U.S. patent application number 11/749531 was filed with the patent office on 2008-02-07 for 8-azaprostaglandin derivatives and medical use thereof.
This patent application is currently assigned to ONO PHARMACEUTICAL CO., LTD.. Invention is credited to Nobutaka Abe, Shinsei Fujimura, Tohru Kambe, Kaoru Kobayashi, Takayuki Maruyama, Toru Maruyama, Toshihiko Nagase, Yoshihiko Nakai, Akio Nishiura, Kiyoto Sakata, Kousuke Tani, Hideyuki Yoshida.
Application Number | 20080033033 11/749531 |
Document ID | / |
Family ID | 32775163 |
Filed Date | 2008-02-07 |
United States Patent
Application |
20080033033 |
Kind Code |
A1 |
Kambe; Tohru ; et
al. |
February 7, 2008 |
8-AZAPROSTAGLANDIN DERIVATIVES AND MEDICAL USE THEREOF
Abstract
The pharmaceutical composition comprising the compound of the
invention having 8-azaprostaglandin skeleton represented by formula
(I) ##STR1## (wherein, all the symbols have the same meanings as
that of the specification.) a salt thereof, a solvate thereof or a
cyclodextrin clathrate thereof, or a prodrug thereof and them as
active ingredient have EP.sub.4 agonistic action and thus are
considered useful for the prevention and/or treatment of
immunological diseases, asthma, neuronal cell death, arthritis,
lung failure, pulmonary fibrosis, pulmonary emphysema, bronchitis,
chronic obstructive pulmonary disease, liver damage, acute
hepatitis, nephritis, renal insufficiency, hypertension, myocardial
ischemia, systemic inflammatory response syndrome, sepsis,
hemophagous syndrome, macrophage activation syndrome, Still's
disease, Kawasaki disease, burn, systemic granulomatosis,
ulcerative colitis, Crohn's disease, hypercytokinemia at dialysis,
multiple organ failure, shock and glaucoma, etc. Furthermore, the
compounds also have an action of accelerating bone formation, so it
is expected to be useful for the prevention and/or treatment of
diseases associated with loss in bone mass, for example, primary
osteoporosis, secondary osteoporosis, bone metastasis of cancer,
hypercalcemia, Paget's disease, bone loss, osteonecrosis, bone
formation after bone operation, alternative treatment for bone
grafting.
Inventors: |
Kambe; Tohru; (Mishima-gun,
JP) ; Maruyama; Toru; (Mishima-gun, JP) ;
Kobayashi; Kaoru; (Mishima-gun, JP) ; Tani;
Kousuke; (Mishima-gun, JP) ; Nakai; Yoshihiko;
(Mishima-gun, JP) ; Nagase; Toshihiko;
(Mishima-gun, JP) ; Maruyama; Takayuki;
(Mishima-gun, JP) ; Sakata; Kiyoto; (Mishima-gun,
JP) ; Yoshida; Hideyuki; (Mishima-gun, JP) ;
Fujimura; Shinsei; (Mishima-gun, JP) ; Nishiura;
Akio; (Mishima-gun, JP) ; Abe; Nobutaka;
(Mishima-gun, JP) |
Correspondence
Address: |
SUGHRUE-265550
2100 PENNSYLVANIA AVE. NW
WASHINGTON
DC
20037-3213
US
|
Assignee: |
ONO PHARMACEUTICAL CO.,
LTD.
|
Family ID: |
32775163 |
Appl. No.: |
11/749531 |
Filed: |
May 16, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10542724 |
Jul 20, 2005 |
7256211 |
|
|
PCT/JP04/00419 |
Jan 20, 2004 |
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11749531 |
May 16, 2007 |
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Current U.S.
Class: |
514/424 ;
514/439; 514/469; 548/152; 548/186; 548/217; 548/551 |
Current CPC
Class: |
A61P 3/14 20180101; A61P
11/00 20180101; A61P 37/06 20180101; C07D 417/12 20130101; A61P
19/02 20180101; A61P 15/10 20180101; A61P 9/12 20180101; A61P 19/10
20180101; A61P 13/12 20180101; A61P 37/02 20180101; A61P 15/06
20180101; A61P 43/00 20180101; A61P 37/00 20180101; A61P 25/28
20180101; A61P 9/10 20180101; A61P 9/00 20180101; A61P 25/00
20180101; A61P 11/06 20180101; C07D 417/14 20130101; A61P 1/02
20180101; A61P 15/00 20180101; A61P 1/16 20180101; A61P 17/14
20180101; A61P 19/08 20180101; A61P 29/00 20180101; A61P 31/04
20180101; A61P 13/00 20180101; A61P 1/04 20180101; A61P 21/02
20180101; A61P 1/06 20180101; A61P 7/06 20180101; A61P 27/06
20180101 |
Class at
Publication: |
514/424 ;
514/439; 514/469; 548/152; 548/186; 548/217; 548/551 |
International
Class: |
A61K 31/41 20060101
A61K031/41; A61K 31/4015 20060101 A61K031/4015; C07D 207/18
20060101 C07D207/18; C07D 257/04 20060101 C07D257/04 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 21, 2003 |
JP |
P. 2003-11936 |
Aug 8, 2003 |
JP |
P. 2003-289954 |
Claims
1. A compound represented by formula (I) ##STR63## wherein is a
single bond or double bond, is .alpha.-configuration,
.beta.-configuration or a voluntary mixture of
.alpha.-configuration and .beta.-configuration, D is --COOR.sup.1
or tetrazoryl, R.sup.1 is hydrogen or C1-4 alkyl, G is ringA or
C1-4 alkylene, ringA is ##STR64## R.sup.2 is a halogen atom, C1-4
alkyl or C1-4 alkoxy, p is 0 or an integer of 1-4, when p is 2 or
more, plural R.sup.2's are the same or different, Y is a single
bond or --S--, T is oxygen or sulfur, X is --CH.sub.2--, --O-- or
--S--, ringB is C3-7 cycloalkyl optionally substituted, ##STR65##
wherein R.sup.3 is (1) a halogen atom, (2) C1-4 alkyl optionally
substituted with 1-5 of halogen atom(s), (3) C1-4 alkoxy optionally
substituted with 1-5 of halogen atom(s), (4) C1-4 alkyl substituted
with C1-4 alkoxy, (5) phenyl or (6) 3- to 15-membered mono-, bi- or
tri-heterocyclic aryl containing 1 to 4 hetero atom(s) selected
from oxygen, nitrogen and sulfur atom(s) which may be partially or
fully saturated, and (5) phenyl or (6) heterocyclic aryl in R.sup.3
is optionally substituted with 1-3 of (a) halogen atom(s), (b) C1-4
alkyl, (c) C1-4 alkoxy and/or (d) nitro, q is 0 or an integer of
1-5, when q is 2 or more, plural R.sup.3's are the same or
different, n is an integer of 1-4, a salt thereof, a solvate
thereof, a cyclodextrin clathrate thereof, or a prodrug
thereof.
2. The compound according to claim 1, which is selected from the
group consisting of: (1)
4-[(2-{(4S)-4-[(1E,3S)-4-(3-ethylphenyl)-3-hydroxybut-1-enyl]-2-oxo-1,3-t-
hiazolidine-3-yl]ethyl)sulfanyl]butanoic acid, (2)
4-[(2-{(4S)-4-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazolidi-
ne-3-yl}ethyl)sulfanyl]butanoic acid, (3)
4-{[2-((4S)-4-{(1E,3S)-4-[4-fuloro-3-(trifluoromethyl)phenyl]-3-hydroxybu-
t-1-enyl}-2-oxo-1,3-thiazolidine-3-yl)ethyl]sulfanyl}butanoic acid,
(4)
4-[(2-{(4S)-4-[(1E,3S)-4-(3,5-difluorophenyl)-3-hydroxybut-1-enyl]-2-oxo--
1,3-thiazolidine-3-yl}ethyl)sulfanyl]butanoic acid, (5)
4-[(2-{(4S)-4-[(1E,3S)-3-hydroxy-4-(3-propylphenyl)but-1-enyl]-2-oxo-1,3--
thiazolidine-3-yl]ethyl)sulfanyl]butanoic acid, (6)
4-[(2-{(4S)-4-[(1E,3S)-4-(3-ethyl-4-fulorophenyl)-3-hydroxybut-1-enyl]-2--
oxo-1,3-thiazolidine-3-yl}ethyl)sulfanyl]butanoic acid, (7)
4-[(2-{(4S)-4-[(1E,3S)-4-(3,4-difluorophenyl)-3-hydroxybut-1-enyl]-2-oxo--
1,3-thiazolidine-3-yl}ethyl)sulfanyl)butanoic acid. (8)
4-{[2-((4S)-4-{(1E,3S)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]but-1-enyl]-
-2-oxo-1,3-thiazolidine-3-yl}ethyl)sulfanyl]butanoic acid, (9)
4-[2-{(4S)-4-[(1E,3S)-4-(4-fuloro-3-methylphenyl)-3-hydroxybut-1-enyl]-2--
oxo-1,3-thiazolidine-3-yl}ethyl)sulfanyl]butanoic acid, (10)
4-[(2-{(4S)-4-[(1E,3S)-4-(3-fulorophenyl)-3-hydroxybut-1-enyl]-2-oxo-1,3--
thiazolidine-3-yl}ethyl)sulfanyl]butanoic acid, (11)
4-[(2-{(4S)-4-[(1E,3S)-4-(3-chloro-4-fulorophenyl)-3-hydroxybut-1-enyl]-2-
-oxo-1,3-thiazolidine-3-yl}ethyl)sulfanyl]butanoic acid, (12)
4-{[2-((4S)-4-{(1E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]but-1-enyl}-2-
-oxo-1,3-thiazolidine-3-yl)ethyl]sulfanyl}butanoic acid, (13)
7-{(2R)-2-[(1E,3S)-4-(4-fulorophenyl)-3-hydroxybut-1-enyl]-5-thioxopyrrol-
idine-1-yl}heptanoic acid, (14)
7-{(2R)-2-[(1E,3S)-4-(3,5-difluorophenyl)-3-hydroxybut-1-enyl]-5-thioxopy-
rrolidine-1-yl}heptanoic acid, (15)
7-((2R)-2-{(1E,3S)-4-[4-fuloro-3-(trifluoromethyl)phenyl]-3-hydroxybut-1--
enyl}-5-thioxopyrrolidine-1-yl)heptanoic acid, (16)
7-{(2R)-2-[(1E,3S)-4-(4-fuloro-3-methylphenyl)-3-hydroxybut-1-enyl]-5-thi-
oxopyrrolidine-1-yl}heptanoic acid, (17)
7-{(2R)-2-[(1E,3S)-4-(3-ethyl-4-fulorophenyl)-3-hydroxybut-1-enyl]-5-thio-
xopyrrolidine-1-yl}heptanoic acid, (18)
7-((2R)-2-{(1E,3S)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]but-1-enyl}-5-t-
hioxopyrrolidine-1-yl)heptanoic acid, (19)
7-{(2R)-2-[(1E,3S)-4-(3-fulorophenyl)-3-hydroxybut-1-enyl]-5-thioxopyrrol-
idine-1-yl}heptanoic acid, (20)
7-{(2R)-2-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-5-thioxopyrrolidine-1-yl-
}heptanoic acid, (21)
7-{(2R)-2-[(1E,3S)-4-(3,4-difluorophenyl)-3-hydoroxybut-1-enyl]-5-thioxop-
yrrolidine-1-yl}heptanoic acid, (22)
7-{(2R)-2-[(1E,3S)-4-(3-chloro-4-fulorophenyl)-3-hydroxybut-1-enyl]-5-thi-
oxopyrrolidine-1-yl}heptanoic acid, (23)
7-{(2R)-2-[(1E,3S)-4-(3-ethylphenyl)-3-hydroxybut-1-enyl]-5-thioxopyrroli-
dine-1-yl}heptanoic acid, (24)
7-{(2R)-2-[(1E,3S)-3-hydroxy-4-(3-propylphenyl)but-1-enyl]-5-thioxopyrrol-
idine-1-yl}heptanoic acid.
3. The compound according to claim 1, which is represented by
formula (I-1): ##STR66## wherein G.sup.1 is ringA.sup.1 or C1-4
alkylene, ringA.sup.1 is ##STR67## wherein left-pointing arrow
represents binding to S, and right-pointing arrow represents
binding to COOR.sup.1, ringB.sup.1 is C3-7 cycloalkyl, ##STR68##
ringB.sup.1 may be substituted with a halogen atom, C1-4 alkyl,
phenyl, methoxymethyl, trifluoromethyl and/or trifluoromethoxy,
other symbols have the same meanings as described in claim 1, and
wherein when T is oxygen, X is --CH.sub.2--, and when n is an
integer of 2-4, G.sup.1 is ringA.sup.1.
4. The compound according to claim 3, which is selected from the
group consisting of: (1)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-phenylphenyl)-17,18,19,20-tetranol-
-5-thia-8-aza-10-oxaprost-13-enoic acid, (2)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-ethylphenyl)-17,18,19,20-tetranol--
5-thia-8-aza-10-oxaprost-13-enoic acid, (3)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chloro-4-fulorophenyl)-17,18,19,20-
-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid, (4)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(naphthalene-2-yl)-17,18,19,20-tetran-
ol-5-thia-8-aza-10-oxaprost-13-enoic acid, (5)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethoxyphenyl)-17,18,19,2-
0-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid, (6)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fuloro-3-phenylphenyl)-17,18,19,20-
-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid, (7)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fuloro-3-methylphenyl)-17,18,19,20-
-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid, (8)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3,5-difulorophenyl)-17,18,19,20-tetr-
anol-5-thia-8-aza-10-oxaprost-13-enoic acid, (9)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-fulorophenyl)-17,18,19,20-tetranol-
-5-thia-8-aza-10-oxaprost-13-enoic acid, (10)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fuloro-3-trifuloromethylphenyl)-17-
,18,19,20-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid, (11)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-trifuloromethylphenyl)-17,18,19,20-
-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid, (12)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3,4-difulorophenyl)-17,18,19,20-tetr-
anol-5-thia-8-aza-10-oxaprost-13-enoic acid, (13)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranol-5-thia-8--
aza-10-oxaprost-13-enoic acid, (14)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranol-
-5-thia-8-aza-10-oxaprost-13-enoic acid, (15)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-t-
etranol-5-thia-8-aza-10-oxaprost-13-enoic acid, (16)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-ethyl-4-fulorophenyl)-17,18,19,20--
tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid, (17)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-phenyl-5-(4-carboxythiazol-2-yl)-1,2,-
3,4,17,18,19,20-octanol-5-thia-8-aza-10-oxaprost-13-ene, (18)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxythiazol--
2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-aza-10-oxaprost-13-ene,
(19)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fulorophenyl)-5-(4-carboxythiazol--
2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-aza-10-oxaprost-13-ene,
(20)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(naphthalene-2-yl)-5-(4-carboxythiazo-
l-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-aza-10-oxaprost-13-ene,
(21)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-phenylphenyl)-5-(4-carboxythiazol--
2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-aza-10-oxaprost-13-ene,
(22)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-phenylphenyl)-5-(5-carboxythiophen-
e-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene, (23)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(naphthalene-2-yl)-5-(5-carboxythioph-
ene-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
(24)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fuloro-3-phenylphenyl)-5-(5-carbox-
ythiophene-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
(25)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-ethylphenyl)-5-(5-carboxythio-
phene-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
(26)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(5-carboxythiophen-
e-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene, (27)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethoxyphenyl)-5-(5-carbo-
xythiophene-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
(28)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fuloro-3-phenylphenyl)-5-(4-c-
arboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
(29)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-ethylphenyl)-5-(4-carboxythia-
zol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
(30)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(naphthalene-2-yl)-5-(4-carboxythiazo-
l-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene, (31)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethoxyphenyl)-5-(4-carbo-
xythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
(32)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chloro-4-fulorophenyl)-5-(4-c-
arboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
(33)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-cyclopropyl-5-(4-carboxythiazol--
2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene, (34)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-cyclohexyl-5-(4-carboxythiazol-2-yl)--
1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene, (35)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fulorophenyl)-5-(5-carboxythiazol--
2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene, (36)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-cyclobutyl-5-(4-carboxythiazol-2-yl)--
1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene, (37)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-chlorophenyl)-5-(4-carboxythiazol--
2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene, (38)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-cycloheptyl-5-(4-carboxythiazol-2-yl)-
-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene, (39)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(indane-2-yl)-5-(4-carboxythiazol-2-y-
l)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene, (40)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(tetrahydropyran-4-yl)-5-(4-carboxyth-
iazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
(41)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(7-methylnaphthalene-2-yl)-5-(4-carbo-
xythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
(42)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fulorophenyl)-17,18,19,20-tet-
ranol-5,10-dithia-8-azaprost-13-enoic acid, (43)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fulorophenyl)-17,18,19,20-tetranol-
-6-thia-8-azaprost-13-enoic acid, (44)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranol-
-6-thia-8-azaprost-13-enoic acid, and (45)
(15.alpha.,13E)-9-thioxo-15-hydroxy-16-(4-fulorophenyl)-17,18,19,20-tetra-
nol-5-thia-8-azaprost-13-enoic acid.
5. The compound according to claim 1, which is represented by
formula (I-2): ##STR69## wherein G.sup.2 is ##STR70## wherein
left-pointing arrow represents binding to --(CH.sub.2).sub.2--, and
right-pointing arrow represents binding to D, R.sup.4 is (1) a
halogen atom, (2) C1-4 alkyl (3) C1-4 alkoxy, (4) C1-4 alkyl
optionally substituted with 1-5 of halogen atom(s), (5) C1-4 alkoxy
optionally substituted with 1-5 of halogen atom(s), (6) phenyl or
(7) 3- to 15-membered mono-, bi- or tri-heterocyclic aryl
containing 1 to 4 hetero atom(s) selected from oxygen, nitrogen and
sulfur atom(s) which may be partially or fully saturated, and (6)
phenyl or (7) heterocyclic in the R.sup.4 may be substituted with
1-3 of (a) a halogen atom(s), (b) C1-4 alkyl (c) C1-4 alkoxy and/or
(d) nitro, r is an integer 1 to 5, and other symbols have the same
meanings as described in claim 1.
6. The compound according to claim 5, which is selected from the
group consisting of: (1)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3,5-dimethy-
lphenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid, (2)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(benzothi-
azol-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid, (3)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(4-fulor-
ophenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid, (4)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(5-methylbenzothiazol-2-yl)phenyl)-
-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-1-
3-ene, (5)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(5-methyl-
benzoxazol-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid, (6)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(6-methylbenzoxazol-2-yl)phenyl)-5-
-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13--
ene, (7)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3--
(6-methylbenzoxazol-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-
-enoic acid, (8)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(4-methyl-
benzothiazol-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid, (9)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(4-methylbenzothiazol-2-yl)phenyl)-
-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-1-
3-ene, (10)
(15.alpha.,13E)-1,6-(2-fuloro-1,4-interphenylene)-9-oxo-15-hydroxy-16-(3--
methylphenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,
(11)
(15.alpha.,13E)-1,6-(3-methyl-1,4-interphenylene)-9-oxo-15-hydroxy-16-(3--
methylphenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,
(12)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(5,7-dimethylbenzoxazol-2-yl)pheny-
l)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-
-13-ene, (13)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(5-chlorobenzothiazol-2-yl)phenyl)-
-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-1-
3-ene, (14)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(5-chloro-
benzothiazol-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid, (15)
(15.alpha.)-9-oxo-15-hydroxy-16-(3-(2,4-dimethylphenyl)phenyl)-5-(4-carbo-
xythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
(16)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(3,4-dimethylphenyl)phenyl)-5-
-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13--
ene, (17)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-
,4-difluorophenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid, (18)
(15.alpha.,13E)-1,6-(2-methyl-1,4-interphenylene)-9-oxo-15-hydroxy-1-
6-(3-methylphenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid, (19)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(5-chlorobenzoxazol-2-yl)phen-
yl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azapros-
t-13-ene, (20)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-methyl-4--
fulorophenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,
(21)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-chloro-4--
fulorophenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,
(22)
(15.alpha.,13E)-1,6-(3-methoxy-1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-
-methylphenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid, (23)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethoxyphenyl)-17,18,19,2-
0-tetranol-5-thia-8-azaprost-13-enoic acid, (24)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3,5-difluorophenyl)-17,18,19,20-tetr-
anol-5-thia-8-azaprost-13-enoic acid, (25)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(phenyl)phenyl)-17,18,19,20-tetran-
ol-5-thia-8-azaprost-13-enoic acid, (26)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(4-fulorophenyl)phenyl)-17,18,19,2-
0-tetranol-5-thia-8-azaprost-13-enoic acid, and (27)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-phenyl-4-fulorophenyl)-17,18,19,20-
-tetranol-5-thia-8-azaprost-13-enoic acid.
7. A pharmaceutical composition comprising the compound represented
by formula (I) according to claim 1, a salt thereof, a solvate
thereof, a cyclodextrin clathlate thereof, or a prodrug thereof,
and a pharmaceutically acceptable carrier.
8. An EP4 agonist comprising the compound represented by formula
(I) according to claim 1, a salt thereof, a solvate thereof or a
cyclodextrin clathlate thereof, or a prodrug thereof, and a
pharmaceutically acceptable carrier.
9. A method for preventing and/or treating EP4-mediated disease,
which comprises administrating to a mammal an effective amount of
the compound represented by formula (I) according to claim 1, a
salt thereof, a solvate thereof or a cyclodextrin clathrate
thereof, or a prodrug thereof.
Description
[0001] This application is a divisional of pending U.S. application
Ser. No. 10/542,724 (Confirmation No. 5408) filed Jul. 20, 2005,
which is a National Stage application of PCT Application No.
PCT/JP04/00419, filed Jan. 20, 2004, which claims priority of
Japanese Patent Application Nos. JP 2003-011936, filed Jan. 21,
2003, and JP 2003-289954, filed Aug. 8, 2003, the disclosure of
each of which is incorporated herein by reference in its
entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to the compounds having
8-azaprostaglandin skeleton useful for pharmaceuticals and the
pharmaceutical composition comprising them as an active
ingredient.
BACKGROUND OF THE INVENTION
[0003] Prostaglandin E.sub.2 (abbreviated as PGE.sub.2) has been
known as a metabolite in the arachidonate cascade. It has been
known that PGE.sub.2 possesses cyto-protective activity, uterine
contractive activity, a pain-inducing effect, a promoting effect on
peristaltic movement, an awakening effect, a suppressive effect on
gastric acid secretion, hypotensive activity and diuretic activity
and so on.
[0004] A recent study has proved existence of various PGE subtype
receptors possessing a different physical role from each other. At
present, four receptor subtypes are known and they are called
EP.sub.1, EP.sub.2, EP.sub.3, and EP.sub.4 (Negishi M., et al., J.
Lipid Mediators Cell Signaling, 12, 379-391 (1995)).
[0005] Among these, it is thought that EP.sub.4 subtype receptor
relates to inhibition of TNF-.alpha. production and acceleration of
IL-10 production. Therefore, the compounds which can bind on
EP.sub.4 subtype receptor are expected to be useful for the
prevention and/or treatment of immunological diseases (autoimmune
disease such as amyotrophic lateral sclerosis (ALS), multiple
sclerosis, Sjoegren's syndrome, chronic rheumarthrosis and systemic
lupus erythematosus, etc., and rejection after organ
transplantation, etc.), asthma, neuronal cell death, arthritis,
lung failure, pulmonary fibrosis, pulmonary emphysema, bronchitis,
chronic obstructive pulmonary disease, liver damage, acute
hepatitis, nephritis (acute nephritis, chronic nephritis), renal
insufficiency, hypertension, myocardial ischemia, systemic
inflammatory response syndrome, sepsis, hemophagous syndrome,
macrophage activation syndrome, Still's disease, Kawasaki disease,
burn, systemic granulomatosis, ulcerative colitis, Crohn's disease,
hypercytokinemia at dialysis, multiple organ failure, shock and
glaucoma, etc. It is also thought that EP.sub.4 subtype receptor
relates to protecting of mucosa. Therefore, the compounds which can
bind on EP.sub.4 subtype receptor are expected to be useful for the
prevention and/or treatment of ulcer of gastrointestinal tract such
as gastric ulcer and duodenal ulcer, etc. and stomatitis. It is
also thought that EP.sub.4 subtype receptor relates to hair growth
function. Therefore, the compounds which can bind on EP.sub.4
subtype receptor are expected to be useful for the prevention
and/or treatment of hair-disadvantaged and alopecia. Furthermore,
it is also thought that EP.sub.4 subtype receptor relates to
maturation of cervix. Therefore, the compounds which can bind on
EP.sub.4 subtype receptor are expected to be useful for the
promoter of (maturation of) cervix.
[0006] Furthermore, the compounds which can bind on EP.sub.4
subtype receptor also have an action of accelerating bone
formation, so it is expected to be useful for the prevention and/or
treatment of diseases associated with loss in bone mass, for
example, [0007] 1) primary osteoporosis (e.g., primary osteoporosis
followed by aging, postmenopausal primary osteoporosis, primary
osteoporosis followed by ovariectomy, etc.), [0008] 2) secondary
osteoporosis (e.g., glucocorticoid-induced osteoporosis,
hyperthyroidism-induced osteoporosis, immobilization-induced
osteoporosis, heparin-induced osteoporosis,
immunosuppressive-induced osteoporosis, osteoporosis due to renal
failure, inflammatory osteoporosis, osteoporosis followed by
Cushing's syndrome, rheumatoid osteoporosis, etc.), [0009] 3) bone
diseases such as bone metastasis of cancer, hypercalcemia, Paget's
disease, bone loss (alveolar bone loss, mandibular bone loss,
childhood idiopathic bone loss, etc.), osteonecrosis, etc. Besides
treatment of the above diseases, the present invention also
includes a pharmaceutical composition for accelerating bone
formation after bone operation (e.g., bone formation after
fractures, bone formation after bone grafting, bone formation after
operation of artificial joint, bone formation after spinal fusion
and bone formation after the other operation for bone regeneration,
etc.), or promoting treatment thereof, or alternative treatment for
bone grafting.
[0010] It is also thought that EP.sub.4 subtype receptor relates to
induction of physiological sleeping and suppression of blood
platelet aggregation, so the compounds which can bind on EP.sub.4
subtype receptor are expected to be useful for the prevention
and/or treatment of sleep disorder and thrombosis.
[0011] The compounds which can bind on EP.sub.4 subtype receptor
selectively do not have inducing pain which may be caused by
EP.sub.1 and uterine contraction which may be caused by EP.sub.3,
so they are thought to be agents having no effect on the above
actions.
