
CA 02238723 1998-OS-27
Ar is optionally lower-alkyl-substituted phenyl group or
thienyl group;
X is oxygen atom;
R1 is phenyl group which may be substituted with lower
alkoxy group or five- to six-membered heteroaryl group which
may be substituted with lower alkyl group;
RZ is lower alkynyl group or lower alkyl group which may
be substituted with one to three substituent ( s ) selected from
a group consisting of hydroxyl group and halogen atom; and
R, is phenyl group which is substituted with lower alkoxy
group(s);
(4)arylethenesulfonamide derivatives represented by the
formula (I) or pharmaceutically acceptable salts thereof in
which
Ar is phenyl group or thienyl group;
R1 is pyrimidinyl group;
RZ is lower alkyl group which may be substituted with
halogen atom(s);
R3 is phenyl group which is substituted with lower alkoxy
group(s);
Rg is hydrogen atom or lower alkyl group; and
RS is hydrogen atom; or
(5) arylethenesulfonamide derivatives represented by the
formula (I) or pharmaceutically acceptable salts thereof
m
CA 02238723 1998-OS-27
selected from a group consisting of the following compounds as
well as salts thereof:
N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-
pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide,
N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-
4-pyrimidinyl]-2-phenylethenesulfonamide,
N-[6-(2-fluoroethoxy)-5-(2-methoxyphenoxy)-2-(2-
pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide,
N-[6-(2-propynyloxy)-5-(2-methoxyphenoxy)-2-(2-
pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide,
N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-
4-pyrimidinyl]-1-methyl-2-phenylethenesulfonamide,
N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-
4-pyrimidinyl]-1-ethyl-2-phenylethenesulfonamide, and
N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-
4-pyrimidinyl]-2-(2-thienyl)ethenesulfonamide.
Further, the present invention relates to a
pharmaceutical composition which contains tire
arylethenesulfonamide derivative or pharmaceutically
acceptable salt thereof and a pharmaceutically acceptable
carrier anc~, particularly, it relates to endothelia receptor
antagonists. More particularly, it relates to preventive or
therapeutic agents for diseases in which endothelia receptor
is participated such as essential hypertension, pulmonary
hypertension, hypertension induced by erythropoietin,
12
CA 02238723 1998-OS-27
hypertension induced by cyclosporin A, bronchial asthma, acute
renal failure, chronic renal failure, glomerular nephritis,
renal failure induced by cyclosporin, acute myocardial
infarction, unstable angina, congestive heart failure,
cerebrovascular spasm mostly after subarachnoid hemorrhage,
cerebroischemic disturbance, urinary incontinence, benign
prostatic hypertrophy, arteriosclerosis, Raynaud's syndrome,
diabetic peripheral circulatory disturbance, diabetic renal
diseases, preeclampsia, premature delivery, digestive ulcer,
hepatic failure, rheumatism, restenosis after PTCA, chronic
respiratory failure, chronic obstructive pulmonary diseases,
cor pulmonale, acute respiratory failure, pulmonary edema,
ischemic hepatic disturbance, adult respiratory distress
syndrome, interstitial pneumonia, pulmonary fibrosis, glaucoma,
osteoarthritis, chronic articular rheumatism, hepatic
cirrhosis, inflammatory bowel diseases (IBD), cancer, etc.
The compound (I) of the present invention will be
illustrated in detail as follows.
The term "lower" used in the definitions for the groups
in the formula ( I ) of the present specification means a straight
or branched carbon chain having from one to six carbon( s ) unless
otherwise mentioned.
Accordingly, examples of "lower alkyl group" are methyl
group, ethyl group, propyl group, isopropyl group, butyl group,
isobutyl group,sec-butyl group,tert-butyl group,pentyl group,
13
CA 02238723 1998-OS-27
isopentyl group, neopentyl group, tert-pentyl group, 1-
methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl
group, hexyl group, isohexyl group, 1-methylpentyl group,
2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl
group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group,
1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-
dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group,
1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group,
1-ethyl-1-methylpropyl group andl-ethyl-2-methylpropyl group.
Among them, those having from one to four carbon ( s ) are preferred
and methyl group, ethyl group, propyl group and isopropyl group
are particularly preferred.
"Lower alkenyl group" is a straight or branched alkenyl
group having from two to six carbons and its specific examples
are vinyl group, allyl group, 1-propenyl group, 1-methylvinyl
group, 1-butenyl group, 2-butenyl group, 3-butenyl group,
2-methyl-1-propenyl group, 2-methylallyl group, 1-methyl-1-
propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl
group, 4-pentenyl group, 3-methyl-1-butenyl group, 3-
methyl-2-butenyl group, 3-methyl-3-butenyl group, 2-methyl-
1-butenyl group, 2-methyl-2-butenyl group, 2-methyl-3-butenyl
group, 1-methyl-1-butenyl group, 1-methyl-2-butenyl group,
1-methyl-3-butenyl group, 1,1-dimethylallyl group, 1,2-
dimethyl-1-propenyl group, 1,2-dimethyl-2-propenyl group,
1-ethyl-1-propenyl group, 1-ethyl-2-propenyl group, 1-hexenyl
14
CA 02238723 1998-OS-27
group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group,
5-hexenyl group, 1,1-dimethyl-1-butenyl group, 1,1-
dimethyl-2-butenyl group, 1,1-dimethyl-3-butenyl group,
3,3-dimethyl-1-butenyl group, 1-methyl-1-pentenyl group, 1-
methyl-2-pentenyl group, 1-methyl-3-pentenyl group, 1-
methyl-4-pentenyl group, 4-methyl-1-pentenyl group, 4-
methyl-2-pentenyl group and 4-methyl-3-pentenyl group and,
among them, alkenyl group having from three to four carbons is
preferred.
"Lower alkynyl group" is a straight or branched alkynyl
group having from two to six carbons and its examples are ethynyl
group, 1-propynyl group, 2-propynyl group, 1-butynyl group,
2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group,
1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-
pentynyl group, 3-methyl-1-butynyl group, 2-methyl-3-butynyl
group, 1-methyl-2-butynyl group, 1-methyl-3-butynyl group,
1,1-dimethyl-2-propynyl group, 1-hexynyl group, 2-hexynyl
group, 3-hexynyl group, 4-hexynyl group and 5-hexynyl group.
Among them, the alkynyl group having from three to four carbons
is preferred.
"Aryl group" in the "optionally substituted aryl group"
stands for an aromatic hydrocarbon group. Preferably, it is
an aryl group having from 6 to 14 carbons and its examples are
phenyl group, naphthyl group, indenyl group, anthryl group and
CA 02238723 1998-OS-27
phenanthryl group. More preferably, it is phenyl group and
naphthyl group.
Those groups may be substituted with one or more
substituent ( s ) or, preferably, with one to f ive substituent ( s ) .
Any substituent may be used therefor so far as it is a substituent
which is commonly used as a substituent for aryl group.
Preferred examples are lower alkyl group ( said lower alkyl may
be substituted with from one to four substituent(s) selected
from a group consisting of halogen atom, lower alkoxy group,
carboxyl group, amino group and mono- or di-lower alkylamino
group), lower alkoxy group, lower alkoxycarbonyl group,
carboxyl group, halogen atom, nitro group, cyano group, amino
group, mono- or di-lower alklamino group, hydroxyl group and
C1_3 alkylenedioxy group . '
The term "five- to six-membered heteroaryl group" in
"optionally substituted five- to six-membered heteroaryl group"
stands for five- to six-membered monocyclic heteroaryl group
containing from one to four hetero atoms) selected from
nitrogen atom, sulfur atom and oxygen atom and its specific
examples are furyl group, thienyl group, pyrrolyl group,
imidazolyl group, pyrazolyl group, thiazolyl group,
isothiazolyl group, oxazolyl group, isoxazolyl group,
triazolyl group, oxadiazolyl group, thiadiazolyl group,
tetrazolyl group, pyridyl group, pyrimidinyl group,
pyridazinyl group and pyrazinyl grow.
16
CA 02238723 1998-OS-27
Preferred examples of "optionally substituted five- to
six-membered heteroaryl group" for Ar in the present invention
are furyl group, thienyl group, pyrrolyl group, imidazolyl
group, thiazolyl group, isothiazolyl group, oxazolyl group and
isoxazolyl group and particularly preferred examples are furyl
group and thienyl group. Examples of the preferred groups for
R1 are furyl group, thienyl group, thiazolyl group, pyridyl
group and pyrimidinyl group and, pariticularly preferably,
pyrimidinyl group.
Those groups may be substituted_with one or more any
substituent(s) or,preferably,from one to foursubstituent(s).
Any substituent may be used so far as it is a substituent which
is commonly used as a substituent for heteroaryl group.
Preferred examples are lower alkyl group ( said lower alkyl group
may be substituted with from one to four substituent ( s ) selected
from a group consisting of halogen atom, lower alkoxy group,
carboxyl group, amino group and mono- or di-lower alkyl-amino
group), lower alkoxy group, lower alkoxycarbonyl group;
carboxyl group, halogen atom, nitro group, cyano group, amino
group or mono- or di-lower alkyl-amino group.
Preferred "cycloalkyl group" is a cycloalkyl group having
from three to eight carbons. Its specific examples are
cyclopropyl group, cyclobutyl group, cyclopentyl group,
cyclohexyl group, cycloheptyl group and cyclooctyl group and
1~
CA 02238723 1998-OS-27
preferred examples are cyclopropyl group, cyclobutyl group,
cyclopentyl group and cyclohexyl group.
Examples of "lower alkoxy group" are methoxy group, ethoxy
group, propoxy group, isopropoxy group, butoxy group, isobutoxy
group, sec-butoxy group, tert-butoxy group, pentyloxy group
(amyloxy group), isopentyloxy group, tert-pentyloxy group,
neopentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy
group, 1-ethylpropoxy group and hexyloxy group. Among them,
those having from one to four carbons are preferred and methoxy
group and ethoxy group are particularly preferred.
Examples of "halogen atom" are fluorine atom, chlorine
atom, bromine atom and iodine atom and preferred examples are
fluorine atom and chlorine atom.
Zower alkyl group which is substituted with halogen
atoms) in "optionally halogen-substituted lower alkyl group"
is a group in which one or more hydrogen atoms) is/are
substituted with the above-mentioned halogen atom(s).
Preferably, it is lower alkyl group substituted with one to four
halogen atom(s)such aschloromethyl group,fluoromethyl group,
bromomethyl group, iodomethyl group, dichloromethyl group,
difluoromethyl group, dibromomethyl group, trichloromethyl
group, trifluoromethyl group, 2-chloroethyl group, 2-
fluoroethyl group, 2-bromoethyl group, 2-iodoethyl group,
2,2-dichloroethyl group, 2,2-difluoroethyl group, 2,2-
dibromoethyl group, 2,2,2-trichloroethyl group, 2,2,2-
18
CA 02238723 1998-OS-27
trifluoroethyl group,l-chloroethyl group,l-fluoroethyl group,
1-bromoethyl group,l-iodoethyl group,l,2-dichloroethyl group,
1,2-difluoroethyl group, 1,1-dibromoethyl group, 1,2,2-
trichloroethyl group, 1,2,2-trifluoroethyl group, 1-bromo-
2-chloroethyl group, 3-chloropropyl group, 3-fluoropropyl
group, 3,3-dichloropropyl group, 3,3-difluoropropyl group,
3,3,3-trifluoropropyl group, 4-chlorobutyl group and 5-
fluoropentyl group. Among them, lower alkyl group having from
1 to 3 carbon( s ) substituted with from 1 to 3 chlorine or fluorine
atoms) is preferred and particularly preferred one is
trifluoroemethyl group.
"Lower alkoxycarbonyl group" is a group in which an ester
is formed from carboxyl group and a straight or branched alcohol
having from one to six carbons) and its examples are
methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl
group, isopropoxycarbonyl group, butoxycarbonyl group,
isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-
butoxycarbonyl group, pentyloxycarbonyl group;
isopentyloxycarbonyl group, neopentyloxycarbonyl group,
tert-pentyloxycarbonyl group and hexyloxycarbonyl group.
Among them, those having from one to four carbon ( s ) are preferred
and methoxycarbonyl group and ethoxycarbonyl group are
particularly preferred.
"Lower alkylthio group" is a group in which hydrogen atom
of the mercapto group is substituted with the above-mentioned
19
CA 02238723 1998-OS-27
"lower alkyl group" and its specific examples are methylthio
group, ethylthio group, propylthio group, isopropylthio group,
butylthio group, isobutylthio group, pentylthio group,
isopentylthio group and hexylthio group. Among them,alkylthio
group having from one to four carbon ( s ) are preferred and those
having from one to three carbons) such as methylthio group,
ethylthio group, propylthio group and isopropylthio group are
particularly preferred.
Examples of "lower alkylsulfinyl group" are
methylsulfinyl group, ethylsulfinyl group, propylsulfinyl
group, isopropylsulfinyl group, butulsulfinyl group,
isobutylsulfinyl group, pentylsulfinyl group,
isopentylsulfinyl group, hexylsulfinyl group and
isohexylsulfinyl group. Among them, alkylsulfinyl group
having from one to four carbon ( s ) are preferred and those having
from one to three carbons) such as methylsulfinyl group,
ethylsulfinyl group, propylsulfinyl group and isoproplsulfinyl
group are particularly preferred.
