U.S. patent application number 10/021060 was filed with the patent office on 2003-01-30 for naphthyloxy acetic acid derivatives and a pharmaceutical composition comprising them as an active ingredient.
Invention is credited to Hamanaka, Nobuyuki, Nagao, Yuuki, Torisu, Kazuhiko.
Application Number | 20030023096 10/021060 |
Document ID | / |
Family ID | 26437215 |
Filed Date | 2003-01-30 |
United States Patent
Application |
20030023096 |
Kind Code |
A1 |
Nagao, Yuuki ; et
al. |
January 30, 2003 |
Naphthyloxy acetic acid derivatives and a pharmaceutical
composition comprising them as an active ingredient
Abstract
The naphthyloxyacetic acid derivatives of the formula (I) 1
wherein A is H, -(alkylene)COOR.sup.1,
-(alkylene)CONR.sup.2R.sup.3, -(alkylene)OH, -(alkylene)tetrazole,
-(alkylene)CN; E is single bond or alkylene; G is --S--, --SO--,
--SO.sub.2--, --O-- or --NR.sup.4--; L is alkylene,
--(CH.sub.2).sub.m--CH.dbd.CH--(CH.sub.2).sub.n-- or
--(CH.sub.2).sub.x--CH(OH)--(CH.sub.2).sub.y--; M is phenyl,
phenyl(thio, oxy, amino), diphenylmethyl, diphenylmethyl(thio, oxy,
amino), and pharmaceutical composition comprising them as an active
ingradient. The compounds of the formula (I) can combine PGE.sub.2
receptor and exhibit the activity to antagonize or agonize for
PGE.sub.2 receptor. Therefore, they are useful as
anti-hyperlipemia, for the prevention of abortion, for analgesics,
as antidiarrheals, sleep inducer, diuretic, anti-diabetes,
abortient, cathartics, antiulcer, anti-gastritis or
antihypertensive etc.
Inventors: |
Nagao, Yuuki; (Mishima-gun,
JP) ; Torisu, Kazuhiko; (Mishima-gun, JP) ;
Hamanaka, Nobuyuki; (Mishima-gun, JP) |
Correspondence
Address: |
STEVENS, DAVIS, MILLER & MOSHER, L.L.P.
Suite 850
1615 L Street, N.W.
Washington
DC
20036
US
|
Family ID: |
26437215 |
Appl. No.: |
10/021060 |
Filed: |
December 19, 2001 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10021060 |
Dec 19, 2001 |
|
|
|
09765676 |
Jan 22, 2001 |
|
|
|
09765676 |
Jan 22, 2001 |
|
|
|
09440674 |
Nov 16, 1999 |
|
|
|
09440674 |
Nov 16, 1999 |
|
|
|
09000102 |
Jan 26, 1998 |
|
|
|
Current U.S.
Class: |
548/252 ;
558/389; 560/37; 560/56; 560/9; 564/162; 564/164; 564/170; 568/28;
568/39; 568/631 |
Current CPC
Class: |
C07C 217/28 20130101;
C07C 69/712 20130101; C07C 317/18 20130101; C07C 323/21 20130101;
C07C 43/23 20130101; C07C 233/18 20130101; C07C 323/16 20130101;
C07C 59/68 20130101; C07C 2602/10 20170501; C07D 257/04 20130101;
C07C 59/70 20130101; C07C 217/60 20130101; C07C 317/22 20130101;
C07C 255/16 20130101 |
Class at
Publication: |
548/252 ;
558/389; 560/9; 560/37; 560/56; 564/162; 564/164; 564/170; 568/28;
568/39; 568/631 |
International
Class: |
C07D 257/04; C07C
321/26; C07C 255/07 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 2, 1996 |
JP |
PCT/JP96/01833 |
Jul 26, 1995 |
JP |
7-209279 |
Claims
What we claim is:
1) A naphthyloxyacetic acid derivative of the general formula. (I)
349wherein A is (i) hydrogen, (ii) --(C1-4 alkylene)--COOR.sup.1 in
which R.sup.1 is hydrogen or C1-4 alkyl, (iii) --(C1-4
alkylene)--CONR.sup.2R.s- up.3 in which R.sup.2 and R.sup.3 each,
independently, is hydrogen or C1-4 alkyl, (iv) --(C1-4
alkylene)--OH, (v) --(C1-4 alkylene)-tetrazolyl or (vi) --(C1-4
alkylene)--CN; E is (i) single bond or (ii) C1-6 alkylene; G is
--S--, --SO--, --SO.sub.2--, --O-- or --NR.sup.4-- in which,
R.sup.4 is hydrogen or C1-4 alkyl; L is (i) C1-6 alkylene, (ii)
R-(CH.sub.2).sub.m--CH.dbd.CH--(CH.sub.2).sub.n-- in which m is 0
or an integer of 1-3, n is 0 or an integer of 1-3 or (iii)
--(CH.sub.2).sub.x--CH(OH)--(CH.sub.2).sub.y-- in which x is an
integer of 1-3, y is 0 or an integer of 1-3; M is 350in which each
phenyl group may be substituted by 1-3 of C1-4 alkyl, C1-4 alkoxy,
halogen, nitro or trifluoromethyl; in the formula 351 352is single
bond or double bond; with the proviso that, (1) when G is --SO-- or
--SO.sub.2--, M is neither 353in which each phenyl group may be
substituted by 1-3 of C1-4 alkyl, C1-4 alkoxy, halogen, nitro or
trifluoromethyl, (2) when m in L is 0, G is --SO-- or --SO.sub.2--,
(3) when n in L is 0, M is 354in which each phenyl group may be
substituted by 1-3 of C1-4 alkyl, C1-4 alkoxy, halogen, nitro or
trifluoromethyl, (4) when y in L is 0, M is 355in which each phenyl
group may be substituted by 1-3 of C1-4 alkyl, C1-4 alkoxy,
halogen, nitro or trifluoromethyl, (5) when A is hydrogen, L is
--(CH.sub.2).sub.m--CH.dbd.CH--(CH.sub.2).sub.n-- or
--(CH.sub.2).sub.x--CH(OH)--(CH.sub.2).sub.y-- in which m, n, x and
y are the same meaning as defined in claim 1, and (6) tetrazolyl in
A is 356or non-toxic salt thereof, non-toxic acid addition salt
thereof or their hydrate.
2) A compound according to claim 1, wherein A is --(C1-4
alkylene)--COOR.sup.1.
3) A compound according to claim 1, wherein A is --(C1-4
alkylene)--CONR.sup.2 R.sup.3, --C1-4 alkylene)--OH, --(C1-4
alkylene)-tetrazolyl or --(C1-4 alkylene)--CN.
4) A compound according to claim 1, wherein A is hydrogen.
5) A compound according to claim 1-5, wherein L is
--(CH.sub.2).sub.m--CH.- dbd.CH--(CH.sub.2).sub.n--or
--(CH.sub.2).sub.x--CH(OH)--(CH.sub.2).sub.y-- -.
6) A compound according to claim 5, wherein G is --S--, --SO-- or
--SO.sub.2--.
7) A compound according to claim 5, wherein G is --O--.
8) A compound according to claim 5, wherein G is --NR.sup.4--.
9) A compound according to claim 6, which is (1)
1-[2-(5-hydroxy-1-naphthy- l)ethylthio]-3-phenoxy-2RS-propanol, (2)
1-[2-(5-hydroxy-1-naphthyl)ethyls- ulfinyl]-3-phenoxy-2RS-propanol,
(3) 1-[2-(5-hydroxy-1-naphthyl)ethylsulfo-
nyl]-3-phenoxy-2RS-propanol, (4)
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-p- henoxy-2R-propanol, (5)
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenoxy-2S- -propanol, (6)
1-(5-hydroxy-1-naphthyl)methylthio-3-phenoxy-2RS-propanol, (7)
1-(5-hydroxy-1-naphthyl)methylsulfinyl-3-phenoxy-2RS-propanol, (8)
1-(5-hydroxy-1-naphthyl)methylsulfonyl-3-phenoxy-2RS-propanol, (9)
2-[3-(5-hydroxy-1-naphthyl)propylthio]-1-phenyl-1 RS-ethanol, (10)
2-[3-(5-hydroxy-1-naphthyl)propylsulfinyl]-1-phenyl-1 RS-ethanol,
(11) 2-[3-(5-hydroxy-1-naphthyl)propylsulfonyl]-1-phenyl-1
RS-ethanol, (12)
1-(5-hydroxy-1-naphthyl)thio-3-phenoxy-2RS-propanol, (13)
1-(5-hydroxy-1-naphthyl)sulfinyl-3-phenoxy-2RS-propanol, (14)
1-(5-hydroxy-1-naphthyl)sulfonyl-3-phenoxy-2RS-propanol, (15)
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-(4-chlorophenoxy)-2RS-propanol,
(16)
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-(4-methylphenoxy)-2RS-propan-
ol, (17)
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-(4-methoxyphenoxy)-2RS-pr-
opanol, (18)
1-[2-(5-hydroxy-1-naphthyl)ethylthiol-3-diphenylmethoxy-2RS-p-
ropanol, (19)
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-[1-phenyl-1-(4-chlor-
ophenyl)-methoxy]-2RS-propanol, (20)
1-[2-(5-hydroxy-1-naphthyl)ethylthio]- -3-phenylthio-2RS-propanol,
(21) 1-(5-hydroxy-1-naphthyl)methylthio-3-diph-
enylmethoxy-2RS-propanol, (22)
1-(5-hydroxy-1-naphthyl)methylthio-3-[1-phe-
nyl-1-(4-chlorophenyl)-methoxy]-2RS-propanol, (23)
2-{5-[2-(2RS-hydroxy-3--
phenoxypropylthio)ethyl]-1-naphthyloxy}-acetic acid methyl ester,
(24)
2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfinyl)ethyl]-1-naphthyloxy}acetic
acid methyl ester,
(25)2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfonyl)ethyl-
]-1-naphthyloxy}-acetic acid methyl ester, (26)
2-{5-(2-(2R-hydroxy-3-phen-
oxypropylthio)ethyl]-1-naphthyloxy}acetic acid methyl ester, (27)
2-{5-[2-(2S-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}acetic
acid methyl ester, (28)
2-[5-(2RS-hydroxy-3-phenoxypropylthio)methyl-1-naphthy- loxy]acetic
acid methyl ester, (29) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfi-
nyl)methyl-1-naphthyloxy]acetic acid methyl ester, (30)
2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)methyl-1-naphthyloxy]acetic
acid methyl ester, (31)
2-{5-[3-(2RS-hydroxy-2-phenylethylthio)propyl]-1--
naphthyloxy}acetic acid methyl ester, (32)
2-{5-[3-(2RS-hydroxy-2-phenylet-
hylsulfinyl)propyl]-1-naphthyloxy}acetic acid methyl ester, (33)
2-{5-[3-(2RS-hydroxy-2-phenylethylsulfonyl)propyl]-1-naphthyloxy}acetic
acid methyl ester, (34)
2-[5-(2RS-hydroxy-3-phenoxypropylthio)-1-naphthyl- oxy]acetic acid
methyl ester, (35) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfin-
yl)-1-naphthyloxy]acetic acid methyl ester, (36)
2-[5-(2RS-hydroxy-3-pheno- xypropylsulfonyl)-1-naphthyloxy]acetic
acid methyl ester, (37)
2-[5-(3-styrylsulfonylpropyl)-1-naphthyloxy]acetic acid methyl
ester, (38) 2-[5-(3-styrylsulfinylpropyl)-1-naphthyloxy]acetic acid
methyl ester, (39)
2-{5-[2-(2RS-hydroxy-3-(4-chlorophenoxy)propylthio)ethyl]-1-n-
aphthyloxy}acetic acid methyl ester, (40)
2-{5-[2-(2RS-hydroxy-3-(4-methyl-
phenoxy)propylthio)ethyl]-1-naphthyloxy}acetic acid methyl ester,
(41)
2-{5-[2-(2RS-hydroxy-3-(4-methoxyphenoxy)propylthio)ethyl]-1-naphthyloxy}-
acetic acid methyl ester, (42)
2-{5-[2-(2RS-hydroxy-3-diphenylmethoxypropy-
lthio)ethyl]-1-naphthyloxy}-acetic acid methyl ester, (43)
2-{5-[2-(2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propylthio)-et-
hyl]-1-naphthyloxy}acetic acid methyl ester, (44)
2-{5-[2-(2RS-hydroxy-3-p-
henylthiopropylthio)ethyl]-1-naphthyloxy}acetic acid methyl ester,
(45)
2-[5-(2RS-hydroxy-3-diphenylmethoxypropylthio)methyl-1-naphthyloxy]-aceti-
c acid methyl ester, (46)
2-{5-[2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)-
methoxy)propylthio]-methyl-1-naphthyloxy}acetic acid methyl ester,
(47)
2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}-acetic
acid, (48)
2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfinyl)ethyl]-1-naphthyl-
oxy}acetic acid, (49)
2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfonyl)ethyl]--
1-naphthyloxy}-acetic acid, (50)
2-{5-[2-(2R-hydroxy-3-phenoxypropylthio)e-
thyl]-1-naphthyloxy}-acetic acid, (51)
2-{5-[2-(2S-hydroxy-3-phenoxypropyl-
thio)ethyl]-1-naphthyloxy}-acetic acid, (52)
2-[5-(2RS-hydroxy-3-phenoxypr-
opylthio)methyl-1-naphthyloxy]-acetic acid, (53)
2-[5-(2RS-hydroxy-3-pheno-
xypropylsulfinyl)methyl-1-naphthyloxy]acetic acid, (54)
2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)methyl-1-naphthyloxy]acetic
acid, (55)
2-{5-[3-(2RS-hydroxy-2-phenylethylthio)propyl]-1-naphthyloxy}a-
cetic acid, (56)
2-[5-(2RS-hydroxy-3-phenoxypropylthio)-1-naphthyloxy]acet- ic acid,
(57) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)-1-naphthyloxy]ace-
tic acid, (58)
2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)-1-naphthyloxy] acetic
acid, (59) 2-[5-(3-styrylsulfinylpropyl)-1-naphthyloxy]acetic acid,
(60) 2-[5-(3-styrylsulfonylpropyl)-1-naphthyloxy]acetic acid, (61)
2-{5-[2-(2RS-hydroxy-3-(4-chlorophenoxy)propylthio)ethyl]-1-naphthyloxy}a-
cetic acid, (62)
2-{5-[2-(2RS-hydroxy-3-(4-methylphenoxy)propylthio)ethyl]-
-1-naphthyloxy}acetic acid, (63)
2-{5-[2-(2RS-hydroxy-3-(4-methyoxyphenoxy-
)propylthio)ethyl]-1-naphthyloxy}acetic acid, (64)
2-{5-[2-(2RS-hydroxy-3--
diphenylmethoxypropylthio)ethyl]-1-naphthyloxy}-acetic acid, (65)
2-{5-[2-(2RS-hydroxy-3-phenylthiopropylthio)ethyl]-1-naphthyloxy}acetic
acid, (66) 2-[5-(2RS-hydroxy-3-diphenylmethoxypropylthio)
methyl-1-naphthyloxy]acetic acid, (67)
1-cyanlomethoxy-5-[2-(2RS-hydroxy--
3-phenoxypropylthio)-ethyl]naphthalene, (68) 1-cyano
methoxy-5-{2-[2RS-hydroxy-3-(4-chlorophenoxy)propylthio]ethyl}-naphthalen-
e, (69)
1-cyanomethoxy-5-{2-[2RS-hydroxy-3-(4-methylphenoxy)propylthio]eth-
yl} naphthalene, (70)
1-cyanomethoxy-5-{2-[2RS-hydroxy-3-(4-methoxyphenoxy-
)-propylthio]ethyl}naphthalene, (71)
1-cyanomethoxy-5-[2-(2RS-hydroxy-3-di-
phenylmethoxypropylthio)-ethyl]naphthalene, (72)
1-cyanomethoxy-5-[2-(2RS--
hydroxy-3-phenylthiopropylthio)-ethyl]naphthalene, (73)
1-cyanomethoxy-5-[(2RS-hydroxy-3-diphenylmethoxy)propylthiomethyl]-naphth-
alene, (74)
2-{5-[2-(2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)pro-
pylthio)-ethyl]-1-naphthyloxy}ethanol, (75)
2-{5-[2-(2RS-hydroxy-3-phenyla-
minopropylthio)ethyl]-1-naphthyloxy}ethanol, (76)
1-(tetrazol-5-ylmethoxy)-
-5-{2-{2RS-hydroxy-3-(4-methyoxyphenoxy)-propylthio]ethyl}naphthalene,
(77)
N-methyl-{5-[2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)-prop-
ylthio]methyl-1-naphthyloxy}acetic acid amide, (78)
1-{2-[5-hydroxy-1-(1,2,3,4-tetrahydronaphthyl)]ethylthio}-3-phenoxy-2RS-p-
ropanol, (79)
2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-(5,6,7,8-t-
etrahydro-naphthyloxy)}acetic acid methyl ester, (80)
2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-(5,6,7,8-tetrahydro-nap-
hthyloxy)}acetic acid or (81)
1-cyanomethoxy-5-[2-(2RS-hydroxy-3-phenoxypr-
opylthio)ethyl]-5,6,7,8-tetrahydronaphthalene.
10) A compound according to claim 7, which is
(1)1-[2-(5-hydroxy-1-naphthy- l)ethoxy]-3-phenoxy-2RS-propanol, (2)
2-{5-[2-(2RS-hydroxy-3-phenoxypropox- y)ethyl]-1-naphthyloxy}acetic
acid methyl ester or (3)
2-{5-[2-(2RS-hydroxy-3-phenoxypropoxy)ethyl]-1-naphthyloxy}acetic
acid.
11) A compound according to claim 8, which is (1)
1-[2-(5-hydroxy-1-naphth- yl)ethylamino]-3-phenoxy-2RS-propanol or
(2) 2-{5-[2-(2RS-hydroxy-3-pheoxy-
propylamino)ethyl]-1-naphthyloxy}acetic acid.
12) A pharmaceutical composition which comprises a
naphthyloxyacetic acid derivative of the formula (I) depicted in
claim 1, non-toxic salt thereof, non-toxic acid addition salt
thereof or their hydrate.
13) A prostaglandin E2 antagonist or agonist which comprises a
naphthyloxyacetic acid derivative of the formula (I) depicted in
claim 1, non-toxic salt thereof, non-toxic acid addition salt
thereof or their hydrate.
Description
FIELD OF TECHNOLOGY
[0001] This invention is related to the naphthyloxyacetic acid
derivatives. More particularly, this invention is related to (1)
the naphthyloxyacetic acid derivatives of the formula (1) 2
[0002] wherein all symbols are the same meaning as hereafter
defined, or non-toxic salts thereof, acid addition salts thereof or
their hydrates and (2) a pharmaceutical composition (Prostaglandin
E.sub.2 (PGE.sub.2) antagonists or agonists) which comprises them
as an active ingredient.
BACKGROUND
[0003] PGE.sub.2 has been known as metabolite in the arachidonate
cascade. In addition, the recent progress in the molecule
biological technology makes the existence of three PGE.sub.2
receptors clear as shown in the following and have been making the
relationship between each receptor and appearance of biological
activity clear. For example, EP, receptor may cause contraction of
the smooth muscle of digestive canal or bronchus etc. and promote
the release of neurotransmitter. The representative activity of
EP.sub.2 receptor is relaxation of smooth muscle of bronchus or
ileum etc. or vasodilatation and reduce of the blood pressure due
to relaxation of vascular smooth muscle. As the activity of
EP.sub.3 receptor, uterine muscle contraction, suppression of
gastric acid secretion, inhibition of reabsorption of water and ion
by vasopressin in renes, inhibition of fat decomposition in fat
tissue, inhibition of release of neurotransmitter and
glucose-decomposition by gulcagon in liver cell etc. have been
known. In addition, recently, the existence of fourth receptor is
suggested. (Biochemistry Vol. 66, No. 3, pp. 218-231 (1994)).
[0004] Therefor, to antagonize PGE.sub.2 receptor means to suppress
the effects above mentioned, so such an activity is linked to
inhibit diuretic, to inhibit hyperlipemia, to inhibit reduce of
blood sugar, to inhibit uterine contraction, to have analgesic
action, to inhibit digestive peristalsis, to induce sleep.
Therefor, PGE.sub.2 receptor antagonists are considered to be
useful as anti-hyperlipemia, for the prevention of abortion, for
analgesics, or as antidiarrheals or sleep inducer.
[0005] To agonize for PGE.sub.2 receptor means to promote the
effects above mentioned, so such an activity is linked to have
diuretic, to promote hyperlipemia, to promote reduce of blood
sugar, to contractile uterine, to promote digestive peristalsis, to
suppress gastric acid secretion or to reduce blood pressure.
Therefor, PGE.sub.2 receptor agonists are considered to be useful
for diuretic, anti-diabetes, abortient, cathartics, antiulcer,
anti-gastritis or antihypertensive.
[0006] In such a background, a lot of compounds which agonize or
antagonize for PGE.sub.2 receptors have been proposed.
[0007] For example, in the specification of EP-0657422, it is
disclosed that the compounds of the formula (A) 3
[0008] wherein R.sup.tA is --COOR.sup.4A in which R.sup.4A is
hydrogen or C1-4 alkyl, --CONR.sup.5AR.sup.6A in which R.sup.5A and
R.sup.6A each, independently, is hydrogen, C1-4 alkyl or C1-4 alkyl
substituted by 1 of hydroxy or --CH.sub.2OH, 4
[0009] in which A.sup.A is single bond or C1-4 alkylene or 5
[0010] in which A.sup.A is 6
[0011] in which mA is 0, 1, 2, 3, 4, nA is 0, 1, 2, 3, 4, and mA+nA
is 2, 3, 4, B.sup.A is --NR.sup.3ASO.sub.2-- or
--SO.sub.2NR.sup.3A-- in which R.sup.3A is hydrogen, C1-4 alkyl or
--CH.sub.2COOR.sup.7A in which R.sup.7A is hydrogen or R.sup.4aA,
in which R.sup.4aA is C1-4 alkyl,
[0012] R.sup.2A is (i) C1-6 alkyl, C2-6 alkenyl or C2-6
alkynyl,
[0013] (ii) C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl substituted by
1, 2 or 3 of phenyl, C4-7 cycloalkyl or phenyl substituted by 1, 2
or 3 substituents selected from C1-4 alkyl, C1-4 alkoxy or halogen
or
[0014] (iii) naphthyl,
[0015] in the formula 7 8
[0016] is single bond or double bond,
[0017] or non-toxic salts thereof, are useful as PGE.sub.2
antagonist or agonist.
