U.S. patent application number 10/238623 was filed with the patent office on 2003-10-02 for omega-cycloalkyl-prostaglandin e2 derivatives.
Invention is credited to Ohuchida, Shuichi, Tani, Kousuke.
Application Number | 20030186939 10/238623 |
Document ID | / |
Family ID | 26374500 |
Filed Date | 2003-10-02 |
United States Patent
Application |
20030186939 |
Kind Code |
A1 |
Tani, Kousuke ; et
al. |
October 2, 2003 |
Omega-cycloalkyl-prostaglandin E2 derivatives
Abstract
A .omega.-cycloalkyl-prostaglandin E.sub.2 derivatives of the
formula (I) 1 wherein R is carboxy or hydroxymethyl; R.sup.1 is
oxo, methylene or halogen atom; R.sup.2 is H, OH or C1-4 alkoxy;
R.sup.3 is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkyl,
C2-8 alkenyl or C2-8 alkynyl substituted by 1-3 of substituent
selected from halogen atom, C1-4 alkoxy, C3-7 cycloalkyl, phenyl,
or phenyl substituted by 1-3 of substituent selected from halogen
atom, C1-4 alkyl, C1-4 alkoxy, nitro, trifluoromethyl; n is 0-4;
and non-toxic salt thereof, prodrug thereof and cyclodextrin
clathrate thereof can strongly bind on EP.sub.2 subtype receptor.
Therefore, they are useful for prevention and/or treatment of
immune disease (autoimmune disease, organ transplantation, etc.),
asthma, abnormal bone formation, neuron cell death, liver damage,
abortion, premature birth or retina neuropathy of glaucoma etc.
Inventors: |
Tani, Kousuke; (Mishima-gun,
JP) ; Ohuchida, Shuichi; (Mishima-gun, JP) |
Correspondence
Address: |
STEVENS DAVIS MILLER & MOSHER, LLP
1615 L STREET, NW
SUITE 850
WASHINGTON
DC
20036
US
|
Family ID: |
26374500 |
Appl. No.: |
10/238623 |
Filed: |
September 11, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10238623 |
Sep 11, 2002 |
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09570728 |
May 12, 2000 |
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09570728 |
May 12, 2000 |
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09018565 |
Feb 4, 1998 |
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6110969 |
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Current U.S.
Class: |
514/58 ; 514/679;
514/691; 514/729; 536/103; 568/325; 568/367; 568/660; 568/816 |
Current CPC
Class: |
C07C 405/00
20130101 |
Class at
Publication: |
514/58 ; 514/691;
514/679; 514/729; 536/103; 568/325; 568/367; 568/660; 568/816 |
International
Class: |
A61K 031/557; C08B
037/16 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 4, 1997 |
JP |
9-035499 |
Nov 6, 1997 |
JP |
9-319169 |
Claims
What we claim is:
1. A .omega.-cycloalkyl-prostaglandin E.sub.2 derivatives of the
formula (I) 463wherein R is carboxy or hydroxymethyl; R.sup.1 is
oxo, methylene or halogen atom; R.sup.2 is hydrogen atom, hydroxy
or C1-4 alkoxy; R.sup.3 is (i) hydrogen atom, (ii) C1-8 alkyl,
(iii) C2-8 alkenyl, (iv) c2-8 alkynyl or (v) C1 -8 alkyl, C2-8
alkenyl or C2-8 alkynyl, each substituted by 1-3 substituents,
being same or different, selected from (1)-(5): (1) halogen atom,
(2) C1-4 alkoxy, (3) C3-7 cycloalkyl, (4) phenyl, or (5) phenyl
substituted by 1-3 substituents selected from halogen atom, C1-4
alkyl, C1-4 alkoxy, nitro or trifluoromethyl; n is 0-4; 464is
single bond or double bond; 465is double bond or triple bond; 466is
single bond, double bond or triple bond; with the proviso that, (1)
when 5-6 position is triple bond, 13-14 position is not triple
bond, (2) when 13-14 position is double bond, double bond represent
E, Z or EZ mixture form; non-toxic salt thereof, prodrug thereof
and cyclodextrin clathrate thereof.
2. A compound according to claim 1, wherein prodrug of the compound
of the formula (I) described in claim 1 is the compound of formula
(IA) 467wherein R.sup.10 is C1-6 alkyl, the other symbols are the
same meaning as hereinbefore defined.
3. A compound according to claim 1, wherein prodrug of the compound
of the formula (I) described in claim 1 is the compound of formula
(IB) 468wherein R.sup.12 and R.sup.13 each, independently, is
hydrogen atom or C1-6 alkyl, the other symbols are the same meaning
as hereinbefore defined.
4. A compound according to claim 1, wherein prodrug of the compound
of the formula (I) described in claim 1 is the compound of formula
(IC) 469wherein R.sup.11 is C1-4 alkyl, C1-4 alkoxy, phenyl,
phenyl-C1-4 alkyl, R.sup.14--OOC--C1-4 alkyl or R.sup.14--OOC--C2-4
alkenyl (in which R is hydrogen atom, C1-4 alkyl), the other
symbols are the same meaning as hereinbefore defined.