Examples of "lower alkanesulfonyl group" are
methanesulfonyl group, ethanesulfonyl group, propanesulfonyl
group, isopropanesulfonyl group, butanesulfonyl group,
isobutanesulfonyl group, pentanesulfonyl group,
isopentanesulfonyl group, hexanesulfonyl group and
isohexanesulfonyl group. Among-them, alkylsulfonyl groups
having from one to four carbon ( s ) are preferred and those having
CA 02238723 1998-OS-27
from one to three carbons) such as methanesulfonyl group,
ethanesulfonyl group, propanesulfonyl group and iso-
propanesulfonyl group are particularly preferred.
"Mono- or di-lower alkyl-amino group" is an amino group
in which one or two hydrogen atoms) is/are substituted with
the above-mentioned alkyl group(s). In the case of di-lower
alkyl-amino group, the two alkyl groups may be either same or
different. Examples of the mono-(lower alkyl)-amino group are
methylamino group, ethylamino group, propylamino group,
isopropylamino group, butylamino group, isobutylamino group,
sec-butylamino group, tert-butylamino group and pentylamino
group while examples of di-(lower alkyl)-amino group are
dimethylamino group, diethylamino group, dipropylamino group,
methylethylamino group, methylpropylamino group,
methylisopropylamino group, methylbutylamino group,
methylisobutylamino group, ethylpropylamino group and
ethylisopropylamino group.
Specific examples of "C1_3 alkylenedioxy group" are
methylenedioxy group, ethylenedioxy group and propylenedioxy
group.
In the compounds of the present invention, there are
geometrical isomers such as cis- and trans-compounds [or (E)
compound and ( Z ) compound] due to double bonds and the present
invention covers each of the separated isomer [ (E) compound or
( Z ) compound ] and a mixture thereof . In the present invention,
21
CA 02238723 1998-OS-27
the compound in which the groups R4 and RS are in a trans-
configuration is particularly preferred.
Besides the above, geometrical isomers and tautomers may
be present depending upon the types of the substituents and the
present invention covers each of the separated isomers and a
mixture thereof.
In addition, compounds of the present invention may have
asymmetric carbon atoms and optical isomers [ (R) compound and
( S ) compound ] due to that may be present . The present invention
covers a mixture of those optical isomers and also a compound
separated therefrom.
The compound ( I ) of the present invention may form an acid
addition salt or, depending upon the type of the substituent ( s ) ,
salt with a base may be formed as well. Such a salt is a
pharmaceutically acceptable salt and its specific examples are
acid addition salt such as a salt with inorganic acid (for
example, hydrochloric acid, hydrobromic acid, hydroiodic acid,
sulfuric acid, nitric acid and phosphoric acid) or organic acid
( for example, formic acid, acetic acid, propionic acid, oxalic
acid, malonic acid, succinic acid, fumaric acid, malefic acid,
lactic acid, malic acid, tartaric acid, citric acid,
methanesulfonic acid, ethanesulfonic acid, aspartic acid and
glutamic acid) and a salt with base such as inorganic base (for
example, sodium, potassium, magnesium, calcium and aluminum)
22
CA 02238723 1998-OS-27
and organic base (for example, methylamine, ethylamine,
ethanolamine, lys ine and ornithine ) as well as ammonium salt .
The present invention further covers various kinds of
hydrates and solvates of the compounds (I) of the present
invention and salts thereof as well as polymorphic crystals.
(Manufacturing Methods)
Compounds of the present invention and pharmaceutically
acceptable salts thereof may be manufactured by application of
various known synthetic methods utilizing the characteristics
based upon the type of their fundamental skeleton or
substituents. At that time, it is sometimes effective in the
manufacturing technique that, depending upon the type of the
functional group, said functional group is substituted with an
appropriate protective group, that is a group which can be easily
converted to said functional group. After that, the protective
group is removed if necessary whereupon a desired compound is
afforded. Examples of such a functional group are hydroxyl
group and carboxyl group while examples of the protective group
therefor are those which are mentioned, for example, in
"Protective Groups in Organic Synthesis" (second edition) by
Greene and wuts and they may be appropriately used depending
upon the reaction conditions.
Representative manufacturing methods of the compounds of
the present invention will be given as hereunder.
23
CA 02238723 1998-OS-27
First Manufacturing Method.
Rz
Y~R3 Rz-X11 (III) 'X Y~Rs
(II) \~ (I)
R v N ~ NHSOz- CR,,= CR5 -A r R i N ~ NHSOz- CR,~= CRS-A r
(In the formulae, Z is a leaving group such as halogen
atom and organic sulfonic acid residue; and M is hydrogen atom
or alkali metal atom)
Examples of the sulfonic acid residue are
alkanesulfonyloxy group such as methanesulfonyloxy group and
ethanesulfonyloxy group and aromatic sulfonyloxy group such as
benzenesulfonyloxy group and toluenesulfonyloxy group
(particularly, p-toluenesulfonyloxy group).
Examples of the alkali metal atom are sodium and
potassium.
Compound of the present invention ( I ) is obtained by the
reaction of a compound represented by the formula ( II ) having
an appropriate leaving group with alcohol, thiol, amine or
alkali metal substituent represented by the formula (III) to
conduct etherization or N-alkylation.
It is advantageous to conduct this reaction in such a
manner that the compound ( II ) is made to react with the compound
( III ) in an amount corresponding to the reaction in the presence
24
CA 02238723 1998-OS-27
or absence of an inert solvent such as benzene, xylene,
tetrahydrofuran(THF),ether,dioxane,dimethylformamide(DMF),
dimethyl sulfoxide, methylene chloride, dichloromethane,
dichloroethane and chloroform in the presence of, if necessary,
inorganic base such as sodium, sodium hydride, sodium hydroxide,
potassium hydroxide and potassium carbonate or organic base
such as trimethylamine, triethylamine, pyridine, picoline,
lutidine and N,N-dimethylaniline with cooling, at room
temperature or with warming depending upon the reaction.
Second Manufacturing Method
Ra.X
Y~R3 Rz-Z (V) N \ Y~R3
(IV) (I)
Ri N~ NHSOz-CR,~ CRS-Ar Ri N NHSOz-CRS=CRS-Ar
Compound of the present invention ( I ) can be manufactured
by the reaction of a compound of a formula ( IV ) having hydroxyl
group, mercapto group or alkali metal substitute thereof with
a compound of a formula ( V ) having an appropriate leaving group .
The compound can be conducted by the same manner as in
the First Manufacturing Method.
CA 02238723 1998-OS-27
Third Manufacturing Method
Rz'X ~ R3 RZ'X
Y OHC-Ar (VII) ~R3
(YI) ~ N~ ~ Y (VIII)
R, N NHSOZ-CHI R ~
,/ ' N NHSOZ- CHz - CH -~1 r
OH
RZ' X
Y~Rs
R ~~ CI)
, N NHS02- CH - CH -~1 r
Compound of the present invention ( I ) can be manufactured
as follows. Thus, a methanesulfonic acid derivative of a
formula (VI) is made to react with a benzaldehyde derivative
of a formula ( VII ) ( the first step ) and the resulting alcohol
compound of a formula (VIII) is subjected to a dehydrating
reaction (the second step).
It is advantageous to conduct the first step in such a
manner that a methanesulfonic acid derivative (VI) is made to
react with a benzaldehyde derivative ( VII ) in a corresponding
26
CA 02238723 1998-OS-27
amount to the reaction in an inert solvent such as diethyl ether,
THF, DMF and benzene in the presence of a base such as sodium
hydride, potassium carbonate, sodium carbonate, n-butyl
lithium and N,N,N',N'-tetramethylethylenediamine at the
temperature range of from -60°C to warm temperature.
It is advantageous to conduct the second step in such a
manner that the alcohol compound (VIII) is kept at room
temperature to with warming in an inert solvent such as benzene
and methylene chloride.
If desired, a dehydrating agent such as pyrimidinium
p-toulenesulfonate, sulfuric acid and mesyl chloride-
triethylamine may be added thereto.
As hereunder, representative methods for the manufacture
of starting materials will be mentioned in detail.
Manufacturing Method A
Z _ Z R
N ~ y ( I X) M NHSOZ-CR,, = CRS -~1 r (X) N ~ y' 3 -
~ (II)
R/ \
N Z Ri N~ NHSOZ-CR,,=CRS-Ar
The starting compound (II) in the First Manufacturing
Method can be prepared by the reaction of pyrimidine dihalide
(IX) with arylethenesulfonamide (X) or a salt thereof. The
pyrimidine dihalide (IX) can be manufactured by a method
27
CA 02238723 1998-OS-27
mentioned in the Japanese Laid-Open Patent Publication Hei-
05/222,003 or a method similar thereto. Salt (X) of the
arylethenesulfonamide can be manufactured by the reaction of
a free sulfonamide with an appropriate inorganic base.
Manufacturing Method B
Y~R3 ~ Y~R3
R ~~ (II) --. ~~ (IV)
i N ~ NHSOl- CR,~ CRS-~1 r R i N ~ NHSOZ- CR,~ CRS- A r
The compound (IV) which is a starting material for the
Second Manufacturing Method is prepared by the reaction of a
halide of a formula ( II ) with a sulfurizing agent such as sodium
hydrosulfide, hydroxide such as sodium hydroxide or aminating
agent such as ammonia.
The compound in which X is a sulfur atom in the above
formulae_is prepared by a sulfurizing reaction.
It is advantageous to conduct the reaction in such a manner
that the halide ( II ) is made to react with a sulfurizing agent
such as hydrogen sulfide and sodium hydrosulfide in an amount
corresponding to the reaction in an inert solvent such as toluene,
benzene, chloroform, THF and DMF at room temperature to with
warming.
28
CA 02238723 1998-OS-27
Manufacturing Method C
Z
y~R3 Z
(IX) ~ M-NHSO~- CH3 (XI) N ~ y~Rs
N~ Z R ~ (XI I)
N NHSOZ-CH3
R2' Y
Y~R
Rz-Xh1 ( I I I ) N w
(YI)
N NHS02-CH3
The starting material (vI) in the Third Manufacturing
Method is prepared as follows . Thus , the compound ( IX ) is made
to react with a methanesulfonamide derivative ( XI ) ( the first
step) and the resulting compound (XII) is made to react with
a compound (IIr) (the second step).
With regard to the first step, it is advantageous to
conduct the reaction under the same conditions as in the
Manufacturing Method A.
With regard to the second step, it is advantageous to
conduct the reaction under the same conditions as in the First
Manufacturing Method.
The reaction product obtained by each of the above-
mentioned manufacturing methods is liberated and purified as
29
CA 02238723 1998-OS-27
a free compound or salt or solvate thereof such as a hydrate.
Salt can be manufactured by means of a common salt-forming
reaction.
Isolation and purification can be conducted by means of
common chemical operations such as extraction, concentration,
evaporation, crystallization, filtration, recrystallization
and various chromatographic techniques.
Each of the isomers can be separated by common means
utilizing the physico-chemical differencesbetween the isomers.
In the case of optical isomers for example, they can be separated
by common racemic resolution means such as fractional
crystallization and chromatography. With regard to an optical
isomer, it is also possible to synthesize said isomer from an
appropriate optically active starting compound.
(Industrial Applicability)
The compounds of the present invention have an affinity
to endothelin receptors and they especially have a high affinity
to an ETA receptor which is one of subtypes of the endothelin
receptors.
Accordingly, the compounds of the present invention
exhibit an action of competitively inhibiting the binding of
endothelin to receptors and can be used for the treatment of
various diseases in which endothelin is participated such as
cardiovascular diseases. Examples of such diseases are
CA 02238723 1998-OS-27
essential hypertension, pulmonary hypertension, hypertension
induced by erythropoietin, hypertension induced by cyclosporin
A, bronchial asthma, acute renal failure, chronic renal failure,
glomerular nephritis, renal insufficiency induced by
cyclosporin, acute myocardial infarction, unstable angina,
congestive heart failure, cerebrovascular spasm mostly after
subarachnoid hemorrhage, cerebroischemic disturbance, urinary
incontinence, benign prostatic hypertrophy, arteriosclerosis,
Raynaud's syndrome, diabetic peripheral circulatory
disturbance, diabetic renal diseases, preeclampsia, premature
delivery, digestive ulcer, hepatic failure, rheumatism,
restenosis after PTCA, chronic respiratory failure, chronic
obstructive pulmonary diseases, cor pulmonale, acute
respiratory failure, pulmonary edema, ischemic hepatic
disturbance, adult respiratory distresssyndrome,interstitial
pneumonia, pulmonary fibrosis, glaucoma, osteoarthritis,
chronic articular rheumatism, hepatic cirrhosis, inflammatory
bowel diseases and cancer. -
In addition, the compounds of the present invention 'show
excellent absorption per os and, further, their sustaining
property is good as well.
Action of the compounds of the present invention was
ascertained by the following pharmacological tests.