[0012] As the EP4 agonistic compound, reported is the compound
represented by formula (Ia) (cf. WO03/009872): ##STR2##
[0013] wherein is a single bond or a double bond,
[0014] R.sup.19a and R.sup.20a are each independently, a hydrogen
atom, C1-10 alkyl or a halogen atom,
[0015] T.sup.a is oxygen or sulfur,
[0016] X.sup.a is --CH.sub.2--, --O-- or --S--,
[0017] A.sup.a is A.sup.1a or A.sup.2a,
[0018] A.sup.1a is C2-8 straight-chain alkylene optionally
substituted with 1-2 of C1-4 alkyl, C2-8 straight-chain alkenylene
optionally substituted with 1-2 of C1-4 alkyl or C2-8
straight-chain alkynylene optionally substituted with 1-2 of C1-4
alkyl,
[0019] A.sup.2a is -G.sup.1a-G.sup.2a-G.sup.3a-,
[0020] G.sup.1a is C1-4 straight-chain alkylene optionally
substituted with 1-2 of C1-4 alkyl, C2-4 straight-chain alkenylene
optionally substituted with 1-2 of C1-4 alkyl or C2-4
straight-chain alkynylene optionally substituted with 1-2 of C1-4
alkyl,
[0021] G.sup.2a is --Y.sup.a--, -(ring1.sup.a)-,
--Y.sup.a-(ring1.sup.a)-, -(ring1.sup.a)-Y.sup.a-- or
--Y.sup.a--(C1-4 alkylene)-(ring1.sup.a),
[0022] Y.sup.a is --S--, --SO--, --SO.sub.2--, --O-- or
--NR.sup.1a--,
[0023] R.sup.1a is a hydrogen atom, C1-10 alkyl or C2-10 acyl,
[0024] G.sup.3a is a bond, C1-4 straight-chain alkylene optionally
substituted with 1-2 of C1-4 alkyl, C2-4 straight-chain alkenylene
optionally substituted with 1-2 of C1-4 alkyl or C2-4
straight-chain alkynylene optionally substituted with 1-2 of C1-4
alkyl,
[0025] D.sup.a is D.sup.1a or D.sup.2a,
[0026] D.sup.1a is --COOH, --COOR.sup.2a, tetrazol-5-yl or
CONR.sup.3aSO.sub.2R.sup.4a,
[0027] R.sup.2a is C1-10 alkyl, phenyl, C1-10 alkyl substituted
with phenyl or biphenyl,
[0028] R.sup.3a is a hydrogen atom or C1-10 alkyl,
[0029] R.sup.4a is C1-10 alkyl or phenyl,
[0030] D.sup.2a is (1) --CH.sub.2OH, (2) --CH.sub.2OR.sup.5a, (3)
hydroxy, (4) --OR.sup.5a, (5) formyl, (6) --CONR.sup.6aR.sup.7a,
(7) --CONR.sup.6aSO.sub.2R.sup.8a, (8) --CO--(NH-amino acid
residue-CO).sub.m--OH, (9) --O--(CO-amino acid residue
--NH).sub.m--H, (10) --COOR.sup.9a, (11) --OCO--R.sup.10a, (12)
--COO-Z.sup.1a-Z.sup.2a-Z.sup.3a, or ##STR3##
[0031] R.sup.5a is C1-10 alkyl,
[0032] R.sup.6a and R.sup.7a are each independently, a hydrogen
atom or C1-10 alkyl,
[0033] R.sup.8a is C1-10 alkyl substituted with phenyl,
[0034] R.sup.9a is (1) C1-10 alkyl substituted with biphenyl
optionally substituted with 1-3 of C1-10 alkyl, C1-10 alkoxy or a
halogen atom or (2) biphenyl substituted with 1-3 of C1-10 alkyl,
C1-10 alkoxy or a halogen atom,
[0035] R.sup.10a is phenyl or C1-10 alkyl,
[0036] m is 1 or 2,
[0037] Z.sup.1a is C1-15 alkylene, C2-15 alkenylene or C2-15
alkynylene,
[0038] Z.sup.2a is (1) --CO--, (2) --OCO--, (3) --COO--, (4)
--CONR.sup.11a--, (5) --NR.sup.12aCO--, (6) --O--, (7) --S--, (8)
--SO--, (9) --SO.sub.2--, (10) --NR.sup.13a--, (11)
--NR.sup.14aCONR.sup.15a--, (12) --NR.sup.16aCOO--, (13)
--OCONR.sup.17a-- or (14) --OCOO--,
[0039] Z.sup.3a is (1) a hydrogen atom, (2) C1-15 alkyl, (3) C2-15
alkenyl, (4) C2-15 alkynyl, (5) ring2.sup.a or (6) C1-10 alkyl
substituted with C1-10 alkoxy, C1-10 alkylthio, C1-10
alkyl-NR.sup.18a-- or ring2.sup.a,
[0040] R.sup.11a, R.sup.12a, R.sup.13a, R.sup.14a, R.sup.15a,
R.sup.16a, R.sup.17a and R.sup.18a are each independently, a
hydrogen atom or C1-15 alkyl, R.sup.11a and Z.sup.3a may be taken
together with the nitrogen atom to which they are attached to form
5- to 7-membered saturated monoheterocyclic ring, and said
heterocyclic ring may contain other one hetero atom selected from
oxygen, nitrogen and sulfur atom,
[0041] E.sup.a is E.sup.1a or E.sup.2a,
[0042] E.sup.1a is C3-7 cycloalkyl or ring3.sup.a,
[0043] E.sup.2a is C3-7 cycloalkyl, ring4.sup.a or ring5.sup.a,
[0044] ring1.sup.a and ring5.sup.a are optionally substituted with
1-3 of R.sup.21a and/or R.sup.22a,
[0045] ring3.sup.a is optionally substituted with 1-2
R.sup.21a,
[0046] C3-7 cycloalkyl represented by E.sup.2a is substituted with
one of R.sup.21a or R.sup.22a, and optionally substituted with
another 1-2 of R.sup.21a and/or R.sup.22a,
[0047] ring4.sup.a is substituted with one of R.sup.22a, optionally
substituted with another 1-2 of R.sup.21a and/or R.sup.22a, and
optionally substituted with a heterocyclic ring formed by
R.sup.11a, Z.sup.3a and the nitrogen to which Z.sup.3a is attached
or ring2.sup.a may be substituted with R.sup.23a,
[0048] R.sup.21a is C1-10 alkyl, C1-10 alkoxy, a halogen atom,
nitro, C1-10 alkyl substituted with 1-3 of halogen atom(s) or
phenyl,
[0049] R.sup.22a is (1) C2-10 alkenyl, (2) C2-10 alkynyl, (3) C1-10
alkylthio, (4) hydroxy, (5) --NR.sup.24aR.sup.25a, (6) C1-10 alkyl
substituted with C1-10 alkoxy, (7) C1-10 alkyl substituted with
C1-10 alkoxy substituted with 1-3 of halogen atom(s), (8) C1-10
alkyl substituted with --NR.sup.24aR.sup.25a, (9) ring6.sup.a, (10)
--O-ring7.sup.a, (11) C1-10 alkyl substituted with ring7.sup.a,
(12) C2-10 alkenyl substituted with ring7.sup.a, (13) C2-10 alkynyl
substituted with ring7.sup.a, (14) C1-10 alkoxy substituted with
ring7.sup.a, (15) C1-10 alkyl substituted with --O-ring7.sup.a,
(16) --COOR.sup.26a or (17) C1-10 alkoxy substituted with 1-3 of
halogen atom(s),
[0050] R.sup.24a, R.sup.25a and R.sup.26a are each independently, a
hydrogen atom or C1-10 alkyl,
[0051] R.sup.23a is (1) C1-15 alkyl, (2) C2-15 alkenyl, (3) C2-15
alkynyl or (4) C1-10 alkyl substituted with C1-10 alkoxy, C1-10
alkylthio or C1-10 alkyl-NR.sup.27a--,
[0052] R.sup.27a is a hydrogen atom or C1-10 alkyl,
[0053] ring1.sup.a, ring2.sup.a, ring5.sup.a, ring6.sup.a and
ring7.sup.a are (1) C3-15 mono-, bi- or tri-carbocyclic aryl which
may be partially or fully saturated or (2) 3- to 15-membered mono-,
bi- or tri-heterocyclic aryl containing 1 to 4 hetero atom(s)
selected from oxygen, nitrogen and sulfur atom(s) which may be
partially or fully saturated,
[0054] ring3.sup.a and ring4.sup.a are thienyl, phenyl or
furyl,
[0055] ring6.sup.a and ring7.sup.a may be substituted with 1-3 of
R.sup.28a,
[0056] R.sup.28a is (1) C1-10 alkyl, (2) C2-10 alkenyl, (3) C2-10
alkynyl, (4) C1-10 alkoxy, (5) C1-10 alkyl substituted with C1-10
alkoxy, (6) halogen atom, (7) hydroxy, (8) C1-10 alkyl substituted
with 1-3 of halogen atom(s) or (9) C1-10 alkyl substituted with
C1-10 alkoxy substituted with 1-3 of halogen atom(s), and
[0057] wherein (1) when T.sup.a is an oxygen atom, X.sup.a is
CH.sub.2--, A.sup.a is A.sup.1a, and D.sup.a is D.sup.1a, then
E.sup.a is E.sup.2a,
[0058] (2) ring5.sup.a is not C3-7 cycloalkyl, phenyl, thienyl nor
furyl,
[0059] (3) ring6.sup.a is phenyl, then phenyl have at least one
R.sup.28a. The present invention is the selective invention in the
WO03/009872 and the compounds in the present invention are included
within the compound represented by formula (Ia).
[0060] In addition, the specification of U.S. Pat. No. 4,177,346
discloses the compound represented by formula (A) ##STR4##
[0061] wherein Q.sup.A is selected from the group consisting of
--COOR.sup.3A, tetrazol-5-yl and --CONHR.sup.4A;
[0062] A.sup.A is a single bond or a cis-double bond;
[0063] B.sup.A is a single bond or a trans-double bond;
[0064] U.sup.A is ##STR5##
[0065] R.sup.2A is selected from the group consisting of
.alpha.-thienyl, phenyl, phenoxy, mono-substituted phenyl and
mono-substituted phenoxy, and said substituent is selected from the
group consisting of chlorine, fluorine, phenyl, methoxy,
trifluoromethyl and C1-3 alkyl;
[0066] R.sup.3A is selected from the group consisting of hydrogen,
C1-5 alkyl, phenyl and p-biphenyl;
[0067] R.sup.4A is selected from the group consisting of
--COR.sup.5A and --SO.sub.2R.sup.5A;
[0068] R.sup.5A is selected from the group consisting of phenyl and
C1-5 alkyl, and
[0069] a C5 epimer thereof, the salt of alkali metal and alkaline
earth metals and ammonium salt of the compound which have
carboxylate or tetrazol-5-yl.
[0070] And in the specification of JP-A-2001-181210, it is
disclosed that the selective EP.sub.4 receptor agonist represented
by above-mentioned formula (A) is useful for the treatment of
osteoporosis.
[0071] And the specification of United Kingdom Patent No. 1,553,595
discloses the pyrrolidone derivatives represented by formula (B)
##STR6##
[0072] wherein R.sup.1B is a straight- or branched-chain, saturated
or unsaturated, aliphatic hydrocarbon radical having up to 10
carbon atoms, or a cycloaliphatic hydrocarbon radical having 3 to 7
carbon atoms, which radicals may be unsubstituted or substituted
with one or more of the following: e) a cycloalkyl group of 3 to 7
carbon atoms, f) a phenyl, thienyl or furyl group which may carry
one or two substituents selected from optionally halogenated alkyl
group of 1 to 3 carbon atoms, halogen atoms and alkoxy group of 1
to 4 carbon atoms,
[0073] R.sup.2B is a straight- or branched-chain, saturated or
unsaturated, aliphatic or cycloaliphatic hydrocarbon radical having
up to 6 carbon atoms, or an araliphatic hydrocarbon radical having
7 or 8 carbon atoms, and
[0074] nB is the integer 2, 3 or 4, and
[0075] a free acid, and the physiologically acceptable e.g. metal
or amine, a salt thereof.
[0076] In the specifications of United Kingdom Patent No.
1,569,982, and United Kingdom Patent No. 1,583,163, the compound
close to the compound represented by formula (B) is disclosed.
[0077] Further, the specification of U.S. Pat. No. 4,320,136
discloses the compound represented by formula (C) ##STR7##
[0078] wherein A.sup.C is --CH.dbd.CH-- (cis or trans),
--C.ident.C-- or --CH.sub.2CH.sub.2--;
[0079] R.sup.C is hydrogen, C1-C12 n-alkyl, branched alkyl or
cycloalkyl, etc.;
[0080] R.sup.1C is hydrogen, methyl or ethyl;
[0081] R.sup.2C is phenyl or mono- or di-substituted phenyl, said
substituent is selected from the group consisting of, fluorine,
chlorine, methyl, methoxy, nitro or trifluoromethyl;
[0082] when R.sup.2C is phenyl or substituted phenyl, nC is 0-2,
the definitions of the symbols are excerpt.
[0083] Further, in the specification of WO02/042268 it was
disclosed that the compound is EP.sub.4 receptor subtype
agonist.
SUMMARY OF THE INVENTION
[0084] PGE.sub.2 receptors have four subtypes, they are called
EP.sub.1, EP.sub.2, EP.sub.3 and EP.sub.4 respectively, and they
have different pharmacological action respectively. Thus, if new
compound can be found out to specifically bind on EP4 receptor and
to weakly bind on the other subtypes, the compound does not express
other action. So, it is possible for the compound to be drug having
little side effect and it is necessary to found out such a
drug.
[0085] In contrast, a lot of EP4 agonistic compounds have ever
found out, but they have prostanoic acid skeleton, and when they
are administered by systemic administration, such as oral
administration, intravenous administration, etc., there is concern
about side effect, such as the effect on circulatory systems, e.g.
blood pressure decreased, heart rate increase, etc., diarrhea, etc.
Therefore, there was large problem that the dosage capable of
safety administration is limited.
[0086] As a result of the present inventors made further
investigation to find out the compound which specifically binds on
EP.sub.4 receptor, averts the above-mentioned side effect and shows
strong agonistic activity, they found out that the compound
represented by formula (I) accomplished these purposes and
completed the present invention.
[0087] The present inventors also thought that the therapeutic
agent (treatment of diseases associated with loss in bone mass,
particularly) without side-effect in systemic administration can be
created, if EP.sub.4 agonist which is the compound of the invention
can be administered topically. They also conceived that the
therapeutic agent (treatment of diseases associated with decrease
in bone mass, particularly) without side-effect in systemic
administration and with less frequency of administration can be
created, if the EP.sub.4 agonist which can be a sustained release
formulation in the topical administration can be found out.
[0088] Further, the present inventors found out the compound which
binds on both EP.sub.4 and EP.sub.2 subtype receptor. The compound
which binds to both EP.sub.4 and EP.sub.2 subtype receptor is
expected additive or multiplier effect when treatment of the
disease associated with both subtype receptors.
[0089] The present invention relates to the followings: 1. A
compound represented by formula (I) ##STR8##
[0090] wherein is a single bond or double bond,
[0091] is .alpha.-configuration, .beta.-configuration or a
voluntary mixture of .alpha.-configuration and
.beta.-configuration,
[0092] D is --COOR.sup.1 or tetrazoryl,
[0093] R.sup.1 is hydrogen or C1-4 alkyl,
[0094] G is ringA or C1-4 alkylene,
[0095] ringA is ##STR9##
[0096] R.sup.2 is a halogen atom, C1-4 alkyl or C1-4 alkoxy,
[0097] p is 0 or an integer of 1-4,
[0098] when p is 2 or more, plural R.sup.2's are the same or
different,
[0099] Y is a single bond or --S--,
[0100] T is oxygen or sulfur,
[0101] X is --CH.sub.2--, --O-- or --S--,
[0102] ringB is C3-7 cycloalkyl optionally substituted,
##STR10##
[0103] wherein R.sup.3 is (1) a halogen atom, (2) C1-4 alkyl
optionally substituted with 1-5 of halogen atom(s), (3) C1-4 alkoxy
optionally substituted with 1-5 of halogen atom(s), (4) C1-4 alkyl
substituted with C1-4 alkoxy, (5) phenyl or (6) 3- to 15-membered
mono-, bi- or tri-heterocyclic aryl containing 1 to 4 hetero
atom(s) selected from oxygen, nitrogen and sulfur atom(s) which may
be partially or fully saturated, and
[0104] (5) phenyl or (6) heterocyclic aryl in R.sup.3 is optionally
substituted with 1-3 of (a) halogen atom(s), (b) C1-4 alkyl, (c)
C1-4 alkoxy and/or (d) nitro,
[0105] q is 0 or an integer of 1-5,
[0106] when q is 2 or more, plural R.sup.3's are the same or
different,
[0107] n is an integer of 1-4,
[0108] a salt thereof, a solvate thereof, a cyclodextrin clathrate
thereof, or a prodrug thereof.
2. The compound according to above-mentioned 1, which is selected
from the group consisting of:
[0109] (1)
4-[(2-{(4S)-4-[(1E,3S)-4-(3-ethylphenyl)-3-hydroxybut-1-enyl]-2-oxo-1,3-t-
hiazolidine-3-yl]ethyl)sulfanyl]butanoic acid, [0110] (2)
4-[(2-{(4S)-4-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazolidi-
ne-3-yl}ethyl)sulfanyl]butanoic acid, [0111] (3)
4-{[2-{(4S)-4-{(1E,3S)-4-[4-fuloro-3-(trifluoromethyl)phenyl]-3-hydroxybu-
t-1-enyl}-2-oxo-1,3-thiazolidine-3-yl)ethyl]sulfanyl}butanoic acid,
[0112] (4)
4-[(2-{(4S)-4-[(1E,3S)-4-(3,5-difluorophenyl)-3-hydroxybut-1-enyl]-2-oxo--
1,3-thiazolidine-3-yl}ethyl)sulfanyl]butanoic acid, [0113] (5)
4-[(2-{(4S)-4-[(1E,3S)-3-hydroxy-4-(3-propylphenyl)but-1-enyl]-2-oxo-1,3--
thiazolidine-3-yl]ethyl)sulfanyl]butanoic acid, [0114] (6)
4-[(2-{(4S)-4-[(1E,3S)-4-(3-ethyl-4-fulorophenyl)-3-hydroxybut-1-enyl]-2--
oxo-1,3-thiazolidine-3-yl}ethyl)sulfanyl]butanoic acid, [0115] (7)
4-[(2-{(4S)-4-[(1E,3S)-4-(3,4-difluorophenyl)-3-hydroxybut-1-enyl]-2-oxo--
1,3-thiazolidine-3-yl}ethyl)sulfanyl)butanoic acid. [0116] (8)
4-{[2-((4S)-4-{(1E,3S)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]but-1-enyl]-
-2-oxo-1,3-thiazolidine-3-yl}ethyl)sulfanyl]butanoic acid, [0117]
(9)
4-[2-{(4S)-4-[(1E,3S)-4-(4-fuloro-3-methylphenyl)-3-hydroxybut-1-enyl]-2--
oxo-1,3-thiazolidine-3-yl}ethyl)sulfanyl]butanoic acid, [0118] (10)
4-[(2-{(4S)-4-[(1E,3S)-4-(3-fulorophenyl)-3-hydroxybut-1-enyl]-2-oxo-1,3--
thiazolidine-3-yl}ethyl)sulfanyl]butanoic acid, [0119] (11)
4-[(2-{(4S)-4-[(1E,3S)-4-(3-chloro-4-fulorophenyl)-3-hydroxybut-1-enyl]-2-
-oxo-1,3-thiazolidine-3-yl}ethyl)sulfanyl]butanoic acid, [0120]
(12)
4-{[2-((4S)-4-{(1E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]but-1-enyl}-2-
-oxo-1,3-thiazolidine-3-yl)ethyl]sulfanyl}butanoic acid, [0121]
(13)
7-{(2R)-2-[(1E,3S)-4-(4-fulorophenyl)-3-hydroxybut-1-enyl]-5-thioxopyrrol-
idine-1-yl}heptanoic acid, [0122] (14)
7-{(2R)-2-[(1E,3S)-4-(3,5-difluorophenyl)-3-hydroxybut-1-enyl]-5-thioxopy-
rrolidine-1-yl}heptanoic acid, [0123] (15)
7-((2R)-2-{(1E,3S)-4-[4-fuloro-3-(trifluoromethyl)phenyl]-3-hydroxybut-1--
enyl}-5-thioxopyrrolidine-1-yl)heptanoic acid, [0124] (16)
7-{(2R)-2-[(1E,3S)-4-(4-fuloro-3-methylphenyl)-3-hydroxybut-1-enyl]-5-thi-
oxopyrrolidine-1-yl}heptanoic acid, [0125] (17)
7-{(2R)-2-[(1E,3S)-4-(3-ethyl-4-fulorophenyl)-3-hydroxybut-1-enyl]-5-thio-
xopyrrolidine-1-yl}heptanoic acid, [0126] (18)
7-((2R)-2-{(1E,3S)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]but-1-enyl}-5-t-
hioxopyrrolidine-1-yl)heptanoic acid, [0127] (19)
7-{(2R)-2-[(1E,3S)-4-(3-fulorophenyl)-3-hydroxybut-1-enyl]-5-thioxopyrrol-
idine-1-yl}heptanoic acid, [0128] (20)
7-{(2R)-2-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-5-thioxopyrrolidine-1-yl-
}heptanoic acid, [0129] (21)
7-{(2R)-2-[(1E,3S)-4-(3,4-difluorophenyl)-3-hydoroxybut-1-enyl]-5-thioxop-
yrrolidine-1-yl}heptanoic acid, [0130] (22)
7-{(2R)-2-[(1E,3S)-4-(3-chloro-4-fulorophenyl)-3-hydroxybut-1-enyl]-5-thi-
oxopyrrolidine-1-yl}heptanoic acid, [0131] (23)
7-{(2R)-2-[(1E,3S)-4-(3-ethylphenyl)-3-hydroxybut-1-enyl]-5-thioxopyrroli-
dine-1-yl}heptanoic acid, [0132] (24)
7-{(2R)-2-[(1E,3S)-3-hydroxy-4-(3-propylphenyl)but-1-enyl]-5-thioxopyrrol-
idine-1-yl}heptanoic acid. 3. The compound according to
above-mentioned 1, which is represented by formula (I-1):
##STR11##
[0133] wherein G.sup.1 is ringA.sup.1 or C1-4 alkylene,
[0134] ringA.sup.1 is ##STR12##
[0135] wherein left-pointing arrow represents binding to S, and
right-pointing arrow represents binding to COOR.sup.1,
[0136] ringB.sup.1 is C3-7 cycloalkyl, ##STR13##
[0137] ringB.sup.1 may be substituted with a halogen atom, C1-4
alkyl, phenyl, methoxymethyl, trifluoromethyl and/or
trifluoromethoxy,
[0138] other symbols have the same meanings as described in
above-mentioned 1, and
[0139] wherein when T is oxygen, X is --CH.sub.2--, and
[0140] when n is an integer of 2-4, G.sup.1 is ringA.sup.1.
4. The compound according to above-mentioned 3, which is selected
from the group consisting of:
[0141] (1)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-phenylphenyl)-17,18,19,20-tetranol-
-5-thia-8-aza-10-oxaprost-13-enoic acid, [0142] (2)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-ethylphenyl)-17,18,19,20-tetranol--
5-thia-8-aza-10-oxaprost-13-enoic acid, [0143] (3)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chloro-4-fulorophenyl)-17,18,19,20-
-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid, [0144] (4)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(naphthalene-2-yl)-17,18,19,20-tetran-
ol-5-thia-8-aza-10-oxaprost-13-enoic acid, [0145] (5)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethoxyphenyl)-17,18,19,2-
0-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid, [0146] (6)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fuloro-3-phenylphenyl)-17,18,19,20-
-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid, [0147] (7)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fuloro-3-methylphenyl)-17,18,19,20-
-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid, [0148] (8)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3,5-difluorophenyl)-17,18,19,20-tetr-
anol-5-thia-8-aza-10-oxaprost-13-enoic acid, [0149] (9)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-fulorophenyl)-17,18,19,20-tetranol-
-5-thia-8-aza-10-oxaprost-13-enoic acid, [0150] (10)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fuloro-3-trifluoromethylphenyl)-17-
,18,19,20-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid, [0151]
(11)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-trifuloromethylphenyl)-17,18,19,20-
-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid, [0152] (12)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3,4-difulorophenyl)-17,18,19,20-tetr-
anol-5-thia-8-aza-10-oxaprost-13-enoic acid, [0153] (13)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranol-5-thia-8--
aza-10-oxaprost-13-enoic acid, [0154] (14)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranol-
-5-thia-8-aza-10-oxaprost-13-enoic acid, [0155] (15)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-t-
etranol-5-thia-8-aza-10-oxaprost-13-enoic acid, [0156] (16)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-ethyl-4-fulorophenyl)-17,18,19,20--
tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid, [0157] (17)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-phenyl-5-(4-carboxythiazol-2-yl)-1,2,-
3,4,17,18,19,20-octanol-5-thia-8-aza-10-oxaprost-13-ene, [0158]
(18)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxythiazol--
2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-aza-10-oxaprost-13-ene,
[0159] (19)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fulorophenyl)-5-(4-carboxyth-
iazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-aza-10-oxaprost-13-ene,
[0160] (20)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(naphthalene-2-yl)-5-(4-carboxythiazo-
l-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-aza-10-oxaprost-13-ene,
[0161] (21)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-phenylphenyl)-5-(4-carboxythiazol--
2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-aza-10-oxaprost-13-ene,
[0162] (22)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-phenylphenyl)-5-(5-carboxyth-
iophene-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
[0163] (23)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(naphthalene-2-yl)-5-(5-carboxythioph-
ene-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
[0164] (24)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fuloro-3-phenylphenyl)-5-(5-c-
arboxythiophene-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene-
, [0165] (25)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-ethylphenyl)-5-(5-carboxythiophene-
-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene, [0166]
(26)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(5-carboxythiophen-
e-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
[0167] (27)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethoxyphenyl)-5-(5--
carboxythiophene-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-en-
e, [0168] (28)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fuloro-3-phenylphenyl)-5-(4-carbox-
ythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
[0169] (29)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-ethylphenyl)-5-(4-carboxythiazol-2-
-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene, [0170]
(30)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(naphthalene-2-yl)-5-(4-carboxythiazo-
l-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
[0171] (31)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethoxyphenyl)-5-(4--
carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
[0172] (32)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chloro-4-fulorophenyl)-5-(4-carbox-
ythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
[0173] (33)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-cyclopropyl-5-(4-carboxythiazol-2-yl)-
-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene, [0174] (34)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-cyclohexyl-5-(4-carboxythiazol-2-yl)--
1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene, [0175] (35)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fulorophenyl)-5-(5-carboxythiazol--
2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene, [0176]
(36)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-cyclobutyl-5-(4-carboxythiazol-2-yl)--
1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene, [0177] (37)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-chlorophenyl)-5-(4-carboxythiazol--
2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene, [0178]
(38)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-cycloheptyl-5-(4-carboxythiazol-2-yl)-
-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene, [0179] (39)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(indane-2-yl)-5-(4-carboxythiazol-2-y-
l)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene, [0180]
(40)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(tetrahydropyran-4-yl)-5-(4-carboxyth-
iazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
[0181] (41)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(7-methylnaphthalene-2-yl)-5-(4--
carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
[0182] (42)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fulorophenyl)-17,18,19,20-tetranol-
-5,10-dithia-8-azaprost-13-enoic acid, [0183] (43)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fulorophenyl)-17,18,19,20-tetranol-
-6-thia-8-azaprost-13-enoic acid, [0184] (44)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranol-
-6-thia-8-azaprost-13-enoic acid, and [0185] (45)
(15.alpha.,13E)-9-thioxo-15-hydroxy-16-(4-fulorophenyl)-17,18,19,20-tetra-
nol-5-thia-8-azaprost-13-enoic acid. 5. The compound according to
above-mentioned 1, which is represented by formula (I-2):
##STR14##
[0186] wherein G.sup.2 is ##STR15##
[0187] wherein left-pointing arrow represents binding to
--(CH.sub.2).sub.2--, and right-pointing arrow represents binding
to D,
[0188] R.sup.4 is (1) a halogen atom, (2) C1-4 alkyl (3) C1-4
alkoxy, (4) C1-4 alkyl optionally substituted with 1-5 of halogen
atom(s), (5) C1-4 alkoxy optionally substituted with 1-5 of halogen
atom(s), (6) phenyl or (7) 3- to 15-membered mono-, bi- or
tri-heterocyclic aryl containing 1 to 4 hetero atom(s) selected
from oxygen, nitrogen and sulfur atom(s) which may be partially or
fully saturated, and (6) phenyl or (7) heterocyclic in the R.sup.4
may be substituted with 1-3 of (a) a halogen atom(s), (b) C1-4
alkyl (c) C1-4 alkoxy and/or (d) nitro,
[0189] r is an integer 1 to 5, and
[0190] other symbols have the same meanings as described in
above-mentioned 1.