5. A compound according to claim 1, wherein R is carboxy.
6. A compound according to claim 1, wherein R is hydroxymethyl.
7. A compound according to claim 2, which is (1) (5Z, 11.alpha.,
13E)-11, 16-dihydroxy-9-oxo-17, 17-propanoprosta-5, 13-dienoic
acid.cndot.methylester, (2) (5Z, 11.alpha., 16RS)-11,
16-dihydroxy-9-oxo-17, 17-propanoprosta-5-ene-13-ynoic
acid.cndot.methylester, (3) (11.alpha., 13E)-11,
16-dihydroxy-9-oxo-17, 17-propanoprosta-13-ene-5-ynoic
acid.cndot.methylester, (4) (5Z, 11.alpha., 16RS)-11,
16-dihydroxy-9-oxo-17, 17-propanoprosta-5-enoic
acid.cndot.methylester, (5) (5Z, 11.alpha., 13E)-11,
16-dihydroxy-20-methyl-9-oxo-17, 17-propanoprosta-5, 13-dienoic
acid.cndot.methylester, (6) (5Z, 11.alpha., 13E)-11,
16-dihydroxy-20-ethyl-9-oxo-17, 17-propanoprosta-5, 13-dienoic
acid.cndot.methylester, (7) (5Z, 11.alpha., 13E)-20-chloro-11,
16-dihydroxy-9-oxo-17, 17-propanoprosta-5, 13-dienoic
acid.cndot.methylester, (8) (5Z, 11.alpha., 13E)-11,
16-dihydroxy-9-oxo-18-phenyl-17, 17-propano-19, 20-dinorprosta-5,
13-dienoic acid.cndot.methylester, (9) (5Z, 11.alpha., 13E)-11,
16-dihydroxy-9-oxo-17, 17-propanoprosta-5, 13, 19-trienoic
acid.cndot.methylester, (10) (5Z, 11.alpha., 13E)-11,
16-dihydroxy-20-methyl-9-oxo-17, 17-propanoprosta-5,
13-diene-19-ynoic acid.cndot.methylester, (11) (5Z, 11.alpha.,
13E)-17, 17-butano-11, 16-dihydroxy-9-oxoprosta-5, 13-dienoic
acid.cndot.methylester, (12) (5Z, 11.alpha., 13E)-11,
16-dihydroxy-9-oxo-17, 17-pentanoprosta-5, 13-dienoic
acid.cndot.methylester, (13) (5Z, 11.alpha., 13E)-18-cyclohexyl-11,
16-dihydroxy-9-oxo-17, 17-propano-19, 20-dinorprosta-5, 13-dienoic
acid.cndot.methylester, (14) (5Z, 11.alpha., 13E)-11,
16-dihydroxy-9-oxo-17, 17-propano-20-norprosta-5, 13-dienoic
acid.cndot.methylester, (15) (5Z, 11.alpha., 13E)-17,
17-propano-19, 20-methano-11, 16-dihydroxy-9-oxoprosta-5,
13-dienoic acid.cndot.methylester, (16) (5Z, 11.alpha., 13E)-17,
17-propano-20,20-methylene-11, 16-dihydroxy-9-oxoprosta-5,
13-dienoic acid.cndot.methylester, (17) (5Z, 11.alpha., 13E)-17,
17-propano-20-methoxy-11, 16-dihydroxy-9-oxoprosta-5, 13-dienoic
acid.cndot.methylester, (18) (5Z, 11.alpha., 13E)-17,
17-propano-20-fluoro-11, 16-dihydroxy-9-oxoprosta-5, 13-dienoic
acid.cndot.methylester, (19) (5Z, 11.alpha., 13E)-17,
17-propano-19-methyl-11, 16-dihydroxy-9-oxoprosta-5, 13-dienoic
acid.cndot.methylester, (20) (5Z, 11.alpha., 13E)-17,
17-propano-11, 16-dihydroxy-9-oxo-20-norprosta-5, 13, 18-trienoic
acid.cndot.methylester, (21) (5Z, 13E)-17,
17-propano-16-hydroxy-9-oxopro- sta-5, 13-dienoic
acid.cndot.methylester, (22) (5Z, 11.alpha., 13E)-17,
17-propano-11-methoxy-16-hydroxy-9-oxoprosta-5, 13-dienoic
acid.cndot.methylester, (23) (5Z, 11.alpha., 13E)-17,
17-propano-11-methoxy-16-hydroxy-9-oxo-19-methylprosta-5,
13-dienoic acid.cndot.methylester, (24) (5Z, 11.alpha., 13E)-17,
17-propano-11-methoxy-16-hydroxy-9-oxo-19, 20-methanoprosta-5,
13-dienoic acid.cndot.methylester, (25) (5Z, 11.alpha., 13E)-17,
17-propano-11-methoxy-16-hydroxy-9-oxo-20-norprosta-5, 13-dienoic
acid.cndot.methylester, (26) (5Z, 11.alpha., 13E)-17,
17-propano-11-methoxy-16-hydroxy-9-oxoprosta-5, 13, 19-trienoic
acid.cndot.methylester, (27) (5Z, 11.alpha., 13E)-17,
17-propano-11, 16-dihydroxy-9,9-methyleneprosta-5, 13-dienoic
acid.cndot.methylester, (28) (5Z, 9.beta., 11.alpha., 13E)-17,
17-propano-11, 16-dihydroxy-9-fluoro-prosta-5, 13-dienoic
acid.cndot.methylester, (29) (5Z, 9.beta., 11.alpha., 13E)-17,
17-propano-11, 16-dihydroxy-9-chloro-20- -norprosta-5, 13-dienoic
acid.cndot.methylester, (30) (5Z, 9.beta., 11.alpha., 13E)-17,
17-propano-11, 16-dihydroxy-9-chloroprosta-5, 13, 19-trienoic
acid.cndot.methylester, (31) (5Z, 9.beta., 11.alpha., 13E)-17,
17-propano-19, 20-methano-11, 16-dihydroxy-9-chloroprosta-5,
13-dienoic acid.cndot.methylester, (32) (5Z, 9.beta., 11.alpha.,
13E)-17, 17-propano-11, 16-dihydroxy-9-chloro-19-methylprosta-5,
13-dienoic acid.cndot.methylester, (33) (5Z, 9.beta., 11.alpha.,
13E)-17, 17-propano-11, 16-dihydroxy-9-chloroprosta-5, 13-dienoic
acid.cndot.methylester, (34) (5Z, 9.alpha., 11.alpha., 13E)-17,
17-propano-11, 16-dihydroxy-9-chloro-prosta-5, 13-dienoic
acid.cndot.methylester, (35) (5Z, 11.alpha., 13E)-17,
17-propano-11, 16-dihydroxy-9-oxo-19, 20-dinorprosta-5, 13-dienoic
acid.cndot.methylester, (36) (5Z, 11.alpha., 13E)-17,
17-propano-11, 16-dihydroxy-9-oxo-18, 19, 20-trinorprosta-5,
13-dienoic acid.cndot.methylester, (37) (5Z, 9.beta., 11.alpha.,
13E)-17, 17-propano-11, 16-dihydroxy-9-chloro-19, 20-dinorprosta-5,
13-dienoic acid.cndot.methylester, or (38) (5Z, 9.beta., 11.alpha.,
13E)-17, 17-propano-11, 16-dihydroxy-9-chloro-18, 19,
20-trinorprosta-5, 13-dienoic acid.cndot.methylester in the form of
the more or less polar stereoisomer on the 16-position or a mixture
thereof.
8. A compound according to claim 3, which is (1) (5Z, 11.alpha.,
13E)-17, 17-propano-11, 16-dihydroxy-9-oxoprosta-5, 13-dienoic acid
amide in the form of the more or less polar stereoisomer on the
16-position or a mixture thereof.
9. A compound according to claim 4, which is (1) (5Z, 8Z,
11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9-acetyloxy-prosta-5, 8, 13-trienoic
acid.cndot.methylester in the form of the more or less polar
stereoisomer on the 16-position or a mixture thereof.
