U.S. patent application number 13/453434 was filed with the patent office on 2012-08-09 for pharmaceutical composition for treatment of diseases associated with decrease in bone mass comprising ep4 agonist as active ingredient.
This patent application is currently assigned to ONO PHARMACEUTICAL CO., LTD.. Invention is credited to Nobutaka Abe, Tohru Kambe, Kaoru Kobayashi, Takayuki Maruyama, Toru Maruyama, Akio Nishiura, Hideyuki Yoshida.
Application Number | 20120202773 13/453434 |
Document ID | / |
Family ID | 27347210 |
Filed Date | 2012-08-09 |
United States Patent
Application |
20120202773 |
Kind Code |
A1 |
Maruyama; Toru ; et
al. |
August 9, 2012 |
PHARMACEUTICAL COMPOSITION FOR TREATMENT OF DISEASES ASSOCIATED
WITH DECREASE IN BONE MASS COMPRISING EP4 AGONIST AS ACTIVE
INGREDIENT
Abstract
A pharmaceutical composition for topical administration for
prevention and/or treatment of diseases associated with decrease in
bone mass comprising an EP.sub.4 agonist as an active ingredient.
An EP.sub.4 agonist, in which includes a compound possessing
prostaglandin skeleton as a representative, possesses promoting
action on bone formation, so it is useful for prevention and/or
treatment of diseases associated with decrease in bone mass (bone
diseases such as primary osteoporosis, secondary osteoporosis, bone
metastasis of cancer, hypercalcemia, Paget's disease, bone loss and
bone necrosis, postoperative osteogenesis, alternative therapy for
bone grafting).
Inventors: |
Maruyama; Toru;
(Mishima-gun, JP) ; Kobayashi; Kaoru;
(Mishima-gun, JP) ; Kambe; Tohru; (Mishima-gun,
JP) ; Maruyama; Takayuki; (Mishima-gun, JP) ;
Yoshida; Hideyuki; (Mishima-gun, JP) ; Nishiura;
Akio; (Mishima-gun, JP) ; Abe; Nobutaka;
(Mishima-gun, JP) |
Assignee: |
ONO PHARMACEUTICAL CO.,
LTD.
Osaka
JP
|
Family ID: |
27347210 |
Appl. No.: |
13/453434 |
Filed: |
April 23, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12549136 |
Aug 27, 2009 |
8207223 |
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13453434 |
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10484500 |
Jan 22, 2004 |
7608637 |
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PCT/JP2002/007385 |
Jul 22, 2002 |
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12549136 |
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Current U.S.
Class: |
514/58 ; 514/424;
536/103; 544/372; 546/278.4; 548/129; 548/132; 548/180; 548/188;
548/224; 548/232; 548/243; 548/253; 548/467; 548/517; 548/525;
548/527; 548/551; 977/773; 977/915 |
Current CPC
Class: |
A61K 9/19 20130101; A61P
19/10 20180101; A61P 21/00 20180101; A61P 1/16 20180101; A61K
31/4015 20130101; A61P 35/04 20180101; A61K 9/1647 20130101; A61P
3/14 20180101; A61P 1/04 20180101; A61P 9/10 20180101; A61K 31/559
20130101; A61P 15/08 20180101; A61P 25/20 20180101; A61P 37/00
20180101; A61P 19/08 20180101; A61P 1/02 20180101; A61P 13/12
20180101; A61P 19/00 20180101; A61P 11/00 20180101; A61P 11/06
20180101; A61P 9/12 20180101; A61P 43/00 20180101; A61P 19/02
20180101; A61P 25/00 20180101; A61P 41/00 20180101; A61P 17/02
20180101; A61P 17/14 20180101; A61P 29/00 20180101; A61P 31/04
20180101; A61P 37/02 20180101; A61K 9/0019 20130101; A61K 9/2054
20130101; A61K 31/5575 20130101; A61P 35/00 20180101; A61P 7/08
20180101; C07C 405/0033 20130101; A61P 25/28 20180101; A61P 7/02
20180101; A61K 31/41 20130101 |
Class at
Publication: |
514/58 ; 548/551;
514/424; 536/103; 548/527; 548/517; 548/525; 548/188; 548/243;
548/132; 548/129; 548/232; 548/467; 544/372; 546/278.4; 548/224;
548/180; 548/253; 977/773; 977/915 |
International
Class: |
A61K 31/4015 20060101
A61K031/4015; C08B 37/16 20060101 C08B037/16; A61K 31/724 20060101
A61K031/724; C07D 409/06 20060101 C07D409/06; C07D 405/10 20060101
C07D405/10; C07D 405/06 20060101 C07D405/06; C07D 417/12 20060101
C07D417/12; C07D 413/12 20060101 C07D413/12; C07D 417/14 20060101
C07D417/14; C07D 263/24 20060101 C07D263/24; C07D 403/12 20060101
C07D403/12; C07D 409/12 20060101 C07D409/12; C07D 409/14 20060101
C07D409/14; C07D 401/12 20060101 C07D401/12; A61P 19/08 20060101
A61P019/08; C07D 413/14 20060101 C07D413/14; C07D 207/26 20060101
C07D207/26 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 23, 2001 |
JP |
2001-222148 |
Aug 7, 2001 |
JP |
2001-239895 |
Mar 1, 2002 |
JP |
2002-56449 |
Claims
1-19. (canceled)
20. A compound selected from the group of formula (I-3)
##STR03652## wherein is is (1) single bond or (2) double bond,
R.sup.19-3 and R.sup.20-3 are each independently, (1) hydrogen
atom, (2) C1-10 alkyl or (3) halogen atom, T.sup.3 is (1) oxygen
atom or (2) sulfur atom, X.sup.3 is (1) --CH.sub.2--, (2) --O-- or
(3) --S--, A.sup.3 is A.sup.1-3 or A.sup.2-3, A.sup.1-3 is (1) C2-8
straight-chain alkylene optionally substituted by 1-2 C1-4 alkyl,
(2) C2-8 straight-chain alkenylene optionally substituted by 1-2
C1-4 alkyl or (3) C2-8 straight-chain alkynylene optionally
substituted by 1-2 C1-4 alkyl, A.sup.2-3 is
-G.sup.1-3-G.sup.2-3-G.sup.3-3-, G.sup.1-3 is (1) C1-4
straight-chain alkylene optionally substituted by 1-2 C1-4 alkyl,
(2) C2-4 straight-chain alkenylene optionally substituted by 1-2
C1-4 alkyl or (3) C2-4 straight-chain alkynylene optionally
substituted by 1-2 C1-4 alkyl, G.sup.2-3 is (1) --Y.sup.3--, (2)
-(ring1.sup.3)-, (3) --Y.sup.3-(ring1.sup.3)-, (4)
-(ring1.sup.3)-Y.sup.3-- or (5) --Y.sup.3--(C1-4
alkylene)-(ring1.sup.3)-, Y.sup.3 is (1) --S--, (2) --SO--, (3)
--SO.sub.2--, (4) --O-- or (5) --NR.sup.1-3--, R.sup.1-3 is (1)
hydrogen atom, (2) C1-10 alkyl or (3) C2-10 acyl, G.sup.3-3 is (1)
bond, (2) C1-4 straight-chain alkylene optionally substituted by
1-2 C1-4 alkyl, (3) C2-4 straight-chain alkenylene optionally
substituted by 1-2 C1-4 alkyl or (4) C2-4 straight-chain alkynylene
optionally substituted by 1-2 C1-4 alkyl, D.sup.3 is D.sup.1-3 or
D.sup.2-3, D.sup.1-3 is (1) --COOH, (2) --COOR.sup.2-3, (3)
tetrazol-5-yl or (4) CONR.sup.3-3SO.sub.2R.sup.4-3, R.sup.2-3 is
(1) C1-10 alkyl, (2) phenyl, (3) C1-10 alkyl substituted by phenyl
or (4) biphenyl, R.sup.3-3 is (1) hydrogen atom or (2) C1-10 alkyl,
R.sup.4-3 is (1) C1-10 alkyl or (2) phenyl, D.sup.2-3 is (1)
--CH.sub.2OH, (2) --CH.sub.2OR.sup.5-3, (3) hydroxy, (4)
--OR.sup.5-3, (5) formyl, (6) --CONR.sup.6-3R.sup.7-3, (7)
--CONR.sup.6-3SO.sub.2R.sup.8-3, (8) --CO--(NH-amino acid
residue-CO).sub.m-3--OH, (9) --O--(CO-- amino acid residue
--NH).sub.m-3--H, (10) --COOR.sup.9-3, (11) --OCO--R.sup.10-3, (12)
--COO--Z.sup.1-3--Z.sup.2-3--Z.sup.3-3, ##STR03653## R.sup.5-3 is
C1-10 alkyl, R.sup.6-3 and R.sup.7-3 are each independently, (1)
hydrogen atom or (2) C 1-10 alkyl, R.sup.8-3 is C 1-10 alkyl
substituted by phenyl, R.sup.9-3 is (1) C 1-10 alkyl substituted by
biphenyl optionally substituted by 1-3 C1-10 alkyl, C1-10 alkoxy or
halogen atom or (2) biphenyl substituted by 1-3 C1-10 alkyl, C1-10
alkoxy or halogen atom, R.sup.10-3 is (1) phenyl or (2) C1-10
alkyl, m-3 is 1 or 2, Z.sup.1-3 is (1) C1-15 alkylene, (2) C2-15
alkenylene or (3) C2-15 alkynylene, Z.sup.2-3 is (1) --CO--, (2)
--OCO--, (3) --COO--, (4) --CONR.sup.11-3--, (5) --NR.sup.12-3CO--,
(6) --O--, (7) --S--, (8) --SO--, (9) --SO.sub.2--, (10)
--NR.sup.13-3--, (11) --NR.sup.14-3CONR.sup.15-3--, (12)
--NR.sup.16-3COO--, (13) --OCONR.sup.17-3-- or (14) --OCOO--,
Z.sup.3-3 is (1) hydrogen atom, (2) C1-15 alkyl, (3) C2-15 alkenyl,
(4) C2-15 alkynyl, (5) ring2.sup.3 or (6) C1-10 alkyl substituted
by C1-10 alkoxy, C1-10 alkylthio, C1-10 alkyl-NR.sup.18-3-- or
ring2.sup.3, R.sup.11-3, R.sup.12-3, R.sup.13-3, R.sup.14-3,
R.sup.15-3, R.sup.16-3, R.sup.17-3 and R.sup.18-3 are each
independently, (1) hydrogen atom or (2) C1-15 alkyl, R.sup.11-3 and
Z.sup.3-3 may be taken together with the nitrogen atom to which
they are attached to form 5 to 7 membered saturated
monoheterocyclic ring, and the heterocyclic ring may contain other
one hetero atom selected from oxygen, nitrogen and sulfur atom,
E.sup.3 is E.sup.1-3 or E.sup.2-3, E.sup.1-3 is (1) C3-7 cycloalkyl
or (2) ring3.sup.3, E.sup.2-3 is (1) C3-7 cycloalkyl, (2)
ring4.sup.3 or (3) ring5.sup.3, ring1.sup.3 and ring5.sup.3are
optionally substituted by 1-3 R.sup.21-3 and/or R.sup.22-3,
ring3.sup.3 is optionally substituted by 1-2 R.sup.21-3, C3-7
cycloalkyl represented by E.sup.2-3 is substituted by one of
R.sup.21-3 or R.sup.22-3, and optionally substituted by another 1-2
R.sup.21-3 and/or R.sup.22-3, ring4.sup.3 is substituted by one of
R.sup.22-3, optionally substituted by another 1-2 R.sup.21-3 and/or
R.sup.22-3, and optionally substituted by heterocyclic ring formed
by R.sup.11-3, Z.sup.3-3 and the nitrogen to which Z.sup.3-3 is
attached or ring2.sup.3 may be substituted by R.sup.23-3,
R.sup.21-3 is (1) C1-10 alkyl, (2) C1-10 alkoxy, (3) halogen atom,
(4) nitro, (5) C1-10 alkyl substituted by 1-3 halogen atom(s) or
(6) phenyl, R.sup.22-3 is (1) C2-10 alkenyl, (2) C2-10 alkynyl, (3)
C1-10 alkylthio, (4) hydroxy, (5) --NR.sup.24-3R.sup.25-3, (6)
C1-10 alkyl substituted by C1-10 alkoxy, (7) C1-10 alkyl
substituted by C1-10 alkoxy substituted by 1-3 halogen atom(s), (8)
C1-10 alkyl substituted by --NR.sup.24-3R.sup.25-3, (9)
ring6.sup.3, (10) --O-ring7.sup.3, (11) C1-10 alkyl substituted by
ring7.sup.3, (12) C2-10 alkenyl substituted by ring7.sup.3, (13)
C2-10 alkynyl substituted by ring7.sup.3, (14) C1-10 alkoxy
substituted by ring7.sup.3, (15) C1-10 alkyl substituted by
--O-ring7.sup.3, (16) --COOR.sup.26-3 or (17) C1-10 alkoxy
substituted by 1-3 halogen atom(s), R.sup.24-3, R.sup.25-3 and
R.sup.26-3 are each independently, (1) hydrogen atom or (2) C 1-10
alkyl, R.sup.23-3 is (1) C1-15 alkyl, (2) C2-15 alkenyl, (3) C2-15
alkynyl or (4) C1-10 alkyl substituted by C1-10 alkoxy, C1-10
alkylthio or C1-10 alkyl-NR.sup.27-3--, R.sup.27-3 is (1) hydrogen
atom or (2) C1-10 alkyl, ring1.sup.3, ring2.sup.3, ring5.sup.3,
ring6.sup.3 and ring7.sup.3 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 selected from oxygen, nitrogen and sulfur
atom(s) which may be partially or fully saturated, ring3.sup.3 and
ring4.sup.3 are (1) thienyl, (2) phenyl or (3) furyl, ring6.sup.3
and ring7.sup.3 may be substituted by 1-3 R.sup.28-3, R.sup.28-3 is
(1) C1-1 0 alkyl, (2) C2-10 alkenyl, (3) C2-10 alkynyl, (4) C1-10
alkoxy, (5) C1-10 alkyl substituted by C1-10 alkoxy, (6) halogen
atom, (7) hydroxy, (8) C1-10 alkyl substituted by 1-3 halogen
atom(s) or (9) C1-10 alkyl substituted by C1-10 alkoxy substituted
by 1-3 halogen atom(s), and wherein (1) when T.sup.3 is oxygen
atom, X.sup.3 is CH.sub.2--, A.sup.3 is A.sup.1-3, and D.sup.3 is
D.sup.1-3, E.sup.3 is E.sup.2-3, (2) ring5.sup.3 is not C3-7
cycloalkyl, phenyl, thienyl nor furyl, (3) ring6.sup.3 is phenyl,
then phenyl have at least one R.sup.28-3, or a non-toxic salt
thereof, or a cyclodextrin clathrate thereof.
21. The compound according to claim 20, wherein --Y.sup.3-- group
in A.sup.3 group of a compound of formula (I-3) is --S-- group.
22. The compound according to claim 20, which is a compound
selected from the group consisting of (1)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-t-
etranor-8-azaprost-13-enoic acid ethyl ester, (2)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-t-
etranor-8-azaprost-13-enoic acid, (3)
(5S,15.alpha.,13E)-5-methyl-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-1-
7,18,19,20-tetranor-8-azaprost-13-enoic acid, (4)
(15.alpha.,13E)-5,5-dimethyl-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)--
17,18,19,20-tetranor-8-azaprost-13-enoic acid, (5)
(15.alpha.,13E)-5,5-ethano-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17-
,18,19,20-tetranor-8-azaprost-13-enoic acid, (6)
(5R,15.alpha.,13E)-5-methyl-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-1-
7,18,19,20-tetranor-8-azaprost-13-enoic acid, (7)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(2,2,2-trifluoroethoxymethyl)pheny-
l)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (8)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-2,3,4,17,18,1-
9,20-heptanor-1,5-(2,5-interthienylene)-8-azaprost-13-enoic acid,
(9)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chloro-4-hydroxyphenyl)-17,18,19,2-
0-tetranor-8-azaprost-13-enoic acid, (10)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-((E)-1-propenylphenyl)-17,18,19,20-te-
tranor-8-azaprost-13-enoic acid, (11)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(2-fluorophenyl)phenyl)-17,18,19,2-
0-tetranor-8-azaprost-13-enoic acid, (12)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(4-fluorophenyl)phenyl)-17,18,19,2-
0-tetranor-8-azaprost-13-enoic acid, (13)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(5-methylfuran-2-yl)phenyl)-17,18,-
19,20-tetranor-8-azaprost-13-enoic acid, (14)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(naphthalen-2-yl)-17,18,19,20-tetrano-
r-8-azaprost-13-enoic acid, (15)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(2-methoxyphenyl)phenyl)-17,18,19,-
20-tetranor-8-azaprost-13-enoic acid, (16)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(2-hydroxyphenyl)phenyl)-17,18,19,-
20-tetranor-8-azaprost-13-enoic acid, (17)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(3-hydroxyphenyl)phenyl)-17,18,19,-
20-tetranor-8-azaprost-13-enoic acid, (18)
(15.alpha.,13E)-1,5-(2,5-interthienylene)-9-oxo-15-hydroxy-16-(3-chloroph-
enyl)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic acid, (19)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-cyclopropylphenyl)-17,18,19,20-tet-
ranor-8-azaprost-13-enoic acid, (20)
(13E)-9-oxo-15-hydroxy-16,16-difluoro-16-(3-methoxymethylphenyl)-17,18,19-
,20-tetranor-8-azaprost-13-enoic acid, (21)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-benzyloxyphenyl)-17,18,19,20-tetra-
nor-8-azaprost-13-enoic acid, (22)
(15.alpha.,5Z,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,2-
0-tetranor-8-azaprost-5,13-dienoic acid, (23)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(benzofuran-2-yl)phenyl)-17,18,19,-
20-tetranor-8-azaprost-13-enoic acid, (24)
(15.alpha.,13E)-2,7-(1,3-interphenylene)-9-oxo-15-hydroxy-16-(3-methylphe-
nyl)-3,4,5,6,17,18,19,20-octanor-8-azaprost-13-enoic acid, (25)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(2-phenylethynyl)phenyl)-17,18,19,-
20-tetranor-8-azaprost-13-enoic acid, (26)
(15.alpha.,13E)-2,7-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-methylphe-
nyl)-3,4,5,6,17,18,19,20-octanor-8-azaprost-13-enoic acid, (27)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-2,6-(1,3-interphenyl-
ene)-3,4,5,17,18,19,20-heptanor-8-azaprost-13-enoic acid, (28)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-1,5-(2,5-interthieny-
lene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic acid, (29)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-5-(5-(5-oxo-1,2,4-ox-
adiazol-3-ypthiophen-2-yl)-1,2,3,4,17,18,19,20-octanor-8-azaprost-13-ene,
(30)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-1,5-(2,5-interf-
urylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic acid, (31)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-3,7-(2,5-interthieny-
lene)-4,5,6,17,18,19,20-heptanor-8-azaprost-13-enoic acid, (32)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-5-(5-(tetrazol-5-yl)-
thiophen-2-yl)-1,2,3,4,17,18,19,20-octanor-8-azaprost-13-ene, (33)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(naphthalen-1-yl)-17,18,19,20-tetrano-
r-8-azaprost-13-enoic acid, (34)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-t-
etranor-5-thia-8-azaprost-13-enoic acid, (35)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid, (36)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-cyclopropyloxymethylphenyl)-17,18,-
19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (37)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(2,2,2-trifluoroethoxymethyl)pheny-
l)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (38)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid, (39)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-cyclopentyl-17,18,19,20-tetranor-5-th-
ia-8-azaprost-13-enoic acid, (40)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(thiophen-2-yl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid, (41)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-
-tetranor-5-thia-8-azaprost-13-enoic acid, (42)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-5-thia-8--
azaprost-13-enoic acid, (43)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid, (44)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid, (46)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetr-
anor-5-thia-8-azaprost-13-enoic acid, (47)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(naphthalen-2-yl)-17,18,19,20-tetrano-
r-5-thia-8-azaprost-13-enoic acid, (48)
(15.alpha.,13E)-2,3-methano-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19-
,20-tetranor-5-thia-8-azaprost-13-enoic acid, (49)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-t-butylphenyl)-17,18,19,20-tetrano-
r-5-thia-8-azaprost-13-enoic acid, (50)
(13E)-9-oxo-15-hydroxy-16a-methyl-16-phenyl-17,18,19,20-tetranor-5-thia-8-
-azaprost-13-enoic acid, (51)
(13E)-9-oxo-15-hydroxy-16.beta.-methyl-16-phenyl-17,18,19,20-tetranor-5-t-
hia-8-azaprost-13-enoic acid, (52)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-ethylphenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid, (53)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluoro-3-trifluoromethylphenyl)-17-
,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (54)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluoro-3-methylphenyl)-17,18,19,20-
-tetranor-5-thia-8-azaprost-13-enoic acid, (55)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chloro-4-fluorophenyl)-17,18,19,20-
-tetranor-5-thia-8-azaprost-13-enoic acid, (56)
(15.beta.,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid, (57)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(5-carboxythiazol--
2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (58)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-4-(3-hydroxyisoxazol-
-5-yl)-1,2,3,17,18,19,20-heptanor-5-thia-8-azaprost-13-ene, (59)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-2-(5-oxo-1,2,4-oxadi-
azol-3-yl)-1,17,18,19,20-pentanor-5-thia-8-azaprost-13-ene, (60)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-2-(5-oxo-1,2,4-thiad-
iazol-3-yl)-1,17,18,19,20-pentanor-5-thia-8-azaprost-13-ene, (61)
(15.alpha.,13E)-1-methoxy-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,2-
0-tetranor-5-thia-8-azaprost-13-ene, (62)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-5-(4-carboxythiazol--
2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (63)
(15.alpha.,13E)-1-methoxy-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,2-
0-tetranor-5-thia-8-azaprost-13-ene, (64)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-5-(5-(5-oxo-1,2,4-ox-
adiazol-3-yl)thiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-1-
3-ene, (65)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-
-5-thia-8-aza-10-oxaprost-13-enoic acid, (66)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-aza-10-oxaprost-13-enoic acid, (67)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-
-5-thia-8-aza-10-oxaprost-13-enoic acid, (68)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylaminomethylphenyl)-17,18,19,-
20-tetranor-5-thia-8-azaprost-13-enoic acid hydrochloride, (69)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-ethyl-4-fluorophenyl)-17,18,19,20--
tetranor-5-thia-8-azaprost-13-enoic acid, (70)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(5-methylfuran-2-yl)-17,18,19,20-tetr-
anor-5-thia-8-azaprost-13-enoic acid, (71)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(2-methyloxazol-5-yl)-17,18,19,20-tet-
ranor-5-thia-8-azaprost-13-enoic acid, (72)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(benzofuran-2-yl)-17,18,19,20-tetrano-
r-5-thia-8-azaprost-13-enoic acid, (73)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(5-ethylfuran-2-yl)-17,18,19,20-tetra-
nor-5-thia-8-azaprost-13-enoic acid, (74)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4,5-dimethylfuran-2-yl)-17,18,19,20--
tetranor-5-thia-8-azaprost-13-enoic acid, (75)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylfuran-2-yl)-17,18,19,20-tetr-
anor-5-thia-8-azaprost-13-enoic acid, (76)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-nitrophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid, (77)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylisoxazol-5-yl)-17,18,19,20-t-
etranor-5-thia-8-azaprost-13-enoic acid, (78)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-t-
etranor-8-azaprost-13-en-1-ol, (79)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-t-
etranor-5-thia-8-azaprost-13-en-1-ol, (80)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetr-
anor-8-azaprost-13-en-1-ol, (81)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-
-8-azaprost-13-en-1-ol, (82)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-en-1-ol, (83)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-5-thia-8--
azaprost-13-en-1-ol, (84)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-en-1-ol, (85)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-en-1-ol, (86)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-en-1-ol, (87)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-en-1-ol, (88)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-
-tetranor-5-thia-8-azaprost-13-en-1-ol, (89)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-ethylphenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-en-1-ol, (90)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3
,4-difluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol,
(91)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluoro-3-trifluoromethylpheny-
l)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (92)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluoro-3-methylphenyl)-17,18,19,20-
-tetranor-5-thia-8-azaprost-13-en-1-ol, (93)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chloro-4-fluorophenyl)-17,18,19,20-
-tetranor-5-thia-8-azaprost-13-en-1-ol, (94)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-1,5-(2,5-interthieny-
lene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-en-1-ol, (95)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(5-hydroxymethylth-
iazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene,
(96) (15
a,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-
-aza-10-oxaprost-13-en-1-ol, (97)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-aza-10-oxaprost-13-en-1-ol, (98)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-3,7-(2,5-interthieny-
lene)-4,5,6,17,18,19,20-heptanor-8-azaprost-13-en-1-ol, (99)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-ethyl-4-fluorophenyl)-17,18,19,20--
tetranor-5-thia-8-azaprost-13-en-1-ol, (100)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(5-methylfuran-2-yl)-17,18,19,20-tetr-
anor-5-thia-8-azaprost-13-en-1-ol, (101)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(5-ethylfuran-2-yl)-17,18,19,20-tetra-
nor-5-thia-8-azaprost-13-en-1-ol, (102)
(15.alpha.)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetra-
nor-8-azaprostanoic acid ethyl ester, (103)
(15.alpha.)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetra-
nor-8-azaprostanoic acid, (104)
(15.alpha.)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-t-
hia-8-azaprostanoic acid, (105)
(15.alpha.)-9-oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-tet-
ranor-5-thia-8-azaprostanoic acid, (106)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-t-
etranor-8-azaprost-13-enoic acid N-mesylamide, (107)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-t-
etranor-8-azaprost-13-enoic acid N-phenylsulfonylamide, (108)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-t-
etranor-8-azaprost-13-enoic acid N-benzylsulfonylamide, (109)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-1,5-(2,5-interthieny-
lene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic acid
N-benzylsulfonylamide, (110)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-5-(5-benzylsulfonylc-
arbamoylthiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene-
, (111)
(15.alpha.,13E)-9-thioxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,2-
0-tetranor-5-thia-8-azaprost-13-enoic acid butyl ester, (112)
(15.alpha.,13E)-9-thioxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetra-
nor-5-thia-8-azaprost-13-enoic acid, (113)
(15.alpha.,13E)-9-thioxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,2-
0-tetranor-8-azaprost-13-enoic acid, (114)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-en-1-yl t-butoxycarbonylglycylglycinate,
(115)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-en-1-yl glycylglycinate monohydrochloride,
(116)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-en-1-yl glycinate methanesulfonic acid salt,
(117)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-en-1-yl tryptophanate bis-trifluoroacetic
acid salt, (118)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-te-
tranor-5-thia-8-azaprost-13-en-1-yl tyrosinate trifluoroacetic acid
salt, (119)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-te-
tranor-5-thia-8-azaprost-13-enoic acid isopropyloxycarbonylmethyl
ester, (120)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-te-
tranor-5-thia-8-azaprost-13-enoic acid dimethylaminocarbonylmethyl
ester, (121)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-te-
tranor-5-thia-8-azaprost-13-enoic acid ethyl ester, (122)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid butyl ester, (123)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-1,5-(2,5-interthieny-
lene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-en-1-al, (124)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-en-1-al, (125)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-aminophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid, (126)
(15.alpha.,13E)-1-benzoyloxy-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetra-
nor-8-azaprost-13-ene, (127)
(15.alpha.,13E)-1-butanoyloxy-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetr-
anor-8-azaprost-13-ene, (128)
(15.alpha.,13E)-1-(2-aminoacetyloxy)-9-oxo-15-hydroxy-16-phenyl-17,18,19,-
20-tetranor-8-azaprost-13-ene trifluoromethanesulfonic acid salt,
(129)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid 2-pentanoyloxyethyl ester, (130)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azapros-
t-13-enoic acid 4-phenylbenzyl ester, (131)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azapros-
t-13-enoic acid 2-dimethylaminoethyl ester hydrochloride, (132)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid 2-hexanoyloxyethyl ester, (133)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid 2-heptanoyloxyethyl ester, (134)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid 2-octanoyloxyethyl ester, (135)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid
N-heptanoyl-N-methylcarbamoylmethyl ester, (136)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic
acid(4-hexylpiperazin-1-yl)carbonylmethyl ester, (137)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid
N-ethyl-N-(2-diethylaminoethyl)carbamoylmethyl ester, (138)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid
2-(2-(dipropylamino)acetyloxy)ethyl ester, (139)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid 2-(2-(diethylamino)acetyloxy)ethyl
ester, (140)
(15a,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid nonanoyloxymethyl ester, (141)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-aminophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid, (142)
(15.alpha.,13E)-1,5-(2,5-interthienylene)-9-oxo-15-hydroxy-16-(4-fluoroph-
enyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoic acid,
(143)
(15.alpha.,13E)-1,5-(2,5-interthienylene)-9-oxo-15-hydroxy-16-(3-chloro-4-
-fluorophenyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoic
acid, (144)
(15.alpha.,13E)-1,5-(2,5-interthienylene)-9-oxo-15-hydroxy-16-(4-fl-
uoro-3-trifluoromethylphenyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-
-13-enoic acid, (145)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid ethyl ester, (147)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(benzofuran-2-yl)phenyl)-17,18,19,-
20-tetranor-5-thia-8-azaprost-13-enoic acid, (148)
(15.alpha.)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxythiazol-2-yl-
)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane, (149)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-methylphe-
nyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic acid, (150)
(15.alpha.,13E)-7-(6-carboxyindol-3-yl)-9-oxo-15-hydroxy-16-(3-methylphen-
yl)-1,2,3,4,5,6,17,18,19,20-decanor-8-azaprost-13-ene, (151)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxythiazol--
2-yl)-1,2,3,4,17,18,19,20-octanor-8-azaprost-13-ene, (152)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxyoxazol-2-
-yl)-1,2,3,4,17,18,19,20-octanor-8-azaprost-13-ene, (153)
(15.alpha.,13E)-1,7-(2,5-interthienylene)-9-oxo-15-hydroxy-16-(3-methylph-
enyl)-2,3,4,5,6,17,18,19,20-nonanor-8-azaprost-13-enoic acid, (154)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(benzofur-
an-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic
acid, (155)
(15.alpha.,13E)-1,5-(2,5-interthienylene)-9-oxo-15-hydroxy-16-(3-(b-
enzofuran-2-yl)phenyl)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic
acid, (156)
(15.alpha.,13E)-3,3-Ethano-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,-
20-tetranor-5-thia-8-azaprost-13-enoic acid, (157)
(15.alpha.,13E)-1,5-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(4-fluorophe-
nyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoic acid,
(158)
(15.alpha.,13E)-1,5-(1,3-interphenylene)-9-oxo-15-hydroxy-16-(4-fluorophe-
nyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoic acid,
(159)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(4-fluoromethylbenzyloxy)phenyl)-1-
7,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (160)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(pyridin-3-ylmethoxy)phenyl)-17,18-
,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (161)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-cyclopropyl-17,18,19,20-tetranor-5-th-
ia-8-azaprost-13-enoic acid, (162)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-phenyl-5-(4-carboxythiazol-2-yl)-1,2,-
3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (163)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxythiazol--
2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (164)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(pyridin-2-ylmethoxy)phenyl)-17,18-
,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (165)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(pyridin-4-ylmethoxy)phenyl)-17,18-
,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (166)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(pyridin-2-yl)phenyl)-17,18,19,20--
tetranor-5-thia-8-azaprost-13-enoic acid, (167)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-cyclopentyl-5-(4-carboxythiazol-2-yl)-
-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (168)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(2,2,2-trifluoroethoxymethyl)pheny-
l)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-
-13-ene, (169)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(benzofuran-2-yl)phenyl)-5-(4-carb-
oxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene,
(170)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(5-methylfuran-2-yl)-5-(4-carbo-
xythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene,
(171)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-5-(6-carboxypy-
ridin-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene,
(172)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid dibutylcarbamoylmethyl ester,
(173)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid 2-(2,2-diethylpentanoyloxy)ethyl
ester, (174)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-te-
tranor-5-thia-8-azaprost-13-enoic acid
2-(adamantan-1-ylcarbonyloxy)ethyl ester, (175)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid
2-(1-ethyl-1-methylbutanoyloxy)ethyl ester, (176)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-(2-(1-ethyl-1-m-
ethylbutanoyloxy)ethoxycarbonyl)thiazol-2-yl)-1,2,3,4,17,18,19,20-octanor--
5-thia-8-azaprost-13-ene, (177)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3,4-dihydroxyphenyl)-17,18,19,20-tet-
ranor-5-thia-8-azaprost-13-enoic acid, (178)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(2-methyl-
phenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic
acid, (179)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(3-methyl-
phenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic
acid, (180)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(4-methyl-
phenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic
acid, (181)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(4-triflu-
oromethylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic
acid, (182)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(3,5-ditr-
ifluoromethylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoi-
c acid, (183)
(15.alpha.,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(4-t-buty-
lphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic
acid, (184)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-phenylphenyl)-5-(4-carboxyth-
iazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene,
(185)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(4-methylphenyl)phenyl)-5-(4-carbo-
xythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene,
(186)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(4-chlorophenyl)phenyl)-5-(4-
-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene-
, (187)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(4-methoxyphenyl)phenyl)-5--
(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-e-
ne, (188)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(naphthalen-2-yl)phenyl)--
17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (189)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(benzoxazol-2-yl)phenyl)-17,18,19,-
20-tetranor-5-thia-8-azaprost-13-enoic acid, (190)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(benzothiazol-2-yl)phenyl)-17,18,1-
9,20-tetranor-5-thia-8-azaprost-13-enoic acid, (191)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(naphthalen-2-yl)phenyl)-5-(4-carb-
oxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene,
(192)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(benzoxazol-2-yl)phenyl)-5-(-
4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-en-
e, (193)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(benzothiazol-2-yl)phenyl)-
-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-1-
3-ene, (194)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(isoindolin-2-yl)phenyl)-17,18,19,-
20-tetranor-5-thia-8-azaprost-13-enoic acid, (195)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(indol-5-yl)phenyl)-17,18,19,20-te-
tranor-5-thia-8-azaprost-13-enoic acid, (196)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(isoindolin-2-yl)phenyl)-5-(4-carb-
oxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene,
and (197)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(indol-5-yl)phenyl)-5-(4-car-
boxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene,
or a non-toxic salt thereof, or a cyclodextrin clathrate
thereof.
23. The compound according to claim 22, which is a compound
selected from the group consisting of (2)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-t-
etranor-8-azaprost-13-enoic acid, (25)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-(2-phenylethynyl)phenyl)-17,18,19,-
20-tetranor-8-azaprost-13-enoic acid, (34)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-t-
etranor-5-thia-8-azaprost-13-enoic acid, (35)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid, (38)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid, (70)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(5-methylfuran-2-yl)-17,18,19,20-tetr-
anor-5-thia-8-azaprost-13-enoic acid, (86)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-en-1-ol, (121)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid ethyl ester, (122)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid butyl ester, (129)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid 2-pentanoyloxyethyl ester, (132)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid 2-hexanoyloxyethyl ester, (133)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid 2-heptanoyloxyethyl ester, (134)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid 2-octanoyloxyethyl ester, (135)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid
N-heptanoyl-N-methylcarbamoylmethyl ester, (136)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic
acid(4-hexylpiperazin-1-yl)carbonylmethyl ester, (137)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid
N-ethyl-N-(2-diethylaminoethyl)carbamoylmethyl ester, (138)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid
2-(2-(dipropylamino)acetyloxy)ethyl ester, (139)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid 2-(2-(diethylamino)acetyloxy)ethyl
ester, (140)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-te-
tranor-5-thia-8-azaprost-13-enoic acid nonanoyloxymethyl ester,
(172)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid dibutylcarbamoylmethyl ester,
(173)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid 2-(2,2-diethylpentanoyloxy)ethyl
ester, (174)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-te-
tranor-5-thia-8-azaprost-13-enoic acid
2-(adamantan-1-ylcarbonyloxy)ethyl ester, (175)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid
2-(1-ethyl-1-methylbutanoyloxy)ethyl ester, or a non-toxic salt
thereof, or cyclodextrin clathrate thereof
24. The compound according to claim 20, which is
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid or a non-toxic salt thereof, or a
cyclodextrin clathrate thereof.
25. A pharmaceutical composition comprising a compound selected
from the group of formula (I-3) ##STR03654## wherein is (1) single
bond or (2) double bond, R.sup.19-3 and R.sup.20-3 are each
independently, (1) hydrogen atom, (2) C1-10 alkyl or (3) halogen
atom, T.sup.3 is (1) oxygen atom or (2) sulfur atom, X.sup.3 is (1)
--CH.sub.2--, (2) --O-- or (3) --S--, A.sup.3 is A.sup.1-3 or
A.sup.2-3, A.sup.1-3 is (1) C2-8 straight-chain alkylene optionally
substituted by 1-2 C1-4 alkyl, (2) C2-8 straight-chain alkenylene
optionally substituted by 1-2 C1-4 alkyl or (3) C2-8 straight-chain
alkynylene optionally substituted by 1-2 C1-4 alkyl, A.sup.2-3 is
-G.sup.1-3-G.sup.2-3-G.sup.3-3-, G.sup.1-3 is (1) C1-4
straight-chain alkylene optionally substituted by 1-2 C1-4 alkyl,
(2) C2-4 straight-chain alkenylene optionally substituted by 1-2
C1-4 alkyl or (3) C2-4 straight-chain alkynylene optionally
substituted by 1-2 C1-4 alkyl, G.sup.2-3 is (1) --Y.sup.3--, (2)
-(ring1.sup.3)-, (3) --Y.sup.3-(ring1.sup.3)-, (4)
-(ring1.sup.3)-Y.sup.3-- or (5) --Y.sup.3--(C1-4
alkylene)-(ring1.sup.3)-, Y.sup.3 is (1) --S--, (2) --SO--, (3)
--SO.sub.2--, (4) --O-- or (5) --NR.sup.1-3--, R.sup.1-3 is (1)
hydrogen atom, (2) C1-10 alkyl or (3) C2-10 acyl, G.sup.3-3 is (1)
bond, (2) C1-4 straight-chain alkylene optionally substituted by
1-2 C1-4 alkyl, (3) C2-4 straight-chain alkenylene optionally
substituted by 1-2 C1-4 alkyl or (4) C2-4 straight-chain alkynylene
optionally substituted by 1-2 C1-4 alkyl, D.sup.3 is D.sup.1-3 or
D.sup.2-3, D.sup.1-3 is (1) --COOH, (2) --COOR.sup.2-3, (3)
tetrazol-5-yl or (4) CONR.sup.3-3SO.sub.2R.sup.4-3, R.sup.2-3 is
(1) C1-10 alkyl, (2) phenyl, (3) C1-10 alkyl substituted by phenyl
or (4) biphenyl, R.sup.3-3 is (1) hydrogen atom or (2) C1-10 alkyl,
R.sup.4-3 is (1) C1-10 alkyl or (2) phenyl, D.sup.2-3 is (1)
--CH.sub.2OH, (2) --CH.sub.2OR.sup.5-3, (3) hydroxy, (4)
--OR.sup.5-3, (5) formyl, (6) --CONR.sup.6-3R.sup.7-3, (7)
--CONR.sup.6-3SO.sub.2R.sup.8-3, (8) --CO--(NH-amino acid
residue-CO).sub.m-3--OH, (9) --O--(CO-- amino acid residue
--NH).sub.m-3--H, (10) --COOR.sup.9-3, (11) --OCO--R.sup.10-3, (12)
--COO--Z.sup.1-3--Z.sup.2-3--Z.sup.3-3, ##STR03655## R.sup.5-3 is
C1-10 alkyl, R.sup.6-3 and R.sup.7-3 are each independently, (1)
hydrogen atom or (2) C1-10 alkyl, R.sup.8-3 is C1-10 alkyl
substituted by phenyl, R.sup.9-3 is (1) C1-10 alkyl substituted by
biphenyl optionally substituted by 1-3 C1-10 alkyl, C1-10 alkoxy or
halogen atom or (2) biphenyl substituted by 1-3 C1-10 alkyl, C1-10
alkoxy or halogen atom, R.sup.10-3 is (1) phenyl or (2) C1-10
alkyl, m-3 is 1 or 2, Z.sup.1-3 is (1) C1-15 alkylene, (2) C2-15
alkenylene or (3) C2-15 alkynylene, Z.sup.2-3 is (1) --CO--, (2)
--OCO--, (3) --COO--, (4) --CONR.sup.11-3--, (5) --NR.sup.12-3CO--,
(6) --O--, (7) --S--, (8) --SO--, (9) --SO.sub.2--, (10)
--NR.sup.13-3--, (11) --NR.sup.14-3CONR.sup.15-3--, (12)
--NR.sup.16-3COO--, (13) --OCONR.sup.17-3-- or (14) --OCOO--,
Z.sup.3-3 is (1) hydrogen atom, (2) C1-15 alkyl, (3) C2-15 alkenyl,
(4) C2-15 alkynyl, (5) ring2.sup.3 or (6) C1-10 alkyl substituted
by C1-10 alkoxy, C1-10 alkylthio, C1-10 alkyl-NR.sup.18-3-- or
ring2.sup.3, R.sup.11-3, R.sup.12-3, R.sup.13-3, R.sup.14-3,
R.sup.15-3, R.sup.16-3, R.sup.17-3 and R.sup.18-3 are each
independently, (1) hydrogen atom or (2) C1-15 alkyl, R.sup.11-3 and
Z.sup.3-3 may be taken together with the nitrogen atom to which
they are attached to form 5 to 7 membered saturated
monoheterocyclic ring, and the heterocyclic ring may contain other
one hetero atom selected from oxygen, nitrogen and sulfur atom,
E.sup.3 is E.sup.1-3 or E.sup.2-3, E.sup.1-3 is (1) C3-7 cycloalkyl
or (2) ring3.sup.3, E.sup.2-3 is (1) C3-7 cycloalkyl, (2)
ring4.sup.3 or (3) ring5.sup.3, ring1.sup.3 and ring5.sup.3are
optionally substituted by 1-3 R.sup.21-3 and/or R.sup.22-3,
ring3.sup.3 is optionally substituted by 1-2 R.sup.21-3, C3-7
cycloalkyl represented by E.sup.2-3 is substituted by one of
R.sup.21-3 or R.sup.22-3, and optionally substituted by another 1-2
R.sup.21-3 and/or R.sup.22-3, ring4.sup.3 is substituted by one of
R.sup.22-3, optionally substituted by another 1-2 R.sup.21-3 and/or
R.sup.22-3, and optionally substituted by heterocyclic ring formed
by R.sup.11-3, Z.sup.3-3 and the nitrogen to which Z.sup.3-3 is
attached or ring2.sup.3 may be substituted by R.sup.23-3,
R.sup.21-3 is (1) C1-10 alkyl, (2) C1-10 alkoxy, (3) halogen atom,
(4) nitro, (5) C1-10 alkyl substituted by 1-3 halogen atom(s) or
(6) phenyl, R.sup.22-3 is (1) C2-10 alkenyl, (2) C2-10 alkynyl, (3)
C1-10 alkylthio, (4) hydroxy, (5) --NR.sup.24-3R.sup.25-3, (6)
C1-10 alkyl substituted by C1-10 alkoxy, (7) C1-10 alkyl
substituted by C1-10 alkoxy substituted by 1-3 halogen atom(s), (8)
C1-10 alkyl substituted by --NR.sup.24-3R.sup.25-3, (9)
ring6.sup.3, (10) --O-ring7.sup.3, (11) C1-10 alkyl substituted by
ring7.sup.3, (12) C2-10 alkenyl substituted by ring7.sup.3, (13)
C2-10 alkynyl substituted by ring7.sup.3, (14) C1-10 alkoxy
substituted by ring7.sup.3, (15) C1-10 alkyl substituted by
--O-ring7.sup.3, (16) --COOR.sup.26-3 or (17) C1-10 alkoxy
substituted by 1-3 halogen atom(s), R.sup.24-3, R.sup.25-3 and
R.sup.26-3 are each independently, (1) hydrogen atom or (2) C1-10
alkyl, R.sup.23-3 is (1) C1-15 alkyl, (2) C2-15 alkenyl, (3) C2-15
alkynyl or (4) C1-10 alkyl substituted by C1-10 alkoxy, C1-10
alkylthio or C1-10 alkyl-NR.sup.27-3--, R.sup.27-3 is (1) hydrogen
atom or (2) C1-10 alkyl, ring1.sup.3, ring2.sup.3, ring5.sup.3,
ring6.sup.3 and ring7.sup.3 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 selected from oxygen, nitrogen and sulfur
atom(s) which may be partially or fully saturated, ring3.sup.3 and
ring4.sup.3 are (1) thienyl, (2) phenyl or (3) furyl, ring6.sup.3
and ring7.sup.3 may be substituted by 1-3 R.sup.28-3, R.sup.28-3 is
(1) C1-10 alkyl, (2) C2-10 alkenyl, (3) C2-10 alkynyl, (4) C1-10
alkoxy, (5) C1-10 alkyl substituted by C1-10 alkoxy, (6) halogen
atom, (7) hydroxy, (8) C1-10 alkyl substituted by 1-3 halogen
atom(s) or (9) C1-10 alkyl substituted by C1-10 alkoxy substituted
by 1-3 halogen atom(s), and wherein (1) when T.sup.3 is oxygen
atom, X.sup.3 is CH.sub.2--, A.sup.3 is A.sup.1-3, and D.sup.3 is
D.sup.1-3, E.sup.3 is E.sup.2-3, (2) ring5.sup.3 is not C3-7
cycloalkyl, phenyl, thienyl nor furyl, (3) ring6.sup.3 is phenyl,
then phenyl have at least one R.sup.28-3, or a non-toxic salt
thereof, or a cyclodextrin clathrate thereof, as an active
ingredient.
26. A sustained release formulation comprising a compound selected
from the group of formula (I-3) ##STR03656## wherein is (1) single
bond or (2) double bond, R.sup.19-3 and R.sup.20-3 are each
independently, (1) hydrogen atom, (2) C1-10 alkyl or (3) halogen
atom, T.sup.3 is (1) oxygen atom or (2) sulfur atom, X.sup.3 is (1)
--CH.sub.2--, (2) --O-- or (3) --S--, A.sup.3 is A.sup.1-3 or
A.sup.2-3, A.sup.1-3 is (1) C2-8 straight-chain alkylene optionally
substituted by 1-2 C1-4 alkyl, (2) C2-8 straight-chain alkenylene
optionally substituted by 1-2 C1-4 alkyl or (3) C2-8 straight-chain
alkynylene optionally substituted by 1-2 C1-4 alkyl, A.sup.2-3 is
-G.sup.1-3-G.sup.2-3-G.sup.3-3-, G.sup.1-3 is (1) C1-4
straight-chain alkylene optionally substituted by 1-2 C1-4 alkyl,
(2) C2-4 straight-chain alkenylene optionally substituted by 1-2
C1-4 alkyl or (3) C2-4 straight-chain alkynylene optionally
substituted by 1-2 C1-4 alkyl, G.sup.2-3 is (1) --Y.sup.3--, (2)
-(ring1.sup.3)-, (3) --Y.sup.3-(ring1.sup.3)-, (4)
-(ring1.sup.3)-Y.sup.3-- or (5) --Y.sup.3--(C1-4
alkylene)-(ring1.sup.3)-, Y.sup.3 is (1) --S--, (2) --SO--, (3)
--SO.sub.2--, (4) --O-- or (5) --NR.sup.1-3--, R.sup.1-3 is (1)
hydrogen atom, (2) C1-10 alkyl or (3) C2-10 acyl, G.sup.3-3 is (1)
bond, (2) C1-4 straight-chain alkylene optionally substituted by
1-2 C1-4 alkyl, (3) C2-4 straight-chain alkenylene optionally
substituted by 1-2 C1-4 alkyl or (4) C2-4 straight-chain alkynylene
optionally substituted by 1-2 C1-4 alkyl, D.sup.3 is D.sup.1-3 or
D.sup.2-3, D.sup.1-3 is (1) --COOH, (2) --COOR.sup.2-3, (3)
tetrazol-5-yl or (4) CONR.sup.3-3SO.sub.2R.sup.4-3, R.sup.2-3 is
(1) C1-10 alkyl, (2) phenyl, (3) C1-10 alkyl substituted by phenyl
or (4) biphenyl, R.sup.3-3 is (1) hydrogen atom or (2) C1-10 alkyl,
R.sup.4-3 is (1) C1-10 alkyl or (2) phenyl, D.sup.2-3 is (1)
--CH.sub.2OH, (2) --CH.sub.2OR.sup.5-3, (3) hydroxy, (4)
--OR.sup.5-3, (5) formyl, (6) --CONR.sup.6-3R.sup.7-3, (7)
--CONR.sup.6-3SO.sub.2R.sup.8-3, (8) --CO--(NH-amino acid
residue-CO).sub.m-3--OH, (9) --O--(CO-- amino acid residue
--NH).sub.m-3--H, (10) --COOR.sup.9-3, (11) --OCO---R.sup.10-3,
(12) --COO--Z.sup.1-3--Z.sup.2-3--Z.sup.3-3, ##STR03657## R.sup.5-3
is C1-10 alkyl, R.sup.6-3 and R.sup.7-3 are each independently, (1)
hydrogen atom or (2) C1-10 alkyl, R.sup.8-3 is C1-10 alkyl
substituted by phenyl, R.sup.9-3 is (1) C1-10 alkyl substituted by
biphenyl optionally substituted by 1-3 C1-10 alkyl, C1-10 alkoxy or
halogen atom or (2) biphenyl substituted by 1-3 C1-10 alkyl, C1-10
alkoxy or halogen atom, R.sup.10-3 is (1) phenyl or (2) C1-10
alkyl, m-3 is 1 or 2, Z.sup.1-3 is (1) C1-15 alkylene, (2) C2-15
alkenylene or (3) C2-15 alkynylene, Z.sup.2-3 is (1) --CO--, (2)
--OCO--, (3) --COO--, (4) --CONR.sup.11-3--, (5) --NR.sup.12-3CO--,
(6) --O--, (7) --S--, (8) --SO--, (9) --SO.sub.2--, (10)
--NR.sup.13-3--, (11) --NR.sup.14-3CONR.sup.15-3--, (12)
--NR.sup.16-3COO--, (13) --OCONR.sup.17-3-- or (14) --OCOO--,
Z.sup.3-3 is (1) hydrogen atom, (2) C1-15 alkyl, (3) C2-15 alkenyl,
(4) C2-15 alkynyl, (5) ring2.sup.3 or (6) C1-10 alkyl substituted
by C1-10 alkoxy, C1-10 alkylthio, C1-10 alkyl-NR.sup.18-3-- or
ring2.sup.3, R.sup.11-3, R.sup.12-3, R.sup.13-3, R.sup.14-3,
R.sup.15-3, R.sup.16-3, R.sup.17-3 and R.sup.18-3 are each
independently, (1) hydrogen atom or (2) C1-15 alkyl, R.sup.11-3 and
Z.sup.3-3 may be taken together with the nitrogen atom to which
they are attached to form 5 to 7 membered saturated
monoheterocyclic ring, and the heterocyclic ring may contain other
one hetero atom selected from oxygen, nitrogen and sulfur atom,
E.sup.3 is E.sup.1-3 or E.sup.2-3, E.sup.1-3 is (1) C3-7 cycloalkyl
or (2) ring3.sup.3, E.sup.2-3 is (1) C3-7 cycloalkyl, (2)
ring4.sup.3 or (3) ring5.sup.3, ring1.sup.3 and ring5.sup.3are
optionally substituted by 1-3 R.sup.21-3 and/or R.sup.22-3,
ring3.sup.3 is optionally substituted by 1-2 R.sup.21-3, C3-7
cycloalkyl represented by E.sup.2-3 is substituted by one of
R.sup.21-3 or R.sup.22-3, and optionally substituted by another 1-2
R.sup.21-3 and/or R.sup.22-3, ring4.sup.3 is substituted by one of
R.sup.22-3, optionally substituted by another 1-2 R.sup.21-3 and/or
R.sup.22-3, and optionally substituted by heterocyclic ring formed
by R.sup.11-3, Z.sup.3-3 and the nitrogen to which Z.sup.3-3 is
attached or ring2.sup.3 may be substituted by R.sup.23-3,
R.sup.21-3 is (1) C1-10 alkyl, (2) C1-10 alkoxy, (3) halogen atom,
(4) nitro, (5) C1-10 alkyl substituted by 1-3 halogen atom(s) or
(6) phenyl, R.sup.22-3 is (1) C2-10 alkenyl, (2) C2-10 alkynyl, (3)
C1-10 alkylthio, (4) hydroxy, (5) --NR.sup.24-3R.sup.25-3, (6)
C1-10 alkyl substituted by C1-10 alkoxy, (7) C1-10 alkyl
substituted by C1-10 alkoxy substituted by 1-3 halogen atom(s), (8)
C1-10 alkyl substituted by --NR.sup.24-3R.sup.25-3, (9)
ring6.sup.3, (10) --O-ring7.sup.3, (11) C1-10 alkyl substituted by
ring7.sup.3, (12) C2-10 alkenyl substituted by ring7.sup.3, (13)
C2-10 alkynyl substituted by ring7.sup.3, (14) C1-10 alkoxy
substituted by ring7.sup.3, (15) C1-10 alkyl substituted by
--O-ring7.sup.3, (16) --COOR.sup.26-3 or (17) C1-10 alkoxy
substituted by 1-3 halogen atom(s), R.sup.24-3, R.sup.25-3 and
R.sup.26-3 are each independently, (1) hydrogen atom or (2) C1-10
alkyl, R.sup.23-3 is (1) C1-15 alkyl, (2) C2-15 alkenyl, (3) C2-15
alkynyl or (4) C1-10 alkyl substituted by C1-10 alkoxy, C1-10
alkylthio or C1-10 alkyl-NR.sup.27-3--, R.sup.27-3 is (1) hydrogen
atom or (2) C1-10 alkyl, ring1.sup.3, ring2.sup.3, ring5.sup.3,
ring6.sup.3 and ring7.sup.3 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 selected from oxygen, nitrogen and sulfur
atom(s) which may be partially or fully saturated, ring3.sup.3 and
ring4.sup.3 are (1) thienyl, (2) phenyl or (3) furyl, ring6.sup.3
and ring7.sup.3 may be substituted by 1-3 R.sup.28-3, R.sup.28-3 is
(1) C1-10 alkyl, (2) C2-10 alkenyl, (3) C2-10 alkynyl, (4) C1-10
alkoxy, (5) C1-10 alkyl substituted by C1-10 alkoxy, (6) halogen
atom, (7) hydroxy, (8) C1-10 alkyl substituted by 1-3 halogen
atom(s) or (9) C1-10 alkyl substituted by C1-10 alkoxy substituted
by 1-3 halogen atom(s), and wherein (1) when T.sup.3 is oxygen
atom, X.sup.3 is CH.sub.2--, A.sup.3 is A.sup.1-3, and D.sup.3 is
D.sup.1-3, E.sup.3 is E.sup.2-3, (2) ring5.sup.3 is not C3-7
cycloalkyl, phenyl, thienyl nor furyl, (3) ring6.sup.3 is phenyl,
then phenyl have at least one R.sup.28-3, or a non-toxic salt
thereof, or a cyclodextrin clathrate thereof.
27. The formulation according to claim 26, wherein the sustained
release formulation is a microsphere, a microcapsule, a nanosphere
or a film.
28. A method for prevention and/or treatment of diseases associated
with decrease in bone mass comprising administrating to a subject
an effective amount of a compound of
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid or a non-toxic salt thereof, or a
cyclodextrin clathrate thereof.
29. The method according to claim 28, wherein the disease
associated with decrease in bone mass is fracture.
Description
[0001] This application is a continuation of U.S. Ser. No.
10/484,500, filed Jan. 22, 2004, which is a 371 of PCT/JP02/07385,
filed Jul. 22, 2002, which claims priority to JP 2001-222148, filed
Jul. 23, 2001; JP 2001-239895, filed Aug. 7, 2001; and JP
2002-56449, filed Mar. 1, 2002, all of which are incorporated
herein by reference in their entirety.
TECHNICAL FIELD
[0002] The present invention relates to [0003] (1) a pharmaceutical
composition for topical administration for prevention and/or
treatment of diseases associated with decrease in bone mass
comprising an EP.sub.4 agonist as an active ingredient, [0004] (2)
a sustained release formulation comprising the agonist as an active
ingredient, [0005] (3) a prostaglandin derivative of formula
(I-2)
##STR00001##
[0006] (wherein all symbols have the same meaning as defined
hereinafter),
[0007] or a non-toxic salt thereof, or a cyclodextrin clathrate
thereof, and a process for the preparation thereof and a
pharmaceutical composition comprising thereof as an active
ingredient,
[0008] 0(4) an 8-azaprostaglandin derivative of formula (I-3)
##STR00002##
[0009] (wherein all symbols have the same meaning as defined
hereinafter),
[0010] or a non-toxic salt thereof, or a cyclodextrin clathrate
thereof, and a process for the preparation thereof and a
pharmaceutical composition comprising thereof as an active
ingredient, and [0011] (5) a compound selected from the group
consisting of [0012] (1)
(15a,13E)-9-0xo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-8-
azaprost-13-enoic acid, [0013] (2)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-phenylphenyl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid, [0014] (3)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid, [0015] (4)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid, [0016] (5)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid, [0017] (6)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-methylphenyl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid, [0018] (7)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(2-methylphenyl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid, [0019] (8)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(2-fluorophenyl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid, [0020] (9)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-
-tetranor-8-azaprost-13-enoic acid, [0021] (10)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methoxyphenyl)-17,18,19,20-tetrano-
r-8-azaprost-13-enoic acid, [0022] (11)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-ethylphenyl)-17,18,19,20-tetranor--
8-azaprost-13-enoic acid, [0023] (12)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetr-
anor-8-azaprost-13-enoic acid, [0024] (13)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3,5-difluorophenyl)-17,18,19,20-tetr-
anor-8-azaprost-13-enoic acid, [0025] (14)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid, [0026] (15)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-ethoxyphenyl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid, [0027] (16)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-isopropyloxyphenyl)-17,18,19,20-te-
tranor-8-azaprost-13-enoic acid, [0028] (17)
(15.alpha.,5Z,13E)-9-Oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19-
,20-tetranor-8-azaprost-5,13-dienoic acid, [0029] (18)
(15.alpha.,5Z,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetra-
nor-8-azaprost-5,13-dienoic acid, [0030] (19)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3,5-dimethylphenyl)-17,18,19,20-tetr-
anor-8-azaprost-13-enoic acid, [0031] (20)
(15.alpha.,5Z,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetra-
nor-8-azaprost-5,13-dienoic acid, [0032] (21)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetr-
anor-8-azaprost-5,13-dienoic acid, [0033] (22)
(15.alpha.,5Z,13E)-9-Oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetra-
nor-8-azaprost-5,13-dienoic acid, [0034] (23)
(15.alpha.,5Z,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetra-
nor-8-azaprost-5,13-dienoic acid, [0035] (24)
(15.alpha.)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-8-a-
zaprostanoic acid and [0036] (25)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azapros-
t-13-enoic acid 3-phenylphenyl ester,
[0037] or a non-toxic salt thereof, or a cyclodextrin clathrate
thereof, and a process, for the preparation thereof and a
pharmaceutical composition comprising thereof as an active
ingredient.
BACKGROUND ART
[0038] Prostaglandin E2 (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 digestive
peristalsis, an awakening effect, a suppressive effect on gastric
acid secretion, hypotensive activity and diuretic activity and so
on.
[0039] 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)).
[0040] It is thought that EP.sub.4 subtype receptor relates to
inhibition of producing TNF-.alpha. and acceleration of producing
IL-10. 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 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, myocardiac
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, and shock etc.
[0041] 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 EP4 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.
[0042] 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 decrease in bone mass, for
example, [0043] 1) primary osteoporosis (e.g., primary osteoporosis
followed by aging, postmenopausal primary osteoporosis, primary
osteoporosis followed by ovariectomy etc.), [0044] 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.), [0045] 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.
[0046] 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.
[0047] It is also thought that EP.sub.4 subtype receptor relates to
induction of physiological sleeping and suppression of blood
platelet aggregation, so such compounds are expected to be useful
for the prevention and/or treatment of sleep disorder and
thrombosis
[0048] The compound which can bind an EP.sub.4 receptor selectively
do not have inducing pain which may be caused by EP.sub.1, uterine
relaxation which may be caused by EP.sub.2 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.
[0049] In the specification of U.S. Pat. No.4,177,346, it is
disclosed that the compound of formula (A)
##STR00003##
[0050] (wherein Q.sup.A is selected from the group consisting of
--COOR.sup.3A, tetrazol-5-yl and --CONHR.sup.4A;
[0051] A.sup.A is single bond or cis-double bond;
[0052] B.sup.A is single bond or trans-double bond;
##STR00004##
[0053] R.sup.2A is selected from the group consisting of
.alpha.-thienyl, phenyl, phenoxy, mono-substituted phenyl and
mono-substituted phenoxy, and the substituent is selected from the
group consisting of chloro, fluoro, phenyl, methoxy,
trifluoromethyl and C1-3 alkyl;
[0054] R.sup.3A is selected from the group consisting of hydrogen,
C1-5 alkyl, phenyl and p-biphenyl;
[0055] R.sup.4A is selected from the group consisting of
--COR.sup.5A and --SO.sub.2R.sup.5A;
[0056] R.sup.5A is selected from the group consisting of phenyl and
C1-5 alkyl),
[0057] and a C5 epimer thereof, the salt of alkali metal and
alkaline earth metals and ammounium salt of the compound which have
carboxylate or tetrazol-5-yl.
[0058] And in the specification of JP-A-2001-181210, it is
disclosed that the selective EP4 receptor agonist of formula (A) is
useful for the treatment of osteoporosis.
[0059] And in the specification of United Kingdom Patent
No.1,553,595, the pyrrolidone derivatives of formula (B)
##STR00005##
[0060] (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 by one or more of the following: [0061] e) a cycloalkyl
group of 3 to 7 carbon atoms, [0062] 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,
[0063] 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
[0064] nB is the integer 2,3 or 4, the definitions of the symbols
are excerpt), and a corresponding acid, a salt, especially the
physiologically acceptable e.g. metal or amine, a salt thereof is
disclosed.
[0065] 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 of formula (B) is disclosed.
[0066] In the specification of U.S. Pat. No.4,320,136, the compound
of formula (C)
##STR00006##
[0067] (wherein A.sup.C is CH.dbd.CH (cis or trans), C.ident.C or
CH.sub.2CH.sub.2;
[0068] R.sup.C is H, C1-C12 n-alkyl, branched alkyl or cycloalkyl
etc.;
[0069] R.sup.1C is H, CH.sub.3 or C.sub.2H.sub.5;
[0070] R.sup.2C is phenyl or mono- or di-substituted phenyl, the
substituent is selected from is selected from the group consisting
of, F, Cl, CH.sub.3, OCH.sub.3, NO.sub.2 or CF.sub.3; when R.sup.2C
is phenyl or substituted phenyl, nC is 0-2, the definitions of the
symbols are excerpt) is disclosed.