6. The compound according to above-mentioned 5, which is selected
from the group consisting of
[0191] (1)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3,5-dimethy-
lphenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,
[0192] (2)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(benz-
othiazol-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid, [0193] (3)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(4-fulorophe-
nyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid, [0194]
(4)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(5-methylbenzothiazol-2-yl)phenyl)-
-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-1-
3-ene, [0195] (5)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(5-methyl-
benzoxazol-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid, [0196] (6)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(6-methylbenzoxazol-2-yl)phenyl)-5-
-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13--
ene, [0197] (7)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(6-methyl-
benzoxazol-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid, [0198] (8)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(4-methyl-
benzothiazol-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid, [0199] (9)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(4-methylbenzothiazol-2-yl)phenyl)-
-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-1-
3-ene, [0200] (10)
(15.alpha.,13E)-1,6-(2-fuloro-1,4-interphenylene)-9-oxo-15-hydroxy-16-(3--
methylphenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,
[0201] (11)
(15.alpha.,13E)-1,6-(3-methyl-1,4-interphenylene)-9-oxo-15-hydroxy-16-(3--
methylphenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,
[0202] (12)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(5,7-dimethylbenzoxazol-2-yl)pheny-
l)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-
-13-ene, [0203] (13)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(5-chlorobenzothiazol-2-yl)phenyl)-
-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-1-
3-ene, [0204] (14)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(5-chloro-
benzothiazol-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid, [0205] (15)
(15.alpha.)-9-oxo-15-hydroxy-16-(3-(2,4-dimethylphenyl)phenyl)-5-(4-carbo-
xythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
[0206] (16)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(3,4-dimethylphenyl)phenyl)-5-(4-c-
arboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene,
[0207] (17)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3,4-difluor-
ophenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,
[0208] (18)
(15.alpha.,13E)-1,6-(2-methyl-1,4-interphenylene)-9-oxo-15-hydroxy-1-
6-(3-methylphenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid, [0209] (19)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(5-chlorobenzoxazol-2-yl)phenyl)-5-
-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13--
ene, [0210] (20)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-methyl-4--
fulorophenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,
[0211] (21)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-chloro-4--
fulorophenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid,
[0212] (22)
(15.alpha.,13E)-1,6-(3-methoxy-1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-
-methylphenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid, [0213] (23)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethoxyphenyl)-17,18,19,2-
0-tetranol-5-thia-8-azaprost-13-enoic acid, [0214] (24)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3,5-difluorophenyl)-17,18,19,20-tetr-
anol-5-thia-8-azaprost-13-enoic acid, [0215] (25)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(phenyl)phenyl)-17,18,19,20-tetran-
ol-5-thia-8-azaprost-13-enoic acid, [0216] (26)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(4-fulorophenyl)phenyl)-17,18,19,2-
0-tetranol-5-thia-8-azaprost-13-enoic acid, and [0217] (27)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-phenyl-4-fulorophenyl)-17,18,19,20-
-tetranol-5-thia-8-azaprost-13-enoic acid. 7. A pharmaceutical
composition comprising the compound represented by formula (I)
according to above-mentioned 1, a salt thereof, a solvate thereof,
a cyclodextrin clathlate thereof, or a prodrug thereof. 8. An EP4
agonist comprising the compound represented by formula (I)
according to above-mentioned 1, a salt thereof, a solvate thereof
or a cyclodextrin clathlate thereof, or a prodrug thereof. 9. A
method for preventing and/or treating EP4-mediated disease, which
comprises administrating to a mammal an effective amount of the
compound represented by formula (I) according to claim 1, a salt
thereof, a solvate thereof or a cyclodextrin clathrate thereof, or
a prodrug thereof. 10. Use of the compound represented by formula
(I) according to above-mentioned 1, a salt thereof, a solvate
thereof, a cyclodextrin clathrate thereof, or a prodrug thereof for
the manufacture of an EP4 agonist. 11. A method for preparing the
compound represented by formula (I) according to the
above-mentioned 1, a salt thereof, a solvate thereof, a
cyclodextrin clathrate thereof, or a prodrug thereof.
[0218] In the specification, C1-4 alkyl means methyl, ethyl,
propyl, butyl and the isomers thereof.
[0219] In the specification, C1-4 alkylene means methylene,
ethylene, trimethylene, tetramethylene and the isomers thereof.
[0220] In the specification, C1-4 alkoxy means methoxy, ethoxy,
propoxy, butoxy and the isomers thereof.
[0221] In the specification, C3-7 cycloalkyl means cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
[0222] In the specification, halogen atom means fluorine, chlorine,
bromine and iodine.
[0223] In the specification, substituent in the C3-7 cycloalkyl
optionally with substituent represented by ringB means (1) halogen
atom, (2) C1-4 alkyl optionally substituted with 1-5 of halogen
atom(s), (3) C1-4 alkoxy optionally substituted with 1-5 of halogen
atom(s), (4) C1-4 alkyl substituted with C1-4 alkoxy, (5) phenyl or
(6) 3- to 15-membered mono-, bi-, or tri-heterocyclic aryl may be
partially or fully saturated containing 1 to 4 hetero atom(s)
selected from oxygen, nitrogen and sulfur atom(s). Among these, (5)
phenyl or (6) heterocyclic ring may be substituted with 1-3 of (a)
halogen atom(s), (b) C1-4 alkyl, (3) C1-4 alkoxy and/or (d)
nitro.
[0224] In the specification, C1-4 alkyl substituted with 1-5 of
halogen atom(s) represented by R.sup.4 means fuloromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl,
iodomethyl, diiodomethyl, triiodomethyl, fuloroethyl,
difluoroethyl, trifluoroethyl, tetrafuloroethyl, pentafuloroethyl,
chloroethyl, dichloroethyl, trichloroethyl, tetrachloroethyl,
pentachloroethyl, fuloropropyl, difluoropropyl, trifluoropropyl,
tetrafuloropropyl, pentafuloropropyl, chloropropyl, dichloropropyl,
trichloropropyl, tetrachloropropyl, pentachloropropyl, fulorobutyl,
difulorobutyl, trifulorobutyl, tetrafulorobutyl, pentafulorobutyl,
chlorobutyl, dichlorobutyl, trichlorobutyl, tetrachlorobutyl,
pentachlorobutyl and the isomers thereof.
[0225] In the specification, C1-4 alkyl optionally substituted with
1-5 of halogen atom(s) represented by R.sup.3 means the same
meaning as that of the above mentioned C1-4 alkyl or C1-4 alkyl
substituted with 1-5 of halogen atom(s) represented by R.sup.4.
[0226] In the specification, C1-4 alkoxy substituted with 1-5 of
halogen atom(s) represented by R.sup.4 means fuloromethoxy,
difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy,
trichloromethoxy, bromomethoxy, dibromomethoxy, tribromomethoxy,
iodomethoxy, diiodomethoxy, triiodomethoxy, fuloroethoxy,
difluoroethoxy, trifluoroethoxy, tetrafuloroethoxy,
pentafuloroethoxy, chloroethoxy, dichloroethoxy, trichloroethoxy,
tetrachloroethoxy, pentachloroethoxy, fuloropropoxy,
difluoropropoxy, trifluoropropoxy, tetrafuloropropoxy,
pentafuloropropoxy, chloropropoxy, dichloropropoxy,
trichloropropoxy, tetrachloropropoxy, pentachloropropoxy,
fulorobutoxy, difluorobutoxy, trifluorobutoxy, tetarfulorobutoxy,
pentafulorobutoxy, chlorobutoxy, dichlorobutoxy, trichlorobutoxy,
tetrachlorobutoxy, pentachlorobutoxy and the isomers thereof.
[0227] In the specification, C1-4 alkoxy optionally substituted
with 1-5 of halogen atom(s) represented by R.sup.3 has the same
meaning as that of the above-mentioned C1-4 alkoxy or C1-4 alkoxy
substituted with 1-5 of halogen atom(s) represented by R.sup.4.
[0228] In the specification, 3- to 15-membered mono-, bi-, or
tri-heterocyclic aryl may be partially or fully saturated
containing 1 to 4 hetero atom(s) selected from oxygen, nitrogen and
sulfur atom(s) represented by R.sup.3 or R.sup.4 means, pyrrole,
imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,
pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine,
thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole,
isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine,
oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,
thiadiazepine, indole, isoindole, indolizine, benzofuran,
isobenzofuran, benzothiophene, isobenzothiophene,
dithianaphthalene, indazole, quinoline, isoquinoline, quinolizine,
purine, phthalazine, pteridine, naphthyridine, quinoxaline,
quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole,
chromene, benzoxepine, benzoxazepine, benzoxadiazepine,
benzothiepine, benzothiazepine, benzothiadiazepine, benzazepine,
benzodiazepine, benzofurazan, benzothiadiazole, benzotriazole,
carbazole, beta-carboline, acridine, phenazine, dibenzofuran,
xanthene, dibenzothiophene, phenothiazine, phenoxazine,
phenoxathiin, thianthrene, phenanthridine, phenanthroline,
perimidine, aziridine, azetidine, pyrroline, pyrrolidine,
imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline,
tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine,
tetrahydropyridine, piperidine, dihydropyrazine,
tetrahydropyrazine, piperazine, dihydropyrimidine,
tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine,
tetrahydropyridazine, perhydropyridazine, dihydroazepine,
tetrahydroazepine, perhydroazepine, dihydrodiazepine,
tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane,
dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran,
dihydrooxepine, tetrahydrooxepine, perhydrooxepine, thiirane,
thietane, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,
tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine,
perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine),
dihydroisoxazole, tetrahydroisoxazole (isoxazolidine),
dihydrothiazole, tetrahydrothiazole (thiazolidine),
dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),
dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole,
tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine,
tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine,
dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine,
dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine,
dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine),
dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine,
tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine,
perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine,
perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane,
indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran,
dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,
perhydrobenzothiophene, dihydroisobenzothiophene,
perhydroisobenzothiophene, dihydroindazole, perhydroindazole,
dihydroquinoline, tetrahydroquinoline, perhydroquinoline,
dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,
dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,
dihydronaphthyridine, tetrahydronaphthyridine,
perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline,
perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline,
perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline,
perhydrocinnoline, benzoxathiane, dihydrobenzoxazine,
dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole,
perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole,
dihydrobenzimidazole, perhydrobenzimidazole, dihydrobenzazepine,
tetrahydrobenzazepine, dihydrobenzodiazepine,
tetrahydrobenzodiazepine, benzodioxepane, dihydrobenzoxazepine,
tetrahydrobenzoxazepine, dihydrocarbazole, tetrahydro carbazole,
perhydrocarbazole, dihydroacridine, tetrahydroacridine,
perhydroacridine, dihydrodibenzofuran, dihydrodibenzothiophene,
tetrahydrodibenzofuran, tetrahydrodibenzothiophene,
perhydrodibenzofuran, perhydrodibenzothiophene, dioxolane, dioxane,
dithiolane, dithiane, dioxaindan, benzodioxane, chroman,
benzodithiolane, benzodithiane, 8-aza-1,4-dioxaspiro[4.5]decane,
3-azaspiro[5.5]undecane, 1,3,8-triazaspiro[4.5]decane and so
on.
[0229] In the specification, a connectable bond represented by Y
means that --(CH.sub.2).sub.2-- binds directly to G.
[0230] In the present invention, unless otherwise specified, the
symbol means that the .alpha.-configuration substituent, the symbol
means that the .beta.-configuration substituent, the symbol means
.alpha.-configuration, .beta.-configuration or a voluntary mixture
of .alpha.-configuration and .beta.-configuration, and the symbol
means that there is a voluntary mixture of .alpha.-configuration
and .beta.-configuration as would be clear to the person skilled in
the art.
[0231] Unless otherwise specified, all isomers are included in the
present invention. For example, alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, alkylene alkenylene and alkynylene group means
straight-chain or branched-chain ones. In addition, isomers on
double bond, ring, fused ring (E-, Z-, cis-, trans-isomer), isomers
generated from asymmetric carbon atom(s) (R-, S-isomer, .alpha.-,
.beta.-configuration, enantiomer, diastereomer), optically active
isomers (D-, L-, d-, l-isomer), polar compounds generated by
chromatographic separation (more polar compound, less polar
compound), equilibrium compounds, rotational isomers, mixtures
thereof at voluntary ratios and racemic mixtures are also included
in the present invention.
[0232] The compounds represented by formula (I) may be converted
into the salts by conventional means. As salts, pharmaceutically
acceptable salts are preferred.
[0233] The salts include salts of alkali metals, salts of alkaline
earth metals, ammonium salts, amine salts, acid addition salts and
so on.
[0234] As the salts, water soluble salts are preferred. The
suitable salts include for example, salts of alkali metals (e.g.
potassium, sodium, lithium, etc.), salts of alkaline earth metals
(e.g. calcium, magnesium, etc.), ammonium salts (e.g.
tetramethylammonium salt, tetrabutylammonium salt, etc.),
pharmaceutical acceptable salts of organic amine (e.g.
triethylamine, methylamine, dimethylamine, cyclopentylamine,
benzylamine, phenethylamine, piperidine, monoethanolamine,
diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine,
N-methyl-D-glucamine, etc.).
[0235] As acid addition salts, water soluble salts are preferred.
The suitable acid addition salts include for example, salts of
inorganic acids (e.g. hydrochloride, hydrobromide, hydroiodide,
sulfate, phosphate, nitrate, etc.), and salts of organic acids
(e.g. acetate, trifluoroacetate, lactate, tartrate, oxalate,
fumarate, maleate, benzoate, citrate, methanesulfonate,
ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate,
glucuronate, gluconate, etc.).
[0236] The compounds represented by formula (I) and salts thereof
may be converted into the solvate.
[0237] Non-toxic and water-soluble solvates are preferred. The
suitable solvates include for example, hydrates, solvates of the
alcohols (e.g. ethanol, etc.), and so on.
[0238] The compounds represented by formula (I) or pharmaceutically
acceptable salts thereof are all preferred. They include
concretely, the compounds described in Example or pharmaceutically
acceptable salts thereof.
[0239] The compounds of the present invention may be converted into
the corresponding cyclodextrin clathrates by the method described
in the specification of JP-B-50-3362 (U.S. Pat. No. 4,054,736),
52-31404 or 61-52146 using .alpha.-, .beta.- or
.gamma.-cyclodextrin or a mixture thereof. Converting into the
corresponding cyclodextrin clathrates serves to increase the
stability and solubility in water of the compounds, and therefore
it is preferred in the use for pharmaceuticals.
[0240] The prodrug of the compounds represented by formula (I)
means a compound is the compound represented by formula (I) by
reaction with enzymes, gastric acids and so on within an organism.
The prodrug of the compounds represented by formula (I) include,
when the compounds represented by formula (I) have amino, the
prodrug is the compounds the amino of which is acylated, alkylated,
phosphorylated (e.g. the compounds are that the amino of the
compounds represented by formula (I) is eicosanoated, alanylated,
pentylaminocarbonylated,
(5-methyl-2-oxo-1,3-dioxolane-4-yl)methoxycarbonylated,
tetrahydrofuranated, pyrrolidylmethylated, pivaloyloxymethylated,
acetoxymethylated, tert-butylated, etc.); when the compounds
represented by formula (I) have hydroxyl, the prodrug is the
compounds the hydroxyl of which are acylated, alkylated,
phosphorylated, borated (e.g. the compounds are that the hydroxyl
of the compounds represented by formula (I) are acetylated,
palmitoylated, propanoylated, pivaloylated, succinylated,
fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.);
when the compounds represented by formula (I) have carboxyl, the
prodrug is the compound the carboxyl of which are esterified,
amidated (e.g. the compounds are that the carboxyl of the compounds
represented by formula (I) is ethylesterified, isopropylesterified,
phenylesterified, carboxymethylesterified,
dimethylaminomethylesterified, pivaloyloxymethylesterified,
ethoxycarbonyloxyethylesterified, phthalidylesterified,
(5-methyl-2-oxo-1,3-dioxolene-4-yl) methylesterified,
cyclohexyloxycarbonylethylesterified, methylamidated, etc.); and so
on. In addition, the above-mentioned carboxyl may be esterified
with alcohol or phenol, for example ##STR16## and so on. These
alcohol or phenol may be substituted with carboxyl and so on.
[0241] These compounds can be manufactured by the conventional
methods. In addition, the prodrugs of the compounds represented by
formula (I) may be either solvates or non-solvates.
[0242] EP4 agonists of the present invention have only to have EP4
agonistic action, whichever they are selective EP4 agonist, or
non-selective EP4 agonist is allowed. Selective EP4 agonist is
preferred.
[0243] In the present invention, 13-14 position being a double bond
is preferred in the formula (I), (I-1) and (I-2).
[0244] In the present invention, hydroxyl of 15 position being
.alpha.-configuration is preferred in the formula (I), (I-1) and
(I-2).
[0245] In the present invention, each group represented by ring A,
ring B, D, G, T, X, Y, R.sup.1, R.sup.2 and R.sup.3 is all
preferred in the formula (I), (I-1) and (I-2). In particular, the
group described below is preferred.
[0246] In the present invention, as ringA, ##STR17## (wherein, all
the symbols have the same meanings as the above-mentioned.) is
preferred in the formula (I).
[0247] In the present invention, as ringB, ##STR18## (wherein, all
the symbols have the same meanings as the above-mentioned.) is
preferred in the formula (I).
[0248] In the present invention, as D, COOR.sup.1 is preferred in
the formula (I) and (I-2).
[0249] In the present invention, as G, ringA, trimethylene or
tetramethylene is preferred in the formula (I).
[0250] In the present invention, as T, oxygen atom or sulfur atom
is preferred in the formula (I) and (I-1).
[0251] In the present invention, as X, --CH.sub.2--, --O-- or --S--
is preferred in the formula (I) and (I-1).
[0252] In the present invention, as Y, connectable bond or --S-- is
preferred in the formula (I).
[0253] In the present invention, as R.sup.1, hydrogen atom, methyl
or isopropyl is preferred in the formula (I), (I-1) and (I-2).
[0254] In the present invention, as R.sup.2, fluorine, chlorine,
methyl or methoxy is preferred in the formula (I).
[0255] In the present invention, as R.sup.3, fluorine, chlorine,
methyl, ethyl, propyl, trifluoromethyl, trifluoromethoxy or
methoxymethyl is preferred in the formula (I).
[0256] In the present invention, each group represented by
ringA.sup.1, ringB.sup.1, and G.sup.1 is all preferred in the
formula (I-1). In particular, the group described below is
preferred.
[0257] In the present invention, as ringA.sup.1, ##STR19##
(wherein, all the symbols have the same meanings as the
above-mentioned.) is preferred in the formula (I-1).
[0258] In the present invention, as ringB.sup.1, ##STR20##
(wherein, all the symbols have the same meanings as the
above-mentioned.) is preferred in the formula (I-1).
[0259] In the present invention, as G.sup.1, ringA.sup.1,
trimethylene or tetramethylene is preferred in the formula
(I-1).
[0260] In the present invention, each group represented by G.sup.2
and R.sup.4 is all preferred in the formula (I-2). In particular,
the group described below is preferred. In the present invention,
as G.sup.2, ##STR21## (wherein, all the symbols have the same
meanings as the above-mentioned.) is preferred in the formula
(I-2).
[0261] In the present invention, as R.sup.4, fluorine, methyl,
trifluoromethoxy, phenyl or heterocyclic ring is preferred in the
formula (I-2).
[0262] In the present invention, n is preferably 1 or 2 in the
formula (I), (I-1) and (I-2).
[0263] In the present invention, p is preferably 0 or 1 in the
formula (I), (I-1) and (I-2).
[0264] In the present invention, q is preferably 1 or 2 in the
formula (I), (I-1) and (I-2).
[0265] In the present invention, r is preferably 1 or 2 in the
formula (I), (I-1) and (I-2).
[0266] In the present invention, all the compounds described in
Examples are preferred.
Processes for the Preparation of the Compound of the Present
Invention
[0267] The compound of the present invention represented by formula
(I) can be prepared by the processed described in WO03/009872, the
following processes, the pursuant these processes, and the
processes shown in Examples. Still, ingredients may be used as
salts in the following each processes for the preparation. As these
salts, the salts described as the salts in the above-mentioned
formula (I) are used. [1] Among the compounds represented by
formula (I), the compound 13-14 position of which is a double bond,
i.e. the compound represented by formula (I-A) ##STR22##
[0268] (wherein, all the symbols have the same meanings as the
above-mentioned.) can be prepared by the following processes.
[0269] The compound represented by formula (I-A) can be prepared by
subjecting to a reduction reaction a compound represented by
formula (II), ##STR23##
[0270] (wherein, B.sup.II, D.sup.II and G.sup.II have the same
meanings as that of B, D and G, but carboxyl, hydroxyl, amino and
mercapto included the group represented by B.sup.II, D.sup.II and
G.sup.II are, if necessary, protected. The other symbols have the
same meanings as the above-mentioned.), additionally, if necessary,
by subjecting to a deprotection reaction of protecting group.
[0271] The above-mentioned reduction reaction is known, for
example, it can be performed under the reductant
(borane.tetrahydrofuran complex, borane.dimethylsulfide complex,
diborane, etc.) and asymmetry induced agent
((R)-2-methyl-CBS-oxazaborolidine,
(S)-2-methyl-CBS-oxazaborolidine, etc.), in organic solvents
(tetrahydro furan, dimethoxyethane, toluene, methylene chloride,
diethylether, 1,4-dioxane, etc.) at the temperature of -20 to
50.degree. C.
[0272] The deprotection reaction of a protective group for
carboxyl, hydroxyl, amino, or mercapto is known, and it includes;
[0273] (1) alkaline hydrolysis, [0274] (2) deprotection reaction
under acidic conditions, [0275] (3) deprotection reaction by
hydrogenolysis, [0276] (4) deprotection reaction of a silyl group,
[0277] (5) deprotection reaction using metals, [0278] (6)
deprotection reaction using metal complexes, and so on.
[0279] These methods are described concretely as follows.
[0280] (1) The deprotection reaction by alkaline hydrolysis is, for
example, carried out in an organic solvent (e.g. methanol,
tetrahydrofuran, or 1,4-dioxane, etc.) using a hydroxide of an
alkali metal (e.g. sodium hydroxide, potassium hydroxide, or
lithium hydroxide, etc.), a hydroxide alkaline earth metal (e.g.
barium hydroxide, or calcium hydroxide, etc.), or a carbonate (e.g.
sodium carbonate or potassium carbonate, etc.), or an aqueous
solution thereof, or a mixture thereof at a temperature of 0 to
40.degree. C.
[0281] (2) The deprotection reaction under acidic conditions is
carried out, for example, in an organic solvent (e.g. methylene
chloride, chloroform, 1,4-dioxane, ethyl acetate, or anisole, etc.)
in the presence or absence of 2,2,2-trifluoroethanol in an organic
acid (e.g. acetic acid, trifluoroacetic acid, methansulfonic acid,
or p-tosylate, etc.), or an inorganic acid (e.g. hydrochloric acid,
or sulfuric acid, etc.) or a mixture thereof (e.g. hydrogen
bromide/acetic acid, etc.) at a temperature of 0 to 100.degree.
C.
[0282] (3) The deprotection reaction by hydrogenolysis is carried
out, for example, in a solvent (e.g. ethers (e.g., tetrahydrofuran,
1,4-dioxane, dimethoxyethane, or diethylether, etc.), alcohols
(e.g., methanol, or ethanol, etc.), benzenes (e.g. benzene, or
toluene, etc.), ketones (e.g. acetone, or methylethylketone, etc.),
nitriles (e.g. actetonitrile, etc.), amides (e.g.,
dimethylformamide, etc.), water, ethyl acetate, acetic acid, or a
mixed solvent of at least two of these, etc.) in the presence of a
catalyst (e.g. palladium-carbon, palladium black, palladium
hydroxide-carbon, platinum oxide, or Raney nickel, etc.) under the
hydrogen atmosphere at normal pressure or under pressurization, or
in the presence of ammonium formate at a temperature of 0 to
200.degree. C.
(4) The deprotection reaction of a silyl group is carried out, for
example, in a water-miscible organic solvent (e.g. tetrahydrofuran,
or acetonitrile, etc.) using tetrabutylammonium fluoride at a
temperature of 0 to 40.degree. C.
[0283] (5) The deprotection reaction using metals is carried out,
for example, in an acidic solvent (e.g. acetic acid, pH4.2-7.2
buffer solution, or a mixture of a solution thereof and an organic
solvent of tetrahydrofran, etc.) in the presence of zinc powder, if
necessary sonicating, at the temperature of 0 to 40.degree. C.