10. A compound according to claim 5, which is (1) (5Z, 11.alpha.,
13E)-11, 16-dihydroxy-9-oxo-17, 17-propanoprosta-5, 13-dienoic
acid, (2) (5Z, 11.alpha., 13E)-11, 16-dihydroxy-20-methyl-9-oxo-17,
17-propanoprosta-5, 13-dienoic acid, (3) (5Z, 11.alpha., 13E)-11,
16-dihydroxy-20-ethyl-9-oxo- -17, 17-propanoprosta-5, 13-dienoic
acid, (4) (5Z, 11.alpha., 13E)-20-chloro-11, 16-dihydroxy-9-oxo-17,
17-propanoprosta-5, 13-dienoic acid, (5) (5Z, 11.alpha., 13E)-11,
16-dihydroxy-9-oxo-18-phenyl-17, 17-propano-19, 20-dinorprosta-5,
13-dienoic acid, (6) (5Z, 11.alpha., 13E)-11,
16-dihydroxy-9-oxo-17, 17-propanoprosta-5, 13-19-trienoic acid, (7)
(5Z, 11.alpha., 13E)-11, 16-dihydroxy-20-methyl-9-oxo-17,
17-propanoprosta-5, 13-diene-19-ynoic acid, (8) (5Z, 11.alpha.,
13E)-17, 17-butano-11, 16-dihydroxy-9-oxoprosta-5, 13-dienoic acid,
(9) (5Z, 11.alpha., 13E)-1 , 16-dihydroxy-9-oxo-17,
17-pentanoprosta-5, 13-dienoic acid, (10) (5Z, 11.alpha.,
13E)-18-cyclohexyl-11, 16-dihydroxy-9-oxo-17, 17-propano-19,
20-dinorprosta-5, 13-dienoic acid, (11) (5Z, 11.alpha., 13E)-11,
16-dihydroxy-9-oxo-17, 17-propano-20-norprosta-5, 13-dienoic acid,
(12) (5Z, 11.alpha., 16RS)-11, 16-dihydroxy-9-oxo-17,
17-propanoprosta-5-enoic acid, (13) (5Z, 11.alpha., 16RS )-11,
16-dihydroxy-9-oxo-17, 17-propanoprosta-5-ene-13-ynoic acid, (14)
(11.alpha., 13E)-11, 16-dihydroxy-9-oxo-17,
17-propanoprosta-13-ene-5-yno- ic acid, (15) (5Z, 11.alpha.,
13E)-17, 17-propano-19, 20-methano-11, 16-dihydroxy-9-oxoprosta-5,
13-dienoic acid, (16) (5Z, 11.alpha., 13E)-17, 17-propano-20,
20-methylene-11, 16-dihydroxy-9-oxoprosta-5, 13-dienoic acid, (17)
(5Z, 11.alpha., 13E)-17, 17-propano-20-methoxy-11,
16-dihydroxy-9-oxoprosta-5, 13-dienoic acid, (18) (5Z, 11.alpha.,
13E)-17, 17-propano-20-fluoro-11, 16-dihydroxy-9-oxoprosta-5,
13-dienoic acid, (19) (5Z, 11.alpha., 13E)-17,
17-propano-19-methyl-11, 16-dihydroxy-9-oxoprosta-5, 13-dienoic
acid, (20) (5Z, 11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9-oxo-20-norprosta-5, 13, 18-trienoic acid, (21) (5Z,
11.alpha., 13Z)-17, 17-propano-11, 16-dihydroxy-9-oxoprosta-5,
13-dienoic acid, (22) (5Z, 13E)-17,
17-propano-16-hydroxy-9-oxoprosta-5, 13-dienoic acid, (23) (5Z,
11.alpha., 13E)-17, 17-propano-11-methoxy-16-hydroxy-9-oxoprosta-5,
13-dienoic acid, (24) (5Z, 11.alpha., 13E)-17,
17-propano-11-methoxy-16-h- ydroxy-19-methyl-9-oxoprosta-5,
13-dienoic acid, (25) (5Z, 11.alpha., 13E)-17,
17-propano-11-methoxy-16-hydroxy-9-oxo-19, 20-methanoprosta-5,
13-dienoic acid, (26) (5Z, 11.alpha., 13E)-17,
17-propano-11-methoxy-16-h- ydroxy-9-oxo-20-norprosta-5, 13-dienoic
acid, (27) (5Z, 11.alpha., 13E)-17,
17-propano-11-methoxy-16-hydroxy-9-oxoprosta-5, 13, 19-trienoic
acid, (28) (5Z, 11.alpha., 13E)-17, 17-propano-1 , 16-dihydroxy-9,
9-methyleneprosta-5, 13-dienoic acid, (29) (5Z, 9.beta., 11.alpha.,
13E)-17, 17-propano-11, 16-dihydroxy-9-fluoro-prosta-5, 13-dienoic
acid, (30) (5Z, 9.beta., 11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9-chloro-20-norprosta-5, 13-dienoic acid, (31) (5Z,
9.beta., 11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9-chloroprosta-5, 13, 19-trienoic acid, (32) (5Z,
9.beta., 11.alpha., 13E)-17, 17-propano-19, 20-methano-11,
16-dihydroxy-9-chloroprosta-5, 13-dienoic acid, (33) (5Z, 9.beta.,
11.alpha., 13E)-17, 17-propano-11, 16-dihydroxy-9-chloro-19-meth-
ylprosta-5, 13-dienoic acid, (34) (5Z, 9.beta., 11.alpha., 13E)-17,
17-propano-11, 16-dihydroxy-9-chloroprosta-5, 13-dienoic acid, (35)
(5Z, 9.alpha., 11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9-chloro-prosta- -5, 13-dienoic acid, (36) (5Z,
11.alpha., 13E)-17, 17-propano-11, 16-dihydroxy-9-oxo-19,
20-dinorprosta-5, 13-dienoic acid, (37) (5Z, 11.alpha., 13E)-17,
17-propano-11, 16-dihydroxy-9-oxo-18, 19, 20-trinorprosta-5,
13-dienoic acid, (38) (5Z, 9.beta., 11.alpha., 13E)-17,
17-propano-11, 16-dihydroxy-9-chloro-19, 20-dinorprosta-5,
13-dienoic acid, or (39) (5Z, 9.beta., 11.alpha., 13E)-17,
17-propano-11, 16-dihydroxy-9-chloro-18, 19, 20-trinorprosta-5,
13-dienoic acid in the form of the more or less polar stereoisomer
on the 16-position or a mixture thereof.
11. A compound according to claim 6, which is (1) (5Z, 11.alpha.,
13E)-17, 17-propano-11, 16-dihydroxy-9-oxoprosta-5, 13-diene-1-ol
in the form of the more or less polar stereoisomer on the
16-position or a mixture thereof.
12. A process for the preparation of a compound of the formula
(1-1) 470(wherein all the symbols are the same meaning hereinbefore
defined in claim 1) which comprises hydrolysis using enzyme or
hydrolysis in an alkaline condition of a compound of formula (IA)
471 (wherein all the symbols are the same meaning hereinbefore
defined and R.sup.10 is C1-C6 alkyl)
13. A process for the preparation of a compound of the formula
(I-2) 472 (wherein all the symbols are the same meaning as
hereinbefore defined in claim 1) those in which R is oxo, i.e., the
compounds of formula (I-2A) 473 (wherein all the symbols are the
same meaning as hereinbefore defined) which comprises elimination
of the protecting group in an acidic condition of a compound of
formula (IIA) 474 (wherein R.sup.20 is hydrogen atom, hydroxy
protecting group to elimination in an acidic condition or C1-4
alkoxy, R.sup.40 is hydroxy protecting group to remove in an acid
condition, the other symbols are the same meaning as hereinbefore
defined).
14. A process for the preparation of a compound of the formula
(I-2) 475(wherein all the symbols are the same meaning as
hereinbefore defined in claim 1) those in which R.sup.1 is
methylene, i.e., the compounds of formula (I-2B) 476 (wherein all
the symbols are the same meaning as hereinbefore defined) which
comprises reduction of a compound of formula (IA-4) 477 (wherein
all the symbols are the same meaning as hereinbefore defined and
R.sup.10 is C1-C6 alkyl).
15. A process for the preparation of a compound of the formula
(I-2) 478(wherein all the symbols are the same meaning as
hereinbefore defined in claim 1) those in which R.sup.1 is halogen
atom, i.e., the compounds of formula (I-2C) 479(wherein R.sup.15 is
halogen atom, the other symbols are the same meaning as
hereinbefore defined) which comprises reduction of a compound of
formula (IA-5) 480 (wherein R.sup.15 is halogen atom, the other
symbols are the same meaning as hereinbefore defined and R.sup.10
is C1-C6 alkyl).