[0071] In the specification of WO00/03980, it is disclosed that the
compound of formula (I-1) is useful as EP.sub.4 receptor binding
agent.
[0072] In the specification of WO01/37877, it is disclosed that the
EP.sub.4 receptor agonist of formula (I-1) is useful for treatment
of diseases associated with decrease in bone mass.
[0073] It is disclosed that the EP.sub.4 receptor agonist of
formulae (A) and (I-1) is useful for treatment of diseases
associated with bone, there is a general description about topical
administration. Therefore it is unproved that topical
administration of the EP.sub.4 receptor agonist is useful for
treatment of diseases associated with bone experimentally.
[0074] Four PGE.sub.2 subtype receptors possessing a different
physical role from each other exist, and each subtype is called
EP.sub.1, EP.sub.2, EP.sub.3, and EP.sub.4 and has a different
pharmacological action. So the compounds which can bind on EP.sub.4
subtype receptor selectively and binds on the other subtype
receptors weakly may be the drug with less side effect, because
they show no any other activities. Therefore it is in need of
finding the drug like this.
[0075] On the other hand, a lot of compounds which have the
EP.sub.4 agonistic activity are found until now. However, all of
them have a prostanoid skeleton, so it is thought that they
influence circulatory system (e.g. blood pressure lowered or
increasing of the heart rate), or cause side-effect such as
diarrhea when they are administered by systemic administration such
as oral administration or intravenous infusion. Therefore, they
have significant problem that there is a limitation of the dose
that can be administered safely.
[0076] As a disease associated with EP.sub.4 agonist, a lot of
studies of diseases associated with decrease in bone mass have been
done. It is also thought that systemic administration causes
side-effects, so development of the drug with less side effects is
expected. Finding a long-acting pharmaceutical which can be
administrated topically is also expected.
DISCLOSURE OF THE INVENTION
[0077] The present inventors have studied to find out the compounds
which can bind on EP.sub.4 subtype receptor specifically, and which
have strong agonistic activity. Finally, the compounds of formulae
(I-2) and (I-3) were found out to meet this purpose, and this
invention was accomplished.
[0078] The present inventors found out the compound which binds on
both EP.sub.4 and EP.sub.2 subtype receptor. The compound which
binds on 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 receptor.
[0079] The present inventors also thought that we can create the
therapeutic agent (treatment of diseases associated with decrease
in bone mass, particularly) with no side-effect in systemic
administration if EP.sub.4 agonist can be administered topically.
We also conceived that we can create the therapeutic agent
(treatment of diseases associated with decrease in bone mass,
particularly) with no side-effect in systemic administration and
with less frequency of administration if we can find the EP.sub.4
agonist which can be a sustained release formulation and which can
be administered topically.
[0080] Therefore the present inventors made further investigation
to solve the former purpose to find that the purpose of the present
invention can be accomplished by using a sustained release
formulation of the compound of formulae (I-1), (I-2) and (I-3), and
completed the present invention.
[0081] The compounds of formulae (1-2) and (I-3) is completely
novel.
[0082] The present invention relates to [0083] i) a pharmaceutical
composition for topical administration for prevention and/or
treatment of diseases associated with decrease in bone mass
comprising an EP.sub.4 agonist as an active ingredient, [0084] ii)
a sustained release formulation comprising an EP.sub.4 agonist as
an active ingredient, [0085] iii) a pharmaceutical composition for
topical administration for prevention and/or treatment of diseases
associated with decrease in bone mass comprising a sustained
release formulation comprising an EP.sub.4 agonist as an active
ingredient, [0086] iv) a pharmaceutical composition for prevention
and/or treatment of diseases associated with decrease in bone mass,
characterized by topical administration of the formulation
comprising a compound selected from the group of formula (I-1)
##STR00007##
[0087] wherein R.sup.1-1 is hydroxy, C1-6 alkyloxy, or
NR.sup.6-1R.sup.7-1, wherein R.sup.6-1 and R.sup.7-1 are each
independently, hydrogen atom or C1-4 alkyl,
[0088] R.sup.2-1 is oxo, halogen, or O--COR.sup.8-1, wherein
R.sup.8-1 is C1-4 alkyl, phenyl or phenyl(C1-4 alkyl),
[0089] R.sup.3-1 is hydrogen atom or hydroxy,
[0090] R.sup.4a-1 and R.sup.4b-1 are each independently, hydrogen
atom or C1-4 alkyl,
[0091] R.sup.5-1 is phenyl substituted by the group listed below:
[0092] (i) 1 to 3 of
[0093] C1-4 alkyloxy-C1-4 alkyl,
[0094] C2-4 alkenyloxy-C1-4 alkyl,
[0095] C2-4 alkynyloxy-C1-4 alkyl,
[0096] C3-7 cycloalkyloxy-C1-4 alkyl,
[0097] C3-7 cycloalkyl(C1-4 alkyloxy)-C1-4 alkyl,
[0098] phenyloxy-C1-4 alkyl,
[0099] phenyl-C1-4 alkyloxy-C1-4 alkyl,
[0100] C1-4 alkylthio-C1-4 alkyl,
[0101] C2-4 alkenylthio-C1-4 alkyl,
[0102] C2-4 alkynylthio-C1-4 alkyl,
[0103] C3-7 cycloalkylthio-C1-4 alkyl,
[0104] C3-7 cycloalkyl(C1-4 alkylthio)-C1-4 alkyl or
[0105] phenylthio-C1-4 alkyl or phenyl-C1-4 alkylthio-C1-4 alkyl,
[0106] (ii) C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyl,
[0107] C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyloxy,
[0108] C1-4 alkyloxy-C1-4 alkyl and hydroxy,
[0109] C1-4 alkyloxy-C1-4 alkyl and halogen,
[0110] C1-4 alkylthio-C1-4 alkyl and C1-4 alkyl,
[0111] C1-4 alkylthio-C1-4 alkyl and C1-4 alkyloxy,
[0112] C1-4 alkylthio-C1-4 alkyl and hydroxy or
[0113] C1-4 alkylthio-C1-4 alkyl and halogen, [0114] (iii)
haloalkyl or hydroxy-C1-4 alkyl, or [0115] (iv) C1-4 alkyl and
hydroxy;
[0116] is single bond or double bond,
[0117] wherein when R.sup.2-1 is O--COR.sup.8-1, C8-9 position is
double bond,
[0118] or a non-toxic salt thereof, or a cyclodextrin clathrate
thereof as an active ingredient, [0119] v) the sustained release
formulation comprising a compound selected from the group of
formula (I-1), or a non-toxic salt thereof, or a cyclodextrin
clathrate thereof as an active ingredient, [0120] vi) a
pharmaceutical composition for prevention and/or treatment of
diseases associated with decrease in bone mass, characterized by
topical administration of the formulation comprising a compound
selected from the group of formula (I-2)
##STR00008##
[0121] wherein R.sup.1-2 is [0122] (1) --CO--(NH-amino acid
residue-CO).sub.m-2--OH, [0123] (2) --COO--Y.sup.2--R.sup.9-2,
[0124] (3) --COO--Z.sup.1-2--Z.sup.2-2--Z.sup.3-2,
[0125] wherein Y.sup.2 is bond or C1-10 alkylene,
[0126] R.sup.9-2 is (1) phenyl or (2) biphenyl optionally
substituted by 1-3 C1-10 alkyl, C1-10 alkoxy or halogen atom,
[0127] Z.sup.1-2 is [0128] (1) C1-15 alkylene, [0129] (2) C2-15
alkenylene or [0130] (3) C2-15 alkynylene,
[0131] Z.sup.2-2 is [0132] (1) --CO--, [0133] (2) --OCO--, [0134]
(3) --COO--, [0135] (4) --CONR.sup.11-2--, [0136] (5)
--NR.sup.12-2CO--, [0137] (6) --O--, [0138] (7) --S--, [0139] (8)
--SO--, [0140] (9) --SO.sub.2--, [0141] (10) --NR.sup.13-2, [0142]
(11) --NR.sup.14-2CONR.sup.15-2, [0143] (12) --NR.sup.16-2COO--,
[0144] (13) --OCONR.sup.17-2-- or [0145] (14) --OCOO--,
[0146] Z.sup.3-2 is [0147] (1) hydrogen atom, [0148] (2) C1-15
alkyl, [0149] (3) C2-15 alkenyl, [0150] (4) C2-15 alkynyl, [0151]
(5) ring1.sup.2 or [0152] (6) C1-10 alkyl substituted by C1-10
alkoxy, C1-10 alkylthio, C1-10 alkyl-NR.sup.18-2-- or
ring1.sup.2,
[0153] ring1.sup.2 is [0154] (1) C3-15 mono-, bi- or
tri-carbocyclic aryl which may be partially or fully saturated or
[0155] (2) 3 to 15 membered mono-, bi- or tri-heterocyclic aryl
containing 1 to 4 hetero atom selected from oxygen, nitrogen and
sulfur atom(s) which may be partially or fully saturated,
[0156] R.sup.11-2, R.sup.12-2, R.sup.13-2, R.sup.14-2, R.sup.15-2,
R.sup.16-2, R.sup.17-2 and R.sup.18-2 are each independently,
hydrogen atom or C1-15 alkyl,
[0157] R.sup.11-2 and Z.sup.3-2 may be taken together with the
nitrogen atom to which they are attached to form 5 to 7 membered
saturated monoheterocyclic ring, and the heterocyclic ring may
contain another one hetero atom selected from oxygen, nitrogen and
sulfur atom,
[0158] ring1.sup.2 and saturated monoheterocyclic ring formed by
R.sup.11-2, Z.sup.3-2 and the nitrogen atom to which Z.sup.3-2 is
attached may be substituted by 1-3 group(s) selected from [0159]
(1) C1-15 alkyl, [0160] (2) C2-15 alkenyl, [0161] (3) C2-15 alkynyl
and [0162] (4) C1-10 alkyl substituted with C1-10 alkoxy, C1-10
alkylthio or C1-10 alkyl-NR.sup.19-2,
[0163] R.sup.19-2 is hydrogen atom or C1-10 alkyl,
[0164] m-2 is 1 or 2,
[0165] other symbols are same meaning as defined hereinbefore,
[0166] or a non-toxic salt thereof, or a cyclodextrin clathrate
thereof as an active ingredient, [0167] vii) the sustained release
formulation comprising a compound selected from the group of
formula (I-2), or a non-toxic salt thereof, or a cyclodextrin
clathrate thereof as an active ingredient, [0168] viii) a
pharmaceutical composition for prevention and/or treatment of
diseases associated with decrease in bone mass, characterized by
topical administration of the formulation comprising a compound
selected from the group of formula (1-3)
##STR00009##
[0169] wherein is (1) single bond or (2) double bond,
[0170] R.sup.19-3 and R.sup.20-3 are each independently, (1)
hydrogen atom, (2) C1-10 alkyl or (3) halogen atom,
[0171] T.sup.3 is (1) oxygen atom or (2) sulfur atom,
[0172] X.sup.3 is (1) --CH.sub.2--, (2) --O-- or (3) --S--,
[0173] A.sup.3 is A.sup.1- 3 or A.sup.2-3,
[0174] A.sup.1-3 is [0175] (1) C2-8 straight-chain alkylene
optionally substituted by 1-2 C1-4 alkyl, [0176] (2) C2-8
straight-chain alkenylene optionally substituted by 1-2 C1-4 alkyl
or [0177] (3) C2-8 straight-chain alkynylene optionally substituted
by 1-2 C1-4 alkyl,
[0178] A.sup.2-3 is -G.sup.13-G.sup.2-3-G.sup.3-3-,
[0179] G.sup.1-3 is [0180] (1) C1-4 straight-chain alkylene
optionally substituted by 1-2 C1-4 alkyl, [0181] (2) C2-4
straight-chain alkenylene optionally substituted by 1-2 C1-4 alkyl
or [0182] (3) C2-4 straight-chain alkynylene optionally substituted
by 1-2 C1-4 alkyl,
[0183] G.sup.2-3 is [0184] (1) --Y.sup.3--, [0185] (2)
-(ring1.sup.3)-, [0186] (3) --Y.sup.3-(ring1.sup.3)-, [0187] (4)
-(ring1.sup.3)-Y.sup.3-- or [0188] (5) --Y.sup.3--(C1-4
alkylene)-(ring1.sup.3)-,
[0189] Y.sup.3 is (1) --S--, (2) --SO--, (3) --SO.sub.2--, (4)
--O-- or (5) --NR.sup.1-3--,
[0190] R.sup.1-3 is (1) hydrogen atom, (2) C1-10 alkyl or (3) C2-10
acyl,
[0191] G.sup.3-3 is [0192] (1) bond, [0193] (2) C1-4 straight-chain
alkylene optionally substituted by 1-2 C1-4 alkyl, [0194] (3) C2-4
straight-chain alkenylene optionally substituted by 1-2 C1-4 alkyl
or [0195] (4) C2-4 straight-chain alkynylene optionally substituted
by 1-2 C1-4 alkyl,
[0196] D.sup.3 is D.sup.1-3 or D.sup.2-3,
[0197] D.sup.1-3 is [0198] (1) --COOH, [0199] (2) --COOR.sup.2-3,
[0200] (3) tetrazol-5-yl or [0201] (4)
CONR.sup.3-3SO.sub.2R.sup.4-3,
[0202] R.sup.2-3 is (1) C1-10 alkyl, (2) phenyl, (3) C1-10 alkyl
substituted by phenyl or (4) biphenyl,
[0203] R.sup.3-3 is (1) hydrogen atom or (2) C1-10 alkyl,
[0204] R.sup.4-3 is (1) C1-10 alkyl or (2) phenyl,
[0205] D.sup.2-3 is [0206] (1) --CH.sub.2OH, [0207] (2)
--CH.sub.2OR.sup.5-3, [0208] (3) hydroxy, [0209] (4) --OR.sup.5-3,
[0210] (5) formyl, [0211] (6) --CONR.sup.6-3R.sup.7-3, [0212] (7)
--CONR.sup.6-3SO.sub.2R.sup.8-3, [0213] (8) --CO--(NH-amino acid
residue-CO).sub.m-3--OH, [0214] (9) --O--(CO-- amino acid residue
--NH).sub.m-3--H, [0215] (10) --COOR.sup.9-3, [0216] (11)
--OCO--R.sup.10-3, [0217] (12)
--COO--Z.sup.103--Z.sup.2-3--Z.sup.3-3,
##STR00010##
[0218] R.sup.5-3 is C1-10 alkyl,
[0219] R.sup.6-3 and R.sup.7-3 are each independently, (1) hydrogen
atom or (2) C1-10 alkyl,
[0220] R.sup.8-3 is C1-10 alkyl substituted by phenyl,
[0221] R.sup.9-3 is (1) C1-10 alkyl substituted by biphenyl
optionally substituted by 1-3 C1-10 alkyl, C1-10 alkoxy or halogen
atom or (2) biphenyl substituted by 1-3 C1-10 alkyl, C1-10 alkoxy
or halogen atom,
[0222] R.sup.10-3 is (1) phenyl or (2) C1-10 alkyl,
[0223] m-3 is 1 or 2,
[0224] Z.sup.1-3 is (1) C1-15 alkylene, (2) C2-15 alkenylene or (3)
C2-15 alkynylene,
[0225] Z.sup.2-3 is (1) --CO--, (2) --OCO--, (3) --COO--, (4)
--CONR.sup.11-3, (5) --NR.sup.12-3CO--, (6) --O--, (7) --S--, (8)
--SO--, (9) --SO.sub.2--, (10) --NR.sup.13-3--, (11)
--NR.sup.14-3CONR.sup.15-3--, (12) --NR.sup.16-3COO--, (13)
--OCONR.sup.17-3-- or (14) --OCOO--,
[0226] Z.sup.3-3 is (1) hydrogen atom, (2) C1-15 alkyl, (3) C2-15
alkenyl, (4) C2-15 alkynyl, (5) ring2.sup.3 or (6) C1-10 alkyl
substituted by C1-10 alkoxy, C1-10 alkylthio, C1-10
alkyl-NR.sup.18-3-- or ring2.sup.3,
[0227] R.sup.11-3, R.sup.12-3, R.sup.13-3, R.sup.14-3, R.sup.15-3,
R.sup.16-3, R.sup.17-3 and R.sup.18-3 are each independently, (1)
hydrogen atom or (2) C1-15 alkyl,
[0228] R.sup.11-3 and Z.sup.3-3 may be taken together with the
nitrogen atom to which they are attached to form 5 to 7 membered
saturated monoheterocyclic ring, and the heterocyclic ring may
contain other one hetero atom selected from oxygen, nitrogen and
sulfur atom,
[0229] E.sup.3 is E.sup.1-3 or E.sup.2-3,
[0230] E.sup.1-3 i.sub.s [0231] (1) C3-7 cycloalkyl or [0232] (2)
ring3.sup.3,
[0233] E.sup.2-3 is [0234] (1) C3-7 cycloalkyl, [0235] (2)
ring4.sup.3 or [0236] (.sup.3) ring5.sup.3,
[0237] ring1.sup.3 and ring5.sup.3are optionally substituted by 1-3
R.sup.21-3 and/or R.sup.22-3,
[0238] ring3.sup.3 is optionally substituted by 1-2 R.sup.21-3,
[0239] C3-7 cycloalkyl represented by E.sup.2-3 is substituted by
one of R.sup.21-3 or R.sup.22-3, and optionally substituted by
another 1-2 R.sup.21-3 and/or R.sup.22-3,
[0240] ring4.sup.3 is substituted by one of R.sup.22-3, optionally
substituted by another 1-2 R.sup.21-3 and/or R.sup.22-3, and
[0241] optionally substituted by heterocyclic ring formed by
R.sup.11-3, Z.sup.3-3 and the nitrogen to which Z.sup.3-3 is
attached or ring2.sup.3 may be substituted by R.sup.23-3,
[0242] R.sup.21-3 is (1) C1-10 alkyl, (2) C1-10 alkoxy, (3) halogen
atom, (4) nitro, (5) C1-10 alkyl substituted by 1-3 halogen atom(s)
or (6) phenyl,
[0243] R.sup.22-3 is (1) C2-10 alkenyl, (2) C2-10 alkynyl, (3)
C1-10 alkylthio, (4) hydroxy, (5) --NR.sup.24-3R.sup.25-3, (6)
C1-10 alkyl substituted by C1-10 alkoxy, (7) C1-10 alkyl
substituted by C1-10 alkoxy substituted by 1-3 halogen atom(s), (8)
C1-10 alkyl substituted by --NR.sup.24-3R.sup.25-3, (9)
ring6.sup.3, (10) --O-ring7.sup.3, (11) C1-10 alkyl substituted by
ring7.sup.3, (12) C2-10 alkenyl substituted by ring7.sup.3, (13)
C2-10 alkynyl substituted by ring7.sup.3, (14) C1-10 alkoxy
substituted by ring7.sup.3, (15) C1-10 alkyl substituted by
--O-ring7.sup.3, (16) --COOR.sup.26-3 or (17) C1-10 alkoxy
substituted by 1-3 halogen atom(s)(s),
[0244] R.sup.24-3, R.sup.25-3 and R.sup.26-3 are each
independently, (1) hydrogen atom or (2) C1-10 alkyl,
[0245] R.sup.23-3 is (1) C1-15 alkyl, (2) C2-15 alkenyl, (3) C2-15
alkynyl or (4) C1-10 alkyl substituted by C1-10 alkoxy, C1-10
alkylthio or C1-10 alkyl-NR.sup.27-3--,
[0246] R.sup.27-3 is (1) hydrogen atom or (2) C1-10 alkyl,
[0247] ring1.sup.3, ring2.sup.3, ring5.sup.3, ring6.sup.3 and
ring7.sup.3 are [0248] (1) C3-15 mono-, bi- or tri-carbocyclic aryl
which may be partially or fully saturated or [0249] (2) 3 to 15
membered mono-, bi- or tri-heterocyclic aryl containing 1 to 4
hetero atom selected from oxygen, nitrogen and sulfur atom(s) which
may be partially or fully saturated,
[0250] ring3.sup.3 and ring4.sup.3 are (1) thienyl, (2) phenyl or
(3) furyl,
[0251] ring6.sup.3 and ring7.sup.3 may be substituted by 1-3
R.sup.28-3,
[0252] R.sup.28-3 is (1) C1-10 alkyl, (2) C2-10 alkenyl, (3) C2-10
alkynyl, (4) C1-10 alkoxy, (5) C1-10 alkyl substituted by C1-10
alkoxy, (6) halogen atom, (7) hydroxy, (8) C1-10 alkyl substituted
by 1-3 halogen atom(s) or (9) C1-10 alkyl substituted by C1-10
alkoxy substituted by 1-3 halogen atom(s), and
[0253] wherein [0254] (1) when T.sup.3 is oxygen atom, X.sup.3 is
CH.sub.2--, A.sup.3 is A.sup.1-3, and D.sup.3 is D.sup.1-3, E.sup.3
is E.sup.2-3, [0255] (2) ring5.sup.3 is not C3-7 cycloalkyl,
phenyl, thienyl nor furyl, [0256] (3) ring6.sup.3 is phenyl, then
phenyl have at least one R.sup.28-3,
[0257] or a non-toxic salt thereof, or a cyclodextrin clathrate
thereof as an active ingredient, [0258] ix) the sustained release
formulation comprising a compound selected from the group of
formula (I-3), or a non-toxic salt thereof, or a cyclodextrin
clathrate thereof as an active ingredient, [0259] x) a
prostaglandin derivative of formula (I-2)
##STR00011##
[0260] wherein all symbols have the same meaning as defined in
vi),
[0261] or a non-toxic salt thereof, or a cyclodextrin clathrate
thereof, [0262] xi) a process for the preparation of a
prostaglandin derivative of formula (I-2), or a non-toxic salt
thereof, or a cyclodextrin clathrate thereof, [0263] xii) a
pharmaceutical composition comprising of a prostaglandin derivative
of formula (I-2), or a non-toxic salt thereof, or a cyclodextrin
clathrate thereof as an active ingredient, [0264] xiii) a compound
selected from the group of formula (I-3)
##STR00012##
[0265] wherein all symbols have the same meaning as defined in
viii),
[0266] or a non-toxic salt thereof, or a cyclodextrin clathrate
thereof [0267] xiv) a process for the preparation of an
8-azaprostaglandin derivative of formula (I-3), or a non-toxic salt
thereof, or a cyclodextrin clathrate thereof, [0268] xv) a
pharmaceutical composition comprising of an 8-azaprostaglandin
derivative of formula (I-3), or a non-toxic salt thereof, or a
cyclodextrin clathrate thereof as an active ingredient, [0269] xvi)
a pharmaceutical composition for prevention and/or treatment of
diseases associated with decrease in bone mass, characterized by
topical administration of the formulation comprising a compound
selected from the group consisting of [0270] (1)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid, [0271] (2)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-phenylphenyl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid, [0272] (3)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid, [0273] (4)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid, [0274] (5)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid, [0275] (6)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(4-methylphenyl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid, [0276] (7)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(2-methylphenyl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid, [0277] (8)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(2-fluorophenyl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid, [0278] (9)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-
-tetranor-8-azaprost-13-enoic acid, [0279] (10)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methoxyphenyl)-17,18,19,20-tetrano-
r-8-azaprost-13-enoic acid, [0280] (11)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-ethylphenyl)-17,18,19,20-tetranor--
8-azaprost-13-enoic acid, [0281] (12)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetr-
anor-8-azaprost-13-enoic acid, [0282] (13)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3,5-difluorophenyl)-17,18,19,20-tetr-
anor-8-azaprost-13-enoic acid, [0283] (14)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid, [0284] (15)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-ethoxyphenyl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid, [0285] (16)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-isopropyloxyphenyl)-17,18,19,20-te-
tranor-8-azaprost-13-enoic acid, [0286] (17)
(15.alpha.,5Z,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19-
,20-tetranor-8-azaprost-5,13-dienoic acid, [0287] (18)
(15.alpha.,5Z,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetra-
nor-8-azaprost-5,13-dienoic acid, [0288] (19)
(15a,13E)-9-oxo-15-hydroxy-16-(3,5-dimethylphenyl)-17,18,19,20-tetranor-8-
-azaprost-13-enoic acid, [0289] (20)
(15.alpha.,5Z,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetra-
nor-8-azaprost-5,13-dienoic acid, [0290] (21)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetr-
anor-8-azaprost-5,13-dienoic acid, [0291] (22)
(15.alpha.,5Z,13E)-9-oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetra-
nor-8-azaprost-5,13-dienoic acid, [0292] (23)
(15.alpha.,5Z,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetra-
nor-8-azaprost-5,13-dienoic acid, [0293] (24)
(15.alpha.)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-8-a-
zaprostanoic acid, and [0294] (25)
(15.alpha.,13E)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azapros-
t-13-enoic acid 3-phenylphenyl ester,
[0295] or a non-toxic salt thereof, or a cyclodextrin clathrate
thereof as an active ingredient,
[0296] or the sustained release formulation comprising a compound
selected from the former group, or a non-toxic salt thereof, or a
cyclodextrin clathrate thereof as an active ingredient,
[0297] or a compound selected from the former group, or a non-toxic
salt thereof, or a cyclodextrin clathrate thereof, and a process
for the preparation thereof and a pharmaceutical composition
comprising thereof as an active ingredient.
[0298] In the present invention, C1-4 alkyl means methyl, ethyl,
propyl, butyl and the isomers thereof.
[0299] In the present invention, C1-10 alkyl means methyl, ethyl,
propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the
isomers thereof.
[0300] In the present invention, C1-15 alkyl means methyl, ethyl,
propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl,
dodecyl, tridecyl, tetradecyl, pentadecyl and the isomers
thereof.
[0301] In the present invention, C2-10 alkenyl means ethenyl,
propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl,
decenyl and the isomers thereof.
[0302] In the present invention, C2-15 alkenyl means ethenyl,
propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl,
decenyl, undecenyl, dodecenyl, tetradecenyl, pentadecenyl and the
isomers thereof.
[0303] In the present invention, C2-10 alkynyl means ethynyl,
propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl,
decynyl and the isomers thereof
[0304] In the present invention, C2-15 alkynyl means ethynyl,
propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl,
decynyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl,
pentadecynyl and the isomers thereof.
[0305] In the present invention, straight-chain C1-4 alkylene means
methylene, ethylene, trimethylene and tetramethylene.
[0306] In the present invention, straight-chain C2-8 alkylene means
methylene, ethylene, trimethylene, tetramethylene, pentamethylene,
hexamethylene, heptamethylene and octamethylene.
[0307] In the present invention, C1-4 alkylene means methylene,
ethylene, trimethylene, tetramethylene and the isomers thereof
[0308] In the present invention, C1-10 alkylene means methylene,
ethylene, trimethylene, tetramethylene, pentamethylene,
hexamethylene, heptamethylene, octamethylene, nonamethylene,
decamethylene and the isomers thereof
[0309] In the present invention, C1-15 alkylene means methylene,
ethylene, trimethylene, tetramethylene, pentamethylene,
hexamethylene, heptamethylene, octamethylene, nonamethylene,
decamethylene, undecamethylene, dodecamethylene, tridecamethylene,
tetradecamethylene, pentadecamethylene and the isomers thereof
[0310] In the present invention, straight-chain C2-4 alkenylene
means ethenylene, propenylene, butenylene and the isomers
thereof.
[0311] In the present invention, straight-chain C2-8 alkenylene
means C2-8 alkenylene which has 1 to 2 double bond(s). It means
ethenylene, propenylene, butenylene, pentenylene, hexenylene,
heptenylene, octenylene, pentadienylene, hexadienylene,
heptadienylene and octadienylene.
[0312] In the present invention, C2-15 alkenylene means ethenylene,
propenylene, butenylene, pentenylene, hexenylene, heptenylene,
octenylene, nonenylene, decenylene, undecenylene, dodecenylene,
tridecenylene, tetradecenylene, pentadecenylene and the isomers
thereof.
[0313] In the present invention, straight-chain C2-4 alkynylene
means ethynylene, propynylene, butynylene.
[0314] In the present invention, straight-chain C2-8 alkynylene
means C2-8 alkenylene which has 1 to 2 triple bond(s). It means
ethynylene, propynylene, butynylene, butadiynylene, pentynylene,
pentadiynylene, hexynylene, hexadiynylene, heptynylene,
heptadiynylene, octynylene, octadiynylene.
[0315] In the present invention, C2-15 alkynylene means ethynylene,
propynylene, butynylene, pentynylene, hexynylene, heptynylene,
octynylene, nonynylene, decynylene, undecynylene, dodecynylene,
tridecynylene, tetradecynylene, pentadecynylene and the isomers
thereof.
[0316] In the present invention, C1-10 alkoxy means methoxy,
ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy,
nonyloxy, decyloxy and the isomers thereof.
[0317] In the present invention, C1-10 alkylthio means methylthio,
ethylthio, propylthio, butylthio, pentylthio, hexylthio,
heptylthio, octylthio, nonylthio, decylthio and the isomers
thereof.
[0318] In the present invention, halogen atom means chloride,
bromide, fluoride and iodide atom.
[0319] In the present invention, biphenyl means 2-phenylphenyl,
3-phenylphenyl or 4-phenylphenyl.
[0320] In the present invention, C2-10 acyl means ethanoyl,
propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl,
nonanoyl, decanoyl and the isomers thereof.
[0321] In the present invention, phenylene means benzene ring which
has two connectable bonds, i.e.,
##STR00013##
[0322] Any position can be substituted, and 1,4- or
1,3-disubstituted one is preferable.
[0323] In the present invention, thienylene means thiophene ring
which has two connectable bonds, i.e.,
##STR00014##
[0324] Any position can be substituted, and 2,5-disubstituted one
is preferable.
[0325] In the present invention, furylene means furan ring which
has two connectable bonds, i.e.,
##STR00015##
[0326] Any position can be substituted, and 2,5-disubstituted one
is preferable.
[0327] In the present invention, thiazolylene means thiazole ring
which has two connectable bonds, i.e.,
##STR00016##
[0328] Any position can be substituted, and 2,5-disubstituted one
is preferable.
[0329] In the present invention, oxazolylene means oxazole ring
which has two connectable bonds, i.e.,
##STR00017##
[0330] Any position can be substituted, and 2,5-disubstituted one
is preferable.
[0331] In the present invention, C3-5cycloalkylene means
cyclopropyl, cyclobutyl or cyclopenthyl which have two connectable
bonds, i.e.,
##STR00018##
[0332] Any position can be substituted, and 1,1-disubstituted one
is preferable.
[0333] In the present invention, amino acid residue means the amino
acid residue of natural amino acid or abnormal amino acid. Natural
amino acids or abnormal amino acid include, for example, glycine,
alanine, valine, leucine, isoleucine, serine, threonine, cystein,
methionine, proline, asparagine, glutamine, phenylalanine,
tyrosine, tryptophan, aspartic acid, glutamic acid, lysine,
arginine, histidine, .beta.-alanine, cystathionine, cystine,
homoserine, isoleucine, lanthionine, norleucine, norvaline,
ornithine, sarcosine, thyronine.
[0334] When the amino acid residue has other amino groups, the
amino acid with protecting group is included the former amino acid
residue.
[0335] A protecting group of amino group includes, for example,
benzyloxycarbonyl, t-butoxycarbonyl, trifluoroacetyl,
9-fluorenylmethoxycarbonyl.
[0336] In the present invention, 5 to 7 membered saturated
mono-heterocyclic ring means 5 to 7 membered saturated
mono-heterocyclic ring which may contains another one hetero atom
selected from oxygen, nitrogen and sulfur atom. It includes, for
example, pyrrolidine, imidazolidine, pyrazolidine, piperidine,
piperazine, perhydropyridazine, perhydroazepine, perhydrodiazepine,
tetrahydrooxazole(oxazolidine), tetrahydroisoxazole(isoxazolidine),
tetrahydrothiazole(thiazolidine),
tetrahydroisothiazole(isothiazolidine), tetrahydrooxazine,
perhydrooxazepine, tetrahydrothiazine, perhydrothiazepine,
morpholine, thiomorpholine ring.
[0337] In the present invention, C3-15 mono-, bi- or
tri-carbocyclic ring which may be partially or fully saturated also
includes spirocarbocyclic ring and bridged carbocyclic ring. It
includes, for example, cyclopropane, cyclobutane, cyclopentane,
cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane,
cycloundecane, cyclododecane, cyclotridecane, cyclotetradecane,
cyclopentadecane, cyclopropene, cyclobutene, cyclopentene,
cyclohexene, cycloheptene, cyclooctene, cyclopentadiene,
cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene,
pentalene, perhydropentalene, azulene, perhydroazulene, indene,
perhydroindene, indane, naphthalene, dihydronaphthalene,
tetrahydronaphthalene, perhydronaphthalene, heptalene,
perhydroheptalene, biphenylene, as-indacene, s-indacene,
acenaphthylene, acenaphthene, fluorene, phenalene, phenanthrene,
anthracene,9,10-dihydroanthracene, spiro[4.4]nonane,
spiro[4.5]decane, spiro[5.5]undecane, bicyclo[2.2.1]heptane,
bicyclo[2.2.1]hept-2-ene, bicyclo[3.1.1]heptane,
bicyclo[3.1.1]hept-2-ene, bicyclo[3.3.1]-2-heptene,
bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene, adamantane,
noradamantane etc.
[0338] In the present invention, among the 3 to 15 membered mono-,
bi- or tri-heterocyclic aryl which may be partially or fully
saturated containing 1 to 4 hetero atom(s) selected from oxygen,
nitrogen and sulfur atom(s), 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) includes, for example,
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 ring etc.
[0339] The 3 to 15 membered mono-, bi- or tri-heterocyclic aryl
which may be partially or fully saturated containing 1 to 4 hetero
atom(s) selected from oxygen, nitrogen and sulfur atom(s) includes
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, tetrahydrocarbazole,
perhydrocarbazole, dihydroacridine, tetrahydroacridine,
perhydroacridine, dihydrodibenzofuran, dihydrodibenzothiophene,
tetrahydrodibenzofuran, tetrahydrodibenzothiophene,
perhydrodibenzofuran, perhydrodibenzothiophene, dioxolane, dioxane,
dithiolane, dithiane, dioxaindan, benzodioxane, chroman,
benzodithiolane, benzodithiane, 8-aza-1,4-jioxaspiro[4.5]decane,
3-azaspiro[5.5]undecane, 1,3,8-triazaspiro[4.5]decane ring
[0340] In the present invention, C1-6 alkyloxy means methoxy,
ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the isomers
thereof.
[0341] In the present invention, C1-4 alkyloxy means methoxy,
ethoxy, propoxy, butoxy and the isomers thereof.
[0342] In the present invention, C1-4 alkylthio means methylthio,
ethylthio, propylthio, butylthio and the isomers thereof.
[0343] In the present invention, C2-4 alkenyloxy means ethenyloxy,
propenyloxy, butenyloxy and the isomers thereof.
[0344] In the present invention, C2-4 alkenylthio means
ethenylthio, propenylthio, butenylthio and the isomers thereof.
[0345] In the present invention, C2-4 alkynyloxy means ethynyloxy,
propynyloxy, butynyloxy and the isomers thereof.
[0346] In the present invention, C2-4 alkynylthio means
ethynylthio, propynylthio, butynylthio and the isomers thereof.
[0347] In the present invention, C3-7 cycloalkyl means cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the isomers
thereof.
[0348] In the present invention, C3-7 cycloalkyloxy means
cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy,
cycloheptyloxy and the isomers thereof.
[0349] In the present invention, C3-7 cycloalkylthio means
cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio,
cycloheptylthio and the isomers thereof.
[0350] 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-, .alpha.-,
.beta.-isomer, enantiomer, diastereomer), optically active isomers
(D-, L-, d-, l-isomer), polar compounds generated by
chromatographic separation (more polar compound, less polar
compound), equilibrium compounds, mixtures thereof at voluntary
ratios and racemic mixtures are also included in the present
invention.
[0351] In the present invention, unless otherwise specified, the
symbol means that the substituent attached thereto is behind the
sheet (i.e., .alpha.-configuration), the symbol means that the
substituent attached thereto is in front of the sheet (i.e.,
.beta.-configuration), the symbol means .alpha.-configuration,
.beta.-configuration or a mixture of .alpha.-configuration and
.beta.-configuration, and the symbol means that there is a mixture
of .alpha.-configuration and .beta.-configuration as would be clear
to the person skilled in the art.
[0352] The compound of the present invention may be converted into
the corresponding non-toxic salt by conventional methods.
[0353] Non-toxic salts of the compounds of the present invention
include all pharmaceutically acceptable salts, and water-soluble
salts are preferred.
[0354] Non-toxic salts of the compounds of the present invention,
for example, include: 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.), salts of organic amines (e.g.
triethylamine, methylamine, dimethylamine, cyclopentylamine,
benzylamine, phenethylamine, piperidine, monoethanolamine,
diethanolamine, tris(hydroxymethyl)methylamine, lysine, arginine,
N-methyl-D-glucamine, etc.) and acid addition salts (salts of
inorganic acids (e.g. hydrochloride, hydrobromide, hydroiodide,
sulfate, phosphate, nitrate, etc.), salts of organic acids (e.g.
acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate,
maleate, benzoate, citrate, methanesulfonate, ethanesulfonate,
benzenesulfonate, toluenesulfonate, isethionate, glucuronate,
gluconate, etc.), etc.).
[0355] Non-toxic salts of the compounds of the present invention
include solvates thereof or solvates of the salts of alkali metals,
salts of alkaline earth metals, ammonium salts, salts of organic
amines and acid addition salts of the compounds of the present
invention.
[0356] Non-toxic and water-soluble solvates are preferred. Solvates
of the compounds of the present invention, for example, include:
hydrates, solvates of the alcohols (ethanol etc.), etc.
[0357] 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, 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 useful in the use for pharmaceuticals.
[0358] It is enough to use the compound of the present invention as
the EP.sub.4 agonist if it has EP.sub.4 agonistic activity. Both a
selective EP.sub.4 agonist and a non-selective EP.sub.4 agonist can
be used.
[0359] Furthermore, the EP.sub.4 agonists of the present invention
include the ones which will be found newly in future as well as
known ones at present.
[0360] For example, the EP.sub.4 agonists known at present are
prostaglandin E.sub.1 (PGE.sub.1), prostaglandin E.sub.2
(PGE.sub.2), 13,14-dihydroprostaglandin E.sub.1, the compound
described in WO00/54808, the compound described in WO01/37877, the
compound described in JP-A-2001-181210, the compounds of formulae
(I-1), (I-2) and (I-3) described in WO00/03980. Prostaglandin
E.sub.2, the compounds of formulae (I-1), (I-2) and (I-3) is more
preferable.
[0361] Among the compounds of formula (I-3) of the present
invention, A.sup.3 is preferably A.sup.1-3 or A.sup.2-3. More
preferably, A.sup.3 is A.sup.2-3.
[0362] Among the compounds of formula (I-3) of the present
invention, G.sup.1-3 is preferably (1) C1-4 straight-chain alkylene
optionally substituted by 1-2 C1-4 alkyl, or (2) C2-4
straight-chain alkenylene optionally substituted by 1-2 C1-4 alkyl.
1) C1-4 straight-chain alkylene optionally substituted by 1-2 C1-4
alkyl is more preferable.
[0363] Among the compounds of formula (I-3) of the present
invention, G.sup.2-3 is preferably (1) --Y.sup.3--, (2)
-(ring1.sup.3)-, or (3) --Y.sup.3-(ring1.sup.3)-. 1) --Y.sup.3-- is
more preferable.
[0364] Among the compounds of formula (I-3) of the present
invention, Y.sup.3 is preferably --S-- or --O--. --S-- is more
preferable.
[0365] Among the compounds of formula (I-3) of the present
invention, G.sup.3-3 is preferably (1) bond, (2) C1-4
straight-chain alkylene optionally substituted by 1-2 C1-4 alkyl,
or (3) C2-4 straight-chain alkenylene optionally substituted by 1-2
C1-4 alkyl. (2) C1-4 straight-chain alkylene optionally substituted
by 1-2 C1-4 alkyl is more preferable.
[0366] Among the compounds of formula (I-3), T.sup.3 is preferably
oxygen atom or sulfur atom. Oxygen atom is more preferable.
[0367] Among the compounds of formula (I-3), X.sup.3 is preferably
--CH.sub.2--, --O-- or --S--. --CH.sub.2-- is more preferable.
[0368] Among the compounds of formula (I-3), D.sup.3 is preferably
--COOH, --COOR.sup.2-3, --COOR.sup.9-3--,
COO--Z.sup.1-3--Z.sup.2-3--Z.sup.3-3, tetrazol-5-yl,
##STR00019##
--COOH, --COOR.sup.2-3, --COOR.sup.9-3-- or
COO--Z.sup.1-3--Z.sup.2-3--Z.sup.3-3 is more preferable. --COOH or
COO--Z.sup.1-3--Z.sup.2-3--Z.sup.3-3 is most preferable.
[0369] Among the compounds of formula (I-3), R.sup.19-3 and
R.sup.20-3 are preferably hydrogen atom.
[0370] Among the compounds of formula (I-3), E.sup.3 is preferably
ring3.sup.3, ring4.sup.3 or ring5.sup.3.
[0371] Among the compounds of formula (I-3), ring3.sup.3 is
preferably phenyl.
[0372] Among the compounds of formula (I-3), ring4.sup.3 is
preferably phenyl.
[0373] Among the compounds of formula (I-3), ring5.sup.3 is
preferably C5-10 mono- or bi-carbocyclic aryl which may be
partially or fully saturated, or 5 to 10 membered mono- or
bi-heterocyclic aryl containing 1 to 2 hetero atom selected from
oxygen, nitrogen and sulfur atom(s) which may be partially or fully
saturated. The 5 to 10 membered mono- or bi-heterocyclic aryl
containing 1 to 2 hetero atom selected from oxygen, nitrogen and
sulfur atom(s) which may be partially or fully saturated is
preferably furan, thiophene, oxazole, thiazole, imidazole,
pyridine, pyrimidine, benzofuran, indole, benzothiazole.
[0374] Among the compounds of formula (I-3), the hydroxy of
15-position is preferably .alpha.-configuration.
[0375] Among the compounds of formula (I-3), C13-14 is preferably
double bond.
[0376] Among the compounds of formula (I-3), Z.sup.1-3 is
preferably C1-15 alkylene. C1-8 alkylene is more preferable. C1-4
alkylene is most preferable.
[0377] Among the compounds of formula (I-3), Z.sup.2-3 is
preferably --CO--, --OCO--, --COO--, --CONR.sup.11-3--,
--OCOMR.sup.17-3, -- or --OCOO--. --OCO--, --OCONR.sup.17-3,
--OCOO-- is more preferable.
[0378] Among the compounds of formula (I-3), Z.sup.3-3 is
preferably C1-15 alkyl or C1-10 alkyl substituted by C1-10 alkoxy,
C1-10 alkylthio, C1-10 alkyl-NR.sup.18-3-- or ring2.sup.3. C4-12
alkyl is more preferable.
[0379] Among the compounds of formula (I-2), R.sup.1-2 is
preferably --COO--Y.sup.2--R.sup.9-2 or
--COO--Z.sup.1-2-Z.sup.2-2--Z.sup.3-2.
COO--Z.sup.1-2--Z.sup.2-2--Z.sup.3-2 is more preferable.
[0380] Among the compounds of formula (I-2), Z.sup.1-2 is
preferably C1-15 alkylene. C1-8 alkylene is more preferable. C1-4
alkylene is most preferable.
[0381] Among the compounds of formula (1-2), Z.sup.2-2 is
preferably --CO--, --OCO--, --COO--, --CONR.sup.11-2--,
--OCONR.sup.17-2-- or --OCOO--. --OCO--, --CONR.sup.17-2-- or
--OCOO-- is more preferable.
[0382] Among the compounds of formula (I-2), Z.sup.3-2 is
preferably C1-15 alkyl, C1-10 alkyl substituted by C1-10 alkoxy,
C1-10 alkylthio, C1-10 alkyl-NR.sup.18-2-- or ring1.sup.2. C4-12
alkyl is more preferable.
[0383] Among the compounds of formula (I-3), preferable compounds
are the compound of formula (I-3-A-1)
##STR00020##
(wherein all symbols are the same meanings as defined
hereinbefore), the compound of formula (I-3-A-2)
##STR00021##
(wherein all symbols are the same meanings as defined
hereinbefore), the compound of formula (I-3-A-3)
##STR00022##
(wherein all symbols are the same meanings as defined
hereinbefore), the compound of formula (I-3-A-4)
##STR00023##
(wherein all symbols are the same meanings as defined
hereinbefore), and the compound of formula (I-3-A-5)
##STR00024##
(wherein all symbols are the same meanings as defined
hereinbefore).
[0384] Among the compounds of formula (I-2), preferable compounds
are the compound of formula (I-2-A-1)
##STR00025##
(wherein all symbols are the same meanings as defined
hereinbefore), the compound of formula (I-2-A-2)
##STR00026##
(wherein all symbols are the same meanings as defined
hereinbefore), the compound of formula (I-2-A-3)
##STR00027##
(wherein all symbols are the same meanings as defined
hereinbefore), the compound of formula (I-2-A-4)
##STR00028##
(wherein all symbols are the same meanings as defined
hereinbefore), the compound of formula (I-2-A-5)
##STR00029##
(wherein all symbols are the same meanings as defined
hereinbefore), and the compound of formula (I-2-A-6)
##STR00030##
(wherein all symbols are the same meanings as defined
hereinbefore).
[0385] Among the compounds of formula (I-1), preferable compounds
are the compound of formula (I-1-A-1)
##STR00031##
(wherein all symbols are the same meanings as defined
hereinbefore), the compound of formula (I-1-A-2)
##STR00032##
(wherein all symbols are the same meanings as defined
hereinbefore), the compound of formula (I-1-A-3)
##STR00033##
(wherein all symbols are the same meanings as defined
hereinbefore), the compound of formula (I-1-A-4)
##STR00034##
(wherein all symbols are the same meanings as defined
hereinbefore), the compound of formula (I-1-A-5)
##STR00035##
(wherein all symbols are the same meanings as defined
hereinbefore), and the compound of formula (I-1-A-6)
##STR00036##
(wherein all symbols are the same meanings as defined
hereinbefore).
[0386] Specifically, the compounds of the present invention are the
compounds shown in the following tables 1 to 120, the compounds
described in the Examples and non-toxic salts thereof.