(1) Test on Inhibition of Binding of Endothelin (ET-1)
to Human ETA Receptor
31
CA 02238723 1998-OS-27
(Operating Method)
cDNA of human ETA receptor was obtained from mRNA of human
lung by means of an RT-PCR and then transferred into pEF-BOS,
a vector for expression, to prepare plasmid. The prepared
plasmid was added to a culture of COS-1 cells (cell strain
derived from renal cells of African green monkey) with
DEAF-dextran and cDNA of human ETA was transfected to COS-1 cells .
Then it was incubated for three days in a conventional DMEM
( containing 10~ of FBS ) and the COS-1 cells recovered therefrom
were suspended in a hypotonic buffer ( l OmM Tris-HCl and 5mM EDTA;
pH 7.4) followed by homogenizing the cells using a Polytron.
The suspension in which the cells were homogenized was subjected
to an ultracentrifugation ( 100, OOOG for 30 minutes at 4°C ) , the
resulting precipitate (cell membrane fraction) was re-
suspended in a Tris buffer ( 50mM Tris-HC1 and 10 mM MgCl2; pH
7.4) and the suspension was preserved by freezing at -80°C
(protein amount: about 1 mg/ml).
In conducting the experiment of binding the receptor, the
frozen cell membrane sample was melted and resuspended in an
incubation buffer (50 mM Tris-HCl, 10 mM MgCla and 0.01 bovine
serum albumin; pH 7.4). The membrane suspension (200 ,C.t 1)
containing 1 . 25 ,C.~ g as a membrane protein, 25 ,u 1 of an incubation
buffer containing a test compound in various concentrations and
25 ,(.C 1 of [l2sl] ET-1 (specific activity: 2,200 Ci/mM; final
concentration: 25 ,c.C M) were incubated together at 25°C for three
32
CA 02238723 1998-OS-27
hours and then filtered through a glass fiber filter using a
Brandel cell harvester. Measurement of radioactivity on the
glass fiber filter was conducted by means of a gamma-counter
(counting efficiency: 81~). Nonspecific binding was
determined by the use of a test buffer containing O.1,C.LM of
ET-1 . Inhibiting activity of the test compound to [ l2sl ] ET-1
was calculated as a concentration (ICso) necessary for
inhibiting 50~ of the specific binding.
(Results)
The compounds of the present invention strongly
suppressed the binding of ET-1 to human ETA receptor. The result
is shown in the following table.
33
CA 02238723 1998-OS-27
Table 1
Tested Compound ICso ( nM)
Example 1 1.6
Example 2 3.1
Example 6 4.8
Example 8 2.9
Example 13 5.5
Example 22 9.5
Example 27 5.9
Example 32 5.1
Example 33 7.7
Example 34 9.7
Example 37 1.6
Example 38 3.3
Example 39 2.8
Example 42 1.5
Example 45 4.4 -
Example 47 3.0
( 2 ) Test on Inhibition of Contraction Induced by ET-1 in
Ring Preparation Sample of Rat Aorta
(Operating Method)
Ring preparations having a length of 2 mm were prepared
from thoracic aorta of male Wistar rats (body weight: 300 to
34
CA 02238723 1998-OS-27
350 g). Internal cavity of the ring was lightly rubbed by
sanitary cotton to remove the endothelium. Each of the ring
preparations was mounted with a resting tension of 1 g in an
organ bath filled with 10 ml of a Krebs-Henseleit solution
bubbled with 95~ of Co2 and 5~ of oa. The tension generated from
the ring preparation was recorded isometrically. After
incubating for ten minutes together with a test compound, ET-1
was added to the organ bath in a cumulative manner. The
antagonistic activity of the test compound to ET-1 receptor was
calculated as a concentration (pAa) of the test compound
necessary for transferring the ET-1 concentration-response
curve two-fold to the right hand direction from the width (dose
ratio) of transfer to the right hand direction of the
concentration-response curve of ET-1 of the test compound of
various concentrations.
(Results)
The compounds of the present invention strongly
suppressed the contraction which was induced by ET-1 in artery
ring sample of rats.
(3) Test on Inhibition of Big ET-1-induced Pressor
Responses in Pithed Rats
(Operating Method)
Male Wistar rats (body weight: 25-350 g) were
anesthetized by sodium pentobarbital (60 mg/kg, i.p.) and a
cannula for artificial ventilation was inserted into a trachea.
CA 02238723 1998-OS-27
'_.
Spinal cord was broken by inserting a rod made of steel thereinto
and then the rat was connected to an artificial respirator. A
catheter for measuring the systemic arterial blood pressure was
inserted into a carotid artery while another catheter for
administering big ET-1 was inserted into a femoral vein. After
30 minutes from the oral administration of a test compound at
doses of 0.1 to 10 mg/kg, the rat was pithed and then big ET-1
was intravenously administered at doses of 0.1 to 3.2 nmol/kg
in a cumulative manner. Activity of the test compound was
evaluated by the dose (DRZ value) whereby the dose-response
curve of pressor responses by big ET-1 to the right hand
direction to an extent of two-fold.
(Results)
Oral administration of the compounds of the present
invention exhibited an excellent suppressive action to big
ET-1-induced pressor responses in pithed rats. The results are
shown in the following Table.
36
CA 02238723 1998-OS-27
Table 2
Tested Compound DR2 (mg/kg)
Example 2 0.61
Example 38 0.65
Example 42 1.85
Comparative 32
Com ound*
*: Comparative Compound: a compound mentioned in Example 67 of
the Japanese Laid-Open Patent Publication Hei-05/222,003
(generic name: Bosentan)
HO
I
i
N~ ~ 0 0 Me
~ NHS 2
~N ~ ~.-Bu
(4) Test on Inhibition of Big ET-1-induced Pressor
Responses in Conscious Rats
Male wistar rats (body weight: 250 to 350 g) were
anesthetized by sodium pentobarbital (60 mg/kg, i.p.). A
catheter for measuring the systemic arterial blood pressure was
inserted into a carotid artery while another catheter for
37
CA 02238723 1998-OS-27
administering big ET-1 was inserted into a jugular vein.
Experiment was conducted after two to three days from the
operation. Thus, big ET-1 was intravenously administered to
conscious rats at a dose of 0.5 nmol/kg every one hour. After
30 minutes from the third administration of big ET-1, a test
compound was orally administered at doses of 0.3 to 3 mg/kg.
Activity of the test compound was evaluated by an inhibition
of big ET-1-induced pressor responses.
(Results)
As a result of the test, the compounds of the present
invention exhibited an excellent suppressive action to big
ET-1-induced pressor responses in conscious rats.
A pharmaceutical composition containing the compound of
the present invention (I) or salts thereof and a
pharmaceutically acceptable carrier can be prepared by a
commonly-used method from one or more of the compound
represented by a formula ( I ) or a salt thereof and pharmaceutical
carrier, filler and other additives which are commonly used far
preparing a pharmaceutical preparation. Administration may be
either by oral administration using tablets, pills, capsules,
granules, powder and liquid or by parenteral administration
using intravenous or intramuscular injections, suppositories
and percutaneous agents.
With regard to a solid composition for oral
administration according to the present invention, tablets,
38
CA 02238723 1998-OS-27
powder, granules, etc. are used. In such a solid composition,
one or more active substance ( s ) is /are mixed with at least one
inert diluent such as lactose, mannitol, glucose,
hydroxypropylcellulose, microcrystalline cellulose, starch,
polyvinylpyrrolidone and magnesium metasilicate aluminate.
The composition may also contain additives) other than the
inert diluent such as lubricant (e. g. magnesium stearate,
disintegrating agent (e. g. calcium cellulose glycolate),
stabilizer (e. g. lactose) and auxiliary solubilizer (e. g.
glutamic acid and aspartic acid). Tablets and pills may, if
necessary be coated with sugar coat or gastric or enteric film
such as sucrose, gelatin, hydroxypropylcellulose and
hydroxypropylmethyl-cellulose phthalate.
The liquid composition for oral administration includes
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, elixiers, etc. and contains commonly used inert
diluents such as pure water and ethanol. Besides the inert
diluents~ the composition may also contain auxiliary agenl;s
such as moisturizers and suspending agents as well as sweeteners,
seasoning agents, aromatic agents and antiseptics.
Injectionsfor parenteral administration include aseptic
aqueous or nonaqueous solutions, suspensions and emulsions.
Aqueous solutions and suspensions contain, for example,
distilled water for injections and a physiological saline
solution. Nonaqueous solutions and suspensions contain, for
39
CA 02238723 1998-OS-27
example, propylene glycol, polyethylene glycol, plant oil such
as olive oil, alcohols such as ethanol, Polysolvate 80 (trade
name), etc. Such compositions may further contain auxiliary
agents such as antiseptics, moisturizers, emulsifiers,
dispersing agents, stabilizers (e. g. lactose) and auxiliary
solubilizers (e.g. glutamic acid and aspartic acid). They can
be made aseptic by means of, for example, filtration passing
through a bacterial conserving filter, compounding with aseptic
agent, or irradiation. They may also be used by manufacturing
an aseptic solid composition followed by dissolving in aseptic
water or aseptic solvent for injection before use.
In the case of oral administration, daily dose is usually
from about 0.001 to 30 mg/kg body weight or, preferably, 0.1
to 5 mg/kg and this is administered at a time or by dividing
into two to four times a day. In the case of an intravenous
administration, an appropriate dose per day is from about 0.001
to 30 mg/kg body weigh and it is administered at a time or by
dividing into two or more times a day. The dose may be suitably ,.
decided for each case by taking symptom, age, sex, etc. into
consideration.
(Best Mode for Conducting the Invention)
The present invention will be illustrated in more detail
by means of the following examples. The compounds of the
present invention are not limited to the compounds which are
CA 02238723 1998-OS-27
mentioned in the following examples only. Incidentally, the
methods for the manufacture of the starting compounds used in
the examples will be given as referential examples.
Referential Example 1.
Sodium hydride ( 60~ ) (480 mg) was added to a solution of
1.00 g of 2-phenylethenesulfonamide in 10 ml of
dimethylformamide with ice cooling followed by stirring at room
temperature for 15 minutes . To this reaction solution was added
1.91 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2-(2-
pyrimidinyl)-pyrimidine with stirring. The reaction mixture
was stirred at room temperature for 2.5 hours and poured into
a mixture of 1N hydrochloric acid and ice. The resulting
crystals were collected by filtration and pulverized in hot
ethanol. After allowing to cool, the crystals were collected
by filtration to give 1.91 g of N-[6-chloro-5-(2-
methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-
phenylethenesulfonamide.
Referential Example 2. -
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-2-(3-methylphenyl)ethenesulfonamide was
prepared by the same manner as in Referential Example 1.
Referential Example 3.
N-[6-Chloro-5-(4-methoxycarbonyl-2-propylphenoxy)-2-
(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide
was prepared by the-same manner as in Referential Example 1.
41
CA 02238723 1998-OS-27
4,6-Dichloro-5-(4-methoxycarbonyl-2-propylphenoxy)-2-
(2-pyrimidinyl)-pyrimidine which is astarting material for the
above-prepared compound was synthesized as follows.
To 3.00 g of 4,6-dihydroxy-5-(4-methoxycarbonyl-2-
propylphenoxy)-2-(2-pyrimidinyl)-pyrimidine were added 10 ml
of phosphorus oxychloride and 1 . 2 ml of collidine and the mixture
was heated to reflux for four hours with stirring. The reaction
solution was poured into ice water followed by extracting with
chloroform. The chloroform layer was washed with a saturated
sodium chloride solution, dried over anhydrous magnesium
sulfate and filtered. The filtrate was concentrated in vacuo
and the crystals in the residue were pulverized in ether and
collected by filtration to give 1.76 g of 4,6-dichloro-5-
(4-methoxycarbonyl-2-propylphenoxy)-2-(2-pyrimidinyl)-
pyrimidine.
The compounds of the following Referential Examples were
synthesized by the same manner as in Referential Example 1.
Referential Example 4.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-trifluoromethyl-4-
pyrimidinyl]-2-phenylethenesulfonamide.
Referential Example 5.
N-[6-Chloro-2-cyclopropyl-5-(2-methoxyphenoxy)-4-
pyrimidinyl]-2-phenylethenesulfonamide.
Referential Example 6.
42
CA 02238723 1998-OS-27
N-[6-Chloro-5-(2-methoxyphenoxy)-2-phenyl-4-
pyrimidinyl]-2-phenylethenesulfonamide.
Referential Example 7.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(4-trifluoro-
methylphenyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Referential Example 8.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(3-nitrophenyl)-4-
pyrimidinyl]-2-phenylethenesulfonamide.
Referential Example 9.
N-[6-Chloro-2-(3,5-dimethoxyphenyl)-5-(2-methoxy-
phenoxy)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Referential Example 10.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(3-methoxyphenyl)-
4-pyrimidinyl]-2-phenylethenesulfonamide.
Referential Example 11.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(3,4-methylene-
dioxyphenyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Referential Example 12. --
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(3,4,5-trimethoxy-
phenyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Referential Example 13.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyridyl)-4-
pyrimidinyl]-2-phenylethenesulfonamide.
Referential Example 14.
43
CA 02238723 1998-OS-27
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4-
pyrimidinyl]-2-phenylethenesulfonamide.