[0284] (6) The deprotection reaction using metal complexes is
carried out, for example, in an organic solvent (e.g. methylene
chloride, N,N-dimethylformamide, tetrahydrofran, ethyl acetate,
acetonitrile, 1,4-dioxane, ethanol, etc.), water, or a mixture
thereof, in the presence of a trap reagent (e.g. tributyltine
hydride, triethylsilane, dimedone, morpholine, diethylamine,
pyrrolidine, etc.), an organic acid (e.g. acetic acid, formic acid,
2-ethyl hexanoic acid, etc.) and/or salts of organic acid (e.g.,
sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, etc.), in the
presence or absence of a phosphine reagent (e.g.
triphenylphosphine, etc.), using metal complexes (e.g.
tetrakistriphenylphosphinepalladium(0),
dichlorobis(triphenylphosphine)palladium(II), palladium
acetate(II), tris(triphenylphosphine)rhodium(I) chloride, etc.) at
the temperature of 0 to 40.degree. C.
[0285] In addition, the deprotection reaction except the
above-mentioned processes can be carried out, for example, by the
process described in T. W. Greene, Protective Groups in Organic
Synthesis, Wiley, New York, 1999.
[0286] The protection group for carboxyl includes, for example,
methyl, ethyl, allyl, t-butyl, trichloroethyl, benzyl (Bn),
phenacyl, p-methoxybenzyl, trytyl, 2-chlorotrytyl, or a solid phase
carrier bound of a structure thereof and so on.
[0287] The protection group for hydroxyl includes, for example,
methyl, trytyl, methoxymethyl (MOM), 1-ethoxyethyl (EE),
methoxyethoxymethyl (MEM), 2-tetrahydropyranyl (THP),
trimethylsyryl (TMS), triethylsyryl (TES), t-butyldimethylsyryl
(TBDMS), t-butyldiphenylsyryl (TBDPS), acetyl (Ac), pivaloyl,
benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc),
2,2,2-trichloroethoxycarbonyl (Troc), and so on.
[0288] The protection group of amino includes benzyloxycarbonyl,
t-butoxycarbonyl, allyloxycarbonyl (Alloc),
1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc), trifluoroacetyl,
9-fluorenylmethoxycarbonyl, benzyl (Bn), p-methoxybenzyl,
benzyloxymethyl (BOM), 2-(trimethylsyryl)ethoxymethyl (SEM) and so
on.
[0289] The protection group of mercapto includes, for example,
benzyl, methoxybenzyl, methoxymethyl (MOM), 2-tetrahydropyranyl
(THP), diphenylmethyl, acetyl (Ac) and so on.
[0290] The protective group for carboxyl, hydroxyl, amino or
mercapto is not particularly limited to the above mentioned groups,
so long as it can be easily and selectively left. For example,
those described in T. W. Greene, Protective Groups in Organic
Synthesis, Wiley, New York, 1999 can be used.
[0291] As is easily understood by those skilled in the art, an
object compound of the present invention can be produced easily by
using a different deprotection reaction depending on usage. [2]
Among the compounds represented by formula (I), the compound 13-14
position of which is a single bond, i.e. the compound represented
by formula (I-B) ##STR24## (wherein, all the symbols have the same
meanings as the above-mentioned.) can be prepared by the following
processes.
[0292] The compound represented by formula (I-B) can be prepared by
subjecting to a hydrogeneration reaction a compound represented by
formula (III), ##STR25## (wherein, B.sup.III, D.sup.III and
G.sup.III have the same meanings as that of B, D and G, but
carboxyl, hydroxyl, amino and mercapto included the group
represented by B.sup.III, D.sup.III and G.sup.III are, if
necessary, protected. R.sup.III is a hydrogen atom or protection
group of hydroxyl. The other symbols have the same meanings as the
above-mentioned.), additionally, if necessary, by subjecting to a
deprotection reaction of protecting group.
[0293] The hydrogeneration reaction is known, for example, it can
be performed in organic solvents (ethers (e.g. tetrahydrofuran,
1,4-dioxane dimethoxyethane, diethylether, etc.), alcohols (e.g.
methanol, ethanol, etc.), benzenes (e.g. benzene, toluene, etc.),
ketones (e.g. acetone, methylethylketone, etc.), nitriles (e.g.
acetonitrile, etc.), amides (e.g. N,N-dimethylformamide, etc.) in
the presence of a catalyst (e.g. palladium-carbon, palladium black,
palladium hydroxide, platinum oxide, or Raney nickel, etc.), under
the hydrogen atmosphere at normal pressure or under pressurization,
or in the presence of ammonium formate at a temperature of 0 to
200.degree. C.
[0294] The deprotection reaction of protection group can be carried
out by the same method as that of the above-mentioned. [3] Among
the compounds represented by formula (I), the compound is that T is
an oxygen atom and X is --CH.sub.2--, i.e. the compound represented
by formula (I--C) ##STR26## (wherein, all the symbols have the same
meanings as the above-mentioned.) can be prepared by the following
processes.
[0295] The compound represented by formula (I-C) can be prepared by
subjecting to a reductive amination reaction a compound represented
by formula (IV), ##STR27## (wherein, R.sup.IV is a protection group
of carboxylic acid. The other symbols have the same meanings as the
above-mentioned.) and the compound represented by formula (V),
OHC--(CH.sub.2).sub.n-1--Y-G.sup.IV-D.sup.IV (V) (wherein, D.sup.IV
and G.sup.IV have the same meanings as the above-mentioned. And if
necessary, carboxyl, hydroxyl, amino and mercapto included groups
represented by D.sup.IV and G.sup.IV may be protected. The other
symbols have the same meanings as the above-mentioned.),
additionally, if necessary, by subjecting to a deprotection
reaction of protecting group.
[0296] The reactive amination reaction is known, for example, it
can be performed in organic solvents (e.g. ethyl acetate,
dichloroethane, methylene chloride, N,N-dimethylformamido,
tetrahydrofuran, acetic acid and the mixture thereof, etc.), in the
presence of reductant (e.g. triacetoxy sodium boron hydride, sodium
boron cyano hydride, sodium boron hydride, zinc boron hydride,
diisobutylalminum hydride, etc.) at a temperature of -15 to
100.degree. C., or in organic solvents (e.g. ethyl acetate,
dichloroethane, methylene chloride, methanol, ethanol, acetic acid,
etc.) in the presence of a catalyst (e.g. palladium-carbon,
palladium black, palladium hydroxide, platinum oxide, or Raney
nickel, etc.), under the hydrogen atmosphere at normal pressure or
under pressurization at a temperature of 0 to 80.degree. C.
[0297] The deprotection reaction of protection group can be carried
out by the same method as that of the above-mentioned.
[0298] The compounds represented by formula (II), (III), (IV) and
(V) used in the present invention are known in themselves, or can
be easily prepared by known method, for example, the method
described in Comprehensive Organic Transformations: A Guide to
Functional Group Preparations, 2nd Edition, Richard C. Larock,
Wiley & Sons Inc, 1999.
[0299] In each reaction in the present specification, as it is
clear for those skilled in the art, a reaction with heat can be
carried out using water bath, oil bath, sand bath, or
microwave.
[0300] In each reaction in the present specification, a reaction
may be carried out by using a solid-phase supported reagent
supported in the high polymer (e.g. polystyrene, polyacrylamide,
polypropylene, polyethyleneglycol, etc.).
[0301] In each reaction in the present specification, reaction
products may be purified in an ordinary manner, for example,
through normal-pressure or reduced-pressure distillation, or
through high-performance liquid chromatography with silica gel or
magnesium silicate, thin-layer chromatography, ion-exchange resin,
scavenger resin or column chromatography, or through washing or
recrystallization and so on. The purification may be effected in
each reaction stage or after some reaction stages.
Toxicity:
[0302] Toxicity of the compound represented by formula (I), the
salt thereof, the solvate thereof or cyclodextrin clathlate
thereof, or the prodrug thereof is very low, and it is safe enough
to use as a pharmaceutical agent.
Industrial Availability
Application to Pharmaceutical Preparations:
[0303] The compounds of the invention represented by formula (I)
act on PGE receptor EP.sub.4 subtype specifically and strongly and
thus are considered useful for the prevention and/or treatment of
immunological diseases (autoimmune diseases such as amyotrophic
lateral sclerosis (ALS), multiple sclerosis, Sjoegren's syndrome,
chronic rheumarthrosis and systemic lupus erythematosus, etc., and
rejection after organ transplantation, etc.), asthma, neuronal cell
death, arthritis, lung failure, pulmonary fibrosis, pulmonary
emphysema, bronchitis, chronic obstructive pulmonary disease, liver
damage, acute hepatitis, nephritis (acute nephritis, chronic
nephritis), renal insufficiency, hypertension, myocardial ischemia,
systemic inflammatory response syndrome, sepsis, hemophagous
syndrome, macrophage activation syndrome, Still's disease, Kawasaki
disease, burn, systemic granulomatosis, ulcerative colitis, Crohn's
disease, hypercytokinemia at dialysis, multiple organ failure,
shock and glaucoma and so on. It is also thought that EP.sub.4
subtype receptor relates to protecting of mucosa. Therefore, the
compounds which can bind on EP.sub.4 subtype receptor are expected
to be useful for the prevention and/or treatment of ulcer of
gastrointestinal tract such as gastric ulcer and duodenal ulcer and
so on, and stomatitis. It is also thought that EP.sub.4 subtype
receptor relates to hair growth function. Therefore, the compounds
which can bind on EP.sub.4 subtype receptor are expected to be
useful for the prevention and/or treatment of hair-disadvantaged
and alopecia. Furthermore, it is also thought that EP.sub.4 subtype
receptor relates to maturation of cervix. Therefore, the compounds
which can bind on EP.sub.4 subtype receptor are expected to be
useful for the promoter of maturation of cervix.
[0304] Furthermore, the compounds which can bind on EP.sub.4
subtype receptor also have an action of accelerating bone
formation, so it is expected to be useful for the prevention and/or
treatment of diseases associated with loss in bone mass, for
example,
1) primary osteoporosis (e.g., primary osteoporosis followed by
aging, postmenopausal primary osteoporosis, primary osteoporosis
followed by ovariectomy, etc.),
[0305] 2) secondary osteoporosis (e.g., glucocorticoid-induced
osteoporosis, hyperthyroidism-induced osteoporosis,
immobilization-induced osteoporosis, heparin-induced osteoporosis,
immunosuppressive-induced osteoporosis, osteoporosis due to renal
failure, inflammatory osteoporosis, osteoporosis followed by
Cushing's syndrome, rheumatoid osteoporosis, etc.), and
[0306] 3) bone diseases such as bone metastasis of cancer,
hypercalcemia, Paget's disease, bone loss (alveolar bone loss,
mandibular bone loss, childhood idiopathic bone loss, etc.),
osteonecrosis, etc. Besides treatment of the above diseases, the
present invention also includes a pharmaceutical composition for
accelerating bone formation after bone operation (e.g., bone
formation after fractures, bone formation after bone grafting, bone
formation after operation of artificial joint, bone formation after
spinal fusion and bone formation after the other operation for bone
regeneration, etc.), or promoting treatment thereof, or alternative
treatment for bone grafting.
[0307] It is also thought that EP.sub.4 subtype receptor relates to
induction of physiological sleeping and suppression of blood
platelet aggregation, the compounds which can bind on EP4 receptor
selectively are expected to be useful for the prevention and/or
treatment of sleep disorder and thrombosis.
[0308] The compound which can bind on EP.sub.4 receptor selectively
do not have inducing pain which may be caused by EP.sub.1 and
uterine contraction which may be caused by EP.sub.3, so they are
thought to be agents having no effect on the above actions.
[0309] Among the compounds represented by formula (I) are those
which bind EP.sub.4 receptor as well as EP.sub.2 receptor. The
compound which binds on EP.sub.2 receptor is considered useful for
the prevention and/or treatment of immunological diseases
(autoimmune diseases such as amyotrophic lateral sclerosis (ALS),
multiple sclerosis, Sjoegren's syndrome, chronic rheumarthrosis and
systemic lupus erythematosus, etc., and rejection after organ
transplantation, etc.), asthma, neuronal cell death, premature
birth, miscarriage, pars nervosa retinae trouble such a glaucoma,
erectile dysfunction, arthritis, lung failure, pulmonary fibrosis,
pulmonary emphysema, bronchitis, chronic obstructive pulmonary
disease, liver damage, acute hepatitis, shock, nephritis, renal
insufficiency, circulatory system disorder (e.g., hypertension,
myocardial ischemia, chronic arterial obstruction, vibration
disease), systemic inflammatory response syndrome, sepsis,
hemophagous syndrome, macrophage activation syndrome, Still's
disease, Kawasaki disease, burn, systemic granulomatosis,
ulcerative colitis, Crohn's disease, hypercytokinemia at dialysis,
multiple organ failure and bone disease (e.g., fracture,
refracture, intractable fracture, bone union insufficiency,
pseudarthrosis, osteomalacia, bone Paget's disease, spondylism,
transfer of cancer to bone, osteroarthritis, destruction of
bone/cartilage due to these analogous diseases, etc.) and so on.
The compound which binds on EP.sub.2 receptor is also considered
useful as an agent for accelerating the osteogenesis/treatment
after bone surgery (e.g., osteogenesis after fracture, osteogenesis
after bone graft, osteogenesis after artificial arthrogenesis,
osteogenesis after spinal fusion, osteogenesis after surgery for
such as, multiple myeloma, lung cancer, breast cancer, etc.,
osteogenesis after other bone repair, etc.) or substitute for bone
transfer. This compound is further considered useful as an agent
for accelerating the regeneration of peridontium in peridontium
disease.
[0310] The compound which binds to both EP.sub.4 receptor and
EP.sub.2 receptor can be expected to exert an additive or
synergistic effect on diseases related to both the receptors.
[0311] The compound represented by formula (I) or the salt thereof,
the solvate thereof or the cyclodextrin clathlate thereof, or the
prodrug thereof may be administered in combination with other
pharmaceutical preparations to accomplish the following
purposes:
1) To compensate for and/or enhance the preventive and/or treatment
effect of the compound to be combined;
2) To improve the kinetics/absorption of the compound to be
combined and reduce the dose of the compound; and/or
3) To eliminate the side effect of the compound to be combined
[0312] The compound represented by formula (I) and other
pharmaceutical preparations may be administered in the form of
formulation having these components incorporated in one preparation
or may be administered in separate preparations. In the case where
these pharmaceutical preparations are administered in separate
preparations, they may be administered simultaneously or at
different times. In the latter case, the compound represented by
formula (I) may be administered before the other pharmaceutical
preparations. Alternatively, the other pharmaceutical preparations
may be administered before the compound represented by formula (I).
The method for the administration of these pharmaceutical
preparations may be the same or different.
[0313] The diseases on which the preventive and/or treatment effect
of the above-mentioned combined preparations works are not
specifically limited but may be those for which the preventive
and/or treatment effect of the compound represented by formula (I)
is compensated for and/or enhanced.
[0314] Examples of the other pharmaceutical preparations for
compensating for and/or enhancing the preventive and/or treatment
effect of the compound represented by formula (I) on bone diseases
include phosphodiesterase-4 inhibitor, bisphosphonate preparation,
vitamin D preparation, calcium adjuvant, estrogen preparation,
calcitonin preparation, isoflavone-based preparation, anabolic
steroid preparation, vitamin K preparation, cathepsin K inhibitor,
prostaglandins, statin, parathyroid hormones, growth factors and so
on.
[0315] Examples of the other pharmaceutical preparations for
compensating for and/or enhancing the preventive and/or treatment
effect of the compound represented by formula (I) on chronic
obstructive pulmonary diseases and/or asthma include
phosphodiesterase-4 inhibitor, steroids, .beta..sub.2
adrenoreceptor stimulant, leukotriene receptor antagonist,
thromboxane synthetase inhibitor, thromboxane A.sub.2 receptor
antagonist, mediator releasing inhibitor, antihistamines, xanthine
derivatives, anticholinergic agent, cytokine inhibitor,
prostaglandins, forskolin, elastase inhibitor, metalloproteinase
inhibitor, expectorant, antibiotic and so on.
[0316] Examples of the other pharmaceutical preparations for
compensating for and/or enhancing the preventive and/or treatment
effect of the compound represented by formula (I) on arthritis or
chronic articular rheumatism include metalloproteinase inhibitor,
immunosuppressant, nonsteroidal antiinflammatory drugs (NSAID),
steroids, phosphodiesterase-4 inhibitor and so on.
[0317] Examples of the other pharmaceutical preparations for
compensating for and/or enhancing the preventive and/or treatment
effect of the compound represented by formula (I) on erectile
dysfunction include phosphodiesterase-5 inhibitor and so on.
[0318] Examples of the other pharmaceutical preparations for
compensating for and/or enhancing the preventive and/or treatment
effect of the compound represented by formula (I) on shock include
elastase inhibitor and so on.
[0319] Examples of the other pharmaceutical preparations for
compensating for and/or enhancing the preventive and/or treatment
effect of the compound represented by formula (I) on colitis
include NO synthase inhibitor, poly(ADP-ribose)polymerase
inhibitor, phosphodiesterase-4 inhibitor, elastase inhibitor,
interleukin-8 antagonist and so on.
[0320] Examples of the other pharmaceutical preparations for
compensating for and/or enhancing the preventive and/or treatment
effect of the compound represented by formula (I) on acute/chronic
nephritis include steroids, phosphodiesterase-4 inhibitor,
nonsteroidal antiinflammatory drugs, thromboxane A.sub.2 receptor
antagonist, leukotriene receptor antagonist, angiotensin II
antagonist, angiotensin converting enzyme inhibitor, diuretic and
so on.
[0321] Examples of the other pharmaceutical preparations for
compensating for and/or enhancing the preventive and/or treatment
effect of the compound represented by formula (I) on hypertension
include calcium antagonist, angiotensin II antagonist, angiotensin
converting enzyme inhibitor, phosphodiesterase-4 inhibitor,
diuretic and so on.
[0322] Examples of the phosphodiesterase-4 inhibitor include
rolipram, cilomilast (trade name: Ariflo), Bay 19-8004, NIK-616,
cipamfylline (BGL-61063), atizolam (CP-80633), SCH-351591, YM-976,
V-11294A, PD-168787, D-4386, IC-485 and so on.
[0323] Examples of the phosphodiesterase-5 inhibitor include
sildenafil and so on.
[0324] Examples of the bisphonate preparation include sodium
alendronate, disodium chlodronate, disodium pamidronate, disodium
ethydronate, ivandronate, disodium incadronate, minodronate,
olpadronate, sodium risedronate, tildronate, zoledronate and so
on.
[0325] Examples of the calcitonin preparation include calcitonin,
elcatonin and so on.
[0326] Examples of the prostaglandins (hereinafter abbreviated as
"PG") include PG receptor agonist, PG receptor antagonist and so
on.
[0327] Examples of PG receptor include PGE receptors (EP.sub.1,
EP.sub.2, EP.sub.3, and EP.sub.4), PGD receptors (DP), PGF
receptors (FP), PGI receptors (IP) and so on.
[0328] Examples of the steroids for external application include
clobetasol propionate, diflorasone acetate, fluocinonide,
mometasone furancarboxylate, betametasone dipropionate,
betametasone butyropropionate, betametasone valerate,
difluprednate, budesonide, diflucortolone valerate, amcinonide,
halcinonide, dexamethasone, dexamethasone propionate, dexamethasone
valerate, dexamethasone acetate, hydrocortisone acetate,
hydrocortisone butyrate, hydrocortisone acetopropionate, deprodone
propionate, prednisolone valeroacetate, fluocinolone acetonide,
beclometasone propionate, triamcinolone acetonide, flumethasone
pivalate, alclometasone propionate, clobetasone butyrate,
prednisolone, beclometasone propionate, fludroxycortide and so
on.
[0329] Examples of the steroids for internal use or injection
include cortisone acetate, hydrocortisone, hydrocortisone sodium
phosphate, hydrocortisone sodium succinate, fludrocortisone
acetate, prednisolone, prednisolone acetate, prednisolone sodium
succinate, prednisolone butylacetate, prednisolone sodium
phosphate, halopredon acetate, methyl prednisolone, methyl
prednisolone acetate, methyl prednisolone sodium succinate,
triamicinolon, triamicinolon acetate, triamicinolon acetonide,
dexamethasone, dexamethasone acetate, dexamethasone sodium
phosphate, dexamethasone palmitate, paramethasone acetate,
betametasone and so on.
[0330] Examples of the steroids as an inhalant include
beclomethasone propionate, fluticasone propionate, budesonide,
flunisolide, triamicinolon, ST-126P, ciclesonide, dexamethasone
palomitionate, monometasone furancarbonate, prasterone sulfonate,
deflazacort, methyl prednisolone sreptanate, methyl prednisolone
sodium succinate and so on.
[0331] Examples of the .beta..sub.2 adrenoreceptor stimulant
include fenoterol hydrobromide, salbutamol sulfate, terbutaline
sulfate, formoterol fumarate, salmeterol xinafoate, isoprotenol
sulfate, orciprenalin sulfate, chloroprenalin sulfate, epinephrine,
trimetoquinol hydrochloride, hexoprenalinmesyl sulfate, procaterol
hydrochloride, tulobuterol hydrochloride, tulobuterol, pirbuterol
hydrochloride, clenbuterol hydrochloride, mabuterol hydrochloride,
ritodrine hydrochloride, bambuterol, dopexamin hydrochloride,
meradrin tartrate, AR-C68397, levosalbutamol, R,R-formoterol,
KUR-1246, KUL-7211, AR-C89855, S-1319 and so on.
[0332] Examples of the leukotriene receptor antagonist include
pranlukast hydrate, montelukast, zafirlukast, seratrodast, MCC-847,
KCA-757, CS-615, YM-158, L-740515, CP-195494, LM-1484, RS-635,
A-93178, S-36496, BIIL-284, ONO-4057 and so on.
[0333] Examples of the thromboxane synthetase inhibitor include
ozagrel hydrochloride, imitrodast sodium and so on.
[0334] Examples of the thromboxane A.sub.2 receptor antagonist
include seratrodast, ramatroban, domitroban calcium hydrate,
KT-2-962 and so on.
[0335] Examples of the mediator releasing inhibitor include
tranilast, sodium cromoglicate, anlexanox, repirinast, ibudilast,
tazanolast, pemilolast potassium and so on.
[0336] Examples of the antihistamines include ketotifen fumarate,
mequitazine, azelastine hydrochloride, oxatomide, terfenadine,
emedastine fumarate, epinastine hydrochloride, astemizole, ebastin,
cetirizine hydrochloride, bepotastine, fexofenadine, lolatadine,
deslolatadine, olopatadine hydrochloride, TAK-427, ZCR-2060,
NIP-530, mometasone furoate, mizolastine, BP-294, andolast,
auranofin, acribastin and so on.
[0337] Examples of the xanthine derivatives include aminophylline,
thoeophyline, doxophylline, cipamphilline, diprophilline and so
on.
[0338] Examples of the anticholinergic agent include ipratropium
bromide, oxitropium bromide, flutropium bromide, temiverine,
tiotropium bromide, revatropate (UK-112166) and so on.
[0339] Examples of the cytokine inhibitor include suplatast
tosilate (trade name: IPD) and so on.
[0340] Examples of the expectorant include foeniculated ammonia
spirit, sodium hydrogen carbonate, bromhexine hydrochloride,
carbocisteine, ambroxol hydrochloride, sustained release ambroxol
hydrochloride, methylcysteine hydrochloride, acetyl cysteine,
L-ethylcysteine hydrochloride, tyloxapol and so on.
[0341] Examples of the growth factors include fibroblast growth
factor (FGF), vascular endothelium growth factor (VEGF), hepatocyte
growth factor (HGF), insulin-like growth factor and so on.
[0342] Examples of the nonsteroid-based antiphlogistic include
sasapyrine, sodium salicylate, aspirin, aspirin dialuminate
formulation, diflunisal, indomethacin, suprofen, ufenamate,
dimethylisopropyl azulen, bufexamac, felbinac, diclofenac, tolmetin
sodium, clinoril, fenbufen, napmetone, proglumetacin, indomethacin
farnesil, acemetacin, proglumetacin maleate, amfenac sodium,
mofezolac, etodolac, ibuprofen, ibuprofen piconol, naproxen,
flurbiprofen, flurbiprofen axethyl, ketoprofen, fenoprofen calcium,
tiaprofen, oxaprozin, pranoprofen, loxoprofen sodium,
aluminoprofen, zaltoprofen, mefenamic adid, aluminum mefenamate,
tolfenamic acid, floctafenine, ketophenylbutazone, oxyfenbutazone,
piroxicam, tenoxicam, anpiroxicam, napageln cream, epirizole,
tiaramide hydrochloride, tinoridine hydrochloride, emorfazone,
sulpryrine, Migrenin, Saridon, Sedes G, Amipylo N, Sorbon, pyrine
system antipyretics, acetaminophen, phenacetin, dimethothiazine
mesylate, simetride formulation, antipyrine system aphipyretics and
so on.
[0343] Examples of the diuretic include mannitol, furosemide,
acetazolamide, diclofenamide, matazolamide, trichlormethiazide,
mefruside, spinolactone, aminophylline and so on.
[0344] The weight proportion of the compound represented by formula
(I) and the other pharmaceutical preparations is not specifically
limited.
[0345] Arbitrary two or more of the other pharmaceutical
preparations may be administered in combination.
[0346] Examples of the other pharmaceutical preparations for
compensating for and/or enhancing the preventive and/or treatment
effect of the compound represented by formula (I) include not only
those which have so far been found but also those which will be
found on the basis of the above-mentioned mechanism.
[0347] In order to use the compound of the invention represented by
formula (I) or the compound represented by formula (I) in
combination with the other pharmaceutical preparations, these
compounds are normally administered to the entire of human body or
topically orally or parenterally.
[0348] The dose of these compounds depends on the age, weight and
symptom of the patient, the remedial value, the administration
method, the treatment time, etc. In practice, however, these
compounds are administered orally once or several times per day
each in an amount of from 1 ng to 100 mg per adult, parenterally
once or several times per day each in an amount of from 0.1 ng to
10 mg per adult or continuously administered into vein for 1 hour
to 24 hours per day.
[0349] It goes without saying that the dose of these compounds may
be less than the above-mentioned value or may need to exceed the
above-mentioned range because the dose varies under various
conditions as mentioned above.
[0350] When the compounds of the invention represented by formula
(I) or the compound represented by formula (I) is administered in
combination with the other pharmaceutical preparations, they are
used in the form of solid or liquid agent for oral administration,
injection, agent for external application, suppository, eye drops
or inhalant for parenteral administration or the like.
[0351] Examples of the solid agent for oral administration include
tablet, pill, capsule, powder, and pellet. Examples of the capsule
include hard capsule, and soft capsule.