TABLE-US-00001 TABLE 1 (I-3-A-1-1) ##STR00037## No. E.sup.3 1
##STR00038## 2 ##STR00039## 3 ##STR00040## 4 ##STR00041## 5
##STR00042## 6 ##STR00043## 7 ##STR00044## 8 ##STR00045## 9
##STR00046## 10 ##STR00047## 11 ##STR00048## 12 ##STR00049## 13
##STR00050## 14 ##STR00051## 15 ##STR00052## 16 ##STR00053## 17
##STR00054## 18 ##STR00055## 19 ##STR00056## 20 ##STR00057## 21
##STR00058## 22 ##STR00059## 23 ##STR00060## 24 ##STR00061## 25
##STR00062## 26 ##STR00063## 27 ##STR00064## 28 ##STR00065## 29
##STR00066## 30 ##STR00067## 31 ##STR00068## 32 ##STR00069## 33
##STR00070## 34 ##STR00071## 35 ##STR00072##
TABLE-US-00002 TABLE 2 (I-3-A-1-2) ##STR00073## No. E.sup.3 1
##STR00074## 2 ##STR00075## 3 ##STR00076## 4 ##STR00077## 5
##STR00078## 6 ##STR00079## 7 ##STR00080## 8 ##STR00081## 9
##STR00082## 10 ##STR00083## 11 ##STR00084## 12 ##STR00085## 13
##STR00086## 14 ##STR00087## 15 ##STR00088## 16 ##STR00089## 17
##STR00090## 18 ##STR00091## 19 ##STR00092## 20 ##STR00093## 21
##STR00094## 22 ##STR00095## 23 ##STR00096## 24 ##STR00097## 25
##STR00098## 26 ##STR00099## 27 ##STR00100## 28 ##STR00101## 29
##STR00102## 30 ##STR00103## 31 ##STR00104## 32 ##STR00105## 33
##STR00106## 34 ##STR00107## 35 ##STR00108##
TABLE-US-00003 TABLE 3 (I-3-A-1-3) ##STR00109## No. E.sup.3 1
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TABLE-US-00004 TABLE 4 (I-3-A-1-4) ##STR00145## No. E.sup.3 1
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TABLE-US-00005 TABLE 5 (I-3-A-1-5) ##STR00181## No. E.sup.3 1
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TABLE-US-00006 TABLE 6 (I-3-A-1-6) ##STR00217## No. D.sup.3 1
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TABLE-US-00007 TABLE 7 (I-3-A-1-7) ##STR00233## No. D.sup.3 1
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TABLE-US-00008 TABLE 8 (I-3-A-1-8) ##STR00249## No. D.sup.3 1
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TABLE-US-00009 TABLE 9 (I-3-A-1-9) ##STR00265## No. D.sup.3 1
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TABLE-US-00010 TABLE 10 (I-3-A-1-10) ##STR00281## No. D.sup.3 1
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TABLE-US-00011 TABLE 11 (I-3-A-2-1) ##STR00297## No. E.sup.3 1
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TABLE-US-00012 TABLE 12 (I-3-A-2-2) ##STR00333## No. E.sup.3 1
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TABLE-US-00013 TABLE 13 (I-3-A-2-3) ##STR00369## No. E.sup.3 1
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TABLE-US-00014 TABLE 14 (I-3-A-2-4) ##STR00405## No. E.sup.3 1
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TABLE-US-00015 TABLE 15 (I-3-A-2-5) ##STR00441## No. E.sup.3 1
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TABLE-US-00016 TABLE 16 (I-3-A-2-6) ##STR00477## No. D.sup.3 1
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TABLE-US-00017 TABLE 17 (I-3-A-2-7) ##STR00493## No. D.sup.3 1
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TABLE-US-00018 TABLE 18 (I-3-A-2-8) ##STR00509## No. D.sup.3 1
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TABLE-US-00019 TABLE 19 (I-3-A-2-9) ##STR00525## No. D.sup.3 1
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TABLE-US-00020 TABLE 20 (I-3-A-2-10) ##STR00541## No. D.sup.3 1
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TABLE-US-00021 TABLE 21 (I-3-A-3-1) ##STR00557## No. E.sup.3 1
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TABLE-US-00022 TABLE 22 (I-3-A-3-2) ##STR00593## No. E.sup.3 1
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TABLE-US-00023 TABLE 23 (I-3-A-3-3) ##STR00629## No. E.sup.3 1
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TABLE-US-00024 TABLE 24 (I-3-A-3-4) ##STR00665## No. E.sup.3 1
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TABLE-US-00025 TABLE 25 (I-3-A-3-5) ##STR00701## No. E.sup.3 1
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TABLE-US-00026 TABLE 26 (I-3-A-3-6) ##STR00737## No. D.sup.3 1
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TABLE-US-00027 TABLE 27 (I-3-A-3-7) ##STR00753## No. D.sup.3 1
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TABLE-US-00028 TABLE 28 (I-3-A-3-8) ##STR00769## No. D.sup.3 1
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TABLE-US-00029 TABLE 29 (I-3-A-3-9) ##STR00785## No. D.sup.3 1
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TABLE-US-00030 TABLE 30 (I-3-A-3-10) ##STR00801## No. D.sup.3 1
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TABLE-US-00031 TABLE 31 (I-3-A-4-1) ##STR00817## No. E.sup.3 1
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TABLE-US-00032 TABLE 32 (I-3-A-4-2) ##STR00853## No. E.sup.3 1
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TABLE-US-00033 TABLE 33 (I-3-A-4-3) ##STR00889## No. E.sup.3 1
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TABLE-US-00034 TABLE 34 (I-3-A-4-4) ##STR00925## No. E.sup.3 1
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TABLE-US-00035 TABLE 35 (I-3-A-4-5) ##STR00961## No. E.sup.3 1
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TABLE-US-00036 TABLE 36 (I-3-A-4-6) ##STR00997## No. D.sup.3 1
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TABLE-US-00037 TABLE 37 (I-3-A-4-7) ##STR01013## No. D.sup.3 1
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TABLE-US-00038 TABLE 38 (I-3-A-4-8) ##STR01029## No. D.sup.3 1
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TABLE-US-00039 TABLE 39 (I-3-A-4-9) ##STR01045## No. D.sup.3 1
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TABLE-US-00040 TABLE 40 (I-3-A-4-10) ##STR01061## No. D.sup.3 1
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TABLE-US-00041 TABLE 41 (I-3-A-5-1) ##STR01077## No. E.sup.3 1
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TABLE-US-00042 TABLE 42 (I-3-A-5-2) ##STR01113## No. E.sup.3 1
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TABLE-US-00043 TABLE 43 (I3-A-5-3) ##STR01149## No. E.sup.3 1
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TABLE-US-00044 TABLE 44 (I-3-A-5-4) ##STR01185## No. E.sup.3 1
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TABLE-US-00045 TABLE 45 (I-3-A-5-5) ##STR01221## No. E.sup.3 1
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TABLE-US-00046 TABLE 46 (I-3-A-5-6) ##STR01257## No. D.sup.3 1
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TABLE-US-00047 TABLE 47 (I-3-A-5-7) ##STR01273## No. D.sup.3 1
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TABLE-US-00048 TABLE 48 (I-3-A-5-8) ##STR01289## No. D.sup.3 1
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TABLE-US-00049 TABLE 49 (I-3-A-5-9) ##STR01305## No. D.sup.3 1
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TABLE-US-00050 TABLE 50 (I-3-A-5-10) ##STR01321## No. D.sup.3 1
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TABLE-US-00051 TABLE 51 (I-3-A-1-11) ##STR01337## No. E.sup.3 1
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TABLE-US-00052 TABLE 52 (I-3-A-2-11) ##STR01373## No. E.sup.3 1
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TABLE-US-00053 TABLE 53 (I-3-A-3-11) ##STR01409## No. E.sup.3 1
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TABLE-US-00054 TABLE 54 (I-3-A-4-11) ##STR01445## No. E.sup.3 1
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##STR01478## 34 ##STR01479## 35 ##STR01480##
TABLE-US-00055 TABLE 55 (I-3-A-1-12) ##STR01481## No. E.sup.3 1
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##STR01514## 34 ##STR01515## 35 ##STR01516##
TABLE-US-00056 TABLE 56 (I-3-A-2-12) ##STR01517## No. E.sup.3 1
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##STR01550## 34 ##STR01551## 35 ##STR01552##
TABLE-US-00057 TABLE 57 (I-3-A-3-12) ##STR01553## No. E.sup.3 1
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##STR01586## 34 ##STR01587## 35 ##STR01588##
TABLE-US-00058 TABLE 58 (I-3-A-4-12) ##STR01589## No. E.sup.3 1
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##STR01622## 34 ##STR01623## 35 ##STR01624##
TABLE-US-00059 TABLE 59 (I-3-A-1-13) ##STR01625## No. E.sup.3 1
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##STR01658## 34 ##STR01659## 35 ##STR01660##
TABLE-US-00060 TABLE 60 (I-3-A-2-13) ##STR01661## No. E.sup.3 1
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##STR01694## 34 ##STR01695## 35 ##STR01696##
TABLE-US-00061 TABLE 61 (I-3-A-3-13) ##STR01697## No. E.sup.3 1
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##STR01730## 34 ##STR01731## 35 ##STR01732##
TABLE-US-00062 TABLE 62 (I-3-A-4-13) ##STR01733## No. E.sup.3 1
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##STR01766## 34 ##STR01767## 35 ##STR01768##
TABLE-US-00063 TABLE 63 (I-3-A-1-14) ##STR01769## No. E.sup.3 1
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##STR01802## 34 ##STR01803## 35 ##STR01804##
TABLE-US-00064 TABLE 64 (I-3-A-2-14) ##STR01805## No. E.sup.3 1
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##STR01838## 34 ##STR01839## 35 ##STR01840##
TABLE-US-00065 TABLE 65 (I-3-A-3-14) ##STR01841## No. E.sup.3 1
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##STR01874## 34 ##STR01875## 35 ##STR01876##
TABLE-US-00066 TABLE 66 (I-3-A-4-14) ##STR01877## No. E.sup.3 1
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##STR01882## 6 ##STR01883## 7 ##STR01884## 8 ##STR01885## 9
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##STR01910## 34 ##STR01911## 35 ##STR01912##
TABLE-US-00067 TABLE 67 (I-2-A-1-1) ##STR01913## No. R.sup.5-1 1
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##STR01922## 10 ##STR01923## 11 ##STR01924## 12 ##STR01925## 13
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##STR01930## 18 ##STR01931## 19 ##STR01932## 20 ##STR01933## 21
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##STR01942## 30 ##STR01943##
TABLE-US-00068 TABLE 68 (I-2-A-1-2) ##STR01944## No. R.sup.5-1 1
##STR01945## 2 ##STR01946## 3 ##STR01947## 4 ##STR01948## 5
##STR01949## 6 ##STR01950## 7 ##STR01951## 8 ##STR01952## 9
##STR01953## 10 ##STR01954## 11 ##STR01955## 12 ##STR01956## 13
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##STR01969## 26 ##STR01970## 27 ##STR01971## 28 ##STR01972## 29
##STR01973## 30 ##STR01974##
TABLE-US-00069 TABLE 69 (I-2-A-1-3) ##STR01975## No. R.sup.5-1 1
##STR01976## 2 ##STR01977## 3 ##STR01978## 4 ##STR01979## 5
##STR01980## 6 ##STR01981## 7 ##STR01982## 8 ##STR01983## 9
##STR01984## 10 ##STR01985## 11 ##STR01986## 12 ##STR01987## 13
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##STR02000## 26 ##STR02001## 27 ##STR02002## 28 ##STR02003## 29
##STR02004## 30 ##STR02005##
TABLE-US-00070 TABLE 70 (I-2-A-1-4) ##STR02006## No. R.sup.5-1 1
##STR02007## 2 ##STR02008## 3 ##STR02009## 4 ##STR02010## 5
##STR02011## 6 ##STR02012## 7 ##STR02013## 8 ##STR02014## 9
##STR02015## 10 ##STR02016## 11 ##STR02017## 12 ##STR02018## 13
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##STR02035## 30 ##STR02036##
TABLE-US-00071 TABLE 71 (I-2-A-1-5) ##STR02037## No. R.sup.1-2 1
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##STR02042## 6 ##STR02043## 7 ##STR02044## 8 ##STR02045## 9
##STR02046## 10 ##STR02047## 11 ##STR02048## 12 ##STR02049## 13
##STR02050## 14 ##STR02051## 15 ##STR02052##
TABLE-US-00072 TABLE 72 (I-2-A-1-6) ##STR02053## No. R.sup.1-2 1
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##STR02058## 6 ##STR02059## 7 ##STR02060## 8 ##STR02061## 9
##STR02062## 10 ##STR02063## 11 ##STR02064## 12 ##STR02065## 13
##STR02066## 14 ##STR02067## 15 ##STR02068##
TABLE-US-00073 TABLE 73 (I-2-A-1-7) ##STR02069## No. R.sup.1-2 1
##STR02070## 2 ##STR02071## 3 ##STR02072## 4 ##STR02073## 5
##STR02074## 6 ##STR02075## 7 ##STR02076## 8 ##STR02077## 9
##STR02078## 10 ##STR02079## 11 ##STR02080## 12 ##STR02081## 13
##STR02082## 14 ##STR02083## 15 ##STR02084##
TABLE-US-00074 TABLE 74 (I-2-A-2-1) ##STR02085## No. R.sup.5-1 1
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##STR02090## 6 ##STR02091## 7 ##STR02092## 8 ##STR02093## 9
##STR02094## 10 ##STR02095## 11 ##STR02096## 12 ##STR02097## 13
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##STR02114## 30 ##STR02115##
TABLE-US-00075 TABLE 75 (I-2-A-2-2) ##STR02116## No. R.sup.5-1 1
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##STR02121## 6 ##STR02122## 7 ##STR02123## 8 ##STR02124## 9
##STR02125## 10 ##STR02126## 11 ##STR02127## 12 ##STR02128## 13
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##STR02133## 18 ##STR02134## 19 ##STR02135## 20 ##STR02136## 21
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##STR02141## 26 ##STR02142## 27 ##STR02143## 28 ##STR02144## 29
##STR02145## 30 ##STR02146##
TABLE-US-00076 TABLE 76 (I-2-A-2-3) ##STR02147## No. R.sup.5-1 1
##STR02148## 2 ##STR02149## 3 ##STR02150## 4 ##STR02151## 5
##STR02152## 6 ##STR02153## 7 ##STR02154## 8 ##STR02155## 9
##STR02156## 10 ##STR02157## 11 ##STR02158## 12 ##STR02159## 13
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##STR02172## 26 ##STR02173## 27 ##STR02174## 28 ##STR02175## 29
##STR02176## 30 ##STR02177##
TABLE-US-00077 TABLE 77 (I-2-A-2-4) ##STR02178## No. R.sup.5-1 1
##STR02179## 2 ##STR02180## 3 ##STR02181## 4 ##STR02182## 5
##STR02183## 6 ##STR02184## 7 ##STR02185## 8 ##STR02186## 9
##STR02187## 10 ##STR02188## 11 ##STR02189## 12 ##STR02190## 13
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##STR02207## 30 ##STR02208##
TABLE-US-00078 TABLE 78 (I-2-A-2-5) ##STR02209## No. R.sup.1-2 1
##STR02210## 2 ##STR02211## 3 ##STR02212## 4 ##STR02213## 5
##STR02214## 6 ##STR02215## 7 ##STR02216## 8 ##STR02217## 9
##STR02218## 10 ##STR02219## 11 ##STR02220## 12 ##STR02221## 13
##STR02222## 14 ##STR02223## 15 ##STR02224##
TABLE-US-00079 TABLE 79 (I-2-A-2-6) ##STR02225## No. R.sup.1-2 1
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##STR02230## 6 ##STR02231## 7 ##STR02232## 8 ##STR02233## 9
##STR02234## 10 ##STR02235## 11 ##STR02236## 12 ##STR02237## 13
##STR02238## 14 ##STR02239## 15 ##STR02240##
TABLE-US-00080 TABLE 80 (I-2-A-2-7) ##STR02241## No. R.sup.1-2 1
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##STR02246## 6 ##STR02247## 7 ##STR02248## 8 ##STR02249## 9
##STR02250## 10 ##STR02251## 11 ##STR02252## 12 ##STR02253## 13
##STR02254## 14 ##STR02255## 15 ##STR02256##
TABLE-US-00081 TABLE 81 (I-2-A-3-1) ##STR02257## No. R.sup.5-1 1
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##STR02266## 10 ##STR02267## 11 ##STR02268## 12 ##STR02269## 13
##STR02270## 14 ##STR02271## 15 ##STR02272## 16 ##STR02273## 17
##STR02274## 18 ##STR02275## 19 ##STR02276## 20 ##STR02277## 21
##STR02278## 22 ##STR02279## 23 ##STR02280## 24 ##STR02281## 25
##STR02282## 26 ##STR02283## 27 ##STR02284## 28 ##STR02285## 29
##STR02286## 30 ##STR02287##
TABLE-US-00082 TABLE 82 (I-2-A-3-2) ##STR02288## No. R.sup.5-1 1
##STR02289## 2 ##STR02290## 3 ##STR02291## 4 ##STR02292## 5
##STR02293## 6 ##STR02294## 7 ##STR02295## 8 ##STR02296## 9
##STR02297## 10 ##STR02298## 11 ##STR02299## 12 ##STR02300## 13
##STR02301## 14 ##STR02302## 15 ##STR02303## 16 ##STR02304## 17
##STR02305## 18 ##STR02306## 19 ##STR02307## 20 ##STR02308## 21
##STR02309## 22 ##STR02310## 23 ##STR02311## 24 ##STR02312## 25
##STR02313## 26 ##STR02314## 27 ##STR02315## 28 ##STR02316## 29
##STR02317## 30 ##STR02318##
TABLE-US-00083 TABLE 83 (I-2-A-3-3) ##STR02319## No. R.sup.5-1 1
##STR02320## 2 ##STR02321## 3 ##STR02322## 4 ##STR02323## 5
##STR02324## 6 ##STR02325## 7 ##STR02326## 8 ##STR02327## 9
##STR02328## 10 ##STR02329## 11 ##STR02330## 12 ##STR02331## 13
##STR02332## 14 ##STR02333## 15 ##STR02334## 16 ##STR02335## 17
##STR02336## 18 ##STR02337## 19 ##STR02338## 20 ##STR02339## 21
##STR02340## 22 ##STR02341## 23 ##STR02342## 24 ##STR02343## 25
##STR02344## 26 ##STR02345## 27 ##STR02346## 28 ##STR02347## 29
##STR02348## 30 ##STR02349##
TABLE-US-00084 TABLE 84 (I-2-A-3-4) ##STR02350## No. R.sup.5-1 1
##STR02351## 2 ##STR02352## 3 ##STR02353## 4 ##STR02354## 5
##STR02355## 6 ##STR02356## 7 ##STR02357## 8 ##STR02358## 9
##STR02359## 10 ##STR02360## 11 ##STR02361## 12 ##STR02362## 13
##STR02363## 14 ##STR02364## 15 ##STR02365## 16 ##STR02366## 17
##STR02367## 18 ##STR02368## 19 ##STR02369## 20 ##STR02370## 21
##STR02371## 22 ##STR02372## 23 ##STR02373## 24 ##STR02374## 25
##STR02375## 26 ##STR02376## 27 ##STR02377## 28 ##STR02378## 29
##STR02379## 30 ##STR02380##
TABLE-US-00085 TABLE 85 (I-2-A-3-5) ##STR02381## No. R.sup.1-2 1
##STR02382## 2 ##STR02383## 3 ##STR02384## 4 ##STR02385## 5
##STR02386## 6 ##STR02387## 7 ##STR02388## 8 ##STR02389## 9
##STR02390## 10 ##STR02391## 11 ##STR02392## 12 ##STR02393## 13
##STR02394## 14 ##STR02395## 15 ##STR02396##
TABLE-US-00086 TABLE 86 (I-2-A-3-6) ##STR02397## No. R.sup.1-2 1
##STR02398## 2 ##STR02399## 3 ##STR02400## 4 ##STR02401## 5
##STR02402## 6 ##STR02403## 7 ##STR02404## 8 ##STR02405## 9
##STR02406## 10 ##STR02407## 11 ##STR02408## 12 ##STR02409## 13
##STR02410## 14 ##STR02411## 15 ##STR02412##
TABLE-US-00087 TABLE 87 (I-2-A-3-7) ##STR02413## No. R.sup.1-2 1
##STR02414## 2 ##STR02415## 3 ##STR02416## 4 ##STR02417## 5
##STR02418## 6 ##STR02419## 7 ##STR02420## 8 ##STR02421## 9
##STR02422## 10 ##STR02423## 11 ##STR02424## 12 ##STR02425## 13
##STR02426## 14 ##STR02427## 15 ##STR02428##
TABLE-US-00088 TABLE 88 (I-2-A-4-1) ##STR02429## No. R.sup.5-1 1
##STR02430## 2 ##STR02431## 3 ##STR02432## 4 ##STR02433## 5
##STR02434## 6 ##STR02435## 7 ##STR02436## 8 ##STR02437## 9
##STR02438## 10 ##STR02439## 11 ##STR02440## 12 ##STR02441## 13
##STR02442## 14 ##STR02443## 15 ##STR02444## 16 ##STR02445## 17
##STR02446## 18 ##STR02447## 19 ##STR02448## 20 ##STR02449## 21
##STR02450## 22 ##STR02451## 23 ##STR02452## 24 ##STR02453## 25
##STR02454## 26 ##STR02455## 27 ##STR02456## 28 ##STR02457## 29
##STR02458## 30 ##STR02459##
TABLE-US-00089 TABLE 89 (I-2-A-4-2) ##STR02460## No. R.sup.5-1 1
##STR02461## 2 ##STR02462## 3 ##STR02463## 4 ##STR02464## 5
##STR02465## 6 ##STR02466## 7 ##STR02467## 8 ##STR02468## 9
##STR02469## 10 ##STR02470## 11 ##STR02471## 12 ##STR02472## 13
##STR02473## 14 ##STR02474## 15 ##STR02475## 16 ##STR02476## 17
##STR02477## 18 ##STR02478## 19 ##STR02479## 20 ##STR02480## 21
##STR02481## 22 ##STR02482## 23 ##STR02483## 24 ##STR02484## 25
##STR02485## 26 ##STR02486## 27 ##STR02487## 28 ##STR02488## 29
##STR02489## 30 ##STR02490##
TABLE-US-00090 TABLE 90 (I-2-A-4-3) ##STR02491## No. R.sup.5-1 1
##STR02492## 2 ##STR02493## 3 ##STR02494## 4 ##STR02495## 5
##STR02496## 6 ##STR02497## 7 ##STR02498## 8 ##STR02499## 9
##STR02500## 10 ##STR02501## 11 ##STR02502## 12 ##STR02503## 13
##STR02504## 14 ##STR02505## 15 ##STR02506## 16 ##STR02507## 17
##STR02508## 18 ##STR02509## 19 ##STR02510## 20 ##STR02511## 21
##STR02512## 22 ##STR02513## 23 ##STR02514## 24 ##STR02515## 25
##STR02516## 26 ##STR02517## 27 ##STR02518## 28 ##STR02519## 29
##STR02520## 30 ##STR02521##
TABLE-US-00091 TABLE 91 (I-2-A-4-4) ##STR02522## No. R.sup.5-1 1
##STR02523## 2 ##STR02524## 3 ##STR02525## 4 ##STR02526## 5
##STR02527## 6 ##STR02528## 7 ##STR02529## 8 ##STR02530## 9
##STR02531## 10 ##STR02532## 11 ##STR02533## 12 ##STR02534## 13
##STR02535## 14 ##STR02536## 15 ##STR02537## 16 ##STR02538## 17
##STR02539## 18 ##STR02540## 19 ##STR02541## 20 ##STR02542## 21
##STR02543## 22 ##STR02544## 23 ##STR02545## 24 ##STR02546## 25
##STR02547## 26 ##STR02548## 27 ##STR02549## 28 ##STR02550## 29
##STR02551## 30 ##STR02552##
TABLE-US-00092 TABLE 92 (I-2-A-4-5) ##STR02553## No. R.sup.1-2 1
##STR02554## 2 ##STR02555## 3 ##STR02556## 4 ##STR02557## 5
##STR02558## 6 ##STR02559## 7 ##STR02560## 8 ##STR02561## 9
##STR02562## 10 ##STR02563## 11 ##STR02564## 12 ##STR02565## 13
##STR02566## 14 ##STR02567## 15 ##STR02568##
TABLE-US-00093 TABLE 93 (I-2-A-4-6) ##STR02569## No. R.sup.1-2 1
##STR02570## 2 ##STR02571## 3 ##STR02572## 4 ##STR02573## 5
##STR02574## 6 ##STR02575## 7 ##STR02576## 8 ##STR02577## 9
##STR02578## 10 ##STR02579## 11 ##STR02580## 12 ##STR02581## 13
##STR02582## 14 ##STR02583## 15 ##STR02584##
TABLE-US-00094 TABLE 94 (I-2-A-4-7) ##STR02585## No. R.sup.1-2 1
##STR02586## 2 ##STR02587## 3 ##STR02588## 4 ##STR02589## 5
##STR02590## 6 ##STR02591## 7 ##STR02592## 8 ##STR02593## 9
##STR02594## 10 ##STR02595## 11 ##STR02596## 12 ##STR02597## 13
##STR02598## 14 ##STR02599## 15 ##STR02600##
TABLE-US-00095 TABLE 95 (I-2-A-5-1) ##STR02601## No. R.sup.5-1 1
##STR02602## 2 ##STR02603## 3 ##STR02604## 4 ##STR02605## 5
##STR02606## 6 ##STR02607## 7 ##STR02608## 8 ##STR02609## 9
##STR02610## 10 ##STR02611## 11 ##STR02612## 12 ##STR02613## 13
##STR02614## 14 ##STR02615## 15 ##STR02616## 16 ##STR02617## 17
##STR02618## 18 ##STR02619## 19 ##STR02620## 20 ##STR02621## 21
##STR02622## 22 ##STR02623## 23 ##STR02624## 24 ##STR02625## 25
##STR02626## 26 ##STR02627## 27 ##STR02628## 28 ##STR02629## 29
##STR02630## 30 ##STR02631##
TABLE-US-00096 TABLE 96 (I-2-A-5-2) ##STR02632## No. R.sup.5-1 1
##STR02633## 2 ##STR02634## 3 ##STR02635## 4 ##STR02636## 5
##STR02637## 6 ##STR02638## 7 ##STR02639## 8 ##STR02640## 9
##STR02641## 10 ##STR02642## 11 ##STR02643## 12 ##STR02644## 13
##STR02645## 14 ##STR02646## 15 ##STR02647## 16 ##STR02648## 17
##STR02649## 18 ##STR02650## 19 ##STR02651## 20 ##STR02652## 21
##STR02653## 22 ##STR02654## 23 ##STR02655## 24 ##STR02656## 25
##STR02657## 26 ##STR02658## 27 ##STR02659## 28 ##STR02660## 29
##STR02661## 30 ##STR02662##
TABLE-US-00097 TABLE 97 (I-2-A-5-3) ##STR02663## No. R.sup.5-1 1
##STR02664## 2 ##STR02665## 3 ##STR02666## 4 ##STR02667## 5
##STR02668## 6 ##STR02669## 7 ##STR02670## 8 ##STR02671## 9
##STR02672## 10 ##STR02673## 11 ##STR02674## 12 ##STR02675## 13
##STR02676## 14 ##STR02677## 15 ##STR02678## 16 ##STR02679## 17
##STR02680## 18 ##STR02681## 19 ##STR02682## 20 ##STR02683## 21
##STR02684## 22 ##STR02685## 23 ##STR02686## 24 ##STR02687## 25
##STR02688## 26 ##STR02689## 27 ##STR02690## 28 ##STR02691## 29
##STR02692## 30 ##STR02693##
TABLE-US-00098 TABLE 98 (I-2-A-4-4) ##STR02694## No. R.sup.5-1 1
##STR02695## 2 ##STR02696## 3 ##STR02697## 4 ##STR02698## 5
##STR02699## 6 ##STR02700## 7 ##STR02701## 8 ##STR02702## 9
##STR02703## 10 ##STR02704## 11 ##STR02705## 12 ##STR02706## 13
##STR02707## 14 ##STR02708## 15 ##STR02709## 16 ##STR02710## 17
##STR02711## 18 ##STR02712## 19 ##STR02713## 20 ##STR02714## 21
##STR02715## 22 ##STR02716## 23 ##STR02717## 24 ##STR02718## 25
##STR02719## 26 ##STR02720## 27 ##STR02721## 28 ##STR02722## 29
##STR02723## 30 ##STR02724##
TABLE-US-00099 TABLE 99 (I-2-A-5-5) ##STR02725## No. R.sup.1-2 1
##STR02726## 2 ##STR02727## 3 ##STR02728## 4 ##STR02729## 5
##STR02730## 6 ##STR02731## 7 ##STR02732## 8 ##STR02733## 9
##STR02734## 10 ##STR02735## 11 ##STR02736## 12 ##STR02737## 13
##STR02738## 14 ##STR02739## 15 ##STR02740##
TABLE-US-00100 TABLE 100 (I-2-A-5-6) ##STR02741## No. R.sup.1-2 1
##STR02742## 2 ##STR02743## 3 ##STR02744## 4 ##STR02745## 5
##STR02746## 6 ##STR02747## 7 ##STR02748## 8 ##STR02749## 9
##STR02750## 10 ##STR02751## 11 ##STR02752## 12 ##STR02753## 13
##STR02754## 14 ##STR02755## 15 ##STR02756##
TABLE-US-00101 TABLE 101 (I-2-A-5-7) ##STR02757## No. R.sup.1-2 1
##STR02758## 2 ##STR02759## 3 ##STR02760## 4 ##STR02761## 5
##STR02762## 6 ##STR02763## 7 ##STR02764## 8 ##STR02765## 9
##STR02766## 10 ##STR02767## 11 ##STR02768## 12 ##STR02769## 13
##STR02770## 14 ##STR02771## 15 ##STR02772##
TABLE-US-00102 TABLE 102 (I-2-A-6-1) ##STR02773## No. R.sup.5-1 1
##STR02774## 2 ##STR02775## 3 ##STR02776## 4 ##STR02777## 5
##STR02778## 6 ##STR02779## 7 ##STR02780## 8 ##STR02781## 9
##STR02782## 10 ##STR02783## 11 ##STR02784## 12 ##STR02785## 13
##STR02786## 14 ##STR02787## 15 ##STR02788## 16 ##STR02789## 17
##STR02790## 18 ##STR02791## 19 ##STR02792## 20 ##STR02793## 21
##STR02794## 22 ##STR02795## 23 ##STR02796## 24 ##STR02797## 25
##STR02798## 26 ##STR02799## 27 ##STR02800## 28 ##STR02801## 29
##STR02802## 30 ##STR02803##
TABLE-US-00103 TABLE 103 (I-2-A-6-2) ##STR02804## No. R.sup.5-1 1
##STR02805## 2 ##STR02806## 3 ##STR02807## 4 ##STR02808## 5
##STR02809## 6 ##STR02810## 7 ##STR02811## 8 ##STR02812## 9
##STR02813## 10 ##STR02814## 11 ##STR02815## 12 ##STR02816## 13
##STR02817## 14 ##STR02818## 15 ##STR02819## 16 ##STR02820## 17
##STR02821## 18 ##STR02822## 19 ##STR02823## 20 ##STR02824## 21
##STR02825## 22 ##STR02826## 23 ##STR02827## 24 ##STR02828## 25
##STR02829## 26 ##STR02830## 27 ##STR02831## 28 ##STR02832## 29
##STR02833## 30 ##STR02834##
TABLE-US-00104 TABLE 104 (I-2-A-6-3) ##STR02835## No. R.sup.5-1 1
##STR02836## 2 ##STR02837## 3 ##STR02838## 4 ##STR02839## 5
##STR02840## 6 ##STR02841## 7 ##STR02842## 8 ##STR02843## 9
##STR02844## 10 ##STR02845## 11 ##STR02846## 12 ##STR02847## 13
##STR02848## 14 ##STR02849## 15 ##STR02850## 16 ##STR02851## 17
##STR02852## 18 ##STR02853## 19 ##STR02854## 20 ##STR02855## 21
##STR02856## 22 ##STR02857## 23 ##STR02858## 24 ##STR02859## 25
##STR02860## 26 ##STR02861## 27 ##STR02862## 28 ##STR02863## 29
##STR02864## 30 ##STR02865##
TABLE-US-00105 TABLE 105 (I-2-A-6-4) ##STR02866## No. R.sup.5-1 1
##STR02867## 2 ##STR02868## 3 ##STR02869## 4 ##STR02870## 5
##STR02871## 6 ##STR02872## 7 ##STR02873## 8 ##STR02874## 9
##STR02875## 10 ##STR02876## 11 ##STR02877## 12 ##STR02878## 13
##STR02879## 14 ##STR02880## 15 ##STR02881## 16 ##STR02882## 17
##STR02883## 18 ##STR02884## 19 ##STR02885## 20 ##STR02886## 21
##STR02887## 22 ##STR02888## 23 ##STR02889## 24 ##STR02890## 25
##STR02891## 26 ##STR02892## 27 ##STR02893## 28 ##STR02894## 29
##STR02895## 30 ##STR02896##
TABLE-US-00106 TABLE 106 (I-2-A-6-5) ##STR02897## No. R.sup.1-2 1
##STR02898## 2 ##STR02899## 3 ##STR02900## 4 ##STR02901## 5
##STR02902## 6 ##STR02903## 7 ##STR02904## 8 ##STR02905## 9
##STR02906## 10 ##STR02907## 11 ##STR02908## 12 ##STR02909## 13
##STR02910## 14 ##STR02911## 15 ##STR02912##
TABLE-US-00107 TABLE 107 (I-2-A-6-6) ##STR02913## No. R.sup.1-2 1
##STR02914## 2 ##STR02915## 3 ##STR02916## 4 ##STR02917## 5
##STR02918## 6 ##STR02919## 7 ##STR02920## 8 ##STR02921## 9
##STR02922## 10 ##STR02923## 11 ##STR02924## 12 ##STR02925## 13
##STR02926## 14 ##STR02927## 15 ##STR02928##
TABLE-US-00108 TABLE 108 (I-2-A-6-7) ##STR02929## No. R.sup.1-2 1
##STR02930## 2 ##STR02931## 3 ##STR02932## 4 ##STR02933## 5
##STR02934## 6 ##STR02935## 7 ##STR02936## 8 ##STR02937## 9
##STR02938## 10 ##STR02939## 11 ##STR02940## 12 ##STR02941## 13
##STR02942## 14 ##STR02943## 15 ##STR02944##
TABLE-US-00109 TABLE 109 (I-1-A-1-1) ##STR02945## No. R.sup.5-1 1
##STR02946## 2 ##STR02947## 3 ##STR02948## 4 ##STR02949## 5
##STR02950## 6 ##STR02951## 7 ##STR02952## 8 ##STR02953## 9
##STR02954## 10 ##STR02955## 11 ##STR02956## 12 ##STR02957## 13
##STR02958## 14 ##STR02959## 15 ##STR02960## 16 ##STR02961## 17
##STR02962## 18 ##STR02963## 19 ##STR02964## 20 ##STR02965## 21
##STR02966## 22 ##STR02967## 23 ##STR02968## 24 ##STR02969## 25
##STR02970## 26 ##STR02971## 27 ##STR02972## 28 ##STR02973## 29
##STR02974## 30 ##STR02975##
TABLE-US-00110 TABLE 110 (I-1-A-1-2) ##STR02976## No. R.sup.5-1 1
##STR02977## 2 ##STR02978## 3 ##STR02979## 4 ##STR02980## 5
##STR02981## 6 ##STR02982## 7 ##STR02983## 8 ##STR02984## 9
##STR02985## 10 ##STR02986## 11 ##STR02987## 12 ##STR02988## 13
##STR02989## 14 ##STR02990## 15 ##STR02991## 16 ##STR02992## 17
##STR02993## 18 ##STR02994## 19 ##STR02995## 20 ##STR02996## 21
##STR02997## 22 ##STR02998## 23 ##STR02999## 24 ##STR03000## 25
##STR03001## 26 ##STR03002## 27 ##STR03003## 28 ##STR03004## 29
##STR03005## 30 ##STR03006##
TABLE-US-00111 TABLE 111 (I-1-A-2-1) ##STR03007## No. R.sup.5-1 1
##STR03008## 2 ##STR03009## 3 ##STR03010## 4 ##STR03011## 5
##STR03012## 6 ##STR03013## 7 ##STR03014## 8 ##STR03015## 9
##STR03016## 10 ##STR03017## 11 ##STR03018## 12 ##STR03019## 13
##STR03020## 14 ##STR03021## 15 ##STR03022## 16 ##STR03023## 17
##STR03024## 18 ##STR03025## 19 ##STR03026## 20 ##STR03027## 21
##STR03028## 22 ##STR03029## 23 ##STR03030## 24 ##STR03031## 25
##STR03032## 26 ##STR03033## 27 ##STR03034## 28 ##STR03035## 29
##STR03036## 30 ##STR03037##
TABLE-US-00112 TABLE 112 (I-1-A-2-2) ##STR03038## No. R.sup.5-1 1
##STR03039## 2 ##STR03040## 3 ##STR03041## 4 ##STR03042## 5
##STR03043## 6 ##STR03044## 7 ##STR03045## 8 ##STR03046## 9
##STR03047## 10 ##STR03048## 11 ##STR03049## 12 ##STR03050## 13
##STR03051## 14 ##STR03052## 15 ##STR03053## 16 ##STR03054## 17
##STR03055## 18 ##STR03056## 19 ##STR03057## 20 ##STR03058## 21
##STR03059## 22 ##STR03060## 23 ##STR03061## 24 ##STR03062## 25
##STR03063## 26 ##STR03064## 27 ##STR03065## 28 ##STR03066## 29
##STR03067## 30 ##STR03068##
TABLE-US-00113 TABLE 113 (I-1-A-3-1) ##STR03069## No. R.sup.5-1 1
##STR03070## 2 ##STR03071## 3 ##STR03072## 4 ##STR03073## 5
##STR03074## 6 ##STR03075## 7 ##STR03076## 8 ##STR03077## 9
##STR03078## 10 ##STR03079## 11 ##STR03080## 12 ##STR03081## 13
##STR03082## 14 ##STR03083## 15 ##STR03084## 16 ##STR03085## 17
##STR03086## 18 ##STR03087## 19 ##STR03088## 20 ##STR03089## 21
##STR03090## 22 ##STR03091## 23 ##STR03092## 24 ##STR03093## 25
##STR03094## 26 ##STR03095## 27 ##STR03096## 28 ##STR03097## 29
##STR03098## 30 ##STR03099##
TABLE-US-00114 TABLE 114 (I-1-A-3-2) ##STR03100## No. R.sup.5-1 1
##STR03101## 2 ##STR03102## 3 ##STR03103## 4 ##STR03104## 5
##STR03105## 6 ##STR03106## 7 ##STR03107## 8 ##STR03108## 9
##STR03109## 10 ##STR03110## 11 ##STR03111## 12 ##STR03112## 13
##STR03113## 14 ##STR03114## 15 ##STR03115## 16 ##STR03116## 17
##STR03117## 18 ##STR03118## 19 ##STR03119## 20 ##STR03120## 21
##STR03121## 22 ##STR03122## 23 ##STR03123## 24 ##STR03124## 25
##STR03125## 26 ##STR03126## 27 ##STR03127## 28 ##STR03128## 29
##STR03129## 30 ##STR03130##
TABLE-US-00115 TABLE 115 (I-1-A-4-1) ##STR03131## No. R.sup.5-1 1
##STR03132## 2 ##STR03133## 3 ##STR03134## 4 ##STR03135## 5
##STR03136## 6 ##STR03137## 7 ##STR03138## 8 ##STR03139## 9
##STR03140## 10 ##STR03141## 11 ##STR03142## 12 ##STR03143## 13
##STR03144## 14 ##STR03145## 15 ##STR03146## 16 ##STR03147## 17
##STR03148## 18 ##STR03149## 19 ##STR03150## 20 ##STR03151## 21
##STR03152## 22 ##STR03153## 23 ##STR03154## 24 ##STR03155## 25
##STR03156## 26 ##STR03157## 27 ##STR03158## 28 ##STR03159## 29
##STR03160## 30 ##STR03161##
TABLE-US-00116 TABLE 116 (I-1-A-4-2) ##STR03162## No. R.sup.5-1 1
##STR03163## 2 ##STR03164## 3 ##STR03165## 4 ##STR03166## 5
##STR03167## 6 ##STR03168## 7 ##STR03169## 8 ##STR03170## 9
##STR03171## 10 ##STR03172## 11 ##STR03173## 12 ##STR03174## 13
##STR03175## 14 ##STR03176## 15 ##STR03177## 16 ##STR03178## 17
##STR03179## 18 ##STR03180## 19 ##STR03181## 20 ##STR03182## 21
##STR03183## 22 ##STR03184## 23 ##STR03185## 24 ##STR03186## 25
##STR03187## 26 ##STR03188## 27 ##STR03189## 28 ##STR03190## 29
##STR03191## 30 ##STR03192##
TABLE-US-00117 TABLE 117 (I-1-A-5-1) ##STR03193## No. R.sup.5-1 1
##STR03194## 2 ##STR03195## 3 ##STR03196## 4 ##STR03197## 5
##STR03198## 6 ##STR03199## 7 ##STR03200## 8 ##STR03201## 9
##STR03202## 10 ##STR03203## 11 ##STR03204## 12 ##STR03205## 13
##STR03206## 14 ##STR03207## 15 ##STR03208## 16 ##STR03209## 17
##STR03210## 18 ##STR03211## 19 ##STR03212## 20 ##STR03213## 21
##STR03214## 22 ##STR03215## 23 ##STR03216## 24 ##STR03217## 25
##STR03218## 26 ##STR03219## 27 ##STR03220## 28 ##STR03221## 29
##STR03222## 30 ##STR03223##
TABLE-US-00118 TABLE 118 (I-1-A-5-2) ##STR03224## No. R.sup.5-1 1
##STR03225## 2 ##STR03226## 3 ##STR03227## 4 ##STR03228## 5
##STR03229## 6 ##STR03230## 7 ##STR03231## 8 ##STR03232## 9
##STR03233## 10 ##STR03234## 11 ##STR03235## 12 ##STR03236## 13
##STR03237## 14 ##STR03238## 15 ##STR03239## 16 ##STR03240## 17
##STR03241## 18 ##STR03242## 19 ##STR03243## 20 ##STR03244## 21
##STR03245## 22 ##STR03246## 23 ##STR03247## 24 ##STR03248## 25
##STR03249## 26 ##STR03250## 27 ##STR03251## 28 ##STR03252## 29
##STR03253## 30 ##STR03254##
TABLE-US-00119 TABLE 119 (I-1-A-6-1) ##STR03255## No. R.sup.5-1 1
##STR03256## 2 ##STR03257## 3 ##STR03258## 4 ##STR03259## 5
##STR03260## 6 ##STR03261## 7 ##STR03262## 8 ##STR03263## 9
##STR03264## 10 ##STR03265## 11 ##STR03266## 12 ##STR03267## 13
##STR03268## 14 ##STR03269## 15 ##STR03270## 16 ##STR03271## 17
##STR03272## 18 ##STR03273## 19 ##STR03274## 20 ##STR03275## 21
##STR03276## 22 ##STR03277## 23 ##STR03278## 24 ##STR03279## 25
##STR03280## 26 ##STR03281## 27 ##STR03282## 28 ##STR03283## 29
##STR03284## 30 ##STR03285##
TABLE-US-00120 TABLE 120 (I-1-A-6-2) ##STR03286## No. R.sup.5-1 1
##STR03287## 2 ##STR03288## 3 ##STR03289## 4 ##STR03290## 5
##STR03291## 6 ##STR03292## 7 ##STR03293## 8 ##STR03294## 9
##STR03295## 10 ##STR03296## 11 ##STR03297## 12 ##STR03298## 13
##STR03299## 14 ##STR03300## 15 ##STR03301## 16 ##STR03302## 17
##STR03303## 18 ##STR03304## 19 ##STR03305## 20 ##STR03306## 21
##STR03307## 22 ##STR03308## 23 ##STR03309## 24 ##STR03310## 25
##STR03311## 26 ##STR03312## 27 ##STR03313## 28 ##STR03314## 29
##STR03315## 30 ##STR03316##
[0387] Among the compounds of formula (I-1), preferable compounds
are the compound described in the Example of WO00/03980. More
preferable compounds are the Compound (1) to (8) listed below.
Compound (1)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid methyl ester
##STR03317##
[0388] Compound (2)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methyl-4-hydroxyphen-
yl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid methyl ester
##STR03318##
[0389] Compound (3)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-ethoxymethylphenyl)--
17,18,19,20-tetranor-5-thiaprost-13-enoic acid methyl ester
##STR03319##
[0390] Compound (4)
(9.beta.,11.alpha.,15.alpha.,13E)-9-Fluoro-11,15-dihydroxy-16-(3-methoxyme-
thylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid methyl
ester
##STR03320##
[0391] Compound (5)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
##STR03321##
[0392] Compound (6)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methyl-4-hydroxyphen-
yl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
##STR03322##
[0393] Compound (7)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-ethoxymethylphenyl)--
17,18,19,20-tetranor-5-thiaprost-13-enoic acid
##STR03323##
[0394] Compound (8)
(9.beta.,11.alpha.,15.alpha.,13E)-9-Fluoro-11,15-dihydroxy-16-(3-methoxyme-
thylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
##STR03324##
[0395] Process for Producing Compounds of the Invention
[0396] Among the compounds of the invention, those of formula (I-1)
can be produced according to the methods described in
WO00/03980.
[0397] Among the compounds of the invention, those of formula (I-3)
can be produced according to the methods mentioned below or
according to the methods described in the Examples mentioned
below.
1) Among the compounds of formula (I-3), those in which T.sup.3 is
oxygen and the 13-14 position is a double bond, or that is, those
of formula (IA):
##STR03325##
[0398] wherein all symbols have the same meanings as defined
above,
can be produced according to the methods mentioned below.
[0399] The compounds of formula (IA) can be produced by reducing a
compound of formula (II):
##STR03326##
[0400] wherein A.sup.3', D.sup.3' and E.sup.3' have the same
meanings as A.sup.3, D.sup.3 and E.sup.3, respectively, but the
hydroxyl, the amino, the carboxyl or the formyl in the group
represented by A.sup.3', D.sup.3' and E.sup.3' may be protected, if
necessary; and the other symbols have the same meanings as defined
above,
[0401] and then optionally removing the protective group from the
resulting product.
[0402] The reaction for reduction is known, and it may be effected,
for example, by processing the compound in an organic solvent
(e.g., tetrahydrofuran, dimethoxyethane, toluene, methylene
chloride, diethyl ether, dioxane) in the presence of a reducing
agent (e.g., borohydride-tetrahydrofuran complex,
borohydride-dimethyl sulfide complex, diborane) and an asymmetric
inducer (e.g., (R)-2-methyl-CBS-oxazaborolysine,
(S)-2-methyl-CBS-oxazaborolysine) at -20 to 50.degree. C.
[0403] The removal of the protective group may be effected
according to the methods mentioned below.
[0404] The reaction for removing the protective group for carboxyl,
hydroxyl, amino or formyl is well known, including, for example,
the following: [0405] (1) alkali hydrolysis, [0406] (2)
deprotection under acidic condition, [0407] (3) deprotection
through hydrogenolysis, [0408] (4) silyl deprotection, [0409] (5)
deprotection with metal, [0410] (6) deprotection with organic
metal.
[0411] These methods are described concretely. [0412] (1) The
deprotection through alkali hydrolysis may be effected, for
example, in an organic solvent (e.g., methanol, tetrahydrofuran,
dioxane) by the use of an alkali metal hydroxide (e.g., sodium
hydroxide, potassium hydroxide, lithium hydroxide), an alkaline
earth metal hydroxide (e.g., barium hydroxide, calcium hydroxide)
or a carbonate (e.g., sodium carbonate, potassium carbonate), or an
aqueous solution thereof or their mixture, at 0 to 40.degree. C.
[0413] (2) The deprotection under acidic condition may be effected,
for example, in an organic solvent (e.g., dichloromethane,
chloroform, dioxane, ethyl acetate, anisole) with an organic
solvent (e.g., acetic acid, trifluoroacetic acid, methanesulfonic
acid, p-toluenesulfonic acid) or an inorganic acid (e.g.,
hydrochloric acid, sulfuric acid) or their mixture (hydrogen
bromide/acetic acid), at 0 to 100.degree. C. [0414] (3) The
deprotection through hydrogenolysis may be effected, for example,
in a solvent (e.g., ether-type (e.g., tetrahydrofuran, dioxane,
dimethoxyethane, diethyl ether), alcohol-type (e.g., methanol,
ethanol), benzene-type (e.g., benzene, toluene), ketone-type (e.g.,
acetone, methyl ethyl ketone), nitrile-type (e.g., acetonitrile),
amide-type (e.g., dimethylformamide), water, ethyl acetate, acetic
acid, or mixed solvent of two or more of these), in the presence of
a catalyst (e.g., palladium-carbon, palladium-black, palladium
hydroxide, platinum oxide, Raney nickel), in a normal-pressure or
increased-pressure hydrogen atmosphere or in the presence of
ammonium formate, at 0 to 200.degree. C. [0415] (4) The silyl
deprotection may be effected, for example, in a water-miscible
organic solvent (e.g., tetrahydrofuran, acetonitrile) by the use of
tetrabutylammonium fluoride, at 0 to 40.degree. C. [0416] (5) The
deprotection with metal may be effected, for example, in an acidic
solvent (acetic acid, buffer having pH of from 4.2 to 7.2, or
mixture of their solution with organic solvent such as
tetrahydrofuran) in the presence of zinc powder with or without
ultrasonic waves applied thereto, at 0 to 40.degree. C. [0417] (6)
The deprotection with metal complex may be effected, for example,
in an organic solvent (e.g., dichloromethane, dimethylformamide,
tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol),
water or their mixed solvent, in the presence of a trapping reagent
(e.g., tributyltin hydride, triethylsilane, dimedone, morpholine,
diethylamine, pyrrolidine), an organic acid (e.g., acetic acid,
formic acid, 2-ethylhexanoic acid) and/or an organic acid salt
(e.g., sodium 2-ethylhexanoate, potassium 2-ethylhexanoate), in the
presence or absence of a phosphine-type reagent (e.g., triphenyl
phosphine), by the use of a metal complex
(tetrakistriphenylphosphine palladium(0),
dichlorobis(triphenylphosphine) palladium(II), palladium(II)
acetate, chlorotris(triphenylphosphine) rhodium(I)), at 0 to
40.degree. C.
[0418] Apart from the above, the deprotection may also be effected,
for example, according to the methods described in T. W. Greene,
Protective Groups in Organic Synthesis, Wiley, New York, 1999.
[0419] The carboxyl-protective group includes, for example, methyl,
ethyl, allyl, t-butyl, trichloroethyl, benzyl (Bn), and
phenacyl.
[0420] The hydroxyl-protective group includes, for example, methyl,
trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxyethyl
(MEM), 2-tetrahydropyranyl (THP), trimethylsilyl (TMS),
triethylsilyl (TES), t-butyldimethylsilyl (TBDMS),
t-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl, benzoyl,
benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc), and
2,2,2-trichloroethoxycarbonyl (Troc).
[0421] The amino-protective group includes, for example,
benzyloxycarbonyl, t-butoxycarbonyl, allyloxycarbonyl (Alloc),
1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc), trifluoroacetyl,
9-fluorenylmethoxycarbonyl, benzyl (Bn), p-methoxybenzyl,
benzyloxymethyl (BOM), and 2-(trimethylsilyl)ethoxymethyl
(SEM).
[0422] The formyl-protective group is, for example, acetal (e.g.,
dimethylacetal).
[0423] The carboxyl, hydroxyl, amino or formyl-protective may be
any others than those mentioned above, capable of being readily and
selectively removed, and are not specifically defined. For example,
those described in T. W. Greene, Protective Groups in Organic
Synthesis, 3rd Ed., Wiley, New York, 1999 may be used.
[0424] The intended compounds of the invention may be readily
produced through selective use of the deprotecting reaction, which
could be readily understood by anyone skilled in the art.
2) Among the compounds of formula (I-3), those in which T.sup.3 is
oxygen and the 13-14 position is a single bond, or that is, those
of formula (IB):
##STR03327##
[0425] wherein all symbols have the same meanings as defined
above,
[0426] can be produced according to the methods mentioned
below.
[0427] The compounds of formula (IB) can be produced by
hydrogenating a compound of formula (III):
##STR03328##
[0428] wherein R.sup.29-3 represents hydrogen, or a
hydroxyl-protective group, and the other symbols have the same
meanings as defined above,
[0429] and then optionally removing the protective group from the
resulting product.
[0430] The reaction for hydrogenation is known, and it may be
effected, for example, by processing the compound in an organic
solvent (e.g., ether-type (e.g., tetrahydrofuran, dioxane,
dimethoxyethane, diethyl ether), alcohol-type (e.g., methanol,
ethanol), benzene-type (e.g., benzene, toluene), ketone-type (e.g.,
acetone, methyl ethyl ketone), nitrile-type (e.g., acetonitrile),
amide-type (e.g., dimethylformamide), water, ethyl acetate, acetic
acid, or mixed solvent of two or more of these), in the presence of
a catalyst (e.g., palladium-carbon, palladium-black, palladium
hydroxide, platinum oxide, Raney nickel), in a normal-pressure or
increased-pressure hydrogen atmosphere or in the presence of
ammonium formate, at 0 to 200.degree. C.
[0431] The removal of the protective group may be effected in the
same manner as herein.
3) Among the compounds of formula (I-3), those in which T.sup.3 is
sulfur, or that is, those of formula (IC):
##STR03329##
[0432] wherein all symbols have the same meanings as defined
above,
[0433] can be produced according to the methods mentioned
below.
[0434] The compounds of formula (IC) can be produced by
thioamidating a compound of formula (IV):
##STR03330##
[0435] wherein all symbols have the same meanings as defined
above,
[0436] and then optionally removing the protective group from the
resulting product.
[0437] The reaction for thioamidation is known, and it may be
effected, for example, by processing the compound in an organic
solvent (e.g., toluene, diethyl ether, methylene chloride,
chloroform, dioxane, tetrahydrofuran) in the presence of a
thionating agent (e.g., Rawson reagent (2,4-b
is(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulfide),
diphosphorus pentoxide) at 0 to 150.degree. C.
[0438] The removal of the protective group may be effected in the
same manner as herein.
4) Among the compounds of formula (I-3), those in which D.sup.3 is
--CH.sub.2OH, or that is, those of formula (ID):
##STR03331##
[0439] wherein all symbols have the same meanings as defined
above,
[0440] can be produced according to the methods mentioned
below.
[0441] The compounds of formula (ID) can be produced by reducing a
compound of formula (V):
##STR03332##
[0442] wherein R.sup.30-3 represents C1-10 alkyl, and the other
symbols have the same meanings as defined above,
[0443] and then optionally removing the protective group from the
resulting product.
[0444] The reaction for reduction is known, and it may be effected,
for example, by processing the compound in an organic solvent
(e.g., tetrahydrofuran, dimethoxyethane, diethyl ether,
dimethylformamide, dioxane, methanol, ethanol, isopropanol) or in
its aqueous solution, in the presence of a reducing agent (e.g.,
sodium borohydride, lithium borohydride), at 0 to 70.degree. C.
[0445] The removal of the protective group may be effected in the
same manner as herein.
5) Among the compounds of formula (I-3), those in which D.sup.3 is
--CONR.sup.3-3SO.sub.2R.sup.4-3, --CONR.sup.6-3R.sup.7-3,
--CONR.sup.6-3SO.sub.2R.sup.8-3, or --CO--(NH-amino acid
residue-CO).sub.m-3--OH, or that is, those of formula (IE):
##STR03333##
[0446] wherein D.sup.3' represents --CONR.sup.3-3SO.sub.2R.sup.4-3,
--CONR.sup.6-3R.sup.7-3, --CONR.sup.6-3SO.sub.2R.sup.8-3, or
--CO--(NH-amino acid residue-CO).sub.m-3--OH, and the other symbols
have the same meanings as defined above,
[0447] can be produced according to the methods mentioned
below.
[0448] The compounds of formula (IE) can be produced by amidating a
compound of formula (VI):
##STR03334##
[0449] wherein all symbols have the same meanings as defined
above,
[0450] with a compound of formula (VII-1):
H--NR.sup.3-3SO.sub.2R.sup.4-3 (VII-1)
[0451] wherein all symbols have the same meanings as defined
above,
[0452] or a compound of formula (VII-2):
H--NR.sup.6-3R.sup.7-3 (VII-2)
[0453] wherein all symbols have the same meanings as defined
above,
or a compound of formula (VII-3)
H--NR.sup.6-3SO.sub.2R.sup.8-3 (VII-3)
[0454] wherein all symbols have the same meanings as defined
above,
or a compound of formula (VII-4):
H--(NH-amino acid residue-CO).sub.m-3--OH (VII-4)
[0455] wherein all symbols have the same meanings as defined above,
but the amino, the hydroxyl or the carboxyl in the compound of
formula (VII-4) may be protected, if necessary,
[0456] and then optionally removing the protective group from the
resulting product.
[0457] The reaction for amidation is known, for example, including
the following: [0458] (1) with acid halide, [0459] (2) with mixed
acid halide, [0460] (3) with condensing agent.
[0461] These methods are described concretely. [0462] (1) The
method with an acid halide comprises, for example, reacting the
carboxylic acid with an acid-halogenating agent (e.g., oxalyl
chloride, thionyl chloride) in an organic solvent (e.g.,
chloroform, dichloromethane, diethyl ether, tetrahydrofuran) or in
the absence of a solvent, at -20.degree. C. to a reflux
temperature, followed by reacting the resulting acid halide with
the amine in an inert organic solvent (e.g., chloroform,
dichloromethane, diethyl ether, tetrahydrofuran) in the presence of
a base (pyridine, triethylamine, dimethylaniline,
dimethylaminopyridine, diisopropylethylamine), at 0 to 40.degree.
C. If necessary, the acid halide may be reacted in an organic
solvent (e.g., dioxane, tetrahydrofuran) by the use of an aqueous
alkali solution (e.g., aqueous sodium bicarbonate, sodium hydroxide
solution) at 0 to 40.degree. C. [0463] (2) The method with a mixed
acid anhydride comprises, for example, reacting the carboxylic acid
with an acid halide (e.g., pivaloyl chloride, tosyl chloride, mesyl
chloride) or an acid derivative (e.g., ethyl chloroformate,
isobutyl chloroformate) in an organic solvent (e.g., chloroform,
dichloromethane, diethyl ether, tetrahydrofuran) or in no solvent,
in the presence of a base (e.g., pyridine, triethylamine,
dimethylaniline, dimethylaminopyridine, diisopropylethylamine), at
0 to 40.degree. C., followed by reacting the resulting mixed acid
anhydride with the amine in an organic solvent (e.g., chloroform,
dichloromethane, diethyl ether, tetrahydrofuran) at 0 to 40.degree.
C. [0464] (3) The method with a condensing agent comprises, for
example, reacting the carboxylic acid with the amine in an organic
solvent (e.g., chloroform, dichloromethane, dimethylformamide,
diethyl ether, tetrahydrofuran) or in no solvent, in the presence
or absence of a base (e.g., pyridine, triethylamine,
dimethylaniline, dimethylaminopyridine) by the use of a condensing
agent (e.g., 1,3-dicyclohexylcarbodiimide (DCC),
1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC),
1,1'-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide,
1-propanephosphonic acid cyclic anhydride (PPA)), and by the use of
or with no use of 1-hydroxybenzotriazole (HOBt) or
1-methanesulfonyloxybenzotriazole, at 0 to 40.degree. C.
[0465] Preferably, the reactions (1), (2) and (3) are all effected
in an inert gas (e.g., argon, nitrogen) atmosphere with no
water.
[0466] The removal of the protective group may be effected in the
same manner as herein.
6) Among the compounds of formula (I-3), those in which D.sup.3 is
--O--(CO-amino acid residue-NH).sub.m-3--H or --OCO--R.sup.10-3, or
that is, those of formula (IF):
##STR03335##
[0467] wherein D.sup.3''' represents --O--(CO-amino acid
residue-NH).sub.m-3--H or --OCO--R.sup.10-3, and the other symbols
have the same meanings as defined above,
can be produced according to the methods mentioned below.
[0468] The compounds of formula (IF) can be produced by esterifying
a compound of formula (VIII):
##STR03336##
[0469] wherein R.sup.31-3 represents --OH or --CH.sub.2OH, and the
other symbols have the same meanings as defined above,
[0470] with a compound of formula (IX-1):
HO--(CO-amino acid residue-NH).sub.m-3--H (IX-1)
[0471] wherein all symbols have the same meanings as defined above,
but the amino, the hydroxyl or the carboxyl in the compound of
formula (IX-1) may be protected, if necessary,
[0472] or a compound of formula (IX-2):
HOOC--R.sup.10-3 (IX-2)
[0473] wherein R.sup.10-3 has the same meaning as above,
[0474] and then optionally removing the protective group from the
resulting product.
[0475] The reaction for esterification is known, for example,
including the following: [0476] (1) with acid halide, [0477] (2)
with mixed acid halide, [0478] (3) with condensing agent.
[0479] These methods are described concretely. [0480] (1) The
method with an acid halide comprises, for example, reacting the
carboxylic acid with an acid-halogenating agent (e.g., oxalyl
chloride, thionyl chloride) in an organic solvent (e.g.,
chloroform, dichloromethane, diethyl ether, tetrahydrofuran) or in
the absence of a solvent, at -20.degree. C. to a reflux
temperature, followed by reacting the resulting acid halide with
the alcohol in the presence of a base (pyridine, triethylamine,
dimethylaniline, dimethylaminopyridine, diisopropylethylamine), in
an inert organic solvent (e.g., chloroform, dichloromethane,
diethyl ether, tetrahydrofuran) at 0 to 40.degree. C. If necessary,
the acid halide may be reacted in an organic solvent (e.g.,
dioxane, tetrahydrofuran) by the use of an aqueous alkali solution
(e.g., aqueous sodium bicarbonate, sodium hydroxide solution) at 0
to 40.degree. C. [0481] (2) The method with a mixed acid anhydride
comprises, for example, reacting the carboxylic acid with an acid
halide (e.g., pivaloyl chloride, tosyl chloride, mesyl chloride) or
an acid derivative (e.g., ethyl chloroformate, isobutyl
chloroformate) in an organic solvent (e.g., chloroform,
dichloromethane, diethyl ether, tetrahydrofuran) or in no solvent,
in the presence of a base (e.g., pyridine, triethylamine,
dimethylaniline, dimethylaminopyridine, diisopropylethylamine), at
0 to 40.degree. C., followed by reacting the resulting mixed acid
anhydride with the alcohol in an organic solvent (e.g., chloroform,
dichloromethane, diethyl ether, tetrahydrofuran) at 0 to 40.degree.
C. [0482] (3) The method with a condensing agent comprises, for
example, reacting the carboxylic acid with the amine in an organic
solvent (e.g., chloroform, dichloromethane, dimethylformamide,
diethyl ether, tetrahydrofuran) or in no solvent, in the presence
or absence of a base (e.g., pyridine, triethylamine,
dimethylaniline, dimethylaminopyridine) by the use of a condensing
agent (e.g., 1,3-dicyclohexylcarbodiimide (DCC),
1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC),
1,1'-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide,
1-propanephosphonic acid cyclic anhydride (PPA)), and by the use of
or with no use of 1-hydroxybenzotriazole (HOBt), at 0 to 40.degree.
C.
[0483] Preferably, the reactions (1), (2) and (3) are all effected
in an inert gas (e.g., argon, nitrogen) atmosphere with no
water.
[0484] The removal of the protective group may be effected in the
same manner as herein.
7) Among the compounds of formula (I-3), those in which D.sup.3 is
formyl, or that is, those of formula (IG):
##STR03337##
[0485] wherein all symbols have the same meanings as defined
above,
[0486] can be produced according to the methods mentioned
below.
[0487] The compounds of formula (IG) can be produced by oxidizing a
compound of formula (X):
##STR03338##
[0488] wherein all symbols have the same meanings as defined
above,
and then optionally removing the protective group from the
resulting product.
[0489] The reaction for oxidation is known, for example, including
the following: [0490] (1) Swern oxidation, [0491] (2) oxidation
with Dess-Martin reagent, [0492] (3) oxidation with TEMPO
reagent.
[0493] These methods are described concretely. [0494] (1) The
method of Swern oxidation comprises, for example, reacting oxalyl
chloride with dimethyl sulfoxide in an organic solvent (e.g.,
chloroform, dichloromethane) at -78.degree. C., and then reacting
the resulting solution with the alcohol compound, and further with
a tertiary amine (e.g., triethylamine, N,N-diisopropylethylamine,
N-methylmorpholine, N-ethylpiperidine,
diazabicyclo[5.4.0]undec-7-ene) at -78 to 20.degree. C. [0495] (2)
The method with a Dess-Martin reagent comprises, for example,
processing the compound in an organic solvent (e.g., chloroform,
dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile,
t-butyl alcohol) in the presence of a Dess-Martin reagent
(1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one), in the
presence or absence of a base (e.g., pyridine) at 0 to 40.degree.
C. [0496] (3) The method with a TEMPO reagent comprises, for
example, processing the compound in an organic solvent (e.g.,
chloroform, dichloromethane, tetrahydrofuran, toluene,
acetonitrile, ethyl acetate, water) or in a mixed solvent thereof,
in the presence of a TEMPO reagent
(2,2,6,6-tetramethyl-1-piperidinyloxy, free radical) and a
re-oxidizing agent (aqueous hydrogen peroxide, sodium hypochlorite,
3-chloroperbenzoic acid, iodobenzene diacetate, potassium
peroxymonosulfate (Oxon, trade name)), in the presence or absence
of a quaternary ammonium salt (e.g., tetrabutylammonium chloride,
tetrabutylammonium bromide), in the presence or absence of an
inorganic salt (e.g., sodium bromide, potassium bromide), in the
presence or absence of an inorganic base (e.g., sodium
hydrogencarbonate, sodium acetate), at 20 to 60.degree. C.
[0497] The oxidation is not limited to the above, and may be any
other capable of readily and selectively oxidizing the alcohol into
a ketone. For example, herein employable is any of Johns oxidation,
oxidation with PCC (pyridinium chlorochromate), oxidation with
sulfur trioxide-pyridine complex, or those described in
Comprehensive Organic Transformations (Richard C. Larock, VCH
Publishers, Inc., (1989), pp. 604-614).
[0498] The removal of the protective group may be effected in the
same manner as herein.
8) Among the compounds of formula (I-3), those in which D.sup.3 is
--COOR.sup.2-3, --COOR.sup.9-3, or
--COO--Z.sup.1-3--Z.sup.2-3--Z.sup.3-3, or that is, those of
formula (IH):
##STR03339##
[0499] wherein D.sup.3'''' represents --COOR.sup.2-3,
--COOR.sup.9-3, or --COO--Z.sup.1-3--Z.sup.2-3--Z.sup.3-3, and the
other symbols have the same meanings as defined above,
[0500] can be produced according to the methods mentioned
below.
[0501] The compounds of formula (IH) can be produced by esterifying
a compound of formula (VI):
##STR03340##
[0502] wherein all symbols have the same meanings as defined
above,
[0503] with a compound of formula (XI-1):
R.sup.31-3--R.sup.2-3 (XI-1)
[0504] wherein R.sup.31-3 represents hydroxyl or halogen, and the
other symbols have the same meanings as defined above,
or a compound of formula (XI-2):
R.sup.31-3--R.sup.9-3 (XI-2)
[0505] wherein all symbols have the same meanings as defined
above,
[0506] or a compound of formula (XI-3):
R.sup.31-3--Z.sup.1-3-1--Z.sup.2-3-1--Z.sup.3-3-1 (XI-3)
[0507] wherein Z.sup.1-3-1, Z.sup.2-3-1 and Z.sup.3-3-1 have the
same meanings as Z.sup.1-3, Z.sup.2-3 and Z.sup.3-3, respectively,
but the hydroxyl, the amino, the carboxyl or the formyl in the
group of Z.sup.1-3-1--Z.sup.2-3-1--Z.sup.3-3-1 may be optionally
protected, if necessary,
[0508] and then optionally removing the protective group from the
resulting product.
[0509] The esterification with the compound of formulae (XI-1),
(XI-2) and (XI-3) in which R.sup.31-3 is hydroxyl may be effected
in the same manner as above.
[0510] The esterification with the compound of formulae (XI-1),
(XI-2) and (XI-3) in which R.sup.31-3 is halogen may be effected,
for example, in an organic solvent (e.g., dimethylformamide,
tetrahydrofuran, dioxane, diethyl ether, dimethylacetamide), in the
presence of a base (e.g., potassium carbonate, cesium carbonate,
sodium carbonate, potassium hydrogencarbonate, sodium
hydrogencarbonate, potassium hydroxide, sodium hydroxide) at 0 to
150.degree. C.
[0511] The removal of the protective group may be effected in the
same manner as herein.
9) Among the compounds of formula (I-3), those in which the
substituent of E.sup.3 is amino can be produced through reduction
of nitro.
[0512] The reaction for nitro reduction is known, and it may be
effected, for example through hydrogenolysis and reduction with
organic metal.
[0513] The reaction for hydrogenolysis is known, and the
deprotection through hydrogenolysis may be effected, for example,
in an inert solvent (e.g., ether-type (e.g., tetrahydrofuran,
dioxane, dimethoxyethane, diethyl ether), alcohol-type (e.g.,
methanol, ethanol), benzene-type (e.g., benzene, toluene),
ketone-type (e.g., acetone, methyl ethyl ketone), nitrile-type
(e.g., acetonitrile), amide-type (e.g., dimethylformamide), water,
ethyl acetate, acetic acid, or mixed solvent of two or more of
these), in the presence of a hydrogenation catalyst (e.g.,
palladium-carbon, palladium-black, palladium, palladium hydroxide,
platinum dioxide, nickel, Raney nickel, ruthenium chloride), in the
presence or absence of an inorganic acid (e.g., hydrochloric acid,
sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric
acid) or an organic acid (e.g., acetic acid, p-toluenesulfonic
acid, oxalic acid, trifluoroacetic acid, formic acid), in a
normal-pressure or increased-pressure hydrogen atmosphere or in the
presence of ammonium formate at 0 to 200.degree. C. In place of the
acid, if used, its salt may also be used.
[0514] The reaction for reduction with organic metal is known, and
it may be effected, for example, in a water-miscible solvent (e.g.,
ethanol, methanol) in the presence or absence of aqueous
hydrochloric acid solution by the use of an organic metal (e.g.,
zinc, iron, tin, tin chloride, iron chloride) at 50 to 150.degree.
C.
10) Among the compounds of formula (I-3), those in which T.sup.3 is
oxygen and X.sup.3 is --CH.sub.2--, or that is, those of formula
(IJ):
##STR03341##
[0515] wherein all symbols have the same meanings as defined
above,
[0516] can be produced according to the methods mentioned
below.
[0517] The compounds of formula (IJ) can be produced through
reductive amination of a compound of formula (XII):
##STR03342##
[0518] wherein all symbols have the same meanings as defined
above,
[0519] with a compound of formula (XIII):
OHC-A.sup.3''-D.sup.3' (XIII)
[0520] wherein A.sup.3'' represents A.sup.1'-3 or A.sup.2'-3,
[0521] A.sup.1'-3 represents [0522] 1) linear C1-7 alkylene
optionally substituted by one or two C1-4 alkyl(s), [0523] 2)
linear C2-7 alkenylene optionally substituted by one or two C1-4
alkyl(s), or [0524] 3) linear C2-7 alkynylene optionally
substituted by one or two C1-4 alkyl(s),
[0525] A.sup.2'-3 represents -G.sup.1'-3-G.sup.2-3-G.sup.3-3-,
[0526] G.sup.1'-3 represents [0527] 1) a single bond, [0528] 2)
linear C1-3 alkylene optionally substituted by one or two C1-4
alkyl(s), [0529] 3) linear C2-3 alkenylene optionally substituted
by one or two C1-4 alkyl(s), or [0530] 4) linear C2-3 alkynylene
optionally substituted by one or two C1-4 alkyl(s),
[0531] and the other symbols have the same meanings as defined
above,
[0532] and then optionally removing the protective group from the
resulting product.
[0533] The reaction for reductive amination is known, and it may be
effected, for example, in an organic solvent (e.g., ethyl acetate,
dichloroethane, dichloromethane, dimethylformamide,
tetrahydrofuran, acetic acid, or their mixture) in the presence of
a reducing agent (e.g., sodium triacetoxyborohydride, sodium
borocyanohydride, sodium borohydride, zinc borohydride,
diisobutylaluminium hydride) at -15 to 100.degree. C., or in an
organic solvent (e.g., ethyl acetate, dichloroethane,
dichloromethane, methanol, ethanol, acetic acid, or their mixture)
in the presence of a catalyst (e.g., palladium-carbon,
palladium-black, palladium hydroxide, platinum oxide, Raney nickel)
in a normal-pressure or increased-pressure hydrogen atmosphere at 0
to 200.degree. C.
[0534] The removal of the protective group may be effected in the
same manner as herein.
[0535] Among the compounds of the invention, those of formula (I-2)
can be produced according to the methods mentioned below or
according to the methods described in the Examples mentioned
below.
1) Among the compounds of formula (I-2), those in which R.sup.1-2
is --CO--(NH-amino acid residue-CO).sub.m-2--OH, or that is, those
of formula (IK):
##STR03343##
[0536] wherein R.sup.1-2-1 represents --CO--(NH-amino acid
residue-CO).sub.m-2--OH, and the other symbols have the same
meanings as defined above,
[0537] can be produced according to the methods mentioned
below.
[0538] The compounds of formula (IK) can be produced through
amidation of a compound of formula (I-1) in which R.sup.1-1 is
hydroxy, or that is, a compound of formula (I-1-1):
##STR03344##
[0539] wherein all symbols have the same meanings as defined
above,
[0540] with a compound of formula (XIV):
H--(NH-amino acid residue-CO).sub.m-2--OH (XIV)
[0541] wherein all symbols have the same meanings as defined above,
but the amino, the hydroxyl or the carboxyl in the compound of
formula (XIV) may be optionally protected, if necessary,
and then optionally removing the protective group from the
resulting product.
[0542] The amidation and the deprotection may be effected in the
same manner as above.
2) Among the compounds of formula (I-2), those in which R.sup.1-2
is --COO--Y.sup.2--R.sup.9-2, or
--COO--Z.sup.1-2--Z.sup.2-2--Z.sup.2-3, or that is, those of
formula (IL):
##STR03345##
[0543] wherein R.sup.1-3-2 represents --COO--Y.sup.2--R.sup.9-2, or
--COO--Z.sup.1-2--Z.sup.2-2--Z.sup.2-3, and the other symbols have
the same meanings as defined above,
[0544] can be produced according to the methods mentioned
below.
[0545] The compounds of formula (IL) can be produced through
esterification of a compound of formula (I-1-1):
##STR03346##
[0546] wherein all symbols have the same meanings as defined
above,
[0547] with a compound of formula (XV-1):
R.sup.23-2--Y.sup.2--R.sup.9-2 (XV-1)
[0548] wherein R.sup.23-2 represents hydroxyl or halogen, and the
other symbols have the same meanings as defined above,
[0549] or a compound of formula (XV-2):
R.sup.23-2--Z.sup.1-2-1--Z.sup.2-2-1--Z.sup.3-2-1 (XV-2)
[0550] wherein Z.sup.1-2-1, Z.sup.2-2-1 and Z.sup.3-2-1 have the
same meanings as Z.sup.1-2, Z.sup.2-2 and Z.sup.3-2, respectively,
but the hydroxyl, the amino, the carboxyl or the formyl in the
group of Z.sup.1-2-1--Z.sup.2-2-1--Z.sup.3-2-1 may be optionally
protected, if necessary,
[0551] and then optionally removing the protective group from the
resulting product.
[0552] The esterification with the compound of formulae (XV-1) and
(XV-2) in which R.sup.23-2 is hydroxyl may be effected in the same
manner as above.
[0553] The esterification with the compound of formulae (XV-1) and
(XV-2) in which R.sup.23-2 is halogen may be effected also in the
same manner as above.
[0554] The deprotection may be effected also in the same manner as
above.
[0555] The compounds of formulae (II), (VII-1), (VII-2), (VII-3),
(IX-1), (IX-2), (XI-1), (XI-2), (XII), (XIII), (XIV), (XV-1) and
(XV-2) are per se known, or are readily produced in known
methods.
[0556] For example, the compounds of formulae (II) and (XII) can be
produced according to the following reaction processes 1, 2 and
3.
[0557] In these reaction processes, Boc represents
t-butoxycarbonyl, R.sup.32-3 represents hydroxyl-protective, Ac
represents an acetyl group, R.sup.33-3 represents halogen,
R.sup.34-3 represents C1-3 alkylene, R.sup.35-3 represents C1-4
alkylene, R.sup.36-3 represents an amino-protective group, and the
other symbols have the same meanings as defined above.
##STR03347##
##STR03348##
##STR03349##
[0558] In the reaction processes 1, 2 and 3, the starting compounds
of formulae (XVI), (XVII), (XXIII), (XXVII), (XXVIII), (XXXII) and
(XXXIII) are known, or are readily produced in known methods.
[0559] The reaction product in each reaction stage in this
description may be purified in an ordinary manner, for example,
through normal-pressure or reduced-pressure distillation, or
through high-performance liquid chromatography, thin-layer
chromatography or column chromatography with silica gel or
magnesium silicate, or through washing or recrystallization. The
purification may be effected in every reaction stage or after some
reaction stages.
INDUSTRIAL APPLICABILITY
Application to Pharmaceutical Preparations:
[0560] The compounds of the invention represented by formulae (I-2)
and (I-3) act on PGE receptor EP.sub.4 subtype specifically and
strongly and thus are considered useful for prevention and/or
treatment of immunodiseases (e.g., autoimmune diseases such as
amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjogren's
syndrome, chronic rheumatism and systemic lupus erythematosus,
rejection after organ implantation) and diseases such as asthma,
death of neurocyte, arthritis, lung disorder, fibroid lung,
pulmonary emphysema, bronchitis, chronic obstructive respiratory
disease, hepatopathy, acute hepatitis, nephritis (acute nephritis,
chronic nephritis), renal insufficiency, hypertension, myocardial
ischemia, systemic inflammatory response syndrome, septicemia,
hemophagocytosis syndrome, macrophage activation syndrome, still
disease, Kawasaki Disease, thermal burn, systemic granuloma,
ulcerative colitis, Crohn disease, hypercytokinemia during
dialysis, multiple organ dysfunction syndrome and shock. EP.sub.4
receptor also takes part in mucous membrane protective action and
thus is considered useful for prevention and/or treatment of
digestive tract ulcer such as gastric ulcer and duodenal ulcer and
stomatitis. EP.sub.4 receptor further takes part in trichogenous
action and hair growing action and is considered useful for
prevention and/or treatment of alopecia. Moreover, EP.sub.4
receptor takes part in maturation of cervical canal and thus is
considered useful as a cervical canal maturing agent.