Referential Example 15.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(3-pyridyl)-4-
pyrimidinyl]-2-phenylethenesulfonamide.
Referential Example 16.
N-[6-Chloro-2-(6-chloro-3-pyridyl)-5-(2-methoxy-
phenoxy)-4-pyri.midinyl]-2-phenylethenesulfonamide.
Referential Example 17.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(6-trifluoro-
methyl-3-pyridyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Referential Example 18.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-thienyl)-4-
pyrimidinyl]-2-phenylethenesulfonamide.
Referential Example 19.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(3-thienyl)-4-
pyrimidinyl]-2-phenylethenesulfonamide.
Referential Example 20.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-methyl-4-
thiazolyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Referential Example 21.
N-[6-Chloro-2-(3-furyl-5-(2-methoxyphenoxy)-4-
pyrimidinyl]-2-phenylethenesulfonamide.
Referential Example 22.
44
CA 02238723 1998-OS-27
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-1-methyl-2-phenylethenesulfonamide.
Referential Example 23.
N-[6-Chloro-5-(2-methoxyphenoxy)=2-(2-pyrimidinyl)-4-
pyrimidinyl]-1-ethyl-2-phenylethenesulfonamide.
Referential Example 24.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-2-(4-methylphenyl)ethenesulfonamide.
Referential Example 25.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-2-(4-tent-butylphenyl)ethenesulfonamide.
Referential Example 26.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-2-(4-chlorophenyl)ethenesulfonamide.
Referential Example 27.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-2-(2-thienyl)ethenesulfonamide.
Referential Example 28.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pvrimidinvll-2-(4-trifluorophenvl)ethenesulfonamidate.
Referential Example 29.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-2-(4-methoxyphenyl)ethenesulfonamide.
Referential Example 30.
CA 02238723 1998-OS-27
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-2-(2-naphthyl)ethenesulfonamide.
Referential Example 31.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-2-(1-naphthyl)ethenesulfonamide.
Referential Example 32.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-2-(2-chlorophenyl)ethenesulfonamide.
Referential Example 33.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-2-(4-methoxycarbonylphenyl)ethenesulfonamide.
Referential Example 34.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-2-(3-thienyl)ethenesulfonamide.
Referential Example 35.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-2-(3-chlorophenyl)ethenesulfonamide.
Referential Example 36. -
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-2-phenyl-1-propylethenesulfonamide.
Referential Example 37.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-2-methyl-2-phenylethenesulfonamide.
Referential Example 38.
46
CA 02238723 1998-OS-27
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-2-(2-methylphenyl)ethenesulfonamide.
Referential Example 39.
N-[6-Chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-2-(2,4,6-trimethylphenylphenyl)ethenesulfon-
amide.
Example 1.
Sodium (230 mg) was dissolved in 5.6 ml of ethylene glycol
and 495 mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-
pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide was
added thereto under ice cooling with stirring. The reaction
mixture was stirred at 80°C for three hours and poured into a
mixture of 1N hydrochloric acid and ice. The crystals separated
out therefrom were collected by filtration and the resulting
crystals were purified by a silica gel column chromatography
(chloroform-methanol - 20:1) to give 500 mg of N-[6-(2-
hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4- -
pyrimidinyl]-2-phenylethenesulfonamide.
To a methanolic solution of 104 mg of the resulting
sulfonamide derivative was added 2 ml of O.1N ethanolic KOH
solution followed by concentrating in vacuo. The resulting
solid was pulverized in ether and collected by filtration to
give 84 mg of potassium N-[6-(2-hydroxyethoxy)-5-(2-
47
CA 02238723 1998-OS-27
methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-
phenylethenesulfonamidate.
Example 2.
Sodium (181 mg) was dissolved in 10 ml of methanol and
400 mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-
pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide was
added with stirring at room temperature. The reaction mixture
was stirred at room temperature for three hours and poured into
a mixture of 1N hydrochloric acid and ice. The crystals
separated out therefrom were collected by filtration and the
resulting crystals were purified by a silica gel column
chromatography (chloroform-methanol = 40:1). The resulting
yellow amorphous substance was crystallized in ether and
collected by filtration to give 273 mg of N-[6-methoxy-5-
(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-
phenylethenesulfonamide.
Compounds of the following Examples 3 to 6 were prepared
by the same manner as in Example 2.
Example 3.
N-[6-ethoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-2-phenylethenesulfonamide.
Example 4.
N-[5-(2-Methoxyphenoxy)-6-propoxy-2-(2-pyrimidinyl)-
4-pyrimidinyl]-2-phenylethenesulfonamide.
Example 5.
48
CA 02238723 1998-OS-27
N-[6-Cyclopropylmethoxy-5-(2-methoxyphenoxy)-2-(2-
pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Example 6.
N-[6-(2-Methoxyethoxy)-5-(2-methoxyphenoxy)-2-(2-
pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Example 7.
Sodium ( 181 mg) was added to 10 ml of isopropyl alcohol
and, after one hour, 100 ml of isopropyl alcohol was added
thereto followed by heating at 60°C to dissolve. To this
reaction solution was added 400 mg of N-[6-chloro-5-(2-
methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenyl-
ethenesulfonamide with stirring at room temperature. The
reaction mixture was stirred at room temperature for 1 .25 hours
and then at 60°C for 45 minutes followed by pouring into a mixture
of 1N hydrochloric acid and ice. The solution was extracted
with chloroform and the chloroform layer was dried over
anhydrous magnesium sulfate followed by filtering. The
filtrate was concentrated in vacuo and the resulting residue
was purified by a silica gel column chromatography (ethyl
acetate). The resultina amorphous substance was crystallized
in ether and collected by filtration to give 57 mg of N-[6-
isopropoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-2-phenylethenesulfonamide.
Example 8.
49
CA 02238723 1998-OS-27
To a solution of 258 mg of fluoroethanol in 20 ml of
dimethylformamide was added 194 mg of sodium hydride ( 60~ ) with
ice cooling followed by stirring for 30 minutes. To this
reaction solution was added 400 mg of N-[6-chloro-5-(2-
methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenyl-
ethenesulfonamide with stirring under ice cooling followed by
stirring for 30 minutes. The reaction mixture was stirred at
room temperature for two hours and poured into a mixture of 1N
hydrochloric acid and ice. This solution was extracted with
chloroform and the chloroform layer was dried over anhydrous
magnesium sulfate and filtered. The filtrate was concentrated
in vacuo and the resulting residue was purified by a silica gel
column chromatography (chloroform-methanol - 40:1). The
resulting amorphous substance was crystallized in ether and
collected by filtration to give 240 mg of N-[6-(2-
fluoroethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-2-phenylethenesulfonamide.
Compounds of the following Examples 9 to 10 were prepared
by the same manner as in Example 8.
Example 9.
N-[6-(2,2-Difluoroethoxy)-5-(2-methoxyphenoxy)-2-(2-
pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Example 10.
N-[5-(2-Methoxyphenoxy)-2-(2-pyrimidinyl)-6-(2,2,2-
trifluoroethoxy)-4-pyrimidinyl]-2-phenylethenesulfonamide.
CA 02238723 1998-OS-27
Example 11.
Sodium ( 693 mg) was added to and dissolved in 18 .2 ml of
aminoethanol. To this reaction solution was added 3.00 g of
N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-2-phenylethenesulfonamide with stirring at room
temperature. The reaction mixture was stirred at 60°C for one
hour and then at 80°C for two hours followed by pouring into
a mixture of 1N hydrochloric acid and ice. This solution was
neutralized with a saturated sodium bicarbonate solution and
extracted with ethyl acetate and the ethyl acetate layer was
dried over anhydrous magnesium sulfate and filtered. The
filtrate was concentrated in vacuo and the resulting residue
was purified by a silica gel column chromatography
(chloroform-methanol - 20:1). The resulting amorphous
substance was pulverized in ether and collected by filtration
to give 2.40 g of N-(6-(2-hydroxyethylamino)-5-(2-
methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-
phenylethenesulfonamide.
Example 12.
Sodium (1.031 g) was dissolved in 20.130 g of 1,3-
propanediol and 2.091 g of N-(6-chloro-5-(2-
methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenyl-
ethenesulfonamide was added thereto with stirring at room
temperature. The reaction mixture was stirred at room
temperature for 50 minutes and then at 60°C for 50 minutes and
51
CA 02238723 1998-OS-27
poured into a mixture of 1N hydrochloric acid and ice. This
was extracted with ethyl acetate and the ethyl acetate layer
was dried over anhydrous magnesium sulfate and filtered. The
filtrate was concentrated in vacuo and the resulting residue
was purified by a silica gel column chromatography
(chloroform-methanol = 100:1to 20:1). The resulting syrup was
crystallized in ether and collected by filtration to give 1.817
g of N-[6-(3-hydroxypropyloxy)-5-(2-methoxyphenoxy)-2-(2-
pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Example 13.
Sodium (185 mg) was dissolved in 5 ml of 2-propyn-1-of
and 390 mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-
pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide was
added thereto with stirring at room temperature. The reaction
mixture was stirred at 60°C for one hour and poured into a mixture
of 1N hydrochloric acid and ice. This was extracted with ethyl
acetate and the ethyl acetate layer was dried over anhydrous
magnesium sulfate and filtered. The filtrate was concentrated
in vacuo and the resulting residue was purified by a silica gel
column chromatography (chloroform-methanol = 100:1 to 30:1).
The resulting syrup was crystallized in ether and collected
filtration to give 342 mg of N-[6-(2-propynyloxy)-5-(2-
methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenyl-
ethenesulfonamide.
Example 14.
52
CA 02238723 1998-OS-27
Sodium (315 mg) was dissolved in 7.7 ml of ethylene glycol
and 700mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-
pyrimidinyl)-4-pyrimidinyl]-2-(3-methylphenyl)ethenesulfon-
amide was added thereto with stirring. The reaction mixture
was stirred at 90°C for 30 minutes and poured into a mixture
of 1N hydrochloric acid and ice. Crystals separated out
therefrom were collected by filtration and the resulting
crystals were purified by a silica gel column chromatography
(chloroform-methanol - 20:1). The resulting amorphous
substance was crystallized in ether and collected filtration
to give 533 mg of N-[6-(2-hydroxyethoxy)-5-(2-methoxy-
phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(3-methyl-
phenyl)ethenesulfonamide.
Example 15.
(a) To 508 mg of N-[6-methoxy-5-(2-methoxyphenoxy)-2-
(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide
was added 10 .3 ml of ethanolic 0 . 1M potassium hydroxide solution
followed- by stirring overnight. Crystals separated out
therefrom were collected by filtration and recrystallized from
ethanol-water to give 330 mg of potassium N-[6-methoxy-5-
(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-
phenylethenesulfonamidate.
(b) To 1.00 g of N-[6-methoxy-5-(2-methoxyphenoxy)-2-
(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide
were added 10 ml of ethanol-water (4:1) and 110 mg of sodium
53
CA 02238723 1998-OS-27
methoxide followed by heating to reflux. To this was added 18
ml of ethanol-water ( 4 :1 ) so that the crystals were completely
dissolved. This was filtered when hot, the filtrate was stirred
at room temperature and the crystals separated out therefrom
were collected by filtration. The crystals were washed with
ethanol-water (4:1) to give 80 mg of~sodium N-[6-methoxy-5-
(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-
phenylethenesulfonamidate monohydrate.
Example 16.
Sodium (356 mg) was dissolved in 20 ml of methanol and
900 mg of N-[6-chloro-5-(4-methoxycarbonyl-2-propyl-
phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethene-
sulfonamide was added thereto with stirring at room temperature.
The reaction mixture was stirred at room temperature for five
hours and forty minutes, at 60°C for one hour and fifty minutes
and at room temperature overnight. After that, the mixture
was poured into a mixture of 1N hydrochloric acid and ice.
Crystals separated out therefrom were collected by filtration
and the resulting crystals were purified by a silica gel column
chromatography (chloroform-ethanol - 20:1). The resulting
amorphous substance was crystallized in ether and collected by
filtration to give 452 mg of N-[6-methoxy-5-(4-
methoxycarbonyl-2-propylphenoxy)-2-(2-pyrimidinyl)-4-
pyrimidinyl]-2-phenylethenesulfonamide.
Example 17.
54
CA 02238723 1998-OS-27
Sodium methoxide (336 mg) was added to a solution of 320
mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-trifluoromethyl-4-
pyrimidinyl]-2-phenylethenesulfonamide in 10 ml of N,N-
dimethylformamide followed by stirring overnight. The
reaction mixture was poured into a mixture of ice and 1N
hydrochloric acid and the solid separated out therefrom was
collected by filtration. This solid was purified by a silica
gel column chromatography (chloroform) and the resulting oil
was crystallized from ether to give 210 mg of N-[6-
methodxy-5-(2-methoxyphenoxy)-2-trifluoromethyl-4-,
pyrimidinyl]-2-phenylethenesulfonamide.
Compounds of the following Examples 18 to 25 were prepared
by the same manner as in Example 17 except that, if necessary,
the reaction was conducted at room temperature or by heating
up to the temperature of 110°C. Incidentally, the compound
forming a salt was synthesized by subjecting to the same
salt-forming reaction as in Example 15.