16. A process for the preparation of a prodrug compound of the
formula 481(wherein all the symbols are the same meaning as
hereinbefore defined in claim 1 and R.sup.10 is C1-C6 alkyl) those
in which R.sup.2 is hydrogen atom or hydroxy, i.e., the compounds
of formula (IA-1) 482 (wherein R.sup.22 is hydrogen atom or
hydroxy, the other symbols are the same meaning as hereinbefore
defined and R.sup.10 is C1-C6 alkyl which comprises hydrolysis in
an acidic condition of a compound of formula (III) 483 (wherein
R.sup.21 hydrogen atom or hydroxy protecting group to elimination
in an acid condition, the other symbols are the same meaning as
hereinbefore defined and R.sup.10 is C1-C6 alkyl; R.sup.20 is
hydrogen atom, hydroxy protecting group to elimination in an acidic
condition or C1-4 alkoxy; and R.sup.40 is hydroxy protecting group
to remove in an acid condition).
17. A process for the preparation of a prodrug compound of the
formula (IA) 484(wherein all the symbols are the same meaning as
hereinbefore defined in claim 1 and R.sup.10 is C1-C6 alkyl) those
in which R.sup.2 is C1-4 alkoxy, i.e., the compounds of formula
(IA-2) 485 (wherein R.sup.23 is C1-4 alkoxy, the other symbols are
the same meaning as hereinbefore defined) which comprises
O-alkylation of the compounds of the formula (IA-1) 486 (wherein
all the symbols are the same meaning as hereinbefore defined and
R.sup.22 is hydrogen atom or hydroxy) those in which R.sup.22 is
hydroxy, i.e., a compound of formula (IA-3) 487 (wherein all the
symbols are the same meaning as hereinbefore defined).
18. A process for the preparation of a prodrug compound of the
formula (IB) 488(wherein all the symbols are the same meaning as
hereinbefore defined in claim 1 and R.sup.12 and R.sup.13 each,
independently, is hydrogen atom or C1-C6 alkyl) which comprises
amidation of the compounds of the formula (I-1) 489 (wherein all
the symbols are the same meaning as hereinbefore defined) with the
compounds of the formula (IV) 490 (wherein all the symbols are the
same meaning as hereinbefore defined).
19. A process for the preparation of a prodrug compound of the
formula (IC) 491(wherein all the symbols are the same meaning as
hereinbefore defined in claim 1 and R.sup.10 is C1-C6 alkyl;
R.sup.11 is C1-C4 alkyl, C1-C4 alkoxy, phenyl, phenyl-C1-C4 alkyl,
R.sup.14--OOC--C1-C4 alkyl or R.sup.14--OOC--C2-4 alkenyl (in which
R.sup.14 is hydrogen atom, C1-4 alkyl) which comprises hydrolysis
in an acidic condition of the compounds of the formula (V) 492
(wherein all the symbols are the same meaning as hereinbefore
defined and R.sup.20 is hydrogen atom, hydroxy protecting group to
elimination in an acidic condition or C1-4 alkoxy, R.sup.40 is
hydroxy protecting group to remove in an acid condition.
20. A pharmaceutical composition which comprises, as active
ingredient, an effective amount of a compound of the formula (I)
depicted in claim 1, a non-toxic salt thereof, a prodrug thereof or
a cyclodextrin clathrate thereof, with a carrier or coating.
21. A method for the prevention and/or the treatment in animals,
including man, of diseases induced by EP.sub.2 subtype receptor,
which comprises the administration to a patient of an effective
amount of a compound of the formula (I) depicted in claim 1, a
non-toxic salt thereof, a prodrug thereof or a cyclodextrin
clathrate thereof.
22. A method for the prevention and/or treatment in animals,
including man, of autoimmuno diseases, organ transplantation,
asthma, abnormal bone formation, neuronal cell death, liver damage,
abortion, premature birth or retina neuropathy of glaucoma, which
comprises the administration to a patient of an effective amount of
a compound of the formula (I) depicted in claim 1, a non-toxic salt
thereof, a prodrug thereof or a cyclodextrin clathrate thereof.
Description
FIELD OF INVENTION
[0001] This invention is related to
.omega.-cycloalkyl-prostaglandin E.sub.2 derivatives. More
particularly, this invention is related to:
[0002] (1) .omega.-cycloalkyl-prostaglandin E.sub.2 derivatives of
the formula (I) 2
[0003] wherein all the symbols are the same meaning as hereafter
defined, non-toxic salt thereof, prodrug thereof and cyclodextrin
clathrate thereof.
BACKGROUND
[0004] Prostaglandin E.sub.2 (abbreviated as PGE.sub.2 hereafter)
has been known as metabolite in the arachidonate cascade. It has
been known that PGE.sub.2 has cyto-protective activity, uterine
contractile activity, a pain-inducing effect, a promoting effect of
digestive peristalsis, an awakening effect, a suppressive effect of
gastric acid secretion, hypotensive activity and diuretic activity
etc.
[0005] In a recent study, it was found that PGE.sub.2 receptor was
divided into some subtype which possess different physiological
roles from each other. At present four receptor subtype are known
and they are called as 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)).
[0006] The present inventors investigated to find new compounds
which bind on each receptor specifically, we found that the
compounds of the present invention could bind strongly on EP.sub.2
subtype receptor and achieved the present invention.
[0007] The compounds of the formula (I) of the present invention
possess a binding activity for EP.sub.2 subtype receptor strongly.
Therefore, they are useful for prevention and/or treatment of
immunologic diseases (autoimmune diseases, organ transplantation,
etc.), asthma, abnormal bone formation, neuronal cell death, liver
damage, abortion, premature birth or retina neuropathy of glaucoma
etc.
[0008] Among the compounds of the present invention of the formula
(I), compounds which bind weakly on receptor subtypes except for
EP.sub.2 and another arachidonic acid metabolism receptor
(thromboxane receptor, PGI.sub.2 receptor, etc.) do not exhibit
other effects and therefore, it is thought that such compounds will
be useful as medical agents which have less side-effects.
[0009] On the other hand, many patent applications of PG
derivatives are known. The following application is mentioned for
example.
[0010] In the specification of U.S. Pat. No. 4,132,738, a compound
of the formula (A) 3
[0011] wherein
[0012] R.sup.1A and R.sup.2A is hydrogen atom;
[0013] R.sup.3A is hydrogen atom, or together with R.sup.4A is a
methylene chain of 4 carbon atoms such that a cycloalkyl of 6
carbon atoms inclusive is formed, or together with R.sup.4A is a
bicycloalkenyl or bicycloalkyl moiety having the formula 4
[0014] (in which pA is an integer having a value of from 0 to 1 and
qA is an integer having a value of from 2 to 3 and wherein the
double bond of such bicycloalkenyl is in the qA bridge);
[0015] R.sup.4A together with R.sup.3A forms a cycloalkyl or
bicycloalkyl or bicycloalkenyl as defined above, or together with
R.sup.5A is a methylene chain of 3 carbon atoms such that a
cycloalkyl of 4 carbon atoms inclusive is formed;
[0016] R.sup.5A is hydrogen atom, or together with R.sup.4A forms a
cycloalkyl as defined above; and
[0017] R.sup.6A is hydrogen atom or straight-chain alkyl having
from 1 to 8 carbon atoms; are disclosed as having an inhibitory
activity on prostaglandin like.