[0352] In such a solid agent for internal application, one or more
active materials are used in the form of preparation produced by an
ordinary method singly or in admixture with a vehicle (e.g.,
lactose, mannitol, glucose, microcrystalline cellulose, starch,
etc.), binder (e.g., hydroxypropyl cellulose, polyvinyl
pyrrolidone, magnesium metasilicoaluminate, etc.), disintegrant
(e.g., calcium fibrinoglycolate, etc.), glidant (e.g., magnesium
stearate, etc.), stabilizer, dissolution aid (e.g., glutamic acid,
aspartic acid, etc.) or the like. The solid agent may be coated
with a coating agent (e.g., white sugar, gelatin, hydroxypropyl
cellulose, hydroxypropyl methyl cellulose phthalate, etc.) or two
or more layers. Alternatively, the solid agent may be capsulized by
an absorbable material such as gelatin.
[0353] Examples of the liquid agent for oral administration include
pharmaceutically acceptable aqueous solution, suspension, emulsion,
syrup, and elixir. In such a liquid agent, one or more active
agents are dissolved, suspended or emulsified in a commonly used
diluent (e.g., purified water, ethanol, mixture thereof, etc.).
Furthermore, such a liquid agent may comprise a wetting agent, a
suspending agent, an emulsifier, a sweetening agent, a flavor, a
preservative, a buffer, etc.
[0354] The agent for parenteral administration may be in the form
of, e.g., ointment, gel, cream, wet compress, paste, liniment,
nebula, inhalant, spray, aerosol, eye drops, collunarium or the
like. These agents each contain one or more active materials and
are prepared by any known method or commonly used formulation.
[0355] The ointment is prepared by any known or commonly used
formulation. For example, one or more active materials are
triturated or dissolved in a base to prepare such an ointment. The
ointment base is selected from known or commonly used materials. In
some detail, higher aliphatic acid or higher aliphatic acid ester
(e.g., adipic acid, myristic acid, palmitic acid, stearic acid,
oleic acid, adipic acid ester, myristic acid ester, palmitic acid
ester, stearic acid ester, oleic acid ester, etc.), wax (e.g.,
beeswax, whale wax, ceresin, etc.), surface active agent (e.g.,
polyoxyethylenealkylether phosphoric acid ester, etc.), higher
alcohol (e.g., cetanol, stearyl alcohol, setostearyl alcohol,
etc.), silicon oil (e.g., dimethyl polysiloxane, etc.), hydrocarbon
(e.g., hydrophilic petrolatum, white petrolatum, purified lanolin,
liquid paraffin, etc.), glycol (e.g., ethylene glycol, diethylene
glycol, propylene glycol, polyethylene glycol, macrogol, etc.),
vegetable oil (e.g., castor oil, olive oil, sesame oil, turpentine
oil), animal oil (mink oil, vitelline oil, squalane, squalene),
water, absorption accelerator and rash preventive may be used
singly or in admixture of two or more thereof. The base may further
comprise a humectant, a preservative, a stabilizer, an antioxidant,
a perfume, etc.
[0356] The gel is prepared by any known or commonly used
formulation. For example, one or more active materials are
dissolved in a base to prepare such a gel. The gel base is selected
from known or commonly used materials. For example, lower alcohol
(e.g., ethanol, isopropyl alcohol, etc.), gelling agent (e.g.,
carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, ethyl cellulose, etc.), neutralizing agent (e.g.,
triethanolamine, diisopropanolamine, etc.), surface active agent
(e.g., polyethylene glycol monostearate, etc.), gums, water,
absorption accelerator, and rash preventive are used singly or in
admixture of two or more thereof. The gel base may further comprise
a preservative, an antioxidant, a perfume, etc.
[0357] The cream is prepared by any known or commonly used
formulation. For example, one or more active materials are
dissolved in a base to prepare such a cream. The cream base is
selected from known or commonly used materials. For example, higher
aliphatic acid ester, lower alcohol, hydrocarbon, polyvalent
alcohol (e.g., propylene glycol, 1,3-butylene glycol, etc.), higher
alcohol (e.g., 2-hexyl decanol, cetanol, etc.), emulsifier (e.g.,
polyoxyethylene alkyl ethers, aliphatic acid esters, etc.), water,
absorption accelerator, and rash preventive are used singly or in
admixture of two or more thereof. The cream base may further
comprise a preservative, an antioxidant, a perfume, etc.
[0358] The wet compress is prepared by any known or commonly used
formulation. For example, one or more active materials are
dissolved in a base to prepare a kneaded mixture which is then
spread over a support to prepare such a wet compress. The wet
compress base is selected from known or commonly used materials.
For example, thickening agent (e.g., polyacrylic acid, polyvinyl
pyrrolidone, gum arabic, starch, gelatin, methyl cellulose, etc.),
wetting agent (e.g., urea, glycerin, propylene glycol, etc.),
filler (e.g., kaolin, zinc oxide, talc, calcium, magnesium, etc.),
water, dissolution aid, tackifier, and rash preventive may be used
singly or in admixture of two or more thereof. The wet compress
base may further comprise a preservative, an antioxidant, a
perfume, etc.
[0359] The pasting agent is prepared by any known or commonly used
formulation. For example, one or more active materials are
dissolved in a base to prepare a kneaded mixture which is then
spread over a support to prepare such a pasting agent. The pasting
agent base is selected from known or commonly used materials. For
example, polymer base, fat and oil, higher aliphatic acid,
tackifier and rash preventive may be used singly or in admixture of
two or more thereof. The pasting agent base may further comprise a
preservative, an antioxidant, a perfume, etc.
[0360] The liniment is prepared by any known or commonly used
formulation. For example, one or more active materials are
dissolved, suspended or emulsified in water, alcohol (e.g.,
ethanol, polyethylene glycol, etc.), higher aliphatic acid,
glycerin, soap, emulsifier, suspending agent, etc., singly or in
combination of two or more thereof, to prepare such a liniment. The
liniment may further comprise a preservative, an antioxidant, a
perfume, etc.
[0361] The nebula, inhalant, spray and aerozol each may comprise a
commonly used diluent, additionally, a stabilizer such as sodium
hydrogen sulfite and a buffer capable of providing isotonicity such
as isotonic agent (e.g., sodium chloride, sodium citrate, or citric
acid, etc.). For the process for the preparation of spray,
reference can be made to U.S. Pat. Nos. 2,868,691 and
3,095,355.
[0362] The injection for parenteral administration consists of
solid injection used to be dissolved or suspended in the form of
solution, suspension, emulsion and a solvent to be dissolved before
use. The injection is prepared by dissolving, suspending or
emulsifying one or more active materials in a solvent. As such a
solvent there may be used distilled water for injection,
physiological saline, vegetable oil, alcohol such as propylene
glycol, polyethylene glycol and ethanol, etc., singly or in
combination thereof. The injection may further comprise a
stabilizer, a dissolution aid (e.g., glutamic acid, aspartic acid,
Polysolvate 80 (trade name), etc.), a suspending agent, an
emulsifier, a soothing agent, a buffer, a preservative, etc. The
injection is sterilized at the final step or prepared by an aseptic
process. Alternatively, an aseptic solid agent such as freeze-dried
product which has previously been prepared may be rendered aseptic
or dissolved in an aseptic distilled water for injection or other
solvents before use.
[0363] The eye drops for parenteral administration may be in the
form of liquid, suspension, emulsion, formulation to be dissolved
before use, or ointment or may be dissolved in a solvent in
use.
[0364] These eye drops are prepared by any known method. For
example, one or more active materials are dissolved, suspended or
emulsified in a solvent. As such a solvent for eye drops there may
be used sterilized purified water, physiological saline and other
aqueous or nonaqueous solvents (e.g., vegetable oil, etc.), singly
or in combination thereof. The eye drops may comprise an isotonic
agent (e.g., sodium chloride, concentrated glycerin, etc.), a
buffering agent (e.g., sodium phosphate, sodium acetate, etc.), a
surface active agent (e.g., Polysolvate 80 (trade name), polyoxyl
stearate 40, polyoxyethylene-hardened castor oil, etc.), a
stabilizer (sodium citrate, sodium edentate, etc.), a preservative
(e.g., benzalconium chloride, Paraben, etc.), etc. properly
selectively as necessary. The eye drops are sterilized at the final
step or prepared by an aseptic process. Alternatively, an aseptic
solid agent such as freeze-dried product which has previously been
prepared may be rendered aseptic or dissolved in aseptic distilled
water for injection or other solvent before use.
[0365] The inhalant for parenteral administration may be in the
form of aerosol, powder for inhalation or liquid for inhalation.
The liquid for inhalation may be dissolved or suspended in water or
other proper medium in use.
[0366] These inhalants are prepared by a known method.
[0367] For example, the liquid for inhalation is prepared from
materials properly selected from preservatives (e.g., benzalconium
chloride, Paraben, etc.), colorants, buffering agents (e.g., sodium
phosphate, sodium acetate, etc.), isotonic agents (e.g., sodium
chloride, concentrated glycerin, etc.), thickening agents (e.g.,
carboxyvinyl polymer, etc.), absorption accelerators, etc. as
necessary.
[0368] The powder for inhalation is prepared from materials
properly selected from glidants (e.g., stearic acid and salt
thereof, etc.), binders (e.g., starch, dextrin, etc.), vehicles
(e.g., lactose, cellulose, etc.), colorants, preservatives (e.g.,
benzalconium chloride, Paraben, etc.), absorption accelerators,
etc., if necessary.
[0369] In order to administer the liquid for inhalation, a sprayer
(e.g., atomizer, nebulizer, etc.) is normally used. In order to
administer the powder for inhalation, a powder inhaler is normally
used.
[0370] Other examples of the composition for parenteral
administration include suppository for rectal administration and
pessary for vaginal administration prepared by an ordinary
formulation comprising one or more active materials.
[Local Application]
[0371] Referring to the local administration of the invention,
EP.sub.4 agonist may be locally administered to site of disease
(particularly bone diseases involved in loss of bone mass). The
form of EP.sub.4 agonist is not limited to its administration
method. EP.sub.4 agonist may be in the form of injection, solid
agent such as embedding agent, pellet and powder, ointment to be
administered to intramuscular, subcutaneous, organic or articular
site.
[0372] The sustained release formulation of the invention is not
limited to its form so far as EP.sub.4 agonist can be continuously
administered to site of disease (particularly bone diseases
involved in loss of bone mass). The sustained release formulation
may be in the form of, e.g., sustained release injection (e.g.,
microcapsuled formulation, microspheric formulation, nanospheric
formulation), embedding formulation (e.g., film-like formulation)
or the like.
[0373] The microcapsuled formulation, microspheric formulation and
nanospheric formulation of the invention each are a finely divided
pharmaceutical composition with an biodegradable polymer comprising
as active components the compound represented by formula (I)
optionally in combination with other pharmaceutical
preparations.
[0374] Examples of the biodegradable polymer of the invention
include aliphatic acid ester polymers and copolymers thereof,
polyacrylic acid esters, polyhydroxybutyric acids, polyalkylene
oxalates, polyorthoesters, polycarbonates, and polyaminoacids.
These compounds may be used singly or in admixture of two or more
thereof. Examples of the aliphatic acid ester polymers and
copolymers thereof include polylactic acid, polyglycolic acid,
polycitric acid, polymalic acid, and lactic acid-glycolic acid
copolymer. These compounds may be used singly or in admixture of
two or more thereof. Besides these compounds,
poly-.alpha.-cyanoacrylic acid esters, poly-.beta.-hydroxybutyric
acids, polytrimethyleneoxalates, polyorthoesters,
polyorthocarbonates, polyethylene carbonates,
poly-.gamma.-benzyl-L-glutamic acids and poly-L-alanines may be
used singly or in admixture of two or more thereof. Preferred among
these compounds are polylactic acids, polyglycolic acids and lactic
acid-glycolic acid copolymers, more preferably lactic acid-glycolic
acid copolymers.
[0375] The average molecular weight of these biodegradable polymers
to be used in the invention is preferably from about 2,000 to
800,000, more preferably from about 5,000 to 200,000. For example,
the polylactic acid preferably has a weight-average molecular
weight of from about 5,000 to 100,000, more preferably from about
6,000 to 50,000. The polylactic acid can be synthesized according
to any known preparation method per se. In the lactic acid-glycolic
acid copolymer, the composition ratio of the lactic acid to the
glycolic acid is preferably from about 100/0 to 50/50 (w/w),
particularly from about 90/10 to 50/50. The weight-average
molecular weight of the lactic acid-glycolic acid copolymer is
preferably from about 5,000 to 100,000, more preferably from about
10,000 to 80,000. The lactic acid-glycolic acid copolymer can be
synthesized according to any known preparation method per se.
[0376] The term "weight-average molecular weight" as used herein is
meant to indicate molecular weight in polystyrene equivalence
determined by gel permeation chromatography (GPC).
[0377] The above-mentioned biodegradable polymer may be changed
depending on the intensity of pharmacological activity of the
compounds represented by formula (I) and the desired medicines to
be released so far as the above-mentioned aims of the invention are
accomplished. For example, the biodegradable polymer may be used in
an amount of from about 0.2 to 10,000 times (by weight), preferably
from about 1 to 1,000 times (by weight), more preferably from about
1 to 100 times (by weight) that of the physiologically active
material.
[0378] Examples of the process for the preparation of microspheric,
microcapsuled and nanospheric formulations include submerged drying
method (e.g., o/w method, w/o/w method, etc.), phase separation
method, spray drying method, granulation method by ultracritical
fluid, and methods analogous thereto.
[0379] The submerged drying method (o/w method) and spray drying
method will be further described hereinafter.
[0380] (1) In the submerged drying method (o/w method), a solution
of a biodegradable polymer in an organic solvent is prepared at
first. The organic solvent to be used in the preparation of the
microspheric, microcapsuled and nanospheric formulations preferably
has a boiling point of 120.degree. C. or less. Examples of the
organic solvent employable herein include halogenated hydrocarbons
(e.g., methylene chloride, chloroform, etc.), aliphatic esters
(e.g., ethyl acetate, etc.), ethers, aromatic hydrocarbons, and
ketones (e.g., acetone, etc.). These compounds may be used in
admixture of two or more at a proper ratio. Preferred among these
organic solvents are methylene chloride and acetonitrile,
particularly methylene chloride. The concentration of the
biodegradable polymer in the organic solution depends on the
molecular weight of the biodegradable polymer, the kind of the
organic solvent, etc., but is normally predetermined to be from
about 0.01 to 80% (v/w), preferably from about 0.1 to 70% (v/w),
more preferably from about 1 to 60% (v/w).
[0381] The compound represented by formula (I) or is then added to
and dissolved in the solution of the biodegradable polymer in an
organic solvent thus obtained, optionally in combination with other
pharmaceutical preparations. The amount of the compound represented
by formula (I) to be added optionally in combination with the other
pharmaceutical preparations depends on the kind of the
pharmaceutical preparations to be added, the action of the
pharmaceutical preparations in osteogenesis, the duration of the
action, etc. but is normally from about 0.001% to 90% (w/w),
preferably from about 0.01% to 80% (w/w), more preferably from
about 0.3 to 30% (w/w) as calculated in terms of concentration in
the solution of biodegradable polymer in an organic solvent.
[0382] Subsequently, the organic solution thus prepared is added to
an aqueous phase which is then processed by an agitator, emulsifier
or the like to form an o/w emulsion. The volume of the aqueous
phase during this procedure is predetermined to be from about 1 to
10,000 times, preferably from about 2 to 5,000 times, particularly
from about 5 to 2,000 times that of the oil phase. An emulsifier
may be added to the aqueous phase which is an external phase. As
such an emulsifier there may be normally used any material capable
of forming a stable o/w emulsion. Examples of the emulsifier
employable herein include anionic surface active agents, nonionic
surface active agents, polyoxyethylene castor oil derivatives,
polyvinyl pyrrolidone, polyvinyl alcohol, carboxymethyl cellulose,
lecitine, and gelatin. These compounds may be used in proper
combination. The concentration of the emulsifier in the external
aqueous phase is preferably from about 0.001% to 20% (w/w), more
preferably from about 0.01% to 10% (w/w), particularly from about
0.05% to 5% (w/w).
[0383] The evaporation of the solvent which is an oil phase can be
accomplished by any commonly used method. In some detail, the
evaporation of the solvent may be effected at ordinary pressure or
gradually falling pressure with stirring by an agitator, magnetic
stirrer or the like or may be effected while the pressure is being
adjusted using a rotary evaporator. The microspheric formulation
thus obtained is then fractionated by centrifugal separation or
filtration. The microspheric formulation is washed with a surface
active agent solution, alcohol or the like several times to remove
the free compound represented by formula (I), optionally in
combination with other pharmaceutical preparations, and the
emulsifier from the surface thereof, again dispersed in distilled
water or a dispersant containing a vehicle (e.g., mannitol,
sorbitol, lactose, etc.), and then freeze-dried. In the
above-mentioned o/w method, the microspheric formulation may be
prepared by a method involving the dispersion of the compound
represented by formula (I) in a solvent of a biodegradable polymer
in an organic solvent, optionally in combination with other
pharmaceutical preparations, i.e., s/o/w method.
[0384] (2) In order to prepare the microspheric formulation by the
spray drying method, an organic solvent or emulsion having the
biodegradable polymer and the compound represented by formula (I),
optionally in combination with other pharmaceutical preparations,
dissolved therein is sprayed into the drying chamber of a spray
dryer apparatus (spray dryer) through a nozzle so that the organic
solvent or water in the atomized droplets is evaporated in an
extremely short period of time to prepare a microspheric
formulation. Examples of the nozzle employable herein include two
liquid nozzle, pressure nozzle, and rotary disc. It is useful to
spray an organic solvent or an aqueous solution of an aggregation
inhibitor (e.g., mannitol, lactose, gelatin, etc.) at the same time
with the spray of o/w emulsion as necessary for the purpose of
inhibiting the aggregation of microspheres. The microspheric
formulation thus obtained is then put under reduced pressure
optionally under heating to remove water and solvent more
completely.
[0385] Examples of the film formulation include film material
obtained by dissolving the above-mentioned biodegradable polymer
and compound represented by formula (I), optionally in combination
with other pharmaceutical preparations, in an organic solvent, and
then subjecting the solution to evaporation to dryness and gelled
material obtained by dissolving the above-mentioned biodegradable
polymer and compound represented by formula (I), optionally in
combination with other pharmaceutical preparations, in a proper
solvent, and then adding a granulating agent (e.g., cellulose,
polycarbonate, etc.) to the solution.
[0386] The microsphere, microcapsule and nanosphere of the
invention may be used as they are. Alternatively, a spherical,
rod-like, acicular, pelletized, film or cream pharmaceutical
composition may be processed as a starting material to provide
preparations in various forms.
[0387] Furthermore, this preparation may be used as a parenteral
for local administration (e.g., injection such as intramuscular
injection, subcutaneous injection, injection to organs, and
injection to articular site, solid agent such as embedding agent,
pellet and powder, liquid agent such as suspension, ointment,
etc.). For example, in order to make an injection from the
microspheric formulation, the microspheric formulation is suspended
with a dispersant, a preservative, an isotonic agent, a buffer, a
pH adjustor, etc. to make an aqueous suspension as a practical
preparation for injection. Alternatively, the microspheric
formulation may be dispersed with a vegetable oil optionally in
admixture with a phospholipid such as lecitine or with a
middle-chain aliphatic acid triglyceride (e.g., Mygliol-812) to
make an oil suspension as an injection which can be practically
used.
[0388] The particle diameter of the microspheric formulation may be
arbitrary so far as it suffices the desired dispersibility and
passage through syringe if the preparation is used as a suspension
for injection. By way of example, the average particle diameter of
the microspheric formulation is from about 0.1 to 300 .mu.m,
preferably from about 1 to 150 .mu.m, more preferably from about 2
to 100 .mu.m. The pharmaceutical composition of the invention is
preferably in the form of suspension as above-mentioned. The
pharmaceutical composition of the invention is also preferably in
particulate form. This is because the pharmaceutical composition
gives less excessive pain to patients when administered through a
syringe for use in ordinary subcutaneous or intramuscular
injection. It is particularly preferred that the pharmaceutical
composition of the invention be in the form of injection. Examples
of the method for rendering the microspheric formulation aseptic
include method which is aseptic throughout the entire steps, method
involving sterilization by gamma rays, and method involving the
addition of preservative. However, the invention is not limited to
these methods.
[0389] The pharmaceutical composition of the invention can be used
for the treatment of bone diseases involved in loss of bone mass
because the compound represented by formula (I), optionally in
combination with other pharmaceutical preparations, can be
gradually released normally for 1 week to 3 months, though
depending on the kind and added amount of the biodegradable
polymer. Among these bone disease treatments, particularly, the
treatment of fracture often requires that the affected part be
fixed and covered with a plaster bandage and the administration of
pharmaceutical preparations be conducted only once rather than
frequently. Accordingly, the pharmaceutical preparations thus
administered are required to accelerate treatment continuously.
Thus, the pharmaceutical composition of the invention is useful
particularly in this treatment.
[0390] The dose of the pharmaceutical composition of the invention
depends on the kind, content and form of the compound represented
by formula (I), optionally in combination with other pharmaceutical
preparations, the duration of release of pharmaceutical
preparations, the animal to be administered, etc., but may be the
effective amount of the compound represented by formula (I),
optionally in combination with other pharmaceutical preparations.
When administered to fracture as a microspheric formulation, for
example, one time dose for adult (weight: 50 kg) is from about
0.001 mg to 500 mg, preferably from about 0.01 mg to 50 mg as
calculated in terms of effective component. The pharmaceutical
composition of the invention may be administered once 1 week to 3
months in the above-mentioned amount.
EFFECT OF THE INVENTION
[0391] The compounds of the present invention bind specifically to
subtype EP4 receptor, hardly to the other subtype receptor such as
EP1, EP3, etc. Therefore, they are thought to hardly have actions
of inducing pain which may be caused by EP.sub.1 and of uterine
contraction which may be caused by EP.sub.3. They have advantages
of generating no side effects with those actions.
DETAILED DESCRIPTION OF THE INVENTION
[0392] The following Examples are intend to illustrate, but not to
limit the present invention.
[0393] The solvents in parentheses at chromatographic separations
section and TLC section show the developing or eluting solvents and
the ratios of the solvents used are indicated by volume.
[0394] Without special explanation, NMR data was determined in
.sup.1H-NMR. And the solvents in parentheses show solvents used in
determination, but in case of no description heavy chloroform used
in determination.
[0395] All compounds described in the specification are named by
organic chemistry nomenclature recommended by IUPAC, or by using of
ACD/Name (Advanced Chemistry Development Inc.).
Example 1
(4R,5E)-4-tert-butoxycarbonylamino-7-oxo-8-(3,5-dimethylphenyl)oct-5-enoic
acid ethyl ester
[0396] Under atmosphere of argon, a suspension of 60% sodium
hydride (50 mg) was added by a solution of dimethyl
(2-oxo-3-(3,5-dimethylphenyl)propyl)phosphonate (373 mg) in
tetrahydrofuran (5 mL) at the temperature of 0.degree. C. The
mixture was stirred for an hour and then a solution of ethyl
(4R)-4-(tert-butoxycarbonylamino)-4-formylbutanoate (298 mg) in
tetrahydrofuran (5 mL) was added to the mixture. The mixture was
stirred for an hour. To the mixture, methyl tert-butyl ether and
water were added, and then IN a solution of sodium hydroxide was
added. The organic layer was washed with saturated brine, dried
over an anhydrous magnesium sulfate, concentrated and was purified
by column chromatography on silica gel (hexane:ethyl acetate=4:1)
to give the title compound (300 mg) having the following physical
data.
[0397] TLC: Rf0.76 (hexane:ethyl acetate=1:1)
Example 2
(4R,5E,7S)-4-tert-butoxycarbonylamino-7-hydroxy-8-(3,5-dimethylphenyl)oct--
5-enoic acid ethyl ester
[0398] Under atmosphere of argon, a solution of the compound
prepared in Example 1 (295 mg) in tetrahydrofuran (7.3 mL) was
added by 1.0 mol/l (R)-2-methyl-CBS-oxazaborolidine/toluene
solution (0.22 mL) at the temperature of 0.degree. C. Then 1.0
mol/l borane tetrahydrofuran complex/tetrahydrofuran solution was
dropped to the mixture, and then the mixture was stirred for 45
minutes. Additionally, 1.0 mol/l
(R)-2-methyl-CBS-oxazaborolidine/toluene solution (0.22 mL) and 1.0
mol/l borane tetrahydrofuran complex/tetrahydrofuran solution were
dropped to the mixture and then the mixture was stirred for 20
minutes at a temperature of 0.degree. C. To the mixture, small
quantity of ethanol and water was added and raised till room
temperature. The mixture was extracted with ethyl acetate. The
organic layer was washed with diluted hydrochloric acid, saturated
sodium bicarbonate water and saturated brine successively, dried
over an anhydrous magnesium sulfate, concentrated and was purified
by column chromatography on silica gel (hexane:ethyl acetate=from
4:1 to 3:1) to give the title compound (251 mg) having the
following physical data.
[0399] TLC: Rf0.59 (hexane:ethyl acetate=1:1);
[0400] NMR: .delta. 6.87, 6.82, 5.72, 5.57, 4.50, 4.33, 4.17-4.09,
2.79, 2.67, 2.32, 2.30, 1.90-1.63, 1.44, 1.26.
Example 3
(4R,5E,7S)-4-amino-7-hydroxy-8-(3,5-dimethylphenyl)oct-5-enoic acid
ethyl ester hydrochloride
[0401] ##STR28##
[0402] A solution of the compound prepared in Example 2 (243 mg) in
ethanol (1 mL) was dropped by 4N hydrochloride/dioxane (0.5 mL) at
a temperature of 0.degree. C. and the mixture was stirred for 3
hours at room temperature. The mixture was concentrated to give the
title compound (205 mg) having the following physical data. The
compound was not purified any more and as is to be used in the next
reaction.
[0403] TLC: Rf0.29 (chloroform:methanol:acetic acid=9:1:0.1);
[0404] NMR: .delta. 6.83, 5.90, 5.54, 4.40-4.34, 4.14, 3.76-3.68,
2.82-2.67, 2.27, 2.26, 2.10-1.94, 1.85-1.72, 1.26
Example 4
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3,5-dimethyl-
phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid methyl
ester
[0405] ##STR29##
[0406] Under atmosphere of argon, a solution of the compound
prepared in Example 3 (195 mg) in dry tetrahydrofuran (2 mL) was
added by a solution of methyl (4-formylmethyl)benzoate (122 mg) in
dry tetrahydrofuran (2 mL) and the mixture was stirred for an hour.
To the mixture, triacetoxy sodium boron hydride (70 mg) was added
and the mixture was stirred overnight at room temperature. The
mixture was added by water and was extracted by ethyl acetate. The
organic layer was washed with water and saturated brine
successively, dried over an anhydrous magnesium sulfate,
concentrated and was purified by column chromatography on silica
gel (hexane:ethyl acetate=from 1:3 to 1:20) to give the title
compound (136 mg) having the following physical data.