[0561] Furthermore, the compound bound to EP.sub.4 receptor has an
osteogenesis accelerating action and thus is considered not only
useful for prevention and/or treatment of bone diseases in which
the amount of bone is decreased, e.g., 1) primary osteoporosis due
to, e.g., aging, menopause, overietomy, 2) secondary osteoporosis
(e.g., glucocorticoid-induced osteoporosis, hyperhyroidismic
osteoporosis, fixed induced osteoporosis, haparin-induced
osteoporosis, immunosuppression-induced osteoporosis, osteoporosis
due to renal insufficiency, inflammatory osteoporosis, osteoporosis
due to Cushing's syndrome, rheumatic osteoporosis), 3) bone
diseases such as transfer of cancer to bone, hypercalcemia,
Behcet's disease, bone deficiency (e.g., alveolar bone deficiency,
mandible deficiency, infantile idiopathic bone deficiency) and
osteonecrosis but also useful as a agent for accelerating the
osteogenesis/treatment after bone surgery (e.g., fracture, bone
graft, artificial arthrogenesis, spinal fusion, other bone repair)
or substitute for bone transfer.
[0562] Moreover, EP.sub.4 acts to induce physiologic sleep and
inhibit platelet aggregation and the compound bound to EP.sub.4
receptor is considered useful for prevention of somnipathy and
thrombosis.
[0563] The compound selectively bound to EP.sub.4 has neither
pain-giving effect presumably attributed to EP.sub.1 nor uterine
contracting effect presumably attributed to EP.sub.3 and thus is
considered to be a pharmaceutical preparation having no such
effects.
[0564] Among the compounds represented by formula (I-3) are those
which are connected to EP.sub.4 receptor as well as EP.sub.2
receptor. The compound connected to EP2 receptor is considered
useful for prevention and/or treatment of immunodiseases (e.g.,
autoimmune diseases such as amyotrophic lateral sclerosis (ALS),
multiple sclerosis, Sjogren's syndrome, chronic rheumatism and
systemic lupus erythematosus, rejection after organ implantation)
and diseases such as asthma, death of neurocyte, premature birth,
miscarriage, pars nervosa retinae trouble such a glaucoma, erectile
insufficiency, arthritis, lung disorder, fibroid lung, pulmonary
emphysema, bronchitis, chronic obstructive respiratory disease,
hepatopathy, acute hepatitis, shock, nephritis, renal
insufficiency, circulatory system disorder (e.g., hypertension,
myocardial ischemia, chronic arterial obstruction, vibration
disease), systemic inflammatory response syndrome, septicemia,
hemophagocytosis syndrome, macrophage activation syndrome, still
disease, Kawasaki Disease, thermal burn, systemic granuloma,
ulcerative colitis, Crohn disease, hypercytokinemia during
dialysis, multiple organ dysfunction syndrome and bone disease
(e.g., fracture, refracture, bone union insufficiency,
pseudarthrosis, osteomalacia, bone Behcet's disease, spondylism,
transfer of cancer to bone, osteroarthritis, destruction of
bone/cartilage due to these analogous diseases). The compound
connected to EP2 receptor is also considered useful as an agent for
accelerating the osteogenesis/treatment after bone surgery (e.g.,
fracture, bone graft, artificial arthrogenesis, spinal fusion,
surgery for multiple myeloma, lung cancer, breast cancer, etc.,
other bone repair) or substitute for bone transfer. This compound
is further considered useful as an agent for accelerating the
regeneration of peridontium in peridontium disease.
[0565] The compound connected both to 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.
[0566] The compound represented by formula (I-1), (I-2) or (I-3) or
nontoxic salt thereof may be administered in combination with other
pharmaceutical preparations to accomplish the following purposes:
[0567] 1) To compensate for and/or enhance the preventive and/or
treatment effect of the compound to be combined; [0568] 2) To
improve the kinetics/absorption of the compound to be combined and
reduce the dose of the compound; and/or [0569] 3) To eliminate the
side effect of the compound to be combined
[0570] The compound represented by formula (I-1), (I-2) or (I-3)
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-1), (I-2) or (I-3) may be administered before the other
pharmaceutical preparations. Alternatively, the other
pharmaceutical preparations may be administered before the compound
represented by formula (I-1), (I-2) or (I-3). The method for the
administration of these pharmaceutical preparations may be the same
or different.
[0571] The diseases on which the preventive and/or treatment effect
of the aforementioned 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-1), (I-2) or (I-3) is compensated for and/or enhanced.
[0572] 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-1), (I-2) or (I-3)
on bone diseases include phosphodiesterases-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 hormone, and growth factors.
[0573] 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-1), (I-2) or (I-3)
on chronic obstructive lung diseases and/or asthma include
phosphodiesterases-4 inhibitor, steroid preparation, .beta..sub.2
adrenoreceptor stimulant, leukotriene receptor antagonist,
thromboxane synthesis enzyme inhibitor, thromboxane A.sub.2
receptor antagonist, mediator liberation inhibitor, antihistamines,
xanthine derivatives, anticholinergic preparation, cytokine
inhibitor, prostaglandins, metaprotease inhibitor, expectorant, and
antibiotic.
[0574] 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-1), (I-2) or (I-3)
on arthritis or chronic articular rheumatism include metaprotease
inhibitor, immunosuppressant, nonsteroid-based antiphlogistic
(NSAID), steroid preparation, and phosphodiesterases-4
inhibitor.
[0575] 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-1), (I-2) or (I-3)
on erectile insufficiency include phosphodiesterases-5
inhibitor.
[0576] 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-1), (I-2) or (I-3)
on shock include elastase inhibitor.
[0577] 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-1), (I-2) or (I-3)
on colitis include steroid preparation, phosphodiesterases-4
inhibitor, nonsteroid-based antiphlogistic, thromboxane A.sub.2
receptor antagonist, leukotriene receptor antagonist, angiotensin
II antagonist, angiotensin converting enzyme inhibitor, and
diuretic.
[0578] 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-1), (I-2) or (I-3)
on hypertension include calcium antagonist, angiotensin II
antagonist, angiotensin converting enzyme inhibitor,
phosphodiesterases-4 inhibitor, and diuretic.
[0579] Examples of the phosphodiesterases-4 inhibitor include
rolipram, cilomilast (trade name: Ariflo), Bay 19-8004, NIK-616,
cilomilast (BY-217), cipamfylline (BGL-61063), atizolam (CP-80633),
SCH-351591, YM-976, V-11294A, PD-168787, D-4386, and IC-485.
[0580] Examples of the phosphodiesterases-5 inhibitor include
sildenafil.
[0581] Examples of the bisphonate preparation include sodium
alendronate, disodium chlodronate, disodium pamidronate, disodium
ethydronate, ivandronate, disodium incadronate, minodronate,
olpadronate, sodium risedronate, tildronate, and zoledronate.
[0582] Examples of the calcitonin preparation include calcitonin,
and elcatonin.
[0583] Examples of the prostaglandins (hereinafter abbreviated as
"PG") include PG receptor agonist, and PG receptor antagonist.
[0584] Examples of PG receptor include PGE receptors (EP.sub.1,
EP.sub.2, EP.sub.3, EP.sub.4), PGD receptors (DP), PGF receptors
(FP), and PGI receptors (IP).
[0585] Examples of the steroid preparation for external application
include clobetasol propionate, diflorasone acetate, fluocinonide,
monometasone furancarboxylate, betamesone dipropionate, betamesone
butyropropionate, betamesone 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 dipropionate,
triamcinonide acetonide, flumethasone pivalate, prednisolone,
beclometasone propionate, and fludroxycortide.
[0586] Examples of the steroid preparation 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, triamicinonolon acetonide,
dexamethasone, dexamethasone acetate, dexamethasone sodium
phosphate, dexamethasone palmitate, paramethasone acetate, and
betamethasone.
[0587] Examples of the steroid preparation as an inhalant include
beclomethasone
[0588] propionate, fluticasone propionate, budesonide, flunisolide,
triamicinolon, ST-126P, ciclesonide, dexamethasone palomitionate,
monometasone furancarboxylate, prasterone sulfonate, deflazacort,
methyl prednisolone sreptanate, and methyl prednisolone sodium
succinate.
[0589] 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, and S-1319.
[0590] Examples of the leukotriene receptor antagonist include
pranlukast hydrate, montelukast, zafirlukast, seratrodast, MCC-847,
KCA-757, CD-615, YM-158, L-740515, CP-195494, LM-1484, RS-635,
A-93178, S-36496, BIIL-284, and ONO-4057.
[0591] Examples of the thromboxane synthesis enzyme inhibitor
include ozagrel hydrochloride, and imitrodast sodium.
[0592] Examples of the thromboxane A.sub.2 receptor antagonist
include seratrodast, ramatroban, domitroban calcium dihydrate, and
KT-2-962.
[0593] Examples of the mediator liberation inhibitor include
tranilast, sodium cromoglicate, anlexanox, repirinast, ibudilast,
tazanolast, and pemilolast sodium.
[0594] 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, and acribastin.
[0595] Examples of the xanthine derivatives include aminophylline,
thoeophyline, doxophylline, cipamphilline, and diprophilline.
[0596] Examples of the anticholinergic preparation include
ipratropium bromide, oxitropium bromide, flutropium bromide,
temiverine, tiotropium bromide, and revatropate (UK-112166).
[0597] Examples of the cytokine inhibitor include suplatast
tosilate (trade name: IPD).
[0598] Examples of the expectorant include foeniculated ammonia
spirit, sodium hydrogencarbonate, bromhexine hydrochloride,
carbocisteine, ambroxol hydrochloride, extended-release ambroxol
hydrochloride, methylcysteine hydrochloride, acetyl cysteine,
L-ethylcysteine hydrochloride, and tyloxapol.
[0599] Examples of the growth factors include fibroblast growth
factor (FGF), vascular endothelium growth factor (VEGF), hepatocyte
growth factor (HGF), and insulin-like growth factor.
[0600] 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,
tiaprofenen, oxaprozin, pranoprofen, loxoprofen sodium,
aluminoprofen, zaltoprofen, mefenamic acid, aluminum mefenamate,
tolfenamic acid, floctafenine, ketophenylbutazone, oxyfenbutazone,
piroxicam, tenoxicam, anpiroxicam, napageln cream, epirizole,
tiaramide hydrochloride, tinoridine hydrochloride, emorfazone,
sulpyrine, Migrenin, Saridon, Sedes G, Amipylo N, Sorbon, pyrine
system antipyretics, acetaminophen, phenacetin, dimethothiazine
mesylate, simetride formulation, and antipyrine system
antipyretics.
[0601] Examples of the diuretic include mannitol, furosemide,
acetazolamide, diclofenamide, matazolamide, trichlormethiazide,
mefruside, spinolactone, and aminophylline.
[0602] The weight proportion of the compound represented by formula
(I-1), (I-2) or (I-3) and the other pharmaceutical preparations is
not specifically limited.
[0603] Arbitrary two or more of the other pharmaceutical
preparations may be administered in combination.
[0604] 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-1), (I-2) or (I-3)
include not only those which have so far been found but also those
which will be found on the basis of the aforementioned
mechanism.
[0605] In order to use the compound of the invention represented by
formulae (I-2) and (I-3) or the compound represented by formula
(I-1), (I-2) or (I-3) in combination with the other pharmaceutical
preparations, these compounds are normally administered to the
entire or local part of human body orally or parenterally.
[0606] 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
00 mg per adult or continuously administered into vein for 1 hour
to 24 hours per day.
[0607] It goes without saying that the dose of these compounds may
be less than the aforementioned value or may need to exceed the
aforementioned range because the dose varies under various
conditions as mentioned above.
[0608] When the compounds of the invention represented by formulae
(I-2) and (I-3) or the compound represented by formula (I-1), (I-2)
or (I-3) 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, dye drops or inhalant for parenteral
administration or the like.
[0609] 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.
[0610] 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),
binder (e.g., hydroxypropyl cellulose, polyvinyl pyrrolidone,
magnesium metasilicoaluminate), disintegrant (e.g., calcium
fibrinoglycolate), glidant (e.g., magnesium stearate), stabilizer,
dissolution aid (e.g., glutamic acid, aspartic acid) or the like.
The solid agent may be coated with a coating agent (e.g., white
sugar, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl
cellulose phthalate) or two or more layers. Alternatively, the
solid agent may be capsulized by an absorbable material such as
gelatin.
[0611] 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).
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.
[0612] The agent for parenteral administration may be in the form
of, e.g., ointment, gel, cream, wet compress, paste, liniment,
nebula, inhalant, spray, 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.
[0613] The ointment is prepared by any known or commonly used
formulation. For example, one or more active materials are
titurated 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), wax (e.g., beeswax,
whale wax, ceresin), surface active agent (e.g.,
polyoxyethylenealkyletherphosphoric acid ester), higher alcohol
(e.g., cetanol, stearyl alcohol, setostearyl alcohol), silicon oil
(e.g., dimethyl polysiloxane), hydrocarbon (e.g., hydrophilic
petrolatum, white petrolatum, purified lanolin, liquid paraffin),
glycol (e.g., ethylene glycol, diethylene glycol, propylene glycol,
polyethylene glycol, macrogol), vegetable oil (e.g., castor oil,
olive oil, sesame oil, turpentine oil), 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.
[0614] 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), gelling agent (e.g.,
carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, ethyl cellulose), neutralizing agent (e.g.,
triethanolamine, diisopropanolamine), surface active agent (e.g.,
polyethylene glycol monostearate), gum, water, absorption
accelerator, and rash preventive are used singly or in admixture of
two or more thereof. The gel base may further comprise a humectant,
an antioxidant, a perfume, etc.
[0615] 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), higher
alcohol (e.g., 2-hexyl decanol, cetanol), emulsifier (e.g.,
polyoxyethylene alkyl ether, aliphatic acid ester), water,
absorption accelerator, and rash preventive are used singly or in
admixture of two or more thereof. The cream base may further
comprise a humectant, an antioxidant, a perfume, etc.
[0616] 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),
wetting agent (e.g., urea, glycerin, propylene glycol), filler
(e.g., kaolin, zinc oxide, talc, calcium, magnesium), 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 humectant, an antioxidant, a perfume, etc.
[0617] 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
humectant, an antioxidant, a perfume, etc.
[0618] 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), 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 humectant, an antioxidant, a perfume,
etc.
[0619] The nebula, inhalant and spray each may comprise a
stabilizer such as sodium hydrogensulfite and a buffer capable of
providing isotonicity such as isotonic agent (e.g., sodium
chloride, sodium citrate, citric acid). For the process for the
preparation of spray, reference can be made to U.S. Pat. Nos.
2,868,691 and 3,095,355. These agents may be in the form of
aerosol.
[0620] The injection for parenteral administration may be in the
form of solution, suspension, emulsion or solid injection to be
dissolved or suspended in a solvent in 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. The injection may further comprise
a stabilizer, a dissolution aid (e.g., glutamic acid, aspartic
acid, Polysolvate 80 (trade name)), 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
solvent before use.
[0621] The eye drops for parenteral administration may be in the
form of liquid, suspension, emulsion or ointment or may be
dissolved in a solvent in use.
[0622] 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), singly or in
combination. The eye drops may comprise an isotonic agent (e.g.,
sodium chloride, concentrated glycerin), a buffering agent (e.g.,
sodium phosphate, sodium acetate), a surface active agent (e.g.,
Polysolvate 80 (trade name), polyoxyl stearate 40,
polyoxyethylene-hardened castor oil), a stabilizer (sodium citrate,
sodium edetate), a preservative (e.g., benzalconium chloride,
Paraben), 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 an aseptic distilled water for injection or other
solvent before use.
[0623] 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.
[0624] These inhalants are prepared by an known method.
[0625] For example, the liquid for inhalation is prepared from
materials properly selected from preservatives (e.g., benzalconium
chloride, Paraben), colorants, buffering agents (e.g., sodium
phosphate, sodium acetate), isotonic agents (e.g., sodium chloride,
concentrated glycerin), thickening agents (e.g., carboxyvinyl
polymer), absorption accelerators, etc. as necessary.
[0626] The powder for inhalation is prepared from materials
properly selected from glidants (e.g., stearic acid and salt
thereof), binders (e.g., starch, dextrin), vehicles (e.g., lactose,
cellulose), colorants, preservatives (e.g., benzalconium chloride,
Paraben), absorption accelerators, etc., if necessary.
[0627] In order to administer the liquid for inhalation, a sprayer
(e.g., atomizer, nebulizer) is normally used. In order to
administer the powder for inhalation, a powder inhaler is normally
used.
[0628] Other examples of the composition for oral administration
include suppository for rectal administration and pessary for
vaginal administration prepared by an ordinary formulation
comprising one or more active materials.
Local Application:
[0629] Referring to the local administration of the invention,
EP.sub.4 agonist may be locally administered to site of disease
(particularly bone diseases in which the amount of bone is
decreased). 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 or
articular site.
[0630] The extended-release preparation is not limited to its form
so far as EP.sub.4 agonist can be continuously administered to site
of disease (particularly bone diseases in which the amount of bone
is decreased). The extended-release preparation may be in the form
of, e.g., extended-release injection (e.g., microcapsuled
preparation, microspheric preparation, nanospheric preparation),
embedding preparation (e.g., film-like preparation) or the
like.
[0631] The microcapsuled preparation, microspheric preparation and
nanospheric preparation of the invention each are a finely divided
pharmaceutical composition with an in vivo degradable polymer
comprising as active components the compound represented by formula
(I-1), (I-2) or (I-3) optionally in combination with other
pharmaceutical preparations.
[0632] Examples of the in vivo degradable 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, polytrimethyleneoxates, 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.
[0633] The average molecular weight of these in vivo degradable
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 cid 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.
[0634] The term "weight-average molecular weight" as used herein is
meant to indicate molecular weight in polystyrene equivalence
determined by gel permeation chromatography (GPC).
[0635] The aforementioned in vivo degradable polymer may be changed
depending on the intensity of pharmacological activity of the
compounds represented by formulae (I-1), (I-2) and (I-3) and the
desired medicines to be released so far as the aforementioned aims
of the invention are accomplished. For example, the in vivo
degradable polymer may be used in an amount of from about 0.2 to
10,000 times, preferably from about 1 to 1,000 times, more
preferably from about 1 to 100 times (by weight) that of the
physiologically active material.
[0636] Examples of the process for the preparation of microspheric,
microcapsuled and nanospheric preparations include submerged drying
method (e.g., o/w method, w/o method, w/o/w method), phase
separation method, spray drying method, granulation method by
ulractritical fluid, and methods analogous thereto.
[0637] The submerged drying method (o/w method) and spray drying
method will be further described hereinafter. [0638] (1) In the
submerged drying method (o/w method), a solution of an in vivo
degradable polymer in an organic solvent is prepared at first. The
organic solvent to be used in the preparation of the microspheric,
microcapsuled and nanospheric preparations preferably has a boiling
point of 120.degree. C. or less. Examples of the organic solvent
employable herein include halogenated hydrocarbons (e.g.,
dichloromethane, chloroform), aliphatic esters (e.g., ethyl
acetate), ethers, aromatic hydrocarbons, and ketones (e.g.,
acetone). These compounds may be used in admixture of two or more
at a proper ratio. Preferred among these organic solvents are
dichloromethane and acetonitrile, particularly dichloromethane. The
concentration of the in vivo degradable polymer in the organic
solution depends on the molecular weight of the in vivo degradable
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).
[0639] The compound represented by formula (I-1), (I-2) or (I-3) is
then added to and dissolved in the solution of the in vivo
degradable polymer in an organic solvent thus obtained, optionally
in combination with other pharmaceutical preparations. The amount
of the compound represented by formula (I-1), (I-2) or (I-3) 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 in vivo degradable
polymer in an organic solvent.
[0640] 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).
[0641] 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 preparation
thus obtained is then fractionated by centrifugal separation or
filtration. The microspheric preparation is washed with a surface
active agent solution, alcohol or the like several times to remove
the free compound represented by formula (I-1), (I-2) or (I-3),
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), and then freeze-dried. In the
aforementioned o/w method, the microspheric preparation may be
prepared by a method involving the dispersion of the compound
represented by formula (I-1), (I-2) or (I-3) in a solvent of an in,
vivo degradable polymer in an organic solvent, optionally in
combination with other pharmaceutical preparations, i.e., s/o/w
method. [0642] (2) In order to prepare the microspheric preparation
by the spray drying method, an organic solvent or emulsion having
the in vivo degradable polymer and the compound represented by
formula (I-1), (I-2) or (I-3), optionally in combination with other
pharmaceutical preparations, dissolved therein is sprayed into the
drying chamber of a spray dryer (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 preparation. 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) at the
same time with the spray of o/w emulsion as necessary for the
purpose of inhibiting the aggregation of microspheres. The
microspheric preparation thus obtained is then put under reduced
pressure optionally under heating to remove water and solvent
therefrom.
[0643] Examples of the film-like preparation include film-like
material obtained by dissolving the aforementioned in vivo
degradable polymer and compound represented by formula (I-1), (I-2)
or (I-3), 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 aforementioned in vivo degradable polymer and
compound represented by formula (I-1), (I-2) or (I-3), optionally
in combination with other pharmaceutical preparations, in a proper
solvent, and then adding a granulating agent (e.g., cellulose,
polycarbonate) to the solution.
[0644] The microsphere, microcapsule and nanosphere of the
invention may be used as they are. Alternatively, a spherical,
rod-like, acicular, pelletized, film-like or cream-like
pharmaceutical composition may be processed as a starting material
to provide preparations in various forms.
[0645] Furthermore, this preparation may be used as a parenteral
for local administration (e.g., injection, solid agent such as
embedding agent, pellet and powder, liquid agent such as
suspension, ointment, etc. to be administered to intramuscular,
subcutaneous, organic or articular site). For example, in order to
make an injection from the microspheric preparation, the
microspheric preparation 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 preparation 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.
[0646] The particle diameter of the microspheric preparation 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 preparation 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 mentioned above. 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 hypodermic 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 preparation 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.
[0647] The pharmaceutical composition of the invention can be used
for the treatment of bone diseases in which the amount of bone is
decreased because the compound represented by formula (I-1), (I-2)
or (I-3), 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 in
vivo degradable polymer. Among these bone disease treatments, 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.
[0648] The dose of the pharmaceutical composition of the invention
depends on the kind, content and form of the compound represented
by formula (I-1), (I-2) or (I-3), 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-1), (I-2) or (I-3), optionally in combination with other
pharmaceutical preparations. When administered to fracture as a
microspheric preparation, 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 aforementioned
amount.
BEST MODE FOR CARRYING OUT THE INVENTION
[0649] The following Reference Examples and Examples are intend to
illustrate, but not to limit the present invention.
[0650] The solvents in parentheses at chromatographic separations
section show the developing or eluting solvents and the ratios of
the solvents used are indicated by volume.
[0651] Without special explanation, NMR data was determined in
CDCl.sub.3 solution. And the solvents in parentheses at NMR data
section show solvents used in determination.
[0652] TBS is t-butyldimethylsilyl, THP is tetrahydropyran-2-yl,
Boc is t-butoxycarbonyl, Me is methyl, Et is ethyl, Ac is acetyl,
Bu is butyl, Ms is mesyl and TMS is trimethylsilyl.
REFERENCE EXAMPLE 1
(5R)-5-t-Butyldimethylsilyloxymethylpyrrolidin-2-one
##STR03350##
[0654] Under atmosphere of argon, a solution of
(5R)-5-hydroxymethylpyrollidin-2-one (10 g) and imidazole (8.8 g)
in dry dimethylformamide (50 mL) was added by a solution of
t-butyldimethylsilyl chloride (15.6 g) in dry dimethylformamide (50
mL) at room temperature, and the mixture was stirred for 5 hours.
To the mixture, a mixed solvent of ethyl acetate and hexane was
added. The diluted solution was washed with water and brine
successively, dried over an anhydrous sodium sulfate, concentrated
under reduced pressure to give the title compound (21.41 g) having
the following physical data.
[0655] TLC: Rf 0.52 (Ethyl Acetate).
REFERENCE EXAMPLE 2
9-Oxo-13-t-butyldimethylsilyloxy-14,15,16,17,18,19,20-heptanor-8-azaprosta-
noic acid ethyl ester
##STR03351##
[0657] Under atmosphere of argon, a suspension of sodium hydride
(3.42 g; 63.1% in oil) in dry tetrahydrofuran (90 mL) was added by
a solution of the compound prepared in Reference Example 1 (20.8 g)
in dry tetrahydrofuran (90 mL) at room temperature. Then
dimethylformamide (180 mL) was added to the mixture, and the
mixture was stirred for 45 minutes at 50.degree. C. To the mixture,
a solution of 7-bromoheptanoic acid ethyl ester (22.4 g) in
dimethylformamide (20 mL) was added, and the mixture was stirred
for 4 hours. After cooling, a mixed solvent of ethyl acetate and
hexane was added. The organic layer was washed with 0.5N
hydrochloric acid, water and brine successively, dried over an
anhydrous sodium sulfate, concentrated under reduced pressure to
give the title compound (34.9 g) having the following physical
data.
[0658] TLC: Rf 0.51 (Ethyl Acetate:Hexane=2:1).
REFERENCE EXAMPLE 3
9-Oxo-13-hydroxy-14,15,16,17,18,19,20-heptanor-8-azaprostanoic acid
ethyl ester
##STR03352##
[0660] To a solution of the compound prepared in Reference Example
2 (34.9 g) in ethanol (43 mL), p-toluenesulfonic acid (2.96 g) was
added, and the mixture was stirred overnight at 50.degree. C. It
was cooled to room temperature, the mixture was added by
triethylamine (2.4 mL), concentrated under reduced pressure and was
purified by column chromatography on silica gel (from ethyl
acetate:hexane=1:1 to ethyl acetate only) to give the title
compound (13.15 g) having the following physical data.
[0661] TLC: Rf 0.18 (Ethyl Acetate);
[0662] NMR: .delta. 4.12 (q, J=7 Hz, 2H), 3.85-3.6 (m, 4H),
3.05-2.9 (m, 1H), 2.55-2.4 (m, 1H), 2.4-2.25 (m, 3H), 2.2-2.05 (m,
1H), 2.0-1.9 (m, 1H), 1.85-1.7 (br, 1H), 1.7-1.2 (m, 8H), 1.27 (t,
J=7 Hz, 3H).
REFERENCE EXAMPLE 4
9-Oxo-12-formyl-13,14,15,16,17,18,19,20-octanor-8-azaprostanoic
acid ethyl ester
##STR03353##
[0664] Under atmosphere of argon, a solution of the compound
prepared in Reference Example 3 (1.25 g) in ethyl acetate (10 mL)
and dry dimethylsulfoxide (7 mL) was added by diisopropylethylamine
(5.1 mL). Then sulfur trioxide pyridine complex (2.32 g) was added
to the mixture on ice bath, and the mixture was stirred for 1 hour
at 0-15.degree. C. Small amount of water was added to the reaction
mixture, the reaction was terminated. Chloroform (10 mL) was added
to the mixture. The organic layer was washed with 0.5N hydrochloric
acid, dried over an anhydrous sodium sulfate, concentrated under
reduced pressure to give the title compound (1.25 g) having the
following physical data, which was used for the next reaction
without purification.
[0665] TLC: Rf 0.45 (Chloroform:Methanol=9:1).
REFERENCE EXAMPLE 5
(13E)-9,15-Dioxo-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azapros-
t-13-enoic acid ethyl ester
##STR03354##
[0667] Under atmosphere of argon, a solution of
3-(3-methoxymethylphenyl)-2-oxopropylphosphonic acid dimethyl ester
(1.81 g) in dry tetrahydrofuran (35 mL) was added by sodium hydride
(222 mg; 63.1% in oil), and the mixture was stirred for 30 minutes
at room temperature. To the suspension, a solution of the compound
prepared in Reference Example 4 (1.25 g) in tetrahydrofuran (5 mL)
was added, and the mixture was stirred for 3 hours. Then ethyl
acetate was added to the mixture. The diluted solution was washed
with water and brine successively, dried over an anhydrous sodium
sulfate, concentrated under reduced pressure and was purified by
column chromatography on silica gel (ethyl acetate:hexane=from 2:1
to 3:1, then ethyl acetate only) to give the title compound (1.23
g) having the following physical data.
[0668] TLC: Rf 0.72 (Chloroform:Methanol=9:1);
[0669] NMR: .delta. 7.35-7.10 (m, 4H), 6.65 (dd, J=16, 8 Hz, 1H),
6.23 (d, J=16 Hz, 1H), 4.42 (s, 2H), 4.2-4.1 (m, 3H), 3.85 (s, 2H),
3.6-3.5 (m, 1H), 3.38 (s, 3H), 2.8-2.65 (m, 1H), 2.5-2.2 (m, 5H),
1.85-1.7 (m, 1H), 1.7-1.5 (m, 2H), 1.5-1.2 (m, 9H).
EXAMPLE 1
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-te-
tranor-8-azaprost-13-enoic acid ethyl ester
##STR03355##
[0671] Under atmosphere of argon, a solution of the compound
prepared in Reference Example 5 (1.23 g) in dry tetrahydrofuran (10
mL) was added by a 1.0M (R)-2-methyl-CBS-oxazaborolidine/toluene
solution (0.57 mL) at room temperature. Then borane tetrahydrofuran
complex (2.32 mL) was dropped to the mixture, and the mixture was
stirred for 45 minutes. To the mixture, 1N hydrochloric acid and
ethyl acetate was added. The organic layer was washed with water
and brine successively, dried over an anhydrous sodium sulfate,
concentrated under reduced pressure and was purified by column
chromatography on silica gel (from ethyl acetate only to ethyl
acetate:hexane=19:1) to give the title compound (1.05 g) having the
following physical data.
[0672] TLC: Rf 0.60 (Chloroform:Methanol=9:1);
[0673] NMR: .delta. 7.38-7.10 (m, 4H), 5.73 (dd, J=15.3, 6.0 Hz,
1H), 5.50 (dd, J=15.3, 8.0 Hz, 1H), 4.48-4.35 (m, 3H), 4.17-3.98
(m, 3H), 3.53-3.36 (m, 4H), 2.92-2.68 (m, 3H), 2.44-2.05 (m, 6H),
1.81-1.20 (m, 12H).
EXAMPLE 2
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-te-
tranor-8-azaprost-13-enoic acid
##STR03356##
[0675] A solution of the compound prepared in Example 1 (1.05 g) in
methanol (5 mL) was added by 2N aqueous sodium hydroxide (4 ml),
and the mixture was stirred overnight. To the mixture, diethyl
ether (10 mL) and water (20 mL) was added, and the mixture was
stirred. 1N hydrochloric acid was added to the aqueous layer to
acidify, then extracted by ethyl acetate. The organic layer was
washed with water and brine successively, dried over an anhydrous
sodium sulfate, concentrated under reduced pressure and was
purified by column chromatography on silica gel (from chloroform
only to chloroform:methanol=100:1, then 50:1, then 25:1) to give
the title compound (837 mg) having the following physical data.
[0676] TLC: Rf 0.41 (Chloroform:Methanol=9:1);
[0677] NMR: .delta. 7.36-7.11 (m, 4H), 5.75 (dd, J=15.3, 6.0 Hz,
1H), 5.51 (dd, J=15.3, 8.0 Hz, 1H), 4.49-4.38 (m, 3H), 4.08-3.99
(m, 1H), 3.50-3.36 (m, 4H), 2.94-2.75 (m, 3H), 2.49-2.14 (m, 6H),
1.79-1.20 (m, 9H).
EXAMPLE 2(a) TO EXAMPLE 2(bbb)
[0678] By the same procedure as describe in Reference Examples 1,
2, 3, 45, Examples 1 and 2 using 7-bromoheptanoic acid ethyl ester
or corresponding halide derivatives, and
3-(3-methoxymethylphenyl)-3-oxopropylphosphonic acid dimethyl ester
or corresponding phosphonic ester derivatives, the compound of the
present invention having the following physical data were
obtained.
EXAMPLE 2(a)
(5S,15.alpha.,13E)-5-Methyl-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17-
,18,19,20-tetranor-8-azaprost-13-enoic acid
##STR03357##
[0680] TLC: Rf 0.28 (Methanol:Chloroform=1:10);
[0681] NMR: .delta. 7.40-7.10 (m, 4H), 5.78 (dd, J=15.2, 5.2 Hz,
1H), 5.55 (dd, J=15.2, 8.4 Hz, 1H), 4.50-4.35 (m, 1H), 4.46 (s,
2H), 4.10-3.95(m, 1H), 3.60-3.35 (m, 1H), 3.42 (s, 3H), 3.00-2.70
(m, 4H), 2.50-2.10 (m, 5H), 1.80-1.00 (m, 8H), 0.91 (d, J=5.8 Hz,
3H).
EXAMPLE 2(b)
(15.alpha.,13E)-5,5-Dimethyl-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-1-
7,18,19,20-tetranor-8-azaprost-13-enoic acid
##STR03358##
[0683] TLC: Rf 0.38 (Chloroform:Methanol=9:1);
[0684] NMR: .delta. 7.33-7.12 (m, 4H), 5.78 (dd, J=15, 5 Hz, 1H),
5.59 (dd, J=15, 8 Hz, 1H), 4.48 (s, 2H), 4.45-4.36 (m, 1H),
4.12-4.03 (m, 1H), 3.51 (dt, J=12, 5 Hz, 1H), 3.43 (s, 3H),
2.91-2.81 (m, 2H), 2.76 (dd, J=14, 8 Hz, 1H), 2.47-2.10 (m, 5H),
1.78-1.63 (m, 1H), 1.61-1.40 (m, 3H), 1.32-1.10 (m, 3H), 0.92 (s,
3H), 0.89 (s, 3H).
EXAMPLE 2(c)
(15.alpha.,13E)-5,5-Ethano-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,-
18,19,20-tetranor-8-azaprost-13-enoic acid
##STR03359##
[0686] TLC: Rf 0.38 (Chloroform:Methanol=9:1);
[0687] NMR: .delta. 7.33-7.13 (m, 4H), 5.81 (dd, J=15, 5 Hz, 1H),
5.61 (dd, J=15, 8 Hz, 1H), 4.46 (s, 2H), 4.48-4.39 (m, 1H),
4.12-4.04 (m, 1H), 3.54 (ddd, J=14, 11, 5 Hz, 1H), 3.43 (s, 3H),
2.98 (ddd, J=14, 11, 5 Hz, 1H), 2.90 (dd, J=14, 9 Hz, 1H),
2.47-2.12 (m, 5H), 1.79-1.52 (m, 4H), 1.36-1.10 (m, 3H), 0.37-0.22
(m, 4H).
EXAMPLE 2(d)
(5R,15.alpha.,13E)-5-Methyl-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17-
,18,19,20-tetranor-8-azaprost-13-enoic acid
##STR03360##
[0689] TLC: Rf 0.55 (Methanol:Chloroform=1:5);
[0690] NMR: .delta. 7.40-7.10 (m, 4H), 5.78 (dd, J=15.4, 5.6 Hz,
1H), 5.54 (dd, J=15.4, 8.4 Hz, 1H), 4.50-4.35 (m, 1H), 4.41 (s,
2H), 4.10-3.98 (m, 1H), 3.60-3.45 (m, 1H), 3.42 (s, 3H), 3.00-2.75
(m, 3H), 2.50-2.10 (m, 5H), 1.80-1.10 (m, 8H), 0.91 (d, J=5.8 Hz,
3H).
EXAMPLE 2(e)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(2,2,2-trifluoroethoxymethyl)phenyl-
)-17,18,19,20-tetranor-8-azaprost-13-enoic acid
##STR03361##
[0692] TLC: Rf 0.38 (Methanol:Ethyl Acetate=1:10);
[0693] NMR: .delta. 7.40-7.10 (m, 4H), 5.75 (dd, J=15.6, 5.6 Hz,
1H), 5.52 (dd, J=15.6, 8.4 Hz, 1H), 4.67 (s, 2H), 4.50-4.35 (m,
1H), 4.10-3.98 (m, 1H), 3.86 (q, J=8.8 Hz, 2H), 3.60-3.35 (m, 1H),
3.00-1.80 (m, 6H), 2.33 (t, J=7.0 Hz, 2H), 1.80-1.55 (m, 3H),
1.55-1.10 (m, 6H).
EXAMPLE 2(f)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor--
8-azaprost-13-enoic acid
##STR03362##
[0695] TLC: Rf 0.36 (Methanol:Ethyl Acetate=1:10);
[0696] NMR: .delta. 7.35-7.15 (m, 3H), 7.15-7.00 (m, 1H), 5.72 (dd,
J=15.8, 5.8 Hz, 1H), 5.48 (dd, J=15.8, 8.2 Hz, 1H), 4.42 (q, J=6.6
Hz, 1H), 4.10-3.98 (m, 1H), 3.60-3.40 (m, 1H), 2.83 (d, J=6.6 Hz,
2H), 3.00-2.10 (m, 4H), 2.34 (t, J=7.2 Hz, 2H), 1.80-1.55 (m, 3H),
1.55-1.10 (m, 6H).
EXAMPLE 2(g)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-2,3,4,17,18,19-
,20-heptanor-1,5-(2,5-interthienylene)-8-azaprost-13-enoic acid
##STR03363##
[0698] TLC: Rf 0.22 (Chloroform:Methanol=9:1);
[0699] NMR: .delta. 7.63 (d, J=3 Hz, 1H), 7.33-7.25 (m, 2H), 7.19
(d, J=8 Hz, 1H), 7.13 (d, J=8 Hz, 1H), 6.81 (d, J=3 Hz, 1H), 5.73
(dd, J=15, 5 Hz, 1H), 5.50 (dd, J=15, 9 Hz, 1H), 4.52 (d, J=11 Hz,
1H), 4.45 (d, J=11 Hz, 1H), 4.40-4.30 (m, 1H), 4.2-3.0 (br), 4.02
(q, J=9 Hz, 1H), 3.46 (s, 3H), 3.50-3.35 (m, 1H), 2.98-2.68 (m,
5H), 2.50-2.10 (m, 3H), 2.00-1.68 (m, 3H).
EXAMPLE 2(h)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-phenylphenyl)-17,18,19,20-tetranor--
8-azaprost-13-enoic acid
##STR03364##
[0701] TLC: Rf 0.32 (Chloroform:Methanol=9:1);
[0702] NMR: .delta. 7.60-7.37 (m, 8H), 7.24-7.17 (d, J=8.2 Hz, 1H),
5.74 (dd, J=15.0, 6.0 Hz, 1H), 5.49 (ddd, J=15.0, 8.6, 1.2 Hz, 1H),
4.51-4.40 (m, 1H), 4.08-3.99 (m, 1H), 3.50-3.39 (m, 1H), 2.91 (d,
J=6.6 Hz, 2H), 2.78-2.64 (m, 1H), 2.42-2.05 (m, 6H), 1.77-1.51 (m,
3H), 1.42-1.06 (m, 6H).
EXAMPLE 2(i)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor--
8-azaprost-13-enoic acid
##STR03365##
[0704] TLC: Rf 0.34 (Chloroform:Methanol=10:1);
[0705] NMR: .delta. 7.22-7.17 (m, 1h), 7.07-6.98 (m, 3H), 5.74 (dd,
J=15.3, 5.7 Hz, 1H), 5.50 (ddd, J=15.3, 8.4, 1.2 Hz, 1H), 4.41 (m,
1H), 4.03 (m, 1H), 3.47 (m, 1H), 2.90-2.70 (m, 3H), 2.40-2.10 (m,
6H), 2.33 (s, 3H), 1.76-1.22 (m, 9H).
EXAMPLE 2(j)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetranor--
8-azaprost-13-enoic acid
##STR03366##
[0707] TLC: Rf 0.30 (Chloroform:Methanol=10:1);
[0708] NMR: .delta. 7.32-7.23 (m, 1H), 6.99-6.90 (m, 3H), 5.72 (dd,
J=15.3, 6.0 Hz, 1H), 5.50 (ddd, J=15.3, 8.4, 1.2 Hz, 1H), 4.42 (m,
1H), 4.03 (m, 1H), 3.46 (m, 1H), 2.85 (d, J=6.0 Hz, 2H), 2.70 (m,
1H), 2.40-2.10 (m, 6H), 1.75-1.20 (m, 9H).
EXAMPLE 2(k)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
8-azaprost-13-enoic acid
##STR03367##
[0710] TLC: Rf 0.47 (Chloroform:Methanol:Water=9:1:0.1);
[0711] NMR: .delta. 7.16 (m, 2H), 7.00 (m, 2H), 5.72 (dd, J=15.4,
6.0 Hz, 1H), 5.49 (dd, J=15.4, 8.2 Hz, 1H), 4.38 (m, 1H), 4.03 (m,
1H), 3.47 (m, 1H), 2.82 (d, J=6.6 Hz, 2H), 2.72 (m, 1H), 2.41-2.31
(m, 2H), 2.34 (t, J=7.2 Hz, 2H), 2.21 (m, 1H), 1.67 (m, 1H),
1.66-1.58 (m, 2H), 1.50-1.20 (m, 6H).
EXAMPLE 2(l)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-methylphenyl)-17,18,19,20-tetranor--
8-azaprost-13-enoic acid
##STR03368##
[0713] TLC: Rf 0.26 (Chloroform:Methanol:Water=9:1:0.1);
[0714] NMR: .delta. 7.12 (d, J=8.2 Hz, 2H), 7.07 (d, J=8.2 Hz, 2H),
5.73 (dd, J=15.4, 5.8 Hz, 1H), 5.47 (dd, J=15.4, 8.8 Hz, 1H), 4.38
(m, 1H), 4.03 (m, 1H), 3.46 (m, 1H), 2.81 (d, J=6.9 Hz, 2H), 2.72
(m, 1H), 2.40-2.27 (m, 4H), 2.34 (s, 3H), 2.21 (m, 1H), 1.72 (m,
1H), 1.67-1.58 (m, 2H), 1.50-1.18 (m, 6H).
EXAMPLE 2(m)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(2-methylphenyl)-17,18,19,20-tetranor--
8-azaprost-13-enoic acid
##STR03369##
[0716] TLC: Rf 0.27 (Chloroform:Methanol=8:1);
[0717] NMR: .delta. 7.28-7.00 (m, 4H), 5.76 (dd, J=15.2, 6.0 Hz,
1H), 5.49 (ddd, J=15.2, 8.4, 0.6 Hz, 1H), 4.42 (m, 1H), 4.04 (m,
1H), 3.46 (m, 1H), 2.87 (d, J=7.0 Hz, 2H), 2.72 (m, 1H), 2.50-2.04
(m, 6H), 2.34 (s, 3H), 1.85-1.10 (m, 9H).
EXAMPLE 2(n)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(2-fluorophenyl)-17,18,19,20-tetranor--
8-azaprost-13-enoic acid
##STR03370##
[0719] TLC: Rf 0.27 (Chloroform:Methanol=8:1);
[0720] NMR: .delta. 7.34-6.94 (m, 4H), 5.74 (dd, J=15.2, 6.0 Hz,
1H), 5.45 (ddd, J=15.2, 8.4, 0.8 Hz, 1H), 4.47 (m, 1H), 4.02 (m,
1H), 3.44 (m, 1H), 3.40-1.90 (m, 9H), 1.80-0.90 (m, 9H).
EXAMPLE 2(o)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20--
tetranor-8-azaprost-13-enoic acid
##STR03371##
[0722] TLC: Rf 0.18 (Chloroform:Methanol=8:1);
[0723] NMR: .delta. 7.60-7.35 (m, 4H), 5.73 (dd, J=15.3, 5.9 Hz,
1H), 5.50 (ddd, J=15.3, 8.3, 0.9 Hz, 1H), 4.46 (m, 1H), 4.03 (m,
1H), 4.00-3.00 (br, 2H), 3.46 (m, 1H), 2.91 (d, J=6.3 Hz, 2H), 2.71
(m, 1H), 2.48-2.06 (m, 5H), 1.76-1.12 (m, 9H).
EXAMPLE 2(p)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methoxyphenyl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid
##STR03372##
[0725] TLC: Rf 0.16 (Chloroform:Methanol=8:1);
[0726] NMR: .delta. 7.23 (dd, J=7.8, 7.8 Hz, 1H), 6.86-6.70 (m,
3H), 5.73 (dd, J=15.3, 6,0 Hz, 1H), 5.48 (dd, J=15.3, 8.4 Hz, 1H),
4.41 (m, 1H), 4.03 (m, 1H), 3.80 (s, 3H), 3.46 (m, 1H), 2.82 (d,
J=6.6 Hz, 2H), 2.71 (m, 1H), 2.50-2.04 (m, 5H), 1.80-1.10 (m,
10H).
EXAMPLE 2(q)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-ethylphenyl)-17,18,19,20-tetranor-8-
-azaprost-13-enoic acid
##STR03373##
[0728] TLC: Rf 0.25 (Chloroform:Methanol:Water=9:1:0.1);
[0729] NMR: .delta. 7.24 (t, J=7.3 Hz, 1H), 7.11-6.97 (m, 3H), 5.74
(dd, J=15.1, 5.9 Hz, 1H), 5.50 (ddd, J=15.1, 8.3, 1.0 Hz, 1H), 4.42
(m, 1H), 4.04 (m, 1H), 3.45 (m, 1H), 2.84-2.80 (m, 2H), 2.75 (m;
1H), 2.63 (q, J=7.8 Hz, 2H), 2.43-2.32 (m, 2H), 2.35 (t, J=7.3 Hz,
2H), 2.21 (m, 1H), 1.71 (m, 1H), 1.68-1.57 (m, 2H), 1.54-1.20 (m,
6H), 1.24 (t, J=7.8 Hz, 3H).
EXAMPLE 2(r)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetra-
nor-8-azaprost-13-enoic acid
##STR03374##
[0731] TLC: Rf 0.30 (Chloroform:Methanol:Water=9:1:0.1);
[0732] NMR: .delta. 7.14-7.00 (m, 3H), 6.92 (m, 1H), 5.71 (dd,
J=15.4, 5.8 Hz, 1H), 5.50 (dd, J=15.4, 8.6 Hz, 1H), 4.38 (m, 1H),
4.04 (m, 1H), 3.44 (m, 1H), 2.82 (d, J=6.6 Hz, 2H), 2.73 (m, 1H),
2.43-2.32 (m, 2H), 2.34 (t, J=7.1 Hz, 2H), 2.22 (m, 1H), 1.69 (m,
1H), 1.65-1.55 (m, 2H), 1.51-1.20 (m, 6H).
EXAMPLE 2(s)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-chloro-4-hydroxyphenyl)-17,18,19,20-
-tetranor-8-azaprost-13-enoic acid
##STR03375##
[0734] TLC: Rf 0.26 (Chloroform:Methanol=9:1);
[0735] NMR: .delta. 7.14 (d, J=2.1 Hz, 1H), 6.94 (dd, J=8.4, 2.1
Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 5.65 (dd, J=15, 6.3 Hz, 1H), 5.41
(ddd, J=15, 8.0, 1.2 Hz, 1H), 4.33 (m, 1H), 4.01 (m, 1H), 3.41 (m,
1H), 2.85-2.62 (m, 3H), 2.57-2.10 (m, 8H), 1.79-1.56 (m,
3H),1.54-1.19 (m, 6H).
[0736] The hydroxyl group bound benzene ring was protected by THP
group, and was removed protecting group by acid before hydrolysis
of the ester (procedure of Example 2)
EXAMPLE 2(t)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3,5-difluorophenyl)-17,18,19,20-tetra-
nor-8-azaprost-13-enoic acid
##STR03376##
[0738] TLC: Rf 0.34 (Chloroform:Methanol=9:1);
[0739] NMR: .delta. 6.80-6.65 (m, 3H), 5.71 (dd, J=15, 5.7 Hz, 1H),
5.50 (dd, J=15, 8.7 Hz, 1H), 4.41 (m, 1H), 4.03 (m, 1H), 3.48 (m,
1H), 3.10-2.50 (m, 4H), 2.47-2.10 (m, 6H), 1.79-1.59 (m, 3H),
1.58-1.20 (m, 6H).
EXAMPLE 2(u)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranor--
8-azaprost-13-enoic acid
##STR03377##
[0741] TLC: Rf 0.26 (Chloroform:Methanol=10:1);
[0742] NMR: .delta. 7.25-7.19 (m, 1H), 7.08-7.00 (m, 3H), 5.75 (dd,
J=15.3, 5.7 Hz, 1H), 5.51 (ddd, J=15.3, 8.4, 0.9 Hz, 1H), 4.41 (m,
1H), 4.05 (m, 1H), 3.48 (m, 1H), 2.90-2.70 (m, 3H), 2.57 (t, J=7.2
Hz, 2H), 2.50-2.10 (m, 5H), 1.80-1.20 (m, 11H), 0.94 (t, J=7.2 Hz,
3H).
EXAMPLE 2(v)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-((E)-1-propenylphenyl)-17,18,19,20-tet-
ranor-8-azaprost-13-enoic acid
##STR03378##
[0744] TLC: Rf 0.30 (Chloroform:Methanol=10:1);
[0745] NMR: .delta. 7.23-7.21 (m, 2H), 7.14 (s, 1H), 7.02 (m, 1H),
6.37 (dd, J=15.6, 1.5 Hz, 1H), 6.27 (dq, J=15.6, 6.3 Hz, 1H), 5.74
(dd, J=15.3, 6.0 Hz, 1H), 5.49 (ddd, J=15.3, 8.4, 1.2 Hz, 1H), 4.41
(m, 1H), 4.02 (m, 1H), 3.45 (m, 1H), 2.83 (d, J=6.9 Hz, 2H), 2.70
(m, 1H), 2.40-2.10 (m, 5H), 1.88 (dd, J=6.3, 1.5 Hz, 3H), 1.80-1.20
(m, 9H).
EXAMPLE 2(w)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(2-fluorophenyl)phenyl)-17,18,19,20-
-tetranor-8-azaprost-13-enoic acid
##STR03379##
[0747] TLC: Rf 0.27 (Chloroform:Methanol=8:1);
[0748] NMR: .delta. 7.60-6.80 (m, 8H), 5.72 (m, 1H), 5.48 (m, 1H),
5.00-3.00 (br, 2H), 4.43 (m, 1H), 4.01 (m, 1H), 3.43 (m, 1H),
2.98-2.60 (m, 3H), 2.48-2.00 (m, 5H), 1.98-0.88 (m, 9H).
EXAMPLE 2(x)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(4-fluorophenyl)phenyl)-17,18,19,20-
-tetranor-8-azaprost-13-enoic acid
##STR03380##
[0750] TLC: Rf 0.27 (Chloroform:Methanol=8:1);
[0751] NMR: .delta. 7.64-7.00 (m, 8H), 5.72 (m, 1H), 5.48 (m, 1H),
4.60-3.00 (br, 2H), 4.45 (m, 1H), 4.02 (m, 1H), 3.44 (m, 1H),
2.96-2.60 (m, 3H), 2.48-2.02 (m, 5H), 1.78-0.78 (m, 9H).
EXAMPLE 2(y)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(5-methylfuran-2-yl)phenyl)-17,18,1-
9,20-tetranor-8-azaprost-13-enoic acid
##STR03381##
[0753] TLC: Rf 0.25 (Chloroform:Methanol=8:1);
[0754] NMR: .delta. 7.60-6.96 (m, 4H), 6.53 (d, J=3.0 Hz, 1H), 6.05
(m, 1H), 5.72 (m, 1H), 5.48 (m, 1H), 4.60-2.80 (br, 2H), 4.44 (m,
1H), 4.02 (m, 1H), 3.44 (m, 1H), 2.96-2.60 (m, 3H), 2.48-2.02 (m,
8H), 1.80-1.06 (m, 9H).
EXAMPLE 2(z)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(naphthalen-2-yl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid
##STR03382##
[0756] TLC: Rf 0.45 (Chloroform:Methanol:Water=9:1:0.1);
[0757] NMR: .delta. 7.83-7.76 (m, 3H), 7.65 (s, 1H), 7.51-7.41 (m,
2H), 7.33 (dd, J=8.5, 1.7 Hz, 1H), 5.77 (dd, J=15.4, 6.1 Hz, 1H),
5.44 (ddd, J=15.4, 8.5, 0.8 Hz, 1H), 4.54 (m, 1H), 4.01 (m, 1H),
3.38 (m, 1H), 3.02 (d, J=6.9 Hz, 2H), 2.63 (m, 1H), 2.37-2.32 (m,
2H), 2.34 (t, J=7.2 Hz, 2H), 2.19 (m, 1H), 1.64 (m, 1H), 1.63-1.55
(m, 2H), 1.40-1.12 (m, 6H).
EXAMPLE 2(aa)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(2-methoxyphenyl)phenyl)-17,18,19,2-
0-tetranor-8-azaprost-13-enoic acid
##STR03383##
[0759] TLC: R10.23 (Chloroform:Methanol=8:1);
[0760] NMR: .delta. 7.50-6.92 (m, 8H), 5.74 (m, 1H), 5.50 (m, 1H),
4.43 (m, 1H), 4.03 (m, 1H), 3.81 (s, 3H), 3.45 (m, 1H), 3.40-1.90
(br, 2H), 3.00-2.64 (m, 3H), 2.48-2.14 (m, 5H), 1.78-1.10 (m,
9H).
EXAMPLE 2(bb)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(2-hydroxyphenyl)phenyl)-17,18,19,2-
0-tetranor-8-azaprost-13-enoic acid
##STR03384##
[0762] TLC: Rf 0.26 (Chloroform:Methanol=8:1);
[0763] NMR: .delta. 7.46-7.08 (m, 7H), 6.97 (m, 1H), 5.72 (m, 1H),
5.47 (m, 1H), 4.42 (m, 1H), 4.02 (m, 1H), 3.43 (m, 1H), 2.98-2.62
(m, 3H), 2.50-2.06 (m, 5H), 1.80-1.08 (m, 9H).
[0764] The hydroxyl group bound benzene ring was protected by THP
group, and was removed protecting group by acid before hydrolysis
of the ester (procedure of Example 2)
EXAMPLE 2(cc)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(3-hydroxyphenyl)phenyl)-17,18,19,2-
0-tetranor-8-azaprost-13-enoic acid
##STR03385##
[0766] TLC: Rf 0.21 (Chloroform:Methanol=8:1);
[0767] NMR: .delta. 7.48-6.80 (m, 8H), 5.70 (dd, J=15.3, 6.3 Hz,
1H), 5.51 (m, 1H), 4.44 (m, 1H), 4.06 (m, 1H), 3.49 (m, 1H),
3.06-2.60 (m, 3H), 2.54-1.96 (m, 5H), 1.82-1.00 (m, 9H).
[0768] The hydroxyl group bound benzene ring was protected by THP
group, and was removed protecting group at final step.
EXAMPLE 2(dd)
(15.alpha.,13E)-1,5-(2,5-Interthienylene)-9-oxo-15-hydroxy-16-(3-chlorophe-
nyl)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic acid
##STR03386##
[0770] TLC: Rf 0.20 (Chloroform:Methanol=10:1);
[0771] NMR: .delta. 7.68 (d, J=3.6 Hz, 1H), 7.23-7.18 (m, 3H), 7.08
(m, 1H), 6.83 (d, J=3.6 Hz, 1H), 5.71 (dd, J=15.3, 6.0 Hz, 1H),
5.48 (ddd, J=15.3, 8.7, 0.9 Hz, 1H), 4.39 (m, 1H), 4.02 (m, 1H),
3.53 (m, 1H), 3.40 (br s, 1H), 2.90-2.70 (m, 5H), 2.50-2.10 (m,
3H), 1.90-1.60 (m, 3H).
EXAMPLE 2(ee)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-cyclopropylphenyl)-17,18,19,20-tetr-
anor-8-azaprost-13-enoic acid
##STR03387##
[0773] TLC: Rf 0.45 (Chloroform:Methanol:Water=9:1:0.1);
[0774] NMR: .delta. 7.19 (t, J=7.7 Hz, 1H), 7.02-6.89 (m, 3H), 5.73
(dd, J=15.4, 5.8 Hz, 1H), 5.48 (ddd, J=15.4, 8.5, 1.0 Hz, 1H), 4.42
(m, 1H), 4.04 (m, 1H), 3.45 (m, 1H), 2.81 (d, J=6.6 Hz, 2H), 2.75
(m, 1H), 2.43-2.30 (m, 2H), 2.32 (t, J=7.1 Hz, 2H), 2.21 (m, 1H),
1.86 (m, 1H), 1.71 (m, 1H), 1.67-1.56 (m, 2H), 1.52-1.19 (m, 6H),
1.00-0.90 (m, 2H), 0.74-0.63 (m, 2H).
EXAMPLE 2(ff)
(13E)-9-Oxo-15-hydroxy-16,16-difluoro-16-(3-methoxymethylphenyl)-17,18,19,-
20-tetranor-8-azaprost-13-enoic acid
##STR03388##
[0776] TLC: Rf 0.34 (Chloroform:Methanol=9:1);
[0777] NMR: .delta. 7.57-7.35 (m, 4H), 5.78-5.59 (m, 2H), 4.61-4.43
(m, 3H), 4.04 (m, 1H), 3.50-3.32 (m, 4H), 2.82 (m, 1H), 2.43-2.10
(m, 5H), 1.72-1.20 (m, 9H).
EXAMPLE 2(gg)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-ethoxyphenyl)-17,18,19,20-tetranor--
8-azaprost-13-enoic acid
##STR03389##
[0779] TLC: Rf 0.48 (Chloroform:Methanol:Water=9:1:0.1);
[0780] NMR: .delta. 7.22 (t, J=7.7 Hz, 1H), 6.81-6.73 (m, 3H), 5.73
(dd, J=15.4, 6.1 Hz, 1H), 5.48 (ddd, J=15.4, 8.5, 1.1 Hz, 1H), 4.41
(m, 1H), 4.03 (m, 1H), 4.02 (q, J=7.1 Hz, 2H), 3.45 (m, 1H), 2.81
(d, J=6.6 Hz, 2H), 2.72 (m, 1H), 2.42-2.32 (m, 4H), 2.21 (m, 1H),
1.76-1.58 (m, 3H), 1.48-1.20 (m, 6H), 1.42 (t, J=7.1 Hz, 3H).
EXAMPLE 2(hh)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-isopropyloxyphenyl)-17,18,19,20-tet-
ranor-8-azaprost-13-enoic acid
##STR03390##
[0782] TLC: Rf 0.45 (Chloroform:Methanol:Water=9:1:0.1);
[0783] NMR: .delta. 7.20 (t, J=7.7 Hz, 1H), 6.80-6.75 (m, 3H), 5.73
(dd, J=15.4, 6.0 Hz, 1H), 5.49 (ddd, J=15.4, 8.5, 1.1 Hz, 1H), 4.55
(m, 1H), 4.40 (m, 1H), 4.04 (m, 1H), 3.54 (m, 1H), 2.80 (d, J=6.6
Hz, 2H), 2.74 (m, 1H), 2.42-2.32 (m, 4H), 2.21 (m, 1H), 1.77-1.58
(m, 3H), 1.50-1.20 (m, 6H), 1.38 (d, J=6.0 Hz, 6H).
EXAMPLE 2(ii)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-benzyloxyphenyl)-17,18,19,20-tetran-
or-8-azaprost-13-enoic acid
##STR03391##
[0785] TLC: Rf 0.49 (Chloroform:Methanol:Water=9:1:0.1);
[0786] NMR: .delta. 7.45-7.28 (m, 5H), 7.23 (t, J=7.7 Hz, 1H),
6.89-6.76 (m, 3H), 5.71 (dd, J=15.4, 6.0 Hz, 1H), 5.45 (ddd,
J=15.4, 8.5, 0.8 Hz, 1H), 5.03 (s, 2H), 4.39 (m, 1H), 4.01 (m, 1H),
3.45 (m, 1H), 2.81 (d, J=6.9 Hz, 2H), 2.71 (m, 1H), 2.41-2.27 (m,
4H),2.20 (m, 1H), 1.75-1.54 (m, 3H), 1.48-1.20 (m, 6H).
EXAMPLE 2(jj)
(15.alpha.,5Z,13E)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-
-tetranor-8-azaprost-5,13-dienoic acid
##STR03392##
[0788] TLC: Rf 0.31 (Chloroform:Methanol=9:1);
[0789] NMR: .delta. 7.32-7.11 (m, 4H), 5.70 (dd, J=16, 5 Hz, 1H),
5.60-5.48 (m, 2H), 5.34-5.25 (m, 1H), 4.44 (s, 2H), 4.50-4.39 (m,
1H), 4.20 (dd, J=15, 5 Hz, 1H), 4.03 (dt, J=8, 5 Hz, 1H), 3.49 (dd,
J=15, 8 Hz, 1H), 3.42 (s, 3H), 2.92-2.78 (m, 2H), 2.50-2.05 (m,
7H), 1.77-1.61 (m, 3H).
EXAMPLE 2(kk)
(15.alpha.,5Z,13E)-9-Oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,-
20-tetranor-8-azaprost-5,13-dienoic acid
##STR03393##
[0791] TLC: Rf 0.27 (Chloroform:Methanol=8:1);
[0792] NMR: .delta. 7.62-7.26 (m, 4H), 5.67 (dd, J=15.6, 5.7 Hz,
1H), 5.62-5.44 (m, 2H), 5.28 (m, 1H), 4.45 (m, 1H), 4.21 (dd,
J=15.0, 6.6 Hz, 1H), 4.03 (m, 1H), 3.80-2.40 (br, 2H), 3.45 (m,
1H), 2.90 (d, J=6.6 Hz, 2H), 2.48-2.02 (m, 7H), 1.76-1.52 (m,
3H).
EXAMPLE 2(ll)
(15.alpha.,5Z,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetran-
or-8-azaprost-5,13-dienoic acid
##STR03394##
[0794] TLC: Rf 0.32 (Chloroform:Methanol=8:1);
[0795] NMR: .delta. 7.19 (dd, J=7.5, 7.5 Hz, 1H), 7.10-7.05 (m,
3H), 5.68 (dd, J=15.6, 5.7 Hz, 1H), 5.61-5.40 (m, 2H), 5.30 (m,
1H), 4.41 (m, 1H), 4.21 (m, 1H), 4.03 (m, 1H), 3.70-2.60 (br, 2H),
3.44 (m, 1H), 2.80 (d, J=6.6 Hz, 2H), 2.48-2.04 (m, 10H), 1.78-1.56
(m, 3H).
EXAMPLE 2(mm)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3,5-dimethylphenyl)-17,18,19,20-tetra-
nor-8-azaprost-13-enoic acid
##STR03395##
[0797] TLC: Rf 0.36 (Chloroform:Methanol=10:1);
[0798] NMR: .delta. 6.88 (s, 1H), 6.81 (s, 2H), 5.74 (dd, J=15.3,
5.7 Hz, 1H), 5.51 (dd, J=15.3, 8.4 Hz, 1H), 4.39 (m, 1H), 4.04 (m,
1H), 3.48 (m, 1H), 2.83-2.69 (m, 3H), 2.50-2.10 (m, 5H), 2.29 (s,
6H), 1.80-1.20 (m, 9H).
EXAMPLE 2(nn)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(benzofuran-2-yl)phenyl)-17,18,19,2-
0-tetranor-8-azaprost-13-enoic acid
##STR03396##
[0800] TLC: Rf 0.26 (Chloroform:Methanol=10:1);
[0801] NMR: .delta. 7.74-7.72 (m, 2H), 7.59-7.50 (m, 2H), 7.39 (m,
1H), 7.32-7.18 (m, 3H), 7.03 (d, J=1.2 Hz, 1H), 5.77 (dd, J=15.3,
6.3 Hz, 1H), 5.51 (ddd, J=15.3, 8.7, 0.9 Hz, 1H), 4.48 (m, 1H),
4.03 (m, 1H), 3.43 (m, 1H), 2.93 (d, J=6.6 Hz, 2H), 2.69(m, 1H),
2.45-2.10 (m, 5H), 1.75-1.10 (m, 9H).