DISCLOSURE OF THE INVENTION
[0018] The present invention is related to
[0019] (1) .omega.-cycloalkyl-prostaglandin E.sub.2 derivatives of
the formula (I) 5
[0020] wherein R is carboxy or hydroxymethyl;
[0021] R.sup.1 is oxo, methylene or halogen atom;
[0022] R.sup.2 is hydrogen atom, hydroxy or C1-4 alkoxy;
[0023] R.sup.3 is (i) hydrogen atom, (ii) C1-8 alkyl, (iii) C2-8
alkenyl, (iv) C2-8 alkynyl or (v)
[0024] C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl, each substituted
by 1-3 substituents, being same or different, selected from
(1)-(5);
[0025] (1) halogen atom,
[0026] (2) C1-4 alkoxy,
[0027] (3) C3-7 cycloalkyl,
[0028] (4) phenyl, or
[0029] (5) phenyl substituted by 1-3 substituents selected from
halogen atom, C1-4 alkyl, C1-4 alkoxy, nitro or
trifluoromethyl;
[0030] n is 0-4; 6
[0031] is single bond or double bond; 7
[0032] is double bond or triple bond; 8
[0033] is single bond, double bond or triple bond; with the proviso
that,
[0034] 1) when 5-6 position is triple bond, 13-14 position is not
triple bond,
[0035] 2) when 13-14 position is double bond represent E or Z form;
non-toxic salt thereof, prodrug thereof and cyclodextrin clathrate
thereof,
[0036] (2) processes for the preparation thereof, and
[0037] (3) pharmaceutical agents containing such a derivative as an
active ingredient.
[0038] In the present invention, prodrug means
[0039] 1) for compounds of formula (I) of the present invention,
those in which R represent COOR.sup.10 (in which R.sup.10 is C1-6
alkyl), i.e., the compounds of formula (IA) 9
[0040] wherein all symbols are the same meaning as hereinbefore
defined
[0041] 2) for compounds of formula (I) of the present invention,
those in which R represent CONR.sup.12R.sup.13 (in which R.sup.12
and R.sup.13 each, independently, is hydrogen atom or C1-6 alkyl),
i.e., the compounds of formula (IB) 10
[0042] wherein all symbols are the same meaning as hereinbefore
defined, or
[0043] 3) for compounds of formula (I) of the present invention,
those in which R represent COOR.sup.10 (in which R.sup.10 is the
same meaning as hereinbefore defined), R.sup.1 represent
R.sup.11--COO (in which R.sup.11 is C1-4 alkyl, C1-4 alkoxy,
phenyl, phenyl-C1-4 alkyl, R.sup.14--OOC-C1-4 alkyl or
R.sup.14--OOC-C2-4 alkenyl (in which R.sup.14 is hydrogen atom or
C1-4 alkyl) 8-9 position is double bond), i.e., the compounds of
formula (IC) 11
[0044] wherein all symbols are the same meaning as hereinbefore
defined.
[0045] In formula (I) or (IC), C1-4 alkyl represented by R.sup.3,
R.sup.11 and R.sup.14 means methyl, ethyl, propyl, butyl and :
isomers thereof.
[0046] In formula (I), (IA) or (IB), C1-6 alkyl represented by
R.sup.10, R.sup.12 and R.sup.13 means methyl, ethyl, propyl, butyl,
pentyl, hexyl and isomers thereof.
[0047] In formula (I), C1-8 alkyl represented by R.sup.3 means
methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and
isomers thereof.
[0048] In formula (I), C2-4 alkenyl represented by R.sup.11 means
vinyl, propenyl, butenyl and isomers thereof.
[0049] In formula (I), C2-8 alkenyl represented by R.sup.3 means
vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and
isomers thereof.
[0050] In formula (I), C2-8 alkenyl represented by R.sup.3 means
ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptenyl, octenyl
and isomers thereof.
[0051] In formula (I), or (IC), C1-4 alkoxy represented by R.sup.2,
R.sup.11 and R.sup.3 means methoxy, ethoxy, propoxy, butoxy and
isomers thereof.
[0052] In formula (I), C3-7 cycloalkyl represented by R.sup.3 means
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and
cycloheptyl.
[0053] In formula (i), a halogen atom represented by R.sup.1 and
R.sup.3 means fluorine, chlorine, bromine and iodine.
[0054] In the present invention, it may be easily understood by
those skilled in the art, unless otherwise specified, the symbol:
12
[0055] indicates that the substituent attached thereto is in front
of the sheet, unless otherwise specified, the symbol: 13
[0056] indicates that the substituent attached thereto is behind
the sheet, unless otherwise specified, the symbol: 14
[0057] indicates that the substituent attached thereto is a mixture
of in front of and behind the sheet or may be in front of or behind
the sheet.
[0058] Unless otherwise specified, all isomers are included in the
present invention. For example, the alkyl, alkenyl and alkynyl
groups include straight-chain and also branched-chain ones. The
double bond in alkenyl group include E, Z and EZ mixture ones.
Isomers generated by the existence of asymmetric carbon atom(s)
e.g. in are included in branched-chain alkyl are included in the
present invention.
[0059] Preferred compounds of the present invention of the formula
(I) are listed in examples, Table 1-14 or prodrug thereof.
1TABLE 1 (Ia) 15 No. n R.sup.3 1 0 16 2 0 17 3 0 18 4 0 19 5 0 20 6
0 21 7 0 22 8 0 23 9 0 24 10 0 25 11 1 26 12 1 27 13 1 28 14 1 29
15 1 30 16 1 31 17 1 32 18 1 33 19 1 34 20 1 35
[0060]
2TABLE 2 (Ib) 36 No. n R.sup.3 1 0 37 2 0 38 3 0 39 4 0 40 5 0 41 6
0 42 7 0 43 8 0 44 9 0 45 10 0 46 11 1 47 12 1 48 13 1 49 14 1 50
15 1 51 16 1 52 17 1 53 18 1 54 19 1 55 20 1 56
[0061]
3TABLE 3 (Ic) 57 No. n R.sup.3 1 0 58 2 0 59 3 0 60 4 0 61 5 0 62 6
0 63 7 0 64 8 0 65 9 0 66 10 0 67 11 1 68 12 1 69 13 1 70 14 1 71
15 1 72 16 1 73 17 1 74 18 1 75 19 1 76 20 1 77
[0062]
4TABLE 4 (Id) 78 No. n R.sup.3 1 0 79 2 0 80 3 0 81 4 0 82 5 0 83 6
0 84 7 0 85 8 0 86 9 0 87 10 0 88 11 1 89 12 1 90 13 1 91 14 1 92
15 1 93 16 1 94 17 1 95 18 1 96 19 1 97 20 1 98
[0063]
5TABLE 5 (Ie) 99 No. n R.sup.3 1 0 100 2 0 101 3 0 102 4 0 103 5 0
104 6 0 105 7 0 106 8 0 107 9 0 108 10 0 109 11 1 110 12 1 111 13 1
112 14 1 113 15 1 114 16 1 115 17 1 116 18 1 117 19 1 118 20 1
119
[0064]
6TABLE 6 (If) 120 No. n R.sup.3 1 0 121 2 0 122 3 0 123 4 0 124 5 0
125 6 0 126 7 0 127 8 0 128 9 0 129 10 0 130 11 1 131 12 1 132 13 1
133 14 1 134 15 1 135 16 1 136 17 1 137 18 1 138 19 1 139 20 1