Example 18.
Potassium N-[2-cyclopropyl-6-methoxy-5-(2-methoxy-
phenoxy)-4-pyrimidinyl]-2-phenylethenesulfonamidate.
Example 19.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-phenyl-4-
pyrimidinyl]-2-phenylethenesulfonamide.
Example 20.
CA 02238723 1998-OS-27
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(4-trifluoro-
methylphenyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Example 21.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(3-nitrophenyl)-
4-pyrimidinyl]-2-phenylethenesulfonamide.
Example 22.
N-[2-(3,5-Dimethoxyphenyl)-6-methoxy-5-(2-methoxy-
phenoxy)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Example 23.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(3-methoxy-
phenyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Example 24.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(3,4-meth-
ylenedioxyphenyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Example 25.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(3,4,5-tri-
methoxyphenyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Compounds of the following Examples 26 to 27 were prepared
by the same manner as in Example 2.
Example 26.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyridyl)-4-
pyrimidinyl]-2-phenylethenesulfonamide.
Example 27.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4-
pyrimidinyl]-2-phenylethenesulfonamide.
56
CA 02238723 1998-OS-27
Compounds of the following Examples 28 to 29 were prepared
by the same manner as in Example 17 except that, if necessary,
the reaction was conducted at room temperature or by heating
up to 110°Co
Example 28.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(3-pyridyl)-4-
pyrimidinyl]-2-phenylethenesulfonamide.
Example 29.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(6-methoxy-3-
pyridyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Example 30.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(6-trifluoro-
methyl-3-pyridyl)-4-pyrimidinyl]-2-phenylethenesulfonamide
was prepared by the same manner as in Example 2.
Compounds of the following Examples 31 to 34 were prepared
by the same manner as in Example 17 except that, if necessary,
the reaction was conducted at room temperature or by heating
up to 110°C .
Example 31.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-thienyl)-4-
pyrimidinyl]-2-phenylethenesulfonamide.
Example 32.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(3-thienyl)-4-
pyrimidinyl]-2-phenylethenesulfonamide.
Example 33.
57
CA 02238723 1998-OS-27
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-methyl-4-
thiazolyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Example 34.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(3-furyl)-4-
pyrimidinyl]-2-phenylethenesulfonamide.
Example 35.
N-[5-(2-Methoxyphenoxy)-6-(2-propynyloxy)-2-(6-
trifluoromethyl-3-pyridyl)-4-pyrimidinyl]-2-phenylethene-
sulfonamide was prepared by the same manner as in Example 13.
Example 36.
N-[6-(2-Hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(6-
trifluoromethyl-3-pyridyl)-4-pyrimidinyl]-2-phenylethene-
sulfonamide was prepared by the same manner as in Example 1.
Compounds of the following Examples 37 to 42 were prepared
by the same manner as in Example 17 except that, if necessary,
the reaction was conducted at room temperature or by heating
up to 110°C. Incidentally, a compound forming a salt was
synthesized by subjecting to a further salt-forming reaction
by the same manner as in Example 15.
Example 37.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-
4-pyrimidinyl]-1-methyl-2-phenylethenesulfonamide.
Example 38.
58
CA 02238723 1998-OS-27
Potassium N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-
pyrimidinyl)-4-pyrimidinyl]-1-ethyl-2-phenylethenesulfon-
amidate.
Example 39.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-
4-pyrimidinyl]-2-(4-methylphenyl)ethenesulfonamide.
Example 40.
Potassium N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-
pyrimidinyl)-4-pyrimidinyl]-2-(4-tert-butylphenyl)ethene-
sulfonamidate.
Example 41.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-
4-pyrimidinyl]-2-(4-chlorophenyl)ethenesulfonamide.
Example 42.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-
4-pyrimidinyl]-2-(2-thienyl)ethenesulfonamide.
Compounds of the following Examples 43 to 45 were prepared
by the same manner as in Example 2. Incidentally, a compourid
forming a salt was synthesized by subjecting to the same
salt-forming reaction as in Example 15.
Example 43.
Potassium N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-
pyrimidinyl)-4-pyrimidinyl]-2-(4-trifluorophenyl)ethene-
sulfonamidate.
Example 44.
59
CA 02238723 1998-OS-27
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-
4-pyrimidinyl]-2-(4-methoxyphenyl)ethenesulfonamide.
Example 45.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-
4-pyrimidinyl]-2-(2-naphthyl)ethenesulfonamide.
Example 46.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-
'4-pyrimidinyl]-2-(1-naphthyl)ethenesulfonamide.
Example 47.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-
4-pyrimidinyl]-2-(2-chlorophenyl)ethenesulfonamide.
Example 48.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-
4-pyrimidinyl]-2-(4-carboxyphenyl)ethenesulfonamide.
Example 49.
Concentrated sulfuric acid (0.1 ml) was added to a
solution of 150 mg of N-[6-methoxy-5-(2-methoxyphenoxy)-2-
(2-pyrimidinyl)-4-pyrimidinyl]-2-(4-carboxyphenyl)ethene-
sulfonamide in 10 ml of methanol followed by stirring overnight
under a refluxing condition. The reaction mixture was
concentrated in vacuo , 1N hydrochloric acid was added thereto
and the mixture was extracted with ethyl acetate. The extract
was washed with a saturated saline solution, dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo
and the resulting solid was recrystallized form ethyl acetate
CA 02238723 1998-OS-27
to give 102 mg of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-
pyrimidinyl)-4-pyrimidinyl]-2-(4-methoxycarbonylphenyl)-
ethenesulfon-amide.
Compounds of the following Examples 50 to 51 were prepared
by the same manner as in Example 2.
Example 50.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-
4-pyrimidinyl]-2-(3-thienyl)ethenesulfonamide.
Example 51.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-
4-pyrimidinyl]-2-(3-chlorophenyl)ethenesulfonamide.
Example 52.
Potassium N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-
pyrimidinyl)-4-pyrimidinyl]-2-phenyl-1-
propylethenesulfonamidate was prepared by the same manner as
in Example 17 and Example 15(a).
Compounds of the following Examples 53 to 55 were prepared
by the same manner as in Example 2.
Example 53.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-
4-pyrimidinyl]-2-methyl-2-phenylethenesulfonamide.
Example 54.
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-
4-pyrimidinyl]-2-(2-methylphenyl)ethenesulfonamide.
Example 55.
61
CA 02238723 1998-OS-27
N-[6-Methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-
4-pyrimidinyl]-2-(2,4,6-trimethylphenyl)ethenesulfonamide.
Structural formulae and physico-chemical properties of
the compounds of the above Referential Examples are shown in
Tables 3 to 4 and structural formulae and physico-chemical
properties of the compounds of Examples are shown in Tables
to $.
Abbreviations used in the tables have the following
meanings.
Ref: Referential Example number
Ex.: Example number
Sa: salt
mp.. melting point
NMR: Nucleomagnetic resonance (DMSO-ds, TMS internal
standard unless otherwise mentioned) 8:
ana: elementary analysis data
tho: theoretical value
fou: found value
m/z: mass analysis data (m/z)
N.P.: used in the next step without purification
Ph: phenyl group
Pmy: pyrimidinyl group
cPr: cyclopropyl group
nPr: n-propyl group
The: thienyl group
62
CA 02238723 1998-OS-27
Naph: naphthyl group
tBu: tert-butyl group
Py: pyridyl group
Thi: thiazolyl group
Fur: furyl group
triMeO: trimethoxy group
diMeO: dimethoxy group
triMe: trimethyl group
63
CA 02238723 1998-OS-27
C~ Table 3
O~Rs
N
~I
R~~N~ NHSOz-CH=CH-~r
Re R3 R, Ar
f
1 2-Me0-Ph2-Pym Ph NMR: 3. 80 (3H. s). 6. 83 (IH. d),
6. 86 (IH, t), 7
. 1 I (IH, t), 7. 13 (IH, d). 7.
46 (3H, m), 7. 7
I-7. 75 (3H, m), 7. 87 (2H, m), 9.
09 (2H, d).
2 2-ide0-Ph2-Pym 3-:He-NMR: 2. 32 (3H, s). 3. 80 (3H, s),
6. 82 (IH, d). 6
Ph . 87 (1H, t), 7. 09 (1H, t), 7. I3
(IH, d), 7. 2
6 (IH, d), 7. 33 (IH, t), 7. 52 (2H,
m), 7. 73
IH. t) 7. 85 (2H, m), 9. 09 (2H,
d).
3 4-i~fe00C-2-Pym Ph I~IMR: 0. 99 (3H, t) , I. 75 (2H,
m) , 2. 84 (2H, m) , 3
2-Pr-Ph . 83(3H, s). 6. 76(1H, d), 7. 45(3H,
m), 7. 7
0-7. 78 (4H, m) . 7. 80-7. 95 (3H,
m) , 9. 1 I (2H
. d).
4 2-iHeO-Ph-CF3 Ph NMR: 3. 79 (3H, s) , 6. 84-6. 90
(2H, m) , 7. O6-7. I
4 (2H, m), 7. 41-7. 49 (4H, m), 7.
65-7. 74 (3H
. m) .
2-He0=PhcPr Ph NMR: 0. 92 (2H. m), 0. 99 (2H, m).
2. 08 (IH, m), 3
. 81(3H, s). 6. 62(IH, d), 6. 84(IH,
t), 7.0
5 (IH, t), 7. 11 (IH, d), 7. 44-7.
48 (4H, m),
7. 64 (IH, d). 7. 74-7. 76 (2H, m).
11. 60 (IH.
brs).
6 2-Me0-PhPh Ph NNR: 3. 83(3H, s). 6. 77(IH, m),
6. 87(1H. m), 7
. 09(1H, m). 7. 14(IH, m). 7. 42-7.
54(6H, m)
7. 57 (IH. d). 7. 76-7. 78 (2H. m),
7. 88 (IH
. d), 8. 24-8. 26 (2H, m) I 1. 95
(IH, brs).
64
CA 02238723 1998-OS-27
7 2-Me0-Ph4-CFA-PhPh NMR: 3. 82(3H, s). 6. 81 (1H. m).
6. 87(IH. m). 7
. 07(1H. m). 7. 14(IH. m), 7. 41-7.
43(3H, m)
7. 56C1H. d), 7. 78-7. 80(ZH. m),
7. 85-7.
9I (3H. m). 8. 44(2H. d). ,
8 2-Me0-Ph3-N0,-PhPh NMR: 3. 83(3H. s). 6. 82(1H. dd),
6. 87(1H, dt),
7. 09(IH. dt), 7. 14(1H. dd). 7.
38-7. 44(3
H. m). 7. 57(LH. d). 7. 72-7. 7~
(2H. m). 7. 8
2(1H, t). 7. 88(IH. d). 8. 39(LH,
dd). 8. 65
(1H, d). 8. 99 (1H, t).
9 Z-Me0-Ph3. 5-diMeOPh L~IMR: 3. 80 (6H. s). 3. 63 (3H.
s). 6. 69 (LH. t), 6
-Ph . 79(IH, d). 6. 87(1H. t). 7. 09(IH,
t). 7. 1
4(1H, d). 7. 40-7. 47(5H. m). 7.
56(IH. d),
7. 68-7. 72 (2H, m), 7. 79 (1H. d).
2-Me0-Ph3-Me0-PhPh NMR: 3. 81 (3H. s), 3. 83(3H. s).
6. 78(IH, dd),
6. 87 ( 1 H, d t ) . 7. 06-7. 16
(3H. m) . 7. 37-7. 4
5 (4H, m). 7. 57 (1H, d), 7. 72-7.
86 (5H. m),
1 I. 96 C1H, brs).
I 2-Me0-Ph~ Ph ~thiR: 3. 82 (3H, s). 6. 13 (2H.
1 i 2). 6. 75 (LH. dd),
0 ~ 6. 85(1H. dt). 7. O1 (1H, d). 7.
07(IH. dt),
~0
7. I3 (LH. dd). 7. 40-7. 47 (3H,
m). 7. 55 (IH.
d). 7. 66 (1H. d). 7. 74-7. 77 (2H,
m). 7. 83 (
IH, d). 7. 86(LH. dd), ll. 9I (IH,
brs)
12 2-Me0-Ph3. 4. Ph 1~IMR: 3. 74 (3H. s). 3. 80 (6H.
5-t s). 3. 82 (3H, s). 6
r i
Me0-Ph . 77(1H. dd). 6. 87(1H. dc). 7. 08(IH,
dt),
7. 13 (1H, dd). 7. 39-7. 45 (3H,
m). 7. 57 (2H.
s). 7. 59-7. 66(3H. m), 7. 74(IH,
d).
13 2-Me0-Ph2-Py Ph NMR: 3. 82 (3H. s). 6. 83-6. 86 (2H.
m), 7. 07 (IH.
t). 7. 13(1H. d). 7. 42-7. 43(3H.
m). 7. 63-
CA 02238723 1998-OS-27
7. 73 (5H. m). 8. 03 (IH, brs). 8.
35 (IH, d),
8. 82 (IH, d).
I4 2-Me0-Ph4-Py Ph YI~iR: 3. 82 (3H. s), 6. 79 (1H,
dd). 6. 86 (1H, dt).