[0018] In the specification of EP-0578847 (corresponding to JP
Patent Application Kokai Hei 6-25074), it is disclosed that the
compounds of the formula (B) 9
[0019] R.sup.1B is hydrogen or C1-4 alkyl,
[0020] R.sup.2B is hydrogen, C1-6 alkyl or phenyl,
[0021] R.sup.3B is (i) C1-15 alkyl,
[0022] (ii) C1-8 alkyl substituted by 1 or 2 of benzene ring, C4-7
cycloalkyl or 4-7 membered monocyclic ring containing one
nitrogen,
[0023] (iii) C10-15 fused tricyclic ring,
[0024] e.sup.B is an integer of 3-5,
[0025] f.sup.B is an integer of 1-3,
[0026] p.sup.B is 0 or an integer of 1-4,
[0027] q.sup.B is 0, 1 or 2,
[0028] s.sup.B is 0 or an integer of 1-3;
[0029] with the proviso that, when 10
[0030] is (iii) or (iv), --(CH.sub.2).sub.p.sup.B-- and
.dbd.CH--(CH.sub.2).sub.s.sup.B-- is bonded at the position a or b
on the ring, and the ring in R.sup.3B may be substituted by one to
three of C1-4 alkyl, C1-4 alkoxy, halogen, nitro or trihalomethyl,
are useful as PGI.sub.2 agonist.
[0031] In the specification of JP Patent Application Kokai Sho
61-267532, it is disclosed that the compounds of the formula
(D)
Ar.sup.1D--X.sup.D--Ar.sup.D--Z.sup.D--(R.sup.D)n.sup.D' (D)
[0032] wherein Ar.sup.1D is a nitrogen, sulfur or oxygen containing
heterocyclic ring or an aromatic ring, Ar.sup.D is a phenyl or
nitrogen, oxygen or sulfur containing heterocyclic ring, Ar.sup.1D
and Ar may be fully substituted or less than fully substituted by
H, CH.sub.3, lower alkyl, aryl, aralkyl, halogen, hydroxy, lower
alkoxy, CF.sub.3, COOH, alkylcarboxy, arylcarboxy, alkylcarbalkoxy,
alkanoyl, formyl, oxo, nitrilo, amino, aminoalkyl, alkylamine,
carboxyamide, aryloxy, nitro, sulfonyl, sulfonamide, thio,
alkylthio, hydroxyalkyl or oxyalkylcarboxy,
[0033] X.sup.D is --O(CHR.sup.1D)n.sup.D--,
--S(O)n.sup.D"--(CHR.sup.1D)n.- sup.D--,
--NR.sup.1D(CHR.sup.1D)n.sup.D--alkylene of up to 2 carbon atoms in
the principal chain and up to a total 4 carbon atoms,
[0034] --C(R.sup.1D).dbd.(CR.sup.1D)--, --C.ident.C--,
--CO(CHR.sup.1D)n.sup.D'--, --CH(OH)--(CHR.sup.1D)n.sup.D--,
--CH.dbd.N--, --CO--O--, --CO--S--, or --CO--N(R.sup.1D)--,
[0035] Z.sup.D is an alkylene containing up to 10 carbon atoms in
principal chain and a total of up to 12 carbon atoms and from 0 to
2 double bonds and the said alkylene chain may be attached to
Ar.sup.D through an oxygen, sulfur or amino nitrogen atom,
[0036] and when n.sup.D' is 2 or more, one of the R.sup.D
substituents may be halogen on an omega carbon of the alkylene
chain Z.sup.D,
[0037] when n.sup.D' is 1, R.sup.D is a substituent attached to one
of the carbon atoms of Z.sup.D selected from the group consisting
of oxo, OR.sup.3D, SR.sup.3D, N(R.sup.2D).sub.2, R.sup.1D and
[0038] --CO R.sup.4D,
[0039] when n D' is 2 or more, one R.sup.D is as previously
defined, and the other R.sup.D is a substituent attached to one of
the carbon atoms of Z.sup.D selected from the group consisting of
oxo, OR.sup.3D, SR.sup.3D, N(R.sup.2D).sub.2, --COR.sup.4D, lactone
and halogen,
[0040] R.sup.1D is H or CH.sub.3,
[0041] R.sup.2Dis H, lower alkyl, aryl or aralkyl,
[0042] R.sup.3Dis H, lower alkyl, lower alkanoyl, aryl, aralkyl or
substituted aryl in which the substituent is halogen, lower alkyl
or lower alkoxy,
[0043] R.sup.4Dis OR.sup.2Dor N(R.sup.2D).sub.2,
[0044] n.sup.D is 0 or 1,
[0045] n.sup.D' is an integer of 1-7,
[0046] n.sup.D" is 0, 1 or 2,
[0047] possess the anti-inflammatory and anti-allergic activity due
to lipoxygenase inhibition.
[0048] In addition, in the specification of (E) U.S. Pat. No.
4,327,022, (F) JP Patent Application Kokai Sho 50-89352 and (G)
U.S. Pat. No. 3,930,672, it is disclosed that the naphthol
derivatives are useful as (1) cardiotonic or anti-bacterial agents,
(2) analgesic, anti-inflammatory and antipyretic agent and (3)
starting material of the compound related to copy paper,
respectively.
DISCLOSURE OF THE INVENTION
[0049] Purpose of the Invention
[0050] The present inventors have been studding in order to find
out PGE.sub.2 antagonist or agonist which have new skeleton in
structure, and then have found out that the naphthyloxy acetic acid
derivatives (compounds of the formula (I) as mentioned hereinafter)
in which thioether, sulfinyl, sulfonyl, ether or amine are
introduced into the side chain are useful as PGE.sub.2 antagonist
or agonist, particularly, the mentioned compounds can bind the
EP.sub.3 receptor strongly. And then, the present invention has
been completed.
[0051] Comparison with Related Art
[0052] The compounds of the formula (A) as mentioned in Related Art
possess --NR.sup.3ASO.sub.2-- or --SO.sub.2NR.sup.3A wherein all
symbols are the same meaning as defined hereinbefore, in the side
chain as basic structure. On the other hand, corresponding part in
the present invention compounds is thioether, sulfinyl, sulfonyl,
ether or amine.
[0053] The compounds of the formula (B), (D) and the compounds
described in (E), (F) and (G) as mentioned in Related Art possess
(1) PGI.sub.2 agnostic activity, (2) anti-inflammatory and
anti-allergic activity due to lipoxygenase inhibition (3)
cardiotonic or anti-bacterial agents, (4) analgesic,
anti-inflammatory and antipyretic agent and (5) starting material
of the compound related to copy paper, respectively. On the other
hand, the present invention compounds possess the PGE.sub.2
antagonistic or agnostic activity.
[0054] That is to say, the present invention provides:
[0055] 1) a naphthyloxyacetic acid derivative of the formula (I)
11
[0056] wherein A is
[0057] (i) hydrogen,
[0058] (ii) --(C1-4 alkylene)--COOR.sup.1 in which R.sup.1 is
hydrogen or C1-4 alkyl,
[0059] (iii) --(C1-4 alkylene)--CONR.sup.2R.sup.3 in which R.sup.2
and R.sup.3 each,
[0060] independently, is hydrogen or C1-4 alkyl,
[0061] (iv) --(C1-4 alkylene)--OH,
[0062] (v) --(C1-4 alkylene)-tetrazolyl or
[0063] (vi) --(C1-4 alkylene)--CN;
[0064] E is (i) single bond or
[0065] (ii) C1-6 alkylene;
[0066] G is --S--, --SO--, --SO.sub.2--, --O-- or --NR.sup.4-- in
which, R.sup.4 is hydrogen or C1-4 alkyl;
[0067] L is (i) C1-6 alkylene,
[0068] (ii) --(CH.sub.2).sub.m--CH.dbd.CH--(CH.sub.2).sub.n-- in
which m is 0 or an integer of 1-3, n is 0 or an integer of 1-3
or
[0069] (iii) --(CH.sub.2).sub.x--CH(OH)--(CH.sub.2).sub.y-- in
which x is an integer of 1-3, y is 0 or an integer of 1-3;
[0070] M is 12
[0071] in which each phenyl group may be substituted by 1-3 of C1-4
alkyl, C1-4 alkoxy, halogen, nitro or trifluoromethyl;
[0072] in the formula 13 14
[0073] is single bond or double bond;
[0074] with the proviso that,
[0075] (1) when G is --SO-- or --SO.sub.2--, M is neither 15
[0076] in which each phenyl group may be substituted by 1-3 of C1-4
alkyl, C1-4 alkoxy, halogen, nitro or trifluoromethyl,
[0077] (2) when m in L is 0, G is --SO-- or --SO.sub.2--,
[0078] (3) when n in L is 0, M is 16
[0079] in which each phenyl group may be substituted by 1-3 of C1-4
alkyl, C1-4 alkoxy, halogen, nitro or trifluoromethyl,
[0080] (4) when y in L is 0, M is 17
[0081] in which each phenyl group may be substituted by 1-3 of C1-4
alkyl, C1-4 alkoxy, halogen, nitro or trifluoromethyl,
[0082] (5) when A is hydrogen, L is
--(CH.sub.2).sub.m--CH.dbd.CH--(CH.sub- .2).sub.n-- in which m and
n are the same meaning as hereinbefore defined, or
--(CH.sub.2).sub.x--CH(OH)--(CH.sub.2).sub.y in which x and y are
the same meaning as hereinbefore defined, and
[0083] (6) tetrazolyl in A is 18
[0084] or non-toxic salt thereof, non-toxic acid addition salt
thereof or their hydrate,
[0085] 2) a compound described in 1), wherein A is --(C1-4
alkylene)--COOR.sup.1,
[0086] 3) a compound described in 1), wherein A is --(C1-4
alkylene)--CONR.sup.2R.sup.3, --C1-4 alkylene)--OH, --(C1-4
alkylene)-tetrazolyl or --(C1-4 alkylene)--CN,
[0087] 4) a compound described in 1), wherein A is hydrogen,
[0088] 5) a compound described in 1)-5), wherein L is
--(CH.sub.2),--CH.dbd.CH--(CH.sub.2).sub.n or
--(CH.sub.2).sub.x--CH(OH)-- -(CH.sub.2).sub.y--,
[0089] 6) a compound described in 5), wherein G is --S--, --SO-- or
--SO.sub.2--,
[0090] 7) a compound described in 5), wherein G is --O--,
[0091] 8) a compound described in 5), wherein G is
--NR.sup.4--,
[0092] 9) a compound described in 6), which is
[0093] (1)
1-[2-(5-hydroxy-1-naphthyl)ethylthiol-3-phenoxy-2RS-propanol,
[0094] (2)
1-[2-(5-hydroxy-1-naphthyl)ethylsulfinyl]-3-phenoxy-2RS-propano-
l,
[0095] (3)
1-[2-(5-hydroxy-1-naphthyl)ethylsulfonyl]-3-phenoxy-2RS-propano-
l,
[0096] (4)
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenoxy-2R-propanol,
[0097] (5)
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenoxy-2S-propanol,
[0098] (6)
1-(5-hydroxy-1-naphthyl)methylthio-3-phenoxy-2RS-propanol,
[0099] (7)
1-(5-hydroxy-1-naphthyl)methylsulfinyl-3-phenoxy-2RS-propanol,
[0100] (8)
1-(5-hydroxy-1-naphthyl)methylsulfonyl-3-phenoxy-2RS-propanol,
[0101] (9) 2-[3-(5-hydroxy-1-naphthyl)propylthio]-1-phenyl-1
RS-ethanol,
[0102] (10) 2-[3-(5-hydroxy-1-naphthyl)propylsulfinyl]-1-phenyl-1
RS-ethanol,
[0103] (11) 2-[3-(5-hydroxy-1-naphthyl)propylsulfonyl]-1-phenyl-1
RS-ethanol,
[0104] (12)
1-(5-hydroxy-1-naphthyl)thio-3-phenoxy-2RS-propanol,
[0105] (13)
1-(5-hydroxy-1-naphthyl)sulfinyl-3-phenoxy-2RS-propanol,
[0106] (14)
1-(5-hydroxy-1-naphthyl)sulfonyl-3-phenoxy-2RS-propanol,
[0107] (15)
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-(4-chlorophenoxy)-2RS--
propanol,
[0108] (16)
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-(4-methylphenoxy)-2RS--
propanol,
[0109] (17)
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-(4-methoxyphenoxy)-2RS-
-propanol,
[0110] (18)
1-(2-(5-hydroxy-1-naphthyl)ethylthio]-3-diphenylmethoxy-2RS-pr-
opanol,
[0111] (19)
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-[1-phenyl-1-(4-chlorop-
henyl)-methoxy]-2RS-propanol,
[0112] (20)
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenylthio-2RS-propano-
l,
[0113] (21)
1-(5-hydroxy-1-naphthyl)methylthio-3-diphenylmethoxy-2RS-propa-
nol,
[0114] (22)
1-(5-hydroxy-1-naphthyl)methylthio-3-[1-phenyl-1-(4-chlorophen-
yl)-methoxy]-2RS-propanol,
[0115] (23)
2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}-
-acetic acid methyl ester,
[0116] (24)
2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfinyl)ethyl]-1-naphthyl-
oxy}acetic acid methyl ester,
[0117]
(25)2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfonyl)ethyl]-1-naphthylo-
xy}-acetic acid methyl ester,
[0118] (26)
2-{5-[2-(2R-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}a-
cetic acid methyl ester,
[0119] (27)
2-{5-[2-(2S-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}a-
cetic acid methyl ester,
[0120] (28)
2-[5-(2RS-hydroxy-3-phenoxypropylthio)methyl-1-naphthyloxy]ace- tic
acid methyl ester,
[0121] (29)
2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)methyl-1-naphthyloxy-
]acetic acid methyl ester,
[0122] (30)
2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)methyl-1-naphthyloxy-
]acetic acid methyl ester,
[0123] (31)
2-{5-[3-(2RS-hydroxy-2-phenylethylthio)propyl]-1-naphthyloxy}a-
cetic acid methyl ester,
[0124] (32)
2-{5-[3-(2RS-hydroxy-2-phenylethylsulfinyl)propyl]-1-naphthylo-
xy}acetic acid methyl ester,
[0125] (33)
2-{5-[3-(2RS-hydroxy-2-phenylethylsulfonyl)propyl]-1-naphthylo- xy}
acetic acid methyl ester,
[0126] (34)
2-[5-(2RS-hydroxy-3-phenoxypropylthio)-1-naphthyloxy]acetic acid
methyl ester,
[0127] (35)
2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)-1-naphthyloxy]aceti- c
acid methyl ester,
[0128] (36)
2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)-1-naphthyloxy]aceti- c
acid methyl ester,
[0129] (37) 2-[5-(3-styrylsulfonylpropyl)-1-naphthyloxy]acetic acid
methyl ester,
[0130] (38) 2-[5-(3-styrylsulfinylpropyl)-1-naphthyloxy]acetic acid
methyl ester,
[0131] (39)
2-{5-[2-(2RS-hydroxy-3-(4-chlorophenoxy)propylthio)ethyl]-1-na-
phthyloxy}acetic acid methyl ester,
[0132] (40)
2-{5-[2-(2RS-hydroxy-3-(4-methylphenoxy)propylthio)ethyl]-1-na-
phthyloxy}acetic acid methyl ester,
[0133] (41)
2-{5-[2-(2RS-hydroxy-3-(4-methoxyphenoxy)propylthio)ethyl]-1-n-
aphthyloxy}acetic acid methyl ester,
[0134] (42)
2-{5-[2-(2RS-hydroxy-3-diphenylmethoxypropylthio)ethyl]-1-naph-
thyloxy}-acetic acid methyl ester,
[0135] (43)
2-{5-[2-(2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)pro-
pylthio)-ethyl]-1-naphthyloxy}acetic acid methyl ester,
[0136] (44)
2-{5-[2-(2RS-hydroxy-3-phenylthiopropylthio)ethyl]-1-naphthylo-
xy}acetic acid methyl ester,
[0137] (45)
2-[5-(2RS-hydroxy-3-diphenylmethoxypropylthio)methyl-1-naphthy-
loxy]-acetic acid methyl ester,
[0138] (46)
2-{5-[2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propyl-
thio]-methyl-1-naphthyloxy}acetic acid methyl ester,
[0139] (47)
2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}-
-acetic acid,
[0140] (48)
2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfinyl)ethyl]-1-naphthyl-
oxy}acetic acid,
[0141] (49)
2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfonyl)ethyl]-1-naphthyl-
oxy}-acetic acid,
[0142] (50)
2-{5-[2-(2R-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}--
acetic acid,
[0143] (51)
2-{5-[2-(2S-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}--
acetic acid,
[0144] (52)
2-[5-(2RS-hydroxy-3-phenoxypropylthio)methyl-1-naphthyloxy]-ac-
etic acid,
[0145] (53)
2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)methyl-1-naphthyloxy-
]acetic acid,
[0146] (54)
2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)methyl-1-naphthyloxy-
]acetic acid,
[0147] (55)
2-{5-[3-(2RS-hydroxy-2-phenylethylthio)propyl]-1-naphthyloxy}a-
cetic acid,
[0148] (56)
2-[5-(2RS-hydroxy-3-phenoxypropylthio)-1-naphthyloxy]acetic
acid,
[0149] (57)
2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)-1-naphthyloxy]aceti- c
acid,
[0150] (58)
2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)-1-naphthyloxy]aceti- c
acid,
[0151] (59) 2-[5-(3-styrylsulfinylpropyl)-1-naphthyloxy]acetic
acid,
[0152] (60) 2-[5-(3-styrylsulfonylpropyl)-1-naphthyloxy]acetic
acid,
[0153] (61)
2-{5-[2-(2RS-hydroxy-3-(4-chlorophenoxy)propylthio)ethyl]-1-na-
phthyloxy}acetic acid,
[0154] (62)
2-{5-[2-(2RS-hydroxy-3-(4-methylphenoxy)propylthio)ethyl]-1-na-
phthyloxy}acetic acid,
[0155] (63)
2-{5-[2-(2RS-hydroxy-3-(4-methyoxyphenoxy)propylthio)ethyl]-1--
naphthyloxy}acetic acid,
[0156] (64)
2-{5-[2-(2RS-hydroxy-3-diphenylmethoxypropylthio)ethyl]-1-naph-
thyloxy}-acetic acid,
[0157] (65)
2-{5-[2-(2RS-hydroxy-3-phenylthiopropylthio)ethyl]-1-naphthylo-
xy}acetic acid,
[0158] (66)
2-[5-(2RS-hydroxy-3-diphenylmethoxypropylthio)methyl-1-naphthy-
loxy]acetic acid,
[0159] (67)
1-cyanlomethoxy-5-[2-(2RS-hydroxy-3-phenoxypropylthio)-ethyl]n-
aphthalene,
[0160] (68)
1-cyanomethoxy-5-{2-[2RS-hydroxy-3-(4-chlorophenoxy)propylthio-
]ethyl}-naphthalene,
[0161] (69)
1-cyanomethoxy-5-{2-[2RS-hydroxy-3-(4-methylphenoxy)propylthio-
]ethyl} naphthalene,
[0162] (70)
1-cyanomethoxy-5-{2-[2RS-hydroxy-3-(4-methoxyphenoxy)-propylth-
io]ethyl}naphthalene,
[0163] (71)
1-cyanomethoxy-5-[2-(2RS-hydroxy-3-diphenylmethoxypropylthio)--
ethyl]naphthalene,
[0164] (72)
1-cyanomethoxy-5-[2-(2RS-hydroxy-3-phenylthiopropylthio)-ethyl-
]naphthalene,
[0165] (73)
1-cyanomethoxy-5-(2RS-hydroxy-3-diphenylmethoxypropylthiomethy-
l)-naphthalene,
[0166] (74)
2-{5-[2-(2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)pro-
pylthio)-ethyl]-1-naphthyloxy}ethanol,
[0167] (75)
2-{5-[2-(2RS-hydroxy-3-phenylaminopropylthio)ethyl]-1-naphthyl-
oxy}ethanol,
[0168] (76)
1-(tetrazol-5-ylmethoxy)-5-{2-{2RS-hydroxy-3-(4-methyoxyphenox-
y)-propylthio]ethyl}naphthalene,
[0169] (77)
N-methyl-{5-[2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy-
)-propylthio]methyl-1-naphthyloxy}acetic acid amide,
[0170] (78)
1-{2-[5-hydroxy-1-(1,2,3,4-tetrahydronaphthyl)]ethylthio}-3-ph-
enoxy-2RS-propanol,
[0171] (79)
2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-(5,6,7,8-tet-
rahydro-naphthyloxy)}acetic acid methyl ester,
[0172] (80)
2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-(5,6,7,8-tet-
rahydro-naphthyloxy)}acetic acid or
[0173] (81)
1-cyanomethoxy-5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-5,-
6,7,8-tetrahydronaphthalene,
[0174] 10) a compound described in 7), which is
[0175] (1)
1-[2-(5-hydroxy-1-naphthyl)ethoxy]-3-phenoxy-2RS-propanol,
[0176] (2)
2-{5-[2-(2RS-hydroxy-3-phenoxypropoxy)ethyl]-1-naphthyloxy}acet- ic
acid methyl ester or
[0177] (3)
2-{5-[2-(2RS-hydroxy-3-phenoxypropoxy)ethyl]-1-naphthyloxy}acet- ic
acid,
[0178] 11) a compound described in 8), which is
[0179] (1)
1-[2-(5-hydroxy-1-naphthyl)ethylamino]-3-phenoxy-2RS-propanol
or
[0180] (2)
2-{5-[2-(2RS-hydroxy-3-pheoxypropylamino)ethyl]-1-naphthyloxy}a-
cetic acid,
[0181] 12) a pharmaceutical composition which comprises a
naphthyloxyacetic acid derivative of the formula (I) depicted in
1), non-toxic salt thereof, non-toxic acid addition salt thereof or
their hydrate as an active ingredient, and
[0182] 13) a pharmaceutical composition (PGE.sub.2 antagonist or
agonist) which comprises a naphthyloxyacetic acid derivative of the
formula (I) depicted in 1), non-toxic salt thereof, non-toxic acid
addition salt thereof or their hydrate as an active ingredient.
DETAILED DESCRIPTION OF THE INVENTION
[0183] In the formula (I), C1-4 alkyl represented by R.sup.1,
R.sup.2, R.sup.3 and R.sup.4, or C1-4 alkyl represented as
substituent of phenyl in M means methyl, ethyl, propyl, butyl and
isomeric groups thereof.
[0184] In the formula (I), C1-4 alkylene in A means methylene,
ethylene, trimethylene, tetramethylene and isomeric groups
thereof.
[0185] In the formula (I), C1-6 alkylene represented by E and L
means methylene, ethylene, trimethylene, tetramethylene,
pentamethylene, hexamethylene and isomeric groups thereof.
[0186] In the formula (I), 1-4 alkoxy in M means methoxy, ethoxy,
propoxy, butoxy and isomeric groups thereof.
[0187] In the formula (I), halogen in M means chlorine, bromine,
fluorine and iodine.