[0407] TLC: Rf0.49 (ethyl acetate);
[0408] NMR: .delta. 7.96, 7.22, 6.89, 6.82, 5.62, 5.36, 4.34, 3.91,
3.77-3.69, 3.07-2.98, 2.93-2.70, 2.40-2.05, 2.29, 1.71-1.50,
1.26
Example 5
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3,5-dimethyl-
phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid
[0409] ##STR30##
[0410] A mixed solution of the compound prepared in Example 4 (130
mg) in 1,2-dimethoxyethane (4 mL) and methanol (4 mL) was added by
2N sodium hydroxide solution and the mixture was stirred for an
hour at room temperature. To the mixture, methyl tert-butyl ether
was added and was extracted by 1N sodium hydroxide solution. The
aqueous layer was acidic added by 2N hydrochloric acid and
extracted by ethyl acetate. The layer of ethyl acetate was washed
with saturated brine, dried over anhydrous magnesium sulfate,
concentrated and was purified by column chromatography on silica
gel (chloroform:methanol=from 100:1 to 20:1) to give the title
compound (125 mg) having the following physical data.
[0411] TLC: Rf0.31 (ethyl acetate);
[0412] NMR: .delta. 8.00, 7.24, 6.88, 6.82, 5.64, 5.38, 4.37,
3.82-3.70, 3.62, 3.10-3.01, 2.94-2.69, 2.40-2.25, 2.29, 2.18-2.06,
1.72-1.60
Example 5(1)-5(26)
[0413] By the same procedure as described in Example 1, 2, 3, 4 and
5 using the corresponding phosphonate derivatives instead of
dimethyl (2-oxo-4-(3,5-dimethylphenyl)butyl)phosphonate and the
corresponding aldehyde derivatives instead of methyl
(4-formylmethyl)benzoate, the following compound of the present
invention were obtained.
Example 5(1)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(benzothia-
zol-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid
[0414] ##STR31##
[0415] TLC: Rf0.54 (chloform:methanol:acetic acid=9:1:0.1);
[0416] NMR: .delta. 8.18-7.86, 7.62-7.10, 5.61, 5.32, 4.46-4.40,
3.76-3.62, 3.07-2.98, 2.93, 2.87-2.75, 2.44-2.22, 2.14-2.02, 1.79,
1.67-1.55.
Example 5(2)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(4-fulorophen-
yl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid
[0417] ##STR32##
[0418] TLC: Rf0.21 (chloroform:methanol=10:1);
[0419] NMR: .delta. 1.64, 2.11, 2.34, 2.83, 2.98, 3.75, 4.34, 5.35,
5.59, 6.97, 7.16, 7.24, 7.99.
Example 5(3)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(5-methylbenzothiazol-2-yl)phenyl)--
5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-
-ene
[0420] ##STR33##
[0421] TLC: Rf0.22 (chloroform:methanol=5:1);
[0422] NMR: .delta. 8.47, 8.14, 8.04, 7.65, 7.52-7.36, 7.21, 5.94,
5.81, 4.63, 4.17, 3.55-3.24, 3.00, 2.84, 2.51, 2.46-2.18, 1.81.
Example 5(4)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(5-methylb-
enzoxazol-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid
[0423] ##STR34##
[0424] TLC: Rf0.58 (chloroform:methanol=5:1);
[0425] NMR(DMSO-d.sub.6): .delta. 8.05, 7.98, 7.81, 7.63, 7.57,
7.46, 7.25-7.18, 5.65, 5.29, 5.05, 4.29, 3.83, 3.46, 2.90-2.60,
2.43, 2.26-1.95, 1.51.
Example 5(5)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(6-methylbenzoxazol-2-yl)phenyl)-5--
(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-e-
ne
[0426] ##STR35##
[0427] TLC: Rf0.35 (chloroform:methanol:acetic acid=9:1:0.1);
[0428] NMR: .delta. 1.75, 2.33, 2.90, 3.34, 3.60, 4.19, 4.49, 5.62,
5.92, 7.20, 7.42, 7.66, 8.05, 8.20.
Example 5(6)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(6-methylb-
enzoxazol-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid
[0429] ##STR36##
[0430] TLC: Rf0.47 (chloroform:methanol:acetic acid=9:1:0.1);
[0431] NMR: .delta. 1.62, 2.21, 2.52, 2.85, 3.70, 4.42, 5.35, 5.62,
7.20, 7.42, 7.62, 7.95, 8.08.
Example 5(7)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(4-methylb-
enzothiazol-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid
[0432] ##STR37##
[0433] TLC: Rf0.25 (chloroform:methanol=10:1);
[0434] NMR: .delta. 1.65, 2.10, 2.30, 2.67, 2.77, 2.95, 3.69, 4.43,
5.34, 5.62, 7.22, 7.41, 7.95, 8.11.
Example 5(8)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(4-methylbenzoxazol-2-yl)phenyl)-5--
(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-e-
ne
[0435] ##STR38##
[0436] TLC: Rf0.41 (chloroform:methanol=5:1);
[0437] NMR: .delta. 1.74, 2.24, 2.37, 2.68, 2.91, 3.29, 3.40, 3.63,
4.20, 4.43, 5.53, 5.88, 7.17, 7.27, 7.35, 7.44, 8.08, 8.16.
Example 5(9)
(15.alpha.,13E)-1,6-(2-fuloro-1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-m-
ethylphenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid
[0438] ##STR39##
[0439] TLC: Rf0.31 (chloroform:methanol=5:1);
[0440] NMR: .delta. 7.90, 7.19, 7.09-6.91, 5.67, 5.40, 4.40, 3.83,
3.71, 3.02, 2.90-2.73, 2.44-2.25, 2.33, 2.14, 1.67.
Example 5(10)
(15.alpha.,13E)-1,6-(3-methyl-1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-m-
ethylphenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid
[0441] ##STR40##
[0442] TLC: Rf0.57 (chloroform:methanol=5:1);
[0443] NMR: .delta. 7.88, 7.84, 7.23-7.15, 7.07-6.97, 5.64, 5.41,
4.37, 3.81, 3.68, 3.06-2.71, 2.48-2.27, 2.38, 2.32, 2.15, 1.68.
Example 5(11)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(5,7-dimethylbenzoxazol-2-yl)phenyl-
)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost--
13-ene
[0444] ##STR41##
[0445] TLC: Rf0.40 (chloroform:methanol:acetic acid=50:10:1);
[0446] NMR: .delta. 1.81, 2.39, 2.83, 3.01, 3.39, 4.15, 4.63, 5.81,
7.01, 7.42, 8.06, 8.14, 8.48.
Example 5(12)
(15.alpha..13E)-9-oxo-15-hydroxy-16-(3-(5-chlorobenzothiazol-2-yl)phenyl)--
5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-
-ene
[0447] ##STR42##
[0448] TLC: Rf0.22 (chloroform:methanol:acetic acid=50:10:1);
[0449] NMR(DMSO-d.sub.6): .delta. 1.55, 2.11, 2.83, 3.20, 3.55,
4.10, 4.25, 5.05, 5.33, 5.72, 7.45, 7.90, 8.15, 8.31.
Example 5(13)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(5-chlorob-
enzothiazol-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid
[0450] ##STR43##
[0451] TLC: Rf0.59 (chloroform:methanol:acetic acid=50:10:1);
[0452] NMR(DMSO-d.sub.6): .delta. 1.52, 2.09, 2.73, 3.46, 3.85,
4.28, 5.06, 5.29, 5.66, 7.20, 7.43, 7.51, 7.81, 7.92, 8.11,
8.18.
Example 5(14)
(15.alpha.)-9-oxo-15-hydroxy-16-(3-(2,4-dimethylphenyl)phenyl)-5-(4-carbox-
ythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0453] ##STR44##
[0454] TLC: Rf0.49 (chloroform:methanol=7:1);
[0455] NMR: .delta. 1.74, 2.23, 2.33, 2.36, 2.88, 3.24, 3.71, 4.12,
4.44, 5.53, 5.82, 7.15, 7.35, 8.07.
Example 5(15)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(3,4-dimethylphenyl)phenyl)-5-(4-ca-
rboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0456] ##STR45##
[0457] TLC: Rf0.49 (chloroform:methanol=7:1);
[0458] NMR: .delta. 1.70, 2.30, 2.31, 2.33, 2.91, 3.13, 3.24, 3.68,
4.10, 4.46, 5.50, 5.82, 7.15, 7.40, 8.06.
Example 5(16)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3,4-difluoro-
phenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic acid
[0459] ##STR46##
[0460] TLC: Rf0.33 (ethyl acetate:methanol=10:1);
[0461] NMR(CD.sub.3OD): .delta. 1.64, 2.23, 2.86, 3.65, 3.92, 4.29,
5.36, 5.64, 7.07, 7.28, 7.94.
Example 5(17)
(15.alpha.,13E)-1,6-(2-methyl-1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-m-
ethylphenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid
[0462] ##STR47##
[0463] TLC: Rf0.60 (chloroform:methanol=5:1);
[0464] NMR: .delta. 7.97, 7.19, 7.10-6.98, 5.63, 5.40, 4.39,
3.82-3.68, 3.00, 2.90-2.69, 2.62, 2.45-2.26, 2.32, 2.12, 1.67.
Example 5(18)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(5-chlorobenzoxazol-2-yl)phenyl)-5--
(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-e-
ne
[0465] ##STR48##
[0466] TLC: Rf0.28 (chloroform:methanol=6:1);
[0467] NMR: .delta. 1.78, 2.34, 2.87, 2.99, 3.29, 3.45, 4.15, 4.60,
5.75, 5.93, 7.44, 7.83, 8.05, 8.12, 8.38.
Example 5(19)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-methyl-4-f-
ulorophenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid
[0468] ##STR49##
[0469] TLC: Rf0.42 (chloroform:methanol=5:1);
[0470] NMR: .delta. 1.65, 2.24, 2.88, 3.77, 4.33, 5.38, 5.62, 6.96,
7.26, 8.01.
Example 5(20)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-chloro-4-f-
ulorophenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid
[0471] ##STR50##
[0472] TLC: Rf0.43 (chloroform:methanol=5:1);
[0473] NMR: .delta. 8.01, 7.29-7.23, 7.06, 5.60, 5.37, 4.36,
3.92-3.72, 3.06-2.71, 2.45-2.25, 2.12, 1.61.
Example 5(21)
(15.alpha.,13E)-1,6-(3-methoxy-1,4-interphenylene)-9-oxo-15-hydroxy-16-(3--
methylphenyl)-2,3,4,5,17,18,19,20-octanol-8-azaprost-13-enoic
acid
[0474] ##STR51##
[0475] TLC: Rf0.45 (chloroform:methanol=5:1);
[0476] NMR: .delta. 7.62, 7.53, 7.21-7.15, 7.08-6.96, 5.63, 5.40,
4.38, 3.88, 3.88-3.63, 3.04, 2.97-2.73, 2.43-2.25, 2.32, 2.11,
1.66.
Example 5(22)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethoxyphenyl)-17,18,19,20-
-tetranol-5-thia-8-azaprost-13-enoic acid
[0477] ##STR52##
[0478] TLC: Rf0.53 (chloroform:methanol=5:1);
[0479] NMR: .delta. 7.34, 7.17-7.07, 5.75, 5.52, 4.44, 4.12, 3.63,
2.97, 2.87, 2.67-2.33, 2.22, 1.98-1.82, 1.69.
Example 5(23)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3,5-difluorophenyl)-17,18,19,20-tetra-
nol-5-thia-8-azaprost-13-enoic acid
[0480] ##STR53##
[0481] TLC: Rf0.53 (chloroform:methanol=5:1);
[0482] NMR: .delta. 6.80-6.64, 5.75, 5.52, 4.43, 4.13, 3.64, 2.99,
2.87, 2.70-2.37, 2.23, 1.98-1.82, 1.70.
Example 5(24)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(phenyl)phenyl)-17,18,19,20-tetrano-
l-5-thia-8-azaprost-13-enoic acid
[0483] ##STR54##
[0484] TLC: Rf0.56 (chloroform:methanol=5:1);
[0485] NMR: .delta. 7.59-7.55, 7.49-7.33, 7.17, 5.76, 5.46, 4.45,
4.09, 3.57, 2.98-2.82, 2.61-2.26, 2.18, 1.92-1.78, 1.63.
Example 5(25)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(4-fulorophenyl)phenyl)-17,18,19,20-
-tetranol-5-thia-8-azaprost-13-enoic acid
[0486] ##STR55##
[0487] TLC: Rf0.54 (chloroform:methanol=5:1);
[0488] NMR: .delta. 7.56-7.51, 7.45-7.35, 7.20-7.10, 5.78, 5.50,
4.47, 4.10, 3.59, 3.00-2.86, 2.61-2.30, 2.21, 1.97-1.80, 1.67.
Example 5(26)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-phenyl-4-fulorophenyl)-17,18,19,20--
tetranol-5-thia-8-azaprost-13-enoic acid
[0489] ##STR56##
[0490] TLC: Rf0.40 (chloroform:methanol=7:1);
[0491] NMR: .delta. 7.56-7.51, 7.48-7.34, 7.28, 7.18-7.06, 5.77,
5.51, 4.43, 4.11, 3.61, 2.95, 2.87, 2.61-2.33, 2.21, 1.95-1.78,
1.67.
Example 6
(4R)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-oxazolidine-2-one
[0492] Under atmosphere of argon, a solution of
(4S)-4-(hydroxymethyl)-1,3-oxazolidine-2-one (34.1 g) in
N,N-dimethylformamide (300 mL) was added by imidazole (25.7 g) and
was cooled down to the temperature of 0.degree. C. To the mixture,
a solution of tert-butyldimethylsilylchloride (48.2 g) in
N,N-dimethylformamide (300 mL) was moderately dropped and the
mixture was stirred overnight at room temperature. The mixture was
diluted with ethyl acetate and water and was washed with saturated
brine. The organic layer was dried over an anhydrous magnesium
sulfate and concentrated to give the title compound (64.8 g) having
the following physical data, which was used for the next reaction
without purification.
[0493] TLC: Rf0.83 (ethyl acetate:methanol=20:1).
Example 7
(4R)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(2-hydroxyethyl)-1,3-oxa-
zolidine-2-one
[0494] Under atmosphere of argon, a solution of the compound
prepared in Example 6 (64.8 g) was dissolved in tetrahydrofuran
(600 mL), cooled down to the temperature of 0.degree. C. and the
mixture was added by potassium tert-butoxide (39.2 g) and then was
stirred for 30 minutes. The mixture was dropped by a solution of
bromo ethyl acetate (38.7 mL) in tetrahydrofuran (50 mL), stirred
for two hours at room temperature, diluted with ethyl acetate and
water and washed with saturated brine. The organic layer was dried
over an anhydrous magnesium sulfate and concentrated. Under
atmosphere of argon, the solution of the obtained residue in
tetrahydrofuran (200 mL) was dropped to a mixed solution of sodium
boron hydride (22.0 g) in ethanol/tetrahydrofuran (400 mL/400 mL)
at a temperature of 0.degree. C. and the mixture was stirred for
three hours at room temperature. The mixture was cooled in the iced
water bath, added by saturated ammonium chloride solution and water
and extracted by ethyl acetate. The organic layer was dried over an
anhydrous magnesium sulfate and concentrated to give the title
compound (70.9 g) having the following physical data, which was
used for the next reaction without purification.
[0495] TLC: Rf0.32 (hexane:ethyl acetate=1:2).
Example 8
S-{2-[(4R)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-oxo-1,3-oxazolidin-
e-3-yl]ethyl}ethane thioate
[0496] Under atmosphere of argon, a solution of the compound
prepared in Example 7 (2.5 g) in tetrahydrofuran (200 mL) was
cooled down, added by triethylamine (10.7 mL),
methanesulfonylchloride (4.19 mL) and the mixture was stirred for
20 minutes. The mixture was added by methanol (1.10 mL), stirred
for 30 minutes and then added by N,N-dimethylformamide (200 mL),
potassium carbonate (12.6 g) and potassium thioacetic acid (10.4 g)
and stirred for three hours at the temperature of 60.degree. C. The
mixture was cooled down to the room temperature, added by
tert-butylmethylether (400 mL) and washed with water and saturated
brine. The obtained organic layer was added by magnesium sulfate
and activated carbon, filtrated, concentrated to give the title
compound (16.0 g) having the following physical data, which was
used for the next reaction without purification.
[0497] TLC: Rf0.63 (hexane:ethyl acetate=1:1).
Example 9
butyl
4-({2-[(4S)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-oxo-1,3-oxa-
zolidine-3-yl]ethyl}thio)butanoate
[0498] Under atmosphere of argon, a solution of the compound
prepared in Example 8 (16.0 g) in tetrahydrofuran (40 mL) was added
by ethyl 4-bromobutanoate (7.83 mL), potassium tert-butoxide (6.17
g) and n-butanol (16.6 mL) and was stirred for three hours and a
half at room temperature, for three hours at a temperature of
50.degree. C., and additionally for an hour at a temperature of
80.degree. C. The mixture was cooled down to the room temperature,
added by tert-butyl methyl ether (400 mL) and washed with water and
saturated brine. The organic layer was dried over an anhydrous
magnesium sulfate, concentrated and the obtained residue was
purified by column chromatography on silica gel (hexane:ethyl
acetate=from 50:1 to 1:1). Under atmosphere of argon, a solution of
the obtained compound in n-butanol (40 mL) was added by potassium
carbonate (12.0 g), stirred overnight at the temperature of
100.degree. C., cooled down to the room temperature and the mixture
was diluted by ethyl acetate to be poured into water. The mixture
was extracted by ethyl acetate and the obtained organic layer was
washed with water and saturated brine. The organic layer was dried
over magnesium sulfate and concentrated to give the title compound
having the following physical data, which was used for the next
reaction without purification.
[0499] TLC: Rf0.72 (hexane:ethyl acetate=1:1).
Example 10
butyl
4-({2-[(4S)-4-(hydroxymethyl)-2-oxo-1,3-oxazolidine-3-yl]ethyl}thio)-
butanoate
[0500] Under atmosphere of argon, a solution of the compound
prepared in Example 9 in tetrahydrofuran (85 mL) was dropped by 1M
tetrabutylammonium fluoride in tetrahydrofuran solution (52 mL) and
stirred for an hour at the room temperature. The mixture was added
by saturated ammonium chloride solution, extracted by ethyl acetate
and the obtained organic layer was washed with water and saturated
brine. The organic layer was dried over magnesium sulfate,
concentrated and purified by column chromatography on silica gel
(hexane:ethyl acetate=1:1 to ethyl acetate) to give the title
compound (11.9 g) having the following physical data.
[0501] TLC: Rf0.08 (hexane:ethyl acetate=1:1).
Example 11
(13E)-9,15-dioxo-16-(3-phenylphenyl)-17,18,19,20-tetranol-5-thia-8-aza-10--
oxaprost-13-enoic acid.n-butylester
[0502] Under atmosphere of argon, the compound purified in Example
10 (150 mg) was dissolved in ethyl acetate/dimethylsulfoxide (3
mL/2 mL) mixed solution, added by diisopropylethylamine (0.49 mL)
and the mixture was cooled down to the temperature of 0.degree. C.
The mixture was added by sulfur trioxide pyridine complex (224 mg),
stirred for an hour and the mixture was added by 2N hydrochloric
acid and ethyl acetate, extracted and washed with water, saturated
sodium bicarbonate solution and saturated brine. The organic layer
was dried over a sodium sulfate. Under atmosphere of argon, the
obtained residue (150 mg) in acetonitrile solution (5 mL) was added
by a suspended solution that a solution of dimethyl
(3-biphenyl-3-yl-2-oxopropyl)phosphonate (179 mg) cooled down to
the temperature of 0.degree. C. in acetonitrile solution (6 mL) was
added by diisopropylethylamine (0.098 mL) and lithium chloride (24
mg), stirred for an hour at the room temperature and prepared, and
stirred for two hours. The mixture was added by water and 2N
hydrochloric acid, extracted by ethyl acetate and washed with
saturated sodium hydrocarbonate solution and saturated brine. The
organic layer was dried over a magnesium sulfate, concentrated and
purified by column chromatography on silica gel (hexane ethyl
acetate=1:1) to give the title compound (240 mg) having the
following physical data.
[0503] TLC: Rf0.32 (hexane:ethyl acetate=1:1).
Example 12
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-phenylphenyl)-17,18,19,20-tetranol--
5-thia-8-aza-10-oxaprost-13-enoic acid.n-butylester
[0504] Under atmosphere of argon, a solution of the compound
prepared in Example 11 (240 mg) in tetrahydrofuran (3 mL) was added
by 1 mol/L (R)-2-methyl-CBS-oxazaborolidine in toluene solution
(0.091 mL) at a temperature of 0.degree. C. The mixture was dropped
by 1 mol/L borane-tetrahydrofuran complex in tetrahydrofuran
solution (0.36 mL) and stirred for an hour. To the mixture, 1N
hydrochloric acid added and the mixture was extracted by ethyl
acetate and washed with 1N hydrochloric acid, saturated sodium
hydrocarbonate solution and saturated brine. The organic layer was
dried over a magnesium sulfate, concentrated and purified by column
chromatography (hexane:ethyl acetate=1:2) to give the title
compound (96 mg) having the following physical data.
[0505] TLC: Rf0.27 (hexane:ethyl acetate=1:2).
Example 13
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-phenylphenyl)-17,18,19,20-tetranol--
5-thia-8-aza-10-oxaprost-13-enoic acid
[0506] ##STR57##
[0507] Under atmosphere of argon, a solution of the compound
prepared in Example 12 (96 mg) in methanol (1 mL) was added by 2N
sodium hydroxide solution (0.28 mL) and stirred for an hour at the
room temperature. The mixture was added by 1N hydrochloric acid and
extracted by ethyl acetate. The organic layer was washed with
saturated brine, dried over an anhydrous sodium sulfate,
concentrated and purified by column chromatography
(chloroform:methanol=from 50:1 to 9:1) to give the title compound
(75 mg) having the following physical data.
[0508] TLC: Rf0.33 (methylene chloride:methanol=9:1);
[0509] NMR: .delta. 1.88, 2.50, 2.96, 3.40, 3.88, 4.34, 4.51, 5.55,
5.90, 7.17, 7.49.
Example 13(1)-13(15)
[0510] By the same procedure as described in Example 11, 12 and 13
using the corresponding phosphate ester instead of dimethyl
(3-biphenyl-3-yl-2-oxopropyl)phosphonate, the following compound of
the present invention were obtained.
Example 13(1)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-ethylphenyl)-17,18,19,20-tetranol-5-
-thia-8-aza-10-oxaprost-13-enoic acid
[0511] TLC: Rf0.45 (methylene chloride:methanol=9:1);
[0512] NMR: .delta. 1.24, 1.89, 2.65, 3.10, 3.45, 3.91, 4.40, 5.58,
5.90, 7.01, 7.11, 7.23.
Example 13(2)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chloro-4-fulorophenyl)-17,18,19,20--
tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid
[0513] TLC: Rf0.36 (methylene chloride:methanol=9:1);
[0514] NMR: .delta. 1.90, 2.65, 3.11, 3.47, 3.91, 4.38, 5.59, 5.88,
7.09, 7.23.
Example 13(3)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(naphthalene-2-yl)-17,18,19,20-tetrano-
l-5-thia-8-aza-10-oxaprost-13-enoic acid
[0515] TLC: Rf0.33 (methylene chloride:methanol=9:1);
[0516] NMR: .delta. 1.85, 2.50, 2.97, 3.34, 3.87, 4.34, 4.55, 5.54,
5.91, 7.32, 7.47, 7.64, 7.80.
Example 13(4)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethoxyphenyl)-17,18,19,20-
-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid
[0517] TLC: Rf0.33 (methylene chloride:methanol=9:1);
[0518] NMR: .delta. 1.91, 2.57, 2.87, 3.10, 3.46, 3.89, 4.41, 5.59,
5.89, 7.11, 7.36.
Example 13(5)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fuloro-3-phenylphenyl)-17,18,19,20--
tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid
[0519] TLC: Rf0.42 (methylene chloride:methanol=9:1);
[0520] NMR: .delta. 1.87, 2.53, 2.87, 3.07, 3.44, 3.89, 4.40, 5.58,
5.90, 7.12, 7.26, 7.46.
Example 13(6)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fuloro-3-methylphenyl)-17,18,19,20--
tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid TLC: Rf0.33
(methanol:chloroform=1:9);
[0521] NMR(CD.sub.3OD): .delta. 1.86, 2.23, 2.40, 2.56, 2.71, 2.83,
2.96, 3.37, 3.91, 4.39, 5.45, 5.85, 6.95.
Example 13(7)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3,5-difluorophenyl)-17,18,19,20-tetra-
nol-5-thia-8-aza-10-oxaprost-13-enoic acid
[0522] TLC: Rf0.30 (methanol:chloroform=1:9);
[0523] NMR: .delta. 1.91, 2.63, 3.10, 3.47, 3.91, 4.41, 5.60, 5.88,
6.72.
Example 13(8)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-fulorophenyl)-17,18,19,20-tetranol--
5-thia-8-aza-10-oxaprost-13-enoic acid
[0524] TLC: Rf0.30 (methanol:chloroform=1:9);
[0525] NMR: .delta. 1.93, 2.58, 2.86, 3.10, 3.44, 3.90, 4.41, 5.57,
5.88, 6.97, 7.30.
Example 13(9)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fuloro-3-trifluoromethylphenyl)-17,-
18,19,20-tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid
[0526] TLC: Rf0.29 (methanol:chloroform=1:9);
[0527] NMR: .delta. 1.90, 2.68, 3.13, 3.48, 3.90, 4.41, 5.61, 5.90,
7.16, 7.41.
Example 13(10)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20--
tetranol-5-thia-8-aza-10-oxaprost-13-enoic acid
[0528] TLC: Rf0.30 (methanol:chloroform=1:9);
[0529] NMR: .delta. 1.90, 2.57, 2.92, 3.10, 3.46, 3.88, 4.42, 5.58,
5.90, 7.45.
Example 13(11)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetra-
nol-5-thia-8-aza-10-oxaprost-13-enoic acid
[0530] TLC: Rf0.29 (methanol:chloroform=1:9);
[0531] NMR: .delta. 1.91, 2.64, 3.12, 3.48, 3.91, 4.40, 5.60, 5.88,
6.92, 7.09.
Example 13(12)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranol-5-thia-8-a-
za-10-oxaprost-13-enoic acid
[0532] TLC: Rf0.31 (methanol:chloroform=1:9);
[0533] NMR: .delta. 1.90, 2.62, 3.06, 3.45, 3.89, 4.38, 5.55, 5.89,
7.28.
Example 13(13)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranol--
5-thia-8-aza-10-oxaprost-13-enoic acid
[0534] TLC: Rf0.32 (methanol:chloroform=1:9);
[0535] NMR: .delta. 0.94, 1.63, 1.92, 2.62, 3.10, 3.45, 3.90, 4.39,
5.58, 5.90, 7.04, 7.22.