EXAMPLE 2(oo)
(15.alpha.,13E)-2,7-(1,3-Interphenylene)-9-oxo-15-hydroxy-16-(3-methylphen-
yl)-3,4,5,6,17,18,19,20-octanor-8-azaprost-13-enoic acid
##STR03397##
[0803] TLC: Rf 0.42 (Chloroform:Methanol:Water=9:1:0.1);
[0804] NMR: .delta. 7.27-6.97 (m, 8H), 5.62 (dd, J=15.4, 5.8 Hz,
1H), 5.41 (ddd, J=15.4, 8.8, 1.1 Hz, 1H), 4.74 (d, J=14.6 Hz, 1H),
4.36 (m, 1H), 3.87 (m, 1H), 3.81 (d, J=14.6 Hz, 1H), 3.60 (s, 2H),
2.78 (d, J=6.6 Hz, 2H), 2.55-2.35 (m, 2H), 2.32 (s, 3H), 2.15 (m,
1H), 1.69 (m, 1H).
EXAMPLE 2(pp)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(2-phenylethynyl)phenyl)-17,18,19,2-
0-tetranor-8-azaprost-13-enoic acid
##STR03398##
[0806] TLC: Rf 0.21 (Chloroform:Methanol=8:1);
[0807] NMR: .delta. 7.60-7.14 (m, 9H), 5.72 (dd, J=15.3, 6.0 Hz,
1H), 5.47 (dd, J=15.3, 8.4 Hz, 1H), 4.43 (m, 1H), 4.03 (m, 1H),
3.46 (m, 1H), 2.94-2.62 (m, 3H), 2.48-2.12 (m, 5H), 1.80-1.16 (m,
9H).
EXAMPLE 2(qq)
(15.alpha.,5Z,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetran-
or-8-azaprost-5,13-dienoic acid
##STR03399##
[0809] TLC: Rf 0.31 (Chloroform:Methanol=8:1);
[0810] NMR: .delta. 7.40-7.00 (m, 4H), 5.66 (dd, J=15.6, 5.7 Hz,
1H), 5.61-5.22 (m, 3H), 4.41 (m, 1H), 4.22 (m, 1H), 4.03 (m, 1H),
3.80-2.80 (br, 2H), 3.44 (m, 1H), 2.90-2.70 (m, 3H), 2.48-2.02 (m,
6H), 1.76-1.54 (m, 3H).
EXAMPLE 2(rr)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetra-
nor-8-azaprost-5,13-dienoic acid
##STR03400##
[0812] TLC: Rf 0.24 (Chloroform:Methanol=8:1);
[0813] NMR: .delta. 7.20-6.84 (m, 3H), 5.66 (dd, J=15.3, 5.7 Hz,
1H), 5.62-5.22 (m, 3H), 4.38 (m, 1H), 4.21 (m, 1H), 4.04 (m, 1H),
4.02-3.00 (br, 2H), 3.46 (m, 1H), 2.79 (d, J=6.6 Hz, 2H), 2.50-2.02
(m, 7H), 1.80-1.54 (m, 3H).
EXAMPLE 2(ss)
(15.alpha.,13E)-2,7-(1,4-Interphenylene)-9-oxo-15-hydroxy-16-(3-methylphen-
yl)-3,4,5,6,17,18,19,20-octanor-8-azaprost-13-enoic acid
##STR03401##
[0815] TLC: Rf 0.25 (Chloroform:Methanol:Water=9:1:0.1);
[0816] NMR: .delta. 7.24-6.96 (m, 8H), 5.62 (dd, J=15.4, 6.0 Hz,
1H), 5.43 (ddd, J=15.4, 8.2, 0.8 Hz, 1H), 4.78 (d, J=14.8 Hz, 1H),
4.37 (m, 1H), 3.89 (m, 1H), 3.77 (d, J=14.8 Hz, 1H), 3.62 (s, 2H),
2.80 (d, J=6.6 Hz, 2H), 2.55-2.37 (m, 2H), 2.36 (s, 3H), 2.15 (m,
1H), 1.74 (m, 1H).
EXAMPLE 2(tt)
(15.alpha.,5Z,13E)-9-Oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetran-
or-8-azaprost-5,13-dienoic acid
##STR03402##
[0818] TLC: Rf 0.28 (Chloroform:Methanol=8:1);
[0819] NMR: .delta. 7.25 (m, 1H), 7.04-6.86 (m, 3H), 5.66 (dd,
J=15.3, 5.7 Hz, 1H), 5.60-5.20 (m, 3H), 4.42 (m, 1H), 4.40-2.80
(br, 2H), 4.21 (m, 1H), 4.03 (m, 1H), 3.44 (m, 1H), 2.90-2.72 (m,
2H), 2.48-2.02 (m, 7H), 1.78-1.56 (m, 3H).
EXAMPLE 2(uu)
(15.alpha.5Z,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetrano-
r-8-azaprost-5,13-dienoic acid
##STR03403##
[0821] TLC: Rf 0.28 (Chloroform:Methanol=8:1);
[0822] NMR: .delta. 7.22-7.10 (m, 2H), 7.05-6.93 (m, 2H), 5.66 (dd,
J=15.6, 5.7 Hz, 1H), 5.61-5.20 (m, 3H), 4.70-3.20 (br, 2H), 4.38
(m, 1H), 4.20 (m, 1H), 4.02 (m, 1H), 3.44 (m, 1H), 2.81 (d, J=6.6
Hz, 2H), 2.48-2.02 (m, 7H), 1.78-1.56 (m, 3H).
EXAMPLE 2(vv)
(15.alpha.5Z,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-2,6-(1,3-interpheny-
lene)-3,4,5,17,18,19,20-heptanor-8-azaprost-13-enoic acid
##STR03404##
[0824] TLC: Rf 0.30 (Chloroform:Methanol=9:1);
[0825] NMR: .delta. 7.25-7.0 (m, 8H), 5.51 (dd, J=15, 6 Hz, 1H),
5.25 (dd, J=15, 8 Hz, 1H), 4.4-4.3 (m, 1H), 3.75-3.65 (m, 1H), 3.62
(s, 2H), 3.65-3.55 (m, 1H), 3.3-2.4 (br), 3.0-2.7 (m, 5H), 2.4-2.2
(m, 2H), 2.1-1.95 (m, 1H), 1.65-1.5 (m, 1H).
EXAMPLE 2(ww)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-1,5-(2,5-interthienyl-
ene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic acid
##STR03405##
[0827] TLC: Rf 0.31 (Chloroform:Methanol:Water=9:1:0.1);
[0828] NMR: .delta. 7.68 (d, J=3.8 Hz, 1H), 7.19 (t, J=7.4 Hz, 1H),
7.07-6.96 (m, 3H), 6.83 (d, J=3.8 Hz, 1H), 5.75 (dd, J=15.4, 6.0
Hz, 1H), 5.47 (ddd, J=15.4, 8.8, 1.1 Hz, 1H), 4.38 (m, 1H), 4.02
(m, 1H), 3.53 (m, 1H), 2.90-2.76 (m, 5H), 2.46-2.37 (m, 2H), 2.33
(s, 3H), 2.21 (m, 1H), 1.90-1.65 (m, 3H).
EXAMPLE 2(xx)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-5-(5-(5-oxo-1,2,4-oxa-
diazol-3-yl)thiophen-2-yl)-1,2,3,4,17,18,19,20-octanor-8-azaprost-13-ene
##STR03406##
[0830] TLC: Rf 0.24 (Chloroform:Methanol=9:1);
[0831] NMR(DMSO-d.sub.6): .delta. 12.98 (br. s, 1H), 7.52 (d, J=4.0
Hz, 1H), 7.22-7.14 (m, 2H), 7.08-6.99 (m, 3H), 5.62 (dd, J=15.0,
6.2 Hz, 1H), 5.30 (dd, J=15.0, 8.8 Hz, 1H), 4.97 (br. s, 1H), 4.16
(m, 1H), 4.00 (m, 1H), 3.28 (m, 2H), 2.81-2.58 (m, 4H), 2.22-2.03
(m, 3H), 1.77-1.50 (m, 3H).
[0832] Hydrolysis of the ester (procedure of Example 2) was not
done. The NH group bound 1,2,4-oxadiazole ring was protected by Boc
group, and was removed protecting group at final step.
EXAMPLE 2(yy)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-1,5-(2,5-interfurylen-
e)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic acid
##STR03407##
[0834] TLC: Rf 0.25 (Chloroform:Methanol=2:1);
[0835] NMR: .delta. 7.20-7.14 (m, 3H), 7.04-6.94 (m, 2H), 6.21 (d,
J=3.6 Hz, 1H), 5.73 (dd, J=15.4, 5.8 Hz, 1H), 5.49 (dd, J=15.4, 8.8
Hz, 1H), 5.14 (brs, 2H), 4.38 (m, 1H), 4.06 (m, 1H), 3.51 (m, 1H),
2.86 (m, 1H), 2.81 (d, J=6.6 Hz, 2H), 2.66 (t, J=7.4 Hz, 2H),
2.48-2.29 (m, 2H), 2.18 (m, 1H), 1.93-1.80 (m, 2H), 1.72 (m,
1H).
EXAMPLE 2(zz)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-3,7-(2,5-interthienyl-
ene)-4,5,6,17,18,19,20-heptanor-8-azaprost-13-enoic acid
##STR03408##
[0837] TLC: Rf 0.48 (Chloroform:Methanol=9:1);
[0838] NMR(CDCl.sub.3+CD.sub.3OD): .delta. 7.25-7.15 (m, 2H),
7.05-6.95 (m, 2H), 6.7-6.6 (m, 2H), 5.72 (dd, J=16, 6 Hz, 1H), 5.45
(dd, J=16, 8 Hz, 1H), 4.78 (d, J=15 Hz, 1H), 4.37 (q, J=6 Hz, 1H),
4.05-3.95 (m, 1H), 3.90 (d, J=15 Hz, 1H), 3.09 (t, J=7 Hz, 2H),
2.83 (d, J=6 Hz, 2H), 2.65 (t, J=7 Hz, 2H), 2.5-2.25 (m, 2H),
2.25-2.1 (m, 1H), 1.8-1.6 (m, 1H).
EXAMPLE 2(aaa)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-5-(5-(tetrazol-5-yl)t-
hiophen-2-yl)-1,2,3,4,17,18,19,20-octanor-8-azaprost-13-ene
##STR03409##
[0840] TLC: Rf 0.52 (Chloroform:Methanol=2:1);
[0841] NMR(DMSO-d.sub.6): .delta. 7.59 (d, J=3.7 Hz, 1H), 7.21-7.13
(m, 2H), 7.08-6.99 (m, 3H), 5.62 (dd, J=15.4, 6.2 Hz, 1H), 5.31
(dd, J=15.4, 8.8 Hz, 1H), 4.97 (br, 1H), 4.17 (m, 1H), 4.02 (m,
1H), 3.33 (m, 1H), 2.82-2.58 (m, 5H), 2.27-2.03 (m, 3H), 1.80-1.49
(m, 3H).
[0842] Hydrolysis of the ester (procedure of Example 2) was not
done. The NH group bound 1,2,4-oxadiazole ring was protected by Boc
group, and was removed protecting group at final step.
EXAMPLE 2(bbb)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(naphthalen-1-yl)-17,18,19,20-tetranor-
-8-azaprost-13-enoic acid
##STR03410##
[0844] TLC: Rf 0.45 (Chloroform:Methanol:Water=9:1:0.1);
[0845] NMR: .delta. 8.04 (m, 1H), 7.87 (m, 1H), 7.76 (m, 1H),
7.57-7.46 (m, 2H), 7.44-7.32 (m, 2H), 5.78 (dd, J=15.4, 6.1 Hz,
1H), 5.45 (ddd, J=15.4, 8.5, 1.1 Hz, 1H), 4.57 (m, 1H), 3.97 (m,
1H), 3.35 (m, 1H), 3.32 (d, J=6.6 Hz, 2H), 2.64 (m, 1H), 2.37-2.32
(m, 2H), 2.34 (t, J=7.1 Hz, 2H), 2.15 (m, 1H), 1.64-1.55 (m, 3H),
1.43-1.15 (m, 6H).
REFERENCE EXAMPLE 6
2-((5R)-5-t-Butyldimethylsilyloxymethyl-2-oxopyrrolidin-1-yl)acetic
acid methyl ester
##STR03411##
[0847] Under atmosphere of argon, a solution of potassium
t-butoxide (11.58 g) in dry tetrahydrofuran (100 mL) was added to
the solution of the compound prepared in Reference Example 1 (21.41
g) in tetrahydrofuran (200 mL) on water bath. After the mixture was
stirred for 1 hour, a solution of bromoacetic acid methyl ester
(9.75 mL) in tetrahydrofuran (50 mL) was added hereto. Then hexane
was added to the mixture. The diluted solution was washed with
water and brine successively, dried over an anhydrous sodium
sulfate, concentrated under reduced pressure and was purified by
column chromatography on silica gel (ethyl acetate:hexane=from 1:2
to 1:1, then 3:1) to give the title compound (22.13 g) having the
following physical data.
[0848] TLC: Rf 0.48 (Ethyl Acetate:Hexane=1:1).
REFERENCE EXAMPLE 7
2-((5R)-5-t-Butyldimethylsilyloxymethyl-2-oxopyrrolidin-1-yl)ethanol
##STR03412##
[0850] To a solution of the compound prepared in Reference Example
6 (22.0 g) in tetrahydrofuran (100 mL), sodium borohydride (8.28 g)
was added, and the mixture was stirred for 5 minutes. Methanol (20
mL) was added hereto, and the mixture was stirred for 15 minutes.
Methanol (30 mL) was added hereto again, and the mixture was
stirred for 1 hour. After water was added to the mixture, ethyl
acetate was added hereto. The organic layer was washed with water
and brine successively, dried over an anhydrous sodium sulfate,
concentrated under reduced pressure to give the title compound
(19.75 g) having the following physical data.
[0851] TLC: Rf 0.43 (Ethyl Acetate).
REFERENCE EXAMPLE 8
(5R)-2-(5-t-Butyldimethylsilyloxymethyl-2-oxopyrrolidinyl)ethyl
thioacetate
##STR03413##
[0853] Under atmosphere of argon, a mixture of the compound
prepared in Reference Example 7 (22.0 g), triethylamine (13.0 mL)
and dry tetrahydrofuran (150 mL) was dropped by mesyl chloride (6.7
mL) at -5.degree. C., and the mixture was stirred for 45 minutes.
After reaction was terminated, methanol (0.81 mL) was added hereto,
and the mixture was stirred for 15 minutes. To the mixture, a
mixture of potassium carbonate (20.0 g), potassium thioacetate and
dry dimethylformamide (150 mL) was added, and the mixture was
stirred for 3 hours at 50.degree. C., then for 2 days at room
temperature. Then mixed solvent of ethyl acetate and hexane was
added to the mixture. The diluted solution was washed with water
and brine successively, dried over an anhydrous sodium sulfate,
concentrated under reduced pressure to give the title compound
(26.8 g) having the following physical data.
[0854] TLC: Rf 0.83 (Ethyl Acetate).
REFERENCE EXAMPLE 9
9-Oxo-13-(t-butyldimethylsilyloxy)-14,15,16,17,18,19,20-heptanor-5-thia-8--
azaprostanoic acid methyl ester
##STR03414##
[0856] Under atmosphere of argon, a solution of the compound
prepared in Reference Example 8 (26.8 g) and 4-iodobutanoic acid
methyl ester (19.9 g) in dry methanol (150 mL) was added by
potassium carbonate (14.0 g), and the mixture was stirred for 2
hours. Then mixed solvent of diethyl ether and ethyl acetate was
added to the mixture. The diluted solution was washed with 0.5N
hydrochloric acid, water and brine successively, dried over an
anhydrous sodium sulfate, concentrated under reduced pressure to
give the title compound (31.28 g) having the following physical
data.
[0857] TLC: Rf 0.67 (Ethyl Acetate:Hexane=1:1).
REFERENCE EXAMPLE 10
9-Oxo-13-hydroxy-14,15,16,17,18,19,20-heptanor-5-thia-8-azaprostanoic
acid methyl ester
##STR03415##
[0859] To a solution of the compound prepared in Reference Example
9 (31.28 g) in methanol (70 mL), p-toluenesulfonic acid monohydrate
(2.41 g) was added, and the mixture was stirred for 4 hours at
50.degree. C. It was cooled to room temperature, the mixture was
added by triethylamine (1.95 mL), concentrated under reduced
pressure and was purified by column chromatography on silica gel
(from ethyl acetate:hexane=1:1 to ethyl acetate:methanol=100:1) to
give the title compound (16.67 g) having the following physical
data.
[0860] TLC: Rf 0.14 (Ethyl Acetate).
REFERENCE EXAMPLE 11
9-Oxo-12-formyl-13,14,15,16,17,18,19,20-octanor-5-thia-8-azaprostanoic
acid methyl ester
##STR03416##
[0862] Under atmosphere of argon, a solution of the compound
prepared in Reference Example 10 (1.04 g) and diisopropylethylamine
(3.8 mL) in mixed solvent of ethyl acetate (6 mL) and
dimethylsulfoxide (6 mL) was added by sulfur trioxide pyridine
complex (1.72 g) on ice bath, and the mixture was stirred for 40
minutes. 0.5N hydrochloric acid was added to the reaction mixture,
then the mixture was extracted by chloroform. The organic layer was
dried over an anhydrous sodium sulfate, concentrated under reduced
pressure to give the title compound (1.0 g) having the following
physical data.
[0863] TLC: Rf 0.50 (Chloroform:Methanol=9:1).
EXAMPLE 3(a) TO EXAMPLE 3(rr)
[0864] By the same procedure as describe in Reference Example 5,
Examples 1 and 2 using the compound prepared in Reference Example
11 or corresponding aldehyde derivatives instead of the compound
prepared in Reference Example 4, the compound of the present
invention having the following physical data were obtained.
EXAMPLE 3(a)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-te-
tranor-5-thia-8-azaprost-13-enoic acid
##STR03417##
[0866] TLC: Rf 0.35 (Methanol:Chloroform=1:5);
[0867] NMR: .delta. 7.40-7.10 (m, 4H), 5.79 (dd, J=15.4, 5.2 Hz,
1H), 5.54 (dd, J=15.4, 8.4 Hz, 1H), 4.50-4.40 (m, 1H), 4.46 (s,
2H), 4.20-4.05 (m, 1H), 3.70-3.50 (m, 1H), 3.42 (s, 3H), 3.20-2.90
(m, 1H), 2.90-2.80 (m, 2H), 2.80-2.10 (m, 9H), 2.00-1.60 (m,
3H).
EXAMPLE 3(b)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid
##STR03418##
[0869] TLC: Rf 0.45 (Methanol:Chloroform=1:5);
[0870] NMR: .delta. 7.30-7.20 (m, 3H), 7.20-7.05 (m, 1H), 5.75 (dd,
J=15.4, 5.4 Hz, 1H), 5.49 (dd, J=15.4, 8.6 Hz, 1H), 4.50-4.35 (m,
1H), 4.20-4.05 (m, 1H), 3.75-3.55 (m, 1H), 3.10-2.85 (m, 1H), 2.85
(d, J=6.6 Hz, 2H), 2.80-2.10 (m, 9H), 2.00-1.80 (m, 2H), 1.80-1.60
(m, 1H).
EXAMPLE 3(c)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-cyclopropyloxymethylphenyl)-17,18,1-
9,20-tetranor-5-thia-8-azaprost-13-enoic acid
##STR03419##
[0872] TLC: Rf 0.47 (Chloroform:Methanol=9:1);
[0873] NMR: .delta. 7.37-7.11 (m, 4H), 5.80 (dd, J=15, 5 Hz, 1H),
5.55 (dd, J=15, 8 Hz, 1H), 4.56 (s, 2H), 4.50-4.40 (m, 1H),
4.17-4.08 (m, 1H), 3.63-3.51 (m, 1H), 3.42-3.36 (m, 1H), 3.11-3.00
(m, 1H), 2.89 (dd, J=14, 6 Hz, 1H), 2.80 (dd, J=14, 8 Hz, 1H),
2.72-2.32 (m, 8H), 2.31-2.17 (m, 1H), 1.98-1.83 (m, 2H), 1.79-1.65
(m, 1H), 0.71-0.49 (m, 4H).
EXAMPLE 3(d)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(2,2,2-trifluoroethoxymethyl)phenyl-
)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid
##STR03420##
[0875] TLC: Rf 0.47 (Chloroform:Methanol=9:1);
[0876] NMR: .delta. 7.38-7.14 (m, 4H), 5.77 (dd, J=15, 6 Hz, 1H),
5.53 (dd, J=15, 8 Hz, 1H), 4.65 (s, 2H), 4.50-4.40 (m, 1H),
4.18-4.08 (m, 1H), 3.86 (q, J=9 Hz, 2H), 3.68-3.55 (m, 1H),
3.08-2.94 (m, 1H), 2.94-2.79 (m, 2H), 2.68-2.32 (m, 8H), 2.32-2.17
(m, 1H), 1.98-1.82 (m, 2H), 1.78-1.63 (m, 1H).
EXAMPLE 3(e)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid
##STR03421##
[0878] TLC: Rf 0.50 (Methanol:Ethyl Acetate=1:5);
[0879] NMR: .delta. 7.30-7.20 (m, 1H), 7.10-7.00 (m, 3H), 5.78 (dd,
J=15.4, 5.4 Hz, 1H), 5.52 (dd, J=15.4, 8.4 Hz, 1H), 4.50-4.40 (m,
1H), 4.20-4.05 (m, 1H), 3.75-3.55 (m, 1H), 3.20-2.10 (m, 14H),
2.00-1.80 (m, 2H), 1.80-1.55 (m, 3H), 0.94 (t, J=7.2 Hz, 3H).
EXAMPLE 3(f)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-cyclopentyl-17,18,19,20-tetranor-5-thi-
a-8-azaprost-13-enoic acid
##STR03422##
[0881] TLC: Rf 0.26 (Chloroform:Methanol=9:1);
[0882] NMR: .delta. 5.75 (dd, J=15.3, 6.0 Hz, 1H), 5.53 (ddd,
J=15.3, 8.0, 1.0 Hz, 1H), 4.29-4.10 (m, 2H), 3.77-3.60 (m, 1H),
3.20-3.08 (m, 1H), 2.79-1.43 (m, 22H), 1.22-1.04 (m, 2H).
EXAMPLE 3(g)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(thiophen-2-yl)-17,18,19,20-tetranor-5-
-thia-8-azaprost-13-enoic acid
##STR03423##
[0884] TLC: Rf 0.18 (Chloroform:Methanol=9:1);
[0885] NMR: .delta. 7.19 (d, J=5.1 Hz, 1H), 6.95 (dd, J=5.1, 3.3
Hz, 1H), 6.86 (d, J=3.3 Hz, 1H), 5.75 (dd, J=15.0, 5.4 Hz, 1H),
5.55 (dd, J=15.0, 8.6 Hz, 1H), 4.48-4.39 (m, 1H), 4.19-4.06 (m,
1H), 3.70-3.59 (m, 1H), 3.42-2.75 (m, 4H), 2.70-2.18 (m, 10H),
1.99-1.84 (m, 2H), 1.79-1.62 (m, 1H).
EXAMPLE 3(h)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20--
tetranor-5-thia-8-azaprost-13-enoic acid
##STR03424##
[0887] TLC: Rf 0.40 (Chloroform:Methanol=9:1);
[0888] NMR: .delta. 7.59-7.38 (m, 4H), 5.82-5.71 (m, 1H), 5.60-5.41
(m, 1H), 4.57-4.40 (m, 1H), 4.20-4.06 (m, 1H), 3.70-3.59 (m, 1H),
3.15-2.81 (m, 3H), 2.80-2.01 (m, 10H), 1.99-1.80 (m, 2H), 1.79-1.60
(m, 1H).
EXAMPLE 3(i)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-5-thia-8-a-
zaprost-13-enoic acid
##STR03425##
[0890] TLC: Rf 0.40 (Chloroform:Methanol=10:1);
[0891] NMR: .delta. 7.32-7.19 (m, 5H), 5.77 (dd, J=15.3, 5.4 Hz,
1H), 5.51 (ddd, J=15.3, 8.4, 1.2 Hz, 1H), 4.41 (m, 1H), 4.11 (m,
1H), 3.62 (m, 1H), 2.95 (m, 1H), 2.86 (d, J=6.6 Hz, 2H), 2.65-2.20
(m, 9H), 2.00-1.80 (m, 2H), 1.70 (m, 1H).
EXAMPLE 3(j)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid
##STR03426##
[0893] TLC: Rf 0.32 (Chloroform:Methanol=10:1);
[0894] NMR: .delta. 7.21 (m, 1H), 7.07-6.98 (m, 3H), 5.78 (dd,
J=15.3, 5.4 Hz, 1H), 5.52 (ddd, J=15.3, 8.7, 1.2 Hz, 1H), 4.43 (m,
1H), 4.11 (m, 1H), 3.62 (m, 1H), 2.95 (m, 1H), 2.83-2.20 (m, 11H),
2.34 (S, 3H), 2.00-1.80 (m, 2H), 1.70 (m, 1H).
EXAMPLE 3(k)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid
##STR03427##
[0896] TLC: Rf 0.38 (Chloroform:Methanol:Water=9:1:0.1);
[0897] NMR: .delta. 7.27 (m, 1H), 7.00-6.89 (m, 3H), 5.75 (dd,
J=15.4, 5.5 Hz, 1H), 5.50 (dd, J=15.4, 8.5 Hz, 1H), 4.42 (m, 1H),
4.11 (m, 1H), 3.62 (m, 1H), 2.92 (m, 1H), 2.84 (d, J=6.9 Hz, 2H),
2.67-2.51 (m, 4H), 2.50-2.41 (m, 2H), 2.38 (t, J=7.1 Hz, 2H), 2.22
(m, 1H), 1.94-1.83 (m, 2H), 1.66 (m, 1H).
[0898] EXAMPLE 3(l)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid
##STR03428##
[0900] TLC: Rf 0.38 (Chloroform:Methanol:Water=9:1:0.1);
[0901] NMR: .delta. 7.20-7.16 (m, 2H), 7.04-6.96 (m, 2H), 5.75 (dd,
J=15.4, 6.0 Hz, 1H), 5.50 (ddd, J=15.4, 8.5, 1.1 Hz, 1H), 4.39 (m,
1H), 4.11 (m, 1H), 3.62 (m, 1H), 2.95 (m, 1H), 2.82 (d, J=6.6 Hz,
2H), 2.67-2.53 (m, 4H), 2.52-2.43 (m, 2H), 2.39 (t, J=7.1 Hz, 2H),
2.22 (m, 1H), 1.94-1.83 (m, 2H), 1.68 (m, 1H).
EXAMPLE 3(m)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetra-
nor-5-thia-8-azaprost-13-enoic acid
##STR03429##
[0903] TLC: Rf 0.24 (Chloroform:Methanol=10:1);
[0904] NMR: .delta. 7.14-7.00 (m, 2H), 6.92 (m, 1H), 5.76 (dd,
J=15.6, 5.4 Hz, 1H), 5.54 (ddd, J=15.6, 8.4, 1.2 Hz, 1H), 4.40 (m,
1H), 4.12 (m, 1H), 3.63 (m, 1H), 3.00 (m, 1H), 2.82-2.10 (m, 11H),
2.00-1.60 (m, 3H).
EXAMPLE 3(n)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(naphthalen-2-yl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid
##STR03430##
[0906] TLC: Rf 0.27 (Chloroform:Methanol=10:1);
[0907] NMR: .delta. 7.82-7.77 (m, 3H), 7.65 (s, 1H), 7.50-7.40 (m,
2H), 7.32 (dd, J=8.4, 1.5 Hz, 1H), 5.80 (dd, J=15.6, 5.1 Hz, 1H),
5.51 (ddd, J=15.6, 8.4, 1.2 Hz, 1H), 4.53 (m, 1H), 4.11 (m, 1H),
3.53 (m, 1H), 3.02 (d, J=6.6 Hz, 2H), 2.86 (m, 1H), 2.60-2.10 (m,
9H), 2.00-1.60 (m, 3H).
EXAMPLE 3(o)
(15.alpha.,13E)-2,3-Methano-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,-
20-tetranor-5-thia-8-azaprost-13-enoic acid
##STR03431##
[0909] TLC: Rf 0.37 (Chloroform:Methanol=10:1);
[0910] NMR: .delta. 7.26-7.19 (m, 3H), 7.09 (m, 1H), 5.73 (dd,
J=15.3, 5.7 Hz, 1H), 5.48 (m, 1H), 4.41 (m, 1H), 4.12 (m, 1H), 3.62
(m, 1H), 3.05-2.20 (m, 9H), 2.83 (d, J=6.3 Hz, 2H), 1.80-1.60 (m,
2H), 1.34 (m, 1H), 0.90 (m, 1H).
EXAMPLE 3(p)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-t-butylphenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid
##STR03432##
[0912] TLC: Rf 0.43 (Chloroform:Methanol=9:1);
[0913] NMR: .delta. 7.38-7.20 (m, 3H), 7.06-6.99 (m, 1H), 5.79 (dd,
J=15.3, 5.4 Hz, 1H), 5.54 (dd, J=15.3, 8.4 Hz, 1H), 4.43 (m, 1H),
4.12 (m, 1H), 3.62 (m, 1H), 3.37-2.20 (m, 14H), 1.99-1.83 (m, 2H),
1.73 (m, 1H), 1.31 (s, 9H).
EXAMPLE 3(q)
(13E)-9-Oxo-15-hydroxy-16a-methyl-16-phenyl-17,18,19,20-tetranor-5-thia-8--
azaprost-13-enoic acid
##STR03433##
[0915] TLC: Rf 0.32 (Chloroform:Methanol=8:1);
[0916] NMR: .delta. 7.40-7.12 (m, 5H), 5.58 (dd, J=15.3, 6.3 Hz,
1H), 5.36 (ddd, J=15.3, 8.4, 0.9 Hz, 1H), 4.26 (m, 1H), 4.02 (m,
1H), 3.90-2.80 (br, 2H), 3.52 (m, 1H), 2.85 (m, 1H), 2.66 (m, 1H),
2.60-2.06 (m, 9H), 1.98-1.80 (m, 2H), 1.61 (m, 1H), 1.35 (d, J=7.2
Hz, 3H).
[0917] Stereochemistry at C15 position is not determined, but this
compound is a single isomer.
EXAMPLE 3(r)
(13E)-9-Oxo-15-hydroxy-16.beta.-methyl-16-phenyl-17,18,19,20-tetranor-5-th-
ia-8-azaprost-13-enoic acid
##STR03434##
[0919] TLC: Rf 0.25 (Chloroform:Methanol=8:1);
[0920] NMR: .delta. 7.42-7.14 (m, 5H), 5.73 (dd, J=15.3, 6.3 Hz,
1H), 5.55 (dd, J=15.3, 8.1 Hz, 1H), 4.24 (dd, J=6.6, 6.3 Hz, 1H),
4.15 (m, 1H), 3.71 (m, 1H), 3.60-2.70 (br, 2H), 3.06 (m, 1H), 2.84
(m, 1H), 2.76-2.14 (m, 9H), 2.00-1.82 (m, 2H), 1.71 (m, 1H), 1.27
(d, J=7.2 Hz, 3H).
[0921] Stereochemistry at C15 position is not determined, but this
compound is a single isomer.
EXAMPLE 3(s)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-ethylphenyl)-17,18,19,20-tetranor-5-
-thia-8-azaprost-13-enoic acid
##STR03435##
[0923] TLC: Rf 0.49 (Chloroform:Methanol=9:1);
[0924] NMR: .delta. 7.24 (m, 1H), 7.13-6.98 (m, 3H), 5.78 (dd,
J=15.4, 5.5 Hz, 1H), 5.52 (ddd, J=15.4, 8.2, 1.1 Hz, 1H), 4.42 (m,
1H), 4.12 (m, 1H), 3.63 (m, 1H), 3.00 (m, 1H), 2.90-2.77 (m, 2H),
2.67-2.35 (m, 10H), 2.23 (m, 1H), 1.95-1.85 (m, 2H), 1.72 (m, 1H),
1.22 (t, J=7.4 Hz, 3H).
EXAMPLE 3(t)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluoro-3-trifluoromethylphenyl)-17,-
18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid
##STR03436##
[0926] TLC: Rf 0.35 (Chloroform:Methanol=8:1);
[0927] NMR: .delta. 7.52-7.35 (m, 2H), 7.14 (dd, J=9.3, 9.3 Hz,
1H), 5.77 (dd, J=15.3, 5.4 Hz, 1H), 5.54 (ddd, J=15.3, 8.1, 0.9 Hz,
1H), 4.42 (m, 1H), 4.14 (m, 1H), 4.06-1.10 (m, 18H).
EXAMPLE 3(u)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluoro-3-methylphenyl)-17,18,19,20--
tetranor-5-thia-8-azaprost-13-enoic acid
##STR03437##
[0929] TLC: Rf 0.26 (Chloroform:Methanol=8:1);
[0930] NMR: .delta. 7.06-6.88 (m, 3H), 5.75 (dd, J=15.3, 5.4 Hz,
1H), 5.51 (dd, J=15.3, 8.4 Hz, 1H), 4.39 (m, 1H), 4.12 (m, 1H),
3.80-2.80 (br, 2H), 3.63 (m, 1H), 2.99 (m, 1H), 2.86-2.06 (m, 14H),
1.98-1.62 (m, 3H).
EXAMPLE 3(v)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-chloro-4-fluorophenyl)-17,18,19,20--
tetranor-5-thia-8-azaprost-13-enoic acid
##STR03438##
[0932] TLC: Rf 0.22 (Chloroform:Methanol=8:1);
[0933] NMR: .delta. 7.24 (m, 1H), 7.13-7.04 (m, 2H), 5.75 (dd,
J=15.3, 5.7 Hz, 1H), 5.51 (ddd, J=15.3, 8.4, 0.9 Hz, 1H), 4.40 (m,
1H), 4.13 (m, 1H), 4.10-3.10 (br, 2H), 3.63 (m, 1H), 2.99 (m, 1H),
2.88-2.14 (m, 11H), 2.00-1.56 (m, 3H).
EXAMPLE 3(w)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid
##STR03439##
[0935] TLC: Rf 0.48 (Chloroform:Methanol=9:1);
[0936] NMR: .delta. 7.32-7.18 (m, 3H), 7.10 (m, 1H), 5.75 (dd,
J=15.0, 6.6 Hz, 1H), 5.41 (dd, J=15.0, 8.7 Hz, 1H), 4.39 (m, 1H),
4.11 (m, 1H), 3.62 (m, 1H), 3.18-2.12 (m, 13H), 1.98-1.82 (m, 2H),
1.60 (m, 1H).
EXAMPLE 3(x)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-5-(5-carboxythiazol-2-
-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene
##STR03440##
[0938] TLC: Rf 0.62 (Chloroform:Methanol:Acetic Acid=18:2:1);
[0939] NMR: .delta. 8.17 (s, 1H), 7.14 (t, J=8 Hz, 1H), 7.0-6.9 (m,
3H), 5.68 (dd, J=15, 7 Hz, 1H), 5.35 (dd, J=15, 9 Hz, 1H), 4.31 (q,
J=7 Hz, 1H), 4.25-4.1 (m, 1H), 3.7-3.55 (m, 1H), 3.4-3.2 (m, 2H),
3.05-2.9 (m, 1H), 2.88 (dd, J=13, 6 Hz, 1H), 2.63 (dd, J=13, 7 Hz,
1H), 2.4-2.25 (m, 5H), 2.25-2.1 (m, 1H), 1.75-1.6 (m, 1H).
EXAMPLE 3(y)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-4-(3-hydroxyisoxazol--
5-yl)-1,2,3,17,18,19,20-heptanor-5-thia-8-azaprost-13-ene
##STR03441##
[0941] TLC: Rf 0.44 (Chloroform:Methanol=8:1);
[0942] NMR: .delta. 7.25-7.16 (m, 3H), 7.08 (m, 1H), 5.87 (s, 1H),
5.72 (dd, J=15.3, 5.7 Hz, 1H), 5.48 (ddd, J=15.3, 8.4, 1.2 Hz, 1H),
4.44 (m, 1H), 4.06 (m, 1H), 3.75-3.52 (m, 3H), 2.93 (m, 1H),
2.88-2.48 (m, 6H), 2.42-2.30 (m, 2H), 2.22 (m, 1H), 1.67 (m,
1H).
[0943] Hydrolysis of the ester (procedure of Example 2) was not
done. The hydroxyl group bound isoxazole ring was protected by
methoxymethyl group, and was removed protecting group at final
step.
EXAMPLE 3(z)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-2-(5-oxo-1,2,4-oxadia-
zol-3-yl)-1,17,18,19,20-pentanor-5-thia-8-azaprost-13-ene
##STR03442##
[0945] TLC: Rf 0.39 (Chloroform:Methanol=9:1);
[0946] NMR: .delta. 7.38-7.15 (m, 3H), 7.14-7.02 (m, 1H), 5.74 (dd,
J=15.3, 6.0 Hz, 1H), 5.46 (ddd, J=15.3, 8.7, 1.0 Hz, 1H), 4.41 (m,
1H), 4.02 (m, 1H), 3.57 (m, 1H), 3.00-2.19 (m, 12H), 2.17-1.60 (m,
3H).
[0947] Hydrolysis of the ester (procedure of Example 2) was not
done. The NH group bound 1,2,4-oxadiazole ring was protected by Boc
group, and was removed protecting group at final step.
EXAMPLE 3(aa)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-2-(5-oxo-1,2,4-thiadi-
azol-3-yl)-1,17,18,19,20-pentanor-5-thia-8-azaprost-13-ene
##STR03443##
[0949] TLC: Rf 0.30 (Chloroform:Methanol=9:1);
[0950] NMR: .delta. 7.37-7.18 (m, 3H), 7.12-7.04 (m, 1H), 5.74 (dd,
J=15.0, 6.0 Hz, 1H), 5.47 (ddd, J=15.0, 8.7, 1.2 Hz, 1H), 4.42 (m,
1H), 4.03 (m, 1H), 3.60 (m, 1H), 3.00-2.70 (m, 4H), 2.69-2.38 (m,
7H), 2.28 (m, 1H), 2.15-1.70 (m, 3H).
[0951] Hydrolysis of the ester (procedure of Example 2) was not
done. The NH group bound 1,2,4-oxadiazole ring was protected by Boc
group, and was removed protecting group at final step.
EXAMPLE 3(bb)
(15.alpha.,13E)-1-Methoxy-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-
-tetranor-5-thia-8-azaprost-13-ene
##STR03444##
[0953] TLC: Rf 0.57 (Chloroform:Methanol=9:1);
[0954] NMR: .delta. 7.32-7.18 (m, 3H), 7.10 (m, 1H), 5.74 (dd,
J=15.4, 5.8 Hz, 1H), 5.51 (ddd, J=15.4, 8.5, 0.8 Hz, 1H), 4.41 (m,
1H), 4.14 (m, 1H), 3.62 (m, 1H), 3.40 (m, 2H), 3.32 (s, 3H), 2.94
(m, 1H), 2.82 (d, J=6.6 Hz, 2H), 2.71-2.48 (m, 4H), 2.42-2.35 (m,
2H), 2.24 (m, 1H), 1.77-1.63 (m, 5H).
[0955] Hydrolysis of the ester (procedure of Example 2) was not
done.
EXAMPLE 3(cc)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-5-(4-carboxythiazol-2-
-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene
##STR03445##
[0957] TLC: Rf 0.18 (Chloroform:Methanol:Acetic Acid=9:1:0.1);
[0958] NMR: .delta. 8.09 (s, 1H), 7.18-7.12 (m, 2H), 7.06-6.95 (m,
2H), 5.79 (dd, J=15.3, 5.7 Hz, 1H), 5.51 (dd, J=15.3, 9.0 Hz, 1H),
4.39 (m, 1H), 4.11 (m, 1H), 3.73 (m, 1H), 3.40-2.19 (m, 10H), 1.74
(m, 1H).
EXAMPLE 3(dd)
(15.alpha.,13E)-1-Methoxy-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-
-tetranor-5-thia-8-azaprost-13-ene
##STR03446##
[0960] TLC: Rf 0.59 (Chloroform:Methanol=9:1);
[0961] NMR: .delta. 7.19-7.15 (m, 2H), 7.04-6.98 (m, 2H), 5.74 (dd,
J=15.3, 5.7 Hz, 1H), 5.50 (ddd, J=15.3, 8.4, 1.2 Hz, 1H), 4.37 (m,
1H), 4.10 (m, 1H), 3.62 (m, 1H), 3.40-3.36 (m, 2H), 3.30 (s, 3H),
2.96 (m, 1H), 2.88-2.75 (m, 2H), 2.69-2.49 (m, 4H), 2.40-2.34 (m,
2H), 2.24 (m, 1H), 1.76-1.64 (m, 5H).
[0962] Hydrolysis of the ester (procedure of Example 2) was not
done.
EXAMPLE 3(ee)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-5-(5-(5-oxo-1,2,4-oxa-
diazol-3-yl)thiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-
-ene
##STR03447##
[0964] TLC: Rf 0.50 (Chloroform:Methanol:Acetic Acid=9:1:0.2);
[0965] NMR(CDCl.sub.3+CD.sub.3OD): .delta. 8.03 (s, 1H), 7.20-7.07
(m, 2H), 7.02-6.94 (m, 2H), 5.72 (dd, J=15.3, 5.7 Hz, 1H), 5.44
(dd, J=15.3, 8.7 Hz, 1H), 4.35 (m, 1H), 4.14 (m, 1H), 3.68 (m, 1H),
3.65-3.10 (m, 3H), 2.91-2.67 (m, 2H), 2.46-2.11 (m, 3H), 1.72 (m,
1H).
[0966] Hydrolysis of the ester (procedure of Example 2) was not
done. The NH group bound 1,2,4-oxadiazole ring was protected by Boc
group, and was removed protecting group at final step.
EXAMPLE 3(ff)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor--
5-thia-8-aza-10-oxaprost-13-enoic acid
##STR03448##
[0968] TLC: Rf 0.35 (Chloroform:Methanol=9:1);
[0969] NMR: .delta. 7.32-7.20 (m, 3H), 7.10 (m, 1H), 5.88 (dd,
J=15.4, 5.2 Hz, 1H), 5.56 (ddd, J=15.4, 8.5, 1.4 Hz, 1H), 4.50-4.29
(m, 2H), 4.43 (dd, J=8.5, 8.2 Hz, 1H), 3.89 (dd, J=8.5, 8.2 Hz,
1H), 3.46 (m, 1H), 3.10 (m, 1H), 2.84-2.80 (m, 2H), 2.77-2.44 (m,
6H), 1.98-1.87 (m, 2H).
EXAMPLE 3(gg)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-aza-10-oxaprost-13-enoic acid
##STR03449##
[0971] TLC: Rf 0.34 (Chloroform:Methanol=9:1);
[0972] NMR: .delta. 7.20-7.13 (m, 2H), 7.08-6.98 (m, 2H), 5.88 (dd,
J=15.4, 5.2 Hz, 1H), 5.57 (ddd, J=15.4, 8.5, 1.4 Hz, 1H), 4.47-4.28
(m, 2H), 4.42 (dd, J=8.5, 8.2 Hz, 1H), 3.91 (dd, J=8.5, 8.2 Hz,
1H), 3.46 (m, 1H), 3.12 (m, 1H), 2.90-2.78 (m, 2H), 2.75-2.43 (m,
6H), 1.97-1.86 (m, 2H).
EXAMPLE 3(hh)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor--
5-thia-8-aza-10-oxaprost-13-enoic acid
##STR03450##
[0974] TLC: Rf 0.35 (Chloroform:Methanol=9:1);
[0975] NMR: .delta. 7.22 (t, J=7.4 Hz, 1H), 7.11-6.97 (m, 3H), 5.90
(dd, J=15.4, 5.2 Hz, 1H), 5.57 (ddd, J=15.4, 8.8, 1.4 Hz, 1H),
4.51-4.28 (m, 3H), 3.91 (dd, J=8.2, 8.0 Hz, 1H), 3.45 (m, 1H), 3.11
(m, 1H), 2.89-2.44 (m, 8H), 2.36 (s, 3H), 1.96-1.85 (m, 2H).
EXAMPLE 3(ii)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylaminomethylphenyl)-17,18,19,2-
0-tetranor-5-thia-8-azaprost-13-enoic acid hydrochloride
##STR03451##
[0977] TLC: Rf 0.11 (Chloroform:Methanol:Acetic Acid=9:1:0.1);
[0978] NMR(CD.sub.3OD): .delta. 7.50-7.30 (m, 4H), 5.76 (dd,
J=15.0, 6.6 Hz, 1H), 5.45 (dd, J=15.0, 8.7 Hz, 1H), 4.40 (m, 1H),
4.24-4.11 (m, 3H), 3.50 (m, 1H), 2.96-2.80 (m, 3H), 2.71 (s, 3H),
2.63-2.43 (m, 3H), 2.42-2.20 (m, 4H), 1.93-1.62 (m, 3H).
[0979] The amino group bound benzene ring was protected by Boc
group, and was removed protecting group at final step.
EXAMPLE 3(jj)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-ethyl-4-fluorophenyl)-17,18,19,20-t-
etranor-5-thia-8-azaprost-13-enoic acid
##STR03452##
[0981] TLC: Rf 0.35 (Chloroform:Methanol=9:1);
[0982] NMR: .delta. 7.08-6.93 (m, 3H), 5.75 (dd, J=15.3, 5.4 Hz,
1H), 5.52 (ddd, J=15.3, 8.7, 1.2 Hz, 1H), 4.40 (m, 1H), 4.12 (m,
1H), 3.62 (m, 1H), 3.00 (m, 1H), 2.87-2.18 (m, 11H), 1.98-1.82 (m,
2H), 1.71 (m, 1H), 1.22 (t, J=7.5 Hz, 3H).
EXAMPLE 3(kk)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(5-methylfuran-2-yl)-17,18,19,20-tetra-
nor-5-thia-8-azaprost-13-enoic acid
##STR03453##
[0984] TLC: Rf 0.34 (Chloroform:Methanol=9:1);
[0985] NMR: .delta. 5.99 (d, J=2.7 Hz, 1H), 5.88 (m, 1H), 5.75 (dd,
J=15.3, 5.4 Hz, 1H), 5.55 (ddd, J=15.3, 8.7, 1.0 Hz, 1H), 4.47 (m,
1H), 4.15 (m, 1H), 3.63 (m, 1H), 3.06 (m, 1H), 2.92-2.78 (m, 2H),
2.75-2.18 (m, 12H), 2.00-1.81 (m, 2H), 1.72 (m, 1H).
EXAMPLE 3(ll)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(2-methyloxazol-5-yl)-17,18,19,20-tetr-
anor-5-thia-8-azaprost-13-enoic acid
##STR03454##
[0987] TLC: Rf 0.35 (Chloroform:Methanol:Acetic Acid=18:2:1);
[0988] NMR: .delta. 6.95 (s, 1H), 5.80 (dd, J=16, 5 Hz, 1H), 5.66
(dd, J=16, 8 Hz, 1H), 4.6-4.5 (m, 1H), 4.25-4.1 (m, 1H), 3.7-3.55
(m, 1H), 3.2-3.05 (m, 1H), 3.0-2.8 (m, 2H), 2.75-2.5 (m, 7H),
2.5-2.35 (m, 4H), 2.35-2.2 (m, 1H), 2.0-1.85 (m, 2H), 1.85-1.7 (m,
1H).
EXAMPLE 3(mm)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(benzofuran-2-yl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid
##STR03455##
[0990] TLC: Rf 0.43 (Chloroform:Methanol=19:1);
[0991] NMR: .delta. 7.55-7.5 (m, 1H), 7.41 (d, J=7 Hz, 1H),
7.25-7.15 (m, 2H), 6.52 (s, 1H), 5.80 (dd, J=15, 6 Hz, 1H), 5.57
(dd, J=15, 8 Hz, 1H), 4.63 (q, J=6 Hz, 1H), 4.15-4.05 (m, 1H), 3.58
(pent, J=7 Hz, 1H), 3.04 (d, J=6 Hz, 2H), 3.0-2.9 (m, 1H), 2.65-2.3
(m, 8H), 2.3-2.1 (m, 1H), 1.95-1.8 (m, 2H), 1.75-1.6 (m, 1H).
EXAMPLE 3(nn)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(5-ethylfuran-2-yl)-17,18,19,20-tetran-
or-5-thia-8-azaprost-13-enoic acid
##STR03456##
[0993] TLC: Rf 0.29 (Chloroform:Methanol=9:1);
[0994] NMR: .delta. 6.00 (d, J=3.0 Hz, 1H), 5.88 (d, J=3.0 Hz, 1H),
5.75 (dd, J=15.3, 5.4 Hz, 1H), 5.55 (ddd, J=15.3, 8.4, 1.0 Hz, 1H),
4.48 (m, 1H), 4.15 (m, 1H), 3.64 (m, 1H), 3.03 (m, 1H), 2.93-2.78
(m, 2H), 2.71-2.18 (m, 12H), 1.99-1.82 (m, 2H), 1.72 (m, 1H), 1.21
(t, J=7.2 Hz, 3H).
EXAMPLE 3(oo)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4,5-dimethylfuran-2-yl)-17,18,19,20-t-
etranor-5-thia-8-azaprost-13-enoic acid
##STR03457##
[0996] TLC: Rf 0.31 (Chloroform:Methanol=9:1);
[0997] NMR: .delta. 5.89 (s, 1H), 5.75 (dd, J=15.3, 5.1 Hz, 1H),
5.55 (dd, J=15.3, 8.7 Hz, 1H), 4.44 (m, 1H), 4.15 (m, 1H), 3.63 (m,
1H), 3.07 (m, 1H), 2.86-2.09 (m, 15H), 1.99-1.63 (m, 6H).
EXAMPLE 3(pp)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylfuran-2-yl)-17,18,19,20-tetra-
nor-5-thia-8-azaprost-13-enoic acid
##STR03458##
[0999] TLC: Rf 0.41 (Chloroform:Methanol=9:1);
[1000] NMR: .delta. 7.24 (d, J=1.8 Hz, 1H), 6.19 (d, J=1.8 Hz, 1H),
5.75 (dd, J=16, 6 Hz, 1H), 5.53 (dd, J=16, 9 Hz, 1H), 4.53-4.44 (m,
1H), 4.18-4.08 (m, 1H), 3.70-3.59 (m, 1H), 3.10-2.97 (m, 1H), 2.83
(d, J=6 Hz, 2H), 2.72-2.32 (m, 8H), 2.30-2.18 (m, 1H), 2.0-1.8 (m,
5H), 1.81-1.64 (m, 1H).
EXAMPLE 3(qq)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-nitrophenyl)-17,18,19,20-tetranor-5-
-thia-8-azaprost-13-enoic acid
##STR03459##
[1002] TLC: Rf 0.59 (Chloroform:Methanol=9:1);
[1003] NMR: .delta. 8.01 (m, 1H), 7.60-7.42 (m, 3H), 5.78 (dd,
J=15.0, 5.4 Hz, 1H), 5.55 (dd, J=15.0, 8.4 Hz, 1H), 4.50 (m, 1H),
4.16 (m, 1H), 3.60 (m, 1H), 3.10-2.18 (m, 13H), 1.98-1.81 (m, 2H),
1.78-1.59 (m, 1H).
EXAMPLE 3(rr)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylisoxazol-5-yl)-17,18,19,20-te-
tranor-5-thia-8-azaprost-13-enoic acid
##STR03460##
[1005] TLC: Rf 0.42 (Chloroform:Methanol=9:1);
[1006] NMR: .delta. 5.96 (s, 1H), 5.79 (dd, J=15.3, 5.1 Hz, 1H),
5.60 (dd, J=15.3, 8.1 Hz, 1H), 4.59 (m, 1H), 4.17 (m, 1H),
4.00-3.20 (m, 2H), 3.10-2.99 (m, 3H), 2.75-2.20 (m, 12H), 1.98-1.80
(m, 2H), 1.71 (m, 1H).
EXAMPLE 4
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-te-
tranor-8-azaprost-13-en-1-ol
##STR03461##
[1008] To a solution of the compound prepared in Example 1 (220 mg)
in tetrahydrofuran (2 mL), lithium borohydride (23 mg) was added at
room temperature, and the mixture was stirred for 2.5 hours at room
temperature then 3 hours at 50.degree. C. After cooling, the
mixture was added by ethanol and water, and extracted by ethyl
acetate. The organic layer was washed with brine, dried over an
anhydrous sodium sulfate, concentrated under reduced pressure and
was purified by column chromatography on silica gel (from ethyl
acetate:hexane=from 50:1 to 10:1) to give the title compound (171
mg) having the following physical data.
[1009] TLC: Rf 0.16 (Ethyl Acetate:Methanol=85:15);
[1010] NMR: .delta. 7.38-7.11 (m, 4H), 5.73 (dd, J=15.3, 6.0 Hz,
1H), 5.50 (ddd, J=15.3, 8.0, 1.2 Hz, 1H), 4.50-4.37 (m, 3H),
4.08-3.99 (m, 1H), 3.62 (t, J=6.6 Hz, 2H), 3.53-3.37 (m, 4H),
2.92-2.70 (m, 3H), 2.46-2.12 (m, 3H), 1.94 (bs, 1H), 1.78-1.20 (m,
12H).
EXAMPLE 4(a) TO EXAMPLE 4(w)
[1011] By the same procedure as describe in Example 4 using
corresponding carboxylic acid ester derivatives instead of the
compound prepared in Example 1, the compound of the present
invention having the following physical data were obtained.
EXAMPLE 4(a)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-te-
tranor-5-thia-8-azaprost-13-en-1-ol
##STR03462##
[1013] TLC: Rf 0.18 (Ethyl Acetate:Methanol=50:1);
[1014] NMR: .delta. 7.35-7.10 (m, 4H), 5.77 (dd, J=15, 6 Hz, 1H),
5.52 (dd, J=15, 9 Hz, 1H), 4.43 (s, 2H), 4.45-4.35 (m, 1H),
4.15-4.05 (m, 1H), 3.70-3.55 (m, 3H), 3.42 (s, 3H), 3.05-2.95 (m,
1H), 2.9-2.75 (m, 2H), 2.7-2.45 (m, 4H), 2.4-2.3 (m, 2H), 2.3-2.15
(m, 1H), 2.1-1.9 (br, 2H), 1.8-1.5 (m, 5H).
EXAMPLE 4(b)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetra-
nor-8-azaprost-13-en-1-ol
##STR03463##
[1016] TLC: Rf 0.18 (Ethyl Acetate);
[1017] NMR: .delta. 7.15-7.00 (m, 2H), 6.93 (m, 1H), 5.72 (dd,
J=15.4, 5.8 Hz, 1H), 5.50 (dd, J=15.4, 9.3 Hz, 1H), 4.38 (m, 1H),
4.03 (m, 1H), 3.62 (t, J=6.3 Hz, 2H), 3.48 (m, 1H), 2.80 (d, J=6.6
Hz, 2H), 2.74 (m, 1H), 2.46-2.26 (m, 2H), 2.22 (m, 1H), 1.76-1.20
(m, 11H).
EXAMPLE 4(c)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor--
8-azaprost-13-en-1-ol
##STR03464##
[1019] TLC: Rf 0.39 (Chloroform:Methanol=9:1);
[1020] NMR: .delta. 7.24-7.18 (m, 3H), 7.08 (m, 1H), 5.71 (dd,
J=15.4, 6.0 Hz, 1H), 5.48 (ddd, J=15.4, 8.2, 0.8 Hz, 1H), 4.42 (m,
1H), 4.04 (m, 1H), 3.63 (t, J=6.6 Hz, 2H), 3.47 (m, 1H), 2.82 (d,
J=6.6 Hz, 2H), 2.72 (m, 1H), 2.44-2.26 (m, 2H), 2.21 (m, 1H),
1.77-1.20 (m, 11H).
EXAMPLE 4(d)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-en-1-ol
##STR03465##
[1022] TLC: Rf 0.17 (Ethyl Acetate);
[1023] NMR: .delta. 7.29-7.19 (m, 3H), 7.08 (m, 1H), 5.74 (dd,
J=15.4, 5.8 Hz, 1H), 5.49 (dd, J=15.4, 8.5 Hz, 1H), 4.40 (m, 1H),
4.10 (m, 1H), 3.70-3.67 (m, 2H), 3.65 (m, 1H), 2.95 (m, 1H), 2.84
(d, J=6.6 Hz, 2H), 2.68-2.47 (m, 4H), 2.40-2.34 (m, 2H), 2.23 (m,
1H), 2.09 (br. s, 1H), 1.75-1.58 (m, 5H).
EXAMPLE 4(e)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-5-thia-8-a-
zaprost-13-en-1-ol
##STR03466##
[1025] TLC: Rf 0.18 (Ethyl Acetate);
[1026] NMR: .delta. 7.37-7.16 (m, 5H), 5.76 (dd, J=15.4, 5.8 Hz,
1H), 5.49 (ddd, J=15.4, 8.5, 1.1 Hz, 1H), 4.42 (m, 1H), 4.09 (m,
1H), 3.71-3.56 (m, 3H), 2.96 (m, 1H), 2.84 (d, J=6.6 Hz, 2H),
2.67-2.43 (m, 4H), 2.41-2.35 (m, 2H), 2.23 (m, 1H), 1.79-1.60 (m,
5H).
EXAMPLE 4(f)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-en-1-ol
##STR03467##
[1028] TLC: Rf 0.32 (Chloroform:Methanol:Water=9:1:0.1);
[1029] NMR: .delta. 7.21 (t, J=7.4 Hz, 1H), 7.19-6.97 (m, 3H), 5.76
(dd, J=15.4, 5.8 Hz, 1H), 5.50 (ddd, J=15.4, 8.5, 1.1 Hz, 1H), 4.40
(m, 1H), 4.10 (m, 1H), 3.68-158 (m, 3H), 2.95 (m, 1H), 2.84-2.78
(m, 2H), 2.67-2.48 (m, 4H), 2.41-2.35 (m, 2H), 2.36 (s, 3H), 2.26
(m, 1H), 1.78-1.62 (m, 5H).
EXAMPLE 4(g)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-en-1-ol
##STR03468##
[1031] TLC: Rf 0.35 (Chloroform:Methanol:Water=9:1:0.1);
[1032] NMR: .delta. 7.29 (m, 1H), 7.01-6.89 (m, 3H), 5.75 (dd,
J=15.4, 5.8 Hz, 1H), 5.50 (ddd, J=15.4, 8.5, 1.1 Hz, 1H), 4.41 (m,
1H), 4.12 (m, 1H), 3.70-3.57 (m, 3H), 2.94 (m, 1H), 2.84 (d, J=6.6
Hz, 2H), 2.66-2.54 (m, 4H), 2.41-2.35 (m, 2H), 2.24 (m, 1H),
1.78-1.60 (m, 5H).
EXAMPLE 4(h)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-en-1-ol
##STR03469##
[1034] TLC: Rf 0.35 (Chloroform:Methanol:Water=9:1:0.1);
[1035] NMR: .delta. 7.20-7.13 (m, 2H), 7.05-6.96 (m, 2H), 5.74 (dd,
J=15.4, 5.5 Hz, 1H), 5.50 (ddd, J=15.4, 8.5, 1.4 Hz, 1H), 4.38 (m,
1H), 4.10 (m, 1H), 3.71-3.57 (m, 3H), 2.95 (m, 1H), 2.82 (d, J=6.9
Hz, 2H), 2.66-2.48 (m, 4H), 2.40-2.33 (m, 2H), 2.24 (m, 1H),
1.78-1.60 (m, 5H).
EXAMPLE 4(i)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-en-1-ol
##STR03470##
[1037] TLC: Rf 0.20 (Ethyl Acetate);
[1038] NMR: .delta. 7.21 (d, J=7.8 Hz, 1H), 7.06 (d, J=7.8 Hz, 1H),
7.04-7.00 (m, 2H), 5.76 (dd, J=15.0, 6.0 Hz, 1H), 5.51 (ddd,
J=15.0, 8.0, 1.2 Hz, 1H), 4.40 (m, 1H), 4.10 (m, 1H), 3.72-3.59 (m,
3H), 2.98 (m, 1H), 2.90-2.78 (m, 2H), 2.73-2.43 (m, 8H), 2.41-2.10
(m, 3H), 1.90 (bs, 1H), 1.80-1.75 (m, 6H), 0.94 (t, J=7.5 Hz,
3H).
EXAMPLE 4(j)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20--
tetranor-5-thia-8-azaprost-13-en-1-ol
##STR03471##
[1040] TLC: Rf 0.20 (Ethyl Acetate);
[1041] NMR: .delta. 7.60-7.30 (m, 4H), 5.76 (dd, J=15.0, 5.7 Hz,
1H), 5.52 (ddd, J=15.0, 8.0, 1.0 Hz, 1H), 4.43 (m, 1H),4.11 (m,
1H), 3.73-3.69 (m, 3H), 3.06-2.83 (m, 3H), 2.72-2.50 (m, 4H),
2.42-2.00 (m, 5H), 1.80-1.53 (m, 5H).
EXAMPLE 4(k)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-ethylphenyl)-17,18,19,20-tetranor-5-
-thia-8-azaprost-13-en-1-ol
##STR03472##
[1043] TLC: Rf 0.43 (Chloroform:Methanol=9:1);
[1044] NMR: .delta. 7.24 (m, 1H), 7.13-6.98 (m, 3H), 5.78 (dd,
J=15.4, 6.0 Hz, 1H), 5.52 (ddd, J=15.4, 8.5, 1.1 Hz, 1H), 4.41 (m,
1H), 4.12 (m, 1H), 3.68-3.57 (m, 3H), 3.00 (m, 1H), 2.90-2.75 (m,
2H), 2.67-2.52 (m, 6H), 2.42-2.35 (m, 2H), 2.25 (m, 1H), 1.77-1.60
(m, 5H), 1.23 (t, J=7.7 Hz, 3H).
EXAMPLE 4(l)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetra-
nor-5-thia-8-azaprost-13-en-1-ol
##STR03473##
[1046] TLC: Rf 0.18 (Ethyl Acetate);
[1047] NMR: .delta. 7.15-7.00 (m, 2H), 6.93 (m, 1H), 5.74 (dd,
J=15.4, 5.5 Hz, 1H), 5.52 (dd, J=15.4, 8.5 Hz, 1H), 4.38 (m, 1H),
4.12 (m, 1H), 3.71-3.57 (m, 3H), 2.98 (m, 1H), 2.80 (d, J=6.9 Hz,
2H), 2.68-2.48 (m, 4H), 2,42-2.36 (m, 2H), 2.25 (m, 1H), 1.77-1.60
(m, 5H).