[0188] In the formula (I), the side chain represented by --O--A may
be connected with any carbon atom at 1st to 4th position,
preferably, at 1st position.
[0189] In the formula (I), the side chain represented by
--E--G--L--M may be connected with any carbon atom at 5th to 8th
position, preferably, at 5th or 6th position.
[0190] Unless otherwise, specified all isomers are included in the
invention. For example, alkyl, alkylene and alkenylene includes
straight-chain or branched-chain ones. Double bond in alkenylene
include structure of configurations E, Z and EZ mixtures. Isomers
generated by asymmetric carbon(s) e.g. branched alkyl are also
included in the present invention. In addition, isomers generated
by sulfinly are also included in the present invention.
[0191] Salts
[0192] The compounds of the present invention of the formula (I)
may be converted into the corresponding salts by known methods per
se. Non-toxic and water-soluble salts are preferable. Suitable
salts, for example, are follows. salts of alkaline metals
(potassium, sodium etc.), salts of alkaline earth metals (calcium,
magnesium etc.), ammonium salts, salts of pharmaceutically
acceptable organic amines (tetramethylammonium, triethylamine,
methylamine, dimethylamine, cyclopentylamine, benzylamine,
phenethylamine, piperidine, monoethanolamine, diethanolamine,
tris(hydroxymethyl)aminomethane, lysine, arginine,
N-methyl-D-glucamine etc.).
[0193] Acid Addition Salts
[0194] The compounds of the formula (I) may be converted into the
corresponding acid additional salts by methods known per se.
Non-toxic and water-soluble acid addition salts are preferable.
Suitable acid addition salts, for example, are salts of inorganic
acids, e.g., hydrochloride, hydrobromide, hydroiodide, sulphate,
phosphate, nitrate etc., or salts of organic acids, e.g., acetate,
trifluoroactate, lactate, tartarate, oxalate, fumarate, maleate,
citrate, benzoate, methanesulphonate, ethanesulphonate,
benzenesulphonate, toluenesulphonate, isethioate, glucuronate,
gluconate etc.
[0195] Preferable Compound
[0196] In the compounds of the formula (I) of the present
invention, the compounds wherein L is
--(CH.sub.2).sub.m--CH.dbd.CH--(CH.sub.2).sub.n-- in which m and n
are the same meaning as hereinbefore defined, or
--(CH.sub.2).sub.x--CH(OH)--(CH.sub.2).sub.y-- in which x and y are
the same meaning as hereinbefore defined, are preferable. The
compounds wherein L is --CH.dbd.CH-- or
--CH.sub.2--CH(OH)--CH.sub.2--, are more preferable.
[0197] Concretely, the following compounds are preferable.
[0198] The compounds of the formula (IA) 19
[0199] The compounds of the formula (IB) 20
[0200] The compounds of the formula (IC) 21
[0201] The compounds of the formula (ID) 22
[0202] The compounds of the formula (IE) 23
[0203] The compounds of the formula (IF) 24
[0204] The compounds of the formula (IG) 25
[0205] The compounds of the formula (IH) 26
[0206] The compounds of the formula (IJ) 27
[0207] The compounds of the formula (IK) 28
[0208] The compounds of the formula (IL) 29
[0209] The compounds of the formula (IM) 30
[0210] The compounds of the formula (IN) 31
[0211] The compounds of the formula (IO) 32
[0212] In the formula (IA), (IB), (IC), (ID), (IE), (IF), (IG),
(IH), (IJ), (IK), (IL), (IM), (IN) and (IO), all symbols are the
same meaning as hereinbefore defined.
[0213] The compounds described in Example and the following
compounds are preferable particularly.
1 (IA) 33 No. G M 1 --S-- 34 2 --S-- 35 3 --S-- 36 4 --SO-- 37 5
--SO-- 38 6 --SO-- 39 7 --SO.sub.2-- 40 8 --SO.sub.2-- 41 9
--SO.sub.2-- 42 10 --NH-- 43
[0214]
2 (IB) 44 No. G M 1 --S-- 45 2 --S-- 46 3 --S-- 47 4 --SO-- 48 5
--SO-- 49 6 --SO-- 50 7 --SO.sub.2-- 51 8 --SO.sub.2-- 52 9
--SO.sub.2-- 53 10 --NH-- 54
[0215]
3 (IC) 55 No. G M 1 --S-- 56 2 --S-- 57 3 --S-- 58 4 --SO-- 59 5
--SO-- 60 6 --SO-- 61 7 --SO.sub.2-- 62 8 --SO.sub.2-- 63 9
--SO.sub.2-- 64 10 --NH-- 65
[0216]
4 (ID) 66 No. G M 1 --S-- 67 2 --S-- 68 3 --S-- 69 4 --SO-- 70 5
--SO-- 71 6 --SO-- 72 7 --SO.sub.2-- 73 8 --SO.sub.2-- 74 9
--SO.sub.2-- 75 10 --NH-- 76
[0217]
5 (IE) 77 No. G M 1 --S-- 78 2 --S-- 79 3 --S-- 80 4 --SO-- 81 5
--SO-- 82 6 --SO-- 83 7 --SO.sub.2-- 84 8 --SO.sub.2-- 85 9
--SO.sub.2-- 86 10 --NH-- 87
[0218]
6 (IF) 88 No. G M 1 --S-- 89 2 --S-- 90 3 --S-- 91 4 --SO-- 92 5
--SO-- 93 6 --SO-- 94 7 --SO.sub.2-- 95 8 --SO.sub.2-- 96 9
--SO.sub.2-- 97 10 --NH-- 98
[0219]
7 (IG) 99 No. G M 1 --S-- 100 2 --S-- 101 3 --S-- 102 4 --SO-- 103
5 --SO-- 104 6 --SO-- 105 7 --SO.sub.2-- 106 8 --SO.sub.2-- 107 9
--SO.sub.2-- 108 10 --NH-- 109
[0220]
8 (IH) 110 No. G M 1 --S-- 111 2 --S-- 112 3 --S-- 113 4 --SO-- 114
5 --SO-- 115 6 --SO-- 116 7 --SO.sub.2-- 117 8 --SO.sub.2-- 118 9
--SO.sub.2-- 119 10 --NH-- 120
[0221]
9 (IJ) 121 No. G M 1 --SO-- 122 2 --SO-- 123 3 --SO.sub.2-- 124 4
--SO-- 125 5 --SO-- 126 6 --SO-- 127 7 --SO.sub.2-- 128 8
--SO.sub.2-- 129 9 --SO.sub.2-- 130 10 --SO-- 131
[0222]
10 (IK) 132 No. G M 1 --SO-- 133 2 --SO-- 134 3 --SO.sub.2-- 135 4
--SO-- 136 5 --SO-- 137 6 --SO-- 138 7 --SO.sub.2-- 139 8
--SO.sub.2-- 140 9 --SO.sub.2-- 141 10 --SO-- 142
[0223]
11 (IL) 143 No. G M 1 --SO-- 144 2 --SO-- 145 3 --SO.sub.2-- 146 4
--SO-- 147 5 --SO-- 148 6 --SO-- 149 7 --SO.sub.2-- 150 8
--SO.sub.2-- 151 9 --SO.sub.2-- 152 10 --SO-- 153
[0224]
12 (IM) 154 No. G M 1 --SO-- 155 2 --SO-- 156 3 --SO.sub.2-- 157 4
--SO-- 158 5 --SO-- 159 6 --SO-- 160 7 --SO.sub.2-- 161 8
--SO.sub.2-- 162 9 --SO.sub.2-- 163 10 --SO-- 164
[0225]
13 (IN) 165 No. G M 1 --S-- 166 2 --S-- 167 3 --S-- 168 4 --SO--
169 5 --SO-- 170 6 --SO-- 171 7 --SO.sub.2-- 172 8 --SO.sub.2-- 173
9 --SO.sub.2-- 174 10 --NH-- 175
[0226]
14 (IO) 176 No. G A 1 --S-- 177 2 --S-- 178 3 --S-- 179 4 --SO--
180 5 --SO-- 181 6 --SO-- 182 7 --SO.sub.2-- 183 8 --SO.sub.2-- 184
9 --SO.sub.2-- 185 10 --NH-- 186 11 --S-- 187
[0227] Method of Preparation for the Compounds of the Present
Invention
[0228] In the compounds of the formula (I) of the present
invention, the compounds of the formula (I-1) 188
[0229] wherein all symbols are the same meaning as hereinbefore
defined may be prepared by the following methods (a)-(b).
[0230] (a) In the compounds of the formula (I-1) of the present
invention, the compounds wherein L is
--(CH.sub.2).sub.x--CH(OH)--(CH.sub.2).sub.y-- or C1-6 alkylene,
i.e., the compounds of the formula (I-1a) 189
[0231] wherein L.sup.a is
--(CH.sub.2).sub.x--CH(OH)--(CH.sub.2).sub.y-- or C1-6 alkylene,
and the other symbols are the same meaning as hereinbefore
defined
[0232] may be prepared from the compounds of the formula (II-a)
190
[0233] wherein L.sup.aa is
--(CH.sub.2).sub.x--CH(OR.sup.aa)--(CH.sub.2).s- ub.y-- in which,
R.sup.aa is the protecting group which may be removed in an acidic
condition, for example, tetrahydropyranyl etc., or C1-6 alkylene,
R.sup.a is the protecting group which may be removed in an acidic
condition or an alkaline condition, for example, methoxymethyl or
ethylcarbonate etc., and the other symbols are the same meaning as
hereinbefore defined, with the proviso that when nitrogen atom in G
or M in the formula (I-1a) is free --NH group, NH group in the
formula (II-a) is protected by the well-known protecting group (for
example, benzyloxycarbonyl (cbz), t-butoxycarbonyl (boc) or
trifluoroacetyl (COCF.sub.3) etc.)
[0234] by removal of hydroxy-protecting group in an acidic
condition, or removal of hydroxy-protecting group in an acidic
condition and an alkaline condition two times, succeedingly, (Which
reaction may be started first.), if necessary, followed by removal
of NH-protecting group.
[0235] This reaction may be carried out by known methods. For
example, the removal of hydroxy-protecting group in an acidic
condition may be carried out in a water-miscible organic solvent
(methanol, ethanol, tetrahydrofuran (THF) etc.), by using organic
acid (acetic acid, p-toluene sulfonic acid, trifluoro acetic acid
or trichloro acetic acid etc.) or inorganic acid (hydrochloric acid
or hydrobromic acid etc.), at 0-90.degree. C. The removal of
hydroxy-protecting group in an alkaline condition may be carried
out in an organic solvent (methanol, ethanol, dimethoxyethane or
mixture thereof etc.), using an aqueous solution of hydroxide of
alkali (sodium hydroxide, potassium hydroxide etc.), hydroxide of
alkaline-earth metals (calcium dihydroxide etc.) or carbonate
(potassium carbonate etc.) at 0-50.degree. C.
[0236] As for removal of NH-protecting group, for example, the
removal of cbz group may be carried out under an atmosphere of
hydrogen gas, in an organic solvent (methanol, ethanol or THF
etc.), by using catalyst (Pd-C, Pd or Ni etc.), at 0-50.degree. C.
The removal of boc may be carried out in a water-miscible organic
solvent (methanol, ethanol or THF etc.), by using organic acid
(acetic acid, p-toluene sulfonic acid, trifluoro acetic acid or
trichloro acetic acid etc.) or inorganic acid (hydrochloric acid or
hydrobromic acid etc.), at 0-90.degree. C. The removal of
COCF.sub.3 may be carried out, for example, in a water-miscible
organic solvent (methanol, ethanol, THF, dimethoxyethane or mixture
thereof etc.), using an aqueous solution of hydroxide of alkali
(sodium hydroxide, potassium hydroxide etc.), hydroxide of
alkaline-earth metals (calcium dihydroxide etc.) or carbonate
(potassium carbonate etc.) at 0-50.degree. C.
[0237] (b) In the present invention compounds of the formula (I-1),
the compounds wherein L is
--(CH.sub.2).sub.m--CH.dbd.CH--(CH.sub.2).sub.n--, i.e., the
compounds of the formula (I-1 b) 191
[0238] wherein L.sup.b is
--(CH.sub.2).sub.m--CH.dbd.CH--(CH.sub.2).sub.n-- -, and the other
symbols are the same meaning as hereinbefore defined
[0239] may be prepared from the compounds of the formula (II-b)
192
[0240] wherein L.sup.bb is
--(CH.sub.2).sub.m--CH.sub.2CH(OR.sup.b)--(CH.s- ub.2).sub.n-- in
which, R.sup.b is the well-known elimination group (for example,
mesyl or tosyl group etc.), and the other symbols are the same
meaning as hereinbefore defined, with the proviso that when
nitrogen atom in G or M in the formula (I-1 b) is free --NH group,
NH group in the formula (II-b) is protected by the well-known
protecting group (for example, cbz, boc or COCF.sub.3 etc.)
[0241] by removal of elimination group, if necessary, followed by
removal of NH-protecting group.
[0242] This reaction may be carried out in an organic solvent
(methanol or ethanol etc.) by adding base (potassium hydroxide,
sodium hydroxide or triethylamine etc.) at 0-100.degree. C. The
removal of NH-protecting group may be carried out by the method
described hereinbefore.
[0243] In the compound of the formula (I) of the present invention,
the compounds of the formula (I-2) of the present invention 193
[0244] wherein A.sup.2 is the same meaning as A other than
hydrogen
[0245] may be prepared by reacting the compounds, in which nitrogen
atom in G or M in the formula (I-1) is free --NH group, NH group is
protected by the well-known protecting group (for example, cbz, boc
or COCF.sub.3 etc.), i.e. the compounds of the formula (II-c)
194
[0246] wherein G.sup.a and M.sup.a are the same meaning as G and M,
respectively, with the proviso that when nitrogen atom in G or M in
the formula (1-2) is free --NH group, NH group is protected by the
well-known protecting group (for example, cbz, boc or COCF.sub.3
etc.) and the other symbols are the same meaning as hereinbefore
defined
[0247] with the compounds of the formula (III)
X.sup.2--A.sup.2a (III)
[0248] wherein X.sup.2 is halogen and A.sup.2a is
[0249] (i) --(C1-4 alkylene)--COOR.sup.1a in which R.sup.1a is C1-4
alkyl,
[0250] (ii) --(C1-4 alkylene)--OR.sup.5, in which R.sup.5 is
tetrahydropyranyl,
[0251] (iii) --(C1-4 alkylene)--CONR.sup.2R.sup.3,
[0252] (iv) --(C1-4 alkylene)-tetrazolyl or
[0253] (v) --(C2-4 alkylene)--CN,
[0254] and the other symbols are the same meaning as hereinbefore
defined, with the proviso that when nitrogen atom in A.sup.2a is
free --NH group, NH group is protected by the well-known protecting
group (for example, cbz, boc or COCF.sub.3 etc.),
[0255] if necessary, followed by hydrolysis in an alkaline
condition or by removal of protecting group.
[0256] The above mentioned O-alkylation is known, and for example,
this reaction may be carried out in a water-miscible organic
solvent (acetone, THF or methylene chloride etc.) in the presence
of a base (potassium carbonate etc.), at 0-50.degree. C.
[0257] The hydrolysis in an alkaline condition is well known. For
example, this reaction may be carried out in a water-miscible
organic solvent (methanol, ethanol, dimethoxyethane or mixture
thereof etc.), using an aqueous solution of hydroxide of alkali
(sodium hydroxide, potassium hydroxide etc.), hydroxide of
alkaline-earth metals (calcium dihydroxide etc.) or carbonate
(potassium carbonate etc.) at 0-50.degree. C. The removal of
protecting group may be carried out by the method described
hereinbefore.
[0258] In the compounds of the formula (I) of the present
invention, the compounds wherein A is --(C1-4
alkylene)-tetrazol-5-yl, i.e. the compounds of the formula (I-3)
195
[0259] in which, A.sup.3 is --(C1-4 alkylene)-tetrazol-5-yl and the
other symbols are the same meaning as hereinbefore defined
[0260] may be also prepared by reacting the compounds of the
formula (I-4) 196
[0261] in which A.sup.4 is --(C1-4 alkylene)--CN and the other
symbols are the same meaning as hereinbefore defined
[0262] with the azide.
[0263] The reaction to introduce a tetrazol-5-yl group from cyano
group with an azide are known, it may be carried out, for example,
on anhydrous condition, using with azide (sodium azide, lithium
azide, potassium azide etc.) in the presence of weak acid (pyridium
chloride, ammonium chloride, dimethylaniline hydrochloride etc.) in
an inert organic solvent (DMF, N-methylpyrrolidone etc.) with
heating.
[0264] In the compounds of the formula (I) of the present
invention, the compounds wherein A is --(C1-4
alkylene)--CONR.sup.2R.sup.3, i.e. the compounds of the formula
(I-5) 197
[0265] in which, As is --(C1-4 alkylene)--CONR.sup.2R.sup.3 in
which R.sup.2 and R.sup.3 are the same meaning as hereinbefore
defined and the other symbols are the same meaning as hereinbefore
defined
[0266] may be also prepared by reacting the compounds of the
formula (I-6) 198
[0267] in which A.sup.6 is --(C1-4 alkylene)--COOR.sup.1a in which
R.sup.1a is the same meaning as hereinbefore defined and the other
symbols are the same meaning as hereinbefore defined
[0268] with the compounds of the formul
HNR.sup.2R.sup.3 (IX)
[0269] in which all symbols are the same meaning as hereinbefore
defined.
[0270] The above reaction to form an amide bond is well known. For
example, this reaction may be carried out in inert organic solvent
(benzene, toluene or methylene chloride etc.), or in the absence of
solvent, using tertiary amine (pyridine or triethylamine etc.) at
0-50.degree. C., or it may be carried out in an organic solvent
(methylene chloride or THF etc.), using a corresponding base, in
the presence or absence of corresponding condensing agents
(2-chloro-N-methylpyridiunium iodide etc.) at 0-40.degree. C.
[0271] The compounds of the formula (II-a) and (II-b) may be
prepared by the known reaction. For example, these compounds may be
prepared according to the method shown in the reaction scheme (1),
(2), (3) or (4) or method described in Example.
[0272] In the compounds of the formula (I-1) of the present
invention, the compounds wherein G is --NH-- and L is
--CH.sub.2--CH(OH)--(CH.sub.2).sub- .y--, i.e. the compounds of the
formula 199
[0273] in which L.sup.d is --CH.sub.2--CH(OH)--(CH.sub.2).sub.y--
in which y is the same meaning as hereinbefore defined and the
other symbols are the same meaning as hereinbefore defined
[0274] may be also prepared according to the method shown in the
reaction scheme (5) or method described in Example.
[0275] In the compounds of the formula (I) of the present
invention, the compounds wherein M is 200
[0276] in which each phenyl may be substituted by the substituent
described hereinbefore and L is
--(CH.sub.2).sub.x--CH(OH)--(CH.sub.2).su- b.y--, i.e. the
compounds of the formula 201
[0277] in which M.sup.b is 202
[0278] in which each phenyl may be substituted by the substituent
described hereinbefore, L.sup.e is
--(CH.sub.2).sub.x--CH(OH)--(CH.sub.2)- .sub.y-- in which x and y
are the same meaning as hereinbefore defined, G.sup.3 is --S--,
--O-- or --NR.sup.4-- and the other symbols are the same meaning as
hereinbefore defined
[0279] may be also prepared according to the method shown in the
reaction scheme (6) or method described in Example.
[0280] In reaction scheme (1), (2), (3), (4), (5) and (6) each
symbol means the following definition or is the same meaning as
defined hereinbefore.
[0281] Et is ethyl,
[0282] Ac is acetyl,
[0283] iPr is isopropyl.
[0284] Ph is phenyl,
[0285] MOM is methoxymethyl,
[0286] 9-BBN is 9-borabicyclo[3.3.1]nonan,
[0287] LAH is lithium aluminum hydride,
[0288] TsCl is tosylchloride,
[0289] AcSK is potassium thioacetate,
[0290] mCPBA is methachloroperbenzoic acid,
[0291] cbz is benzyloxycarbonyl,
[0292] L.sup.c is L.sup.aa, L.sup.bb or C1-6 alkylene,
[0293] E.sup.c is C1-6 alkylene,
[0294] G.sup.1 is --O--, --S--, --SO--, or --SO.sub.2--,
[0295] G.sup.2 is --NR.sup.4--,
[0296] Bu.sub.4NBr is tetrabutylammonium bromide,
[0297] Py is pyridine,
[0298] R.sup.d is 1) acetyl or hydrogen when G.sup.3 is --S--,
[0299] 2) hydrogen when G.sup.3 is --O-- or --NR.sup.4a-- in which
R.sup.4a is C1-4 alkyl,
[0300] 3) NH-protecting group as defined hereinbefore when G.sup.3
is --NH--
[0301] Z is NH-protecting group as defined hereinbefore and
[0302] Ph.sup.a is phenyl may be substituted by 1-3 of C1-4 alkyl,
C1-4 alkoxy, halogen, nitro or trifluoromethyl.
[0303] The compounds of the formula (II-a) are a part of the
compounds of the formula (VII).
[0304] The compounds of the formula (II-b) are a part of the
compounds of the formula (VIII). The compounds of the formula (IV),
(V-O) or (VI) as starting materials may be prepared by the known
methods. For example, these compound may be prepared by the methods
described in Example in the present specification.
[0305] In each reaction in the present specification, obtained
products may be purified by conventional techniques. For example,
purification may be carried out by distillation at atmospheric or
reduced pressure, by high performance liquid chromatography, by
thin layer chromatography or by column chromatography using silica
gel or magnesium silicate, by washing or by recrystallization.
Purification may be carried out after each reaction, or after a
series of reactions.
[0306] The other starting materials and reagents in the present
invention are known per se or may be prepared by known methods. 203
204 205 206 207 208
[0307] Industrial Availability
[0308] Pharmacological Activities
[0309] The compounds of the present invention of the formula (1)
are useful as PGE.sub.2 antagonists or agonists, because they can
bind onto prostaglandin E.sub.2 receptors and have antagonist or
agonist activity against the action thereof.
[0310] As mentioned hereinbefore, to antagonize PGE.sub.2 receptor
is linked to inhibit diuretic, to inhibit hyperlipemia, to inhibit
reduce of blood sugar, to inhibit uterine contraction, to have
analgesic action, to inhibit digestive peristalsis, to induce
sleep. Therefor, PGE.sub.2 antagonists are considered to be useful
as anti-hyperlipemia, for the prevention of abortion, for
analgesics, or as antidiarrheals or sleep inducer.
[0311] As mentioned hereinbefore, to agonize for PGE.sub.2 receptor
is liked to promote diuretic, to promote hyperlipemia, to promote
reduce of blood sugar, to contractile uterine, to promote digestive
peristalsis, to suppress gastric acid secretion or to reduce blood
pressure. Therefor, PGE.sub.2 receptor agonists are considered to
be useful for diuretic, anti-diabetes, abortient, cathartics,
antiulcer, anti-gastritis or antihypertensive.