Example 13(14)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-te-
tranol-5-thia-8-aza-10-oxaprost-13-enoic acid
[0536] TLC: Rf0.32 (methanol:chloroform=1:9);
[0537] NMR: .delta. 1.89, 2.58, 3.20, 3.39, 3.43, 3.92, 4.41, 4.47,
5.63, 5.92, 7.24.
Example 13(15)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-ethyl-4-fulorophenyl)-17,18,19,20-t-
etranol-5-thia-8-aza-10-oxaprost-13-enoic acid
[0538] TLC: Rf0.30 (ethyl acetate);
[0539] NMR: .delta. 1.22, 1.89, 2.62, 3.13, 3.48, 3.92, 4.39, 5.60,
5.90, 6.98.
Example 14(1)-14(5)
[0540] By the same procedure as described in Example 9, 10, 11, 12
and 13 using ethyl 2-bromo-1,3-thiazol-4-carboxylate instead of
ethyl 4-bromobutanoate and the corresponding phosphate ester
instead of dimethyl (3-biphenyl-3-yl-2-oxopropyl)phosphonate, the
following compound of the present invention were obtained.
Example 14(1)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-phenyl-5-(4-carboxythiazol-2-yl)-1,2,3-
,4,17,18,19,20-octanol-5-thia-8-aza-10-oxaprost-13-ene
[0541] ##STR58##
[0542] TLC: Rf020 (chloroform:methanol=5:1);
[0543] NMR: .delta. 2.85, 3.30, 3.54, 3.92, 4.38, 5.53, 5.92, 7.24,
8.10.
Example 14(2)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxythiazol-2-
-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-aza-10-oxaprost-13-ene
[0544] TLC: Rf0.21 (chloroform:methanol=5:1);
[0545] NMR: .delta. 2.33, 2.80, 3.31, 3.57, 3.93, 4.40, 5.55, 5.92,
6.96, 7.06, 7.19, 8.10.
Example 14(3)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fulorophenyl)-5-(4-carboxythiazol-2-
-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-aza-10-oxaprost-13-ene
[0546] TLC: Rf0.14 (chloroform:methanol=5:1);
[0547] NMR: .delta. 2.81, 3.35, 3.59, 3.93, 4.39, 5.57, 5.92, 6.99,
7.13, 8.11.
Example 14(4)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(naphthalene-2-yl)-5-(4-carboxythiazol-
-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-aza-10-oxaprost-13-ene
[0548] TLC: Rf0.26 (methylene:methanol=5:1);
[0549] NMR: .delta. 2.98, 3.38, 3.88, 4.33, 4.53, 5.51, 5.95, 7.30,
7.45, 7.60, 7.78, 8.05.
Example 14(5)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-phenylphenyl)-5-(4-carboxythiazol-2-
-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-aza-10-oxaprost-13-ene
[0550] TLC: Rf0.34 (methylene:methanol=5:1);
[0551] NMR: .delta. 2.27, 2.90, 3.26, 3.55, 3.91, 4.34, 4.49, 5.55,
5.95, 7.15, 7.46, 8.08.
Example 15(1)-15(20)
[0552] By the same procedure as described in Example 6, 7, 8, 9,
10, 11, 12 and 13 using (5R)-5-(hydroxymethyl)pyrrolidine-2-one
instead of (4S)-4-(hydroxymethyl)-1,3-oxazolidine-2-one, the
corresponding bromoester instead of ethyl 4-bromobutanoate and the
corresponding phosphate ester instead of dimethyl
(3-biphenyl-3-yl-2-oxopropyl)phosphonate, the following compound of
the present invention were obtained.
Example 15(1)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-phenylphenyl)-5-(5-carboxythiophen--
2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0553] ##STR59##
[0554] TLC: Rf0.21 (chloroform:methanol=5:1);
[0555] NMR: .delta. 1.69, 2.19, 2.35, 2.89, 3.00, 3.61, 4.09, 4.43,
5.46, 5.73, 7.02, 7.16, 7.38, 7.56, 7.66.
Example 15(2)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(naphthalene-2-yl)-5-(5-carboxythiophe-
n-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0556] TLC: Rf0.21 (chloroform:methanol=5:1);
[0557] NMR: .delta. 1.69, 2.19, 2.34, 2.92, 3.52, 4.05, 4.48, 5.44,
5.74, 7.02, 7.30, 7.44, 7.62, 7.66, 7.78.
Example 15(3)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fuloro-3-phenylphenyl)-5-(5-carboxy-
thiophen-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0558] TLC: Rf0.21 (chloroform:methanol=5:1);
[0559] NMR: .delta. 1.71, 2.16, 2.36, 2.81, 3.04, 3.66, 4.12, 4.38,
5.48, 5.73, 7.03, 7.10, 7.23, 7.41, 7.53, 7.66.
Example 15(4)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-ethylphenyl)-5-(5-carboxythiophen-2-
-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0560] TLC: Rf0.22 (chloroform:methanol=5:1);
[0561] NMR: .delta. 1.23, 1.73, 2.21, 2.38, 2.63, 2.78, 3.06, 3.67,
4.12, 4.39, 5.48, 5.73, 7.00, 7.08, 7.23, 7.69.
Example 15(5)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(carboxythiophen-2--
yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0562] TLC: Rf0.21 (chloroform:methanol=5:1);
[0563] NMR: .delta. 1.72, 2.20, 2.33, 2.38, 2.77, 3.07, 3.66, 4.12,
4.38, 5.47, 5.72, 7.04, 7.19, 7.69.
Example 15(6)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethoxyphenyl)-5-(5-carbox-
ythiophen-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0564] TLC: Rf0.21 (chloroform:methanol=5:1);
[0565] NMR: .delta. 1.72, 2.16, 2.38, 2.83, 3.08, 3.67, 4.12, 4.40,
5.50, 5.72, 7.09, 7.33, 7.69.
Example 15(7)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fuloro-3-phenylphenyl)-5-(4-carboxy-
thiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0566] TLC: Rf0.21 (chloroform:methanol=5:1);
[0567] NMR: .delta. 1.73, 2.34, 2.86, 3.25, 3.74, 4.13, 4.44, 5.54,
5.82, 7.11, 7.26, 7.40, 7.53, 8.07.
Example 15(8)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-ethylphenyl)-5-(4-carobxythiazol-2--
yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0568] TLC: Rf0.21 (chloroform:methanol=5:1);
[0569] NMR: .delta. 1.22, 1.74, 2.31, 2.63, 2.82, 3.25, 3.72, 4.11,
4.42, 5.51, 5.81, 7.00, 7.08, 7.23, 8.08.
Example 15(9)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(naphthalene-2-yl)-5-(4-carboxythiazol-
-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0570] TLC: Rf0.21 (chloroform:methanol=5:1);
[0571] NMR: .delta. 1.72, 2.30, 3.11, 3.65, 4.11, 4.51, 5.50, 5.83,
7.31, 7.46, 7.63, 7.80, 8.05.
Example 15(10)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethoxyphenyl)-5-(4-carbox-
ythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0572] TLC: Rf0.20 (chloroform:methanol=5:1);
[0573] NMR: .delta. 1.73, 2.33, 2.87, 3.27, 3.75, 4.12, 4.42, 5.55,
5.80, 7.11, 7.33, 8.09.
Example 15(11)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chloro-4-fulorophenyl)-5-(4-carboxy-
thiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0574] TLC: Rf0.20 (chloroform:methanol=5:1);
[0575] NMR: .delta. 1.74, 2.34, 2.79, 3.32, 3.74, 4.12, 4.40, 5.54,
5.80, 7.06, 7.24, 8.10.
Example 15(12)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-cyclopropyl-5-(4-carboxythiazol-2-yl)--
1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0576] TLC: Rf0.21 (chloroform:methanol=5:1);
[0577] NMR: .delta. 0.10, 0.50, 0.69, 1.46, 1.80, 2.35, 3.34, 3.47,
3.85, 4.13, 4.29, 5.60, 5.83, 8.10.
Example 15(13)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-cyclohexyl-5-(4-carboxythiazol-2-yl)-1-
,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0578] TLC: Rf0.21 (chloroform:methanol=5:1);
[0579] NMR: .delta. 0.93, 1.35, 1.77, 2.33, 3.33, 3.46, 3.85, 4.14,
4.28, 5.55, 5.79, 8.10.
Example 15(14)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fulorophenyl)-5-(5-carboxythiazol-2-
-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0580] TLC: Rf0.17 (methylene chloride:methanol:acetic
acid=90:10:1);
[0581] NMR: .delta. 1.72, 2.31, 2.77, 3.32, 3.69, 4.13, 4.36, 4.70,
5.52, 5.76, 6.98, 7.15, 8.20.
Example 15(15)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-cyclobutyl-5-(4-carboxythiazol-2-yl)-1-
,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0582] TLC: Rf0.31 (chloroform:methanol=5:1);
[0583] NMR: .delta. 1.72, 2.07, 2.39, 3.34, 3.48, 3.82, 4.12, 5.54,
5.76, 8.10.
Example 15(16)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-chlorophenyl)-5-(4-carboxythiazol-2-
-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0584] TLC: Rf0.42 (chloroform:methanol=4:1);
[0585] NMR: .delta. 1.72, 2.32, 2.80, 3.32, 3.72, 4.11, 4.39, 5.51,
5.78, 7.11, 7.30, 8.09.
Example 15(17)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-chlorophenyl-5-(4-carboxythiazol-2-yl)-
-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0586] TLC: Rf0.52 (chloroform:methanol=4:1);
[0587] NMR: .delta. 1.50, 2.36, 3.43, 3.84, 4.18, 5.55, 5.78,
8.10.
Example 15(18)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(indan-2-yl)-5-(4-carboxythiazol-2-yl)-
-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0588] TLC: Rf0.39 (chloroform:methanol=9:1);
[0589] NMR: .delta. 1.75, 2.43, 3.25, 3.80, 4.14, 4.31, 5.61, 5.84,
7.15, 8.07.
Example 15(19)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(tetrahydropyran-4-yl)-5-(4-carboxythi-
azol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0590] TLC: Rf0.13 (methylene chloride:methanol=5:1);
[0591] NMR: .delta. 1.52, 2.37, 3.42, 3.80, 3.96, 4.15, 4.30, 5.58,
5.82, 8.10.
Example 15(20)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(7-methylnaphthalene-2-yl)-5-(4-carbox-
ythiazol-2-yl)-1,2,3,4,17,18,19,20-octanol-5-thia-8-azaprost-13-ene
[0592] TLC: Rf0.34 (ethyl acetate);
[0593] NMR: .delta. 1.72, 2.33, 2.50, 3.23, 4.11, 4.51, 5.49, 5.82,
7.26, 7.54, 7.70, 7.74, 8.06.
Example 16
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fulorophenyl)-17,18,19,20-tetranol--
5,10-dithia-8-azaprost-13-enoic acid
[0594] ##STR60##
[0595] By the same procedure as described in Example 6, 7, 8, 9,
10, 11, 12 and 13 using
(4S)-4-(hydroxymethyl)-1,3-thiazolidine-2-one instead of
(4S)-4-(hydroxymethyl)-1,3-oxazolidine-2-one,
dimethyl[3-(4-fulorophenyl)-2-oxopropyl]phosphonate instead of
dimethyl(3-biphenyl-3-yl-2-oxopropyl)phosphonate, the compound
having the following physical data of the present invention were
obtained.
[0596] TLC: Rf0.22 (hexane:ethyl acetate=1:3);
[0597] NMR: .delta. 1.90, 2.56, 2.97, 3.39, 3.61, 4.38, 5.64, 5.84,
7.01, 7.17.
Example 17
ethyl
5-({[(2R)-2-(hydroxymethyl)-5-oxopyrrolidine-1-yl]methyl}thio)pentan-
oate
[0598] Under atmosphere of argon, a solution of
(5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyrrolidine-2-one (2
g) in benzene (20 mL) was added by p-toluene sulfonic
acid.monohydrate (166 mg) and paraformic aldehyde (290 mg) and
stirred for an hour at the room temperature. The mixture was added
by ethyl 5-mercaptopentanoate (1.41 g) and stirred heating using
Dean-Stark apparatus for three hours at the temperature of
125.degree. C. The mixture was diluted with tert-butylmethylether
solution, washed with water and saturated brine, dried over an
sodium sulfate, concentrated and purified by column chromatography
on silica gel (ethyl acetate:hexane=1:6). Under atmosphere of
argon, the purified compound (1.9 g) in tetrahyrdorfuran solution
(1.5 mL) was added by 1M tetrabutylammonium fluoride in
tetrahydrofuran (4.7 mL) and stirred for an hour at room
temperature. The mixture was diluted with ethyl acetate and washed
with water and saturated brine. The organic layer was dried over
sodium sulfate, concentrated and purified by column chromatography
on silica gel (ethyl acetate:hexane=1:2) to give the title compound
(1.05 mg) having the following physical data.
[0599] TLC: Rf0.81 (ethyl acetate).
Example 18(1), 18(2)
[0600] By the same procedure as described in Example 11, 12 and 13
using the compound prepared in Example 17 instead of the compound
prepared in Example 10, the corresponding phosphate ester instead
of dimethyl (3-biphenyl-3-yl-2-oxopropyl)phosphonate, the following
compound of the present invention were obtained.
Example 18(1)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fulorophenyl)-17,18,19,20-tetranol--
6-thia-8-azaprost-13-enoic acid
[0601] ##STR61##
[0602] TLC: Rf0.22 (methanol:chloroform=1:10);
[0603] NMR: .delta. 1.70, 2.39, 2.83, 3.48, 4.34, 4.90, 5.40, 5.78,
7.00, 7.15.
Example 18(2)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranol--
6-thia-8-azaprost-13-enoic acid
[0604] TLC: Rf0.22 (methanol:chloroform=1:10);
[0605] NMR: .delta. 1.73, 2.38, 2.81, 3.45, 4.36, 4.89, 5.39, 5.79,
7.04, 7.20.
Example 19
(15.alpha.,13E)-9-oxo-15-{[t-butyl(dimethyl)silyl]oxy}-16-(4-fulorophenyl)-
-17,18,19,20-tetranol-5-thia-8-azaprost-13-enoic acid.n-butyl
ester
[0606] Under atmosphere of argon, a solution of the butyl ester of
the compound prepared in Example (3-1) of WO03/009872 (126 mg) in
N,N-dimethylformamide (3 mL) was added by
tert-butyldimethylsilylchloride (71 mg) and imidazole (32 mg) and
stirred for an hour at the room temperature. The mixture was cooled
down to the room temperature, poured into water and extracted by
ethyl acetate. The obtained organic layer was washed with water and
saturated brine, dried over sodium sulfate, concentrated and
purified by column chromatography on silica gel (hexane:ethyl
acetate=1:1) to give the title compound (158 mg) having the
following physical data.
[0607] TLC: Rf0.24 (hexane:ethyl acetate=1:1).
Example 20
(15.alpha.,13E)-9-thioxo-15-{[t-butyl(dimethyl)silyl]oxy}-16-(4-fulorophen-
yl)-17,18,19,20-tetranol-5-thia-8-azaprost-13-enoic acid.n-butyl
ester
[0608] Under atmosphere of argon, a solution of the compound
prepared in Example 19 in toluene (3 mL) was added by Lawesson
reagent (68 mg) and stirred for 20 minutes at the temperature of
50.degree. C. The mixture was cooled down to the room temperature,
concentrated and the obtained residue was purified by column
chromatography on silica gel (hexane:ethyl acetate=8:1) to give the
title compound (146 mg) having the following physical data.
[0609] TLC: Rf0.20 (hexane:ethyl acetate=4:1).
Example 21
(15.alpha.,13E)-9-thioxo-15-hydroxy-16-(4-fulorophenyl)-17,18,19,20-tetran-
ol-5-thia-8-azaprost-13-enoic acid
[0610] ##STR62##
[0611] By the same procedure as described in Example 10 and 13
using the compound prepared in Example 20 instead of the compound
prepared in Example 9, the following compound of the present
invention were obtained.
[0612] TLC: Rf0.44 (methylene chloride:methanol=9:1);
[0613] NMR: .delta. 1.75, 1.93, 2.28, 2.75, 3.35, 4.13, 4.44, 5.55,
5.79, 7.01, 7.17.
Example 22(1)-22(12)
[0614] By the same procedure as described in Example 11, 12 and 13
using ethyl
4-({2-[(4S)-4-(hydroxymethyl)-2-oxo-1,3-thiazolidine-3-yl]ethyl}thi-
o)butanoate instead of the compound prepared in Example 10 and the
corresponding phosphate ester instead of dimethyl
(3-biphenyl-3-yl-2-oxopropyl)phosphonate, the following compound of
the present invention were obtained.
Example 22(1)
4-[(2-{(4S)-4-[(1E,3S)-4-(3-ethylphenyl)-3-hydroxybut-1-enyl]-2-oxo-1,3-th-
iazolidine-3-yl}ethyl)sulfanil]butyric acid
[0615] NMR: .delta. 1.23, 1.90, 2.55, 2.93, 3.39, 3.59, 4.33, 4.46,
5.67, 5.87, 7.06, 7.25;
[0616] MS(APCI, Neg. 20V):422 (M-H).sup.-;
[0617] TLC: Rf0.43 (ethyl acetate).
Example 22(2)
4-[(2-{(4S)-4-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazolidin-
e-3-yl}ethyl)sulfanil]butyric acid
[0618] NMR: .delta. 1.90, 2.57, 2.96, 3.38, 3.59, 4.32, 4.46, 5.65,
5.86, 7.27;
[0619] MS(APCI, Neg. 20V):394 (M-H).sup.-;
[0620] TLC: Rf0.45 (ethyl acetate).
Example 22(3)
4-{[2-((4S)-4-{(1E,3S)-4-[4-fuloro-3-(trifluoromethyl)phenyl]-3-hydroxybut-
-1-enyl}-2-oxo-1,3-thiazolidine-3-yl)ethyl]sulfanyl}butyric
acid
[0621] NMR: .delta. 1.88, 2.57, 2.97, 3.41, 3.65, 4.40, 5.69, 5.85,
7.15, 7.43;
[0622] MS(APCI, Neg. 20V):480 (M-H).sup.-;
[0623] TLC: Rf0.52 (ethyl acetate).
Example 22(4)
4-[(2-{(4S)-4-[(1E,3S)-4-(3,5-difluorophenyl)-3-hydroxybut-1-enyl]-2-oxo-1-
,3-thiazolidine-3-yl}ethyl)sulfanyl]butyric acid
[0624] NMR: .delta. 1.90, 2.57, 2.96, 3.41, 3.63, 4.41, 5.69, 5.84,
6.72;
[0625] MS(APCI, Neg. 20V):430 (M-H).sup.-;
[0626] TLC: Rf0.58 (ethyl acetate).
Example 22(5)
4-[(2-{(4S)-4-[(1E,3S)-3-hydroxy-4-(3-propylphenyl)but-1-enyl]-2-oxo-1,3-t-
hiazolidine-3-yl}ethyl)sulfanyl]butyric acid
[0627] NMR: .delta. 0.94, 1.64, 1.90, 2.56, 2.94, 3.38, 3.60, 4.32,
4.46, 5.68, 5.87, 7.03, 7.24;
[0628] MS(APCI, Neg. 20V):436 (M-H).sup.-;
[0629] TLC: Rf0.52 (ethyl acetate).
Example 22(6)
4-[(2-{(4S)-4-[(1E,3S)-4-(3-ethyl-4-fulorophenyl)-3-hydroxybut-1-enyl]-2-o-
xo-1,3-thiazolidine-3-yl}ethyl)sulfanyl]butyric acid
[0630] NMR: .delta. 1.22, 1.90, 2.57, 2.95, 3.39, 3.61, 4.32, 4.45,
5.68, 5.86, 6.99, 7.27;
[0631] MS(APCI, Neg. 20V):440 (M-H).sup.-;
[0632] TLC: Rf0.55 (ethyl acetate).
Example 22(7)
4-[(2-{(4S)-4-[(1E,3S)-4-(3,4-difluorophenyl)-3-hydroxybut-1-enyl]-2-oxo-1-
,3-thiazolidine-3-yl}ethyl)sulfanyl]butyric acid
[0633] NMR: .delta. 1.91, 2.74, 3.41, 3.62, 4.39, 5.68, 5.84, 6.92,
7.07;
[0634] MS(APCI, Neg. 20V):430 (M-H).sup.-;
[0635] TLC: Rf0.50 (ethyl acetate).
Example 22(8)
4-{[2-((4S)-4-{(1E,3S)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]but-1-enyl}--
2-oxo-1,3-thiazolidine-3-yl)ethyl]sulfanyl}butyric acid
[0636] NMR: .delta. 1.89, 2.75, 3.39, 3.61, 4.34, 4.49, 5.68, 5.85,
7.45;
[0637] MS(APCI, Neg. 20V):462 (M-H).sup.-;
[0638] TLC: Rf0.50 (ethyl acetate).
Example 22(9)
4-[(2-{(4S)-4-[(1E,3S)-4-(4-fuloro-3-methylphenyl)-3-hydroxybut-1-enyl]-2--
oxo-1,3-thiazolidine-3-yl}ethyl)sulfanyl]butyric acid
[0639] NMR: .delta. 1.91, 2.26, 2.74, 3.40, 3.62, 4.39, 5.67, 5.85,
6.96;
[0640] MS(APCI, Neg. 20V):426 (M-H).sup.-;
[0641] TLC: Rf0.50 (ethyl acetate).
Example 22(10)
4-[(2-{(4S)-4-[(1E,3S)-4-(3-fulorophenyl)-3-hydroxybut-1-enyl]-2-oxo-1,3-t-
hiazolidine-3-yl}ethyl)sulfanyl]butyric acid
[0642] NMR: .delta. 1.91, 2.74, 3.40, 3.61, 4.34, 4.47, 5.66, 5.85,
6.96, 7.28;
[0643] MS(APCI, Neg. 20V):412 (M-H).sup.-;
[0644] TLC: Rf0.50 (ethyl acetate).
Example 22(11)
4-[(2-{(4S)-4-[(1E,3S)-4-(3-chloro-4-fulorophenyl)-3-hydroxybut-1-enyl]-2--
oxo-1,3-thiazolidine-3-yl}ethyl)sulfanyl]butyric acid
[0645] NMR: .delta. 1.90, 2.67, 2.95, 3.04, 3.42, 3.63, 4.39, 5.66,
5.74, 5.83, 7.08, 7.26;
[0646] MS(APCI, Neg, 20V):446 (M-H).sup.-;
[0647] TLC: Rf0.38 (hexane:ethyl acetate:methanol=25:75:2).
Example 22(12)
4-{[2-((4S)-4-{(1E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]but-1-enyl}-2--
oxo-1,3-thiazolidine-3-yl)ethyl]sulfanyl}butyric acid
[0648] NMR: .delta. 1.88, 2.56, 2.86, 2.97, 3.07, 3.39, 3.42, 3.57,
4.32, 4.45, 4.46, 5.65, 5.67, 5.86, 7.13, 7.21, 7.29;
[0649] MS(APCI, Neg, 20V):438 (M-H).sup.-;
[0650] TLC: Rf0.35 (hexane:ethyl acetate:methanol=25:75:2).
Example 23(1)-23(12)
[0651] By the same procedure as described in Example 11, 12 and 13
using butyl
7-[(2R)-2-(hydroxymethyl)-5-thioxo-1-pyrrolidinyl]heptanoate
instead of the compound prepared in Example 10 and the
corresponding phosphate ester instead of dimethyl
(3-biphenyl-3-yl-2-oxopropyl)phosphonate, the following compound of
the present invention were obtained.
Example 23(1)
7-{(2R)-2-[(1E,3S)-4-(4-fulorophenyl)-3-hydroxybut-1-enyl]-5-thioxopyrroli-
dine-1-yl}heptanoic acid
[0652] NMR: .delta. 1.33, 1.67, 2.28, 2.99, 4.06, 4.38, 5.53, 5.75,
7.00, 7.16;
[0653] MS(APCI, Neg. 20V):392 (M-H).sup.-;
[0654] TLC: Rf0.44 (chloroform:methanol=9:1).
Example 23(2)
7-{(2R)-2-[(1E,3S)-4-(3,5-difluorophenyl)-3-hydroxybut-1-enyl]-5-thioxopyr-
rolidine-1-yl}heptanoic acid
[0655] NMR: .delta. 1.34, 1.59, 1.78, 2.24, 2.35, 2.83, 3.04, 4.07,
4.39, 5.56, 5.76, 6.73;
[0656] MS(APCI, Neg. 20V):410 (M-H).sup.-;
[0657] TLC: Rf0.60 (ethyl acetate).
Example 23(3)
7-((2R)-2-{(1E,3S)-4-[4-fuloro-3-(trifluoromethyl)phenyl]-3-hydroxybut-1-e-
nyl}-5-thioxopyrrolidine-1-yl)heptanoic acid
[0658] NMR: .delta. 1.33, 1.58, 1.76, 2.23, 2.34, 2.91, 3.13, 4.06,
4.34, 4.44, 5.58, 5.77, 7.15, 7.42;
[0659] MS(APCI, Neg. 20V):460 (M-H).sup.-;
[0660] TLC: Rf0.61 (ethyl acetate).
Example 23(4)
7-{(2R)-2-[(1E,3S)-4-(4-fuloro-3-methylphenyl)-3-hydroxybut-1-enyl]-5-thio-
xopyrrolidine
[0661] NMR: .delta. 1.33, 1.61, 1.79, 2.23, 2.24, 2.35, 2.76, 2.99,
3.11, 4.07, 4.36, 5.76, 6.97;
[0662] MS(APCI, Neg. 20V):406 (M-H).sup.-;
[0663] TLC: Rf0.58 (ethyl acetate).
Example 23(5)
7-{(2R)-2-[(1E,3S)-4-(3-ethyl-4-fulorophenyl)-3-hydroxybut-1-enyl)-5-thiox-
opyrrolidine-1-yl}heptanoic acid
[0664] NMR: .delta. 1.22, 1.35, 1.60, 1.77, 2.23, 2.35, 2.74, 3.05,
4.06, 4.38, 5.56, 5.77, 6.97, 7.26;
[0665] MS(APCI, Neg. 20V):420 (M-H).sup.-;
[0666] TLC: Rf0.59 (ethyl acetate).
Example 23(6)
7-((2R)-2-{(1E,3S)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]but-1-enyl}-5-th-
ioxopyrrolidine-1-yl)heptanoic acid
[0667] NMR: .delta. 1.30, 1.68, 2.22, 2.34, 3.00, 4.05, 4.33, 4.48,
5.56, 5.78, 7.44;
[0668] MS(APCI, Neg. 20V):442 (M-H).sup.-;
[0669] TLC: Rf0.72 (ethyl acetate).