EXAMPLE 4(m)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluoro-3-trifluoromethylphenyl)-17,-
18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol
##STR03474##
[1049] TLC: Rf 0.47 (Chloroform:Methanol=8:1);
[1050] NMR: .delta. 7.52-7.34 (m, 2H), 7.15 (dd, J=9.6, 9.6 Hz,
1H), 5.76 (dd, J=15.3, 5.4 Hz, 1H), 5.53 (ddd, J=15.3, 8.7, 0.9 Hz,
1H), 4.42 (m, 1H), 4.12 (m, 1H), 3.74-3.54 (m, 3H), 3.26-1.40 (m,
17H).
EXAMPLE 4(n)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluoro-3-methylphenyl)-17,18,19,20--
tetranor-5-thia-8-azaprost-13-en-1-ol
##STR03475##
[1052] TLC: Rf 0.33 (Chloroform:Methanol=8:1);
[1053] NMR: .delta. 7.06-6.90 (m, 3H), 5.75 (dd, J=15.3, 5.4 Hz,
1H), 5.51 (ddd, J=15.3, 8.4, 0.9 Hz, 1H), 4.37 (m, 1H), 4.10 (m,
1H), 3.74-3.56 (m, 3H), 2.99 (m, 1H), 2.86-2.16 (m, 12H), 2.00-1.44
(m, 7H).
EXAMPLE 4(o)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-chloro-4-fluorophenyl)-17,18,19,20--
tetranor-5-thia-8-azaprost-13-en-1-ol
##STR03476##
[1055] TLC: Rf 0.35 (Chloroform:Methanol=8:1);
[1056] NMR: .delta. 7.26 (m, 1H), 7.14-7.04 (m, 2H), 5.74 (dd,
J=15.3, 5.4 Hz, 1H), 5.51 (ddd, J=15.3, 8.7, 0.9 Hz, 1H), 4.39 (m,
1H), 4.11 (m, 1H), 3.78-3.56 (m, 3H), 2.99 (m, 1H), 2.84-1.86 (m,
10H), 1.82-1.54 (m, 6H).
EXAMPLE 4(p)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-1,5-(2,5-interthienyl-
ene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-en-1-ol
##STR03477##
[1058] TLC: Rf 0.22 (Ethyl Acetate);
[1059] NMR: .delta. 7.19 (t, J=7.4 Hz, 1H), 7.08-6.94 (m, 3H), 6.79
(d, J=3.3 Hz, 1H), 6.64 (d, J=3.3 Hz, 1H), 5.69 (dd, J=15.4, 6.0
Hz, 1H), 5.43 (ddd, J=15.4, 8.5, 1.1 Hz, 1H), 4.72 (s, 2H), 4.37
(m, 1H), 4.02 (m, 1H), 3.53 (m, 1H), 2.85-2.74 (m, 5H), 2.44-2.33
(m, 2H), 2.36 (s, 3H), 2.20 (m, 1H), 1.87-1.64 (m, 3H).
EXAMPLE 4(q)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-5-(5-hydroxymethylthi-
azol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene
##STR03478##
[1061] TLC: Rf 0.20 (Ethyl Acetate);
[1062] NMR: .delta. 7.48 (s, 1H), 7.20 (t, J=8 Hz, 1H), 7.1-6.95
(m, 3H), 5.68 (dd, J=15, 6 Hz, 1H), 5.47 (dd, J=15, 9 Hz, 1H), 4.78
(s, 2H), 4.34 (q, J=6 Hz, 1H), 4.13 (q, J=7 Hz, 1H), 3.7-3.6 (m,
1H), 3.4-3.15 (m, 3H), 2.77 (d, J=6 Hz, 2H), 2.4-2.1 (m, 6H),
1.8-1.6 (m, 1H).
EXAMPLE 4(r)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor--
5-thia-8-aza-10-oxaprost-13-en-1-ol
##STR03479##
[1064] TLC: Rf 0.36 (Chloroform:Methanol=9:1);
[1065] NMR: .delta. 7.32-7.20 (m, 3H), 7.10 (m, 1H), 5.86 (dd,
J=15.4, 5.5 Hz, 1H), 5.56 (ddd, J=15.4, 8.8, 1.4 Hz, 1H), 4.48-4.29
(m, 2H), 4.43 (dd, J=8.2, 8.2 Hz, 1H), 3.91 (dd, J=8.2, 8.2 Hz,
1H), 3.70-3.63 (m, 2H), 3.45 (m, 1H), 3.09 (m, 1H), 2.82 (d, J=6.0
Hz, 2H), 2.75-2.56 (m, 4H), 1.78-1.54 (m, 4H).
EXAMPLE 4(s)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-aza-10-oxaprost-13-en-1-ol
##STR03480##
[1067] TLC: Rf 0.37 (Chloroform:Methanol=9:1);
[1068] NMR: .delta. 7.20-7.13 (m, 2H), 7.06-6.98 (m, 2H), 5.87 (dd,
J=15.4, 5.5 Hz, 1H), 5.57 (ddd, J=15.4, 8.5, 1.4 Hz, 1H), 4.44-4.28
(m, 2H), 4.43 (dd, J=8.5, 8.2 Hz, 1H), 3.91 (dd, J=8.5, 8.2 Hz,
1H), 3.69-3.64 (m, 2H), 3.46 (m, 1H), 3.11 (m, 1H), 2.90-2.76 (m,
2H), 2.74-2.55 (m, 4H), 1.78-1.62 (m, 4H).
EXAMPLE 4(t)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-3,7-(2,5-interthienyl-
ene)-4,5,6,17,18,19,20-heptanor-8-azaprost-13-en-1-ol
##STR03481##
[1070] TLC: Rf 0.46 (Ethyl Acetate:Methanol=19:1);
[1071] NMR: .delta. 7.25-7.1 (m, 2H), 7.05-6.95 (m, 2H), 6.66 (d,
J=3 Hz, 1H), 6.62 (d, J=3 Hz, 1H), 5.73 (dd, J=16, 6 Hz, 1H), 5.47
(dd, J=16, 9 Hz, 1H), 4.85 (d, J=15 Hz, 1H), 4.45-4.35 (m, 1H),
4.05-3.95 (m, 1H), 3.88 (d, J=15 Hz, 1H), 3.70 (t, J=6 Hz, 2H),
2.95-2.8 (m, 4H), 2.5-2.3 (m, 2H), 2.25-2.1 (m, 1H), 2.0-1.85 (m,
2H), 1.8-1.6 (m, 1H).
EXAMPLE 4(u)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-ethyl-4-fluorophenyl)-17,18,19,20-t-
etranor-5-thia-8-azaprost-13-en-1-ol
##STR03482##
[1073] TLC: Rf 0.28 (Ethyl Acetate:Methanol=9:1);
[1074] NMR: .delta. 7.06-6.91 (m, 3H), 5.75 (dd, J=15.6, 5.7 Hz,
1H), 5.52 (ddd, J=15.6, 9.0, 1.5 Hz, 1H), 4.39 (m, 1H), 4.10 (m,
1H), 3.72-3.59 (m, 3H), 3.00 (m, 1H), 2.84-2.43 (m, 8H), 2.41-2.19
(m, 3H), 1.90 (bs, 2H), 1.80-1.60 (m, 5H), 1.22 (t, J=7.5 Hz,
3H).
EXAMPLE 4(v)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(5-methylfuran-2-yl)-17,18,19,20-tetra-
nor-5-thia-8-azaprost-13-en-1-ol
##STR03483##
[1076] TLC: Rf 0.35 (Ethyl Acetate:Methanol=19:1);
[1077] NMR: .delta. 5.99 (d, J=3.0 Hz, 1H), 5.88 (m, 1H), 5.76 (dd,
J=15.3, 5.7 Hz, 1H), 5.55 (ddd, J=15.3, 8.4, 1.0 Hz, 1H), 4.42 (m,
1H), 4.11 (m, 1H), 3.74-3.60 (m, 3H), 3.06 (m, 1H), 2.94-2.77 (m,
2H), 2.71-2.50 (m, 4H), 2.43-2.09 (m, 7H), 1.92-1.56 (m, 6H).
EXAMPLE 4(w)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(5-ethylfuran-2-yl)-17,18,19,20-tetran-
or-5-thia-8-azaprost-13-en-1-ol
##STR03484##
[1079] TLC: Rf 0.16 (Ethyl Acetate:Methanol=19:1);
[1080] NMR: .delta. 6.01 (d, J=3.0 Hz, 1H), 5.89 (d, J=3.0 Hz, 1H),
5.75 (dd, J=15.3, 5.4 Hz, 1H), 5.55 (dd, J=15.3, 8.7 Hz, 1H), 4.45
(m, 1H), 4.10 (m, 1H), 3.71-3.59 (m, 3H), 3.03 (m, 1H), 2.92-2.78
(m, 2H), 2.72-2.45 (m, 6H), 2.42-2.10 (m, 4H), 2.00-1.59 (m, 6H),
1.21 (t, J=7.8 Hz, 3H).
EXAMPLE 5
(15.alpha.)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetran-
or-8-azaprostanoic acid ethyl ester
##STR03485##
[1082] Under atmosphere of argon, Palladium on carbon (44 mg) was
added to the solution of the compound prepared in Example 1 (440
mg) in ethanol (10 mL), and argon was displaced by hydrogen. After
the mixture was stirred for 4 hours, the catalyst was removed by
filtration. The filtrate was concentrated under reduced pressure
and was purified by column chromatography on silica gel (ethyl
acetate:methanol=from 50:1 to 20:1) to give the title compound (384
mg) having the following physical data.
[1083] TLC: Rf 0.16 (Ethyl Acetate:Methanol=85:15).
EXAMPLE 6
(15.alpha.)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetran-
or-8-azaprostanoic acid
##STR03486##
[1085] By the same procedure as describe in Example 2 using the
compound prepared in Example 5 (227 mg) instead of the compound
prepared in Example 1, the compound (173 mg) of the present
invention having the following physical data was obtained.
[1086] TLC: Rf 0.45 (Chloroform:Methanol=9:1);
[1087] NMR: .delta. 7.38-7.11(m, 4H), 4.45 (s, 2H), 3.91-3.80 (m,
1H), 3.67-3.53 (m, 2H), 3.42 (s, 3H), 3.00-2.64 (m, 3H), 2.50-2.03
(m, 5H), 1.94-1.89 (m, 1H), 1.86-1.20 (m, 13H).
EXAMPLE 6(a) TO EXAMPLE 6(c)
[1088] By the same procedure as describe in Examples 5 and 6 using
corresponding carboxylic acid ester derivatives instead of the
compound prepared in Example 1, the compound of the present
invention having the following physical data were obtained.
EXAMPLE 6(a)
(15.alpha.)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-8-az-
aprostanoic acid
##STR03487##
[1090] TLC: Rf 0.37 (Chloroform:Methanol=10:1);
[1091] NMR: .delta. 7.22 (t, J=6.9 Hz, 1H), 7.08-6.99 (m, 3H), 3.86
(m, 1H), 3.63-3.54 (m, 2H), 2.92 (m, 1H), 2.80 (dd, J=13.5, 4.8 Hz,
1H), 2.67 (dd, J=13.5, 8.4 Hz, 1H), 2.34 (s, 3H), 2.40-1.20 (m,
18H).
EXAMPLE 6(b)
(15.alpha.)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-th-
ia-8-azaprostanoic acid
##STR03488##
[1093] TLC: Rf 0.32 (Chloroform:Methanol=10:1);
[1094] NMR: .delta. 7.21 (t, J=7.8 Hz, 1H), 7.08-6.98 (m, 3H), 3.90
(m, 1H), 3.78-3.62 (m, 2H), 3.40 (br s, 1H), 3.17 (m, 1H),
2.80-2.30 (m, 10H), 2.34 (s, 3H), 2.14 (m, 1H), 2.00-1.40 (m,
7H).
EXAMPLE 6(c)
(15.alpha.)-9-Oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-tetr-
anor-5-thia-8-azaprostanoic acid
##STR03489##
[1096] TLC: Rf 0.6 (Chloroform:Methanol:Water=9:1:0.1);
[1097] NMR: .delta. 7.57-7.39 (m, 4H), 3.95 (m, 1H), 3.78-3.63 (m,
2H), 3.19 (m, 1H), 2.92-2.67 (m, 4H), 2.65-2.34 (m, 6H), 2.16 (m,
1H), 2.00-1.47 (m, 7H).
REFERENCE EXAMPLE 12
(15.alpha.,13E)-9-Oxo-15-(t-butyldimethylsilyloxy)-16-(3-methoxymethylphen-
yl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid ethyl ester
##STR03490##
[1099] A solution of the compound prepared in Example 1 (1.26 g) in
dimethylformamide (3 mL) was cooled, and was added by the solution
of imidazole (275 mg) and t-butyldimethylsilyl chloride (446 mg) in
dimethylformamide (2 mL). After the mixture was stirred for 1 hour
at room temperature, water was added hereto, and was extracted by
ethyl acetate. The extraction was washed with water and brine
successively, dried over an anhydrous sodium sulfate, concentrated
under reduced pressure to give the title compound (3.39 g) having
the following physical data.
[1100] TLC: Rf 0.62 (Ethyl Acetate).
REFERENCE EXAMPLE 13
(15.alpha.,13E)-9-Oxo-15-(t-butyldimethylsilyloxy)-16-(3-methoxymethylphen-
yl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid
##STR03491##
[1102] To a solution of the compound prepared in Reference Example
12 (420 mg) in mixed solvent of methanol (2 mL) and tetrahydrofuran
(2 mL), 2N aqueous sodium hydroxide (1.2 mL) was added, and the
mixture was stirred for 2 hours. Hydrochloric acid was added to the
mixture to acidify, then was extracted by ethyl acetate. The
extract was washed with brine, dried over an anhydrous sodium
sulfate, concentrated under reduced pressure to give the title
compound (398 mg) having the following physical data.
[1103] TLC: Rf 0.48 (Chloroform:Methanol=8:1).
REFERENCE EXAMPLE 14
(15.alpha.,13E)-9-Oxo-15-(t-butyldimethylsilyloxy)-16-(3-methoxymethylphen-
yl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid N-mesylamide
##STR03492##
[1105] To a solution of the compound prepared in Reference Example
13 (90 mg) in methylene chloride (1 mL), methansulfonamide (41 mg),
dimethylaminopyridine (32 mg) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride (67
mg) was added, and the mixture was stirred overnight at room
temperature. Diluted hydrochloric acid was added to the mixture,
then was extracted by ethyl acetate. The extract was washed with
brine, dried over an anhydrous sodium sulfate, concentrated under
reduced pressure to give the title compound (100 mg) having the
following physical data.
[1106] TLC: Rf 0.23 (Hexane:Ethyl Acetate=1:3).
EXAMPLE 7
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-te-
tranor-8-azaprost-13-enoic acid N-mesylamide
##STR03493##
[1108] To a solution of the compound prepared in Example 14 (100
mg) in tetrahydrofuran (1 mL), tetrabutylammonium fluoride (0.35
mL; 1.0M tetrahydrofuran solution) was added, and the mixture was
stirred for 3 hours at room temperature. The mixture was poured
into cold aqueous ammonium chloride solution, and extracted by
ethyl acetate. The extract was washed with brine, dried,
concentrated under reduced pressure and was purified by column
chromatography on silica gel (from hexane:ethyl acetate=1:3 to
chloroform:methanol=10:1) to give the title compound (35 mg) having
the following physical data.
[1109] TLC: Rf 0.38 (Chloroform:Methanol=8:1);
[1110] NMR: .delta. 9.97 (brs, 1H), 7.38-7.08 (m, 4H), 5.75 (dd,
J=15.3, 5.4 Hz, 1H), 5.50 (dd, J=15.3, 8.1 Hz, 1H), 4.44 (s, 2H),
4.43 (m, 1H), 4.04 (m, 1H), 3.41 (s, 3H), 3.40 (m, 1H), 3.26 (s,
3H), 3.06-2.72 (m, 3H), 2.52-2.10 (m, 5H), 1.86-1.12 (m, 10H).
EXAMPLE 7(a) TO EXAMPLE 7(d)
[1111] By the same procedure as describe in Reference Example 14
and Example 7 using the compound prepared in Reference Example 13
or corresponding carboxylic acid derivatives and corresponding
sulfonamide derivatives instead of methanesulfonamide, the compound
of the present invention having the following physical data were
obtained.
EXAMPLE 7(a)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-te-
tranor-8-azaprost-13-enoic acid N-phenylsulfonylamide
##STR03494##
[1113] TLC: Rf 0.42 (Chloroform:Methanol=8:1);
[1114] NMR: .delta. 9.84 (brs, 1H), 8.05 (d, J=7.2 Hz, 1H),
7.68-7.46 (m, 3H), 7.38-7.08 (m, 5H), 5.75 (dd, J=15.3, 5.4 Hz,
1H), 5.50 (dd, J=15.3, 8.7 Hz, 1H), 4.45 (s, 2H), 4.45 (m, 1H),
4.03 (m, 1H), 3.41 (s, 3H), 3.40 (m, 1H), 3.06-2.68 (m, 3H),
2.54-2.12 (m, 5H), 1.90-1.06 (m, 10H).
EXAMPLE 7(b)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-te-
tranor-8-azaprost-13-enoic acid N-benzylsulfonylamide
##STR03495##
[1116] TLC: Rf 0.44 (Chloroform:Methanol=8:1);
[1117] NMR: .delta. 9.46 (brs, 1H), 7.46-7.04 (m, 9H), 5.71 (dd,
J=15.3, 5.7 Hz, 1H), 5.46 (dd, J=15.3, 8.7 Hz, 1H), 4.63 (s, 2H),
4.42 (s, 2H), 4.40 (m, 1H), 3.98 (m, 1H), 3.37 (s, 3H), 3.30 (m,
1H), 3.00-2.62 (m, 3H), 2.40-2.06 (m, 5H), 1.82-1.08 (m, 10H).
EXAMPLE 7(c)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-1,5-(2,5-interthienyl-
ene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic acid
N-benzylsulfonylamide
##STR03496##
[1119] TLC: Rf 0.12 (Chloroform:Methanol=9:1);
[1120] NMR: .delta. 9.15 (br. s, 1H), 7.52 (d, J=3.9 Hz, 1H),
7.39-7.30 (m, 5H), 7.18-7.11 (m, 2H), 7.03-6.96 (m, 2H), 6.79 (d,
J=3.9 Hz, 1H), 5.71 (dd, J=15.4, 5.8 Hz, 1H), 5.43 (ddd, J=15.4,
8.8, 1.1 Hz, 1H), 4.76 (s, 2H), 4.38 (m, 1H), 4.00 (m, 1H), 3.41
(m, 1H), 2.86-2.74 (m, 5H), 2.38-2.07 (m, 3H), 1.84-1.60 (m,
3H).
EXAMPLE 7(d)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-5-(5-benzylsulfonylca-
rbamoylthiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene
##STR03497##
[1122] TLC: Rf 0.46 (Chloroform:Methanol:Acetic Acid=9:1:0.2);
[1123] NMR: .delta. 8.20 (s, 1H), 7.34 (s, 5H), 7.18-7.07 (m, 2H),
7.02-6.95 (m, 2H), 5.71 (dd, J=15.3, 5.1 Hz, 1H), 5.47 (dd, J=15.3,
9.0 Hz, 1H), 4.73 (s, 2H), 4.37 (m, 1H), 4.03 (m, 1H), 3.63 (m,
1H), 3.39 (m, 1H), 3.28-3.10 (m, 2H), 2.82-2.71 (m, 2H), 2.25-2.03
(m, 3H), 1.75-1.55 (m, 1H).
REFERENCE EXAMPLE 15
(15.alpha.,13E)-9-Thioxo-15-t-butyldimethylsilyloxy-16-(3-methylphenyl)-17-
,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid butyl ester
##STR03498##
[1125] To a solution of
(15.alpha.,13E)-9-oxo-15-t-butyldimethylsilyloxy-16-(3-methylphenyl)-17,1-
8,19,20-tetranor-5-thia-8-azaprost-13-enoic acid butyl ester (170
mg; this compound were obtained by the same procedure as describe
in Reference Example 12 using
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-
-5-thia-8-azaprost-13-enoic acid butyl ester instead of the
compound prepared in Example 1) in toluene (2 mL),
2,4-bis(4-methoxyphenyl),1,3-dithia-2,4-diphosphetan-2,4-disulfide
(Lawesson reagent) (74 mg) was added and the mixture was stirred
for 1 hour at 50.degree. C. After cooling, the reaction mixture was
purified by column chromatography on silica gel (hexane:ethyl
acetate=5:1) to give the title compound (175 mg) having the
following physical data.
[1126] TLC: Rf 0.53 (Hexane:Ethyl Acetate=4:1).
EXAMPLE 8
(15.alpha.,13E)-9-Thioxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetran-
or-5-thia-8-azaprost-13-enoic acid butyl ester
##STR03499##
[1128] To a solution of the compound prepared in Reference Example
15 (160 mg) in tetrahydrofuran (1.4 mL), tetrabutylammonium
fluoride (1.4 mL; 10M tetrahydrofuran solution) was added, and the
mixture was stirred for 3 hours at room temperature. The mixture
was poured into saturated aqueous ammonium chloride solution, and
extracted by ethyl acetate. The extract was washed with water and
brine successively, dried over anhydrous sodium sulfate,
concentrated under reduced pressure and was purified by column
chromatography on silica gel (from hexane:ethyl acetate=2:1 to
ethyl acetate only) to give the title compound (110 mg) having the
following physical data.
[1129] TLC: Rf 0.38 (Hexane:Ethyl Acetate=1:1).
EXAMPLE 9
(15.alpha.,13E)-9-Thioxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetran-
or-5-thia-8-azaprost-13-enoic acid
##STR03500##
[1131] By the same procedure as describe in Example 2 using the
compound prepared in Example 8 instead of the compound prepared in
Example 1, the compound of the present invention having the
following physical data were obtained.
[1132] TLC: Rf 0.40 (Chloroform:Methanol=8:1);
[1133] NMR: .delta. 7.22 (dd, J=7.5, 7.5 Hz, 1H), 7.11-6.95 (m,
3H), 5.82 (dd, J=15.3, 5.1 Hz, 1H), 5.55 (ddd, J=15.3, 8.7, 1.2 Hz,
1H), 4.52-4.38 (m, 2H), 4.13 (m, 1H), 3.37 (m, 1H), 3.10-2.39 (m,
12H), 2.35 (s, 3H), 2.27 (m, 1H), 2.00-1.70 (m, 3H).
EXAMPLE 9(a)
(15.alpha.,13E)-9-Thioxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-
-tetranor-8-azaprost-13-enoic acid
##STR03501##
[1135] By the same procedure as describe in Reference Example 15,
Examples 8 and 9 using the compound prepared in Reference Example
12 instead of
(15.alpha.,13E)-9-oxo-15-t-butyldimethylsilyloxy-16-(3-methylphenyl)-17,1-
8,19,20-tetranor-5-thia-8-azaprost-13-enoic acid butyl ester, the
compound of the present invention having the following physical
data were obtained.
[1136] TLC: Rf 0.31 (Methanol:Chloroform=1:10);
[1137] NMR: .delta. 7.40-7.10 (m, 4H), 5.82 (dd, J=15.4, 5.0 Hz,
1H), 5.59 (dd, J=15.4, 8.4 Hz, 1H), 4.50-4.25 (m, 2H), 4.47 (s,
2H), 4.02-3.85 (m, 1H), 3.43 (s, 3H), 3.38-3.10 (m, 1H), 3.10-2.75
(m, 4H), 2.40-2.15 (m, 2H), 2.33 (t, J=7.2 Hz, 2H), 1.90-1.20 (m,
10H).
REFERENCE EXAMPLE 16
(15.alpha.,13E)-9-Oxo-15-t-butyldimethylsilyloxy-16-(3-methylphenyl)-17,18-
,19,20-tetranor-5-thia-8-azaprost-13-en-1-yl
t-butoxycarbonylglycylglycinate
##STR03502##
[1139] To a solution of
(15.alpha.,13E)-9-oxo-15-t-butyldimethylsilyloxy-16-(3-methylphenyl)-17,1-
8,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol (170 mg; this
compound was prepared by protecting of hydroxy group at C15
position of the methyl ester of the compound prepared in Example
3(j) by t-butyldimethylsilyl group (TBS group) followed by the same
procedure as describe in Example 4) in mixed solvent of methylene
chloride (2 mL) and dimethylformamide (1 mL),
t-Butoxycarbonylglycylglycin (96 mg), methyl
3-methyl-2-fluoropyridinium tosylate (257 mg) and diisopropylamine
(0.18 mL) were added, and the mixture was stirred overnight at room
temperature. The reaction mixture was poured into cold water, and
was extracted by ethyl acetate. The extract was washed with water
and brine successively, dried over anhydrous sodium sulfate,
concentrated under reduced pressure and was purified by column
chromatography on silica gel (from hexane:ethyl acetate=1:2 to
ethyl acetate only) to give the title compound (170 mg) having the
following physical data.
[1140] TLC: Rf 0.53 (Chloroform:Methanol=8:1).
EXAMPLE 10
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-en-1-yl t-butoxycarbonylglycylglycinate
##STR03503##
[1142] To a solution of the compound prepared in Example 16 (170
mg) in dioxane (0.14 mL), 1N hydrochloric acid (0.14 mL) was added,
and the mixture was stirred overnight at room temperature. The
mixture was poured into saturated aqueous sodium chloride solution,
and extracted by ethyl acetate. The extract was dried over
anhydrous sodium sulfate, concentrated under reduced pressure and
was purified by column chromatography on silica gel (from
hexane:ethyl acetate=1:2 to ethyl acetate only, then
chloroform:methanol=30:1) to give the title compound (100 mg)
having the following physical data.
[1143] TLC: Rf 0.33 (Chloroform:Methanol=8:1).
EXAMPLE 11
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-en-1-yl glycylglycinate monohydrochloride
##STR03504##
[1145] To a solution of the compound prepared in Example 10 (65 mg)
in benzene (0.55 mL), 4N hydrogenchloride-ethyl acetate (0.14 mL)
was added, and the mixture was stirred for 2 hours at room
temperature. The mixture was azeotropied with toluene to give the
title compound (54 mg) having the following physical data.
[1146] TLC: Rf 0.41 (Chloroform:Methanol=4:1);
[1147] NMR(CD.sub.3OD): .delta. 7.15 (dd, J=7.5, 7.5 Hz, 1H),
7.08-6.94 (m, 3H), 5.70 (dd, J=15.3, 6.6 Hz, 1H), 5.37 (dd, J=15.3,
8.7 Hz, 1H), 4.33 (m, 1H), 4.24-4.07 (m, 3H), 4.06-3.94 (m, 2H),
3.73 (s, 2H), 3.60-3.40 (m, 2H), 2.95-2.12 (m, 14H), 1.82-1.54 (m,
5H).
EXAMPLE 11(a) TO EXAMPLE 11(c)
[1148] By the same procedure as describe in Reference Example 16,
Examples 10 and 11 using corresponding amino acid derivatives
instead of t-butoxycarbonylglycylglycine, the compound of the
present invention having the following physical data were
obtained.
EXAMPLE 11(a)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-en-1-yl glycinate methanesulfonic acid
salt
##STR03505##
[1150] TLC: Rf 0.27 (Chloroform:Methanol=8:1);
[1151] NMR(CD.sub.3OD): .delta. 7.15 (dd, J=7.5, 7.5 Hz, 1H),
7.06-6.94 (m, 3H), 5.70 (dd, J=15.3, 6.6 Hz, 1H), 5.37 (ddd,
J=15.3, 8.7, 0.9 Hz, 1H), 4.33 (m, 1H), 4.27 (t, J=6.3 Hz, 2H),
4.13 (m, 1H), 3.83 (s, 2H), 3.50 (m, 1H), 2.96-2.10 (m, 15H),
1.88-1.54 (m, 5H).
EXAMPLE 11(b)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-en-1-yl tryptophanate bis-trifluoroacetic acid
salt
##STR03506##
[1153] TLC: Rf 0.40 (Chloroform:Methanol=8:1);
[1154] NMR(CD.sub.3OD): .delta. 7.53 (d, J=8.1 Hz, 1H), 7.39 (d,
J=8.1 Hz, 1H), 7.24-6.92 (m, 7H), 5.67 (dd, J=15.6, 6.6 Hz, 1H),
5.34 (dd, J=15.6, 9.0 Hz, 1H), 4.30 (t, J=6.9 Hz, 2H), 4.28-4.00
(m, 3H), 3.52-3.30 (m, 3H), 2.94-2.60 (m, 3H), 2.56-2.08 (m, 10H),
1.74-1.32 (m, 5H).
EXAMPLE 11(c)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-en-1-yl tyrosinate trifluoroacetic acid
salt
##STR03507##
[1156] TLC: Rf 0.37 (Chloroform:Methanol=8:1);
[1157] NMR(CD.sub.3OD): .delta. 7.22-6.92 (m, 6H), 6.77 (d, J=8.4
Hz, 2H), 5.69 (dd, J=15.3, 6.6 Hz, 1H), 5.36 (dd, J=15.3, 8.7 Hz,
1H), 4.33 (m, 1H), 4.27-4.15 (m, 3H), 4.12 (m, 1H), 3.47 (m, 1H),
3.16-3.04 (m, 2H), 2.96-2.06 (m, 13H), 1.80-1.48 (m, 5H).
EXAMPLE 12
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid isopropyloxycarbonylmethyl
ester
##STR03508##
[1159] To a solution of the compound prepared in Example 3(b) (31.5
mg) in dimethylformamide (0.7 mL), 2-bromoacetic acid isopropyl
ester (16.5 mg) and potassium carbonate (16 mg) was added, and the
mixture was stirred for 1.5 hours at 60.degree. C. After cooling,
the reaction mixture was added by water and ethyl acetate. The
organic layer was washed with water and brine successively, dried
over anhydrous sodium sulfate, concentrated under reduced pressure
and was purified by column chromatography on silica gel
(chloroform:methanol=50:1) to give the title compound (35 mg)
having the following physical data.
[1160] TLC: Rf 0.45 (Chloroform:Methanol=9:1);
[1161] NMR: .delta. 7.32-7.20 (m, 3H), 7.14-7.06 (m, 1H), 5.74 (dd,
J=15.3, 6.0 Hz, 1H), 5.50 (dd, J=15.3, 8.6 Hz, 1H), 5.06 (m, 1H),
4.57 (s, 2H), 4.40 (m, 1H), 4.12 (m, 1H), 3.62 (m, 1H), 2.96 (m,
1H), 2.82 (d, J=6.0 Hz, 2H), 2.71-2.50 (m, 6H), 2.41-2.19 (m, 3H),
2.00-1.90 (m, 2H), 1.73 (m, 1H), 1.25 (d, J=6.3 Hz, 6H).
EXAMPLE 12(a) TO EXAMPLE 12(c)
[1162] By the same procedure as describe in Example 12 using the
compound prepared in Example 3(b) or corresponding carboxylic acid
derivatives and corresponding halide derivatives instead of
2-bromoacetic acid isopropyl ester, the compound of the present
invention having the following physical data were obtained.
EXAMPLE 12(a)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid dimethylaminocarbonylmethyl
ester
##STR03509##
[1164] TLC: Rf 0.35 (Chloroform:Methanol=9:1);
[1165] NMR: .delta. 7.28-7.19 (m, 3H), 7.12-7.08 (m, 1H), 5.77 (dd,
J=15.3, 5.1 Hz, 1H), 5.54 (ddd, J=15.3, 8.7, 1.2 Hz, 1H), 4.70 (s,
2H), 4.40 (m, 1H), 4.15 (m, 1H), 3.54 (m, 1H), 3.04 (m, 1H), 2.95
(s, 3H), 2.91 (s, 3H), 2.82 (d, J=6.0 Hz, 2H), 2.78-2.53 (m, 6H),
2.40-2.18 (m, 3H), 2.03-1.93 (m, 2H), 1.71 (m, 1H).
EXAMPLE 12(b)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid ethyl ester
##STR03510##
[1167] TLC: Rf 0.44 (Chloroform:Methanol=9:1);
[1168] NMR: .delta. 7.21-7.14 (m, 2H), 7.05-6.96 (m, 2H), 5.75 (dd,
J=15.6, 6.0 Hz, 1H), 5.50 (dd, J=15.6, 8.4 Hz, 1H), 4.19 (m, 1H),
4.18-4.03 (m, 3H), 3.60 (m, 1H), 2.97 (m, 1H), 2.85-2.79 (m, 2H),
2.70-2.18 (m, 9H), 2.01-1.82 (m, 3H), 1.79-1.60 (m, 1H), 1.25 (t,
J=7.2 Hz, 3H).
EXAMPLE 12(c)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid butyl ester
##STR03511##
[1170] TLC: Rf 0.47 (Ethyl Acetate:Methanol=20:1);
[1171] NMR: .delta. 7.2-7.1 (m, 2H), 7.05-6.95 (m, 2H), 5.75 (dd,
J=15, 6 Hz, 1H), 5.51 (dd, J=15, 8 Hz, 1H), 4.45-4.35 (m, 1H),
4.15-4.05 (m, 1H), 4.07 (t, J=7 Hz, 2H), 3.7-3.55 (m, 1H), 3.05-2.9
(m, 1H), 2.82 (d, J=7 Hz, 2H), 2.7-2.45 (m, 4H), 2.4-2.3 (m, 4H),
2.3-2.15 (m, 1H), 2.0 (d, J=4 Hz, 1H), 1.95-1.85 (m, 2H), 1.8-1.65
(m, 1H), 1.65-1.55 (m, 2H), 1.45-1.3 (m, 2H), 0.93 (t, J=7 Hz,
3H).
REFERENCE EXAMPLE 17
(15.alpha.,13E)-9-Oxo-15-(tetrahydropyran-2-yloxy)-16-(3-methylphenyl)-1,5-
-(2,5-interthienylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic
acid methyl ester
##STR03512##
[1173] To a solution of
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-1,5-(2,5-interthieny-
lene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic acid methyl
ester (111 mg; this is the methyl ester of the compound prepared in
Example 2(ww)) in toluene (2 mL), dihydropyran (0.5 mL) and
p-toluenesulfonic acid (1 mg) was added, and the mixture was
stirred for 6 hours at room temperature. The mixture was added by
water and ethyl acetate. The organic layer was washed with water
and brine successively, dried over anhydrous sodium sulfate,
concentrated under reduced pressure to give the title compound (146
mg) having the following physical data.
REFERENCE EXAMPLE 18
(15.alpha.,13E)-9-Oxo-15-(tetrahydropyran-2-yloxy)-16-(3-methylphenyl)-1,5-
-(2,5-interthienylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-en-1-ol
##STR03513##
[1175] To a solution of the compound prepared in Reference Example
17 (146 mg) in tetrahydrofuran (2.5 mL), lithium borohydride (62
mg) was added, and the mixture was stirred for 7 hours at
50.degree. C. The mixture was added by water and ethyl acetate. The
organic layer was washed with water and brine successively, dried
over an anhydrous sodium sulfate, concentrated under reduced to
give the title compound (101 mg) having the following physical
data.
REFERENCE EXAMPLE 19
(15.alpha.,13E)-9-Oxo-15-(tetrahydropyran-2-yloxy)-16-(3-methylphenyl)-1,5-
-(2,5-interthienylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-en-1-al
##STR03514##
[1177] Under atmosphere of argon, a solution of the compound
prepared in Reference Example 18 (100 mg) in mixed solvent of ethyl
acetate (1 mL) and dimethylsulfoxide (1.5 mL) was added by
diisopropylethylamine (0.22 mL). Then sulfur trioxide pyridine
complex (100 mg) was added to the mixture on ice bath, and the
mixture was stirred for 15 minutes. Water and ethyl acetatewere
added to the reaction mixture. The organic layer was washed with 1N
hydrochloric acid, saturated aqueous sodium hydrogencarbonate and
brine successively, dried over an anhydrous sodium sulfate,
concentrated under reduced pressure to give the title compound (103
mg) having the following physical data.
[1178] TLC: Rf 0.51 (Ethyl Acetate).
EXAMPLE 13
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-1,5-(2,5-interthienyl-
ene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-en-1-al
##STR03515##
[1180] To a solution of the compound prepared in Reference Example
19 (100 mg) in mixed solvent of acetonitrile (1 mL) and methanol
(0.5 mL), 0.1N hydrochloric acid was added, and the mixture was
stirred for 1 hour at 35.degree. C. Water and ethyl acetate were
added to the reaction mixture. The organic layer was washed with
saturated aqueous sodium hydrogencarbonate and brine successively,
dried over an anhydrous sodium sulfate, concentrated under reduced
pressure and was purified by column chromatography on silica gel
(from ethyl acetate:hexane=4:1 to ethyl acetate only) to give the
title compound (70 mg) having the following physical data.
[1181] TLC: Rf 0.34 (Ethyl Acetate);
[1182] NMR: .delta. 9.80 (s, 1H), 7.60 (d, J=3.9 Hz, 1H), 7.20 (t,
J=7.4 Hz, 1H), 7.08-6.96 (m, 3H), 6.93 (d, J=3.9 Hz, 1H), 5.73 (dd,
J=15.4, 5.8 Hz, 1H), 5.48 (ddd, J=15.4, 8.8, 1.4 Hz, 1H), 4.39 (m,
1H), 4.02 (m, 1H), 3.52 (m, 1H), 2.90-2.77 (m, 5H), 2.47-2.25 (m,
2H), 2.36 (s, 3H), 2.20 (m, 1H), 1.88-1.64 (m, 3H).
EXAMPLE 13(a)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-en-1-al
##STR03516##
[1184] By the same procedure as describe in Reference Examples 17,
18, 19 and Example 13 using the methyl ester of the compound
prepared in Example 3(b) instead of the methyl ester of compound
prepared in Example 2(ww), the compound of the present invention
having the following physical data were obtained.
[1185] TLC: Rf 0.13 (Hexane:Ethyl Acetate=1:5);
[1186] NMR: .delta. 9.80 (t, J=1.5 Hz, 1H), 7.27-7.20 (m, 3H), 7.09
(m, 1H), 5.75 (dd, J=15.6, 5.4 Hz, 1H), 5.51 (ddd, J=15.6, 8.7, 1.2
Hz, 1H), 4.43 (m, 1H), 4.09 (m, 1H), 3.60 (m, 1H), 2.95 (m, 1H),
2.84 (d, J=6.6 Hz, 2H), 2.70-2.20 (m, 9H), 2.00-1.60 (m, 3H).
EXAMPLE 14
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-aminophenyl)-17,18,19,20-tetranor-5-
-thia-8-azaprost-13-enoic acid
##STR03517##
[1188] The solution of
(15.alpha.,13E)-9-oxo-15-hydroxy-16-(3-nitrophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid butyl ester (90 mg, this compound
was prepared by the same procedure as describe in Reference Example
5 and Example 1 using
9-oxo-12-formyl-13,14,15,16,17,18,19,20-octanor-5-thia-8-azaprostanoic
acid butyl ester instead of the compound prepared in Reference
Example 4 and 3-(3-nitrophenyl)-2-oxopropylphosphonic acid dimethyl
ester instead of 3-(3-methoxymethylphenyl)-2-oxopropylphosphonic
acid dimethyl ester) of mixed solvent of methanol (1.4 mL),
tetrahydrofuran (0.9 mL), water (0.45 mL) and acetic acid (0.27 mL)
was added by Zinc powder (37 mg) under atmosphere of argon, and the
mixture was stirred for 30 minutes at room temperature. Water and
ethyl acetate were added to the reaction mixture. The organic layer
was washed with saturated aqueous sodium hydrogencarbonate and
brine successively, dried over an anhydrous sodium sulfate,
concentrated under reduced pressure and was purified by column
chromatography on silica gel (chloroform: methanol=100:1) and
prepared by the same procedure as describe in Example 2 to give the
title compound (44 mg) having the following physical data.
[1189] TLC: Rf 0.46 (Chloroform:Methanol=9:1);
[1190] NMR: .delta. 7.15-7.04 (m, 1H), 6.64-6.50 (m, 3H), 5.75 (dd,
J=15.0, 6.0 Hz, 1H), 5.50 (dd, J=15.0, 8.4 Hz, 1H), 4.40 (m, 1H),
4.10 (m, 1H), 4.00-3.55 (m, 4H), 2.99 (m, 1H), 2.80-2.19 (m, 11H),
1.98-1.80 (m, 2H), 1.78-1.61 (m, 1H).
EXAMPLE 15(a) TO EXAMPLE 15(c)
[1191] By the same procedure as describe in Reference Example 16
and Example 10 using
(15.alpha.,13E)-9-oxo-15-t-butyldimethylsilyloxy-16-phenyl-17,18,19,20-te-
tranor-5-thia-8-azaprost-13-en-1-ol instead of
(15.alpha.,13E)-9-oxo-15-t-butyldimethylsilyloxy-16-(3-methylphenyl)-17,1-
8,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol and corresponding
carboxylic acid derivatives instead of
t-butoxycarbonylglycilglycine, the compound of the present
invention having the following physical data were obtained.
[1192] The compound prepared in Example 15(c) was done by
additional procedure of the same as described in Example 11.
EXAMPLE 15(a)
(15.alpha.,13E)-1-Benzoyloxy-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetran-
or-8-azaprost-13-ene
##STR03518##
[1194] TLC: Rf 0.50 (Chloroform:Methanol=10:1);
[1195] NMR: .delta. 8.05-8.02 (m, 2H), 7.55 (m, 1H), 7.46-7.41 (m,
2H), 7.34-7.18 (m, 5H), 5.73 (dd, J=15.3, 6.0 Hz, 1H), 5.49 (ddd,
J=15.3, 8.4, 1.2 Hz, 1H), 4.40 (m, 1H), 4.31 (t, J=6.6 Hz, 2H),
4.02 (m, 1H), 3.48 (m, 1H), 2.85 (d, J=6.6 Hz, 2H), 2.68 (m, 1H),
2.45-2.10 (m, 3H), 1.80-1.20 (m, 11H).
EXAMPLE 15(b)
(15.alpha.,13E)-1-Butanoyloxy-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetra-
nor-8-azaprost-13-ene
##STR03519##
[1197] TLC: Rf 0.41 (Chloroform:Methanol=10:1);
[1198] NMR: .delta. 7.34-7.19 (m, 5H), 5.73 (dd, J=15.3, 6.3 Hz,
1H), 5.49 (ddd, J=15.3, 8.4, 1.2 Hz, 1H), 4.41 (m, 1H), 4.05 (t,
J=6.6 Hz, 2H), 4.03 (m, 1H), 3.47 (m, 1H), 2.85 (d, J=6.6 Hz, 2H),
2.68 (m, 1H), 2.45-2.10 (m, 5H), 1.80-1.20 (m, 13H), 0.95 (t, J=7.2
Hz, 3H).
EXAMPLE 15(c)
(15.alpha.,13E)-1-(2-Aminoacetyloxy)-9-oxo-15-hydroxy-16-phenyl-17,18,19,2-
0-tetranor-8-azaprost-13-ene trifluoromethanesulfonic acid salt
##STR03520##
[1200] TLC: Rf 0.10 (Chloroform:Methanol=10:1);
[1201] NMR: .delta. 7.32-7.17 (m, 5H), 5.72 (dd, J=15.6, 6.3 Hz,
1H), 5.45 (dd, J=15.6, 8.7 Hz, 1H), 4.39 (m, 1H), 4.19 (t, J=6.3
Hz, 2H), 4.01 (m, 1H), 3.77 (br, 2H), 3.39 (m, 1H), 2.91-2.78 (m,
2H), 2.66 (m, 1H), 2.40-2.10 (m, 3H), 1.75-1.15 (m, 11H).
EXAMPLE 16
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid 2-pentanoyloxyethyl ester
##STR03521##
[1203] A solution of the compound prepared in Example 3(1) (100
mg), 2-pentanoyloxyethanol (370 mg) and triethylamine (0.071 mL) in
ethyl acetate (1.3 mL) was stirred for 5 minutes. The reaction
mixture was added by 1-methanesulfonyloxybenzotriazole (65 mg), and
the mixture was stirred for 3 hours at room temperature. The
reaction mixture was added by water, and was extracted by ethyl
acetate. The extract was washed with water, saturated aqueous
sodium hydrogencarbonate and brine successively, dried over an
anhydrous sodium sulfate, concentrated under reduced pressure and
was purified by column chromatography on silica gel (from ethyl
acetate:hexane=3:1 to ethyl acetate only) to give the title
compound (110 mg) having the following physical data.
[1204] TLC: Rf 0.33 (Ethyl Acetate);
[1205] NMR: .delta. 7.23-7.15 (m, 2H), 7.06-6.97 (m, 2H), 5.76 (dd,
J=15.0, 5.4 Hz, 1H), 5.50 (dd, J=15.0, 8.7 Hz, 1H), 4.40 (m, 1H),
4.27 (s, 4H), 4.10 (m, 1H), 3.60 (m, 1H), 2.98 (m, 1H), 2.82 (d,
J=6.0 Hz, 2H), 2.68-2.20 (m, 11H), 1.96-1.83 (m, 3H), 1.78-1.57 (m,
3H), 1.41-1.29 (m, 2H), 0.92 (t, J=7.2 Hz, 3H).
EXAMPLE 16(a) TO EXAMPLE 16(k)
[1206] By the same procedure as describe in Example 16 using the
compound prepared in Example 3 or corresponding carboxylic acid
derivatives and corresponding alcohol derivatives instead of
2-pentanoyloxyethanol, the compound of the present invention having
the following physical data were obtained.
EXAMPLE 16(a)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-
-13-enoic acid 4-phenylbenzyl ester
##STR03522##
[1208] TLC: Rf 0.57 (Chloroform:Methanol:Water=9:1:0.1);
[1209] NMR: .delta. 7.63-7.56 (m, 4H), 7.48-7.18 (m, 10H), 5.71
(dd, J=15.4, 5.8 Hz, 1H), 5.46 (ddd, J=15.4, 8.2, 1.1 Hz, 1H), 5.17
(s, 2H), 4.40 (m, 1H), 3.99 (m, 1H), 3.44 (m, 1H), 2.82 (d, J=6.6
Hz, 2H), 2.66 (m, 1H), 2.40-2.31 (m, 4H), 2.20 (m, 1H), 1.70-1.61
(m, 3H), 1.50-1.20 (m, 6H).
EXAMPLE 16(b)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-
-13-enoic acid 3-phenylphenyl ester
##STR03523##
[1211] TLC: Rf 0.48 (Hexane:Ethyl Acetate=1:3);
[1212] NMR: .delta. 7.61-7.55 (m, 2H), 7.48-7.17 (m, 11H), 7.05 (m,
1H), 5.72 (dd, J=15.4, 5.8 Hz, 1H), 5.48 (ddd, J=15.4, 8.5, 1.1 Hz,
1H), 4.40 (m, 1H), 4.02 (m, 1H), 3.48 (m, 1H), 2.83 (d, J=6.6 Hz,
2H), 2.72 (m, 1H), 2.59 (t, J=7.4 Hz, 2H), 2.41-2.34 (m, 2H), 2.21
(m, 1H), 1.81-1.62 (m, 3H), 1.54-1.22 (m, 6H).
EXAMPLE 16(c)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-
-13-enoic acid 2-dimethylaminoethyl easter hydrochloride
##STR03524##
[1214] TLC: Rf 0.39 (Chloroform:Methanol=9:1);
[1215] NMR(CD.sub.3OD): .delta. 7.30-7.12 (m, 5H), 5.68 (dd,
J=15.3, 6.6 Hz, 1H), 5.36 (dd, J=15.3, 9.0 Hz, 1H), 4.43-4.29 (m,
3H), 4.07 (m, 1H), 3.45 (m, 2H), 3.38-3.20 (m, 1H), 2.94-2.89 (m,
7H), 2.72 (m, 1H), 2.54 (m, 1H), 2.44-2.17 (m, 5H), 1.76-1.56 (m,
3H), 1.55-1.18 (m, 6H).
EXAMPLE 16(d)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid 2-hexanoyloxyethyl ester
##STR03525##
[1217] TLC: Rf 0.27 (Ethyl Acetate);
[1218] NMR: .delta. 7.21-7.12 (m, 2H), 7.07-6.97 (m, 2H), 5.75 (dd,
J=15.0, 6.0 Hz, 1H), 5.51 (dd, J=15.0, 8.6 Hz, 1H), 4.39 (m, 1H),
4.27 (s, 4H), 4.10 (m, 1H), 3.61 (m, 1H), 2.96 (m, 1H), 2.82 (d,
J=6.6 Hz, 2H), 2.70-2.14 (m, 11H), 1.99-1.82 (m, 3H), 1.79-1.55 (m,
2H), 1.40-1.22 (m, 4H), 0.90 (t, J=7.0 Hz, 3H).
EXAMPLE 16(e)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid 2-heptanoyloxyethyl ester
##STR03526##
[1220] TLC: Rf 0.29 (Ethyl Acetate);
[1221] NMR: .delta. 7.21-7.13 (m, 2H), 7.06-6.97 (m, 2H), 5.75 (dd,
J=15.0, 6.0 Hz, 1H), 5.50 (dd, J=15.0, 8.4 Hz, 1H), 4.39 (m, 1H),
4.27 (s, 4H), 4.10 (m, 1H), 3.61 (m, 1H), 2.97 (m, 1H), 2.82 (d,
J=6.6 Hz, 2H), 2.68-2.16 (m, 11H), 1.97-1.83 (m, 3H), 1.76-1.55 (m,
2H), 1.40-1.20 (m, 6H), 0.89 (t, J=7.0 Hz, 3H).
EXAMPLE 16(f)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid 2-octanoyloxyethyl ester
##STR03527##
[1223] TLC: Rf 0.26 (Ethyl Acetate:Methanol=20:1);
[1224] NMR: .delta. 7.22-7.12 (m, 2H), 7.07-6.97 (m, 2H), 5.75 (dd,
J=15.3, 5.4 Hz, 1H), 5.51 (dd, J=15.3, 8.4 Hz, 1H), 4.45-4.36 (m,
1H), 4.26 (s, 4H), 4.18-4.07 (m, 1H), 3.70-3.57 (m, 1H), 3.02-2.90
(m, 1H), 2.82 (d, J=5.4 Hz, 2H), 2.70-2.50 (m, 4H), 2.45 (t, J=7.2
Hz, 2H), 2.40-2.18 (m, 5H), 1.98-1.86 (m, 3H), 1.80-1.50 (m, 3H),
1.40-1.20 (m, 8H), 0.89 (t, J=7.2 Hz, 3H).
EXAMPLE 16(g)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid N-heptanoyl-N-methylcarbamoylmethyl
ester
##STR03528##
[1226] TLC: Rf 0.69 (Chloroform:Methanol=9:1);
[1227] NMR: .delta. 7.21-7.14 (m, 2H), 7.04-6.97 (m, 2H), 5.75
(ddd, J=15.0, 5.4, 1.2 Hz, 1H), 5.53 (dd, J=15., 8.7 Hz, 1H),
4.73-4.65 (m, 2H), 4.39 (m, 1H), 4.13 (m, 1H), 3.58 (m, 1H),
3.39-3.24 (m, 1H), 3.20-3.10 (m, 1H), 3.06 (m, 1H), 2.93-2.77 (m,
5H), 2.71-2.15 (m, 9H), 2.00-1.89 (m, 2H), 1.78-1.42 (m, 3H),
1.40-1.20 (m, 8H), 0.95-0.82 (m, 3H).
EXAMPLE 16(h)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic
acid(4-hexylpiperazin-1-yl)carbonylmethyl ester
##STR03529##
[1229] TLC: Rf 0.71 (Chloroform:Methanol=9:1);
[1230] NMR: .delta. 7.22-7.12 (m, 2H), 7.06-6.96 (m, 2H), 5.76 (dd,
J=15.3, 5.4 Hz, 1H), 5.52 (dd, J=15.3, 8.7 Hz, 1H), 4.70 (s, 2H),
4.43-4.35 (m, 1H), 4.18-4.07 (m, 1H), 3.70-3.50 (m, 3H), 3.41-3.32
(m, 2H), 3.09-2.97 (m, 1H), 2.81 (d, J=6.6 Hz, 2H), 2.72-2.5 (m,
6H), 2.5-2.2 (m, 9H), 2.01-1.89 (m, 2H), 1.80-1.58 (m, 1H),
1.58-1.41 (m, 2H), 1.41-1.22 (m, 6H), 0.90 (t, J=7.2 Hz, 3H).
EXAMPLE 16(i)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid
N-ethyl-N-(2-diethylaminoethyl)carbamoylmethyl ester
##STR03530##
[1232] TLC: Rf 0.29 (Chloroform:Methanol=9:1);
[1233] NMR: .delta. 7.25-7.10 (m, 2H), 7.05-6.95 (m, 2H), 5.76 (dd,
J=15.0, 5.4 Hz, 1H), 5.60-5.45 (m, 1H), 4.79 and 4.71 (s, 2H), 4.38
(q, J=6.0 Hz, 1H), 4.12 (q, J=7.2 Hz, 1H), 3.65-3.50 (m, 1H),
3.45-3.20 (m, 4), 3.10-2.95 (m, 1H), 2.82 (d, J=6.0 Hz, 2H),
2.75-2.40 (m, 10H), 2.40-2.15 (m, 4H), 2.05-1.85 (m, 2H), 1.80-1.60
(m, 1H), 1.22 and 1.12 (t, J=7.2 Hz, 3H), 1.05 (t, J=7.2 Hz, 3H),
1.04 (t, J=7.2 Hz, 3H).
EXAMPLE 16(j)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid 2-(2-(dipropylamino)acetyloxy)ethyl
ester
##STR03531##
[1235] TLC: Rf 0.47 (Chloroform:Methanol=9:1);
[1236] NMR: .delta. 7.21-7.15 (m, 2H), 7.04-6.97 (m, 2H), 5.76 (dd,
J=15.3, 5.7 Hz, 1H), 5.50 (ddd, J=15.3, 8.4, 1.0 Hz, 1H), 4.40 (m,
1H), 4.37-4.20 (m, 4H), 4.10 (m, 1H), 3.60 (m, 1H), 3.35 (s, 2H),
2.97 (m, 1H), 2.80 (d, J=6.0 Hz, 2H), 2.65-2.19 (m, 13H), 1.97-1.84
(m, 3H), 1.78-1.40 (m, 5H), 0.88 (t, J=7.5 Hz, 6H).
EXAMPLE 16(k)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid 2-(2-(diethylamino)acetyloxy)ethyl
ester
##STR03532##
[1238] TLC: Rf 0.46 (Chloroform:Methanol=9:1);
[1239] NMR: .delta. 7.20-7.14 (m, 2H), 7.06-6.95 (m, 2H), 5.75 (dd,
J=15.3, 5.7 Hz, 1H), 5.50 (dd, J=15.3, 8.4 Hz, 1H), 4.42-4.20 (m,
5H),4.10 (m, 1H), 3.60 (m, 1H), 3.34 (s, 2H), 2.97 (m, 1H), 2.80
(d, J=7.0 Hz, 2H), 2.70-2.17 (m, 13H), 2.00-1.83 (m, 3H), 1.70 (m,
1H), 1.06 (t, J=7.2 Hz, 6H).
EXAMPLE 17
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid nonanoyloxymethyl ester
##STR03533##
[1241] By the same procedure as describe in Example 12 using the
compound prepared in Example 3(1) instead of the compound prepared
in Example 3(b) and nonanoyloxymethyl chloride instead of
2-bromoacetic acid isopropyl ester, the compound of the present
invention having the following physical data were obtained.
[1242] TLC: Rf 0.31 (Hexane:Ethyl Acetate=1:4);
[1243] NMR: .delta. 7.21-7.12 (m, 2H), 7.06-6.96 (m, 2H), 5.81-5.69
(m, 3H), 5.50 (dd, J=15.3, 8.4 Hz, 1H), 4.39 (m, 1H), 4.10 (m, 1H),
3.61 (m, 1H), 3.00-2.78 (m, 3H), 2.69-2.17 (m, 11H), 2.00-1.50 (m,
4H), 1.40-1.19 (m, 10H), 0.88 (t, J=7.2 Hz, 3H).
REFERENCE EXAMPLE 20
(9.alpha.,11.alpha.,15.alpha.,13E)-9-Hydroxy-11,15-bis(tetrahydropyran-2-y-
loxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic
acid
##STR03534##
[1245] To a solution of
(9.alpha.,11.alpha.,15.alpha.,13E)-9-hydroxy-11,15-bis(tetrahydropyran-2--
yloxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoi-
c acid methyl ester (5 g; this is the compound described in
Reference Example 28 of WO00/03980) in methanol (8 mL), 2N aqueous
sodium hydroxide (8.1 mL) was added, and the mixture was stirred
for 1.5 hours at room temperature. After cooling, 2N hydrochloric
acid was added to the aqueous layer to acidify, then the mixture
was extracted by ethyl acetate. The extract was washed with brine,
dried over an anhydrous sodium sulfate, concentrated under reduced
pressure to give the title compound having the following physical
data, which was used for the next reaction without
purification.
[1246] TLC: Rf 0.55 (Ethyl Acetate);
[1247] NMR: .delta. 7.3-7.1 (m, 4H), 5.7-5.3 (m, 2H), 4.8-3.1 (m,
9H), 3.5-3.1 (m, 5H), 3.0-2.0 (m, 10H), 2.0-1.3 (m, 18H).
REFERENCE EXAMPLE 21
(9.alpha.,11.alpha.,15.alpha.,13E)-9-Hydroxy-11,15-bis(tetrahydropyran-2-y-
loxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic
acid 2-nonanoyloxyethyl ester
##STR03535##
[1249] To a solution of the compound prepared in Reference Example
20 in dimethylformamide (16 mL), nonanoic acid 2-bromoethylester
(2.35 g), sodium iodide (121 mg) and potassium carbonate (1.67 g)
were added, and the mixture was stirred for 2 hours at 50.degree.
C. After cooling, the mixture was added by water, and extracted by
ethyl acetate. The extract was washed with water and brine, dried
over an anhydrous sodium sulfate, concentrated under reduced
pressure and was purified by column chromatography on silica gel
(ethyl acetate:hexane=1:1) to give the title compound (6.33 g)
having the following physical data.
[1250] TLC: Rf 0.43 (Hexane:Ethyl Acetate=1:1);
[1251] NMR: .delta. 7.3-7.1 (m, 4H), 5.7-5.3 (m, 2H), 4.75-4.45 (m,
2H), 4.42 (s, 2H), 4.27 (s, 4H), 4.3-3.7 (m, 3H), 3.5-3.2 (m, 5H),
3.0-2.7 (m, 2H), 2.6-2.4 (m, 6H), 2.33 (t, J=7.2 Hz, 2H), 2.3-2.0
(m, 1H), 2.0-1.2 (m, 31H), 0.90 (t, J=7.2 Hz, 3H).
REFERENCE EXAMPLE 22
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-bis(tetrahydropyran-2-yloxy)-16-(3-m-
ethoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
2-nonanoyloxyethyl ester
##STR03536##
[1253] To a solution of the compound prepared in Reference Example
21 (6.33 g) in ethyl acetate (28 mL), diisopropylethylamine (8.35
mL) was added on iced bath. Then sulfur trioxide pyridine complex
(3.82 g) and dimethylsulfoxide (14 mL) were added to the mixture,
and the mixture was stirred for 20 minutes. The reaction mixture
was added by water and was extracted by ethyl acetate. The extract
was washed with water and brine successively, dried over an
anhydrous sodium sulfate, concentrated under reduced pressure and
was purified by column chromatography on silica gel (ethyl
acetate:hexane=1:1) to give the title compound (5.12 g) having the
following physical data.
[1254] TLC: Rf 0.50 (Hexane:Ethyl Acetate=1:1);
[1255] NMR: .delta. 7.3-7.1 (m, 4H), 5.8-5.25 (m, 2H), 4.8-4.5 (m,
2H), 4.42 (s, 2H), 4.4-3.75 (m, 8H), 3.55-3.2 (m, 5H), 3.0-2.65 (m,
3H), 2.65-2.4 (m, 7H), 2.4-2.05 (m, 4H), 1.95-1.2 (m, 28H), 0.88
(t, J=7.2 Hz, 3H).
EXAMPLE 18
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-nonanoyloxyethyl
ester
##STR03537##
[1257] To a solution of the compound prepared in Reference Example
22 (5.12 g) in mixed solvent of methanol (26 mL),
1,2-dimethoxyethane (26 mL) and acetonitrile (26 mL), 0.1N
hydrochloric acid (26 mL) was added, and the mixture was stirred
for 3 hours at 35.degree. C. The reaction mixture was added by
water and was extracted by ethyl acetate. The extract was washed
with saturated aqueous sodium hydrogen carbonate solution and brine
successively, dried over an anhydrous magnesium sulfate,
concentrated under reduced pressure and was purified by column
chromatography on silica gel (ethyl acetate:hexane=from 3:1 to 4:1,
then ethyl acetate only) to give the title compound (2.71 g) having
the following physical data.
[1258] TLC: Rf 0.33 (Ethyl Acetate);
[1259] NMR: .delta. 7.30 (t, J=8.1 Hz, 1H), 7.23-7.11 (m, 3H), 5.76
(dd, J=15.3, 6.0 Hz, 1H), 5.53 (dd, J=15.3, 8.4 Hz, 1H), 4.48-4.39
(m, 3H), 4.26 (s, 4H), 4.00-3.90 (m, 1H), 3.42 (s, 3H), 3.15-3.08
(br, 1H), 2.91 (dd, J=13.5, 5.4 Hz, 1H), 2.83 (dd, J=13.5, 6.9 Hz,
1H), 2.70 (dd, J=18.6, 7.5 Hz, 1H), 2.65-2.50 (m, 2H), 2.52 (t,
J=7.2 Hz, 2H), 2.44 (t, J=7.2 Hz, 2H), 2.36 (t, J=7.2 Hz, 2H),
2.40-2.13 (m, 4H), 1.95-1.82 (m, 3H), 1.74-1.60 (m, 3H), 1.40-1.20
(m, 10H), 0.89 (t, J=7.2 Hz, 3H).
EXAMPLE 18(a) TO EXAMPLE 18(q)
[1260] By the same procedure as describe in Reference Examples 21,
22 and Example 18 using corresponding halides instead of nonanoic
acid 2-bromoethyl ester, the compound of the present invention
having the following physical data were obtained.
EXAMPLE 18(a)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid pivaloyloxymethyl
ester
##STR03538##
[1262] TLC: Rf 0.63 (Chloroform:Methanol=9:1);
[1263] NMR: .delta. 7.33-7.10 (m, 4H), 5.74 (s, 2H), 5.73 (dd,
J=15, 6.0 Hz, 1H), 5.53 (ddd, J=15, 8.7, 0.7 Hz, 1H), 4.48-4.37 (m,
3H), 3.94 (m, 1H), 3.42 (s, 3H), 2.90 (dd, J=13, 5.6 Hz, 1H), 2.83
(dd, J=13, 6.9 Hz, 1H), 2.70 (ddd, J=19, 7.5, 1.1 Hz, 1H),
2.62-2.43 (m, 6H), 2.38-2.12 (m, 3H), 1.95-1.81 (m, 3H), 1.74-1.59
(m, 1H), 1.21 (s, 9H).