140
[0065]
7TABLE 7 (Ig) 141 No. n R.sup.3 1 0 142 2 0 143 3 0 144 4 0 145 5 0
146 6 0 147 7 0 148 8 0 149 9 0 150 10 0 151 11 1 152 12 1 153 13 1
154 14 1 155 15 1 156 16 1 157 17 1 158 18 1 159 19 1 160 20 1
161
[0066]
8TABLE 8 (Ih) 162 No. n R.sup.3 1 0 163 2 0 164 3 0 165 4 0 166 5 0
167 6 0 168 7 0 169 8 0 170 9 0 171 10 0 172 11 1 173 12 1 174 13 1
175 14 1 176 15 1 177 16 1 178 17 1 179 18 1 180 19 1 181 20 1
182
[0067]
9TABLE 9 (Ii) 183 No. n R.sup.3 1 0 184 2 0 185 3 0 186 4 0 187 5 0
188 6 0 189 7 0 190 8 0 191 9 0 192 10 0 193 11 1 194 12 1 195 13 1
196 14 1 197 15 1 198 16 1 199 17 1 200 18 1 201 19 1 202 20 1
203
[0068]
10TABLE 10 (Ij) 204 No. n R.sup.3 1 0 205 2 0 206 3 0 207 4 0 208 5
0 209 6 0 210 7 0 211 8 0 212 9 0 213 10 0 214 11 1 215 12 1 216 13
1 217 14 1 218 15 1 219 16 1 220 17 1 221 18 1 222 19 1 223 20 1
224
[0069]
11TABLE 11 (Ik) 225 No. n R.sup.3 No. n R.sup.3 1 0 226 11 1 227 2
0 228 12 1 229 3 0 230 13 1 231 4 0 232 14 1 233 5 0 234 15 1 235 6
0 236 16 1 237 7 0 238 17 1 239 8 0 240 18 1 241 9 0 242 19 1 243
10 0 244 20 1 245
[0070]
12TABLE 12 (Il) 246 No. n R.sup.3 No. n R.sup.3 1 0 247 11 1 248 2
0 249 12 1 250 3 0 251 13 1 252 4 0 253 14 1 254 5 0 255 15 1 256 6
0 257 16 1 258 7 0 259 17 1 260 8 0 261 18 1 262 9 0 263 19 1 264
10 0 265 20 1 266
[0071]
13TABLE 13 (Im) 267 No. n R.sup.3 No. n R.sup.3 1 0 268 11 1 269 2
0 270 12 1 271 3 0 272 13 1 273 4 0 274 14 1 275 5 0 276 15 1 277 6
0 278 16 1 279 7 0 280 17 1 281 8 0 282 18 1 283 9 0 284 19 1 285
10 0 286 20 1 287
[0072]
14TABLE 14 (In) 288 No. n R.sup.3 No. n R.sup.3 1 0 289 11 1 290 2
0 291 12 1 292 3 0 293 13 1 294 4 0 295 14 1 296 5 0 297 15 1 298 6
0 299 16 1 300 7 0 301 17 1 302 8 0 303 18 1 304 9 0 305 19 1 306
10 0 307 20 1 308
Salts
[0073] The compounds of formula(I) of the present invention may be
converted into a corresponding non-toxic salt by methods known per
se. Non toxic and water-soluble salts are preferable. Suitable
salts, for example, are salts of an alkaline metal (potassium,
sodium, etc.), salts of an alkaline earth metal (calcium,
magnesium, etc.), ammonium salts and salts of
pharmaceutically-acceptable organic amines (tetramethylammonium,
triethylamine, methylamine, dimethylamine, cyclopentylamine,
benzylamine, phenethylamine, piperidine, monoethanolamine,
diethanolamine, tris(hydroxymethyl)methylamine, lysine, arginine,
N-methyl-D-glucamine, etc.).
Cyclodextrin Clathrates
[0074] Cyclodextrin clathrates of .omega.-cycloalkyl-prostaglandin
E.sub.2 derivatives of the formula (I) may be prepared by the
method described in the specification of GB 1351238, which is
herein incorporated by reference, using .alpha.-, .beta.- or
.gamma.-cyclodextrins or a mixture thereof. Converting into their
cyclodextrin clathrates serves to increase the stability and
solubility in water of the compounds, and is therefore, useful in
the use of pharmaceuticals.
Process for the Preparation
[0075] 1) For compounds of formula (I) of the present invention,
those in which R is carboxy, i.e., the compounds of formula (I-1)
309
[0076] wherein all the symbols are the same meaning hereinbefore
defined may be prepared by hydrolysis using enzyme or hydrolysis in
an alkaline condition of a compound of formula (IA) 310
[0077] wherein all the symbols are the same meaning hereinbefore
defined.
[0078] The hydrolysis using enzyme is known. For example,
hydrolysis may be carried out in the mixture of a water-miscible
organic solvent (ethanol, dimethylsulfoxide etc.) and water, in the
presence or absence of buffer, using an ester cleaving enzyme
(esterase, lipase etc.), at a temperature of from 0.degree. C. to
50.degree. C.
[0079] The hydrolysis in an alkaline condition is known. For
example, hydrolysis may be carried out in a water-miscible organic
solvent (ethanol, tetrahydrofuran, dioxan etc.), using aqueous
solution of an alkali (sodium hydroxide, potassium hydroxide,
potassium carbonate etc.), at a temperature of from -10 to
90.degree. C.
[0080] 2) For compounds of formula (I) of the present invention,
those in which R is hydroxymethyl, i.e., in the compounds of
formula (I-2), 311
[0081] wherein all the symbols are the same meaning as hereinbefore
defined;
[0082] those in which R.sup.1 is oxo, i.e., the compounds of
formula (I-2A) 312
[0083] wherein all the symbols are the same meaning as hereinbefore
defined;
[0084] may be prepared by subjecting to elimination of the
protecting group in an acidic condition of a compound of formula
(IIA) 313
[0085] wherein R.sup.20 is hydrogen atom, hydroxy protecting group
to elimination in an acidic condition or C1-4 alkoxy, R.sup.40 is
hydroxy protecting group to remove in an acid condition, the other
symbols are the same meaning as herein before defined.
[0086] The hydroxy protecting group to elimination in an acidic
condition include, for example, t-butyldimethylsilyl,
triphenylmethyl, tetrahydropyran-2-yl etc.
[0087] The hydrolysis in an acidic condition is known. For example,
hydrolysis may be carried out in a water-miscible organic solvent
(tetrahydrofuran, methanol, ethanol, dimethoxyethane, acetonitrile
or mixture thereof etc.), using an inorganic acid (hydrochloric
acid, phosphoric acid, hydrofluoric acid or hydrogen
fluoride-pyridine etc.), or organic acid (acetic acid,
p-toluenesulfonic acid, trichloroacetic acid, etc.) at a
temperature of from 0 to 50.degree. C.
[0088] 3) For compounds of formula (I) of the present invention,
those in which R is hydroxymethyl, i.e., in the compounds of
formula (I-2), 314
[0089] wherein all the symbols are the same meaning as hereinbefore
defined; those in which R.sup.1 is methylene, i.e., the compounds
of formula (I-2B) 315
[0090] wherein all the symbols are the same meaning as hereinbefore
defined;
[0091] may be prepared by subjecting reduction of a compound of
formula (IA-4) 316
[0092] wherein all the symbols are the same meaning as hereinbefore
defined.