[0312] For example, in standard laboratory test, the effects of the
compounds of the present invention were confirmed by inhibitory
effect on binding PGE.sub.2 using expression cell of receptor.
[0313] (i) Binding Assay Using Expression Cell of Prostanoide
Receptor Subtype
[0314] The preparation of membrane fraction was carried out
according to the method of Sugimoto et al (J. Biol. Chem. 267,
6463-6466 (1992)), using expression CHO cell of prostanoide
receptor subtype (mouse EP.sub.3.alpha.).
[0315] The standard assay mixture contained membrane fraction (0.5
mg/ml), [.sup.3H]--PGE.sub.2 in a final volume of 200 ml was
incubated for 1 hour at room temperature. The reaction was
terminated by addition of 3 ml of ice-cold buffer. The mixture was
rapidly filtered through a glass filter (GF/B). The radioactivity
associated with the filter was measured by liquid scintillation
counting.
[0316] Kd and Bmax values were determined from Scatchard plots
(Ann. N.Y. Acad. Sci., 51, 660 (1949)). Non-specific binding was
calculated as the bond in the presence of an excess (2.5 nM) of
unlabeled PGE.sub.2. In the experiment for competition of specific
[.sup.3H]-PGE.sub.2 binding by the compounds of the present
invention, [.sup.3H]--PGE.sub.2 was added at a concentration of 2.5
nM and the compounds of the present invention were at a
concentration of 1 mM.
[0317] Buffer: 10 mM potassium phosphate (pH6.0), 1 mM EDTA, 10 mM
MgCl.sub.2, 0.1 M NaCl.
[0318] The dissociation constant Ki (.mu.M) of each compound was
calculated by the following equation.
Ki=IC50/(1+([C]/Kd))
[0319] The results were shown as follows.
15 dissociation constant Example No. Ki (.mu.M) 3 0.048 3 (2)
0.0099 3 (6) 0.15 3 (8) 2.0 5 0.080 5 (1) 0.0086
[0320] Toxicity
[0321] The toxicity of the compounds of the present invention are
very low and therefore, it is confirmed that these compounds are
safe for use as medicine.
[0322] Application for Pharmaceuticals
[0323] The compounds of the formula (I) of the present invention
are useful for PGE.sub.2 antagonists or agonists, because they can
bind onto PGE.sub.2 receptors and have an activity to antagonize or
agonize for the action thereof.
[0324] As mentioned hereinbefore, to antagonize PGE.sub.2 is linked
to inhibit hyperlipemia, to inhibit uterine contraction, to have
analgesic action, to inhibit digestive peristalsis or to induce
sleep. Therefor, PGE.sub.2 antagonists are considered to be useful
as anti-hyperlipemia, for the prevention of abortion, for
analgesics, or as antidiarrheals or sleep inducer.
[0325] As mentioned hereinbefore, to agonize PGE.sub.2 is linked to
promote diuretic, to promote reduce of blood sugar, to contractile
uterine, to promote digestive peristalsis, to suppress gastric acid
secretion or to reduce blood pressure. Therefor, PGE.sub.2 agonists
are useful for diuretics, anti-diabete abortient, cathartics,
antiulcer, anti-gastritis or antihypertensive.
[0326] For the purpose above described, the compounds of the
formula (I), non-toxic salts thereof and hydrates thereof may be
normally administered systematically or partially, usually by oral
or parenteral administration.
[0327] The doses to be administered are determined depending upon
age, body weight, symptom, the desired therapeutic effect, the
route of administration, and the duration of the treatment etc. In
the human adult, the doses per person per dose are generally
between 1 .mu.g and 100 mg, by oral administration, up to several
times per day, and between 0.1 .mu.g and 10 mg, by parenteral
administration (preferred into vein) up to several times per day,
or continuous administration between 1 and 24 hours per day into
vein.
[0328] As mentioned above, the doses to be used depend upon various
conditions. Therefore, there are cases in which doses lower than or
greater than the ranges specified above may be used.
[0329] On administration of the compounds of the present invention,
it is used as solid compositions, liquid compositions or other
compositions for oral administration, as injections, liniments or
suppositories etc. for parenteral administration.
[0330] Solid compositions for oral administration include
compressed tablets, pills, capsules, dispersible powders, and
granules etc.
[0331] Capsules contain hard capsules and soft capsules.
[0332] In such solid compositions, one or more of the active
compound(s) is or are, admixed with at least one inert diluent such
as lactose, mannitol, mannit, glucose, hydroxypropyl cellulose,
microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium
metasilicate aluminate. The compositions may also comprise, as is
normal practice, additional substances other than inert diluents:
e.g. lubricating agents such as magnesium stearate, disintegrating
agents such as cellulose calcium glycolate, and assisting agents
for dissolving such as glutamic acid or asparaginic acid. The
tablets or pills may, if desired, be coated with film of gastric or
enteric material such as sugar, gelatin, hydroxypropyl cellulose or
hydroxypropyl cellulose phthalate etc., or be coated with two or
more films. And further, coating may include containment within
capsules of absorbable materials such as gelatin.
[0333] Liquid compositions for oral administration include
pharmaceutically-acceptable emulsions, solutions, syrups and
elixirs etc. In such liquid compositions, one or more of the active
compound(s) is or are comprised in inert diluent(s) commonly used
in the art (for example, purified water, ethanol etc.). Besides
inert diluents, such compositions may also comprise adjuvants such
as wetting agents, suspending agents, sweetening agents, flavouring
agents, perfuming agents and preserving agents.
[0334] Other compositions for oral administration include spray
compositions which may be prepared by known methods and which
comprise one or more of the active compound(s). Spray compositions
may comprise additional substances other than inert diluents: e.g.
stabilizing agents such as sodium hydrogen sulfate, stabilizing
agents to give the title compound isotonicity, isotonic buffer such
as sodium chloride, sodium citrate, citric acid. For preparation of
such spray compositions, for example, the method described in the
U.S. Pat. Nos. 2,868,691 or 3,095,355 may be used.
[0335] Injections for parenteral administration include sterile
aqueous or non-aqueous solutions, suspensions and emulsions.
Aqueous solutions or suspensions include distilled water for
injection and physiological salt solution. Non-aqueous solutions or
suspensions include propylene glycol, polyethylene glycol, plant
oil such as olive oil, alcohol such as ethanol, POLYSOLBATE80
(registered trade mark) etc. Such compositions may comprise
additional diluents: e.g. preserving agents, wetting agents,
emulsifying agents, dispersing agents, stabilizing agent, assisting
agents such as assisting agents for dissolving (for example,
glutamic acid, asparaginic acid). They may be sterilized for
example, by filtration through a bacteria-retaining filter, by
incorporation of sterilizing agents in the compositions or by
irradiation. They also be manufactured in the form of sterile solid
compositions and which can be dissolved in sterile water or some
other sterile diluents for injection immediately before used.
[0336] Other compositions for parenteral administration include
liquids for external use, and endemic liniments, ointment,
suppositories and pessaries which comprise one or more of the
active compound(s) and may be prepared by know methods.
[0337] Best Mode to Practice the Invention
[0338] The following reference examples and examples are intended
to illustrate, but not limit, the present invention. The solvents
in parentheses show the developing or eluting solvents and the
ratios of the solvents used are by volume in chromatographic
separations The symbol in the structure is the same meaning as
defined hereinbefore.
REFERENCE EXAMPLE 1
[0339] 209
[0340] To a solution of 2,2-dimethyl-1,3-dioxolane-4-methanol (50
g) and pyridine (50 ml) in methylene chloride (200 ml),
tosylchloride (76.3 g) in methylene chloride (150 ml) was added
dropwise at -20.degree. C. The mixture was stirred for 1 hour at
room temperature. The reaction mixture was added to 2N aqueous
solution of hydrochloric acid (300 ml) and extracted by ethyl
acetate. The organic layer was washed with water and a saturated
aqueous solution of sodium chloride, dried over with anhydrous
magnesium sulfate and concentrated. The residue was purified on
silica gel column chromatography (hexane:AcOEt=3:1) to give the
title compound (95.8 g) having the following physical data.
[0341] TLC: Rf 0.21 (hexane:AcOEt=3:1);
[0342] MS (El): m/z 271 (M.sup.+--CH.sub.3).
REFERENCE EXAMPLE 2
[0343] 210
[0344] A suspension of sodium hydride (1.47 g) in dimethylformamide
(DMF) (20 ml) was cooled to 0.degree. C. The solution of phenol
(3.45 g) in DMF (20 ml) was added dropwise to the suspension. The
mixture was stirred for 1 hour at room temperature. To the mixture,
the solution of the compound prepared in Reference Example 1 (10 g)
in DMF (20 ml) was added. The mixture was stirred for 2 hours at
80.degree. C. The reaction mixture was cooled to room temperature,
poured into iced water and extracted with ether two times. The
organic layer was washed with water and a saturated aqueous
solution of sodium chloride, dried over with anhydrous magnesium
sulfate and concentrated. The residue was purified on silica gel
column chromatography (hexane:AcOEt=9:1) to give the title compound
(6.53 g) having the following physical data.
[0345] TLC: Rf 0.22 (hexane:AcOEt=9:1);
[0346] MS (El): m/z 208 (M.sup.+), 193.
REFERENCE EXAMPLE 3
[0347] 211
[0348] To a solution of the compound prepared in Reference Example
2 (6.37 g) in methanol (30 ml), 2N aqueous solution of hydrochloric
acid (3 ml) was added. The mixture was refluxed for 2 hours. The
reaction mixture was cooled to room temperature, diluted with ethyl
acetate and washed with saturated aqueous solution of sodium
hydrogen carbonate. The organic layer was dried over with anhydrous
magnesium sulfate and concentrated to give the title compound (5.14
g) having the following physical data.
[0349] TLC: Rf 0.40 (AcOEt);
[0350] MS (El): m/z 168 (M.sup.+).
REFERENCE EXAMPLE 4
[0351] 212
[0352] To a solution of the compound prepared in Reference Example
3 (3.5 g) in pyridine (10 ml), the solution of tosylchloride (8 g)
in methylene chloride (10 ml) was added at -20.degree. C. The
mixture was stirred for 1 hour at room temperature. The reaction
mixture was poured into 2N aqueous solution of hydrochloric acid
and extracted with ethyl acetate. The organic layer was washed with
water and a saturated aqueous solution of sodium chloride, dried
over with anhydrous magnesium sulfate and concentrated. The residue
was purified on silica gel column chromatography
(AcOEt:CH.sub.2Cl.sub.2=1:49) to give the title compound (4.96 g)
having the following physical data.
[0353] TLC: Rf 0.31 (hexane:AcOEt=3:2);
[0354] MS (El): m/z 322 (M.sup.+).
REFERENCE EXAMPLE 5
[0355] 213
[0356] To a solution of the compound prepared in Reference Example
4 (9.88 g) and pyridium p-toluene sulfate (100 mg) in methylene
chloride (60 ml), dihydropyran (5.58 ml) was added dropwise at
0.degree. C. The mixture was stirred for 6 hours at room
temperature. Triethylamine (0.2 ml) was added to the mixture. The
solvent was distilled off. The residue was purified on silica gel
column chromatography (hexane:AcOEt=41:9) to give the title
compound (11.79 g) having the following physical data.
[0357] TLC: Rf 0.28 (hexane:AcOEt=4:1);
[0358] MS (El): m/z 406 (M.sup.+).
REFERENCE EXAMPLE 6
[0359] 214
[0360] By using (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol
instead of 2,2-dimethyl-1,3-dioxolane-4-methanol as starting
material, the title compound having the following physical data was
obtained by the same procedure as Reference Example
1.fwdarw.Reference Example 2 .fwdarw.Reference Example 3
.fwdarw.Reference Example 4.fwdarw.Reference Example 5.
[0361] TLC: Rf 0.28 (hexane:AcOEt=4:1);
[0362] MS (El): m/z 406 (M.sup.+).
REFERENCE EXAMPLE 6(1)
[0363] 215
[0364] By using (R)-(-)-2,2-dimethyl-1,3-dioxolane-4-methanol
instead of 2,2-dimethyl-1,3-dioxolane-4-methanol as starting
material, the title compound having the following physical data was
obtained by the same procedure as Reference Example 6.
[0365] TLC: Rf 0.28(hexane:AcOEt=4:1);
[0366] MS (El):m/z 406 (M.sup.+).
REFERENCE EXAMPLE 7
[0367] 216
[0368] To a solution of 1-phenyl-1,2-ethandiol (13.82 g) in
pyridine (50 ml), tosylchloride (21 g) was added for 30 minutes at
-20.degree. C. The reaction mixture was stirred for 30 minutes at
-20.degree. C. and, succeedingly, stirred for 16 hours at room
temperature. The reaction mixture was poured into iced water and
extracted with ether. The organic layer was washed with 2N aqueous
solution of hydrochloric acid, water and saturated aqueous solution
of sodium hydrogen carbonate, succeedingly, dried over with
anhydrous sodium sulphate and concentrated. The residue was
purified on silica gel column chromatography (hexane:AcOEt=3:1) to
give the title compound (18.56 g) having the following physical
data.
[0369] TLC: Rf 0.41 (hexane:AcOEt=2:1);
[0370] MS (El): m/z 292 (M.sup.+).
REFERENCE EXAMPLE 8
[0371] 217
[0372] To a solution of compound prepared in Reference Example 7
(10 g) in methylene chloride (100 ml), dihydropyran (5.76 g) was
added dropwise at room temperature. P-toluene sulfonic acid
(catalytic amount) was added to the mixture. The mixture was
stirred overnight at room temperature. To the reaction mixture,
triethylamine (two drops) was added. The mixture was concentrated.
The reside was dissolved in ethyl acetate. The organic layer was
washed with water and a saturated aqueous solution of sodium
chloride, dried over with anhydrous sodium sulfate and concentrated
to give the title compound (12.9 g) having the following physical
data.
[0373] TLC: Rf 0.50 (hexane:AcOEt=2:1);
[0374] MS (El): m/z 376 (M.sup.+).
REFERENCE EXAMPLE 9
[0375] 218
[0376] To a solution of 5-methoxy-1-tetralone (100 g) in methylene
chloride (500 ml), trimethylsilylcyanide (88 ml) and zinc iodide (3
g) was added. The mixture was stirred overnight at room
temperature. To the reaction solution, water was added. The mixture
was extracted with mixture solvent (AcOEt:hexane=1:1) two times.
The organic layer was washed with water and a saturated aqueous
solution of sodium chloride, dried over anhydrous sodium sulfate
and concentrated. The residue was dissolved in pyridine (370 ml).
Phosphorous oxychloride (POCl.sub.3) (133 ml) was added dropwise to
the solution. The reaction mixture was refluxed for 3 hours and
cooled to room temperature. The reaction mixture was poured into
iced water and extracted with ethyl acetate two times. The organic
layer was washed with water and a saturated aqueous solution of
sodium chloride, dried over anhydrous sodium sulfate and
concentrated. The residue was purified on silica gel column
chromatography (AcOEt:CH.sub.2Cl.sub.2=1:19), and succeedingly,
recrystalized from solvent of AcOEt-hexane to give the title
compound (72 g) having the following physical data.
[0377] TLC: Rf 0.43 (hexane:AcOEt=3:1);
[0378] MS (El): m/z 185 (M.sup.+).
REFERENCE EXAMPLE 10
[0379] 219
[0380] A mixture of compound prepared in Reference Example 9 (60
g), 2,3-dichloro-5,6-dicyano-1,4-benzoquinon (DDQ) (81 g) and
benzene (700 ml) was refluxed for 6 hours. The reaction mixture was
cooled to room temperature. To a reaction solution, mixture solvent
(AcOEt:hexane=1:1) (500 ml) was added. The mixture was filtrated.
The precipitate was washed with mixture solvent (AcOEt:hexane=1:1).
The filtrate was washed with saturated aqueous solution of sodium
hydrogen carbonate four times, dried over with anhydrous sodium
sulfate and concentrated. The reside was recrystalized from
AcOEt-hexane to give the title compound (56.6 g) having the
following physical data.
[0381] TLC: Rf 0.42 (hexane:AcOEt=3:1);
[0382] MS (El):m/z 183 (M.sup.+);
[0383] m.p. 132-133.degree. C.
REFERENCE EXAMPLE 11
[0384] 220
[0385] To a solution of compound prepared in Reference Example 10
(91.6 g) in methylene chloride (500 ml), a solution of boron
triburomide (104 ml) in methylene chloride (100 ml) was added
dropwise at 0.degree. C. The mixture was stirred for 20 hours at
room temperature. The reaction mixture was poured into iced water
and extracted with ethyl acetate two times. The organic layer was
washed with aqueous solution of sodium hydrogen carbonate and a
saturated aqueous solution of sodium chloride, dried over with
anhydrous magnesium sulfate and concentrated to give the title
compound (84.4 g) having the following physical data.
[0386] TLC: Rf 0.32 (hexane:AcOEt=2:1);
[0387] MS (El): m/z 169 (M.sup.+);
[0388] m.p. 198-201.degree. C.
REFERENCE EXAMPLE 12
[0389] 221
[0390] To a solution of compound prepared in Reference Example 11
(82.5 g) in methylene chloride (1000 ml), diisopropylethylamine
(102 ml) and methyoxymethylchloride (41 ml) were added at 0.degree.
C. The mixture was stirred overnight at room temperature. The
solvent was distilled off. The residue was diluted with mixture
solvent (AcOEt:hexane=1:1), washed with water, aqueous solution of
hydrochloric acid, saturated aqueous solution of sodium hydrogen
carbonate and a saturated aqueous solution of sodium chloride
succeedingly, dried over with anhydrous magnesium sulfate and
concentrated. The residue was recrystallized from the mixture
solvent (AcOEt:hexane=1:10) to give the title compound (88.8 g)
having the following physical data.
[0391] TLC: Rf 0.34 (hexane:AcOEt=4:1);
[0392] MS (El):m/z 213 (M.sup.+).
REFERENCE EXAMPLE 13
[0393] 222
[0394] To a solution of compound prepared in Reference Example 12
(95.5 g) in toluene (750 ml), diisobutyl aluminum hydride (324 ml,
1.5 mol/toluene solution) was added at -50.degree. C. The mixture
was heated to 0.degree. C. for 2 hours. The reaction mixture was
cooled to -30.degree. C. Methanol (30 ml) was added to the mixture.
The reaction solution was heated to -5.degree. C. An aqueous
solution of sodium sulfate was added to the mixture. The
precipitate was filtrated. The filtrate was concentrated. The
residue was dissolved in tetrahydrofuran (THF)-AcOEt (100 ml-400
ml). 2N aqueous solution of hydrochloric acid (250 ml) was added to
the solution. The mixture was stirred for 30 minutes. The organic
layer was isolated. The aqueous layer was extracted with ethyl
acetate. The organic layer was washed with an aqueous solution of
sodium hydrogen carbonate and a saturated aqueous solution of
sodium chloride, dried over with anhydrous magnesium sulfate and
concentrated. To the residue, hexane (600 ml) was added. The
mixture was laid for 2 days. The crystal was collected by
filtration to give the title compound (70.6 g) having the following
physical data. In addition, the mother liquor was purified on
silica gel column chromatography (hexane:AcOEt=7:1) to give the
title compound (20.9 g) having the following physical data.
[0395] TLC: Rf 0.33(hexane:AcOEt=3:1);
[0396] MS (El): m/z 216 (M.sup.+).
REFERENCE EXAMPLE 14
[0397] 223
[0398] A mixture of sodium hydride (4.66 g) and dimethylsulfoxide
(DMSO) (100 ml) was stirred for 50 minutes at 80.degree. C. The
reaction mixture was cooled to room temperature. A solution of
methyltriphenylphosphnium bromide (41.6 g) in DMSO (120 ml) was
added dropwise to the reaction mixture in order to adjust reaction
temperature to 20-30.degree. C. The mixture was stirred for 30
minutes at room temperature. To the reaction solution, a solution
of compound prepared in Reference Example 13 (15.56 g) in DMSO (80
ml) was added dropwise. The mixture was stirred for 15 minutes at
room temperature. The reaction mixture was poured into iced water,
extracted with mixture solvent (AcOEt:hexane=1:2) three times. The
organic layer was washed with water and a saturated aqueous
solution of sodium chloride, dried over with anhydrous magnesium
sulfate and concentrated. To the residue, mixture solvent
(ether:hexane=1:4) (200 ml) was added. The mixture was filtrated.
The filtrate was concentrated. The residue was purified on silica
gel column chromatography (hexane:AcOEt=6:1) to give the title
compound (14.2 g) having the following physical data.
[0399] TLC: Rf 0.52 (hexane:AcOEt=4:1);
[0400] MS (El): m/z 214 (M.sup.+).
REFERENCE EXAMPLE 15
[0401] 224
[0402] To a solution of compound prepared in Reference Example 14
(14.2 g) in THF (60 ml), 9-borabicyclo[3.3.1]nonane (9-BBN) (172
ml, 0.5 mol/l THF solution) was added dropwise under an atmosphere
of Argon gas at room temperature. The mixture was stirred for 2.5
hours at room temperature. To the reaction solution, ethanol (30
ml) was added dropwise. In addition, to the mixture, 5N-aqueous
solution of sodium hydroxide (50 ml) was added. An aqueous solution
of hydrogen peroxide (50 ml) was added dropwise to the mixture in
order to adjust reaction temperature to 50-60.degree. C.,. The
reaction mixture was stirred for 30 minutes, poured into iced water
and extracted with ethyl acetate two times. The organic layer was
washed with water and a saturated aqueous solution of sodium
chloride, dried over with anhydrous magnesium sulfate and
concentrated. The residue was purified on silica gel column
chromatography (hexane:AcOEt=7:3) to give the title compound (14.81
g) having the following physical data.
[0403] TLC: Rf 0.38 (hexane:AcOEt=7:3);
[0404] MS (El): m/z 232 (M.sup.+), 202.
REFERENCE EXAMPLE 16
[0405] 225
[0406] To a solution of compound prepared in Reference Example 13
(5.3 g) in methanol (40 ml), sodium boron hydride (910 mg) was
added. The mixture was stirred for 1 hour at room temperature. The
solvent was distilled off. Water was added to the reside. The
mixture was extracted with ethyl acetate. The organic layer was
washed with water and a saturated aqueous solution of sodium
chloride, dried over with anhydrous magnesium sulfate and
concentrated to give the title compound (5.21 g) having the
following physical data.
[0407] TLC: Rf 0.33 (hexane:AcOEt=2:1);
[0408] MS (El): m/z 218 (M.sup.+).