EXAMPLE 18(b)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
1-cyclohexyloxycarbonyloxyethyl ester
##STR03539##
[1265] TLC: Rf 0.63 (Chloroform:Methanol=9:1);
[1266] NMR: .delta. 7.33-7.09 (m, 4H), 6.75 (q, J=5.4 Hz, 1H), 5.73
(dd, J=15, 6.3 Hz, 1H), 5.53 (dd, J=15, 8.6 Hz, 1H), 4.63 (m, 1H),
4.48-4.34 (m, 3H), 3.94 (m, 1H), 3.41 (s, 3H), 2.88 (dd, J=14, 5.6
Hz, 1H), 2.82 (dd, J=14, 6.9 Hz, 1H), 2.69 (ddd, J=19, 7.6, 1.0 Hz,
1H), 2.64-2.41 (m, 6H), 2.37-2.12 (m, 3H), 1.98-1.17 (m, 14H), 1.51
(d, J=5.4 Hz, 3H).
EXAMPLE 18(c)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
N,N-diethylaminocarbonylmethyl ester
##STR03540##
[1268] TLC: Rf 0.18 (Ethyl Acetate:Methanol=50:1);
[1269] NMR: .delta. 7.3-7.1 (m, 4H), 5.76 (dd, J=15, 6 Hz, 1H),
5.55 (dd, J=15, 8 Hz, 1H), 4.70 (s, 2H), 4.42 (s, 2H), 4.5-4.4 (m,
1H), 3.90 (q, J=8 Hz, 1H), 3.41 (s, 3H), 3.37 (q, J=7 Hz, 2H), 3.24
(q, J=7 Hz, 2 H), 2.95-2.8 (m, 2H), 2.69 (dd, J=18, 7 Hz, 1H),
2.65-2.5 (m, 6H), 2.4-2.1 (m, 4H), 2.4-1.8 (m, br), 2.0-1.8 (m,
2H), 1.75-1.6 (m, 1H), 1.22 (t, J=7 Hz, 3H), 1.15 (t, J=7 Hz,
3H).
EXAMPLE 18(d)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-acetyloxyethyl
ester
##STR03541##
[1271] TLC: Rf 0.28 (Ethyl Acetate);
[1272] NMR: .delta. 7.3-7.1 (m, 4H), 5.76 (dd, J=15, 6 Hz, 1H),
5.53 (dd, J=15, 8 Hz, 1H), 4.5-4.4 (m, 3H), 4.27 (s, 4H), 3.94
(brq, 1H), 3.42 (s, 3H), 3.05-3.0 (br, 1H), 2.91 (dd, J=14, 6 Hz,
1H), 2.83 (dd, J=14, 7 Hz, 1H), 2.70 (dd, J=18, 7 Hz, 1H), 2.65-2.5
(m, 2H), 2.51 (t, J=7 Hz, 2H), 2.45 (t, J=7 Hz, 2H), 2.4-2.1 (m,
4H), 2.08 (s, 3H), 1.95-1.8 (m, 3H), 1.8-1.6 (m, 1H).
EXAMPLE 18(e)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid benzoylmethyl
ester
##STR03542##
[1274] TLC: Rf 0.32 (Ethyl Acetate);
[1275] NMR: .delta. 7.92-7.88 (m, 2H), 7.65-7.59 (m, 1H), 7.52-7.46
(m, 2H), 7.34-7.10 (m, 4H), 5.77 (dd, J=15.6, 5.7 Hz, 1H), 5.54
(dd, J=15.6, 8.4 Hz, 1H), 5.35 (s, 2H), 4.50-4.38 (m, 3H),
4.00-3.89 (m, 1H), 3.41 (s, 3H), 2.87-2.54 (m, 9H), 2.41-2.18 (m,
3H), 2.04-1.84 (m, 3H), 1.78-1.65 (m, 1H).
EXAMPLE 18(f)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
isopropyloxycarbonylmethyl ester
##STR03543##
[1277] TLC: Rf 0.30 (Ethyl Acetate);
[1278] NMR: .delta. 7.35-7.12 (m, 4H), 5.75 (dd, J=15.0, 5.7 Hz,
1H), 5.53 (dd, J=15.0, 8.4 Hz, 1H), 5.07 (m, 1H), 4.56 (s, 2H),
4.47-4.37 (m, 3H), 3.93 (m, 1H), 3.42 (s, 3H), 3.05-2.50 (m, 10H),
2.39-2.14 (m, 4H), 1.98-1.83 (m, 3H), 1.78-1.60 (m, 1H), 1.25 (d,
J=6.3 Hz, 6H).
EXAMPLE 18(g)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
N,N-diethylaminocarbonyloxymethyl ester
##STR03544##
[1280] TLC: Rf 0.34 (Ethyl Acetate);
[1281] NMR: .delta. 7.3-7.1 (m, 4H), 5.76 (s, 2H), 5.75 (dd, J=15,
6 Hz, 1H), 5.53 (dd, J=15, 8 Hz, 1H), 4.5-4.35 (m, 3H), 3.93 (brq,
1H), 3.42 (s, 3H), 3.4-3.2 (m, 4H), 2.95-2.8 (m, 2H), 2.70 (dd,
J=19, 8 Hz, 1H), 2.65-2.45 (m, 6H), 2.4-2.1 (m, 4H), 1.95-1.8 (m,
4H), 1.75-1.6 (m, 1H), 1.2-1.05 (m, 6H).
EXAMPLE 18(h)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
t-butyloxycarbonylmethyl ester
##STR03545##
[1283] TLC: Rf 0.36 (Ethyl Acetate);
[1284] NMR: .delta. 7.35-7.12 (m, 4H), 5.73 (dd, J=15.0, 6.0 Hz,
1H), 5.51 (dd, J=15.0, 8.0 Hz, 1H), 4.50 (s, 2H), 4.43-4.35 (m,
3H), 3.99-3.88 (m, 1H), 3.42-3.20 (m, 4H), 2.89-2.15 (m, 11H),
1.95-1.60 (m, 6H), 1.47 (s, 9H).
EXAMPLE 18(i)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
1-isopropyloxycarbonylethyl ester
##STR03546##
[1286] TLC: Rf 0.44 (Ethyl Acetate);
[1287] NMR: .delta. 7.36-7.12 (m, 4H), 5.76 (dd, J=15.0, 5.4 Hz,
1H), 5.53 (dd, J=15.0, 8.4 Hz, 1H), 5.10-4.97 (m, 1H), 4.47-4.38
(m, 3H), 3.99-3.87 (m, 1H), 3.42 (s, 3H), 2.97-2.14 (m, 12H),
1.97-1.61 (m, 7H), 1.46 (d, J=7.2 Hz, 3H), 1.27 and 1.23 (d, J=7.0
Hz, 6H).
EXAMPLE 18(j)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 1-benzoylethyl
ester
##STR03547##
[1289] TLC: Rf 0.37 (Ethyl Acetate);
[1290] NMR: .delta. 7.92 (d, J=8.4 Hz, 2H), 7.63-7.57 (m, 1H),
7.51-7.44 (m, 2H), 7.31-7.25 (m, 1H), 7.19-7.10 (m, 3H), 5.95 (q,
J=7.20 Hz, 1H), 5.74 (ddd, J=15.3, 5.7, 4.2 Hz, 1H), 5.52 (ddd,
J=15.3, 7.5, 1.8 Hz, 1H), 4.47-4.35 (m, 3H), 4.09-3.94 (m, 1H),
3.41 (s, 3H), 3.02-2.13 (m, 14H), 1.97-1.65 (m, 4H), 1.52 (d, J=7.2
Hz, 3H).
EXAMPLE 18(k)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
methoxycarbonylmethyl ester
##STR03548##
[1292] TLC: Rf 0.36 (Chloroform:Methanol=10:1);
[1293] NMR: .delta. 7.32-7.15 (m, 4H), 5.74 (dd, J=15.3, 6.3 Hz,
1H), 5.53 (dd, J=15.3, 8.7 Hz, 1H), 4.62 (s, 2H), 4.42 (m, 2H),
4.39 (m, 1H), 3.94 (m, 1H), 3.76 (s, 3H), 3.41 (s, 3H), 3.24 (brs,
1H), 2.91-2.51 (m, 8H), 2.41-2.14 (m, 4H), 1.95-1.83 (m, 3H),
1.74-1.62 (m, 2H).
EXAMPLE 18(l)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
2-tridecanoyloxyethyl ester
##STR03549##
[1295] TLC: Rf 0.36 (Ethyl Acetate);
[1296] NMR: .delta. 7.3-7.1 (m, 4H), 5.77 (dd, J=15, 6 Hz, 1H),
5.53 (dd, J=15, 8 Hz, 1H), 4.5-4.4 (m, 3H), 4.25 (s, 4H), 4.0-3.9
(brq, 1H), 3.42 (s, 3H), 2.92 (dd, J=14, 5 Hz, 1H), 2.84 (dd, J=14,
7 Hz, 1H), 2.70 (dd, J=19, 8 Hz, 1H), 2.65-2.5 (m, 2H), 2.50 (t,
J=7 Hz, 2H), 2.45 (t, J=7 Hz, 2H), 2.33 (t, J=7 Hz, 2H), 2.4-2.1
(m, 5H), 1.95-1.8 (m, 3H), 1.75-1.5 (m, 3H), 1.4-1.2 (m, 18H), 0.87
(t, J=7 Hz, 3H).
EXAMPLE 18(m)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-heptanoyloxyethyl
ester
##STR03550##
[1298] TLC: Rf 0.35 (Ethyl Acetate);
[1299] NMR: .delta. 7.3-7.1 (m, 4H), 5.74 (dd, J=15, 6 Hz, 1H),
5.52 (dd, J=15, 8 Hz, 1H), 4.5-4.3 (m, 3H), 4.26 (s, 4H), 4.0-3.9
(m, 1H), 3.42 (s, 3H), 3.35-3.3 (br, 1H), 2.89 (dd, J=14, 6 Hz,
1H), 2.81 (dd, J=1 4, 7 Hz, 1H), 2.70 (dd, J=19, 8 Hz, 1H),
2.65-2.5 (m, 2H), 2.52 (t, J=7 Hz, 2H), 2.47 (t, J=7 Hz, 2H),
2.5-2.4 (br, 1H), 2.4-2.15 (m, 5H), 1.95-1.8 (m, 3H), 1.75-1.55 (m,
3H), 1.4-1.2 (m, 6H), 0.90 (t, J=7 Hz, 3H).
EXAMPLE 18(n)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-octanoyloxyethyl
ester
##STR03551##
[1301] TLC: Rf 0.22 (Hexane:Ethyl Acetate=1:1);
[1302] NMR: .delta. 7.35-7.10 (m, 4H), 5.76 (dd, J=15.3, 5.7 Hz,
1H), 5.53 (dd, J=15.3, 8.7 Hz, 1H), 4.48-4.38 (m, 3H), 4.27 (s,
4H), 3.96 (m, 1H), 3.42 (s, 3H), 3.00-2.80 (m, 3H), 2.78-2.40 (m,
7H), 2.39-2.13 (m, 6H), 1.96-1.80 (m, 3H), 1.78-1.57 (m, 3H),
1.40-1.20 (m, 8H), 0.88 (t, J=7.0 Hz, 3H).
EXAMPLE 18(o)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-decanoyloxyethyl
ester
##STR03552##
[1304] TLC: Rf 0.23 (Hexane:Ethyl Acetate=1:1);
[1305] NMR: .delta. 7.36-7.12 (m, 4H), 5.76 (dd, J=15.0, 6.0 Hz,
1H), 5.53 (dd, J=15.0, 8.0 Hz, 1H), 4.44-4.39 (m, 3H), 4.27 (s,
4H), 3.96 (m, 1H), 3.42 (s, 3H), 2.99-2.80 (m, 3H), 2.78-2.40 (m,
7H), 2.39-2.12 (m, 6H), 1.95-1.80 (m, 3H), 1.77-1.60 (m, 3H),
1.39-1.19 (m, 12H), 0.88 (t, J=6.9 Hz, 3H).
EXAMPLE 18(p)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
allyloxycarbonylmethyl ester
##STR03553##
[1307] TLC: Rf 0.58 (Ethyl Acetate);
[1308] NMR: .delta. 7.4-7.1 (m, 4H), 6.0-5.8 (m, 1H), 5.78 (dd,
J=16, 6 Hz, 1H), 5.53 (dd, J=16, 8 Hz, 1H), 5.4-5.25 (m, 2H),
4.7-4.6 (m, 4H), 4.5-4.4 (m, 3H), 4.0-3.85 (m, 1H), 3.42 (s, 3H),
3.0-2.8 (m, 2H), 2.72 (dd, J=19, 10 Hz, 1H), 2.65-2.5 (m, 6H),
2.4-2.1 (m, 4H), 2.0-1.6 (m, 5H).
EXAMPLE 18(q)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid nonanoyloxymethyl
ester
##STR03554##
[1310] TLC: Rf 0.25 (Hexane:Ethyl Acetate=1:4);
[1311] NMR: .delta. 7.35-7.10 (m, 4H), 5.81-5.69 (m, 3H), 5.52 (dd,
J=15.0, 8.7 Hz, 1H), 4.48-4.37 (m, 3H), 3.95 (m, 1H), 3.42 (s, 3H),
3.10 (bs, 1H), 2.92-2.42 (m, 9H), 2.40-2.11 (m, 6H), 1.97-1.80 (m,
3H), 1.78-1.58 (m, 3H), 1.40-1.20 (m, 10H), 0.88 (t, J=7.2 Hz,
3H).
REFERENCE EXAMPLE 23
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-bis(tetrahydropyran-2-yloxy)-16-(3-m-
ethoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
2-(tetrahydropyran-2-yloxy)ethyl ester
##STR03555##
[1313] By the same procedure as describe in Reference Examples 21
and 22 using 1-(tetrahydropyran-2-yloxy)-2-bromoethane instead of
nonanoic acid 2-bromoethyl ester, the title compound having the
following physical data were obtained.
[1314] TLC: Rf 0.51 (Hexane:Ethyl Acetate=1:1).
EXAMPLE 19
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-hydroxyethyl
ester
##STR03556##
[1316] By the same procedure as describe in Example 18 using the
compound prepared in Reference Example 23 instead of the compound
prepared in Reference Example 22, the compound of the present
invention having the following physical data were obtained
[1317] TLC: Rf 0.35 (Ethyl Acetate:Methanol=19:1);
[1318] NMR: .delta. 7.32-7.11 (m, 4H), 5.77 (dd, J=15.3, 5.7 Hz,
1H), 5.54 (dd, J=15.3, 8.1 Hz, 1H), 4.48-4.38 (m, 3H), 4.22-4.17
(m, 2H), 4.00-3.90 (m, 1H), 3.82-3.75 (m, 2H), 3.42 (s, 3H),
3.12-2.91 (br, 1H), 2.92 (dd, J=13.5, 5.4 Hz, 1H), 2.84 (dd,
J=13.5, 6.9 Hz, 1H), 2.71 (dd, J=18.9, 7.5 Hz, 1H), 2.65-2.50 (m,
2H), 2.52 (t, J=7.2 Hz, 2H), 2.47 (t, J=7.2 Hz, 2H), 2.45-2.15 (m,
5H), 1.95-1.8 0 (m, 3H), 1.76-1.60 (m, 1H).
REFERENCE EXAMPLE 24
(9.alpha.,11.alpha.,15.alpha.,13E)-9-Trimethylsilyloxy-11,15-bis(tetrahydr-
opyran-2-yloxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiapros-
t-13-enoic acid
##STR03557##
[1320] Under atmosphere of argon, a solution of the compound
prepared in Reference Example 20 (680 mg) in dry tetrahydrofuran (5
mL), triethylamine (0.94 mL), and trimethylsilyl chloride (0.57 and
catalytic amount of dimethylaminopyridine was added successively at
room temparature, and the mixture was stirred for 5 hour at room
temperature. The reaction mixture was added by water, and was
extracted by ethyl acetate. The extract was washed with brine,
dried over an anhydrous sodium sulfate, concentrated under reduced
pressure to give the title compound having the following physical
data, which was used for the next reaction without
purification.
[1321] TLC: Rf 0.45 (Ethyl Acetate).
REFERENCE EXAMPLE 25
(9.alpha.,11.alpha.,15.alpha.,13E)-9-Hydroxy-11,15-bis(tetrahydropyran-2-y-
loxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic
acid phenyl ester
##STR03558##
[1323] To a solution of the compound prepared in Reference Example
24, triethylamine (0.15 mL) and phenol (53 mg) in acetonitrile (3
mL), 1-hydroxybenzotriazole (50 mg) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydyochloride
(142 mg) was added under atmosphere of argon at room temperature,
and the mixture was stirred for 2 hours at room temperature. The
reaction mixture was added by ethyl acetate, was washed with 1N
hydrochloric acid (twice), water, saturated aqueous sodium hydrogen
carbonate solution and brine successively, dried over an anhydrous
sodium sulfate, concentrated under reduced pressure and was
purified by column chromatography on silica gel (ethyl
acetate:hexane=1:1) to give the title compound (115 mg) having the
following physical data.
[1324] TLC: Rf 0.35 (Hexane:Ethyl Acetate=1:1).
EXAMPLE 20
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid phenyl ester
##STR03559##
[1326] By the same procedure as describe in Reference Example 22
and Example 18 using the compound prepared in Reference Example 25
instead of the compound prepared in Reference Example 21, the
compound of the present invention having the following physical
data were obtained
[1327] TLC: Rf 0.34 (Ethyl Acetate);
[1328] NMR: .delta. 7.4-7.0 (m, 9H), 5.74 (dd, J=15, 6 Hz, 1H),
5.51 (dd, J=15, 8 Hz, 1H), 4.5-4.3 (m, 3H), 3.93 (brq, 1H), 3.42
(s, 3H), 3.2-3.1 (br, 1H), 2.88 (dd, J=14, 6 Hz, 1H), 2.80 (dd,
J=14, 7 Hz, 1H), 2.75-2.5 (m, 7H), 2.4-2.1 (m, 4H), 2.1-1.95 (m,
2H), 2.0-1.85 (m, 1H), 1.8-1.6 (m, 1H).
EXAMPLE 21
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid carboxymethyl
ester
##STR03560##
[1330] To a solution of the compound prepared in Example 18(p) in
dry tetrahydrofuran (1.5 mL),
tetrakis(triphenylphosphine)palladium(0) (15 mg) was added under
atmosphere of argon. The morpholine (68 .mu.L) was dropped into the
mixture, and the mixture was stirred for 30 minutes at room
temperature. The reaction mixture was added by ethyl acetate, was
washed with 1N hydrochloric acid, water, saturated aqueous sodium
hydrogen carbonate solution and brine successively, dried over an
anhydrous sodium sulfate, concentrated under reduced pressure and
was purified by column chromatography on silica gel (ethyl
acetate:acetic acid=100:1) to give the title compound (52 mg)
having the following physical data.
[1331] TLC: Rf 0.30 (Chloroform:Methanol:Acetic Acid=45:5:1);
[1332] NMR: .delta. 7.3-7.1 (m, 4H), 5.80 (dd, J=15, 6 Hz, 1H),
5.57 (dd, J=15, 8 Hz, 1H), 4.58 (s, 2H), 4.47 (s, 2H), 4.5-4.4 (m,
1H), 4.0-3.9 (m, 1H), 3.23 (s, 3H), 2.93 (dd, J=14, 5 Hz, 1H), 2.81
(dd, J=14, 7 Hz, 1H), 2.8-2.5 (m, 7H), 2.5-2.2 (m, 3H), 2.0-1.8 (m,
3H), 1.8-1.65 (m, 1H).
EXAMPLE 22(a) TO EXAMPLE 22(e)
[1333] By the same procedure as describe in Reference Examples 21,
22 and Example 18 using corresponding halides instead of nonanoic
acid 2-bromoethyl ester, the compound of the present invention
having the following physical data were obtained.
EXAMPLE 22(a)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
dipropylcarbamoylmethyl ester
##STR03561##
[1335] TLC: Rf 0.32 (Ethyl Acetate);
[1336] NMR: .delta. 7.32-7.27 (m, 1H), 7.22-7.13 (m, 3H), 5.74 (dd,
J=15.9, 6.3 Hz, 1H), 5.54 (ddd, J=15.9, 8.4, 1.2 Hz, 1H), 4.71 (s,
2H), 4.42 (m, 3H), 3.94 (m, 1H), 3.41 (s, 3H), 3.28 (m, 2H),
3.19-3.08 (m, 3H), 2,95-2.80 (m, 2H), 2.78-2.50 (m, 8H), 2.40-2.18
(m, 3H), 2.00-1.83 (m, 3H), 1.76-1.50 (m, 5H), 0.94 (t, J=7.5 Hz,
3H), 0.88 (t, J=7.5 Hz, 3H).
EXAMPLE 22(b)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
dibutylcarbamoylmethyl ester
##STR03562##
[1338] TLC: Rf 0.36 (Ethyl Acetate);
[1339] NMR: .delta. 7.32-7.26 (m, 1H), 7.22-7.13 (m, 3H), 5.74 (dd,
J=15.6, 6.0 Hz, 1H), 5.54 (dd, J=15.6, 8.4 Hz, 1H), 4.71 (s, 2H),
4.42 (m, 3H), 3.94 (m, 1H), 3.41 (s, 3H), 3.31 (m, 2H), 3.17 (m,
2H), 3.02 (m, 1H), 2.93-2.82 (m, 2H), 2.77-2.50 (m, 8H), 2.40-2.19
(m, 3H), 2.00-1.83 (m, 3H), 1.77-1.43 (m, 5H), 1.41-1.21 (m, 4H),
0.96 (t, J=7.5 Hz, 3H), 0.91 (t, J=7.5 Hz, 3H).
EXAMPLE 22(c)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
4-pentylbenzoylmethyl ester
##STR03563##
[1341] TLC: Rf 0.38 (Hexane:Ethyl Acetate=1:4);
[1342] NMR: .delta. 7.81 (d, J=8.4 Hz, 2H), 7.36-7.23 (m, 3H),
7.21-7.10 (m, 3H), 5.78 (dd, J=15.0, 5.4 Hz, 1H), 5.55 (dd, J=15.0,
8.1 Hz, 1H), 5.33 (s, 2H), 4.47-4.39 (m, 3H), 3.95 (m, 1H), 3.41
(s, 3H), 2.97-2.55 (m, 12H), 2.40-2.18 (m, 4H), 2.03-1.84 (m, 3H),
1.80-1.58 (m, 3H), 1.40-1.22 (m, 4H), 0.89 (t, J=6.6 Hz, 3).
EXAMPLE 22(d)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
1,1-dimethylheptyloxycarbonylmethyl ester
##STR03564##
[1344] TLC: Rf 0.42 (Hexane:Ethyl Acetate=1:4);
[1345] NMR: .delta. 7.35-7.12 (m, 4), 5.76 (dd, J=15.3, 5.7 Hz,
1H), 5.53 (dd, J=15.3, 8.1 Hz, 1H), 4.51-4.40 (m, 5H), 3.95 (m,
1H), 3.42 (s, 3H), 3.00 (bs, 1H), 2.96-2.81 (m, 2H), 2.70 (dd,
J=18.6, 7.5 Hz, 1H), 2.61-2.48 (m, 6H), 2.40-2.19 (m, 4H),
2.00-1.83 (m, 3H), 1.79-1.60 (m, 3H), 1.44 (s, 6H), 1.38-1.20 (m,
8H), 0.88 (t, J=6.6 Hz, 3H).
EXAMPLE 22(e)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
dipentylcarbamoylmethyl ester
##STR03565##
[1347] TLC: Rf 0.33 (Hexane:Ethyl Acetate=1:4);
[1348] NMR: .delta. 7.36-7.12 (m, 4H), 5.76 (dd, J=15.0, 5.4 Hz,
1H), 5.55 (dd, J=15.0, 8.7 Hz, 1H), 4.70 (s, 2H), 4.45-4.39 (m,
3H), 3.95 (m, 1H), 3.41 (s, 3H), 3.30 (m, 2H), 3.17 (m, 2H), 3.00
(bs, 1H), 2.98-2.80 (m, 2H), 2.77-2.50 (m, 8H), 2.40-2.19 (m, 3H),
2.00-1.82 (m, 3H), 1.78-1.50 (m, 5H), 1.40-1.20 (m, 8H), 0.98-0.84
(m, 6H).
EXAMPLE 23
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-octyloxyethyl
ester
##STR03566##
[1350] To a solution of
(11.alpha.,15.alpha.,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl-
)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid (150 mg; this is
the compound described in Example 3 of WO00/03980),
2-octyloxyethanol (296 mg) and triethylamine (0.12 mL) in ethyl
acetate (3 mL), 1-mesyloxybenzotriazole (145 mg) was added, and the
mixture was stirred for 4 hours at room temperature. The reaction
mixture was added by ethyl acetate, The diluted solution was washed
with saturated aqueous sodium hydrogen carbonate solution, water
and brine successively, dried over an anhydrous sodium sulfate,
concentrated under reduced pressure and was purified by column
chromatography on silica gel (from ethyl acetate:hexane=2:1 to
ethyl acetate only) to give the title compound (137 mg) having the
following physical data.
[1351] TLC: Rf 0.22 (Ethyl Acetate:Hexane=3:1);
[1352] NMR: .delta. 7.35-7.15 (m, 4H), 5.75 (dd, J=15.3, 6.0 Hz,
1H), 5.53 (dd, J=15.3, 8.7 Hz, 1H), 4.50-4.37 (m, 3H), 4.22 (t,
J=5.1 Hz, 2H), 4.00-3.90 (m, 1H), 3.62 (t, J=5.1 Hz, 2H), 3.46 (t,
J=6.9 Hz, 2H), 3.42 (s, 3H), 2.90 (dd, J=13.5, 5.4 Hz, 1H), 2.83
(dd, J=13.5, 7.2 Hz, 1H), 2.70 (dd, J=18.6, 7.5 Hz, 1H), 2.65-2.40
(m, 6H), 2.40-2.10 (m, 4H), 1.95-1.80 (m, 4H), 1.80-1.50 (m, 3H),
1. 40-1.20 (m, 10H), 0.90 (t, J=6.9 Hz, 3H).
EXAMPLE 23(a) TO EXAMPLE 23(j)
[1353] By the same procedure as describe in Example 23 using
corresponding alcohol derivatives instead of 2-octyloxyethanol, the
compound of the present invention having the following physical
data were obtained.
EXAMPLE 23(a)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
2-(2,2-dimethylpentanoyloxy)ethyl ester
##STR03567##
[1355] TLC: Rf 0.28 (Ethyl Acetate:Hexane=3:1);
[1356] NMR: .delta. 7.35-7.10 (m, 4H), 5.77 (dd, J=15.3, 5.7 Hz,
1H), 5.53 (dd, J=15.3, 8.4 Hz, 1H), 4.50-4.40 (m, 3H), 4.25 (s,
4H), 4.00-3.90 (m, 1H), 3.41 (s, 3H), 2.96-2.80 (m, 3H), 2.67 (dd,
J=18.3, 7.5 Hz, 1H), 2.65-2.50 (m, 2H), 2.50 (t, J=7.2 Hz, 2H),
2.43 (t, J=7.2 Hz, 2H), 2.40-2.10 (m, 4H), 1.95-1.80 (m, 3H),
1.75-1.60 (m, 1H), 1.55-1.45 (m, 2H), 1.30-1.20 (m, 2H), 0.88 (t,
J=7.2 Hz, 3H).
EXAMPLE 23(b)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 3-butoxypropyl
ester
##STR03568##
[1358] TLC: Rf 0.30 (Ethyl Acetate:Hexane=3:1);
[1359] NMR: .delta. 7.30-7.10 (m, 4H), 5.77 (dd, J=15.3, 5.7 Hz,
1H), 5.53 (dd, J=15.3, 8.4 Hz, 1H), 4.50-4.40 (m, 3H), 4.17 (t,
J=7.2 Hz, 2H), 4.00-3.90 (m, 1H), 3.48 (t, J=7.2 Hz, 2H), 3.42 (s,
3H), 3.40 (t, J=6.6 Hz, 2H), 2.97-2.80 (m, 3H), 2.70 (dd, J=19.2,
7.5 Hz, 1H), 2.65-2.50 (m, 2H), 2.50 (t, J=7.2 Hz, 2H), 2.41 (t,
J=7.2 Hz, 2H), 2.36-2.14 (m, 4H), 1.95-1.82 (m, 3H), 1.75-1.60 (m,
1H), 1.60-1.50 (m, 2H), 1.42-1.30 (m, 2H), 0.92 (t, J=7.2 Hz,
3H).
EXAMPLE 23(c)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-butoxyethyl
ester
##STR03569##
[1361] TLC: Rf 0.32 (Ethyl Acetate);
[1362] NMR: .delta. 7.35-7.11 (m, 4H), 5.75 (dd, J=15.3, 5.7 Hz,
1H), 5.53 (dd, J=15.3, 8.7 Hz, 1H), 4.48-4.39 (m, 3H), 4.21 (m,
2H), 3.95 (m, 1H), 3.61 (m, 2H), 3.46 (t, J=6.6 Hz, 2H), 3.42 (s,
3H), 3.00 (m, 1H), 2.98-2.80 (m, 2H), 2.78-2.18 (m, 11H), 1.98-1.81
(m, 3H), 1.78-1.53 (m, 3H), 1.38 (m, 2H), 0.92 (t, J=7.5 Hz,
3H).
EXAMPLE 23(d)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-pentyloxyethyl
ester
##STR03570##
[1364] TLC: Rf 0.36 (Ethyl Acetate);
[1365] NMR: .delta. 7.35-7.11 (m, 4H), 5.75 (dd, J=15.3, 5.7 Hz,
1H), 5.53 (dd, J=15.3, 8.7 Hz, 1H), 4.48-4.39 (m, 3H), 4.21 (m,
2H), 3.95 (m, 1H), 3.61 (m, 2H), 3.46 (t, J=6.6 Hz, 2H), 3.42 (s,
3H), 2.98-2.80 (m, 3H), 2.78-2.18 (m, 11H), 1.98-1.81 (m, 3H),
1.78-1.53 (m, 3H), 1.38 (m, 4H), 0.92 (t, J=7.5 Hz, 3H).
EXAMPLE 23(e)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-hexyloxyethyl
ester
##STR03571##
[1367] TLC: Rf 0.39 (Ethyl Acetate);
[1368] NMR: .delta. 7.36-7.12 (m, 4H), 5.76 (dd, J=15.3, 5.7 Hz,
1H), 5.53 (dd, J=15.3, 8.7 Hz, 1H), 4.48-4.40 (m, 3H), 4.21 (m,
2H), 3.95 (m, 1H), 3.61 (m, 2H), 3.47-3.40 (m, 5H), 2.98-2.80 (m,
3H), 2.78-2.40 (m, 7H), 2.38-2.18 (m, 4H), 1.97-1.82 (m, 3H), 1.70
(m, 1H), 1.63-1.52 (m, 2H), 1.40-1.25 (m, 6H), 0.88 (t, J=7.2 Hz,
3H).
EXAMPLE 23(f)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
2-(2,2-dimethyloctanoyloxy)ethyl ester
##STR03572##
[1370] TLC: Rf 0.20 (Ethyl Acetate:Hexane=3:1);
[1371] NMR: .delta. 7.35-7.10 (m, 4H), 5.75 (dd, J=15.3, 6.0 Hz,
1H), 5.53 (dd, J=15.3, 8.4 Hz, 1H), 4.50-4.35 (m, 3H), 4.26 (s,
4H), 4.00-3.90 (m, 1H), 3.42 (s, 3H), 3.20-3.10 (br, 1H), 2.90 (dd,
J=13.5, 5.4 H z, 1H), 2.83 (dd, J=13.5, 7.2 Hz, 1H), 2.70 (dd,
J=18.6, 7.2 Hz, 1H), 2.63-2.50 (m, 2H), 2.50 (t, J=7.5 Hz, 2H),
2.43 (t, J=7.2 Hz, 2H), 2.40-2.15 (m, 4H), 1.95-1.80 (m, 3H),
1.80-1.60 (m, 1H), 1.55-1.50 (m, 2H), 1.40-1.15 (m, 8H), 0.90 (t,
J=6.9 Hz, 3H).
EXAMPLE 23(g)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
2-(2,2-diethylpentanoyloxy)ethyl ester
##STR03573##
[1373] TLC: Rf 0.21 (Ethyl Acetate:Hexane=3:1);
[1374] NMR: .delta. 7.35-7.10 (m, 4H), 5.76 (dd, J=15.3, 6.0 Hz,
1H), 5.53 (dd, J=15.3, 8.4 Hz, 1H), 4.50-4.35 (m, 3H), 4.27 (s,
4H), 4.00-3.90 (m, 1H), 3.42 (s, 3H), 3.05-3.00 (br, 1H), 2.92 (dd,
J=13.5, 5.4 H z, 1H), 2.83 (dd, J=13.5, 7.2 Hz, 1H), 2.70 (dd,
J=18.0, 7.2 Hz, 1H), 2.65-2.40 (m, 6H), 2.40-2.10 (m, 4H),
1.95-1.80 (m, 3H), 1.80-1.50 (m, 7H), 1.25-1.10 (m, 2H), 0.90 (t,
J=7.2 Hz, 3H), 0.78 (t, J=7.2 Hz, 6H).
EXAMPLE 23(h)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
4-(4-chlorophenyl)phenyl ester
##STR03574##
[1376] TLC: Rf 0.22 (Hexane:Ethyl Acetate=1:3);
[1377] NMR: .delta. 7.52 (d, J=8.7 Hz, 2H), 7.47 (d, J=8.6 Hz, 2H),
7.40 (d, J=8.6 Hz, 2H), 7.24 (m, 1H), 7.20-7.08 (m, 5H), 5.72 (dd,
J=15.3, 6.6 Hz, 1H), 5.51 (dd, J=15.3, 8.4 Hz, 1H), 4.45-4.30 (m,
3H), 3.95 (m, 1H), 3.63 (bs, 1H), 3.40 (s, 3H), 2.90-2.50 (m, 9H),
2.39-2.13 (m, 3H), 2.09-1.82 (m, 3H), 1.70 (m, 1H).
EXAMPLE 23(i)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
2-(adamantan-1-ylcarbonyloxy)ethyl ester
##STR03575##
[1379] TLC: Rf 0.33 (Ethyl Acetate:Hexane:Methanol=30:10:1);
[1380] NMR: .delta. 7.32-7.11 (m, 4H), 5.75 (dd, J=15.3, 6.0 Hz,
1H), 5.52 (dd, J=15.3, 9.0 Hz, 1H), 4.48-4.36 (m, 3H), 4.31-4.22
(m, 4H), 4.02-3.89 (m, 1H), 3.42 (s, 3H), 3.20-3.12 (br, 1H), 2.90
(dd, J=13.8, 5.4 Hz, 1H), 2.82 (dd, J=13.8, 7.2 Hz, 1H), 2.70 (dd,
J=18.3, 7.2 Hz, 1H), 2.65-2.13 (m, 10H), 2.07-1.97 (m, 3H),
1.96-1.80 (m, 9H), 1.80-1.60 (m, 7H).
EXAMPLE 23(j)
(11.alpha.,15.alpha.,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-
-17,18,19,20-tetranor-5-thiaprost-13-enoic acid
2-(2,2-dipropylpentanoyloxy)ethyl ester
##STR03576##
[1382] TLC: Rf 0.38 (Ethyl Acetate:Hexane:Methanol=30:10:1);
[1383] NMR: .delta. 7.32-7.12 (m, 4H), 5.75 (dd, J=15.3, 6.0 Hz,
1H), 5.52 (dd, J=15.3, 8.7 Hz, 1H), 4.48-4.32 (m, 3H), 4.25 (s,
4H), 4.02-3.88 (m, 1H), 3.42 (s, 3H), 3.27-3.20 (br, 1H), 2.90 (dd,
J=13.5, 5.4 Hz, 1H), 2.82 (dd, J=13.5, 6.9 Hz, 1H), 2.70 (dd,
J=18.3, 7.2 Hz, 1H), 2.65-2.12 (m, 10H), 1.94-1.82 (m, 3H),
1.75-1.60 (m, 1H), 1.55-1.45 (m, 6H), 1.22-1.09 (m, 6H), 0.89 (t,
J=7.2 Hz, 9H).
EXAMPLE 24
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-aminophenyl)-17,18,19,20-tetranor-5-
-thia-8-azaprost-13-enoic acid
##STR03577##
[1385] By the same procedure as describe in Reference Example 5,
Examples 1, 11 and 2 using the compound prepared in Reference
Example 11 instead of the compound prepared in Reference Example 4
and 3-(4-t-butoxycarbonylaminophenyl)-2-oxopropylphosphonic acid
dimethyl ester instead of
3-(3-methoxymethylphenyl)-2-oxopropylphosphonic acid dimethyl
ester, the compound of the present invention having the following
physical data were obtained.
[1386] TLC: Rf 0.17 (Chloroform:Methanol=9:1);
[1387] NMR: .delta. 6.98 (d, J=8.4 Hz, 2H), 6.66 (d, J=8.4 Hz, 2H),
5.73 (dd, J=15.9, 6.3 Hz, 1H), 5.47 (dd, J=15.9, 8.4 Hz, 1H), 4.38
(m, 1H), 4.10 (m, 1H), 3.61 (m, 1H), 3.10-2.15 (m, 15H), 2.00-1.81
(m, 2H), 1.73 (m, 1H).
REFERENCE EXAMPLE 26
(2R)-1-(2-Mesyloxyethyl)-2-t-butyldimethylsilyloxymethylpyrrolidin-5-one
##STR03578##
[1389] Under atmosphere of argon, to a solution of the compound
prepared in Reference Example 7 (11.9 g) in tetrahydrofuran (50
mL), triethylamine (9.07 mL) was added. Then mesyl chloride (3.68
mL) was dropped into the mixture at 0.degree. C., and the mixture
was stirred for 30 minutes. The mixture was added by water and was
extracted by ethyl acetate. The extract was washed with 1N
hydrochloric acid, saturated aqueous sodium hydrogen carbonate
solution and brine successively, dried over an anhydrous sodium
sulfate, concentrated under reduced pressure to give the title
compound having the following physical data, which was used for the
next reaction without purification.
[1390] TLC: Rf 0.46 (Ethyl Acetate).
REFERENCE EXAMPLE 27
(2R)-1-(2-Iodoethyl)-2-t-butyldimethylsilyloxymethylpyrrolidin-5-one
##STR03579##
[1392] Under atmosphere of argon, to a solution of the compound
prepared in Reference Example 26 in acetonitrile (120 mL), sodium
iodide (19.5 g) was added, and the mixture was stirred overnight at
80.degree. C. It was cooled to room temperature, the mixture was
added by water, and extracted by ethyl acetate. The extract was
washed with saturated aqueous sodium hydrogen carbonate solution
and brine successively, dried over an anhydrous magnesium sulfate,
concentrated under reduced pressure and was purified by column
chromatography on silica gel (ethyl acetate:hexane=from 1:3 to 1:1)
to give the title compound (11.3 g) having the following physical
data.
[1393] TLC: Rf 0.63 (Hexane:Ethyl Acetate=1:1);
[1394] NMR: .delta. 3.92 (m, 1H), 3.81-3.69 (m, 2H), 3.62-3.45 (m,
2H), 3.35 (m, 1H), 3.22 (m, 1H), 2.50-2.26 (m, 2H), 2.14 (m, 1H),
1.78 (m, 1H), 0.86 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H).
REFERENCE EXAMPLE 28
5-(2-((2R)-2-t-Butyldimethylsilyloxymethyl-5-oxopyrrolidin-1-yl)ethylthio)-
thiophene-2-carboxylic acid ethyl ester
##STR03580##
[1396] Under atmosphere of argon, to a solution
thiophene-2-carboxylic acid ethyl ester (936 mg) in tetrahydrofuran
(50 mL), sulfur powder (240 mg) was added, and the mixture was
cooled to -78.degree. C. 2.0M lithium diisopropylamide (4.0 mL) was
dropped into the mixture, and was stirred for 35 minutes. Then a
solution of the compound prepared in Reference Example 27 (1.92 g)
in tetrahydrofuran (5 mL) was added, and the mixture was stirred
for 1.5 hour at room temperature. The mixture was poured into
saturated aqueous ammonium chloride solution, and extracted by
t-butyl methyl ether. The extract was washed with saturated aqueous
sodium hydrogen carbonate solution, dried over an anhydrous
magnesium sulfate, concentrated under reduced pressure and was
purified by column chromatography on silica gel (ethyl
acetate:hexane=from 1:3 to 1:1) to give the title compound (1.86 g)
having the following physical data.
[1397] TLC: Rf 0.54 (Hexane:Ethyl Acetate=1:1);
[1398] NMR: .delta. 7.65 (d, J=3.9 Hz, 1H), 7.09 (d, J=3.9 Hz, 1H),
4.32 (q, J=7.5 Hz, 2H), 3.86-3.61 (m, 3H), 3.55 (m, 1H), 3.32 (m,
1H), 3.22-3.00 (m, 2H), 2.50-2.21 (m, 2H), 2.10 (m, 1H), 1.80 (m,
1H), 1.36 (t, J=7.5 Hz, 3H), 0.86 (s, 9H), 0.03 (s, 3H), 0.02 (s,
3H).
REFERENCE EXAMPLE 29
5-(2-((2R)-2-Hydroxymethyl-5-oxopyrrolidin-1-yl)ethylthio)thiophene-2-carb-
oxylic acid ethyl ester
##STR03581##
[1400] Under atmosphere of argon, to a solution of the compound
prepared in Reference Example 28 (1.85 g) in tetrahydrofuran (4
mL), tetrabutylammonium fluoride (6.28 mL) was added, and the
mixture was stirred overnight at room temperature. The mixture was
added by water, and extracted by ethyl acetate. The extract was
washed with brine, dried over an anhydrous sodium sulfate,
concentrated under reduced pressure to give the title compound
(1.15 g) having the following physical data.
[1401] TLC: Rf 0.15 (Ethyl Acetate);
[1402] NMR: .delta. 7.64 (d, J=3.9 Hz, 1H), 7.10 (d, J=3.9 Hz, 1H),
4.33 (q, J=6.9 Hz, 2H), 3.80-3.68 (m, 3H), 3.60 (m, 1H), 3.40 (m,
1H), 3.17 (t, J=7.0 Hz, 2H), 2.58-2.28 (m, 2H), 2.10 (m, 1H),
1.98-1.80 (m, 2H), 1.37 (t, J=7.2 Hz, 3H).
EXAMPLE 25(a) TO EXAMPLE 25(c)
[1403] By the same procedure as describe in Reference Examples 11,
5, Examples 1 and 2 using the compound prepared in Reference
Example 29 instead of the compound prepared in Reference Example 10
and corresponding phosphonic acid ester derivatives instead of
3-(3-methoxymethylphenyl)-2-oxopropylphosphonic acid dimethyl
ester, the compound of the present invention having the following
physical data were obtained.
EXAMPLE 25(a)
(15.alpha.,13E)-1,5-(2,5-Interthienylene)-9-oxo-15-hydroxy-16-(4-fluorophe-
nyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoic acid
##STR03582##
[1405] TLC: Rf 0.20 (Chloroform:Methanol:Acetic Acid=9:1:0.1);
[1406] NMR: .delta. 7.68 (d, J=3.9 Hz, 1H), 7.15 (dd, J=8.4, 5.4
Hz, 2H), 7.06 (d, J=3.9 Hz, 1H), 6.98 (t, J=8.4 Hz, 2H), 5.71 (dd,
J=15.0, 5.4 Hz, 1H), 5.48 (dd, J=15.0, 9.0 Hz, 1H), 4.37 (m, 1H),
4.11 (m, 1H), 3.82-3.30 (m, 2H), 3.19-2.93 (m, 3H), 2.70 (d, J=6.9
Hz, 2H), 2.50-2.18 (m, 3H), 1.71 (m, 1H).
EXAMPLE 25(b)
(15.alpha.,13E)-1,5-(2,5-Interthienylene)-9-oxo-15-hydroxy-16-(3-chloro-4--
fluorophenyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoic
acid
##STR03583##
[1408] TLC: Rf 0.15 (Chloroform:Methanol=9:1);
[1409] NMR: .delta. 7.66 (d, J=4.2 Hz, 1H), 7.22 (d, J=6.9 Hz, 1H),
7.10-7.00 (m, 3H), 5.69 (dd, J=15.3, 5.4 Hz, 1H), 5.48 (dd, J=15.3,
8.7 Hz, 1H), 4.50 (bs, 2H), 4.37 (m, 1H), 4.10 (m, 1H), 3.75-3.60
(m, 1H), 3.20-2.93 (m, 3H), 2.80-2.68 (m, 2H), 2.50-2.12 (m, 3H),
1.70 (m, 1H).
EXAMPLE 25(c)
(15.alpha.,13E)-1,5-(2,5-Interthienylene)-9-oxo-15-hydroxy-16-(4-fluoro-3--
trifluoromethylphenyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-eno-
ic acid
##STR03584##
[1411] TLC: Rf 0.23 (Chloroform:Methanol:Acetic Acid=9:1:0.1);
[1412] NMR: .delta. 7.65 (d, J=3.9 Hz, 1H), 7.50-7.30 (m, 2H),
7.20-7.00 (m, 2H), 5.72 (dd, J=15.3, 5.1 Hz, 1H), 5.51 (dd, J=15.3,
8.7 Hz, 1H), 4.82 (bs, 2H), 4.40 (m, 1H), 4.12 (m, 1H), 3.65 (m,
1H), 3.23-2.93 (m, 3H), 2.90-2.73 (m, 2H), 2.50-2.10 (m, 3H), 1.70
(m, 1H).
REFERENCE EXAMPLE 30
(4R)-4-t-Butoxycarbonylamino-4-formylbutanoic acid ethyl ester
##STR03585##
[1414] Under atmosphere of argon, to a solution of
(4R)-5-hydroxy-4-t-butoxycarbonylaminopentanoic acid ethyl ester
(15.0 g), triethylamine (32.0 mL) and dimethylsulfoxide (39 mL) in
ethyl acetate (120 mL), a solution of sulfur trioxide pyridine
complex (18.3 g) in mixed solvent ethyl acetate (30 mL) and
dimethylsulfoxide (75 mL) was added at 0.degree. C., and the
mixture was stirred for 1 hour. The reaction mixture was added by
water (5 mL) at 0.degree. C. and was added by 1N hydrochloric acid
(240 mL). Separated aqueous layer was extracted by ethyl acetate.
The combined organic layer was washed with water and brine
successively, dried over an anhydrous sodium sulfate, concentrated
under reduced pressure to give the title compound (14.7 g) having
the following physical data.
[1415] TLC: Rf 0.63 (Ethyl Acetate:Hexane=1:1);
[1416] NMR: .delta. 9.60 (s, 1H), 5.25-5.15 (m, 1H), 4.35-4.20 (m,
1H), 4.13 (q, J=7.2 Hz, 2H), 2.50-2.35 (m, 2H), 2.35-2.20 (m, 1H),
2.00-1.85 (m, 1H), 1.43 (s, 9H), 1.27 (t, J=7.2 Hz, 3H).
REFERENCE EXAMPLE 31
(4R,5E)-4-t-Butoxycarbonylamino-7-oxo-8-(4-fluorophenyl)oct-5-enoic
acid ethyl ester
##STR03586##
[1418] Under atmosphere of argon, to a solution sodium hydride
(2.40 g; 62.6% in oil), in tetrahydrofuran (620 mL), a solution of
3-(4-fluorophenyl)-2-oxopropylphosphonic acid dimethyl ester (17.7
g) in tetrahydrofuran (100 mL) was added at 0.degree. C., and the
mixture was stirred for 1 hour. The reaction mixture was added by
the solution of the compound prepared in Reference Example 30 (14.7
g) in tetrahydrofuran (80 mL) at 0.degree. C., and the mixture was
stirred for 20 minutes. The reaction mixture was added by t-butyl
methyl ether (800 mL) and water (800 mL). The organic layer was
washed with water and brine successively, dried over an anhydrous
sodium sulfate, concentrated under reduced pressure to give the
crude title compound (25.3 g). 1 g of the crude compound was
purified by column chromatography on silica gel (ethyl
acetate:hexane=1:3) to give the title compound (636 mg) having the
following physical data.
[1419] TLC: Rf 0.74 (Ethyl Acetate:Hexane=1:1);
[1420] NMR: .delta. 7.20-7.10 (m, 2H), 7.08-6.96(m, 2H), 6.76 (dd,
J=15.3, 5.1 Hz, 1H), 6.24 (d, J=15.3 Hz, 1H), 4.7-4.6 (m, 1H),
4.4-4.25 (m, 1H), 4.14 (q, J=7.2 Hz, 2H), 3.82 (s, 2H), 2.38 (t,
J=7.2 Hz, 2H), 2.00-1.75 (m, 2H), 1.42 (s, 9H), 1.25 (t, J=7.2 Hz,
3H).
REFERENCE EXAMPLE 32
(4R,5E,7S)-4-t-Butoxycarbonylamino-7-hydroxy-8-(4-fluorophenyl)oct-5-enoic
acid ethyl ester
##STR03587##
[1422] To a solution of the compound prepared in Reference Example
31 (5.56 g) and a solution of (R)-2-methyl-CBS-oxazaborolidine (4.3
mL; 1.0M toluene solution) in dry tetrahydrofuran (30 mL), borane
tetrahydrofuran complex (8.6 mL; 1.0M) was added, and the mixture
was stirred for 15 minutes. To the mixture, methanol was added, and
was diluted by ethyl acetate. The diluted solution was washed with
1N hydrochloric acid, water and brine successively, dried over an
anhydrous magnesium sulfate, concentrated under reduced pressure to
give the title compound having the following physical data.
[1423] TLC: Rf 0.80 (Ethyl Acetate);
[1424] NMR: .delta. 7.20-7.09 (m, 2H), 7.02-6.93 (m, 2H), 5.67 (dd,
J=15.6, 5.7 Hz, 1H), 5.52 (dd, J=15.6, 6.0 Hz, 1H), 4.56-4.43 (br,
1H), 4.35-4.27 (m, 1H), 4.20-4.05 (m, 3H), 2.85-2.68 (m, 2H), 2.30
(t, J=6.9 Hz, 2H), 1.90-1.70 (m, 2H), 1.43 (s, 9H), 1.26 (t, J=7.2
Hz, 3H).
REFERENCE EXAMPLE 33
(4R,5E,7S)-4-Amino-7-hydroxy-8-(4-fluorophenyl)oct-5-enoic acid
hydrochloride
##STR03588##
[1426] To a solution of the compound prepared in Reference Example
32 in ethanol (12 mL), 4N hydrogen chloride-dioxane solution (14
mL) was added at 0.degree. C., and the mixture was stirred for 4
hours. The mixture was concentrated under reduced pressure. The
obtained crude was disolved in ethyl acetate (25 mL) with heat,
then cooled to room temperature overnight. The precipitate was
filtrated, washed with cold ethyl acetate, dried to give the title
compound (2.37 g) having the following physical data.
[1427] TLC: Rf 0.05 (Ethyl Acetate);
[1428] NMR(CD.sub.3OD): .delta. 7.28-7.19 (m, 2H), 7.04-6.93 (m,
2H), 5.92 (dd, J=15.6, 4.8 Hz, 1H), 5.53 (dd, J=15.6, 8.7 Hz, 1H),
4.41-4.32 (m, 1H), 4.15 (q, J=7.2 Hz, 2H), 3.80-3.70 (m, 1H), 2.81
(d, J=5.7 Hz, 2H), 2.28 (t, J=6.9 Hz, 2H), 2.09-1.97 (m, 1H),
1.84-1.75 (m, 1H), 1.24 (t, J=7.2 Hz, 3H).
EXAMPLE 26
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid ethyl ester
##STR03589##
[1430] Under atmosphere of argon, to a solution of
4-(formylmethylthio)butanoic acid ethyl ester (1.82 g) in dry
tetrahydrofuran (15 mL), a compound prepared in Reference Example
33 (2.27 g) was added at room temperature, and the mixture was
stirred for 1.5 hours. Then sodium triacetoxyborohydride (2.91 g)
was added to the mixture, and the mixture was stirred overnight at
room temperature. The reaction mixture was diluted by ethyl acetate
The diluted solution was washed with water 1N hydrochloric acid and
brine successively, dried over an anhydrous sodium sulfate,
concentrated under reduced pressure and purified by column
chromatography on silica gel (ethyl acetate:methanol=30:1) to give
the title compound (1.80 g) having the following physical data.
[1431] TLC: Rf 0.33 (Ethyl Acetate).
[1432] TLC: Rf 0.44 (Chloroform:Methanol=9:1);
[1433] NMR: .delta. 7.21-7.14 (m, 2H), 7.05-6.96 (m, 2H), 5.75 (dd,
J=15.6, 6.0 Hz, 1H), 5.50 (dd, J=15.6, 8.4 Hz, 1H), 4.19 (m, 1H),
4.18-4.03 (m, 3H), 3.60 (m, 1H), 2.97 (m, 1H), 2.85-2.79 (m, 2H),
2.70-2.18 (m, 9H), 2.01-1.82 (m, 3H), 1.79-1.60 (m, 1H), 1.25 (t,
J=7.2 Hz, 3H).
EXAMPLE 27
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid
##STR03590##
[1435] By the same procedure as describe in Example 2 using the
compound prepared in Example 26 instead of the compound prepared in
Example 1, the compound of the present invention having the
following physical data were obtained.
[1436] TLC: Rf 0.38 (Chloroform:Methanol:Water=9:1:0.1);
[1437] NMR: .delta. 7.20-7.16 (m, 2H), 7.04-6.96 (m, 2H), 5.75 (dd,
J=15.4, 6.0 Hz, 1H), 5.50 (ddd, J=15.4, 8.5, 1.1 Hz, 1H), 4.39 (m,
1H), 4.11 (m, 1H), 3.62 (m, 1H), 2.95 (m, 1H), 2.82 (d, J=6.6 Hz,
2H), 2.67-2.53 (m, 4H), 2.52-2.43 (m, 2H), 2.39 (t, J=7.1 Hz, 2H),
2.22 (m, 1H), 1.94-1.83 (m, 2H), 1.68 (m, 1H).
EXAMPLE 27(a) TO EXAMPLE 27(i)
[1438] By the same procedure as describe in Reference Examples 31,
32, 33, Examples 26 and 2 using corresponding phosphonic acid ester
derivatives instead of 3-(4-fluorophenyl)-2-oxopropylphosphonic
acid dimethyl ester and corresponding carboxylic acid ester
derivatives instead of 4-(formylmethylthio)butanoic acid ethyl
ester, the compound of the present invention having the following
physical data were obtained.
[1439] The compound prepared in Example 27(b) was done by
additional procedure of the same as described in Example 5 after
the procedure of the same as described in Reference Example 32.
EXAMPLE 27(a)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(benzofuran-2-yl)phenyl)-17,18,19,2-
0-tetranor-5-thia-8-azaprost-13-enoic acid
##STR03591##
[1441] TLC: Rf 0.53 (Chloroform:Methanol=9:1);
[1442] NMR: .delta. 7.76-7.70 (m, 2H), 7.59 (d, J=8.4 Hz, 1H), 7.52
(d, J=8.4 Hz, 1H), 7.40 (dd, J=8.4, 8.4 Hz, 1H), 7.33-7.17 (m, 3H),
7.04 (s, 1H), 5.79 (dd, J=15.3, 5.7 Hz, 1H), 5.51 (dd, J=15.3, 8.4
Hz, 1H), 4.55-4.44 (m, 1H), 4.16-4.07 (m, 1H), 3.68-3.54 (m, 1H),
3.02-2.90 (m, 3H), 2.70-2.10 (m, 9H), 1.92-1.78 (m, 2H), 1.78-1.62
(m, 1H).
EXAMPLE 27(b)
(15.alpha.)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxythiazol-2-yl)-
-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane
##STR03592##
[1444] TLC: Rf 0.19 (Chloroform:Methanol:Acetic Acid=9:1:0.1);
[1445] NMR: .delta. 8.07 (s, 1H), 7.21 (t, J=7.2 Hz, 1H), 7.10-6.95
(m, 3H), 3.97-3.80 (m, 2H), 3.72 (m, 1H), 3.60-3.25 (m, 3H),
2.84-2.63 (m, 2H), 2.55-2.22 (m, 5H), 2.14 (m, 1H), 1.93 (m, 1H),
1.78-1.41 (m, 4H).
EXAMPLE 27(c)
(15.alpha.,13E)-1,6-(1,4-Interphenylene)-9-oxo-15-hydroxy-16-(3-methylphen-
yl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic acid
##STR03593##
[1447] TLC: Rf 0.27 (Chloroform:Methanol=9:1);
[1448] NMR: .delta. 8.02 (d, J=8.1 Hz, 2H), 7.30-7.15 (m, 3H),
7.10-6.97 (m, 3H), 5.64 (dd, J=15.6, 6.3 Hz, 1H), 5.37 (dd, J=15.6,
8.7 Hz, 1H), 4.41-4.32 (m, 1H), 3.83-3.70 (m, 2H), 3.09-2.95 (m,
1H), 2.95-2.75 (m, 4H), 2.48-2.25 (m, 5H), 2.20-2.13 (m, 1H),
1.72-1.58 (m, 1H).
EXAMPLE 27(d)
(15.alpha.,13E)-7-(6-Carboxyindol-3-yl)-9-oxo-15-hydroxy-16-(3-methylpheny-
l)-1,2,3,4,5,6,17,18,19,20-decanor-8-azaprost-13-ene
##STR03594##
[1450] TLC: Rf 0.21 (Dichloromethane:Methanol=9:1);
[1451] NMR(DMSO-d6): .delta. 8.08 (d, J=1.2 Hz, 1H), 7.68 (d, J=8.1
Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.20-7.10 (m, 2H), 7.10-6.95 (m,
3H), 5.60 (dd, J=15.3, 6.6 Hz, 1H), 5.43 (dd, J=15.3, 5.4 Hz, 1H),
4.95-4.80 (m, 2H), 4.37 (q, J=6.6 Hz, 1H), 3.90-3.75 (m, 2H), 2.91
(dd, J=13.5, 6.6 Hz, 1H), 2.70 (dd, J=13.5, 7.5 Hz, 1H), 2.50-2.20
(m, 5H), 2.15-2.00 (m, 1H), 1.75-1.60 (m, 1H).
EXAMPLE 27(e)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxythiazol-2-
-yl)-1,2,3,4,17,18,19,20-octanor-8-azaprost-13-ene
##STR03595##
[1453] TLC: Rf 0.25 (Chloroform:Methanol:Acetic Acid=9:1:0.1);
[1454] NMR: .delta. 8.12 (s, 1H), 7.18 (m, 1H), 7.05-6.97 (m, 3H),
5.75 (dd, J=15.3, 5.7 Hz, 1H), 5.60-5.20 (m, 3H), 4.40 (m, 1H),
4.07 (m, 1H), 3.51 (m, 1H), 3.07-2.85 (m, 3H), 2.79 (d, J=6.6 Hz,
2H), 2.50-2.12 (m, 6H), 2.04-1.90 (m, 2H), 1.70 (m, 1H).
EXAMPLE 27(f)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxyoxazol-2--
yl)-1,2,3,4,17,18,19,20-octanor-8-azaprost-13-ene
##STR03596##
[1456] TLC: Rf 0.21 (Chloroform:Methanol:Acetic Acid=9:1:0.1);
[1457] NMR: .delta. 8.19 (s, 1H), 7.20 (m, 1H), 7.06-6.97 (m, 3H),
5.78 (dd, J=15.3, 6.0 Hz, 1H), 5.50 (ddd, J=15.3, 9.0, 1.2 Hz, 1H),
4.40 (m, 2H), 4.07 (m, 1H), 3.47 (m, 1H), 2.94 (m, 1H), 2.83-2.75
(m, 4H), 2. 50-2.10 (m, 6H), 2.05-1.83 (m, 2H), 1.64 (m, 1H).
EXAMPLE 27(g)
(15.alpha.,13E)-1,7-(2,5-Interthienylene)-9-oxo-15-hydroxy-16-(3-methylphe-
nyl)-2,3,4,5,6,17,18,19,20-nonanor-8-azaprost-13-enoic acid
##STR03597##
[1459] TLC: Rf 0.18 (Dichloromethane:Methanol=9:1);
[1460] NMR: .delta. 7.70 (d, J=3.9 Hz, 1H), 7.21 (t, J=7.8 Hz, 1H),
7.10-6.98 (m, 3H), 6.88 (d, J=3.9 Hz, 1H), 5.75 (dd, J=15.0, 6.0
Hz, 1H), 5.46 (dd, J=15.0, 8.7 Hz, 1H), 4.88 (d, J=16.2 Hz, 1H),
4.50-4.40 (m, 1H), 4.10-4.00 (m, 1H), 3.88 (d, J=16.2 Hz, 1H), 2.82
(d, J=6.6 Hz, 2H), 2.50-2.15 (m, 6H), 1.80-1.70 (m, 1H).
EXAMPLE 27(h)
(15.alpha.,13E)-1,6-(1,4-Interphenylene)-9-oxo-15-hydroxy-16-(3-(benzofura-
n-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic
acid
##STR03598##
[1462] TLC: Rf 0.31 (Dichloromethane:Methanol=9:1);
[1463] NMR: .delta. 7.98 (d, J=8.1 Hz, 2H), 7.78-7.70 (m, 2H), 7.58
(d, J=8.1 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H),
7.34-7.16 (m, 5H), 7.03 (s, 1H), 5.65 (dd, J=15.0, 6.0 Hz, 1H),
5.37 (dd, J=15.0, 7.8 Hz, 1H), 4.50-4.40 (m, 1H), 3.80-3.65 (m,
2H), 3.05-2.60 (m, 5H), 2.40-2.20 (m, 2H), 2.20-2.00 (m, 1H),
1.70-1.55 (m, 1H).
EXAMPLE 27(i)
(15.alpha.,13E)-1,5-(2,5-Interthienylene)-9-oxo-15-hydroxy-16-(3-(benzofur-
an-2-yl)phenyl)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic
acid
##STR03599##
[1465] TLC: Rf 0.59 (Dichloromethane:Methanol:Acetic
Acid=90:10:1);
[1466] NMR: .delta. 7.74-7.68 (m, 2H), 7.61 (d, J=3.9 Hz, 1H), 7.57
(d, J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H),
7.32-7.14 (m, 3H), 7.02 (s, 1H), 6.73 (d, J=3.9 Hz, 1H), 5.75 (dd,
J=15.3, 6.3 Hz, 1H), 5.47 (dd, J=15.3, 8.4 Hz, 1H), 4.50-4.40 (m,
1H), 4.05-3.95 (m, 1H), 3.65-3.40 (m, 1H), 2.90 (d, J=6.9 Hz, 2H),
2.85-2.70 (m, 3H), 2.50-2.10 (m, 3H), 1.85-1.65 (m, 3H).