[0093] The reduction is known. For example, reduction may be
carried out in an inert organic solvent (tetrahydrofuran (THF),
hexane, toluene, etc.), using diisobutylaluminum hydride at a
temperature of from -80 to 0.degree. C.
[0094] 4) For compounds of formula (I) of the present invention,
those in which R is hydroxymethyl, i.e., in the compounds of
formula (I-2), 317
[0095] wherein all the symbols are the same meaning as hereinbefore
defined; those in which R.sup.1 is halogen atom, i.e., the
compounds of formula (I-2C) 318
[0096] wherein R.sup.15 is halogen atom, the other symbols are the
same meaning as hereinbefore defined;
[0097] may be prepared by subjecting reduction of a compound of
formula (IA-5) 319
[0098] wherein all the symbols are the same meaning as hereinbefore
defined.
[0099] The reduction may be carried out by the same method as
hereinbefore described.
[0100] 5) For prodrug compounds of formula (IA) of the present
invention, those in which R.sup.2 is hydrogen atom or hydroxy,
i.e., the compounds of formula (IA-1 ) 320
[0101] wherein R.sup.22 is hydrogen atom or hydroxy, the other
symbols are the same meaning as hereinbefore defined;
[0102] may be prepared by subjecting hydrolysis in an acidic
condition of a compound of formula (III) 321
[0103] wherein R.sup.21 is hydrogen atom or hydroxy protecting
group to elimination in an acid condition, the other symbols are
the same meaning as hereinbefore defined.
[0104] The hydrolysis in an acidic condition may be carried out by
the same method as hereinbefore described.
[0105] 6) For prodrug compounds of formula (IA) of the present
invention, those in which R.sup.2 is C1-4 alkoxy, i.e., the
compounds of formula (IA-2) 322
[0106] wherein R.sup.23 is C1-4 alkoxy, the other symbols are the
same meaning as hereinbefore defined;
[0107] may be prepared by subjecting O-alkylation of the compounds
of the formula (IA-1) those in which R.sup.22 is hydroxy, i.e., a
compound of formula (IA-3) 323
[0108] wherein all the symbols are the same meaning as hereinbefore
defined.
[0109] O-alkylation is known. For example, O-alkylation may be
carried out in an inert organic solvent (THF, diethyl ether, etc.),
using diazoalkane at a temperature of from -30 to 40.degree. C. or
in an inert organic solvent (acetonitrile, etc.), in the presence
of silver oxide, using alkyl iodide at a temperature of from 0 to
40.degree. C.
[0110] 7) The prodrug compounds of formula (IB) of the present
invention may be prepared by subjecting amidation of the compounds
of the formula (I-1) 324
[0111] wherein all the symbols are the same meaning as hereinbefore
defined; with the compounds of the formula (IV) 325
[0112] wherein all the symbols are the same meaning as hereinbefore
defined.
[0113] Amidation is known. For example, amidation may be carried
out in an inert organic solvent (THF, dichloromethane, benzene,
acetone, acetonitrile or mixture thereof etc.), in the presence or
absence of tertiary amine(dimethylaminopyridine, pyridine,
triethylamine, etc.), using condensing agent
(1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)
propyl]carbodiimide (EDC), etc.) at a temperature of from 0 to
50.degree. C.
[0114] 8) The prodrug compounds of formula (IC) of the present
invention may be prepared by subjecting hydrolysis in an acidic
condition of the compounds of the formula (V) 326
[0115] wherein all the symbols are the same meaning as hereinbefore
defined.
[0116] The hydrolysis in an acidic condition may be carried out by
the same method as hereinbefore described.
[0117] The compound of the formula (IIA) may be prepared by
according to the reaction of the following Scheme (J).
[0118] The compound of the formula (V) may be prepared by according
to the reaction of the following Scheme (K).
[0119] The compound of the formula (III) may be separated according
to the type of R.sup.1 and R.sup.21 into the following six types of
compounds. That is,
[0120] 1) R.sup.1 is oxo, R.sup.21 is hydroxy protecting group to
elimination in an acidic condition, i.e., the compound of formula
(IIIA) 327
[0121] wherein R.sup.24 is hydroxy protecting group to elimination
in an acidic condition, the other symbols are the same meaning as
hereinbefore defined,
[0122] 2) R.sup.1 is methylene, R.sup.21 is hydroxy protecting
group to elimination in an acidic condition, i.e., the compound of
formula (IIIB) 328
[0123] wherein all symbols are the same meaning as hereinbefore
defined,
[0124] 3) R.sup.1 is halogen atom, R.sup.24 is hydroxy protecting
group to elimination in an acidic condition, i.e., the compound of
formula (IIIC) 329
[0125] wherein R.sup.15 is halogen atom, the other symbols are the
same meaning as hereinbefore defined,
[0126] 4) R.sup.1 is oxo, R.sup.21 is hydrogen atom, i.e., the
compound of formula (IIID) 330
[0127] wherein all symbols are the same meaning as hereinbefore
defined,
[0128] 5) R.sup.1 is methylene, R.sup.21 is hydrogen atom, i.e.,
the compound of formula (IIIE) 331
[0129] wherein all symbols are the same meaning as hereinbefore
defined,
[0130] 6) R.sup.1 is halogen atom, R.sup.21 is hydrogen atom, i.e.,
the compound of formula (IIIF) 332
[0131] wherein all symbols are the same meaning as hereinbefore
defined.
[0132] The compound of the formula (IIIB) may be prepared from the
compound of the formula (IIIA) according to the reaction of the
following Scheme (A).
[0133] The compound of the formula (IIIC) may be prepared from the
compound of the formula (IIIA) according to the reaction of the
following Scheme (B), (C) or (D).
[0134] The compound of the formula (IIID) may be prepared from the
compound of the formula (IIIA) according to the reaction of the
following Scheme (E).
[0135] The compound of the formula (IIIE) may be prepared from the
compound of the formula (IIID) according to the same reaction of
the following Scheme (A).
[0136] The compound of the formula (IIIF) may be prepared from the
compound of the formula (IIID) according to the same reaction of
the following Scheme (B), (C) or (D).
[0137] The compound of the formula (IIIA) may be prepared by
according to the reaction of the following Scheme (F), (G) or
(H).
[0138] In the Scheme, the symbols represent meanings as follow, or
the same meaning as hereinbefore described.
[0139] Ts is p-toluenesulfonyl;
[0140] Ac is acetyl;
[0141] Ph is phenyl;
[0142] AIBN is 2,2'-azobisisobutylonitrile;
[0143] DIBAL is diisobutylaluminum hydride;
[0144] t-Bu is t-butyl;
[0145] n-Bu is normal butyl;
[0146] c-Hex is cyclohexyl;
[0147] Et is ethyl;
[0148] EE is ethoxyethyl;
[0149] D-(-)-DIPT is D-(-)-diisopropyl tartarate;
[0150] L-(+)-DIPT is L-(+)-diisopropyl tartarate;
[0151] Ti(OiPr).sub.4 is titanium (IV) isopropoxide;
[0152] TBHP is t-butylhydroperoxide;
[0153] Cp.sub.2ZrClH is bis(cyclopentadienyl)zirconium chloride
hydride. 333 334335 336337 338339 340 341 342343 344 345 346 347
348 349
[0154] Each reaction of hereinbefore described reaction Scheme may
be carried out known methods. In the reaction Scheme, The compound
of formula (VI) , (VIII) , (X), (XII), (XIII) , (XI) and (XVI) as
starting materials are known per se or may be prepared by known
methods.