REFERENCE EXAMPLE 17
[0409] 226
[0410] To a solution of compound prepared in Reference Example 13
(3.11 g) in chloroform (30 ml), carbomethoxymethylene
triphenylphosphorane (98% 5.88 g) was added. The mixture was
stirred for 16 hours at room temperature. The reaction mixture was
concentrated. Ether was added to the residue. The precipitate was
filtrated. The filtrate was concentrated. The residue was dissolved
in hexane. The precipitate was filtrated. The filtrate was
concentrated to give the title compound (3.92 g) having the
following physical data.
[0411] TLC: Rf 0.50 (hexane:AcOEt=5:1);
[0412] MS (El): m/z 272 (M.sup.+).
REFERENCE EXAMPLE 18
[0413] 227
[0414] To a solution of compound prepared in Reference Example 17
(3.81 g) in ethyl acetate (70 ml), 10% Pd-C (380 mg) was added. The
mixture was stirred under an atmosphere of H.sub.2 gas for 1 hour.
The reaction solution was filtrated. The filtrate was concentrated
to give the title compound (3.69 g) having the following physical
data.
[0415] TLC: Rf 0.48 (hexane:AcOEt=5:1);
[0416] MS (El): m/z 274 (M.sup.+).
REFERENCE EXAMPLE 19
[0417] 228
[0418] To a suspension of lithium aluminum hydride (2.919) in THF
(50 ml), a solution of compound prepared in Reference Example 18
(12.5 g) in THF (150 ml) was added dropwise at room temperature.
The mixture was stirred for 1 hour at room temperature. A small
amount of ethyl acetate was added to the reaction mixture. A
saturated aqueous solution of anhydrous sodium sulfate was added to
the mixture. The white precipitate was filtrated by Celite
(Registered trade mark). The filtrate was concentrated to give the
title compound (11.35 g) having the following physical data.
[0419] TLC: Rf 0.27 (hexane:AcOEt=2:1);
[0420] MS (El): m/z 246 (M.sup.+).
REFERENCE EXAMPLE 20
[0421] 229
[0422] 6-Hydroxy-2-naphthalene sulfonic acid sodium salt (18 g) was
dissolved in 2N aqueous solution of sodium hydroxide (36.6 ml) with
heating. THF (70 ml) was added to the solution. Ethylchloroformate
(7 ml) was added dropwise to the mixture under cooling with ice.
The mixture was stirred for 3 hours at room temperature. The white
crystal was filtrated, washed with water and THF and dried over
under reduced pressure to give the title compound (16.3 g) having
the following physical data.
[0423] TLC: Rf 0.09 (CHCl.sub.3:MeOH=5:1)
[0424] MS (El): m/z 318 (M.sup.+).
REFERENCE EXAMPLE 21
[0425] 230
[0426] The solution of compound prepared in Reference Example 15
(7.639) in pyridine (20 ml) was cooled to -30.degree. C.
Tosylchloride (8.75 g) was added to the solution. The mixture was
stirred for 2 hours at room temperature. The reaction mixture was
cooled to 0.degree. C. Water (1 ml) was added to the mixture. The
mixture was stirred for 20 minutes at room temperature. The
reaction solution was poured into AcOEt-2N-aqueous solution of
hydrochloric acid (2:1, 400 ml). The organic layer was isolated,
washed with water and saturated aqueous solution of sodium hydrogen
carbonate, dried over with anhydrous magnesium sulfate and
concentrated. The residue was dissolved in acetone (100 ml).
Potassium thioacetate (5.62 g) was added to solution. The mixture
was refluxed for 2 hours. The reaction mixture was cooled to room
temperature, poured into water and extracted with mixture solvent
(AcOEt:hexane=1:2) two times. The organic layer was washed with
water and a saturated aqueous solution of sodium chloride, dried
over with anhydrous magnesium sulfate and concentrated to give the
title compound (9.28 g) having the following physical data.
[0427] TLC: Rf 0.55 (hexane:AcOEt=7:3);
[0428] MS (El): m/z 290 (M.sup.+).
REFERENCE EXAMPLE 21(1)
[0429] 231
[0430] By using compound prepared in Reference Example 16, the
title compound having the following physical data was obtained by
the same procedure of Reference Example 21.
[0431] TLC: Rf 0.40 (hexane:AcOEt=4:1);
[0432] MS (El): m/z 276 (M.sup.+).
REFERENCE EXAMPLE 21 (2)
[0433] 232
[0434] By using compound prepared in Reference Example 19, the
title compound having the following physical data was obtained by
the same procedure of Reference Example 21.
[0435] TLC: Rf 0.57 (hexane:AcOEt=7:3);
[0436] MS (El): m/z 304 (M.sup.+).
REFERENCE EXAMPLE 22
[0437] 233
[0438] To a solution compound prepared in Reference Example 20
(16.3 g) in DMF (150 ml), thionylchloride (18.7 ml) was added
dropwise for 1.5 hours at 0.degree. C. The mixture was stirred for
2.5 hours at room temperature. The reaction mixture was poured into
iced water. The white crystal was filtrated, washed with water and
dried over under reduced pressure to give the title compound (13.4
g) having the following physical data.
[0439] TLC: Rf 0.72 (hexane:AcOEt=1:1);
[0440] MS (El): m/z 314 (M.sup.+).
REFERENCE EXAMPLE 23
[0441] 234
[0442] The compound prepared in Reference Example 22 (13.5 g) was
dissolved in mixture solvent of water (90 ml), conc. sulfuric acid
(18 ml) and THF (100 ml). A powder of zinc (13.9 g) was added to
the solution at 0 C. The mixture was stirred overnight at room
temperature. The reaction solution was filtrated. The filtrate was
distilled off under reduced pressure. The residual aqueous solution
was extracted with ethyl acetate. The organic layer was dried over
with anhydrous magnesium sulfate, and concentrated. The residue was
purified on silica gel column chromatography (hexane:AcOEt=1:1) to
give the title compound (9.4 g) having the following physical
data.
[0443] TLC: Rf 0.22 (hexane:AcOEt=1:1);
[0444] MS (El): m/z 248 (M.sup.+).
REFERENCE EXAMPLE 24
[0445] 235
[0446] To a solution of the compound prepared in Reference Example
21 (4.5 g) and the compound prepared in Reference Example 5 (6.3 g)
in ethanol (30 ml), sodium ethoxide (1.4 g) was added at 0.degree.
C. The mixture was stirred for 1 hour at room temperature. The
reaction mixture was poured into iced water and extracted with
ethyl acetate two times. The organic layer was washed with water
and a saturated aqueous solution of sodium chloride, dried over
with anhydrous magnesium sulfate and concentrated. The residue was
purified on silica gel column chromatography (hexane:AcOEt=6:1) to
give the title compound (6.75 g) having the following physical
data.
[0447] TLC: Rf 0.32 (hexane:AcOEt=5:1)
[0448] MS (El): m/z 482 (M.sup.+).
REFERENCE EXAMPLE 24(1)
[0449] 236
[0450] By using the compound prepared in Reference Example 21 and
the compound prepared in Reference Example 6, the title compound
having the following physical data by the same procedure of
Reference Example 24.
[0451] TLC: Rf 0.32 (hexane:AcOEt=5:1)
[0452] MS (El): m/z 482 (M.sup.+).
REFERENCE EXAMPLE 24(2)
[0453] 237
[0454] By using the compound prepared in Reference Example 21 and
the compound prepared in Reference Example 6(1), the title compound
having the following physical data by the same procedure of
Reference Example 24.
[0455] TLC: Rf 0.32 (hexane:AcOEt=5:1)
[0456] MS (El): m/z 482 (M.sup.+).
REFERENCE EXAMPLE 24(3)
[0457] 238
[0458] By using the compound prepared in Reference Example 21(1)
and the compound prepared in Reference Example 5 the title compound
having the following physical data by the same procedure of
Reference Example 24.
[0459] TLC: Rf 0.32 (hexane:AcOEt=4:1);
[0460] MS (El): m/z 468 (M.sup.+).
REFERENCE EXAMPLE 25
[0461] 239
[0462] To a solution of the compound prepared in Reference Example
21(2) (61 mg) and the compound prepared in Reference Example 8 (75
mg) in ethanol (4 ml), sodium ethoxide (28 mg) was added. The
mixture was stirred for 1 hour at room temperature. The reaction
mixture was concentrated. Water was added to the residue. The
mixture was extracted with ethyl acetate. The organic layer was
washed with water and a saturated aqueous solution of sodium
chloride, dried over with anhydrous sodium sulfate and
concentrated. The residue was purified on silica gel column
chromatography (hexane:AcOEt=5:1) to give the title compound (68
mg) having the following physical data.
[0463] TLC: Rf 0.65(hexane:AcOEt=5:1);
[0464] MS (El): m/z 466 (M.sup.+).
REFERENCE EXAMPLE 26
[0465] 240
[0466] To a solution of sodium hydride (400 mg) in DMF (30 ml), the
compound prepared in Reference Example 23 (2.48 g) was added under
an atmosphere of Argon gas. The mixture was stirred for 30
minutes-at room temperature. A solution of the compound prepared in
Reference Example 5 (4.06 g) in DMF (5 ml) was added dropwise to
the reaction solution at 0.degree. C. The mixture was stirred for 6
hours at room temperature. Water (30 ml) was added to the reaction
solution. The mixture was extracted with ethyl acetate. The organic
layer was dried over with anhydrous magnesium sulfate and
concentrated. The residue was purified on silica gel column
chromatography (hexane:AcOEt=2:1) to give the title compound (3.44
g) having the following physical data.
[0467] TLC: Rf 0.49 (hexane:AcOEt=5:1);
[0468] MS (El): m/z 482 (M.sup.+).
REFERENCE EXAMPLE 27
[0469] 241
[0470] To a suspension of the compound prepared in Reference
Example 24(3) (466 mg) and sodium hydrogen carbonate (170 mg) in
methylene chloride (2 ml), 70% mCPBA (245 mg) was added at
0.degree. C. The mixture was stirred for 1 hour at 0.degree. C.
Water was added to the reaction mixture. The mixture was extracted
with ether. The organic layer was washed with water and a saturated
aqueous solution of sodium chloride, dried over with anhydrous
magnesium sulfate and concentrated. The residue was purified on
silica gel column chromatography (hexane:AcOEt=1:4) to give the
title compound (324 mg) having the following physical data.
[0471] TLC: Rf 0.12 (hexane:AcOEt=1:1);
[0472] MS (El): m/z 468 (M.sup.+--O).
REFERENCE EXAMPLE 27(1)
[0473] 242
[0474] By using the compound prepared in Reference Example 24, the
title compound having the following physical data was obtained by
the same procedure of Reference Example 27.
[0475] TLC: Rf 0.44 (hexane:AcOEt=1:1);
[0476] MS (El): m/z 498 (M.sup.+).
REFERENCE EXAMPLE 27(2)
[0477] 243
[0478] By using the compound prepared in Reference Example 25, the
title compound having the following physical data was obtained by
the same procedure of Reference Example 27.
[0479] TLC: Rf 0.61 (AcOEt);
[0480] MS (El): m/z 482 (M.sup.+).
REFERENCE EXAMPLE 27(3)
[0481] 244
[0482] By using the compound prepared in Reference Example 26, the
title compound having the following physical data was obtained by
the same procedure of Reference Example 27.
[0483] TLC: Rf 0.33 (hexane:AcOEt=1:1);
[0484] MS (El): m/z 498 (M.sup.+).
REFERENCE EXAMPLE 28
[0485] 245
[0486] To a suspension of the compound prepared in Reference
Example 24(3) (466 mg) and sodium hydrogen carbonate (340 mg) in
methylene chloride (3 ml), 70% mCPBA (735 mg) was added at
0.degree. C. The mixture was stirred for 2 hours at 0.degree. C.
Water was added to the reaction mixture. The mixture was extracted
with ether. The organic layer was washed with water and a saturated
aqueous solution of sodium chloride, dried over with anhydrous
magnesium sulfate and concentrated. The residue was purified on
silica gel column chromatography (hexane:AcOEt=2:1) to give the
title compound (300 mg) having the following physical data.
[0487] TLC: Rf 0.37 (hexane:AcOEt=1:1);
[0488] MS (El): m/z 500 (M.sup.+).
REFERENCE EXAMPLE 28(1)
[0489] 246
[0490] By using the compound prepared in Reference Example 24, the
title compound having the following physical data was obtained by
the same procedure of Reference Example 28.
[0491] TLC: Rf 0.49 (hexane:AcOEt=1:1);
[0492] MS (El): m/z 514 (M.sup.+).
REFERENCE EXAMPLE 28(2)
[0493] 247
[0494] By using the compound prepared in Reference Example 25, the
title compound having the following physical data was obtained by
the same procedure of Reference Example 28.
[0495] TLC: Rf 0.27 (hexane:AcOEt=5:1);
[0496] MS (El): m/z 498 (M.sup.+).
REFERENCE EXAMPLE 28(3)
[0497] 248
[0498] By using the compound prepared in Reference Example 26, the
title compound having the following physical data was obtained by
the same procedure of Reference Example 28.
[0499] TLC: Rf 0.35 (hexane:AcOEt=1:1);
[0500] MS (El): m/z 514 (M.sup.+).
REFERENCE EXAMPLE 29
[0501] 249
[0502] To a solution of potassium hydroxide (62 mg) in methanol (10
ml), the compound prepared in Reference Example 26 (446 mg) was;
added at room temperature. The mixture was stirred overnight at
room temperature. 2N aqueous solution of hydrochloric acid was
added to the reaction mixture in order to adjust to pH 7 at
0.degree. C. The mixture was extracted with ethyl acetate. The
organic layer was washed with water and a saturated aqueous
solution of sodium chloride, dried over with anhydrous magnesium
sulfate and concentrated, The white crystal was washed with ether
to give the title compound (341 mg) having the following physical
data.
[0503] TLC: Rf 0.34 (hexane:AcOEt=5:1);
[0504] MS (El): m/z 410 (M.sup.+).
REFERENCE EXAMPLE 29(1)
[0505] 250
[0506] By using the compound prepared in Reference Example 27(3),
the title compound having the following physical data was obtained
by the same procedure of Reference Example 29.
[0507] TLC: Rf 0.31 (hexane:AcOEt=1:1);
[0508] MS (El): m/z 426 (M.sup.+).
REFERENCE EXAMPLE 29(2)
[0509] 251
[0510] By using the compound prepared in Reference Example 28(3),
the title compound having the following physical data was obtained
by the same procedure of Reference Example 29.
[0511] TLC: Rf 0.32 (hexane:AcOEt=1:1);
[0512] MS (El): m/z 442 (M.sup.+).
EXAMPLE 1
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenoxy-2RS-propanol
[0513] 252
[0514] To a solution of the compound prepared in Reference Example
24 (482 mg) in mixture solvent of AcOEt-methanol (3 ml-2 ml), 4N
aqueous solution of hydrochloric acid (3 ml, solution of ethyl
acetate) was added. The mixture was stirred for 2 hours at room
temperature. The reaction solution was concentrated. The residue
was diluted with ethyl acetate, washed with water and a saturated
aqueous solution of sodium chloride, dried over with anhydrous
magnesium sulfate and concentrated. The residue was purified on
silica gel column chromatography (hexane AcOEt=73) to give the
present invention compound (320 mg) having the following physical
data.
[0515] TLC: Rf 0.42 (hexane:AcOEt=2:1);
[0516] MS (APCI): m/z 353 (M.sup.+-1), 169,156;
[0517] NMR (CDCl.sub.3): .delta.8.15-8.08 (1H, m), 7.59 (1H, d,
J=8.6 Hz), 7.45-7.23 (5H, m), 7.02-6.80 (4H, m), 5.35 (1H, s),
4.16-3.98 (3H, m), 3.40-3.30 (2H, m), 3.01-2.68 (5H, m).
EXAMPLE 1(1)
1-[2-(5-hydroxy-1-naphthyl)ethylsulfinyl]-3-phenoxy-2RS-propanol
[0518] 253
[0519] By using the compound prepared in Reference Example 27(1),
the present invention compound having the following physical data
was obtained by the same procedure as Example 1.
[0520] TLC: Rf 0.23 (hexane:AcOEt=1:1);
[0521] MS (El): m/z 370 (M.sup.+).
EXAMPLE 1(2)
1-[2-(5-hydroxy-1-naphthyl)ethylsulfonyl]-3-phenoxy-2RS-propanol
[0522] 254
[0523] By using the compound prepared in Reference Example 28(1),
the present invention compound having the following physical data
was obtained by the same procedure as Example 1.
[0524] TLC: Rf 0.26 (hexane:AcOEt=1:1);
[0525] MS (El): m/z 386 (M.sup.+).
EXAMPLE 1(3)
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenoxy-2R-propanol
[0526] 255
[0527] By using the compound prepared in Reference Example 24(1),
the present invention compound having the following physical data
was obtained by the same procedure as Example 1.
[0528] TLC: Rf 0.42(hexane:AcOEt=2:1);
[0529] MS (APCI): m/z 353 (M.sup.+-1), 169, 156.
EXAMPLE 1(4)
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenoxy-2S-propanol
[0530] 256
[0531] By using the compound prepared in Reference Example 24(2),
the present invention compound having the following physical data
was obtained by the same procedure as Example 1.
[0532] TLC: Rf 0.42 (hexane:AcOEt=2:1);
[0533] MS (APCI): m/z 353 (M.sup.+-1), 169, 156.
EXAMPLE 1(5)
1-(5-hydroxy-1-naphthyl)methylthio-3-phenoxy-2RS-propanol
[0534] 257
[0535] By using the compound prepared in Reference Example 24(3),
the present invention compound having the following physical data
was obtained by the same procedure as Example 1.
[0536] TLC: Rf 0.40(hexane:AcOEt=1:1);
[0537] MS (El): m/z 340 (M.sup.+).
EXAMPLE 1(6)
1-(5-hydroxy-1-naphthyl)methylsulfinyl-3-phenoxy-2RS-propanol
[0538] 258
[0539] By using the compound prepared in Reference Example 27, the
present invention compound having the following physical data was
obtained by the same procedure as Example 1.
[0540] TLC: Rf 0.42 (AcOEt);
[0541] MS (El): m/z 356 (M.sup.+).
EXAMPLE 1(7)
1-(5-hydroxy-1-naphthyl)methylsulfonyl-3-phenoxy-2RS-propanol
[0542] 259
[0543] By using the compound prepared in Reference Example 28, the
present invention compound having the following physical data was
obtained by the same procedure as Example 1.
[0544] TLC: Rf 0.24 (hexane:AcOEt=1:1);
[0545] MS (El): m/z 372 (M.sup.+).
EXAMPLE 1(8)
2-[3-(5-hydroxy-1-naphthyl)propylthio]-1-phenyl-1 RS-ethanol
[0546] 260
[0547] By using the compound prepared in Reference Example 25, the
present invention compound having the following physical data was
obtained by the same procedure as Example 1.
[0548] TLC: Rf 0.33 (hexane:AcOEt=2:1);
[0549] MS (El): m/z 338 (M.sup.+).
EXAMPLE 1(9)
2-[3-(5-hydroxy-1-naphthyl)propylsulfinyl]-1-phenyl-1
RS-ethanol
[0550] 261
[0551] By using the compound prepared in Reference Example 27(2),
the present invention compound having the following physical data
was obtained by the same procedure as Example 1.
[0552] TLC: Rf 0.34 (AcOEt);
[0553] MS (El): m/z 354 (M.sup.+).
EXAMPLE 1(10)
2-[3-(5-hydroxy-1-naphthyl)propylsulfonyl]-1-phenyl-1
RS-ethanol
[0554] 262
[0555] By using the compound prepared in Reference Example 28(2),
the present invention compound having the following physical data
was obtained by the same procedure as Example 1.
[0556] TLC: Rf 0.10 (hexane:AcOEt=2:1);
[0557] MS (El): m/z 370 (M.sup.+).
EXAMPLE 1(11)
1-(5-hydroxy-1-naphthyl)thio-3-phenoxy-2RS-propanol
[0558] 263
[0559] By using the compound prepared in Reference Example 29, the
present invention compound having the following physical data was
obtained by the same procedure as Example 1.
[0560] TLC: Rf 0.40 (hexane:AcOEt=1:1);
[0561] MS (El): m/z 326 (M.sup.+).
EXAMPLE 1(12)
1-(5-hydroxy-1-naphthyl)sulfinyl-3-phenoxy-2RS-propanol
[0562] 264
[0563] By using the compound prepared in Reference Example 29(1),
the present invention compound having the following physical data
was obtained by the same procedure as Example 1.
[0564] TLC: Rf 0.24 (hexane:AcOEt=1:1);
[0565] MS (El): m/z 342 (M.sup.+).
EXAMPLE 1(13)
1-(5-hydroxy-1-naphthyl)sulfonyl-3-phenoxy-2RS-propanol
[0566] 265
[0567] By using the compound prepared in Reference Example 29(2),
the present invention compound having the following physical data
was obtained by the same procedure as Example 1.
[0568] TLC: Rf 0.26 (hexane:AcOEt=1:1);
[0569] MS (El): m/z 358 (M.sup.+).
EXAMPLE 2
2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}acetic
Acid Methyl Ester
[0570] 266
[0571] To a solution of the compound prepared in Example 1 (4.54 g)
in acetone (25 ml), potassium carbonate (2.66 g) and bromoacetic
acid methyl ester (1.46 ml) were added. The mixture was stirred
overnight. Ethyl acetate (25 ml) was added to the reaction mixture.
The mixture was filtrated. The filtrate was concentrated. The
residue was purified on silica gel column chromatography
(hexane:AcOEt=7:3) to give the present invention compound (4.95 g)
having the following physical data.
[0572] TLC: Rf 0.46(AcOEt:benzene=3:17);
[0573] MS (APCI): m/z 409 (M.sup.++1-H.sub.2O).
EXAMPLE 2(1)
2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfinyl)ethyl]-1-naphthyloxy}acetic
Acid Methyl Ester
[0574] 267
[0575] By using the compound prepared in Example 1(1), the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0576] TLC: Rf 0.36 (hexane:AcOEt=1:1);
[0577] MS (El): m/z 442 (M.sup.+).
EXAMPLE 2(2)
2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfonyl)ethyl]-1-naphthyloxy}acetic
Acid Methyl Ester
[0578] 268
[0579] By using the compound prepared in Example 1(2), the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0580] TLC: Rf 0.40 (hexane:AcOEt=1:1);
[0581] MS (El): m/z 458 (M.sup.+).
EXAMPLE 2(3)
2-{5-[2-(2R-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}acetic
Acid Methyl Ester
[0582] 269
[0583] By using the compound prepared in Example 1(3), the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0584] TLC: Rf 0.46 (AcOEt:benzene=3:17);
[0585] MS (APCI): m/z 409 (M.sup.++1-H.sub.2O).
EXAMPLE 2(4)
2-{5-[2-(2S-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}acetic
Acid Methyl Ester
[0586] 270
[0587] By using the compound prepared in Example 1(4), the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0588] TLC: Rf 0.46 (AcOEt:benzene=3:17);
[0589] MS (APCI): m/z 409 (M.sup.++1-H.sub.2O).