Example 23(7)
7-{(2R)-2-[(1E,3S)-4-(3-fulorophenyl)-3-hydroxybut-1-enyl]-5-thioxopyrroli-
dine-1-yl}heptanoic acid
[0670] NMR: .delta. 1.35, 1.70, 2.26, 2.35, 2.95, 4.07, 4.35, 4.43,
5.54, 5.76, 6.95, 7.28;
[0671] MS(APCI, Neg. 20V):392 (M-H).sup.-;
[0672] TLC: Rf0.70 (ethyl acetate).
Example 23(8)
7-{(2R)-2-[(1E,3S)-3-hydroxy-4-phenylbut-1-enyl]-5-thioxopyrrolidine-1-yl}-
heptanoic acid
[0673] NMR: .delta. 1.30, 1.68, 2.24, 2.35, 2.97, 4.07, 4.37, 5.53,
5.77, 7.27;
[0674] MS(APCI, Neg. 20V):374 (M-H).sup.-;
[0675] TLC: Rf0.69 (ethyl acetate).
Example 23(9)
7-{(2R)-2-[(1E,3S)-4-(3,4-difluorophenyl)-3-hydroxybut-1-enyl]-5-thioxopyr-
rolidine-1-yl}heptanoic acid
[0676] NMR: .delta. 1.33, 1.71, 2.28, 2.35, 2.95, 4.07, 4.36, 5.56,
5.76, 6.92, 7.07;
[0677] MS(APCI, Neg. 20V):410 (M-H).sup.-;
[0678] TLC: Rf0.70 (ethyl acetate).
Example 23(10)
7-{(2R)-2-[(1E,3S)-4-(3-chloro-4-fulorophenyl)-3-hydroxybut-1-enyl]-5-thio-
xopyrrolidine-1-yl}heptanoic acid
[0679] NMR: .delta. 1.35, 1.72, 2.25, 2.35, 2.80, 2.99, 3.10, 4.08,
4.38, 5.55, 5.75, 7.08, 7.25;
[0680] MS(APCI, Neg. 20V):426 (M-H).sup.-;
[0681] TLC: Rf0.61 (ethyl acetate).
Example 23(11)
7-{(2R)-2-[(1E,3S)-4-(3-ethylphenyl)3-hydroxybut-1-enyl]-5-thioxopyrrolidi-
ne-1-yl}heptanoic acid
[0682] NMR: .delta. 1.24, 1.35, 1.70, 2.22, 2.34, 2.64, 2.93, 4.06,
4.36, 5.55, 5.79, 7.05, 7.24;
[0683] MS(APCI, Neg. 20V):402 (M-H).sup.-;
[0684] TLC: Rf0.63 (ethyl acetate).
Example 23(12)
7-{(2R)-2-[(1E,3S)-3-hydroxy-4-(3-propylphenyl)but-1-enyl]-5-thioxopyrroli-
dine-1-yl}heptanoic acid
[0685] NMR: .delta. 0.94, 1.35, 1.70, 2.23, 2.34, 2.57, 2.97, 4.06,
4.38, 5.55, 5.79, 7.04, 7.23;
[0686] MS(APCI, Neg. 20V):416 (M-H).sup.-;
[0687] TLC: Rf0.64 (ethyl acetate).
Example 24
3-tert-butyl 4-methyl
(4R)-2,2-dimethyl-1,3-oxazolidine-3,4-dicarboxylate
[0688] Under atmosphere of argon, D-serine.methylester (284 g) and
di-tert-butyl di-carbonate (400 g) were dissolved in acetonitrile
(2000 mL) and the mixture was added by triethylamine (255 mL)
keeping the temperature inside from 6 to 1.degree. C. under icing
down and stirred for an hour and a half at room temperature. The
mixture was filtrated to defecate triethylamine chloride and then
the mother water was concentrated. The obtained residue was
dissolved in ethyl acetate (1500 mL), washed with water (1000 mL)
and saturated brine (1000 mL) and the organic layer was dried over
a sodium sulfate, filtrated and concentrated. Under atmosphere of
argon, the obtained residue (380 g) was added by acetone (3000 mL)
and 2,2-dimethoxypropane (1800 mL), additionally added by boron
trifuloride.diethylether complex (19.3 mL) and stirred for an hour
and a half at room temperature. The mixture was concentrated and
the residue was dissolved in ethyl acetate (1500 mL) and washed
with saturated sodium hydrogen carbonate (1000 mL), water (1000 mL)
and saturated brine (1000 mL). The organic layer was dried over a
sodium sulfate, filtrated and then concentrated to give the title
compound (437 g) having the following physical data, which was used
for the next reaction without purification.
[0689] NMR: .delta. 1.40-1.70, 3.76, 4.00-4.20, 4.37;
[0690] TLC: Rf0.50 (ethyl acetate:hexane=1:4).
Example 25
tert-butyl
(4S)-4-[(1E,3S)-4-(4-fulorophenyl)-3-hydroxy-1-butene-1-yl]-2,2-
-dimethyl-1,3-oxazolidine-3-carboxylate
[0691] Under atmosphere of argon, the compound prepared in Example
24 (387 g) was dissolved in toluene (4500 mL) and dropped by
diisobutylaluminum hydride (1.01M in toluene, 2500 mL) at the
temperature of -78.degree. C. The mixture was stirred for an hour
and a half additionally, diisobutylaluminum hydride discomposed
with methanol (200 mL) and then the temperature was raised
moderately. The mixture was added by 2N hydrochloric acid (7000 mL)
at a temperature of 0.degree. C. and extracted by ethyl acetate
(3000 mL). The organic layer was washed with water (2000 mL) and
saturated brine (2000 mL), dried over a sodium sulfate, filtrated
and then concentrated and the crude aldehyde compound (342 g).
Under atmosphere of argon, sodium hydride (56.8 g) was dissolved in
tetrahydrofuran (2400 mL) and dropped by a solution of dimethyl
3-(4-fulorophenyl)-2-oxopropylphosphonate (391 g) dissolved in
tetrahydrofuran (3600 mL) at a temperature of 50.degree. C. The
suspension of obtained anion was stirred for an hour at the room
temperature and then added by a solution the above-mentioned crude
aldehyde dissolved in tetrahydrofuran (1000 mL). The mixture was
stirred for 15 minutes at the room temperature additionally, added
by saturated ammonium chloride solution (3000 mL) and extracted by
ethyl acetate (3000 mL). The organic layer was washed with water
(2000 mL) and saturated brine (2000 mL), dried over a sodium
sulfate, filtrated and then concentrated. The obtained residue was
purified by column chromatography on silica gel (ethyl
acetate:hexane=from 1:5 to 1:2) to give the enone compound (240
mg). Under atmosphere of argon, borane-tetrahydrofuran complex (716
mL) and (R)-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine
(CBS) (102 mL) were dissolved in tetrahydrofuran (1750 mL) and a
solution of the above-mentioned enone compound dissolved in
tetrahydrofuran (1750 mL) dropped to the mixture keeping the
temperature inside from 5 to 12.degree. C. for three hours. The
mixture was added by methanol (100 mL) to discompose the reagent,
added by ethyl acetate (4000 mL), and washed with 1N hydrochloric
acid (4000 mL), water (2000 mL) and saturated brine (2000 mL). The
organic layer was dried over sodium sulfate, filtrate and then
concentrated and the obtained residue filtrate on silica gel (ethyl
acetate). The solvent was concentrated to give the title compound
(365 g) having the following physical data.
[0692] NMR: .delta. 1.34-1.70, 2.80, 3.68, 4.02, 4.37, 5.67, 6.99,
7.18;
[0693] TLC: Rf0.38 (ethyl acetate:hexane=1:3).
Example 26
(2S,3E,5S)-2-amino-6-(4-fulorophenyl)-3-hexene-1,5-diol.chloride
[0694] The compound prepared in Example 25 (340 g) was dissolved in
methanol (3000 mL) and added by 10% hydrochloric acid/methanol
(3000 mL) below 20.degree. C. The mixture was stirred for three
hours and a half and concentrated. The obtained crystal was
recrystallized by ethanol (300 mL)-ethyl acetate (1200 mL) to give
the title compound (105 g) having the following physical data.
[0695] NMR(DMSO-d.sub.6): .delta. 2.68, 3.40, 3.51, 3.65, 4.17,
5.04, 5.36, 5.54, 5.86, 7.07, 7.23, 7.97;
[0696] TLC: Rf0.10 (methanol:chloroform=1:5).
Example 27
ethyl
4-[(2-{(4S)-4-[(1E,3S)-4-(4-fulorophenyl)-3-hydroxy-1-butene-1-yl]-2-
-oxo-1,3-oxazolidine-3-yl}ethyl)thio]butanoate
[0697] ethyl 4-[(2,2-diethoxyethyl)thio]butanoate (115 g) was
dissolved in a mixed solution of acetonitrile (280 mL) and water
(31.5 mL), added by the compound prepared in Example 26 (95 g) and
p-toluenesulfonic acid monohydrate (11.7 g) successively and under
atmosphere of argon, the mixture was stirred for an hour at the
room temperature. Triacetoxy sodium boron hydride (138 g) was
dissolved in acetonitrile (318.5 mL) and the mixture was dropped by
the above-mentioned imine at 0.degree. C. and stirred overnight.
The mixture was added by ethyl acetate (2000 mL), washed with
saturated sodium hydrogen carbonate solution (1000 mL), water (1000
mL) and saturated brine (1000 mL) and the organic layer was dried
over sodium sulfate, filtrate and concentrated. The obtained
residue was purified by short column on silica gel (from ethyl
acetate only to methanol:methyl acetate=1:5) to give amine compound
(100 g). This amine compound (100 g) and triethylamine (70 mL) was
dissolved in tetrahydrofuran (1000 mL), added by triphosgene (24.8
g) at a temperature of 0.degree. C. and under atmosphere of argon,
the mixture was stirred for three hours. The mixture was added by
ethyl acetate (2000 mL), washed with water (1000 mL) and saturated
brine (1000 mL) and the organic layer was dried over sodium
sulfate, filtrated, concentrated and purified by column on silica
gel (ethyl acetate:hexane=from 1:1 to 2:1 to 4:1) to give the title
compound (80 g) having the following physical data.
[0698] NMR: .delta. 1.26, 1.90, 2.01, 2.42, 2.61, 2.82, 3.07, 3.45,
3.91, 4.12, 4.34, 4.41, 5.58, 5.88, 7.02, 7.17;
[0699] TLC: Rf0.40 (ethyl acetate:hexane=2:1).
Example 28
4-[(2-{(4S)-4-[(1E,3S)-4-(4-fulorophenyl)-3-hydroxy-1-butene-1-yl]-2-oxo-1-
,3-oxazolidine-3-yl}ethyl)thio]butyric acid
[0700] The compound prepared in Example 27 (80 g) was dissolved in
a mixed solution of 1,2-dimethoxyethane (1000 mL) and ethanol (500
mL) and added by 2N sodium hydroxide solution (500 mL) at the
0.degree. C. The mixture was stirred for four hours, added by 2N
hydrochloric acid (500 mL) at the 0.degree. C. and extracted by
ethyl acetate (1000 mL). The organic layer was washed with water
(1000 mL) and saturated brine (100 mL), dried over sodium sulfate,
filtrated, concentrated and the obtained residue was added by ethyl
acetate (80 mL) and hexane (60 mL) and stirred heating for thirty
minutes at 50.degree. C. After bringing back to the room
temperature, the mixture was filtrated to give the title compound
(61 g) having the following physical data.
[0701] White crystal; melting point from 75 to 76.degree. C.;
[0702] NMR: .delta. 1.89, 2.58, 2.82, 3.08, 3.46, 3.90, 4.39, 5.56,
5.87, 7.01, 7.16;
[0703] MS(APCI, Neg. 20V):396 (M-H).sup.-;
[0704] TLC: Rf0.49 (ethyl acetate).
Biological Examples
[0705] For examples, the pharmacological activities of the
compounds of the invention were confirmed in experiments performed
in a laboratory using the cells which express prostanoid receptor
sub-types. Whole operation which was based on the basic genetic
engineering method included that the cells which highly express
genes were prepared and the methods which are ordinary were
applicated. Additionally, the measuring method of the invention is
the method which had advancement of the measurement accuracy and/or
improvement of the measurement sensitivity for evaluating the
compounds of the invention as follows. The detailed experimental
methods showed below.
(i) Experiment for Receptor-Binding Using Cells which Express
Prostanoid Receptor Sub-Types
[0706] According to the method of Sugimoto et al. (J. Biol. Chem.,
267, 6463-6466 (1922)), CHO cells which expressed prostanoid
receptor sub-types (murine EP.sub.1, EP.sub.2, EP.sub.3.alpha., and
EP.sub.4 respectively) were prepared and used as membrane authentic
samples.
[0707] A reaction solution (200 .mu.L) containing the prepared
membrane fraction (0.5 mg/ml) and .sup.3H-PGE.sub.2 was incubated
at room temperature for an hour. The reaction was terminated with
ice cold buffer (3 mL), and the reaction mixture was suction
filtrated under reduced pressure through a glass filter (GF/B), on
which the binding .sup.3H-PGE.sub.2 was trapped, and the binding
radioactivity was measured by means of a liquid scintillator.
[0708] The K.sub.d value was obtained from the Scatchard plots
(Ann. N.Y. Acad. Sci., 51, 660 (1949)). Non-specific binding was
obtained as the binding in the presence of an excess amount (2.5
.mu.M) of unlabelled PGE.sub.2. Measurement of the binding
inhibition for .sup.3H-PGE.sub.2 with the compounds of the
invention was performed by adding .sup.3H-PGE.sub.2 (2.5 nM) and a
series of concentrations of the compounds of the invention. In this
reaction, the following buffer was used in all cases. [0709]
Buffer: 10 mM potassium phosphate (pH6.0), 1 mM EDTA, 10 mM
MgCl.sub.2 and 0.1M NaCl.
[0710] Dissociation constant K.sub.i (.mu.M) of each compounds was
calculated from the following equation.
K.sub.i=IC.sub.50/(1+([C]/K.sub.d));
[0711] The binding activities of all the compounds of the invention
to the EP.sub.4 receptor are shown the K.sub.i value of below 1
.mu.M. For example, the K.sub.i value of the compound of Example 5
was 6.4 nM.
(ii) Activity of EP.sub.4 Receptor Agonist
[0712] Experiment for measurement of the activity of an EP.sub.4
receptor agonist with the cells expressing prostanoid receptor
sub-types.
[0713] According to the method of Nishigaki et al. (FEBS Lett.,
364, 339-341 (1995)), CHO cells which expressed mouse EP.sub.4
receptor sub-types were prepared, inoculated on a 24-well
microplate at 10.sup.5 cells/well, and incubated for 2 days for use
in the experiment. Each well was washed with 500 .mu.L of MEM
(Minimum Essential Medium), added 450 .mu.L of an assay medium (MEM
containing 1 mmol/L of IBMX and 1% BSA), and incubated at
37.degree. C. for 10 minutes. Then, 50 .mu.L of a solution
containing PGE2 alone or PGE2 and a test compound was added to
start the reaction, which was conducted at 37.degree. C. for 10
minutes and terminated with addition of 500 .mu.L of ice-cold
trichloroacetic acid (10% w/v). The reaction mixture was once
treated by freezing (-80.degree. C.) and thawing, and the cells
were removed with a scraper and centrifuged at 13,000 rpm for 3
minutes to give a supernatant, of which the cAMP concentration was
determined with a cAMP assay kit. That is, a buffer solution
provided for the [.sup.125I] cAMP assay kit (Amersham) was added to
125 .mu.L of the above-mentioned supernatant to be 500 .mu.L, which
was mixed with 1 mL of 0.5 mol/L tri-n-octylamine/chloroform
solution to eliminate trichloroaceteic acid contained in chloroform
layer. The aqueous layer as a sample was measured to determine the
cAMP amount contained in the sample according to the method as
described in an instruction provided in the [.sup.125I] cAMP assay
kit.
[0714] The agonistic effect (EC.sub.50 value) of the compounds of
the invention was determined by calculating 50% productivity of
cAMP when the maximum effect of PGE.sub.2 alone was regarded as
100%.
(iii) Inhibitory Effect for TNF-.alpha. Production
[0715] Using of male SD rats, LPS (10 .mu.g/2 mL/kg) was
administered intravenously through the tail of rats, and after a
lapse of 90 minutes the blood was collected in a heparinized
condition from the abdominal vena cava to prepare the plasma. The
amount of TNF-.alpha. in the plasma was determined by an ELISA kit
(Rat TNF-.alpha. Immunoassay kit; Biosource). The compound of the
invention was dissolved in an equimolar amount of 0.02 mol/L sodium
hydroxide solution, diluted with distilled water, and orally
administered 30 minutes before administration of LPS. The
concentration at which the production of TNF-.alpha. was inhibited
by 50% was regarded as the effective concentration (IC.sub.50) when
the concentration of plasma TNF-.alpha. in a control group (LPS
treated but no compound administered) was 100%.
(iv) Inhibitory Effect for Chronic Articular Rheumatism
(1) Collagen Induced Arthritis in Rats
[0716] Experiment was performed according to the method of Osterman
et al. (Inflamm. Res., 44, 258-263). Inducing agents (an emulsion
by adding an equal volume of physiological saline and 2 equivalent
volume of incomplete Freund's adjuvant to 0.3% solution of type II
collagen derived from bovine) 0.1 mL each were administered
intracutaneously to the 4 sites of the back of a female DA/Slc rat.
After a lapse of 1 week, the same inducing agents were further
administered intracutaneously to the tail root to induce arthritis.
At 27th day, the four limbs were respectively scored responding to
the degree of erythema and swelling and assessed as 30 was regarded
as full scores. The compound of invention was dissolved in an
equimolar amount of 0.02 mol/L sodium hydroxide solution, diluted
with distilled water, and orally administered 3 times a day from
the next day of the first administration of inducing agents.
(2) Cocktail Antibodies Induced Arthritis in Mice
[0717] Cocktail of antibodies to type II collagen was intravenously
administered to male DBA/1JNCrj mice at a dose of 2 mg/0.5
ml/mouse. After a lapse of 3 days, lipopolysaccharide was
intraperitoneally administered at a dose of 25 .mu.g/0.1 mL/mouse
to induce arthritis. At 10th day, the four limbs were respectively
scored responding to the degree of erythema and swelling and
assessed as 4 was regarded as full scores. The compound of the
invention was dissolved in an equimolar amount of 0.02 mol/L sodium
hydroxide solution, diluted with distilled water, and orally
administered 3 times a day from 30 minutes before the
administration of lipopolysaccharide.
(v) Effect on the Promotion of Osteogenesis 1
[0718] Female SD rats (11 weeks of age; average weight 271 g) were
employed in 5 rats for each group. Rat was cut open at the lateral
abdomen under anesthesia with pentobarbital to remove the ovary and
then sutured. In a sham group, incision and suture were made but no
removal of the ovary was made.
[0719] From 6 days after the surgical operation, the compounds of
the invention (dissolved in an equimolar amount of 0.02 mol/L
sodium hydroxide solution, and diluted with distilled water) were
orally administered 3 times a day for 2 months. To the control
group and the sham group, physiological saline was administered.
After termination of the test, the animals of each group were
killed and subjected to autopsy. The bone density of trabecular
bone region of left femur was measured by means of an apparatus for
measuring the bone density of peripheral bone (XCT.mu.-960A,
Norland/Stratech).
(vi) Effect on the Promotion of Osteogenesis 2
[0720] Using beagle/CSK canines of approximately 6 months of age,
the effect on the promotion of osteogenesis can be examined.
[0721] The compound of the invention was dissolved in physiological
saline and orally administered over 4 weeks. To the control group
an equal volume of physiological saline was administered. After
termination of administration, the canines of each group were
killed, subjected to autopsy, and the bone area and bone density
were measured.
(1) Measurement of Bone Area
[0722] The removed femur was fixed with 10% buffered formalin
solution and cut in round slices perpendicularly to the bone axis
in 10 mm width at the center position of 25 mm from trochlear
fossa; the surface near the epiphysis was photographed with a
camera at a certain distance, and the picture was sent into a
computer to measure the bone area by image analysis.
(2) Measurement of Bone Density
[0723] The sample of 1 cm width used in (1) was taken radiography
in side view, and the image was sent into a computer to measure the
radiation amount per unit area in the area of a certain width to
obtain the bone density (Micro Focus X-Ray Enlargement Camera
System .mu.FX-1000 (Fujifilm)).
(vii) Effect of Accelerating Bone Fracture Healing 1
[0724] This experiment can be achieved to the method of Markel et
al. (J. Bone and Joint Surgery, 73A, 914-923, 1991). Using
beagle/CSK canines of approximately 6 months of age, the femoral
tibia is fractured under anesthesia and taken radiography
periodically for 3 months to assess the progress of healing. Thus,
the effect of accelerating bone fracture healing can be easily
judged. The compound of the invention was orally administered every
day. Distilled water was administered as control group. When the
effect of accelerating bone fracture healing was confirmed, the
femoral tibia was removed. Additionally the above-mentioned effect
was quantitatively assessed by measuring bone density and bone
strength of the removed femoral tibiae.
(viii) Inhibitory Effect for Gastric Urea
[0725] Indomethacin was orally administered to SD rats at a dose of
20 mg/kg to induce gastric ulcer. After a lapse of 6 hours, the
stomach was removed to measure the ulcerous area of mucosa. The
compound of the invention was orally administered 30 minutes before
administration of indomethacin.
(ix) Effect of Accelerating Bone Fracture Healing 2
[0726] According to the methods of R. Sakai (Bone, 25, 191-196
(1999)), H. Kawaguchi (Endocrinology, 135, 774-781 (1994)) and T.
Hoshino (J. Biomed. Mater. Res., 51, 229-306 (2000)), a bone
fracture model was prepared using male IGS rats of 8 weeks of age.
Hair of the left hind-limb of a rat was cut under anesthesia with
pentobarbital Na, and Viccillin S 500 (500 mg potency) (Meiji
Seika) was intramuscularly injected at a dose of 10 mg potency/100
.mu.L distilled water/body. Then the skin on the fibula (from the
back of knee joint to Achilles' tendon) was incised to ablate the
muscular tissue and the fibula was exposed. The fibula was cut off
with sharp scissors approximately at the central position to make a
fracture site, which was then restored to its former position, and
the incised site was closed by suture with disinfection by iodine
tincture/disinfectant ethanol. After making the fracture site and
before closing the wound operation, a physiological saline solution
containing 0.2% Tween 80 microsphere (containing 0.3 mg/kg as an
active drug; about 60 .mu.L) prepared in Formulation Example 3(1)
was added only once. In addition, the Compound (1) as a control for
comparison was infused continuously for 2 hours twice a day through
a catheter attached to the carotid artery. This was made until the
last day of the experiment. At the 21st day of the experiment, the
rats were subjected to euthanasia with CO.sub.2 gas, and the
connective tissue of the hind-limbs, including muscle, etc., was
eliminated to obtain both of the fibulae. The recovered fibulae
were taken radiographs to assess development of the fracture
healing based on the presence of fracture line and callus
formation, etc., and the bone density and bone strength around the
fracture site were measured.
(1) Measurement of the Bone Density of the Callus Region Using a
Micro Focus X-Ray Enlargement Camera System
[0727] The bone density of the callus region at the fracture site
of the recovered fibula was measured referring to the reports of C.
Matsumoto (Calcif Tissue Int., 55, 324-329 (1999)), Kaoru Yamazaki
(Nihon Rinsyo, 56, 1464-1468 (1998)), and Keiichi Nakagawa (Sentan
Iryo, 4(6), (1996)). Radiophotographs were taken at 4
magnifications using a micro focus X-ray enlargement camera system
(FUJIFILM)/imaging plate (BAS-IP MS 2025; FUJIFILM)) in a radiation
condition of 40 kV tube voltage, 100 .mu.A tube current, and
radiation time 5 seconds. During photographing, a phantom for
quantitative analysis of bone salt for mice (Kyoto Kagaku Co.) was
set together in order to make a standard curve for measurement of
bone density. The image was read by a Bio-imaging Analyzer BAS-1800
(FUJIFILM)/Image reader (FUJIFILM) and processed with an Image
Gauge, ver.3.1.12 (FUJIFILM). Based on the fracture line (surface)
as a callus region, the region of interest (hereinafter sometimes
referred to as ROI) was set at the position of 3 mm in the remote
direction (ankle) and the proximal direction (knee) respectively to
calculate the bone density of each ROI from the standard curve
obtained from the phantom for quantitative analysis of bone salt.
The bone density of the callus region at the fracture side was
calculated from the following equation and represented by mean .+-.
standard error (mg/cm.sup.2). Bone density in callus region={([bone
density in proximal callus region].times.A)+([bone density in
remote callus region].times.B)}/(A+B)
[0728] A represents the ROI area in the proximal callus region;
[0729] B represents the ROI area in the remote callus region.
(2) Measurement of the Bone Strength by a Bending Test at Three
Points
[0730] According to the report of T. Hoshino (J. Biomed. Mater.
Res., 51, 229-306 (2000)), a bending test at three points was
performed. Using an Instron Universal Material Testing Machine Type
5544 (Instron Japan)/Merlin (Instron Japan; version 22043),
breaking strength and energy absorption were measured in a
condition of 2.5 mm/sec of bending rate and 10 mm of sample holder
width. The bone strength data were calculated as relative strength
of the non-fractured side versus the fractured side for the
respective individuals and represented by means .+-. standard error
(% of intact).
(x) Inhibitory Effect on Ulcerous Colitis
[0731] 7% Sodium dextran sulfate (hereinafter abbreviated to as
DSS) was given freely to male C57BL/6 mice. From the beginning of
drinking, the body weight and clinical score were recorded every
other day. The clinical score was calculated as the sum of diarrhea
score (normal: 0, soft feces: 2, diarrhea: 4) and hematochezia
(normal: 0, bleeding: 2, heavy bleeding: 4). At 10 days after
taking of the SDS aqueous solution, the blood was collected from
the vena cava under ethereal anesthesia in the presence of heparin,
and the hematocrit value was measured by a hemocytometer. During a
period of from 0 day to 10th day after taking of the SDS aqueous
solution, the compound of the invention was orally administered
twice a day at a dose of 10, 30, 100 or 300 .mu.g/10 mL/kg.
Formulation Example 1
[0732] The following components were admixed in conventional method
and punched out to obtain 10000 tablets each containing 0.5 mg of
active ingredient. TABLE-US-00001
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-phenylphenyl)- 5.0 g
17,18,19,20-tetranol-5-thia-8-aza-10-oxaprost- 13-enoic acid
Carboxymethylcellulose calcium 20 g Magnesium stearate 10 g Micro
crystalline cellulose 920 g
Formulation Example 2
[0733] The following components were admixed in conventional
method, and the solution 1 mL each was filled into a vial, the
vials was freeze-dried in conventional method to obtain 10000 vials
each containing 0.2 mg of active ingredient. TABLE-US-00002
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-phenylphenyl)- 2.0 g
17,18,19,20-tetranol-5-thia-8-aza-10-oxaprost- 13-enoic acid Mannit
500 g Distilled water 10 L
* * * * *