7. 08(IH. dt). 7. I3(IH, dd). 7.
42-7. 44(3
H. m), 7. 54 (LH, d). 7. 76-7. 79
(2H, m). 7. 8
5(IH, d). 8. 17(2H, dd), 8. 76(2H,
dd).
I5 2-~ie0-Ph3-Py Ph i~tMR: 3. 83 (3H. s). 6. 80 (1H.
d), 6. 87 (1H, t), 7
.09(1H, t). 7.14(IH.d), 7.=13-7.44(3H.
m)
7. 56-7. 59 (2H, m), 7. 76 (2H, m),
7. 85 (IH
d). 8. 58 (IH. d), 8. 74 (IH, m).
9. 39 (1H, s
).
16 2-ue0-Ph6-CI-3-PyPh I~II~iR: 3. 82(3H, s). 6. 81 (1H,
dd). 6. 86(1H, dt),
7. 09(1H, dt)~, 7. 14(1H, dd), 7.40-7.
47(3
H, m), 7. 57 (LH. d), 7. 68 (LH,
d), 7. 75-7. 9
I (ZH, m). 7. 84 (1H, d). 8. 57 (1H,
dd). 9. 16
(1H. d).
17 2-Me0-Ph6-CF3 Ph I~iMR: 3. 99(3H, s). 6. 95(IH. dt).
3- 7. 05(IH, dd).
Py 7. I4(LH, dd), 7. 18-7. 20(1H, m),
7. 24 (1H
. d) . 7. 37-7. 44 (3H, m) . 7. 47-7.
49 (2H, m) ,
7. 91 (1H, d). 8. 04(1H, dd), 8.
51 (1H, d~.
8. 95 (1H, brs). 9. 06 (IH, brs).
18 2-ue0-Ph2-The Ph NMR: 3. 82(3H, s), 6. 77(1H. dd),
6. 84(IH. dt),
7. 07(1H, dt). T. 13(1H. dd), 7.
18(1H. t).
7. 43-7. 45 (3H, m), 7. 55 (IH, d),
7. 75-7. 7
8(5H, m), I I. 94(1H, brs)_
19 2-11e0-Ph3-The Ph NMR: 3. 82 (3H, s). 6. 75 (LH, dd).
6. 86 (1H, dt),
7. 07(LH. dt), 7. 13(1H. dd), 7.
40-7. 47(3
H, m). 7. 55(LH. d), 7. 63(1H, dd).
7. 67 (1H
66
CA 02238723 1998-OS-27
dd), 7. ? 7-7. 80 (2H, m). Z. 86
x (1H. d). 8. 3
Z (1H. dd). I I. 86 (IH, brs).
20 2-1~e0-Ph2 He-4- Ph ~1R: 2. 78(3H. s). 3. 81 (3H, s).
6. 76(IH. dd).
Thi 6. 86(1H, dt). 7. 07(IH, dt), 7.
I3(1H, dd).
7. 42-7. 46 (3H. m) . 7. 74-7. 82
(3H. m) . 7. 8
8 (1H, d). 8. 33 (IH. s). I I. 97
(IH. brs).
2I 2-He0-Ph3-Fur Ph i~MR: 3. 82 (3H. s). 6. 74 (IH,
dd). 6. 86 (IH. dt).
6. 94(IH, d), 7. 07(1H. dt). 7.
I3(IH, dd),
7. 42-7. 47(3H. m), 7. 55(IH, d).
7. 76-7. 8
1 (3H. m). T. 84(IH, d). 8. 38(IH.
s). I3. 34
(IH. brs).
67
CA 02238723 1998-OS-27
Table 4
Cl I ~
N ~ 0
OMe
~~ N ' NHS02 CRA =CRS A r
N
Re R~ RS Ar
f
22 Me H Ph NMR: 2. 20 (3H, s). 3. 8I (3H, s),
6. 82 (1H, d). 6.
88 (lI-I. t), Z. 09 (IH, t), 7. I4(1H,
d), 7. 34-
7.48(6H, m). 7. 65(1H. s). T. 94(1H.
brs). 8
. 95 (2H. m).
nn
c,s Et H Ph NbiR: 1. 06 (3H, m). 2. 6T (2H. m).
3. 8I (3H, s). 6.
80(1H, d). 6. 88(1H, t), 7.09(IH,
t), 7. 14(
IH, d), 7. 36-7. 46(5H. m), 7. 6'I(1H,
s). 8. 0
1 (1H, brs). 8. 96 (2H. m). 11. 99
(1H. brs).
24 H H 4-Me-Ph N1~R: 2. 33 (3H, s). 3. 80 C3H. s),
~ 6. 82 (IH, d). 6.
68
CA 02238723 1998-OS-27
87 (1H, t). 7. 08 (IH, t). ,7. 13
(IH. t), 7. 26
2H, d), 7. 63 (2H, d). 7. 73 (IH.
t), 7. 79-7. 9
0 (2H. m) , 9. 19 (2H. d) .
25 H H 4-tBu-Ph N1TR: 1. 27 (9H, t), 3. 84 (3H, s).
6. 82 (1H. dd). 6
. 87(1H, dt), 7. 09((1H. dt). 7.
14(IH. dd),
7. 45 (2H. d). 7. 68 (2H. d). 7.
74 (1H. t), 7. 8
0-7. 95 (2H. m) , 9. 13 (2H, d) .
26 H H 4-CI-Ph NMR: 3. 80(3H, s). 6. 82(IH, dd).
6. 87(1H, dt).
7. 09(IH, dt). 7. I3(1H, dd), 7.
53(2H, d), 7
. 7I (1H. t). 7. 79 (2H, d). 7. 85-7.
95 (2H, m),
9. 09 (2H, d) _
27 H H 2-The i'i. P.
28 H H 4-CF3-Ph NMR: 3. 81 (3H, s), 6. 81-6. 90(2H,
m). 7. 06-7. 16
(2H. m), 7. 72 (IH, dd), 7. 84 C2H,
d). 7. 92-8
. 08 (4H, m) . 9. I 1 (2H. d) .
29 H H 4-Me0-Ph i~IR: 3. 80 (6H, s) , 6. 77-6. 90
(2H, m) , 7. O 1 (2H, d
). 7. 06-7. I6 (2H. m). 7. 66-7.
90 (5H, m). 9.
1 I (2H. d) .
30 H H 2-Naph I~II~iR: 3. 81 (3H, s). 6. 70-6.
90 (2H, m). 7. 00-7. 20
(2H, m), 7. 40-8. 25 (IOH, m), 9.
13 (2H. d).
31 H H I-t~aph NbIR: 3. 80(3H, s), 6. 85(IH, d).
- 6. 87(lH, dd), 7
. 09 (1H, dd), 7. 14 (1H, d). 7.
54-7. 66 (4H, m)
7. 91 (1H, d), 8. O1 (2H, d). 8.
05 (1H, d). 8
. 16 (1H. d), 8. 60 (1H. d), 8. 94
(2H, d).
3 H H 2-C 1-P V. P.
2 h
33 H H 4-He00C-Ph I~IMR: 3. 8I (3H, s), 3. 87(3H. s).
6. 82(IH, d). 6.
86 (1H. dd). 7. 08 (1H, dd), 7. 14
(IH, d). 7. 7
2 (IH, dd), 7. 87-8. 05 (6H. m),
9. IO (1H, d).
69
CA 02238723 1998-OS-27
34 H H 3-The Iv'MR: 3. 80(3H, s). 6. 82CIH. d),
6. 87 (IH. dd), 7
. 09 (IH. dd). 7. 12 (IH. d). 7.
54 (IH, d). 7. 6
2(IH. d). 7. 64(1H. d). 7. 71 (IH.
dd), 7. 97(
IH. d). 8. 03 (IH. s). 9. 1 1 (ZH.
d).
35 H H 3-CI-Ph ~II~iR: 3. 81 (3H. s). 6. 82(IH.
d), 6. 86(IH. dd). 7
. 09 (IH, dd). 7. 13 (IH. d). 7.
46-7. 53 (2H, m)
. 7. 71 (1H. d). 7. 73 (IH. dd).
7. 85 (IH. d),
7. 87(IH. s). 7. 98(IH. d). 9. 09(2H,
d).
36 nPr H Ph NMK: 0. 85 (3H, t) . I. 57 (2H, m)
, 2. 60 (2H, m) , 3.
81 (3H, s). 6. 78(IH. d), 6. 87C1H,
t). 7. 09(
IH, t), 7. 14(IH, d). 7. 38-7. 45(5H.
m). 7. 6
5 (IH. brs). 8. 02 (IH. m). 8. 94
(2H, m) 12. 0
IH, brs).
37 H Me Ph N. P.
38 H H 2-Me-Ph NMR: 2. 35 C3H, s) . 3. 80 (3H, s)
. 6_ 68-7. 50 (7H, m
7. 60-8. 2 0 C4H, m) , 9. 04 (2H.
m) .
39 H _ 2, 4. 6-triMe-NMR: 2. 23(3H, s), 2. 25(6H, s).
H 3. 80(3H, s). 6.
Ph 82 (1H, d), 6. 88 (IH, dd). 6. 92
(2H, s), 7. 10
(IH, dd). 7. 14CIH, d). 7. 54(1H,
d). 7. 65(1
H. dd). 7. 84 (LH. d). 8. 96 (2H,
d).
CA 02238723 1998-OS-27
Table 5
~~X
N ~ 0 0 Me
I
~N~N~ NHSOz CH=CH-Ar
~N
E -X-R., A S
x. r a
I -OCH.,CHZOHPh K ana: ( C~SH~.,NSO6SK - 0. 8HH0 )
C (~) H (~) N (~) 0 (~) S (~) K (~)
tho 52. 3I 4. 14 I2. 20 I8. 95 5.59
6.8I
f ou 52. 50 4. 40 I 2. 08 5. 43
NMR: 3. 5 I (2H, m) . 3. 84 (3H, s)
, 4. 30 (2H, m) , 4. 8
7 (IH, m), 6. 44 (IH, m). 6. 74 (1H,
m), 6. 88 (IH
. m), 7. 02 (IH, d). 7. I3 (IH. m).
7. 33 (IH, m).
7. 40 (2H, m), 7. 60-7. 62 (3H, m).
8. 20 (IH, d)
. 9. 02 (2H. d)
2 ~ -OMe Ph - mp. : 107-109
NMR: 3. 82 (3H, s). 3. 97 (3H, s),
6. 66 (IH, d), 6. 8
Z (IH, t), ?. 02 (IH, d), 7. 09 (IH,
d). 7. 45 (3H-
m). 7. 60-7. 80 C3H, m), 7. 80 (IH,
d), 7. 98 (I
H, d), 9. 08(2H, d), 11. 46(1H, brs)
3 -OE t Ph - mp. : 173-174C
NMR: I. 07 (3H, m) , 3. 82 (3H, s)
, 4. 37 (2H, m) . 6. 7
4(IH, d). 6. 83(1H, t), 7. 05-7. 10(2H,
m). 7.
46 (3H. m). 7. 68-7. 74 (3H, m), 7.
82 (IH, d). 7
. 99 (IH, d), 9. 08 (2H, d). 11. 43
(IH, brs)
4 -0-nPr Ph - mp..: l6l-I62C
NMR: 0. 62 (3H, t). I. 46 (2H, m),
3. 81 (3H, s), 4. 2
71
CA 02238723 1998-OS-27
6 (2H, m), 6. 76 (1H. ~d). 6. 83 (IH.
t). 7. 04 (1H
. t). 7. 09 (IK d), 7. 45 C3H. m).
7. 67 (IH, m).
7. 73 (2H, m). 7. 82 (IH. d). 7. 99
(IH. d). 9. 0
7 (2H. d). 1 I. 45 (IH, brs)
-OCHx-cPr Ph - mp. : 134-135C
~'I~iR: 0. I3 (2H. m). 0. 35 (2H, m).
1. OI (IH. m), 3. 8
2(3H. s). 4. 19(2H, m). 6. 76(IH. d),
6. 84(IH
. m). 7. 05 (IH. m). 7. IO (iH, d).
7. 45 (3H. m),
7. 67(IH, m), 7. 73(2H. m). 7. SI (IH,
d), 7. 9
8 (IH, d). 9. 06 (2H, d). 1 1. 39 (IH,
brs)
6 -OCH~CH~OCH3Ph - mp. : I29-
~ 1 30C
I~Ii-iR: 3. 08 (3H, s), 3. 40 (2H,
m), 3. 82 (3H. s). 4. 4
7 (2H, m). 6. 77 (IH, d), 6. 83 (IH.
m). 7. 05 (IH
. m). 7. 09 (IH, d). 7. 45 (3H. m),
7. 68 (IH, m),
7. 73 (2H, m). 7. 82 (IH, d). 7. 99
(1H. d). 9. 0
7(2H, m), 11. 41 (1H, brs)
7 -OCH(CH3)aPh - mp.: 145-147C
i'IMR: 0. 95-1. 15 C6H, m). 3. 81 (3H,
s), 5.,32 (IH, m)
6. ?9 (IH, m). 6. 84 (1H, m), 6. 95-7.