EXAMPLE 2(5)
2-[5-(2RS-hydroxy-3-phenoxypropylthio)methyl-1-naphthyloxy]acetic
Acid Methyl Ester
[0590] 271
[0591] By using the compound prepared in Example 1(5), the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0592] TLC: Rf 0.30 (AcOEt:benzene=3:17);
[0593] MS (El): m/z 412 (M.sup.+).
EXAMPLE 2(6)
2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)methyl-1-naphthyloxy]acetic
Acid Methyl Ester
[0594] 272
[0595] By using the compound prepared in Example 1(6), the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0596] TLC: Rf 0.22 (AcOEt);
[0597] MS (El): m/z 412 (M.sup.+-O).
EXAMPLE 2(7)
2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)methyl-1-naphthyloxy]acetic
Acid Methyl Ester
[0598] 273
[0599] By using the compound prepared in Example 1(7), the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0600] TLC: Rf 0.18(AcOEt:benzene=1:4);
[0601] MS (El): m/z 444 (M.sup.+).
EXAMPLE 2(8)
2-{5-[3-(2RS-hydroxy-2-phenylethylthio)propyl]-1-naphthyloxy}acetic
Acid Methyl Ester
[0602] 274
[0603] By using the compound prepared in Example 1(8), the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0604] TLC: Rf 0.35 (hexane:AcOEt=2:1);
[0605] MS (El): m/z 410 (M.sup.+).
EXAMPLE 2(9)
2-{5-[3-(2RS-hydroxy-2-phenylethylsulfinyl)propyl]-1-naphthyloxy}acetic
Acid Methyl Ester
[0606] 275
[0607] By using the compound prepared in Example 1(9), the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0608] TLC: Rf 0.36 (AcOEt);
[0609] MS (El): m/z 426 (M.sup.+).
EXAMPLE 2(10)
2-{5-[3-(2RS-hydroxy-2-phenylethylsulfonyl)propyl]-1-naphthyloxy}acetic
Acid Methyl Ester
[0610] 276
[0611] By using the compound prepared in Example 1(10), the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0612] TLC: Rf 0.10 (hexane:AcOEt=2:1);
[0613] MS (El): m/z 442 (M.sup.+).
EXAMPLE 2(11)
2-[5-(2RS-hydroxy-3-phenoxypropylthio)-1-naphthyloxy]acetic Acid
Methyl Ester
[0614] 277
[0615] By using the compound prepared in Example 1(11), the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0616] TLC: Rf 0.42 (hexane:AcOEt=1:1);
[0617] MS (El): m/z 398 (M.sup.+).
EXAMPLE 2(12)
2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)-1-naphthyloxy]acetic
Acid Methyl Ester
[0618] 278
[0619] By using the compound prepared in Example 1(12), the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0620] TLC: Rf 0.29 (hexane:AcOEt=1:1);
[0621] MS (El): m/z 414 (M.sup.+).
EXAMPLE 2(13)
2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)-1-naphthyloxy]acetic
Acid Methyl Ester
[0622] 279
[0623] By using the compound prepared in Example 1(13), the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0624] TLC: Rf 0.31 (hexane:AcOEt=1:1);
[0625] MS (El): m/z 430 (M.sup.+).
EXAMPLE 3
2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}acetic
Acid
[0626] 280
[0627] To a solution of the compound prepared in Example 2 (4.80 g)
in dimethoxyethane-methanol (30 ml-15 ml), 2N aqueous solution of
sodium hydroxide (8 ml) was added at 0.degree. C. The mixture was
stirred for 1 hour at 0.degree. C. 2N aqueous solution of
hydrochloric acid (8.5 ml) was added to the reaction solution in
order to be neutralized. The mixture was extracted with ethyl
acetate. The organic layer was washed with a saturated aqueous
solution of sodium chloride, dried over with anhydrous magnesium
sulfate and concentrated. The residue was recrystalized from
AcOEt-hexane to give the present invention compound (4.07 g) having
the following physical data.
[0628] TLC: Rf 0.22 (CHCl.sub.3:MeOH=15:1);
[0629] MS (El): m/z 412 (M.sup.+);
[0630] NMR (DMSO-d6): .delta.8.25 (1H, d, J=8 Hz), 7.71 (1H, d, J=8
Hz), 7.50-7.16 (5H, m), 7.02-6.69 (4H, m), 4.78 (2H, s), 4.24-4.38
(7H, m), 2.90-2.53 (2H, m).
EXAMPLE 3(1)
2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfinyl)ethyl]-1-naphthyloxy}acetic
Acid
[0631] 281
[0632] By using the compound prepared in Example 2(1), the present
invention compound having the following physical data was obtained
by the same procedure as Example 3.
[0633] TLC: Rf 0.26 (CHCl.sub.3:MeOH=15:1);
[0634] MS (El): m/z 428 (M.sup.+)
[0635] NMR (DMSO-d6): .delta.8.42 (1H, d, J=8 Hz), 7.73 (1H, d, J=8
Hz), 7.60-7.21 (5H, m), 6.98-6.82 (4H, m), 4.81 (2H, s), 4.76-4.38
(6H, m), 4.06-3.97 (1H, m), 2.90-2.53 (2H, m).
EXAMPLE 3(2)
2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfonyl)ethyl]-1-naphthyloxy}acetic
Acid
[0636] 282
[0637] By using the compound prepared in Example 2(2), the present
invention compound having the following physical data was obtained
by the same procedure as Example 3.
[0638] TLC: Rf 0.18 (CHCl.sub.3:MeOH=15:1);
[0639] MS (El): m/z 444 (M.sup.+), 404, 167, 115;
[0640] NMR (DMSO-d6): .delta.8.22 (1H, d, J=8 Hz), 7.59 (1H, d, J=8
Hz), 7.42 7.14 (7H, m), 6.89-6.66 (2H, m), 4.78 (2H, s), 4.24-3.88
(7H, m), 2.90-2.53 (2H, m).
EXAMPLE 3(3)
2-{5-[2-(2R-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}acetic
Acid
[0641] 283
[0642] By using the compound prepared in Example 2(3), the present
invention compound having the following physical data was obtained
by the same procedure as Example 3.
[0643] TLC: Rf 0.26 (CHCl.sub.3:MeOH:AcOH=19:1:0.1);
[0644] MS (APCI): m/z 411 (M.sup.+-1), 353;
[0645] m.p. 114.0-115.5.degree. C.
[0646] NMR (DMSO-d6): .delta.8.20-8.10 (1H, m), 7.64 (1H, d, J=8.6
Hz), 7.50-7.35 (3H, m), 7.35-7.20 (2H, m), 7.00-6.85 (4H, m), 5.25
(1H, br.), 4.87 (2H, s), 3.96 (3H, m), 3.37-3.22 (2H, m), 2.98-2.65
(4H, m).
EXAMPLE 3(4)
2-{5-[2-(2S-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}acetic
Acid
[0647] 284
[0648] By using the compound prepared in Example 2(4), the present
invention compound having the following physical data was obtained
by the same procedure as Example 3.
[0649] TLC: Rf 0.26 (CHCl.sub.3:MeOH:AcOH=19:1:0.1);
[0650] MS (APCI): m/z 411 (M.sup.+-1), 353;
[0651] m.p. 114.0-115.5.degree. C.;
[0652] NMR (DMSO-d6): .delta.8.20-8.10 (1H, m), 7.64 (1H, d, J=8.6
Hz), 7.50-7.35 (3H, m), 7.35-7.20 (2H, m), 7.00-6.85 (4H, m), 5.25
(1H, br.), 4.87 (2H, s), 3.96 (3H, m), 3.37-3.22 (2H, m), 2.98-2.65
(4H, m).
EXAMPLE 3(5)
2-[5-(2RS-hydroxy-3-phenoxypropylthio)methyl-1-naphthyloxy]acetic
Acid
[0653] 285
[0654] By using the compound prepared in Example 2(5), the present
invention compound having the following physical data was obtained
by the same procedure as Example 3.
[0655] TLC: Rf 0.21 (MeOH:CHCl.sub.3=3:7);
[0656] MS (El): m/z 398 (M.sup.+)
[0657] m.p. 105-107.degree. C.
[0658] NMR (DMSO-d6+CDCl.sub.3): .delta.8.32 (1H, d, J=8 Hz), 7.75
(1H, d, J=8 Hz), 7.58-7.14 (5H, m), 7.00-6.70 (4H, m), 4.78 (2H, s,
CH.sub.2COO), 4.60-3.80 (7H, m), 2.87-2.60 (2H, m).
EXAMPLE 3(6)
2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)methyl-1-naphthyloxy]acetic
Acid
[0659] 286
[0660] By using the compound prepared in Example 2(6), the present
invention compound having the following physical data was obtained
by the same procedure as Example 3.
[0661] TLC: Rf 0.16 (MeOH:CHCl.sub.3=3:7);
[0662] MS (El): m/z 414 (M.sup.+), 396 (M.sup.+R-H.sub.2O);
[0663] NMR (CD.sub.3OD+CDCl.sub.3): .delta.8.45 (1H, d, J=8 Hz),
7.73 (1H, d, J=8 Hz), 7.62-7.38 (3H, m), 7.34-7.19 (2H, m),
7.00-6.82 (4H, m), 5.05-4.40 (5H, m), 4.08-3.96 (2H, m), 3.44-3.05
(2H, m).
EXAMPLE 3(7)
2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)methyl-1-naphthyloxy]acetic
Acid
[0664] 287
[0665] By using the compound prepared in Example 2(,7), the present
invention compound having the following physical data was obtained
by the same procedure as Example 3.
[0666] TLC: Rf 0.17 (MeOH:CH.sub.2Cl.sub.2=1:5);
[0667] MS (El): m/z 430 (M.sup.+)
[0668] m.p. 186-190.degree. C.
[0669] NMR (CD.sub.3OD+CDCl.sub.3): .delta.8.48 (1H, d, J=8 Hz),
7.82 (1H, d, J=8 Hz), 7.70 (1H, d, J=7 Hz), 7.63-7.40 (2H, m),
7.40-7.22 (2H, m), 7.10-6.77 (4H, m), 5.02 (1H, d, J=15 Hz), 4.92
(1H, d, J=15 Hz), 4.81 (2H, s), 4.75-4.54 (1H, m), 4.20-3.70 (2H,
m), 3.40-3.33 (1H, m), 3.33-3.15 (1H, m).
EXAMPLE 3(8)
2-{5-[3-(2RS-hydroxy-2-phenylethylthio)propyl]-1-naphthyloxy}acetic
Acid
[0670] 288
[0671] By using the compound prepared in Example 2(8), the present
invention compound having the following physical data was obtained
by the same procedure as Example 3.
[0672] TLC: Rf 0.13 (MeOH:CH.sub.2Cl.sub.2=1:5);
[0673] MS (El): m/z 396 (M.sup.+), 290, 276;
[0674] NMR (DMSO-d6): .delta.14.00-12.40 (1H, br), 8.12 (1H, d, J=8
Hz), 7.65 (1H, d, J=8 Hz), 7.50-7.16 (8H, m), 6.88 (1H, d, J=7 Hz),
5.47 (1H, m), 4.87 (2H, s), 4.63 (1H, m), 3.06 (2H, m), 2.75 (2H,
m), 2.60-2.40 (2H, m),1.87 (2H, m).
EXAMPLE 3(9)
2-[5-(2RS-hydroxy-3-phenoxypropylthio)-1-naphthyloxy]acetic
Acid
[0675] 289
[0676] By using the compound prepared in Example 2(11), the present
invention compound having the following physical data was obtained
by the same procedure as Example 3.
[0677] TLC: Rf 0.25 (MeOH:CH.sub.2Cl.sub.2=1:5);
[0678] MS (El): m/z 384 (M.sup.+);
[0679] NMR (DMSO-d6): .delta.8.68 (1H, d, J=4 Hz), 8.43 (1H, d, J=8
Hz), 8.40 (1H, d, J=8 Hz), 7.81 (1H, t, J=4 Hz), 7.66 (1H, d, J=4
Hz), 7.61-7.28 (3H, m), 7.01-6.90 (3H, m), 4.92-4.79 (1H, m), 4.87
(2H, s), 4.21-3.83 (4H, m).
EXAMPLE 3(10)
2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)-1-naphthyloxy]acetic
Acid
[0680] 290
[0681] By using the compound prepared in Example 2(12), the present
invention compound having the following physical data was obtained
by the same procedure as Example 3.
[0682] TLC: Rf 0.29 (MeOH:CH.sub.2Cl.sub.2=1:5);
[0683] MS (El): m/z 401 (M.sup.++1)
[0684] NMR (DMSO-d6): .delta.8.68 (1H, d, J=4 Hz), 8.43 (1H, d, J=8
Hz), 8.40 (1H, d, J=8 Hz), 7.81 (1H, t, J=4 Hz), 7.66 (1H, d, J=4
Hz), 7.61-7.28 (3H, m), 7.01-6.90 (3H, m), 4.92-4.79 (1H, m), 4.87
(2H, s), 4.21-3.83 (4H, m).
EXAMPLE 3(11)
2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)-1-naphthyloxy]acetic
Acid
[0685] 291
[0686] By using the compound prepared in Example 2(13), the present
invention compound having the following physical data was obtained
by the same procedure as Example 3.
[0687] TLC: Rf 0.22 (MeOH:CH.sub.2Cl.sub.2=1:5);
[0688] MS (El): m/z 416 (M.sup.+);
[0689] NMR (DMSO-d6): .delta.8.68 (1H, d, J=4 Hz), 8.43 (1H, d, J=8
Hz), 8.40 (1H, d, J=8 Hz), 7.81 (1H, t, J=4 Hz), 7.66 (1H, d, J=4
Hz), 7.61-7.28 (3H, m), 7.01-6.90 (3H, m), 4.92-4.79 (1H, m), 4.87
(2H, s), 4.21-3.83 (4H, m).
EXAMPLE 4
2-[5-(3-styrylsulfonylpropyl)-1-naphthyloxy]acetic Acid Methyl
Ester
[0690] 292
[0691] To a solution of the compound prepared in Example 2(10) (96
mg) in methylene chloride (10 ml), triethylamine (0.091 ml) and
mesylchloride (37.3 ml) were added at 0.degree. C. The mixture was
heated to room temperature and stirred for 30 minutes. Water was
added to the reaction mixture. The mixture was extracted with ethyl
acetate. The organic layer was washed with water and a saturated
aqueous solution of sodium chloride, dried over with anhydrous
sodium sulfate and concentrated. The residue was purified on silica
gel column chromatography (hexane:AcOEt=2:1) to give the present
invention compound (94 mg) having the following physical data.
[0692] TLC: Rf 0.18 (hexane:AcOEt=2:1);
[0693] MS (El): m/z 424 (M.sup.+).
EXAMPLE 4(1)
2-[5-(3-styrylsulfinylpropyl)-1-naphthyloxy]acetic Acid Methyl
Ester
[0694] 293
[0695] By using the compound prepared in Example 2(9), the present
invention compound having the following physical data was obtained
by the same procedure as Example 4.
[0696] TLC: Rf 0.50 (benzene:AcOEt=1:2);
[0697] MS (El): m/z 408 (M.sup.+).
EXAMPLE 5
2-[5-(3-styrylsulfinylpropyl)-1-naphthyloxy]acetic Acid
[0698] 294
[0699] By using the compound prepared in Example 4(1), the present
invention compound having the following physical data was obtained
by the same procedure as Example 3.
[0700] TLC: Rf 0.23(MeOH:CH.sub.2Cl.sub.2=1:5);
[0701] MS (El): m/z 394 (M.sup.+), 378, 320, 242,183;
[0702] NMR (CDCl.sub.3--CD.sub.3OD): .delta.8.38 (0.13H, dd, J=8, 2
Hz), 8.30 (0.87H, d, J=8 Hz), 7.64-7.20 (10H, m), 6.82-6.67 (1.87H,
m), 6.61 (0.13H, d, J=8 Hz), 4.77 (1.74H, s), 4.75 (0.26H, s),
3.30-3.03 (4H, m), 2.40-2.15 (2H, m).
EXAMPLE 5(1)
2-[5-(3-styrylsulfonylpropyl)-1-naphthyloxy]acetic Acid
[0703] 295
[0704] By using the compound prepared in Example 4, the present
invention compound having the following physical data was obtained
by the same procedure as Example 5.
[0705] TLC: Rf 0.26 (MeOH:CH.sub.2Cl.sub.2=1:5);
[0706] MS (El): m/z 410 (M.sup.+), 378, 352, 276, 253, 242,
215;
[0707] NMR (CDCl.sub.3): .delta.8.26 (1H, d, J=8 Hz), 7.57 (1H, d,
J=9 Hz), 7.50-7.13 (9H, m), 7.13-6.40 (1H, br), 6.79 (1H, d, J=15
Hz), 6.65 (1H, d, J=7 Hz), 4.75 (2H, s), 3.19 (2H, t, J=8 Hz), 2.90
(2H, t, J=8 Hz), 2.22 (2H, m).
EXAMPLE 6
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-(4-chlorophenoxy)-2RS-propanol
[0708] 296
[0709] By using 4-chlorophenol instead of phenol in Reference
Example 2, the present invention compound having the following
physical data was obtained by the same procedure as Reference
Example 2.fwdarw.Reference Example 3.fwdarw.Reference Example
4.fwdarw.Reference Example 5.fwdarw.Reference Example
24.fwdarw.Example 1.
[0710] TLC: Rf 0.34 (hexane:AcOEt=2:1);
[0711] MS (APCI): m/z 389, 387 (1:3, M--H.sup.+);
[0712] NMR (CDCl.sub.3): .delta.8.12 (1H, d, J=7.4 Hz), 7.58 (1H,
d, J=8.4 Hz), 7.38 (3H, m), 7.22 (2H, d, J=6.8 Hz), 6.82 (2H, d,
J=6.8 Hz), 6.82 (1H, m), 5.32 (1H, s), 4.07 (1H, m), 3.96 (2H, m),
3.35 (2H, m), 2.96 (2H, m), 2.86 (1H, dd, J=14, 5 Hz), 2.74 (1H,
dd, J=14, 6.8 Hz), 2.66 (1H, d, J=3.4 Hz).
EXAMPLE 6(1)
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-(4-methylphenoxy)-2RS-propanol
[0713] 297
[0714] By using 4-methylphenol instead of phenol in Reference
Example 2, the present invention compound having the following
physical data was obtained by the same procedure as Example 6.
[0715] TLC: Rf 0.35 (hexane:AcOEt=2:1);
[0716] NMR (CDCl.sub.3): .delta.8.11 (1H, d, J=8.4 Hz), 7.58 (1H,
d, J=8.6 Hz), 7.37 (3H, m), 7.07 (2H, d, J=8 Hz), 6.82 (1H, d,
J=7.4 Hz), 6.80 (2H, d, J=8 Hz), 5.39 (1H, s), 4.08 (1H, m), 4.00
(2H, m), 3.35 (2H, m), 2.95 (2H, m), 2.91 (1H, dd, J=13.6, 5.2 Hz),
2.46 (1H, dd, J=13.6, 6.8 Hz), 2.70 (1H, d, J=4 Hz), 2.29 (3H,
s).
EXAMPLE 6(2)
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-(4-methoxyphenoxy)-2RS-propanol
[0717] 298
[0718] By using 4-metyhoxyphenol instead of phenol in Reference
Example 2, the present invention compound having the following
physical data was obtained by the same procedure as Example 6.
[0719] TLC: Rf 0.55 (hexane:AcOEt=2:1).
EXAMPLE 6(3)
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-diphenylmethoxy-2RS-propanol
[0720] 299
[0721] By using diphenylmethanol instead of phenol in Reference
Example 2, the present invention compound having the following
physical data was obtained by the same procedure as Example 6.
[0722] TLC: Rf 0.29 (hexane:AcOEt=2:1);
[0723] NMR (CDCl.sub.3): .delta.8.11(1H, m), 7.57 (1H, d, J=8.6
Hz), 7.34 (13H, m), 6.81 (1H, d, J=7.4 Hz), 5.43 (1H, s), 5.38 (1H,
s), 3.96 (1H, m), 3.52 (2H, d, J=5.6 Hz), 3.31 (2H, m), 2.91 (2H,
m), 2.80 (1H, dd, J=5.3, 13.6 Hz), 2.69 (1H, dd, J=7.2, 13.6 Hz),
2.67 (1H, d, J=4.3 Hz).
EXAMPLE 6(4)
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-[1-phenyl-1-(4-chlorophenyl)methox-
y]-2RS-propanol
[0724] 300
[0725] By using 1-phenyl-1-(4-chlorophenyl)methanol instead of
phenol in Reference Example 2, the present invention compound
having the following physical data was obtained by the same
procedure as Example 6.
[0726] TLC: Rf 0.35 (hexane:AcOEt=2:1);
[0727] NMR (CDCl.sub.3): .delta.8.12 (1H, d, J=9.1 Hz), 7.57 (1H,
d, J=8.4 Hz), 7.33 (12H, m), 6.82 (1H, d, J=7.5 Hz), 5.40 (1H, m),
5.35 (1H, s), 3.94 (1H, m), 3.50 (2H, d, J=4.8 Hz), 3.32 (2H, m),
2.91 (2H, m), 2.73 (3H, m).
EXAMPLE 6(5)
1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenylthio-2RS-propanol
[0728] 301
[0729] By using thiophenol instead of phenol in Reference Example
2, the present invention compound having the following physical
data was obtained by the same procedure as Example 6.
[0730] TLC: Rf 0.41 (hexane:AcOEt=2:1).
EXAMPLE 6(6)
1-(5-hydroxy-1-naphthyl)methylthio-3-diphenylmethoxy-2RS-propanol
[0731] 302
[0732] By using diphenylmethanol instead of phenol in Reference
Example 2, the present invention compound having the following
physical data was obtained by the same procedure as Reference
Example 2 .fwdarw.Reference Example 3.fwdarw.Reference Example
4.fwdarw.Reference Example 5.fwdarw.Reference Example
24(3).fwdarw.Example 1.
[0733] TLC: Rf 0.17 (acetone:benzene=1:19);
[0734] NMR (CDCl.sub.3): .delta.8.15 (1H, dd, J=3.0, 6.6 Hz), 7.69
(1H, d, J=8.6 Hz), 7.32 (13H, m), 6.82 (1H, d, J=7.3 Hz), 5.50 (1H,
s), 5.35 (1H, s), 4.17 (2H, s), 3.94 (1H, m), 3.48 (1H, d, J=5.2
Hz), 2.55-2.77 (3H, m).
EXAMPLE 6(7)
1-(5-hydroxy-1-naphthyl)methylthio-3-[1-phenyl-1-(4-chlorophenyl)methoxy]--
2RS-propanol
[0735] 303
[0736] By using 1-phenyl-1-(4-chlorophenyl)methanol instead of
phenol in Reference Example 2, the present invention compound
having the following physical data was obtained by the same
procedure as Example 6(6).