REFERENCE EXAMPLE 34
(2R)-1-(2-(3-Cyclopentylpropanoyloxy)ethyl)-2-t-butyldimethylsilyloxymethy-
lpyrrolidin-5-one
##STR03600##
[1468] Under atmosphere of argon, to a solution of the compound
prepared in Reference Example 7 (3.78 g) and triethylamine (2.9 mL)
in methylene chloride (30 mL), 3-cyclopentylpropanoyl chloride
(2.67 g) was added at 0.degree. C., and the mixture was stirred for
2 hours. The mixture was poured into water and was extracted by
diethyl ether. The extract was washed with brine, dried over an
anhydrous sodium sulfate, concentrated under reduced pressure to
give the title compound having the following physical data, which
was used for the next reaction without purification.
[1469] TLC: Rf 0.40 (Ethyl Acetate:Hexane=1:1).
REFERENCE EXAMPLE 35
(2R)-1-(2-(3-Cyclopentylpropanoyloxy)ethyl)-2-hydroxymethylpyrrolidin-5-on-
e
##STR03601##
[1471] Under atmosphere of argon, to a solution of the compound
prepared in Reference Example 34 in tetrahydrofuran (20 mL),
tetrabutylammonium fluoride (16.6 mL; 1.0 M tetrahydrofuran
solution) was added at room temperature, and the mixture was
stirred for 2 hours. The mixture was poured into saturated aqueous
ammounium chloride solution, and extracted by ethyl acetate. The
extract was washed with saturated aqueous ammounium chloride
solution and brine successively, dried over an anhydrous sodium
sulfate, concentrated under reduced pressure and purified by column
chromatography on silica gel (from ethyl acetate:hexane=2:1 to
ethyl acetate:methanol=40:1) to give the title compound (2.40 g)
having the following physical data.
[1472] TLC: Rf 0.35 (Ethyl Acetate:Methanol=20:1).
REFERENCE EXAMPLE 36
(2R)-1-(2-(3-Cyclopentylpropanoyloxy)ethyl)-2-formylpyrrolidin-5-one
##STR03602##
[1474] Under atmosphere of argon, to a solution of the compound
prepared in Reference Example 35 (2.40 g) and diisopropylethylamine
(8.7 mL) in mixed solvent of ethyl acetate (15 mL) and
dimethylsulfoxide (15 mL), sulfur trioxide pyridine complex (3.98
g) was added, and the mixture was stirred for 30 minutes. The
reaction mixture was added by small amount of water, and was poured
into 1N hydrochloric acid, and was extracted by ethyl acetate. The
extract was washed with water and brine successively, dried over an
anhydrous magnesium sulfate, concentrated under reduced pressure to
give the title compound having the following physical data, which
was used for the next reaction without purification.
[1475] TLC: Rf 0.57 (Ethyl Acetate:Methanol=20:1).
REFERENCE EXAMPLE 37
(13E)-9,15-Dioxo-16-(4-fluorophenyl)-6-(3-cyclopentylpropanoyloxy)-1,2,3,4-
,5,17,18,19,20-nonanor-8-azaprost-13-ene
##STR03603##
[1477] Under atmosphere of argon, to a solution of
3-(4-fluorophenyl)-2-oxopropylphosphonic acid dimethyl ester (2.31
g) in dry tetrahydrofuran (90 mL), sodium hydride (341 mg; 62.6% in
oil) was added at room temperature, and the mixture was stirred for
30 minutes. Then the compound prepared in Reference Example 36 was
added to the mixture and the mixture was stirred for 1 hour. The
reaction mixture was diluted by t-butyl methyl ether. The diluted
solution was washed with water and brine successively, dried over
an anhydrous magnesium sulfate, concentrated under reduced pressure
to give the title compound having the following physical data,
which was used for the next reaction without purification.
[1478] TLC: Rf 0.75 (Ethyl Acetate:Methanol=20:1).
REFERENCE EXAMPLE 38
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-6-(3-cyclopentylpropa-
noyloxy)-1,2,3,4,5,17,18,19,20-nonanor-8-azaprost-13-ene
##STR03604##
[1480] Under atmosphere of argon, a solution of the compound
prepared in Reference Example 37 and
(R)-2-methyl-CBS-oxazaborolidine (2.7 mL; 1.0 M toluene solution)
in dry tetrahydrofuran (10 mL) was added by borane tetrahydrofuran
complex (5.4 mL; 1.0M tetrahydrofuran solution) at 0.degree. C.,
and the mixture was stirred for 20 minutes. The mixture was added
by methanol, and diluted by ethyl acetate. The organic layer was
washed with 1N hydrochloric acid, water and brine successively,
dried over an anhydrous sodium sulfate, concentrated under reduced
pressure and was purified by column chromatography on silica gel
(from ethyl acetate:hexane:methanol=30:10 :1 to ethyl
acetate:methanol=30:1) to give the title compound (2.58 g) having
the following physical data.
[1481] TLC: Rf 0.50 (Ethyl Acetate:Methanol=20:1).
REFERENCE EXAMPLE 39
(15.alpha.,13E)-9-Oxo-15-t-butyldimethylsilyloxy-16-(4-fluorophenyl)-6-(3--
cyclopentylpropanoyloxy)-1,2,3,4,5,17,18,19,20-nonanor-8-azaprost-13-ene
##STR03605##
[1483] Under atmosphere of argon, a solution of the compound
prepared in Reference Example 38 (2.08 g) and imidazole (0.61 g) in
dimethylformamide (15 mL) was added by t-butyldimethylsilyl
chloride (1.13 g) at room temperature. After the mixture was
stirred overnight, the reaction mixture was diluted by t-butyl
methyl ether. The extract was washed with water and brine
successively, dried over an anhydrous sodium sulfate, concentrated
under reduced pressure was purified by column chromatography on
silica gel (ethyl acetate:hexane=from 1:2 to 1:1) to give the title
compound (1.56 g) having the following physical data.
[1484] TLC: Rf 0.81 (Ethyl Acetate).
REFERENCE EXAMPLE 40
(15.alpha.,13E)-9-Oxo-15-t-butyldimethylsilyloxy-16-(4-fluorophenyl)-6-hyd-
roxy-1,2,3,4,5,17,18,19,20-nonanor-8-azaprost-13-ene
##STR03606##
[1486] To a solution of the compound prepared in Reference Example
39 (1.56 g) in mixed solvent of methanol (5 mL) and
1,2-dimethoxyethane (5 mL), 2N aqueous sodium hydroxide solution (3
mL) was added at room temperature, and the mixture was stirred for
1 hour. The reaction mixture was diluted by t-butyl methyl ether
and tetrahydrofuran. The diluted solution was washed with water and
brine successively, dried over an anhydrous sodium sulfate,
concentrated under reduced pressure to give the title compound
having the following physical data, which was used for the next
reaction without purification.
[1487] TLC: Rf 0.15 (Ethyl Acetate).
REFERENCE EXAMPLE 41
(15.alpha.,13E)-9-Oxo-15-t-butyldimethylsilyloxy-16-(4-fluorophenyl)-6-mes-
yloxy-1,2,3,4,5,17,18,19,20-nonanor-8-azaprost-13-ene
##STR03607##
[1489] Under atmosphere of argon, to a solution of the compound
prepared in Reference Example 40 (600 mg) and triethylamine (0.31
mL) in tetrahydrofuran (6 mL), mesyl chloride (0.14 mL) was added
at 0.degree. C., and the mixture was stirred for 1 hour. The
reaction mixture was diluted by t-butyl methyl ether. The diluted
solution was washed with 1N hydrochloric acid, water and brine
successively, dried over an anhydrous sodium sulfate, concentrated
under reduced pressure to give the title compound having the
following physical data, which was used for the next reaction
without purification
[1490] TLC: Rf 0.60 (Ethyl Acetate).
REFERENCE EXAMPLE 42
(15.alpha.,13E)-9-Oxo-15-t-butyldimethylsilyloxy-16-(4-fluorophenyl)-6-iod-
o-1,2,3,4,5,17,18,19,20-nonanor-8-azaprost-13-ene
##STR03608##
[1492] A suspension of the compound prepared in Reference Example
41 and sodium iodide (450 mg) in acetonitrile (15 mL) was refluxed
for 12 hours. It was cooled to room temperature, the mixture was
poured into water, and extracted by t-butyl methyl ether. The
extract was washed with saturated aqueous sodium thiosulfate
solution and brine successively, dried over an anhydrous sodium
sulfate, concentrated under reduced pressure and was purified by
column chromatography on silica gel (ethyl acetate:hexane=1:2) to
give the title compound (630 mg) having the following physical
data.
[1493] TLC: Rf 0.92 (Ethyl Acetate).
REFERENCE EXAMPLE 43
(15.alpha.,13E)-3,3-Ethano-9-oxo-15-t-butyldimethylsilyloxy-16-(4-fluoroph-
enyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid methyl
ester
##STR03609##
[1495] Under atmosphere of argon, to a solution of the compound
prepared in Reference Example 42 (90 mg) and
2-(1-(acetylthiomethyl)cyclopropyl)acetic acid methyl ester (42 mg)
in dry methanol (2 mL), potassium carbonate (58 mg) was added at
room temperature, and the mixture was stirred for 6 hours. The
reaction mixture was diluted by t-butyl methyl ether. The diluted
solution was washed with saturated aqueous ammounium chloride
solution and brine successively, dried over an anhydrous sodium
sulfate, concentrated under reduced pressure and was purified by
column chromatography on silica gel (ethyl acetate:hexane=from 1:3
to 1:1) to give the title compound (90 mg) having the following
physical data.
[1496] TLC: Rf 0.42 (Ethyl Acetate:Hexane=1:1).
EXAMPLE 28
(15.alpha.,13E)-3,3-Ethano-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,2-
0-tetranor-5-thia-8-azaprost-13-enoic acid
##STR03610##
[1498] By the same procedure as describe in Examples 7 and 2 using
the compound prepared in Reference Example 43 instead of the
compound prepared in Reference Example 14, the compound of the
present invention having the following physical data were
obtained.
[1499] TLC: Rf 0.50 (Chloroform:Methanol=9:1);
[1500] NMR: .delta. 7.22-7.13 (m, 2H), 7.08-6.96 (m, 2H), 5.76 (dd,
J=15.3, 5.7 Hz, 1H), 5.51 (dd, J=15.3, 8.7 Hz, 1H), 4.48-4.38 (m,
1H), 4.16-4.05 (m, 1H), 3.67-3.53 (m, 1H), 3.10-2.95 (m, 1H),
2.88-2.79 (m, 2H), 2.76 (d, J=13.5 Hz, 1H), 2.68-2.50 (m, 4H),
2.43-2.16 (m, 5H), 1.75-1.63 (m, 1H), 0.65-0.50 (m, 4H).
EXAMPLE 28(a) TO EXAMPLE 28(b)
[1501] By the same procedure as describe in Reference Example 43,
Examples 7 and 2 using corresponding derivatives instead of
2-(1-(acetylthiomethyl)cyclopropyl)acetic acid methyl ester, the
compound of the present invention having the following physical
data were obtained.
EXAMPLE 28(a)
(15.alpha.,13E)-1,5-(1,4-Interphenylene)-9-oxo-15-hydroxy-16-(4-fluorophen-
yl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoic acid
##STR03611##
[1503] TLC: Rf 0.45 (Chloroform:Methanol=9:1);
[1504] NMR: .delta. 8.00 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H),
7.20-7.10 (m, 2H), 7.07-6.96 (m, 2H), 5.65 (dd, J=15.3, 5.4 Hz,
1H), 5.47 (dd, J=15.3, 9.3 Hz, 1H), 4.35 (m, 1H), 4.10 (m, 1H),
3.67 (m, 1H), 3.30-3.00 (m, 3H), 2.75 (d, J=6.9 Hz, 2H), 2.48-2.08
(m, 3H), 1.70 (m, 1H).
EXAMPLE 28(b)
(15.alpha.,13E)-1,5-(1,3-Interphenylene)-9-oxo-15-hydroxy-16-(4-fluorophen-
yl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoic acid
##STR03612##
[1506] TLC: Rf 0.45 (Chloroform:Methanol=9:1);
[1507] NMR: 6 8.05 (m, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.58 (d, J=8.4
Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.18-7.02 (m, 2H), 7.01-6.93 (m,
2H), 5.68 (dd, J=15.6, 5.7 Hz, 1H), 5.45 (dd, J=15.6, 8.7 Hz, 1H),
4.60 (bs, 2H), 4.33 (m, 1H), 4.10 (m, 1H), 3.64 (m, 1H), 3.22-2.98
(m, 3H), 2.75 (d, J=6.6 Hz, 2H), 2.50-2.08 (m, 3H), 1.68 (m,
1H).
EXAMPLE 29(a) TO EXAMPLE 29(m)
[1508] By the same procedure as describe in Reference Example 5,
Examples 1 and 2 using the compound prepared in Reference Example
11 or corresponding carboxylic acid ester derivatives instead of
the compound prepared in Reference Example 4 and corresponding
phosphonic acid ester derivatives instead of
3-(3-methoxymethylphenyl)-2-oxopropylphosphonic acid dimethyl
ester, the compound of the present invention having the following
physical data were obtained.
EXAMPLE 29(a)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(4-fluoromethylbenzyloxy)phenyl)-17-
,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid
##STR03613##
[1510] TLC: Rf 0.44 (Chloroform:Methanol=9:1);
[1511] NMR: .delta. 7.65 (d, J=8.1 Hz, 2H), 7.55 (d, J=8.1 Hz, 2H),
7.28-7.20 (m, 1H), 6.88-6.78 (m, 3H), 5.75 (dd, J=15.3, 5.7 Hz,
1H), 5.48 (dd, J=15.3, 8.1 Hz, 1H), 5.12 (s, 2H), 4.41 (q, J=6.3
Hz, 1H), 4.3-3.4 (br), 4.17-4.07 (m, 1H), 3.68-3.57 (m, 1H),
3.01-2.88 (m, 1H), 2.82 (d, J=6.3 Hz, 2H), 2.70-2.10 (m, 9H),
1.96-1.82 (m, 2H), 1.78-1.62 (m, 1H).
EXAMPLE 29(b)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(pyridin-3-ylmethoxy)phenyl)-17,18,-
19,20-tetranor-5-thia-8-azaprost-13-enoic acid
##STR03614##
[1513] TLC: Rf 0.47 (Chloroform:Methanol=9:1);
[1514] NMR: .delta. 8.72 (s, 1H), 8.45 (d, J=3.3 Hz, 1H), 7.85 (d,
J=7.8 Hz, 1H), 7.39 (dd, J=7.8, 3.3 Hz, 1H), 7.16 (dd, J=8.1, 8.1
Hz, 1H), 7.04 (s, 1H), 6.80-6.75 (m, 2H), 5.85 (dd, J=15.3, 4.8 Hz,
1H), 5.62 (dd, J=15.3, 8.7 Hz, 1H), 5.24 (d, J=13.2 Hz, 1H), 5.17
(d, J=13.2 Hz, 1H), 4.35-4.30 (m, 1H), 4.20-4.10 (m, 1H), 3.53-3.40
(m, 1H), 3.30-3.16 (m, 1H), 2.8-2.3 (m, 10H), 2.3-2.1 (m, 1H),
1.95-1.8 (m, 2H), 1.8-1.6 (m, 1H).
EXAMPLE 29(c)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-cyclopropyl-17,18,19,20-tetranor-5-thi-
a-8-azaprost-13-enoic acid
##STR03615##
[1516] TLC: Rf 0.39 (Chloroform:Methanol=9:1);
[1517] NMR: .delta. 5.80 (dd, J=15.6, 6.0 Hz, 1H), 5.58 (ddd,
J=15.6, 8.4, 1.0 Hz, 1H), 4.30 (m, 1H), 4.15 (m, 1H), 3.77-3.05 (m,
4H), 2.77-2.08 (m, 9H), 2.00-1.70 (m, 3H), 1.53-1.41 (m, 2H), 0.72
(m, 1H), 0.60-0.42 (m, 2H), 0.20-0.02 (m, 2H).
EXAMPLE 29(d)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-phenyl-5-(4-carboxythiazol-2-yl)-1,2,3-
,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene
##STR03616##
[1519] TLC: Rf 0.24 (Chloroform:Methanol=9:1);
[1520] NMR: .delta. 8.09 (s, 1H), 7.38-7.14 (m, 5H), 5.80 (dd,
J=15.3, 6.0 Hz, 1H), 5.47 (dd, J=15.3, 8.7 Hz, 1H), 4.40 (m, 1H),
4.21-3.61 (m, 4H), 3.38-3.16 (m, 3H), 2.97-2.79 (m, 2H), 2.52-2.18
(m, 3H), 1.76 (m, 1H).
EXAMPLE 29(e)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxythiazol-2-
-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene
##STR03617##
[1522] TLC: Rf 0.27 (Chloroform:Methanol=9:1);
[1523] NMR: .delta. 8.08 (s, 1H), 7.20 (m, 1H), 7.08-6.95 (m, 3H),
5.80 (dd, J=15.3, 5.7 Hz, 1H), 5.50 (dd, J=15.3, 8.7 Hz, 1H), 4.40
(m, 1H), 4.12 (m, 1H), 3.70 (m, 1H), 3.50-2.95 (m, 5H), 2.85-2.78
(m, 2H), 2.50-2.19 (m, 6H), 1.77 (m, 1H).
EXAMPLE 29(f)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(pyridin-2-ylmethoxy)phenyl)-17,18,-
19,20-tetranor-5-thia-8-azaprost-13-enoic acid
##STR03618##
[1525] TLC: R10.30 (Chloroform:Methanol=9:1);
[1526] NMR: .delta. 8.57 (d, J=5.4 Hz, 1H), 7.80 (dt, J=1.5, 7.5
Hz, 1H), 7.60 (d, 1=7.5 Hz, 1H), 7.32 (m, 1H), 7.22 (t, J=7.8 Hz,
1H), 6.99-6.85 (m, 2H), 6.80 (d, J=7.8 Hz, 1H), 5.85 (dd, J=15.0,
4.8 Hz, 1H), 5.59 (ddd, J=15.0, 8.7, 1.2 Hz, 1H), 5.32 (s, 2H),
4.43 (m, 1H), 4.11 (m, 1H), 3.43 (m, 1H), 3.18 (m, 1H), 2.88-2.18
(m, 13H), 1.97-1.83 (m, 2H), 1.72 (m, 1H).
EXAMPLE 29(g)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(pyridin-4-ylmethoxy)phenyl)-17,18,-
19,20-tetranor-5-thia-8-azaprost-13-enoic acid
##STR03619##
[1528] TLC: Rf 0.30 (Chloroform:Methanol=9:1);
[1529] NMR: .delta. 8.58 (d, J=6.0 Hz, 2H), 7.39 (d, J=6.0 Hz, 2H),
7.22 (t, J=7.8 Hz, 1H), 6.88-6.70 (m, 3H), 5.72 (dd, J=15.3, 5.7
Hz, 1H), 5.45 (dd, J=15.3, 8.1 Hz, 1H), 5.12 (s, 2H), 4.32 (m, 1H),
4.11 (m, 1H), 3.59 (m, 1H), 3.30 (m, 1H), 2.99 (m, 1H), 2.78 (m,
2H), 2.69-2.12 (m, 10H), 1.98-1.80 (m, 2H), 1.63 (m, 1H).
EXAMPLE 29(h)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(pyridin-2-yl)phenyl)-17,18,19,20-t-
etranor-5-thia-8-azaprost-13-enoic acid
##STR03620##
[1531] TLC: Rf 0.37 (Chloroform:Methanol=9:1);
[1532] NMR: .delta. 8.74 (m, 1H), 7.93 (s, 1H), 7.84 (dt, J=1.8,
7.8 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.42
(t, J=7.5 Hz, 1H), 7.37-7.23 (m, 2H), 5.88 (dd, J=15.0, 4.5 Hz,
1H), 5.64 (ddd, J=15.0, 9.0, 1.5 Hz, 1H), 5.45 (bs, 2H), 4.58 (m,
1H), 4.10 (m, 1H), 3.40 (m, 1H), 3.21 (m, 1H), 3.02-2.80 (m, 2H),
2.78-2.10 (m, 9H), 1.99-1.82 (m, 2H), 1.73 (m, 1H).
EXAMPLE 29(i)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-cyclopentyl-5-(4-carboxythiazol-2-yl)--
1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene
##STR03621##
[1534] TLC: Rf 0.22 (Chloroform:Methanol=9:2);
[1535] NMR: .delta. 8.10 (s, 1H), 5.79 (dd, J=15.6, 6.0 Hz, 1H),
5.55 (d, J=15.6, 8.7 Hz, 1H), 4.40-3.63 (m, 5H), 3.58-3.24 (m, 3H),
2.57-2.08 (m, 3H), 1.98-1.40 (m, 10H), 1.10 (m, 2H).
EXAMPLE 29(j)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(2,2,2-trifluoroethoxymethyl)phenyl-
)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost--
13-ene
##STR03622##
[1537] TLC: Rf 0.19 (Chloroform:Methanol=9:2);
[1538] NMR: .delta. 8.08 (s, 1H), 7.37-7.10 (m, 4H), 5.80 (dd,
J=15.3, 5.7 Hz, 1H), 5.52 (dd, J=15.3, 8.4 Hz, 1H), 4.80-4.50 (m,
3H), 4.41 (m, 1H), 4.11 (m, 1H), 3.94-3.62 (m, 4H), 3.39-3.19 (m,
3H), 2.88-2.79 (m, 2H), 2.50-2.17 (m, 3H), 1.72 (m, 1H).
EXAMPLE 29(k)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(benzofuran-2-yl)phenyl)-5-(4-carbo-
xythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene
##STR03623##
[1540] TLC: Rf 0.24 (Chloroform:Methanol:Acetic Acid=9:1:0.1);
[1541] NMR: .delta. 8.05 (s, 1H), 7.80-7.65 (m, 2H), 7.58 (d, J=7.5
Hz, 1H), 7.51 (d, J=7.5 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.35-7.15
(m, 3H), 7.03 (s, 1H), 5.82 (dd, J=15.0, 5.7 Hz, 1H), 5.52 (d,
J=15.0, 8.7 Hz, 1H), 4.50 (m, 1H), 4.19-4.02 (m, 1H), 3.70 (m, 1H),
3.36-3.08 (m, 3H), 3.00-2.82 (m, 2H), 2.50-2.10 (m, 3H), 1.72 (m,
1H).
EXAMPLE 29(l)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(5-methylfuran-2-yl)-5-(4-carboxythiaz-
ol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene
##STR03624##
[1543] TLC: Rf 0.26 (Dichloromethane:Methanol:Acetic
Acid=9:1:0.1);
[1544] NMR: .delta. 8.09 (s, 1H), 5.96 (d, J=3.0 Hz, 1H), 5.90-5.84
(m, 1H), 5.79 (dd, J=15.3, 6.0 Hz, 1H), 5.55 (ddd, J=15.3, 6.0, 1.2
Hz, 1H), 4.45 (q, J=6.3 Hz, 1H), 4.12 (q, J=7.5 Hz, 1H), 3.84-3.72
(m, 1H), 3.46-3.18 (m, 3H), 2.82 (d, J=6.3 Hz, 2H), 2.50-2.20 (m,
3H), 2.24 (s, 3H), 1.80-1.70 (m, 1H).
EXAMPLE 29(m)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-5-(6-carboxypyridin-2-
-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene
##STR03625##
[1546] TLC: Rf 0.21 (Chloroform:Methanol=4:1);
[1547] NMR: .delta. 7.97 (m, 1H), 7.69 (m, 1H), 7.38 (m, 1H),
7.21-7.15 (m, 2H), 7.06-6.97 (m, 2H), 5.75 (dd, J=15.0, 5.7 Hz,
1H), 5.51 (ddd, J=15.0, 8.4, 1.0 Hz, 1H), 4.40 (m, 1H), 4.10 (m,
1H), 3.58 (m, 1H), 3.38-3.15 (m, 3H), 2.83 (d, J=6.6 Hz, 2H),
2.57-2.20 (m, 3H), 1.77 (m, 1H).
EXAMPLE 30(a) TO EXAMPLE 30(e)
[1548] By the same procedure as describe in Example 16 using the
compound prepared in Example 3(l) or Example 29(e) and
corresponding alcohol derivatives instead of 2-pentanoyloxyethanol,
the compound of the present invention having the following physical
data were obtained.
EXAMPLE 30(a)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid dibutylcarbamoylmethyl ester
##STR03626##
[1550] TLC: Rf 0.73 (Chloroform:Methanol=9:1);
[1551] NMR: .delta. 7.17 (m, 2H), 6.99 (m, 2H), 5.75 (dd, J=15.6,
5.1 Hz, 1H), 5.52 (dd, J=15.6, 8.4 Hz, 1H), 4.69 (s, 2H), 4.40 (m,
1H), 4.11 (m, 1H), 3.58 (m, 1H), 3.28 (m, 2H), 3.20-3.00 (m, 3H),
2.81 (d, J=6.6 Hz, 2H), 2.70-2.47 (m, 7H), 2.40-2.18 (m, 3H), 1.95
(m, 2H), 1.88-1.42 (m, 5H), 1.41-1.22 (m, 4H), 1.00-0.83 (m,
6H).
EXAMPLE 30(b)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid 2-(2,2-diethylpentanoyloxy)ethyl
ester
##STR03627##
[1553] TLC: Rf 0.29 (Ethyl Acetate);
[1554] NMR: .delta. 7.22-7.13 (m, 2H), 7.07-6.97 (m, 2H), 5.75 (dd,
J=15.3, 6.0 Hz, 1H), 5.50 (dd, J=15.3, 8.7 Hz, 1H), 4.43-4.32 (m,
1H), 4.25 (s, 4H), 4.18-4.06 (m, 1H), 3.79-3.56 (m, 1H), 3.02-2.88
(m, 1H), 2. 86-2.79 (m, 2H), 2.70-2.48 (m, 4H), 2.48-2.31 (m, 4H),
2.31-2.17 (m, 1H), 1.97-1.82 (m, 3H), 1.78-1.60 (m, 1H), 1.60-1.48
(m, 6H), 1.22-1.10 (m, 2H), 0.89 (t, J=7.2 Hz, 3H), 0.77 (t, J=7.5
Hz, 6H).
EXAMPLE 30(c)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid 2-(adamantan-1-ylcarbonyloxy)ethyl
ester
##STR03628##
[1556] TLC: Rf 0.64 (Dichloromethane:Methanol=9:1);
[1557] NMR: .delta. 7.20-7.10 (m, 2H), 7.05-6.95 (m, 2H), 5.74 (dd,
J=14.7, 6.0 Hz, 1H), 5.50 (ddd, J=14.7, 8.4, 1.5 Hz, 1H), 4.45-4.35
(m, 1H), 4.30-4.20 (m, 4H), 4.15-4.05 (m, 1H), 3.70-3.55 (m, 1H),
3.00-2.90 (m, 1H), 2.81 (d, J=6.0 Hz, 2H), 2.70-2.35 (m, 8H),
2.30-2.15 (m, 1H), 2.05-1.95 (m, 3H), 1.95-1.80 (m, 9H), 1.80-1.60
(m, 6H).
EXAMPLE 30(d)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor--
5-thia-8-azaprost-13-enoic acid
2-(1-ethyl-1-methylbutanoyloxy)ethyl ester
##STR03629##
[1559] TLC: Rf 0.34 (Ethyl Acetate);
[1560] NMR: .delta. 7.20-7.10 (m, 2H), 7.05-6.95 (m, 2H), 5.23 (dd,
J=15.6, 6.0 Hz, 1H), 5.50 (ddd, J=15.6, 8.4, 1.5 Hz, 1H), 4.40-4.30
(m, 1H), 4.27 (s, 4H), 4.15-4.05 (m, 1H), 3.70-3.50 (m, 1H),
3.00-2.90 (m, 1H), 2.81 (d, J=6.6 Hz, 2H), 2.70-2.15 (m, 8H),
1.95-1.85 (m, 3H), 1.75-1.60 (m, 3H), 1.50-1.40 (m, 2H), 1.09 (s,
3H), 0.82 (t, J=7.5 Hz, 6H).
EXAMPLE 30(e)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-(2-(1-ethyl-1-me-
thylbutanoyloxy)ethoxycarbonyl)thiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-
-thia-8-azaprost-13-ene
##STR03630##
[1562] TLC: Rf 0.30 (Ethyl Acetate);
[1563] NMR: .delta. 7.99 (s, 1H), 7.17 (t, J=7.5 Hz, 1H), 7.05-7.00
(m, 1H), 7.00-6.90 (m, 2H), 5.80 (dd, J=15.3, 6.0 Hz, 1H), 5.50
(ddd, J=16.2, 8.7, 1.5 Hz, 1H), 4.56-4.45 (m, 2H), 4.40-4.30 (m,
3H), 4.25-4.15 (m, 1H), 3.75-3.65 (m, 1H), 3.40 (t, J=6.6 Hz, 2H),
3.30-3.15 (m, 1H), 2.80-2.75 (m, 2H), 2.40-2.15 (m, 6H), 2.08 (d,
J=4.5 Hz, 1H), 1.80-1.60 (m, 3H), 1.50-1.40 (m, 2H), 1.09 (s, 3H),
0.80 (t, J=7.5 Hz, 6H).
EXAMPLE 31
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3,4-dihydroxyphenyl)-17,18,19,20-tetr-
anor-5-thia-8-azaprost-13-enoic acid
##STR03631##
[1565] By the same procedure as describe in Reference Example 5,
Examples 1, 7 and 2 using
9-oxo-12-formyl-13,14,15,16,17,18,19,20-octanoyl-5-thia-8-azaprostanoic
acid butyl ester instead of the compound prepared in Reference
Example 4 and
3-(3,4-bis(t-butyldimethylsilyloxy)phenyl)-2-oxopropylphosphonic
acid dimethyl ester instead of
3-(3-methoxymethylphenyl)-2-oxopropylphosphonic acid dimethyl
ester, the compound of the present invention having the following
physical data were obtained.
[1566] TLC: Rf 0.14 (Dichloromethane:Methanol:Acetic
Acid=90:10:1);
[1567] NMR(CD.sub.3OD): .delta. 6.67 (d, J=7.8 Hz, 1H), 6.61 (d,
J=1.8 Hz, 1H), 6.49 (dd, J=7.8, 1.8 Hz, 1H), 5.68 (dd, J=15.3, 7.2
Hz, 1H), 5.33 (dd, J=15.3, 9.0 Hz, 1H), 4.30-4.20 (m, 1H),
4.20-4.10 (m, 1H), 3.55-3.45 (m, 1H), 2.90-2.70 (m, 2H), 2.70-2.15
(m, 10H), 1.95-1.80 (m, 2H), 1.80-1.60 (m, 1H).
EXAMPLE 32
(15.alpha.,13E)-1,6-(1,4-Interphenylene)-9-oxo-15-hydroxy-16-(3-(2-methylp-
henyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic
acid
##STR03632##
[1569] By the same procedure as describe in Reference Examples 31,
32, 33, Examples 26 and 2 using
3-(3-(2-methylphenyl)phenyl)-2-oxopropylphosphonic acid dimethyl
ester instead of 3-(4-fluorophenyl)-2-oxopropylphosphonic acid
dimethyl ester and 4-(formylmethyl)benzoic acid ethyl ester instead
of 4-(formylmethylthio)butanoic acid ethyl ester, the compound of
the present invention having the following physical data were
obtained.
[1570] TLC: Rf 0.41 (Dichloromethane:Methanol=9:1);
[1571] NMR: .delta. 7.99 (d, J=8.4 Hz, 2H), 7.40-7.14 (m, 10H),
5.65 (dd, J=15.3, 6.0 Hz, 1H), 5.39 (dd, J=15.3, 8.7 Hz, 1H),
4.45-4.35 (m, 1H), 3.85-3.70 (m, 2H), 3.05-2.70 (m, 5H), 2.40-2.20
(m, 5H), 2.20-2.00 (m, 1H), 1.70-1.55 (m, 1H).
EXAMPLE 32(a) TO EXAMPLE 32(s)
[1572] By the same procedure as describe in Reference Examples 31,
32, 33, Examples 26 and 2 using corresponding phosphonic acid ester
instead of 3-(3-(2-methylphenyl)phenyl)-2-oxopropylphosphonic acid
dimethyl ester and corresponding carboxylic acid ester derivatives
instead of 4-(formylmethyl)benzoic acid ethyl ester, the compound
of the present invention having the following physical data were
obtained.
EXAMPLE 32(a)
(15.alpha.,13E)-1,6-(1,4-Interphenylene)-9-oxo-15-hydroxy-16-(3-(3-methylp-
henyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic
acid
##STR03633##
[1574] TLC: Rf 0.32 (Dichloromethane:Methanol=9:1);
[1575] NMR: .delta. 7.98 (d, J=8.4 Hz, 2H), 7.50-7.30 (m, 6H),
7.24-7.14 (m, 4H), 5.64 (dd, J=15.3, 6.0 Hz, 1H), 5.36 (dd, J=15.3,
8.4 Hz, 1H), 4.50-4.40 (m, 1H), 3.80-3.65 (m, 2H), 3.00-2.70 (m,
5H), 2.45-2.20 (m, 5H), 2.20-2.00 (m, 1H), 1.70-1.55 (m, 1H).
EXAMPLE 32(b)
(15.alpha.,13E)-1,6-(1,4-Interphenylene)-9-oxo-15-hydroxy-16-(3-(4-methylp-
henyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic
acid
##STR03634##
[1577] TLC: Rf 0.32 (Dichloromethane:Methanol:Water=9:1);
[1578] NMR: .delta. 7.98 (d, J=8.4 Hz, 2H), 7.50-7.44 (m, 3H),
7.44-7.32 (m, 2H), 7.28-7.14 (m, 5H), 5.64 (dd, J=15.6, 6.0 Hz,
1H), 5.36 (dd, J=15.6, 8.7 Hz, 1H), 4.45-4.35 (m, 1H), 3.80-3.65
(m, 2H), 3.00-2.70 (m, 5H), 2.40-2.20 (m, 5H), 2.20-2.00 (m, 1H),
1.70-1.55 (m, 1H).
EXAMPLE 32(c)
(15.alpha.,13E)-1,6-(1,4-Interphenylene)-9-oxo-15-hydroxy-16-(3-(4-trifluo-
romethylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic
acid
##STR03635##
[1580] TLC: Rf 0.51 (Chloroform:Methanol:Acetic Acid=9:1:0.1);
[1581] NMR: .delta. 8.00 (d, J=8.1 Hz, 2H), 7.69 (m, 4H), 7.55-7.13
(m, 6H), 5.65 (dd, J=15.0, 6.0 Hz, 1H), 5.39 (dd, J=15.0, 8.4 Hz,
1H), 4.41 (m, 1H), 3.81-3.69 (m, 2H), 3.10-2.70 (m, 5H), 2.43-1.30
(m, 5H).
EXAMPLE 32(d)
(15.alpha.,13E)-1,6-(1,4-Interphenylene)-9-oxo-15-hydroxy-16-(3-(3,5-ditri-
fluoromethylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic
acid
##STR03636##
[1583] TLC: Rf 0.53 (Chloroform:Methanol:Acetic Acid=9:1:0.1);
[1584] NMR: .delta. 8.01-7.98 (m, 4H), 7.86 (s, 1H), 7.58-7.40 (m,
3H), 7.37-7.20 (m, 3H), 5.68 (dd, J=15.6, 6.0 Hz, 1H), 5.44 (dd,
J=15.6, 8.4 Hz, 1H), 4.43 (m, 1H), 3.83-3.78 (m, 2H), 3.18-2.80 (m,
6H), 2.42-2.22 (m, 2H), 2.14 (m, 1H), 1.65 (m, 1H).
EXAMPLE 32(e)
(15.alpha.,13E)-1,6-(1,4-Interphenylene)-9-oxo-15-hydroxy-16-(3-(4-t-butyl-
phenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic
acid
##STR03637##
[1586] TLC: Rf 0.51 (Chloroform:Methanol:Acetic Acid=9:1:0.1);
[1587] NMR: .delta. 7.98 (d, J=8.4 Hz, 2H), 7.59-7.33 (m, 7H),
7.25-7.16 (m, 3H), 5.63 (dd, J=15.3, 5.7 Hz, 1H), 5.39 (dd, J=15.3,
9.0 Hz, 1H), 4.21 (m,1H), 3.80-3.65 (m, 2H), 3.00-2.68 (m, 6H),
2.40-1.40 (m, 4H), 1.35 (s, 9H).
EXAMPLE 32(f)
(15.alpha.)-9-Oxo-15-hydroxy-16-(3-phenylphenyl)-5-(4-carboxythiazol-2-yl)-
-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane
##STR03638##
[1589] TLC: Rf 0.32 (Chloroform:Methanol:Acetic Acid=9:1:0.1);
[1590] NMR: .delta. 1.72 (m, 1H) 2.30 (m, 3H) 3.06 (m, 7H) 3.68 (m,
1H) 4.11 (m, 1H) 4.47 (m, 1H) 5.51 (dd, J=15.38, 8.79 Hz, 1H) 5.82
(dd, J=15.38, 5.77 Hz, 1H) 7.35 (m, 9H) 8.07 (s, 1H).
EXAMPLE 32(g)
(15.alpha.)-9-Oxo-15-hydroxy-16-(3-(4-methylphenyl)phenyl)-5-(4-carboxythi-
azol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane
##STR03639##
[1592] TLC: Rf 0.33 (Chloroform:Methanol:Acetic Acid=9:1:0.1);
[1593] NMR: .delta. 1.71 (m, 1H) 2.38 (m, 8H) 2.92 (m, 2H) 3.23 (m,
3H) 3.69 (m, 1H) 4.10 (m, 1H) 4.47 (m, 1H) 5.51 (dd, J=15.38, 8.52
Hz, 1H) 5.82 (dd, J=15.38, 5.77 Hz, 1H) 7.31 (m, 8H) 8.01 (s,
1H).
EXAMPLE 32(h)
(15.alpha.)-9-Oxo-15-hydroxy-16-(3-(4-chlorophenyl)phenyl)-5-(4-carboxythi-
azol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane
##STR03640##
[1595] TLC: Rf 0.28 (Chloroform:Methanol:Acetic Acid=9:1:0.1);
[1596] NMR: .delta. 1.69 (m, 1H) 2.30 (m, 3H) 2.90 (m, 2H) 3.44 (m,
6H) 4.11 (m, 1H) 4.46 (m, 1H) 5.52 (dd, J=15.38, 8.79 Hz, 1H) 5.83
(dd, J=15.38, 5.77 Hz, 1H) 7.35 (m, 8H) 8. 07 (s, 1H).
EXAMPLE 32(i)
(15.alpha.)-9-Oxo-15-hydroxy-16-(3-(4-methoxyphenyl)phenyl)-5-(4-carboxyth-
iazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane
##STR03641##
[1598] TLC: Rf 0.32 (Chloroform:Methanol:Acetic Acid=9:1:0.1);
[1599] NMR: .delta. 1.70 (m, 1H) 2.53 (m, 7H) 3.21 (m, 3H) 3.69 (m,
1H) 3.85 (s, 3H) 4.09 (m, 1H) 4.46 (m, 1H) 5.51 (dd, J=15.38, 8.79
Hz, 1H) 5.82 (dd, J=15.38, 6.04 Hz, 1H) 7. 22 (m, 8H) 8.07 (s,
1H).
EXAMPLE 32(j)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(naphthalen-2-yl)phenyl)-17,18,19,2-
0-tetranor-5-thia-8-azaprost-13-enoic acid
##STR03642##
[1601] TLC: Rf 0.46 (Chloroform:Methanol=9:1);
[1602] NMR: .delta. 8.03 (s, 1H), 7.94-7.82 (m, 3H), 7.73 (dd,
J=8.7, 2.1 Hz, 1H), 7.64-7.57 (m, 1H), 7.57-7.40 (m, 4H), 7.21 (d,
J=7.5 Hz, 1H), 5.79 (dd, J=15.3, 6.0 Hz, 1H), 5.49 (ddd, J=15.3,
8.7, 1.2 Hz, 1H), 4.54-4.44 (m, 1H), 4.14-4.04 (m, 1H), 3.66-3.52
(m, 1H), 3.00-2.85 (m, 3H), 2.60-2.10 (m, 9H), 1.90-1.60 (m,
3H).
EXAMPLE 32(k)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(benzoxazol-2-yl)phenyl)-17,18,19,2-
0-tetranor-5-thia-8-azaprost-13-enoic acid
##STR03643##
[1604] TLC: Rf 0.43 (Chloroform:Methanol=9:1);
[1605] NMR: .delta. 8.31 and 8.24 (s, 1H), 8.08 (d, J=7.8 Hz, 1H),
7.82-7.74 (m, 1H), 7.64-7.56 (m, 1H), 7.48(t, J=7.8 Hz, 1H),
7.44-7.34 (m, 3H), 5.89 (dd, J=15.6, 4.5 Hz, 1H), 5.63 (dd, J=15.6,
7.5 Hz, 1H), 4.65-4.55 and 4.55-4.45 (m, 1H), 4.20-4.05 (m, 1H),
3.55-3.40 (m, 1H), 3.30-3.10 (m, 1H), 3.30 (dd, J=13.8, 5.1 Hz,
1H), 2.89 (dd, J=13.8, 8.7 Hz, 1H), 2.75-2.15 (m, 9H), 1.95-1.85
(m, 2H), 1.80-1.60 (m, 1H).
EXAMPLE 32(l)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(benzothiazol-2-yl)phenyl)-17,18,19-
,20-tetranor-5-thia-8-azaprost-13-enoic acid
##STR03644##
[1607] TLC: Rf 0.38 (Chloroform:Methanol=9:1);
[1608] NMR: .delta. 8.14 (s, 1H), 8.09 (d, J=8.1 Hz, 1H), 7.91 (d,
J=7.8 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.56-7.32 (m, 4H), 5.88 (dd,
J=15.0, 5.1 Hz, 1H), 5.61 (ddd, J=15.0, 8.7, 1.5 Hz, 1H), 4.60-4.45
(m, 1H), 4.20-4.05 (m, 1H), 3.55-3.40 (m, 1H), 3.25-3.05 (m, 1H),
3.01 (dd, J=13.8, 4.8 Hz, 1H), 2.88 (dd, J=13.8, 8.7 Hz, 1H),
2.70-2.10 (m, 9H), 1.96-1.82 (m, 2H), 1.80-1.60 (m, 1H).
EXAMPLE 32(m)
(15.alpha.-9-Oxo-15-hydroxy-16-(3-(naphthalen-2-yl)phenyl)-5-(4-carboxythi-
azol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane
##STR03645##
[1610] TLC: Rf 0.40 (Dichloromethane:Methanol:Acetic
Acid=9:1:0.1);
[1611] NMR: .delta. 8.05-8.00 (m, 2H), 7.93-7.82 (m, 3H), 7.71 (dd,
J=8.4, 1.8 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.56-7.47 (m, 4H), 7.42
(t, J=7.8 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 5.84 (dd, J=15.3, 5.7
Hz, 1H), 5.52 (dd, J=15.3, 8.7 Hz, 1H), 4.49 (q, J=6.0 Hz, 1H),
4.15-4.05 (m, 1H), 3.75-3.65 (m, 1H), 3.35-3.05 (m, 3H), 2.95 (dd,
J=7.2, 3.3 Hz, 2H), 2.50-2.10.(m, 3H), 1.80-1.60 (m, 1H).
EXAMPLE 32(n)
(15.alpha.)-9-Oxo-15-hydroxy-16-(3-(benzoxazol-2-yl)phenyl)-5-(4-carboxyth-
iazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane
##STR03646##
[1613] TLC: Rf 0.36 (Dichloromethane:Methanol:Acetic
Acid=9:1:0.1);
[1614] NMR: .delta. 8.45 and 8.32 (s, 1H), 8.12 (s, 1H), 8.06 (d,
J=7.5 Hz, 1H), 7.90-7.82 (m, 1H), 7.64-7.58 (m, 1H), 7.50-7.36 (m,
4H), 5.94 (dd, J=15.6, 4.5 Hz, 1H), 5.78 (dd, J=15.6, 6.3 Hz, 1H),
4.70-4.50 (m, 1H), 4.15 (q, J=7.2 Hz, 1H), 3.60-3.20 (m, 4H), 3.00
(dd, J=14.4, 4.2 Hz, 1H), 2.85 (dd, J=14.4, 9.0 Hz, 1H), 2.50-2.15
(m, 3H), 1.85-1.70 (m, 1H).
EXAMPLE 32(o)
(15.alpha.)-9-Oxo-15-hydroxy-16-(3-(benzothiazol-2-yl)phenyl)-5-(4-carboxy-
thiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane
##STR03647##
[1616] TLC: Rf 0.37 (Dichloromethane:Methanol:Acetic
Acid=9:1:0.1);
[1617] NMR: .delta. 8.29 (s, 1H), 8.20-8.14 (m, 1H), 8.11 (s, 1H),
7.92 (d, J=7.2 Hz., 1H), 7.79 (d, J=7.8 Hz, 1H), 7.60-7.30 (m, 4H),
5.90 (dd, J=15.3, 3.9 Hz, 1H), 5.71 (dd, J=15.3, 9.0 Hz, 1H),
4.60-4.45 (m, 1H), 4.20-4.05 (m, 1H), 3.60-3.15 (m, 4H), 2.98 (dd,
J=14.1, 4.5 Hz, 1H), 2.83 (dd, J=14.1, 9.0 Hz, 1H), 2.50-2.10 (m,
3H), 1.85-1.70 (m, 1H).
EXAMPLE 32(p)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(isoindolin-2-yl)phenyl)-17,18,19,2-
0-tetranor-5-thia-8-azaprost-13-enoic acid
##STR03648##
[1619] TLC: Rf 0.36 (Chloroform:Methanol=9:1);
[1620] NMR: .delta. 1.79 (m, 3H) 2.72 (m, 13H) 3.59 (m, 1H) 4.12
(m, 1H) 4.49 (m, 1H) 4.78 (m, 4H) 5.55 (dd, J=15.66, 8.79 Hz, 1H)
5.81 (dd, J=15.66, 5.49 Hz, 1H) 6.57 (m, 2H) 7.33 (m, 6H).
EXAMPLE 32(q)
(15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-(indol-5-yl)phenyl)-17,18,19,20-tet-
ranor-5-thia-8-azaprost-13-enoic acid
##STR03649##
[1622] TLC: Rf 0.40 (Chloroform:Methanol=9:1);
[1623] NMR: .delta. 2.09 (m, 13H) 2.90 (m, 3H) 3.54 (m, 1H) 4.07
(m, 1H) 4.48 (m, 1H) 5.46 (ddd, J=15.38, 8.79, 1.10 Hz, 1H) 5.78
(dd, J=15.38, 5.77 Hz, 1H) 6.60 (m, 1H) 7.14 (m, 1H) 7.25 (m, 2H)
7.46 (m, 4H) 7.84 (m, 1H) 8.35 (brs., 1H).
EXAMPLE 32(r)
(15.alpha.)-9-Oxo-15-hydroxy-16-(3-(isoindolin-2-yl)phenyl)-5-(4-carboxyth-
iazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane
##STR03650##
[1625] TLC: Rf 0.38 (Dichloromethane:Methanol:Acetic
Acid=9:1:0.1);
[1626] NMR: .delta. 8.04 (s, 1H), 7.70-7.00 (m, 5H), 6.60-6.40 (m,
3H), 6.00-5.75 (m, 1H), 5.65-5.50 (m, 1H), 4.64 (s, 4H),
4.50-4.40(m, 1H), 4.20-4.10 (m, 1H), 3.80-3.60 (m, 1H), 3.50-3.00
(m, 3H), 3.00-2.75 (m, 2H), 2.50-2.10 (m, 3H), 1.85-1.65 (m,
1H).
EXAMPLE 32(s)
(15.alpha.)-9-Oxo-15-hydroxy-16-(3-(indol-5-yl)phenyl)-5-(4-carboxythiazol-
-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane
##STR03651##
[1628] TLC: Rf 0.36 (Dichloromethane:Methanol:Acetic
Acid=9:1:0.1);
[1629] NMR(CD.sub.3OD): .delta. 10.47 (s, 1H), 8.17 and 8.14 (s,
1H), 7.80-7.74 (m, 1H), 7.50-7.22 (m, 6H), 7.14-7.05 (m, 1H),
6.50-6.46 (m, 1H), 5.74 (dd, J=15.0, 6.9 Hz, 1H), 5.28 (dd, J=15.0,
9.0 Hz, 1H), 4.45-4.30 (m, 1H), 4.30-4.15 (m, 1H), 3.55-3.45 (m,
1H), 3.30-3.20 (m, 1H), 3.20-2.70 (m, 4H), 2.35-2.00 (m, 3H),
1.70-1.50 (m, 1H).
FORMULATION EXAMPLE 1
[1630] The following compounds were admixed in conventional method
and punched out to obtain 100 tablets each containing 0.5 mg of
active ingredient.
TABLE-US-00121 (15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methoxy- 250
mg methylphenyl)-17,18,19,20,-tetranor-8- (active ingredient 50 mg)
azaprost-13-enoic acid.cndot..alpha.-cyclodextrin
Carboxymethylcellulose calcium 200 mg Magnesium stearate 100 mg
Micro crystalline cellulose 9.2 g
FORMULATION EXAMPLE 2
[1631] The following components were admixed in a conventional
method, and the solution was sterilized in a conventional method,
placed 1 ml portions into ampoules and freeze-dried in a
conventional method to obtain 100 ampoules each containing 0.2 mg
of active ingredient.
TABLE-US-00122 (15.alpha.,13E)-9-Oxo-15-hydroxy-16-(3-methoxy- 100
mg methylphenyl)-17,18,19,20-tetranor-8- (active ingredient 20 mg)
azaprost-13-enoic acid.cndot..alpha.-cyclodextrin Mannit 5 g
Distilled water 100 ml
FORMULATION EXAMPLE 3
[1632] Polylactate-glycolate copolymer (abbreviated as PLGA)
(polylactate:glycolate=1:1(mol %), weight-average molecular weight
80,000, 90 mg, Mitsui chemical Co., Ltd.) and solution of the
compound of the present invention (10 mg) in methylene chloride (3
mL) were prepared. To 0.1% polyvinylalcohol (Nacalai Tesque)
solution (300 ml) stirred with 6000 rpm by using TK robomix
(Tokusyukika MARK II 2.5 type), the solution prepared above was
added, and the mixture was stirred for 2 minutes at room
temperature to make O/W emulsion. This O/W emulsion was stirred for
3 hours at room temperature, volatilise methylene chloride. After
oil layer was solidified, the residue was centrifugated for 10
minutes with 1000 rpm by using centrifugal machine (Hitachi,
05PR-22). After removing supernatant, the residue was dispersed
with distilled water for injection (35 mL), it was centrifugated
for 10 minutes with 1000 rpm by using centrifugal machine again
(twice), rinsed the sample to remove free drug etc. Finally, after
removing a supernatent and drying a precipitate under reduced
pressure microsphere was prepared.
[1633] The compounds of the present invention which were used for
this microsphere pharmaceutical were showed in the following.
[1634] Formulation Example 3(1): Example 18 [1635] Formulation
Example 3(2): Example 16(f) [1636] Formulation Example 3(3):
Example 16(e)
Test of Formulation 1:
[1637] The microsphere prepared in Formulation Examples 3(1) and
3(2) was added by acetonitrile solution containing proper internal
standard compound and ultrasonicated to disolve. Content of the
compound in the solution was determined by using HPLC, then the
rate of inclusion of the compound in microsphere was calculated by
the equation as shown below.
The rate of inclusion of the compound=Measured content/Theoretical
content multiplied by 100
[1638] The rates of the Formulation Examples 3(1), 3(2) and 3(3)
are 93%, 100% and 96% each.
Test of Formulation 2:
[1639] The microsphere prepared in Formulation Examples 3(1) was
suspended in saline (prepared 10 mg/kg as content of the compound).
The suspension was administered into regio cervicalis posterior of
SD-strain male rat by subcutaneous injection. Blood samples are
collected at regular time intervals after administration under
anesthesia with ether. And plasma separated from the blood was
solid-phase extracted, and the concentration was determined by
using liquid chromatograph mass spectrometer (LC/MS/MS).
[1640] It was confirmed that the blood concentration of the
compound was sustained at the day of 21.
Pharmacological Activity of the Compounds of the Invention
[1641] For example, 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.
(i) Experiment for Receptor-Binding Using Cells Which Express
Prostanoid Receptor Sub-Types
[1642] According to the method of Sugimoto et al. (J. Biol. Chem.,
267, 6463-6466 (1992)), 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.
[1643] 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 1 hour. The reaction was terminated with
ice cold buffer (3 ml), and the reaction mixture was filtered under
suction 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.
[1644] The Kd value was obtained from the Acatchard 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 compound of the invention. In this reaction, the following
buffer was used in all cases. [1645] Buffer: 10 mM potassium
phosphate (pH 6.9), 1 mM EDTA, 10 mM MgCl.sub.2, and 0.1M NaCl.
[1646] Dissociation constant Ki (.mu.M) of each compound was
calculated from the following equation.
Ki=IC.sub.50/(1+([C]/Kd))
[1647] The binding activities of the compounds of the invention to
the EP.sub.4 receptor are shown in Table 121.
TABLE-US-00123 TABLE 121 Example Dissociation Constant Ki (nM) 2
(pp) 0.24 3 (e) 0.71
(ii) Activity of EP.sub.4 Receptor Agonist
[1648] Experiment for measurement of the activity of an EP.sub.4
receptor agonist with the cells expressing prostanoid receptor
sub-types
[1649] 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 PGE.sub.2 alone or PGE.sub.2 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 AMP 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 supernatant to be 500 .mu.l, which was mixed
with 1 ml of 0.5 mol/L tri-n-octylamine/chloroform solution to
eliminate trichloroacetic acid contained in the chloroform layer.
The aqueous layer as a sample was measured to determined the cAMP
amount contained in the sample according to the method as described
in an instruction provided in the [.sup.125I]cAMP assay kit.
[1650] 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%.
[1651] As a result, the compounds of the invention were found to
have a significant and potent activity as EP.sub.4 receptor
agonist.
(iii) Inhibitive Effect for TNF-.alpha. Production
[1652] In male SD rats, LPS (10 .mu.g/2 ml/kg) was injected through
the tail vein, 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 mole/L sodium hydroxide solution, diluted
with distilled water, and orally given 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 plasma TNF-.alpha. concentration
in a control group (LPS-treated but no compound given) was 100%. As
a result, the compound of the invention showed a significant effect
for inhibition of TNF-.alpha. production.
(iv) Inhibitive Effect for Chronic Articular Rheumatism
(1) Arthritis Induced by Collagen in Rats
[1653] Experiment was performed according to the method of Osterman
et al. (Inflamm. Res., 44, 258-263). An inducing agent (an emulsion
prepared by adding an equal volume of physiological saline and 2
equivalent volume of incomplete Freund adjuvant to 0.3% solution of
type II collagen of bovine origin) 0.1 ml each was applied
intracutaneously to the 4 sites of the back of a female DA/Slc rat.
After a lapse of 1 week, the same inducing agent was further
applied intracutaneously to the tail root to induce arthritis. At
27 days the limbs were scored responding to the degree of redness
and edema and assessed as 30 was regarded as full scores. The
compound of the invention was dissolved in an equimolar amount of
0.02 mole/L sodium hydroxide solution, diluted with distilled
water, and orally given 3 times a day from the next day of the
first administration of inducer.
Result:
[1654] The effect of the compound of the invention for
collagen-induced arthritis in rats is shown in Table 122.
TABLE-US-00124 TABLE 122 Arthritic Score Compound Dose (Means .+-.
SE) Example 2 vehicle 24.6 .+-. 1.0 1000 .mu.g/kg 17.3 .+-. 1.5*
Example 3 (b) vehicle 24.6 .+-. 1.0 300 .mu.g/kg 19.3 .+-. 1.4*
Example 3 (l) vehicle 27.0 .+-. 1.2 100 .mu.g/kg 16.3 .+-. 3.0*
Example 3 (kk) vehicle 23.4 .+-. 3.0 100 .mu.g/kg 11.9 .+-. 3.6*
Example 4 (h) vehicle 27.0 .+-. 1.2 300 .mu.g/kg 9.8 .+-. 1.9* *p
< 0.05
[1655] As a result, significant improvement of the condition of
arthritis and inhibition of the increase of limb volume (edema)
were recognized by administration of the compounds of the invention
in comparison with those of a control group (distilled water was
orally given 3 times a day).
(2) Arthritis Induced by Cocktail Antibodies in Mice
[1656] A cocktail of antibodies to type II collagen was
intravenously applied to male DBA/1JNCrj mice at a dose of 2 mg/0.5
ml/mouse. After a lapse of 3 days, lipopolysaccharide was
intraperitoneally applied at a dose of 25 .mu.g/0.1 ml/mouse to
induce arthritis. At 10 days the limbs were respectively scored
responding to the degree of redness and edema and assessed as 4 was
regarded as full scores. The compound of the invention was
dissolved in an equimolar amount of 0.02 mole/L sodium hydroxide
solution, diluted with distilled water, and orally given 3 times a
day from 30 minutes before the administration of
lipopolysaccharide.
[1657] As a result, significant improvement of the condition of
arthritis and inhibition of the increase of limb volume (edema)
were recognized by administration of the compounds of the invention
in comparison with those of a control group (distilled water was
orally given 3 times a day).
(v) Effect on the Promotion of Osteogenesis 1
[1658] 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 anesthetization 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.
[1659] From 6 days after the surgical operation, the compound of
the invention (dissolved in an equimolar amount of 0.02 mole/L
sodium hydroxide solution, and diluted with distilled water) were
orally give 3 times a day for 2 months. To the control group and
the sham group was given physiological saline. After termination of
the test, the animals of each group were killed and subjected to
autopsy. The bone density of the cancellous region of left thigh
bone was measured by means of an apparatus for measuring the bone
density of peripheral bone (XCT-960A, Norland/Stratech).
[1660] As a result, the compound of the invention significantly
increased the bone density when compared with a control group (no
administration).
(vi) Effect on the Promotion of Osteogenesis 2
[1661] Using beagle/CSK dogs of approximately 6 months of age, the
effect on the promotion of osteogenesis can be examined.
[1662] The compound of the invention was dissolved in physiological
saline and orally administered over 4 weeks. To a control group was
give an equal volume of physiological saline. After completion of
the administration, the dogs were killed, subjected to autopsy, and
the area and density of bone were measured.
(1) Measurement of Bone Area
[1663] The removed thigh bone 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 the 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 surface by image analysis.
(2) Measurement of Bone Density
[1664] The sample of I cm in width used in (1) was taken
radiographs in side view, and the picture was sent into a computer
to measure the radiation dose 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 Cure of Bone Fracture 1
[1665] This can be achieved according to the method of Markel et
al. (J. Bone and Joint Surgery, 73A, 914-923, 1991). Using
beagle/CSK dogs of approximately 6 months of age, the femoral tibia
is fractured under anesthesia and taken radiographs periodically
for 3 months to assess the progress of cure. Thus, the effect of
accelerating cure of bone fracture can easily be judged. The
compound of the invention is orally administered everyday. To a
control group is given distilled water. When the effect of
acceleration of cure is recognized, the tibia is removed and the
bone density and strength can be measured to further assess
quantitatively.
(viii) Inhibitive Effect for Gastric Ulcer
[1666] To SD rats was orally administered 20 mg/kg of indomethacin
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. As a result, the compound of the invention
significantly reduced the ulcerous area when compared to the
control group (no administration).
(ix) Effect of Accelerating Cure of Bone Fracture
[1667] 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 with male IGS rats of 8 weeks of age. Hair of
the left hind-limb of a rat was cut under anesthetization 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 tendo Achillis) was incised to ablate the
muscular tissue and expose the fibula. The fibula was cut off
approximately at the central position to make a fracture portion,
which was then restored to its former condition, and the incised
portion was closed by suture with disinfection by iodine
tincture/disinfectant ethanol. After making the fracture portion
and before closing the wound of 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, 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,
and the connective tissue of the hind-limbs, including muscle, was
eliminated to obtain both of the fibulae. The recovered fibulae
were taken radiographs to assess development of the cure of
fracture based on the presence of a fracture line and callus
formation, and the density and strength of the bone around the
fracture portion were measured.
(1) Measurement of the Bone Density of the Callus Region Using a
Micro Focus X-Ray Enlargement Camera System
[1668] The bone density of the callus region at the fracture
position of the recovered fibula was measured referring to the
reports of C. Matsumoto (Calcif Tissue Int, 55, 324-329 (1994)),
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 an analytical 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 in the proximal direction (knee)
respectively to calculate the bone density of each ROI from the
analytical 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 means.+-.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 ) ##EQU00001##
[1669] A represents the ROI area in the proximal callus region;
[1670] B represents the ROI area in the remote callus region.
(2) Measurement of the Bone Strength by a Bending Test at Three
Points
[1671] 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), fracture
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 was 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).
Result:
[1672] The effect of accelerating cure of bone fracture when the
fractured portion was treated only once with microsphere
(containing 0.3 mg/kg as an active drug) prepared in Formulation
Example 3(1) or a reference (physiological saline containing 0.2%
Tween 80) is shown in Table 123.
[1673] The effect of accelerating cure of bone fracture when the
fractured portion was treated only once with microsphere
(containing 1 mg/kg as an active drug) prepared in Formulation
Example 3(3) or a reference (physiological saline containing 0.2%
Tween 80) is shown in Table 123.
TABLE-US-00125 TABLE 123 Bone Density Fracture Strength
(mg/cm.sup.2) (% of intact) Formulation Example 3(1) 60.9 .+-. 4.0
149.8 .+-. 12.4% Reference (Control) 39.8 .+-. 2.7 62.8 .+-.
8.5%
TABLE-US-00126 TABLE 124 Bone Density Fracture Strength
(mg/cm.sup.2) (% of intact) Formulation Example 3(3) 51.6 .+-. 3.8
114.6 .+-. 10.4% Reference (Control) 36.5 .+-. 2.5 55.3 .+-.
5.7%
[1674] The effect of accelerating cure of bone fracture when
Compound (1) (50 ng/kg/min) and a reference (physiological saline)
were administered intravenously for 2 hours twice a day for 21 days
is shown in Table 125.
TABLE-US-00127 TABLE 125 Bone Density Fracture Strength
(mg/cm.sup.2) (% of intact) Compound 42.8 .+-. 2.58 30.4 .+-. 12.4%
Reference (Control) 35.2 .+-. 1.91 55.2 .+-. 9.77%
[1675] As clearly seen from Tables 123 and 124 in comparison with
Table 125, the effect of accelerating cure of bone fracture when
treated only once with microspheres which were prepared in
Formulation Examples 3(1) and 3(3) were much higher than that of
Compound (1) which was administered intravenously for 21 days.
(x) Inhibitive Effect on Ulcerous Colitis
[1676] 7% Sodium dextran sulfate aqueous solution (hereinafter
abbreviated to as SDS) 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: 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. As a result, the compound of the invention showed a
significant inhibitive effect on ulcerous colitis.
* * * * *