15 (2H, m
). 7. 45 (3H. m), 7. 45-8. 90 (4H.
m), 7. 99 (IH.
d), 9. 06 (2H, d). I 1. 34 (1H, brs)
8 -OCH,CH_F Ph - mp. :
1 14-143C
T MR: 3. 82 (3H. s), 4. 40-4. 70 (4H,
m). 6. 79 (IH, d)
6. 83 (1H, m). 7. 05 (1H, m). 7. 10
(1H, d), 7.
45 (3H. m). 7. 68 (IH, m). 7. 74 (2H,
m), 7. 84 (1
H, d), 7. 97(1H. d), 9. 08(2H, d),
II. 47(1H, b
rs)
9 -OCH,CHFZ Ph - p. :
1 m 90-191 C
72
CA 02238723 1998-OS-27
u~fR: 3. 81 (3H, s). :I. 66 (2H. t).
6. 15 (1H. t), 6. 7
9 (1H. d), 6. 83 (1H, m). 7. 05 (IH.
m), 6. 8-1 (1H
d), 7. 45 (3H. m), 7. 70 (1H, m),
7. 74 (2H. m).
?. 86 (1H. d). 7. 97(IH. D), 9. 09
(2H, d). I1.
57 (1H. brs)
-OCHrCF~ Ph - mp. : 204-205
~R: 3. S I (3H, s) . 5. 03 (2II, q)
, 6. 80-6. 86 (2H. m)
7. 04-7. 10 (2H, m), 7. 45 (3H, m),
7. 69 (1H, m
). 7. 74(2H, m). 7. 87(IH, d). 7.
95(IH, d), 9
. 09 (2H. d). 11. 67 (IH, brs)
I -~-HCH.,CH.,OHPh - ana: ( C.,SH.,4N~OSS v 0. 3H.,0 )
I
~
C (~) H (~) N (~) 0 (~) S (~)
tho 57. 09 4. 7I 15. 98 I6. 12 6.
10
f ou 56. 96 4. 44 15. 76 6. 10
~iR(DMSO-dfi, 100C) : 3. 57(4H. m),
3. 88(3H, s),
4. 47 (IH, m). 6. 30-6. 70 (6H m).
6. 70-6. 95
7H, m), 9. 06 (2H, m), 13. 26 (1H,
brs)
I -0 (CHl) Ph - mp. : 190-191 C
2 30H
N1~R(CDC13) : I. 86-I. 92 (2H. m),
3. 56 (2H, d. 1=4. 9
Hz) , 3. 98 (3H, s) , 4. 80 (2H, t.
1=5. 5Hz) . 5. 2
0 (1H, brs), 6. 89 (1H, t), 7. 00
(IH, d, 1=7. 3Hz
7. 10-7. I 4 (2H, m) . 7. 36-7. 40
(4H, m) , 7. 5
7-7. 58 (2H, m), 7. 62 (1H, d). 8.
04 (IH, d). 8.
8I (1H. brs). 8. 95 (2H, d, 1=4. 3Hz)
13 -OCH.,C=CHPh - mp:183-185C
~'1-iR(CDC13) : 2. 45 (1H, t, 1=2.
4Hz). 4. 00 (3H, s).
5. 22 (2H. d. 1=2. 4Hz), 6. 91 (1H,
t). 7. 00 (1H.
d, 1=7. 3Hz), 7. 14 (1H, t). 7. 25-7.
26 (1H, m),
73
CA 02238723 1998-OS-27
c. 38-r. 41 (4H. m). 7. 56-7. 5'l
(2H. m), i. 63
IH, m). 7. 98 (IH, d). 8. 93 (LH.
s). 8. 95 (2H, d
1=4. 9Hz)
1=I -OCH.,CHyOH3-ue- mp. : I67-169C
-Ph 'MR: 2. 34(3H, s). 3. 50(2H. m). 3.
83(3H. s). 4. 3
7 (2H, m) , 4. 69 ( 1 H. m) . 6_ 79-6.
83 (2H, m) . 7.
09-7. IO(2H, m). 7. 26(IH, d). Z.
33(1H. t). 7
. 53(2H. m). T. 69(1H, m), T. 77(1H,
d). 7. 95(
IH. d), 9. 08(2H. d). 11. 43(LH. brs)
I5 -OMe Ph K mp. : 201-203
(a)~ YMR: 3. 80(3H. s). 3. 85(3H, s), 6.
-IO(1H. dd. 1=1.
6. 8. OHz), 6. 73(IH, dt. J=1. 6,
8. OHz). 6. 8?(
lH. dt, J=1. 6. 8. OHz), 7. OI (1H.
dd. J=I. 6. 8. 0
Hz), 7. 12(IH, d. J=l6Hz), 7. 31 (1H,
m). 7. 38
-7. 42 (2H. m). ?. 57-T. 63 (3H. m),
8. 21 (1H. d.
J=I6Hz), 9. 03 (2H, d, J=4. 8Hz).
I5 -OMe Ph 'iamp: 192-195
(b) NISR: 3. 82 (3H. s). 3. 85 (3H, s).
6. 41 (IH. dd. J=1.
-- 6, 7. 6Hz). 6. 74(1H. t. J=T. 6Hz).
6. 88(1H, dt
. 1=I. 6. 7. 6Hz). 7. 02 (1H, d. J=7.
6Hz). Z. 13
1H, d. J=l6Hz). Z. 31 (IH. m). 7.
35-7. 41 (2H, m
), 7. 51-7. 56(2H, m). Z. 63(1H. t,
J=4. 8Hz),
7. 8? (LH, d. J=l6Hz). 9. Ol (2H,
d. 1=4. 8Hz)
74
CA 02238723 1998-OS-27
Table 6
COOMe
Raw,Y I
0
N
N I ~ Pr
~N~ NHSOz CH=CH-Ar
~N
Ex. I -X-R., A r S a
I6 -OMe Ph - mp. : 227-230°
ul~iR: 0. 97(3H, t), I. 71 (2H m), 2. 80(2H, m), 3. g
2 (3H. s). 3. 88 (3H. s). 6. 64 (IH, m). 7. 45 (3H
. m). 7. 60-7. 80 (5H. m). 7. 84 (IH, s). 7. 95 (I
H. m), 9. 07 (2H, d), I I. 70 (IH. brs)
75
CA 02238723 1998-OS-27
Table 7
R
ZX
0
0 Me
N NHSOz-CH=CH
Ex.-X-RZ R 1 S
a
17 -OMe CF3 - NMR: 3. 80 (3H. s), 3. 83 (3H, s).
6. 73 (IH, m), 6.
81 (IH, m). ?. 03 (IH, m). ?. 08
(1H. m). 7. 46-
7. 47 (3H, m), 7. 66-7. 70 (3H, m),
11. 79 (1H, m
)
.
m/z: 482(FAB. M++1)
18 -OMe cPr K NMR: 0. 84 (2H. m). 0. 92 (2H, m).
1. 88 (IH, m), 3.
70 C3H, s), 3. 82 (3H. s), 6. 34
(IH. m). 6. 73
1H, m), 6. 85 (IH, m), 6. 98 (IH,
m), 7. 38-7. 4
76
CA 02238723 1998-OS-27
1 (4H. m) , 7. 52 (2H. m) .
m/z : 530 (F:~B. ~i'~K)
19 -OMe Ph _ mp. : 14?-148°C
N~iR: 3. 85 (3H. s). 3. 92 (3H. s). 6. 66 (1H, d), 6.
82 (1H. t). ?. 04 (IH, t). 7. 10 (1H. d). ?. 43-
7. 51 (6H. m). ?. 56(rH. d). 7. ?4-?. 76(2H. d)
?. 8I (1H, d). 8. 29 (2H. d). I 1. 23 (1H, brs)
20 -OMe 4-CF3-Ph - mp.: 143-144°C
w~iR: 3. 85C3H, s), 3. 94(3H. s), 6. 69(IH, d). 6.
83(LH, t). 7. 03(1H. t). 7. LO(IH. d). 7.42-
7. 43 (3H. m) . ?. 56 (LH. d) . ?. 69-?. 84 (3H. m)
8.48(2H, d). 11. 36(IH, s)_
21 -0Me 3-NOZ Ph - mp. : 235-236°C
~iR: 3_ 84(3H, s). 3. 96(3H, s), 6. ?1 (IH, d). 6.
83(1H. m). 7. 03(IH, m). 7. LO(IH. m). ?. 38-
7. 44 (3H. m) . 7. 56 (1H, d) . 7. 68-?. 74 (2H. m) '
I
. ?. ??-7. 83 (ZH, m). 8. 36 (1H. m). 8_ ?0 (1H.
m). 9. 05(IH, t). lI. 38(LH, brs).
22 -OMe 3. 5-diHeO- - mp. : I64-165°C
ph NMR: 3. 79 (6H. s) . 3. 84 (3H, s) . 3. 92 (3H, s) , 6.
64-6. 70C2H, m), 6. 82(LH. t). 7. 73((IH. t),
7. 09 (1H, d). 7. 40-7. 48 (5H. m). 7. 56 (IH, d
), 7. 64-?. ?0 (2H, m), 7. 72 (LH, d). 11. 23 (1
H, brs).
23 -OMe 3-~IeO-Ph - mp. : 16I-162°C
NMR: 3. 80 (3H, s) . 3. 85 (3H. s) , 3. 92 (3H, s) . 6.
66 (LH. d). 6. 82 CLH. t), 7. 03 (1H, t). 7. 05-
77
CA 02238723 1998-OS-27
7. I3 (2H. m). 7. 38 (1H. t). 7. 35-7.
45 (?H. m)
7. 56(1H, d). ?. 70-7. 74(2H, m),
7. 7 i (1H.
d). 7. 84 (IH. m). 7. 88 (IH, d),
I 1. 26 (IH. s).
24 -0Me ~ ~ - mp. : 158-159C
0' Y ~tMR: 3. 85(3H, s). 3. 90(3H, s),
6. 11 (2H, s). 6.
~- 0
64(IH, d). 6. 83(1H, t). 6. 97-7.
04(2H, m).
7. 09 (IH, d). 7. 42-7. 47 (3H, m).
7. 54 (IH, d)
7. ?1-7. 79 (4H, m). 7. 90 (1H. d).
1 1. 20 (1H
s).
25 -OMe 3, 4. - mp. : I53-I 54C
5-t r
i
Me0-Ph ~IIviR: 3. 73 (3H. s). 3. 78 (6H,
s). 3. 84 (3H, s), 3.
94(3H, s). 6. 64(1H. dd), 6. 82(1H,
dt), 7. 0
3 (IH, dt). 7. 09 (1H. dd), 7. 38-7.
46 C3H. m),
Z 56-7. 72 (6H, m), I 1. 26 (1H, s).
26 -OMe 2-PY mp.: 88-90C
m/z : 530 (FAB. M~+I)
27 -OMe 4-Py - mp. : 212-214C
~tMR: 3. 84 (3H, s) , 3. 93 (3H, s)
. 6. 69 C1H. dd) . 6
. 82 (IH. dt), 7. 03 (1H. dt), 7.
10 (1H, dd). 7
. 43-7. 45 (3H, m). 7. 56 (1H. d),
7. 77-7. 79 (2
H, m). 7. 84(1H. d), 8. 16(2H, dd),
8. 71 (2H,
dd), 11. 43(1H. brs).
28 -OMe 3-Py mp. : I68-169C
NMR: 3. 84(3H, s). 3. 94(3H. s). 6.
68CIH, d). 6.
82 (1H. t). 7. 03 (1H, t), 7. 10 (IH,
d), 7. 43-
7. 44(3H, m). 7. 52(1H, m), 7. 57(IH.
d). 7. 7
4-7. 75(2H, m), 7. 80(IH, d), 8. 56(1H:
d), 8
. 70(1H, d), 9. 44(1H. s). 11. 38(1H,
s).
78
CA 02238723 1998-OS-27
29 -OUe 6-:~ie0-3-Py- p. : 156-I57~
m
~'~iR: 3. 85 (3H. s), 3. 91 (3H, s).
6. 65 (1H, dd). 6
. 82(LH. dt). 6. 89(IH, d). ?. 02(IH.
dt), 7.
09 (LH. dd), Z. 41-?. 47 (3H, m).
7. 55 (1H. d).
?. ? 2-?. 79 (3H, m) , 8. 4? ( 1 H,
dd) . 9. 0? (2H,
d). 1 1. 2? (LH. s).
30 -OMe 6-C)~3-3-Py- mp. : 169-I70. 5C
uRviR: 3. 84 (3H, s). 3. 93 (3H, s).
6. 70 (IH, d). 6.
82 (1H, t). ?. 03 (1H, t). 7. 10 (1H.
dd). 7. 42
-?. 44 (3H. m). 7. ?2-T. ?6 (3H, m).
?. 85 (1H, d
). 8. 38(IH, d). 8. 55(1H, d). 9.
18(1H, s),
11. 49 (1H, brs) _
31 -OMe 2-The - mp. : 180-I81~
i~R: 3. 84(3H, s), 3. 87(3H. s), 6.
65(1H, dd). 6
81 (LH. dt), ?. 02 (IH. t). ?. 09
(LH, dd). 7.