[0737] TLC: Rf 0.28 (hexane:AcOEt=2:1);
[0738] NMR (CDCl.sub.3): .delta.8.16 (1H, dd, J=3.3, 6.3 Hz), 7.69
(1H, d, J=9.5 Hz), 7.29 (12H, m), 6.83 (1H, d, J=7.4 Hz), 5.41 (1H,
s), 5.30 (1H, s), 4.17 (2H, s), 3.91 (1H, m), 3.45 (2H, d, J=5.2
Hz), 2.71 (1H, dd, J=5.2, 13.8 Hz), 2.63 (1H, dd, J=2.3, 7.2 Hz),
2.57 (1H, d, J=4.1 Hz).
REFERENCE EXAMPLE 30
[0739] 304
[0740] To the suspension of sodium hydride (42 mg) in DMF (1 ml),
the solution of the compound prepared in Reference Example 15 (232
mg) in DMF (2 ml) was added at room temperature. To the mixture,
THF (1 ml) and hexamethylphosphoramide (0.2 ml) were added at room
temperature. The mixture was stirred for 30 minutes at room
temperature and for 30 minutes at 40.degree. C. To the mixture, the
solution of the compound prepared in Reference Example 5 (406 mg)
in DMF (2 ml) was added at room temperature. The mixture was
stirred for 6 hours at 50.degree. C. The reaction mixture was added
to the aqueous solution of ammonium chloride, extracted with
diethylether. The organic layer was washed with water and a
saturated aqueous solution of sodium chloride, dried over with
anhydrous sodium sulfate and concentrated. The residue was purified
on silica gel column chromatography (hexane:AcOEt=87:13) to give
the title compound (54.8 mg) having the following physical
data.
[0741] TLC: Rf 0.37 (hexane:AcOEt=3:1);
[0742] NMR (CDCl.sub.3): .delta.8.18 (1H, m), 7.68 (1H, d, J=8 Hz),
7.45-7.20 (5H, m), 7.09 (1H, d, J=8 Hz),7.01-6.83 (3H, m), 5.39
(2H, s), 4.88-4.72 (1H, m), 4.25-3.26 (14H, m), 1.90-1.40 (6H,
m).
REFERENCE EXAMPLE 31
[0743] 305
[0744] To the solution of the compound prepared in Reference
Example 15 (5.0 g) in pyridine (15 ml), tosylchloride (6.28 g) was
added at -20.degree. C. The mixture was stirred for 2 hours at room
temperature. The water (2 ml) was added dropwise to the mixture to
decompose superfluous tosylchloride. To the mixture, 2N aqueous
solution of hydrochloric acid (80 ml) was added. The mixture was
extracted with ethyl acetate. The organic layer was washed with
water and a saturated aqueous solution of sodium chloride, dried
over with anhydrous sodium sulfate and concentrated to obtain crude
tosyl compound. The tosyl compound was dissolved in acetone (25
ml). To the solution, sodium azide (2.8 g) and tetrabutylammonium
bromide (400 mg) were added. The solution was refluxed over night.
To the solution, sodium azide (2.8 g) was added. The solution was
refluxed for 4 hours and cooled. The solvent was distilled off. The
residue was diluted with ethyl acetate, washed with water and a
saturated aqueous solution of sodium chloride, dried over with
anhydrous sodium sulfate and concentrated to give the title
compound (5.38 g) having the following physical data.
[0745] TLC: Rf 0.52 (hexane:AcOEt=7:3).
REFERENCE EXAMPLE 32
[0746] 306
[0747] To the solution of the compound prepared in Reference
Example 31 (1.56 g) in ethyl acetate (20 ml), 5% Pd--C (50 mg) was
added. The mixture was stirred under an atmosphere of H.sub.2 gas
for 5 hours at room temperature. The solution was filtrated by
Celite (Registered trade mark). The filtrate was concentrated and
purified on silica gel column chromatography
(MeOH:CHCl.sub.3=3:97.fwdarw.MeOH:CHCl.sub.3:propylamine=1- 0:90:1)
to give the title compound (1.02 g) having the following physical
data.
[0748] TLC: Rf 0.17 (MeOH:CHCl.sub.3=1:3);
[0749] NMR (CDCl.sub.3): .delta.8.20 (1H, m), 7.69 (1H, d, J=8 Hz),
7.48-7.27 (3H, m), 7.11 (1H, d, J=8 Hz), 5.40 (2H, s), 3.53 (3H,
s), 3.27-3.04 (4H, m), 1.35 (2H, brs, NH.sub.2).
REFERENCE EXAMPLE 33
[0750] 307
[0751] The solution of the compound prepared in Reference Example
32 (300 mg) and (.+-.)-1,2-epoxy-3-phenoxypropane (195 mg) in
iso-propanol (3 ml) was stirred for 2 days at room temperature. The
reaction mixture was concentrated. The residue was purified on
silica gel column chromatography (MeOH:CHCl.sub.3=3:97.fwdarw.1:9)
to give the title compound (270 mg) having the following physical
data.
[0752] TLC: Rf 0.26 (MeOH:CHCl.sub.3=1:9);
[0753] NMR (CDCl.sub.3): .delta.8.22 (1H, m), 7.71 (1H, d, J=8 Hz),
7.47-7.21 (5H, m), 7.11 (1H, d, J=8 Hz), 6.99-6.84 (3H, m), 5.40
(2H, s), 4.15-3.92 (3H, m), 3.55 (3H, s), 3.20 (2H, t, J=8 Hz),
3.13-2.76 (4H, m), 2.53 (2H, brs, OH & NH).
EXAMPLE 7
1-[2-(5-hydroxy-1-naphthyl)ethoxy]-3-phenoxy-2RS-propanol
[0754] 308
[0755] By using the compound prepared in Reference Example 30, the
present invention compound having the following physical data was
obtained by the same procedure as Example 1.
[0756] TLC: Rf 0.18 (hexane:AcOEt=2:1);
[0757] NMR (CDCl.sub.3): .delta.8.11 (1H, m), 7.63 (1H, d, J=8 Hz),
7.46-7.21 (5H, m), 7.02-6.77 (4H, m), 5.49 (1H, s), 4.14 (1H, m),
3.96 (2H, d, J=5 Hz), 3.85 (2H, t, J=7 Hz), 3.63 (2H, m), 3.35 (2H,
t, J=7 Hz), 2.48 (1H, d, J=4 Hz).
EXAMPLE 7(1)
1-[2-(5-hydroxy-1-naphthyl)ethylamino]-3-phenoxy-2RS-propanol
[0758] 309
[0759] By using the compound prepared in Reference Example 33, the
present invention compound having the following physical data was
obtained by the same procedure as Example 1.
[0760] TLC: Rf 0.10 (MeOH:CHCl.sub.3=1:9);
[0761] NMR (CDCl.sub.3+DMSO 1:4): .delta.8.15 (1H, m), 7.54 (1H, d,
J=8 Hz), 7.40-7.20 (5H, m), 7.00-6.84 (4H, m), 4.16-3.90 (3H, m),
3.80-2.50 (3H, br), 3.29 (2H, t, J=7 Hz), 3.14-2.75 (4H, m).
REFERENCE EXAMPLE 34
[0762] 310
[0763] The mixture of the compound prepared in Example 7(1) (150
mg), trifluoroacetic acid ethyl ester (1 ml), triethylamine (0.5
ml) and ethanol (3 ml) was stirred for 5 hours at room temperature.
The reaction mixture was concentrated and purified on silica gel
column chromatography (hexane:AcOEt=5:2) to give the title compound
(155 mg) having the following physical data.
[0764] TLC: Rf 0.53 (hexane:AcOEt=1:1);
[0765] NMR (CDCl.sub.3): rotational isomer, .delta.8.21-8.10 (1H,
m), 7.38 and 7.53 (combined 1H, each d, J=8 Hz), 7.48-7.20 (5H, m),
7.04-6.89 (4H, m), 5.53 (1H, brs), 4.40-3.27 (9H, m), 3.10 and 2.40
(combined 1H, each m). EXAMPLE 8
2-{5-[2-(2RS-hydroxy-3-(4-chlorophenoxy)propylthio)ethyl]-1-naphthyloxy}-a-
cetic Acid Methyl Ester
[0766] 311
[0767] By using the compound prepared in Example 6, the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0768] TLC: Rf 0.27 (acetone:benzene=1:19);
[0769] NMR (CDCl.sub.3): .delta.8.30 (1H, d, J=7.4 Hz), 7.62 (1H,
d, J=8.6 Hz), 7.41 (3H, m), 7.22 (2H, d, J=9 Hz), 6.82 (2H, d, J=9
Hz), 6.72 (1H, d, J=7.4 Hz), 4.83 (2H, s), 4.06 (1H, m), 3.96 (2H,
m), 3.04 (3H, s), 3.35 (2H, m), 2.95 (2H, m), 2.84 (1H, dd, J=14, 5
Hz), 2.73 (1H, dd, J=14, 7 Hz), 2.65 (1H, d, J=4 Hz).
EXAMPLE 8(1)
2-{5-[2-(2RS-hydroxy-3-(4-methylphenoxy)propylthio)ethyl]-1-naphthyloxy}-a-
cetic Acid Methyl Ester
[0770] 312
[0771] By using the compound prepared in Example 6(1), the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0772] TLC: Rf 0.37 (acetone:benzene=1:19);
[0773] NMR (CDCl.sub.3): .delta.8.29 (1H, d, J=8 Hz), 7.64 (1H, d,
J=8.8 Hz), 7.39 (3H, m), 7.07 (2H, d, J=8.8 Hz), 6.80 (2H, d, J=8.8
Hz), 6.72 (1H, d, J=8.8 Hz), 4.82 (2H, s), 4.08 (1H, m), 3.98 (2H,
m), 3.83 (3H, s), 3.45 (2H, t, J=8.6 Hz), 2.94 (2H, t, J=8.6 Hz),
2.88 (2H, dd, J=14, 5.2 Hz), 7.75 (2H, dd, J=14, 6.8 Hz), 2.68 (1H,
d, J=4 Hz), 2.29 (3H, s).
EXAMPLE 8(2)
2-{5-[2-(2RS-hydroxy-3-(4-methoxyphenoxy)propylthio)ethyl]-1-naphthyloxy}--
acetic Acid Methyl Ester
[0774] 313
[0775] By using the compound prepared in Example 6(2), the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0776] TLC: Rf 0.41 (acetone:benzene=1:9);
[0777] NMR (CDCl.sub.3): .delta.8.30 (1H, d, J=7.8 Hz), 7.63 (1H,
d, J=8.6 Hz), 7.41 (3H, m), 6.83 (4H, s), 6.72 (1H, d, J=8.6 Hz),
4.82 (2H, s), 4.05 (1H, m), 3.96 (2H, m), 3.83 (3H, s), 3.77 (3H,
s), 3.34 (2H, t, J=6.6 Hz), 2.93 (2H, t, J=6.6 Hz), 2.88 (1H, dd,
J=14, 5 Hz), 2.75 (1H, dd, J=14, 7.2 Hz), 2.69 (1H, d, J=4 Hz).
EXAMPLE 8(3)
2-{5-[2-(2RS-hydroxy-3-diphenylmethoxypropylthio)ethyl]-1-naphthyloxy}-ace-
tic Acid Methyl Ester
[0778] 314
[0779] By using the compound prepared in Example 6(3), the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0780] TLC: Rf 0.33 (acetone:benzene=1:19);
[0781] NMR (CDCl.sub.3): .delta.8.29 (1H, m), 7.62 (1H, d, J=8.6
Hz), 7.33 (13H, m), 6.72 (1H, d, J=7.7 Hz), 5.39 (1H, s), 4.82 (2H,
s), 3.95 (1H, m), 3.83 (3H, s), 3.53 (2H, d, J=5.7 Hz), 2.90 (2H,
m), 2.79 (1H, dd, J=5.3, 13.6 Hz), 2.69 (1H, dd, J=7.2, 13.6 Hz),
2.63 (1H, d, J=2.8 Hz).
EXAMPLE 8(4)
2-{5-[2-(2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propylthio)-eth-
yl]-1-naphthyloxy}acetic Acid Methyl Ester
[0782] 315
[0783] By using the compound prepared in Example 6(4), the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0784] TLC: Rf 0.26 (acetone:benzene=1:19);
[0785] NMR (CDCl.sub.3): .delta.8.29 (1H, d, J=8.1 Hz), 7.62 (1H,
d, J=8.5 Hz), 7.33 (12H, m), 6.72 (1H, d, J=7.6 Hz), 5.35 (1H, S),
4.82 (2H, s), 3.93 (1H, m), 3.83 (3H, s), 3.50 (1H, d, J=4.8 Hz),
3.32 (2H, m), 2.90 (2H, m), 2.76 (2H, m), 2.60 (1H, d, J=4.3
Hz).
EXAMPLE 8(5)
2-{5-[2-(2RS-hydroxy-3-phenylthiopropylthio)ethyl]-1-naphthyloxy}acetic
Acid Methyl Ester
[0786] 316
[0787] By using the compound prepared in Example 6(5), the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0788] TLC: Rf 0.33 (acetone:benzene=1:19).
EXAMPLE 8(6)
2-[5-(2RS-hydroxy-3-diphenylmethoxypropylthio)methyl-1-naphthyloxy]acetic
Acid Methyl Ester
[0789] 317
[0790] By using the compound prepared in Example 6(6), the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0791] TLC: Rf 0.33 (acetone:benzene=1:19);
[0792] NMR (CDCl.sub.3): .delta.8.33 (1H, m), 7.75 (1H, d, J=8.6
Hz), 7.33 (13H, m), 6.74 (1H, d, J=7.7 Hz), 5.35 (1H, s), 4.82 (2H,
s), 4.18 (2H, s), 3.94 (1H, m), 3.83 (3H, s), 3.48 (2H, d, J=5.2
Hz), 2.71 (1H, dd, J=5.3, 13.9 Hz), 2.59 (1H, dd, J=7.2, 13.9 Hz),
2.58 (1H, d, J=4.1 Hz).
EXAMPLE 8(7)
2-{5-[2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propylthio]methyl--
1-naphthyloxy}acetic Acid Methyl Ester
[0793] 318
[0794] By using the compound prepared in Example 6(7), the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0795] TLC: Rf 0.29 (acetone:benzene=1:19);
[0796] NMR (CDCl.sub.3): .delta.8.33 (1H, m), 7.74 (1H, d, J=8.8
Hz), 7.33 (12H, m), 6.74 (1H, d, J=7.7 Hz), 5.30 (1H, s), 4.82 (2H,
s), 4.17 (2H, s), 3.91 (1H, m), 3.83 (3H, s), 3.44 (2H, d, J=5.2
Hz), 2.70 (1H, dd, J=5.3, 13.9 Hz), 2.62 (1H, dd, J=2.0, 7.2 Hz),
2.54 (1H, d, J=3.8 Hz).
EXAMPLE 8(8)
2-{5-[2-(2RS-hydroxy-3-phenoxypropoxy)ethyl]-1-naphthyloxy}acetic
Acid Methyl Ester
[0797] 319
[0798] By using the compound prepared in Example 7, the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0799] TLC: Rf 0.37 (AcOEt:CH.sub.2Cl.sub.2=1:9);
[0800] NMR (CDCl.sub.3): .delta.8.29 (1H, m), 7.69 (1H, d, J=8 Hz),
7.47-7.20 (5H, m), 7.01-6.82 (3H, m), 6.71 (1H, d, J=8 Hz), 4.82
(2H, s), 4.12 (1H, m), 3.95 (2H, d, J=5.5 Hz), 3.96-3.77 (5H, m),
3.62 (2H, m), 3.35 (2H, t, J=7 Hz), 2.44 (1H, d, J=3 Hz).
EXAMPLE 9
2-{5-[2-(2RS-hydroxy-3-(4-chlorophenoxy)propylthio)ethyl]-1-naphthyloxy}-a-
cetic Acid
[0801] 320
[0802] By using the compound prepared in Example 8, the present
invention compound having the following physical data was obtained
by the same procedure as Example 3.
[0803] TLC: Rf 0.61 (MeOH:CHCl.sub.3:AcOH=1:18:1);
[0804] MS (APCI): m/z 445, 447 (3:1), (M--H)+;
[0805] NMR (DMSO-d6): .delta.13.08 (1H, brs), 8.15 (1H, t, J=4.4
Hz), 7.63 (1H, d, J=8.8 Hz), 7.43 (3H, m), 7.31 (2H, d, J=8.8 Hz),
6.95 (2H, d, J=8.8 Hz), 6.89 (1H, d, J=8.8 Hz), 5.29 (1H, m), 4.87
(2H, S), 3.95 (3H, m), 3.30 (2H, m), 2.90 (2H, t, J=7 Hz), 2.80
(1H, dd, J=14, 4 Hz), 2.70 (1H, dd, J=14, 6 Hz).
EXAMPLE 9(1)
2-{5-[2-(2RS-hydroxy-3-(4-methylphenoxy)propylthio)ethyl]-1-naphthyloxy}-a-
cetic Acid
[0806] 321
[0807] By using the compound prepared in Example 8(1), the present
invention compound having the following physical data was obtained
by the same procedure as Example 3.
[0808] TLC: Rf 0.60 (MeOH:CHCl.sub.3:AcOH=1:18:1);
[0809] MS (APCI): m/z 425 (M--H)+;
[0810] NMR (DMSO-d6): .delta.13.07 (1H, brs), 8.14 (1H, t, J=4.2
Hz), 7.63 (1H, d, J=8.6 Hz), 7.43 (3H, m), 7.07 (2H, d, J=8.2 Hz),
6.89 (1H, d, J=8.6 Hz), 6.72 (2H, d, J=8.2 Hz), 5.23 (1H, d, J=5
Hz), 4.87 (2H, s), 3.95 (3H, m), 3.30 (2H, m), 2.90 (2H, t, J=8
Hz), 2.82 (1H, dd, J=14, 6 Hz), 2.70 (1H, dd, J=14, 6 Hz), 2.22
(3H, s).
EXAMPLE 9(2)
2-{5-[2-(2RS-hydroxy-3-(4-methyoxyphenoxy)propylthio)ethyl]-1-naphthyloxy}-
-acetic Acid
[0811] 322
[0812] By using the compound prepared in Example 8(2), the present
invention compound having the following physical data was obtained
by the same procedure as Example 3.
[0813] TLC: Rf 0.56 (MeOH:CHCl.sub.3:AcOH=1:18:1);
[0814] MS (APCI): m/z 441 (M--H)+;
[0815] NMR (DMSO-d6): .delta.13.07 (1H, brs), 8.14 (1H, t, J=6 Hz),
7.63 (1H, d, J=8.4 Hz), 7.43 (3H, m), 6.89 (1H, d, J=6 Hz), 6.85
(4H, s), 5.22 (1H, d, J=4.4 Hz),4.88 (2H, s), 3.90 (3H, m), 3.69
(3H, s), 3.25 (2H, m), 2.88 (2H, t, J=9 Hz), 2.82 (1H, dd, J=13, 4
Hz), 2.68 (1H, dd, J=13, 6 Hz).
EXAMPLE 9(3)
2-{5-[2-(2RS-hydroxy-3-diphenylmethoxypropylthio)ethyl]-1-naphthyloxy}-ace-
tic Acid
[0816] 323
[0817] By using the compound prepared in Example 8(3), the present
invention compound having the following physical data was obtained
by the same procedure as Example 3.
[0818] TLC: Rf 0.60 (MeOH:CHCl.sub.3:AcOH=10:100:1);
[0819] MS (FAB): m/z 503 (M+1)+, 229, 207;
[0820] NMR (CDCl.sub.3): .delta.8.25 (1H, d, J=8.0 Hz), 7.63 (1H,
d, J=8.4 Hz), 7.33 (13H, m), 6.74 (1H, d, J=7.7 Hz), 5.38 (1H, s),
4.84 (2H, s), 3.94 (1H, m), 3.51 (2H, d, J=4.8 Hz), 3.31 (2H, m),
2.89 (2H, m), 2.78 (1H, dd, J=5.6, 13.8 Hz), 2.66 (1H, dd, J=7.2,
13.8 Hz).
EXAMPLE 9(4)
2-{5-[2-(2RS-hydroxy-3-phenylthiopropylthio)ethyl]-1-naphthyloxy}acetic
Acid
[0821] 324
[0822] By using the compound prepared in Example 8(5), the present
invention compound having the following physical data was obtained
by the same procedure as Example 3.
[0823] TLC: Rf 0.56(MeOH:CHCl.sub.3:AcOH=1:18:1);
[0824] MS (APCI): m/z 427 (M--H)+;
[0825] NMR (DMSO-d6): .delta.13.09 (1H, brs), 8.14 (1H, dd, J=7,
3.2 Hz), 7.62 (1H, d, J=8.6 Hz), 7.50-7.22 (7H, m), 7.22-7.10 (1H,
m), 6.89 (1H, d, J=7.2 Hz), 5.31 (1H, d, J=4.8 Hz), 4.87 (2H, s),
3.78 (1H, m), 3.25 (2H, t, J=8 Hz), 3.16 (1H, dd, J=13, 5 Hz), 3.03
(1H, dd, J=13, 6 Hz), 2.85 (2H, t, J=8 Hz), 2.80 (1H, dd, J=13, 5
Hz), 2.69 (1H, dd, J=13, 6 Hz).
EXAMPLE 9(5)
2-[5-(2RS-hydroxy-3-diphenylmethoxypropylthio)methyl-1-naphthyloxy]acetic
Acid
[0826] 325
[0827] By using the compound prepared in Example 8(6), the present
invention compound having the following physical data was obtained
by the same procedure as Example 3.
[0828] TLC: Rf 0.55 (MeOH:CHCl.sub.3:AcOH=10:100:1);
[0829] MS (FAB): m/z 489 (M+1)+, 338;
[0830] NMR (CDCl.sub.3): .delta.8.30 (1H, m), 7.77 (1H, d, J=8.5
Hz), 7.35 (13H, m), 6.76 (1H, d, J=7.9 Hz), 5.34 (1H, s), 4.85 (2H,
s), 4.16 (2H, s), 3.94 (1H, m), 3.47 (2H, d, J=5.1 Hz), 2.71 (1H,
dd, J=5.2, 13.8 Hz), 2.59 (1H, dd, J=7.2, 13.8 Hz).
EXAMPLE 9(6)
2-{5-[2-(2RS-hydroxy-3-phenoxypropoxy)ethyl]-1-naphthyloxy}acetic
Acid
[0831] 326
[0832] By using the compound prepared in Example 8(8), the present
invention compound having the following physical data was obtained
by the same procedure as Example 3.
[0833] TLC: Rf 0.17 (MeOH:CHCl.sub.3=1:3);
[0834] NMR (DMSO-d6): .delta.13.00 (1H, brs), 8.13 (1H, dd, J=8, 2
Hz), 7.66 (1H, d, J=9 Hz), 7.50-7.20 (5H, m), 6.98-6.82 (4H, m),
5.07 (1H, m), 4.87 (2H, s), 4.00-3.10 (9H, m).
EXAMPLE 10
1-cyanomethoxy-5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]naphthalene
[0835] 327
[0836] By using bromoacetonitrile instead of bromoacetic acid
methyl ester in Example 2 and the compound prepared in Example 1,
the present invention compound having the following physical data
was obtained by the same procedure as Example 2.
[0837] TLC: Rf 0.33 (benzene:AcOEt=17:3);
[0838] NMR (CDCl.sub.3): .delta.8.17 (1H, m), 7.73 (1H, d, J=8 Hz),
7.52-7.23 (5H, m), 7.05-6.85 (4H, m), 4.95 (2H, s, --OCH.sub.2),
4.20-3.96 (3H, m), 3.38 (2H, t, J=7 Hz), 3.03-2.60 (5H, m).
EXAMPLE 10(1)
1-cyanomethoxy-5-{2-[2RS-hydroxy-3-(4-chlorophenoxy)propylthio]ethyl}-naph-
thalene
[0839] 328
[0840] By using the compound prepared in Example 6, the present
invention compound having the following physical data was obtained
by the same procedure as Example 10.
[0841] TLC: Rf 0.45 (acetone:benzene=1:9);
[0842] MS (El): m/z 427, 429 (3:1) (M)+, 387, 389 (3:1)
(M-40)+;
[0843] NMR (CDCl.sub.3): .delta.8.14 (1H, d, J=7.6 Hz), 7.72 (1H,
d, J=8.6 Hz), 7.43 (3H, m), 7.24 (2H, d, J=9.2 Hz), 6.93 (1H, d,
J=7.6 Hz), 6.82 (2H, d, J=9.2 Hz), 4.97 (2H, s), 4.06 (1H, m), 3.97
(2H, m), 3.36 (2H, t, J=7 Hz), 2.95 (2H, t, J=7 Hz), 2.89 (1H, dd,
J=13, 5.2 Hz), 2.75 (1H, dd, J=13, 7 Hz), 2.66 (1H, d, J=4.2
Hz).
EXAMPLE 10(2)
1-cyanomethoxy-5-{2-[2RS-hydroxy-3-(4-methylphenoxy)propylthio]ethyl}-naph-
thalene
[0844] 329
[0845] By using the compound prepared in Example 6(1), the present
invention compound having the following physical data was obtained
by the same procedure as Example 10.
[0846] TLC: Rf 0.45 (acetone:benzene=1:9);
[0847] MS (El): m/z 407 (M)+, 367 (M-40)+;
[0848] NMR (DMSO-d6): .delta.8.14 (1H, t, J=7.6 Hz), 7.73 (1H, d,
J=8.8 Hz), 7.43 (3H, m), 7.08 (2H, d, J=8.8 Hz), 6.94 (1H, d, J=7.6
Hz), 6.80 (2H, d, J=8.2 Hz), 4.96 (2H, s), 4.08 (1H, m), 3.97 (2H,
m), 3.37 (2H, t, J=7 Hz), 2.95 (2H, t, J=7 Hz), 2.90 (1H, dd, J=14,
5.2 Hz), 2.75 (1H, dd, J=14, 6.8 Hz), 2.68 (1H, d, J=4.2 Hz), 2.29
(3H, s).
EXAMPLE 10(3)
1-cyanomethoxy-5-{2-[2RS-hydroxy-3-(4-methoxyphenoxy)propylthio]ethyl}-nap-
hthalene
[0849] 330
[0850] By using the compound prepared in Example 6(2), the present
invention compound having the following physical data was obtained
by the same procedure as Example 10.
[0851] TLC: Rf 0.38 (acetone:benzene=1:9);
[0852] MS (El): m/z 423 (M)+;
[0853] NMR (DMSO-d6): .delta.8.16 (1H, t, J=7.5 Hz), 7.73 (1H, d,
J=8.6 Hz), 7.46 (3H, m), 6.94 (1H, d, J=7 Hz), 6.83 (4H, s), 4.97
(2H, s), 4.06 (1H, m), 3.97 (2H, m), 3.77 (3H, s), 3.37 (2H, t,
J=7.4 Hz), 2.95 (2H, t, J=7.4 Hz), 2.89 (1H, dd, J=14, 6.4 Hz),
2.76 (1H, dd, J=3, 6.8 Hz), 2.68 (1H, d, J=4 Hz).
EXAMPLE 10(4)
1-cyanomethoxy-5-[2-(2RS-hydroxy-3-diphenylmethoxypropylthio)ethyl]-naphth-
alene
[0854] 331
[0855] By using the compound prepared in Example 6(3), the present
invention compound having the following physical data was obtained
by the same procedure as Example 10.
[0856] TLC: Rf 0.32 (acetone:benzene=1:19);
[0857] MS (FAB): m/z 484 (M+1)+, 443, 391, 168;
[0858] NMR (CDCl.sub.3): .delta.8.13 (1H, d, J=9.2 Hz), 7.72 (1H,
d, J=8.7 Hz), 7.34 (13H, m), 6.93 (1H, d, J=7.7 Hz), 5.39 (1H, s),
4.95 (1H, s), 3.95 (1H, m), 3.52 (1H, d, J=5.7 Hz), 3.33 (2H, dd,
J=7.3, 9.7 Hz), 2.90 (2H, m), 2.83 (1H, dd, J=5.3, 13.7 Hz), 2.68
(1H, dd, J=7.2, 13.7 Hz), 2.63 (1H, d, J=4.2 Hz).
EXAMPLE 10(5)
1-cyanomethoxy-5-[2-(2RS-hydroxy-3-phenylthiopropylthio)ethyl]naphthalene
[0859] 332
[0860] By using the compound prepared in Example 6(5), the present
invention compound having the following physical data was obtained
by the same procedure as Example 10.
[0861] TLC: Rf 0.33 (acetone:benzene=1:19);
[0862] MS (El): m/z 409 (M)+;
[0863] NMR (CDCl.sub.3): .delta.8.13 (1H, d, J=7.8 Hz), 7.70 (1H,
d, J=8.8 Hz), 7.47 (1H, d, J=7.2 Hz), 7.42-7.34 (4H, m), 7.34-7.10
(3H, m), 4.97 (2H, s), 3.82 (1H, m), 3.33 (2H, t, J=7 Hz), 3.15
(1H, dd, J=13.8, 5.2 Hz), 3.03 (1H, dd, J=13.8, 6.6 Hz), 2.89 (2H,
t, J=7 Hz), 2.84 (1H, dd, J=13.8, 4.6 Hz), 2.68 (1H, dd, J=13.8,
7.4 Hz).
EXAMPLE 10(6)
1-cyanomethoxy-5-[(2RS-hydroxy-3-diphenylmethoxy)propylthiomethyl]-naphtha-
lene
[0864] 333
[0865] By using the compound prepared in Example 6(6), the present
invention compound having the following physical data was obtained
by the same procedure as Example 10.
[0866] TLC: Rf 0.30 (acetone:benzene=1:19);
[0867] MS (FAB): m/z 302 (M-C13H11)+, 196, 168;
[0868] NMR (CDCl.sub.3): .delta.8.17 (1H, dd, J=2.9, 6.6 Hz), 7.85
(1H, d, J=8.7 Hz), 7.36 (13H, m), 6.95 (1H, d, J=7.7 Hz), 5.35 (1H,
s), 4.96 (2H, s), 4.18 (2H, s), 3.94 (1H, m), 3.49 (2H, d, J=5.3
Hz), 2.71 (1H, dd, J=5.2, 13.7 Hz), 2.59 (1H, dd, J=7.2, 13.7 Hz),
2.56 (1H, d, J=7.3 Hz).
EXAMPLE 11
2-{5-[2-(2RS-hydroxy-3-pheoxypropylamino)ethyl]-1-naphthyloxy}acetic
Acid
[0869] 334
[0870] By using the compound prepared in Reference Example 34, the
present invention compound having the following physical data was
obtained by the same procedure as Example 2.fwdarw.Example 3.
[0871] TLC: Rf 0.37 (MeOH:CHCl.sub.3:AcOH=2:6:1);
[0872] MS (FAB): m/z 396 ((M+H)+);
[0873] NMR (DMSO-d6): .delta.8.18 (1H, d, J=8 Hz), 7.40-7.20 (4H,
m), 7.14-7.07 (4H, m), 6.72-6.60 (2H, m), 4.58 (2H, s), 4.37-2.90
(12H, m).
EXAMPLE 12
2-{5-[2-(2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propylthio)-eth-
yl]-1-naphthyloxy}ethanol
[0874] 335
[0875] By using 2-bromo ethanol instead of bromoacetic acid methyl
ester in Example 2 and the compound prepared in Example 6(4), the
present invention compound having the following physical data was
obtained by the same procedure as Example 2.
[0876] TLC: Rf 0.19 (hexane:AcOEt=2:1);
[0877] MS (APCI): m/z 523 (M+1)+, 305, 215, 201;
[0878] NMR (DMSO-d6): .delta.8.20 (1H, dd, J=2.1, 7.6 Hz), 7.59
(1H, d, J=8.7 Hz), 7.32 (12H, m), 6.84 (1H, d, J=7.8 Hz), 5.34 (1H,
s), 4.27 (2H, m), 4.11 (2H, m), 3.92 (1H, m), 3.49 (2H, d, J=5.4
Hz), 3.32 (2H, dd, J=7.1, 9.6 Hz), 2.90 (2H, m), 2.78 (1H, dd,
J=5.3, 11.7 Hz), 2.70 (1H, dd, J=2.3, 7.1 Hz), 2.61 (1H, d, J=2.5
Hz), 2.08 (1H, m).
REFERENCE EXAMPLE 35
[0879] 336
[0880] To the solution of benzyloxycarbonylaniline (2.32 g) in
anhydrous DMF (30 ml), sodium hydride (426 mg) was added under an
atmosphere of argon gas at 0.degree. C. The mixture was stirred for
30 minutes at room temperature. To the mixture, the compound
prepared in Reference Example 1 (2.65 g) was added. The mixture was
stirred for 1 hour at 80.degree. C. To the reaction mixture, water
was added to decompose the superfluous sodium hydride. The mixture
was extracted with ethyl acetate, washed with water and a saturated
aqueous solution of sodium chloride, dried over with anhydrous
magnesium sulfate and concentrated under the reduced pressure. The
residue was purified on silica gel column chromatography
(hexane:AcOEt=6:1) to give the title compound (2.52 g) having the
following physical data.
[0881] TLC: Rf 0.36 (hexane:AcOEt=4:1).
REFERENCE EXAMPLE 36
[0882] 337
[0883] The solution of the compound prepared in Reference Example
35 (2.52 g) in aqueous 80% acetic acid solution (25 ml) was stirred
for 10 hours at room temperature. The reaction mixture was
concentrated under the reduced pressure. The residue was purified
on silica gel column chromatography (CHCl.sub.3:MeOH=30:1) to give
the title compound (1.69 g) having the following physical data.
[0884] TLC: Rf 0.09 (hexane:AcOEt=1:1).
REFERENCE EXAMPLE 37
[0885] 338
[0886] To the solution of the compound prepared in Reference
Example 36 (328 mg) in pyridine (2.5 ml), tosylchloride (217 mg)
was added under an atmosphere of argon gas at -20 C. The mixture
was stirred for 3.5 hours at room temperature. To the reaction
mixture, a small amount of water was added. The mixture was stirred
for 10 minutes, extracted with ethyl acetate, washed with 1 N
aqueous solution of hydrochloric acid, water and a saturated
aqueous solution of sodium chloride succeedingly, dried over with
anhydrous magnesium sulfate and concentrated under the reduced
pressure to give the title compound (522 mg) having the following
physical data. This residue was used in the next reaction without
purification.
[0887] TLC: Rf 0.55 (hexane:AcOEt=1:1).
REFERENCE EXAMPLE 38
[0888] 339
[0889] To the ethanol (3.0 ml), sodium hydride (56 mg) was added
under an atmosphere of argon gas at 0.degree. C. The mixture was
stirred for 10 minutes. To the mixture, the compound prepared in
Reference Example 21 (310 mg) and the compound prepared in
Reference Example 37 (522 mg) in ethanol (3.0 ml) was added
dropwise. The mixture was stirred for 2 hours at room temperature.
To the reaction mixture, a saturated aqueous solution of ammonium
chloride was added to decompose the superfluous reagent. The
reaction mixture was extracted with ethyl acetate, washed with
water and a saturated aqueous solution of sodium chloride, dried
over with anhydrous magnesium sulfate and concentrated under the
reduced pressure. The residue was purified on silica gel column
chromatography (hexane:AcOEt=3:1) to give the title compound (427
mg) having the following physical data.
[0890] TLC: Rf 0.36 (hexane:AcOEt=2:1).
REFERENCE EXAMPLE 39
[0891] 340
[0892] By using the compound prepared in Reference Example 38, the
title compound having the following physical data was obtained by
the same procedure as Example 1 .fwdarw.Example 12.
[0893] TLC: Rf 0.20 (hexane:AcOEt=1:1);
[0894] NMR (CDCl.sub.3): .delta.8.21 (1H, m), 7.60 (1H, d, J-8.6
Hz), 7.33-7.55 (7H, m), 7.18 (1H, m), 6.85 (1H, d, J=7.6 Hz), 6.69
(1H, m), 4.27 (2H, m), 3.99-4.14 (3H, m), 3.80 (1H, dd, J=6.6, 9.2
Hz), 3.35 (2H, m), 2.91-3.06 (3H, m), 2.78 (1H, dd, J=7.4, 13.8
Hz), 2.11 (1H, t, J=6.4 Hz).
EXAMPLE 13
2-{5-[2-(2RS-hydroxy-3-phenylaminopropylthio)ethyl]-1-naphthyloxy}ethanol
[0895] 341
[0896] To the solution of the compound prepared in Reference
Example 39 (138 mg) in methanol (10 ml), aqueous 40% sodium
hydroxide solution (0.5 ml) was added at room temperature. The
solution was stirred for 7 days. The mixture was concentrated to
the volume of about 3.0 ml, extracted with ethyl acetate, washed
with water and a saturated aqueous solution of sodium chloride,
dried over with anhydrous magnesium sulfate and concentrated under
the reduced pressure. The residue was purified on silica gel column
chromatography (CHCl.sub.3:MeOH=50:1) to give the present invention
compound (116 mg) having the following physical data.
[0897] TLC: Rf 0.62 (MeOH:CHCl.sub.3=1:10);
[0898] MS (APCI): m/z 398 (M+1)+, 380, 245, 215;
[0899] NMR (CDCl.sub.3): .delta.8.21 (1H, dd, J=2.2, 7.6 Hz), 7.59
(1H, d, J=8.6 Hz), 7.34-7.48 (3H, m), 7.12-7.24 (2H, m), 6.85 (1H,
d, J=7.6 Hz), 6.73 (1H, t, J=7.2 Hz), 6.63 (2H, d, J=7.6 Hz), 4.27
(2H, t, J=4.2H), 3.82-4.18 (4H, m), 3.25-3.38 (3H, m), 3.06 (1H,
dd, J=7.4, 13.0 Hz), 2.95 (1H, d, J=8.4 Hz), 2.92 (1H, d, J=9.2
Hz), 2.77 (1H, dd, J=4.4, 13.8 Hz), 2.57-2.68 (2H, m), 2.10 (1H,
m).
EXAMPLE 14
1-(tetrazol-5-yl-methoxy)-5-{2-{2RS-hydroxy-3-(4-methyoxyphenoxy)-propylth-
io]ethyl}naphthalene
[0900] 342
[0901] Under an atmosphere of argon gas, the compound prepared in
Example 10(3) (178 mg), sodium azide (30 mg) and ammonium chloride
(22 mg) were suspended in DMF (5 ml). The suspension was stirred
for 20 hours at 80C. The reaction mixture was cooled to room
temperature. To the mixture, water was added. The mixture was
stirred, extracted with ethyl acetate three times. The organic
layer was washed with water two times and a saturated aqueous
solution of sodium chloride one time, dried over with anhydrous
magnesium sulfate and concentrated. The white powder obtained was
washed with diethylether to give the present invention compound
(120 mg) having the following physical data.
[0902] TLC: Rf 0.53 (MeOH:CHCl.sub.3:AcOH=1:18:1);
[0903] MS (FAB): m/z 467 (M+H)+;
[0904] NMR (DMSO-d6): .delta.8.19 (1H, t, J=5.2 Hz), 7.69 (1H, d,
J=8.4 Hz), 7.49 (1H, d, J=8 Hz), 7.45 (2H, m), 7.16 (1H, d, J=7.4
Hz), 6.84 (4H, s), 5.67 (2H, s), 5.22 (1H, brs), 3.92 (1H, m), 3.90
(2H, m), 3.69 (3H, s), 3.30 (2H, t, J=8.2 Hz), 2.89 (2H, t, J=8.2
Hz), 2.81 (1H, dd, J=13, 5.2 Hz), 2.68 (1H, dd, J=13, 6.2 Hz).
EXAMPLE 15
N-methyl-{5-[2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propylthio]-
-methyl-1-naphthyloxy}acetic Acid Amide
[0905] 343
[0906] To the solution of the compound prepared in Example 8(7)
(325 mg) in THF (3.0 ml), aqueous 40% methylamine solution (0.6 ml)
was added. The solution was stirred for 2.5 hours at 45.degree. C.
The reaction mixture was diluted with ethyl acetate, washed with 1
N aqueous solution of hydrochloric acid, water and a saturated
aqueous solution of sodium chloride, succeedingly, dried over with
anhydrous magnesium sulfate and concentrated under the reduced
pressure. The residue was purified on silica gel column
chromatography (CHCl.sub.3:MeOH=30:1) to give the present invention
compound (312 mg) having the following physical data.
[0907] TLC: Rf 0.64 (MeOH:CHCl.sub.3=1:10);
[0908] MS (FAB): m/z 536 (M+1)+, 334, 261, 228, 201;
[0909] NMR (CDCl.sub.3): .delta.8.18 (1H, m), 7.78 (1H, d, J=8.6
Hz), 7.34 (12H, m), 6.83 (1H, d, J=7.7 Hz), 6.58 (1H, brs), 5.32
(1H, s), 4.70 (2H, s), 4.18 (2H, s), 3.93 (1H, m), 3.46 (2H, d,
J=5.1 Hz), 2.93 (3H, d, J=5.0 Hz), 2.71 (1H, dd, J=5.2, 13.8 Hz),
2.63 (1H, dd, J=1.8, 7.2 Hz), 2.56 (1H, d, J=4.0 Hz).
REFERENCE EXAMPLE 40
[0910] 344
[0911] To the solution of
1-(2-hydroxy-ethyliden)-5-hydroxy-1,2,3,4-tetrah- ydronaphthalene
(2.1 g) in ethanol (15 ml), 10% Pd-C (200 mg) was added under an
atmosphere of argon gas. The mixture was stirred vigorously under
an atmosphere of H.sub.2 gas for 1 hour at room temperature. The
reaction mixture was filtrated by Celite (Registered trade mark).
The filtrate was concentrated under the reduced pressure to give
the title compound (1.74 g) having the following physical data.
[0912] TLC: Rf 0.40 (hexane:AcOEt=2:1).
EXAMPLE 16
1-{2-[5-hydroxy-1-(1,2,
3,4-tetrahydronaphthyl)]ethylthio}-3-phenoxy-2RS-p- ropanol
[0913] 345
[0914] By using the compound prepared from the compound prepared in
Reference Example 40 by the same procedure as Reference Example
12.fwdarw.Reference Example 21, and the compound prepared in
Reference Example 5, the present invention compound having the
following physical data was obtained by the same procedure as
Reference Example 24.fwdarw.Example 1.
[0915] TLC: Rf 0.36 (hexane:AcOEt=2:1);
[0916] NMR (CDCl.sub.3): .delta.7.30 (2H, m), 6.96 (4H, m), 6.75
(1H, d, J=7.9 Hz), 6.61 (1H, d, J=7.9 Hz), 4.75 (1H, m), 4.10 (3H,
m), 2.50-3.00 (7H, m), 1.60-2.05 (6H, m).
EXAMPLE 17
2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-(5,6,7,8-tetrahydro-naph-
thyloxy)}acetic Acid Methyl Ester
[0917] 346
[0918] By using the compound prepared in Example 16, the present
invention compound having the following physical data was obtained
by the same procedure as Example 2.
[0919] TLC: Rf 0.33 (acetone:benzene=1:19);
[0920] NMR (CDCl.sub.3): .delta.7.29 (2H, m), 7.00 (4H, m), 6.82
(1H, d, J=4.6 Hz), 6.52 (1H, d, J=4.8), 4.63 (2H, s), 4.10 (3H, m),
3.80 (3H, s), 2.55-2.97 (8H, m), 1.60-2.10 (6H, m). EXAMPLE 18
2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-(5,6,7,8-tetrahydro-naph-
thyloxy)}acetic Acid
[0921] 347
[0922] By using the compound prepared in Example 17, the present
invention compound having the following physical data was obtained
by the same procedure as Example 3.
[0923] TLC: Rf 0.5 (MeOH:CHCl.sub.3:AcOH=10:100:1);
[0924] MS (APCI): m/z 415 (M-1)+, 357, 263, 93;
[0925] NMR (CDCl.sub.3): .delta.7.30 (2H, m), 6.82-7.13 (5H, m),
6.55 (1H, d, J=8.0 Hz), 4.66 (2H, s), 4.09 (3H, m), 2.50-2.98 (7H,
m), 1.60-2.10 (6H, m).
EXAMPLE 19
1-cyanomethoxy-5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-5,6,7,8-tetrah-
ydronaphthalene
[0926] 348
[0927] By using the compound prepared in Example 16, the present
invention compound having the following physical data was obtained
by the same procedure as Example 10.
[0928] TLC: Rf 0.33 (acetone:benzene=1:19);
[0929] MS (El): m/z 397 (M)+, 304, 286, 245, 213, 184, 173, 157,
145;
[0930] NMR (CDCl.sub.3): .delta.7.30 (2H, m), 7.13 (1H, dd, J=8.0,
8.0 Hz), 6.95 (4H, m), 6.71 (1H, d, J=8.0 Hz), 4.76 (2H, s), 4.10
(3H, m), 2.50-3.00 (8H, m), 1.54-2.08 (6H, m).
FORMULATION EXAMPLE 1
[0931] The following compounds were admixed in conventional method
and punched out to obtain 100 tablets each containing 5 mg of
active ingredient.
16 2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]- 500 mg
1-naphthyloxy}acetic acid Carboxymethylcellulose calcium 200 mg
Magnesium stearate 100 mg Micro crystalline cellulose 9.2 g
* * * * *