1? C1H, dd). 7. 42-7. 46 (3H, m),
?. 56 (1H. d),
?. ?2-Z. 80 (3H, m). ?. 86 (1H, dd),
1 1. 2? (IH
s).
32 -OMe 3-The - mp. : 162-163
Nl-iR: 3. 84 (3H. s). 3. 89 (3H. s),
6. 63 (IH, dd). 6
. 81 (1H, dt), ?. 02(IH. dt), ?. 09(1H,
dd), ?
. 40-T. 46 (3H. m) , 7. 54 (1H. d).
?. 62 (1H, dd)
7. ?0-T. 80 (4H, m), 8. 27 (1H, dd).
I 1_ I7 (LH
s).
33 -011e 2-ue-4-Th- mp. : 90-92 C
i
wiR: 2. 80 (3H. s), 3. 83 (3H, s).
3. 89 (3H. s). 6.
62 (1H. d). 6. 81 (1H, t). 7. O1 (1H.
t). 7. 09
1H, d) . 7. 42-7. 48 (3H. m) , 7.
74-?. 84 (3H, m) ,
79
CA 02238723 1998-OS-27
7. 91 (1H. d). 8. 30 (1H, s). I 1.
31 (1H, s).
34 -OMe 3-Fur - mp. : 170-17IC
~firiR: 3. 84(3H, s), 3. 86(3H, s),
6. 63(1H, dd), 6
. 81 (1H, dt). 6. 95(IH, d). 7. OI
(IH, dt), 7.
08(IH, dd). 7.42-7.46(3H. m). 7. 54(IH,
d).
7. 72-7. 7 8(4H. m), 8. 33(1H, d).
11. 14(1H
. s).
35 -OCHZC=6-CF5-3-Py mp. : 172-174C
CH NI~iR: 3. 49 (IH, s). 3. 84(3H, s).
5. 10 (2H, s), 6.
72 (IH, d). 6. 83 (1H, t). 7. 05 (IH,
t), 7. I1
1H, dd) . 7. 42-7. 44 (3H, m) . 7.
75 (3H, m) . 7.
87 (1H, d), 8. 40 (1H, d), 8. 57 C1H,
d). -9. 20
1H, s), lI. 57(1H, brs).
36 -OCHZCHZ6-CF3-3-Py mp. : 175-176. 5 C
OH WR: 3. 52 (2H, t). 3. 83 (3H, s),
4. 4I (2H, t). 6.
80-6. 86 (2H, m), 7. 05 (IH, dt).
7. 10 (1H, d),
7. 42-7. 43 (3H, m) , 7. 72-7. 76
(3H, m) , 7. 86
(1H, d), 8. 37(IH. d), 8. 53(1H, d).
8. 17(1H
. s). 11. 36 (1H, s).
CA 02238723 1998-OS-27
Table 8
Me0 1
0
OMe
,N N,
~N NHS02-CA4=CRS Ar
Ex. R4 RSAr Sa
37 Me H Ph - mp. : 148-149 .
M-iR: 2. 2I (3H, s), 3. 83(3H, s), 4.
01 (3H, s). 6. 65(
IH, d). 6. 83 (IH. t). 7. 03 (IH, t),
7. 09 (IH, d). 7
. 22-7. 41 (5H, m). 7. 61 (IH, m). 7.
87 (1H, s). 9. I8
(2H, d), I 1. 29 (1H, brs).
38 E H Ph K MHR: 1. 00 (3H, t) . 2. 39 (2H, q) .
t 3. 78 (3H, s) , 3. 83 (
3H. s). 6. 4I (IH, d), 6. 73 (IH, t),
6. 87 (1H, t),
7. 00 (1H, d). 7. 17 (2H, d), 7. 24
(1H, m), 7. 30-
7. 35 (3H, m), 7. 54 (IH, t), 8. 89
(2H, d).
m/z : 596 (FAB, 1~++K)
39 H H 4-ue-Ph - mp. : 165-166
I~IMR: 2. 33 C3H. s). 3. 83 (3H, s),
4. O1 (3H. s), 6. 66 (1H
d), 6. 82 (1H, t), 7. 03 (1H, t). 7.
09 (IH, t). 7. 2
7 (2H, d). 7. 62 (2H. d). 7. 69 C1H,
m), 7. ?2 (1H, d).
7. 92 (IH, d). 9. 09 (2H, d), 11. 42
(1H, brs).
40 H H 4-tBu-PhK NMR: 1. 28 (9H, s), 3. 80 (3H, s). 3.
98 (3H, s), 6. 39 (1
H. d). 6. 73(1H, t). 6. 87(1H. t). 7.
OI C1H, d).
7. 12 (IH, d). 7. 41 (2H, d), 7. 50
(2H, d). 7. 62 (1H
. t). 8. 13 (1H, d). 9. 05 (2H, d).
m/z : 624 (FAB. M'+K)
41 H H 4-CI-Ph - NI~iR: 3. 80 (3H, s). 4. 0I (3H. s).
6. 67 (IH, d). 6. 82
IH, t), 7. 03(1H, t), T. 09(1H, d).
7. 38(2H, d),
81
CA 02238723 1998-OS-27
7. 67 (1H, m). 7. 79-7. 95 (3H, m),
8. 02 (1H, d),
9. 09 (2H, d), 11. 52 C1H, brs).
m/z : 526 (FAB. ~I'+1)
42 H H 2-The - ~IMR: 3. 83 (3H. s). 3. 90 (3H. s).
i 6. 66 (1H, d), 6. 82 (
IH, t), 7. 03 (IH, t). 7. 09 (1H. d),
7. 16 (IH, t),
7. 58(1H, m). 7. 67-7. 71 (2H, m), 7.
76(IH, d),
8. 03(1H, d), 9. 10(2H. d), 11. 48(1H,
brs).
m/z : 498 (FAB, ~I++1)
43 H H 4-CF3-PhK N~4IR: 3. 80 (3H, s). 3. 85 (3H, s),
6. 40 (IH, d), 6. 74
IH, dd), 6. 88 (1H. dd), 7. 02 (1H,
d). 7. 20 (1H, d
), ?. 62 (1H, dd). 7. 79 (2H, d), 7.
85 (2H, d), 8.
43 (1H, d), 9. 06 (2H, d).
m/z: 635 (FAB, a++K-1)
44 H H 4-1~e0-Ph- NMR: 3. 80 (3H, s). 3. 83 (3H, s), 3.
89 (3H, s), 6. 60-
8. 00(11H, m), 9. 10(2H, d).
m/z : 520 (FAB. M++1)
45 H H 2-Ivaph - 1VMR: 3. 83 (3H, s) , 3. 90 C3H, s)
~ , 6. 60-7. 20 (4H, m) ,
~7. 40-8. 30 ( 10H, m) , 9. 13 (2H;
d) .
m/z : 540 (FAB, 12++ I )
46 H H 1-Naph - I'tMR: 3. 83 (3H, s). 3. 89 (3H. s).
6. 69 (1H, d), 6. 82
IH. dd). 7. 03(1H, dd), 7. 10(1H, d).
7. 53-7. 64
(4H, m), 7. 97-8. 08(4H, m), 8. 14(1H,
d). 8. 53C
1H. d). 8. 93(2H, d), 11. 5I (IH, s).
m/z : 540 (FAB. !1~-1 )
47 H H 2-CI-Ph - mp. : 97-98C
wfR: 3. 83(3H, s), 3. 91 (3H, s), 6.
68(1H, d), 6. 82(
1H, t), 7. 03 (1H, t), 7. 09 (IH, d),
7. 46-7. 50 (2
H, m). 7. 5 7 (1H, brd). 7. 66 (IH,
brs), 7. 95 (2H,
82
CA 02238723 1998-OS-27
brs). 8. 14 (IH, brd). 9. 02 (2H. brs).
48 H H 4-HOOC-Ph- mp. : ~250C
uIMR: 3. 83 (3H. s), 3. 90 (3H, s),
6. 68 (IH, d), 6. 82
1H, dd), 7. 03 (1H, dd). 7. 10 (1H,
d), 7. 69 (1H, d
d), 7. 79-7. 93 (3H, m). 8. 05 (2H,
d). 8. 12 (1H. d
). 9. 10 (2H, d), I 1. 59 (IH, s),
13. 15 (1H, s).
49 H H 4-Me00C-- mp. : 178-I79C
Ph N'MR: 3. 83 (3H, s), 3. 87 (3H. s).
3. 89 (3H, s), 6. 67
IH, d), 6. 81 (1H, dd), 7. 02 (IH.
dd), 7. 09 (1H, d
). 7. 69 (IH, dd). 7. 80-?. 96 (3H,
m). 8. 03 (2H, d
). 8. 13 (IH, d), 9. 09 (ZH, d). 1
I. 60 (1H, s).
50 H H 3-The - NMR: 3. 83 (3H, s), 3. 89 (3H. s).
6. 66 (1H, d). 6. 82
1H, dd). 7. 03(IH, dd), 7. IOCIH, d).
7. 53(1H, d
), 7. 62-7. 76 (3H, m), 7. 88 (1H.
d), 8. OI (IH.~s)
9. 09 (2H, d). 11. 42 (IH, s).
m/z: 498 (FAB. M*+1), 520 (FAB. M++Na)
51 H H 3-Cl-Ph - NMR: 3. 83 (3H, s). 3. 90 (3H, s),
6. 68 (1H, d), 6. 82
1H, dd), 7. 03 (1H, dd). 7. 09 (IH.
d). 7. 46-7. 52
(2H. m) , 7. 66-7. 75 (2H, m) . 7.
80 (I l-~ d) , 7. 87
IH, s), 8. 11 (IH, d), 9. 08 (2H, d),
11. 59 (1H, s)
m/z: 526(FAB, M*+1), 548(FAB. M*+~ia)
52 nPr H Ph K NMR: 0. 70(3H, t), 1. 46(2H, m), 2.
34C2H, m), 3. 77(
3H, s), 3. 84(3H, s), 6. 39(1H. dd),
6. 72(IH, dt
). 6. 87(IH, dt), 7. O1 (1H, dd), 7.
I4-7. 17(2H.
m), 7. 23(1H, m), 7. 30-7. 34C2H, m),
7. 3?(1H, s
). 7. 53 CIH, t), 8. 85 (2H, d).
m/z : 6 I 0 (FAB, a*+K)
83
CA 02238723 1998-OS-27
53 H Me Ph - NMR: 2. 23 (3H, d), 3. 79 (3H, s). 3.
85 (3H, s). 6. 40
IH, dd). 6. 73(IH, dt), 6. 87(1H, dt),
7. OI (IH,
dd). 7. 18(1H, d). ?. 26-7. 34(3H, m),
7. 52-7. 5
5 (2H, m), 7. 61 (IH. t), 8. 98 (2H,
d).
m/z : 5 2 8 CFAB, M++Na)
54 H H 2-Me-Ph- NMR: 2. 27 (3H. s). 3. 82 (3H, s), 3.
84 (3H, s), 6. 40
1H, dd). 6. 62-7. 08 (3H, m), 7. 20-7.
39 (4H, m),
7. 56-7. 67 (2H, m). 8. 02 (IH, brd)
m/z : 506 (FAB, M'+I).
55 H H 2, 4, - NMR: 2. 24(9H, s), 3. 82(3H, s), 3.
6-tri 91 (3H, s), 6. 55-
Me-Ph ?. 20 (7H, m), ?. 50-7. 90 (2H, m),
8. 96 (2H, d).
m/z: 534(FAB, M++I), 556(FAB, M++Na)
CA 02238723 1998-OS-27
The compounds whose chemical structural formulae are
given in the following Table 9 can be easily manufactured by
almost the same method mentioned in the above Examples or
Manufacturing Methods or by applying some modifications thereto
which are obvious to the persons skilled in the art.
Abbreviations in the table have the same meanings which
were defined already. Incidentally, "Co." in the table means
a compound number.
CA 02238723 1998-OS-27
Table 9
R~X
N \ 0
N ~ OMe
N
~N NHS02-CR4=CR5 Ar
Co. R~-X- R4 R~ Ar Co. R~-X-R4 RS Ar
I Me0 H H 2-Fur 16 Me0 Me H 2-The
2 Me0 H H 3-Fur 17 Me0 Me ~ 3-The
H
3 Me0 H H .2-Thi 18 Me0 Et H 2-The
4 Me0 H H 4-Thi 19 Me0 Et H 3-The
Me0 ~ H 5-Thi 20 MeS H H Ph
H
6 Me0 H H 2-Py 21 MeS Me H Ph
7 Me0 H H 3-Py 22 MeS Et H Ph
8 Me0 H H 4-Py 23 MeS H H 2-The
( ~
9 Me0 H H 5-Pym 24 MeS H H 3-The
Me0 H H 2-Me0-Ph 25 MeNH H H Ph
~
11 Me0 H H 3-Me0-Ph 26 Met~'Hdie H Ph
~
12 Me0 H H 2-CST-Ph 27 MeNH Et H Ph
I3 Me0 H H 3-CN-Ph 28 MeNH H H 2-The
14 Me0 H H 3-Me-Ph 29 MeuFiH H 3-The
(
I5 Me0 H H 3.4-diMeO-Ph
~6