[0155] For example, in the compound of formula (VI),
(4RS)-5,5-propanooct-1-yn-4-ol is known compound described in the
specification of U.S. Pat. No. 4,132,738.
[0156] In the compound of formula (VIII),
(5Z)-7-((3R)-3-t-butyldimethylsi-
lyloxy-5-oxocyclopent-1-ene)hept-5-enoic acid methylester and in
the compound of formula (X),
(4R)-2-(diethylaminomethyl)-4-t-butyldimethylsil-
yloxy-2-cyclopenten-1-one is known compound described in the
literature of J. Org. Chem., 53, 5590-5592 (1988).
[0157] In the compound of formula (XII),
(4R)-4-t-butyldimethylsilyloxy-2-- cyclopenten-1-one and in the
compound of formula (XIII), 7-iodohept-5-ynoic acid methylester is
known compound described in the literature of J. Am. Chem. Soc.,
110, No. 14, 4718-4726 (1988).
[0158] The compound of formula (XI) is known compound described in
the literature of J. Am. Chem. Soc., 97, 4745-4746 (1975).
[0159] The starting materials and reagents in the present invention
are known per se or may be prepared by known methods.
[0160] In each reaction in the present specification, obtained
products may be purified by conventional techniques. For example,
purification may be carried out by distillation at atmospheric or
reduced pressure, by high performance liquid chromatography, by
thin layer chromatography or by column chromatography using silica
gel or magnesium silicate, by washing or by recrystallization.
Purification may be carried out after each reaction, or after a
series of reactions.
Pharmacological Activities
[0161] The compounds of the present invention of the formula (I)
bind and act on EP.sub.2 receptor which is a subtype of of
PGE.sub.2 receptor.
[0162] For example, in standard laboratory test, the effects of the
compounds of the present invention were confirmed by binding assay
using expression cell of prostanoide receptor subtype.
Binding Assay Using Expression Cell of Prostanoide Receptor
Subtype
[0163] The preparation of membrane fraction was carried out
according to the method of Sugimoto et. al. [J. Biol. Chem. 267,
6463-6466 (1992)], using expression CHO cell of the prostanoide
receptor subtype (mouse EP.sub.1, EP.sub.2, EP.sub.3.alpha.,
EP.sub.4).
[0164] The standard assay mixture contained membrane fraction (0.5
mg/ml), and [.sup.3H]-PGE.sub.2 in a final volume of 200 .mu.l was
incubated for 1 hour at room temperature. The reaction was
terminated by the addition of 3 ml of ice-cold buffer. The mixture
was rapidly filtered through a GF/B glass filter. The radioactivity
associated with the filter was measured by liquid scintillation
counting.
[0165] Kd and Bmax values were determined from Scatchard plots
[Ann. N.Y. Acad. Sci., 51, 660 (1949)]. Non-specific binding was
calculated as the bound in the presence of an excess (2.5 .mu.M) of
unlabeled PGE.sub.2. In the experiment for competition of specific
.sup.3H-PGE2 binding by the compounds of the present invention, 2.5
nM of .sup.3H-PGE2 and various concentrations of compounds of the
present invention were added. The following buffer was used in all
reactions.
[0166] Buffer: 10 mM potassium phosphate (pH 6.0), 1 mM EDTA, 10 mM
MgCl.sub.2, 0.1 M NaCl
[0167] In the example compounds, all of values were shown the more
polar compounds.
[0168] The dissociation constant (Ki) of each compound was
calculated by the following equation.
Ki=IC.sub.50/(1+([C]/Kd))
[0169] The results were shown in Table 15.
15 TABLE 15 Ki (.mu.M) Example No. EP.sub.1 EP.sub.2
EP.sub.3.alpha. EP.sub.4 4 >10 0.092 >10 >10 4(5) >10
0.032 >10 >10 4(10) >10 0.030 >10 >10 6(1) >10
0.036 >10 >10 6(5) >10 0.076 >10 >10 10 >10 0.034
>10 >10 12 >10 0.37 >10 >10 16(1) >10 0.096
>10 >10 17(2) 1.10 0.0009 2.70 0.40
Toxicity
[0170] The toxicity of the compounds of the present invention are
very low and therefore, it is confirmed that these compounds are
safe for pharmaceutical use.
Application for Pharmaceuticals
[0171] The compounds of the present invention of the formula (I)
bind strongly and act on PGE.sub.2 receptor, especially on EP.sub.2
subtype receptor and therefore are useful for prevention and/or
treatment of immunologic diseases (autoimmune diseases, organ
transplantation, etc.), asthma, abnormal bone formation, neuronal
cell death, liver damage, abortion, premature birth or retina
neuropathy of glaucoma etc.
[0172] Among the compounds of the present invention of the formula
(I), compounds which bind weakly on to receptor subtypes except for
EP.sub.2 receptors and another arachidonic acid metabolism
receptors (thromboxane receptor, PGI.sub.2 receptor, etc.) do not
express other effects and therefore it is thought that such
compounds will be a medical agent which have less side-effects.
[0173] For the purpose above described, the compounds of the
formula (I), (IA), (IB) and (IC), prodrug thereof, non-toxic salts
thereof and cyclodextrin clathrate thereof may be normally
administered systematically or partially, usually by oral or
parenteral administration. To convert prodrug, they have merit of
non-stimulant, good-absorbability, good-solubility, etc.
[0174] The doses to be administered are determined depending upon
age, body weight, symptom, the desired therapeutic effect, the
route of administration, and the duration of the treatment etc. In
the human adult, the doses per person per dose are generally
between 1 .mu.g and 100 mg, by oral administration, up to several
times per day, and between 0.1 .mu.g and 10 mg, by parenteral
administration (preferred into vein) up to several times per day,
or continuous administration between 1 and 24 hrs. per day into
vein.
[0175] As mentioned above, the doses to be used depend upon various
conditions. Therefore, there are cases in which doses lower than or
greater than the ranges specified above may be used.
[0176] When administering the compounds of the present invention,
it is used as solid compositions, liquid compositions or other
compositions for oral administration, as injections, liniments or
suppositories etc. for parenteral administration.
[0177] Solid compositions for oral administration include
compressed tablets, pills, capsules, dispersible powders, and
granules.
[0178] Capsules contain hard capsules and soft capsules.
[0179] In such compositions, one or more of the active compound(s)
is or are, admixed with at least one inert diluent such as lactose,
mannitol, mannit, glucose, hydroxypropyl cellulose,
microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium
metasilicate aluminate. The compositions may also comprise, as is
normal practice, additional substances other than inert diluents:
e.g. lubricating agents such as magnesium stearate, disintegrating
agents such as cellulose calcium glycolate, and assisting agents
for dissolving such as glutamic acid, asparaginic acid. The tablets
or pills may, if desired, be coated with film of gastric or enteric
material such as sugar, gelatin, hydroxypropyl cellulose or
hydroxypropyl cellulose phthalate etc., or be coated with two or
more films. And further, coating may include containment within
capsules of absorbable materials such as gelatin.
[0180] Liquid compositions for oral administration include
pharmaceutically-acceptable emulsions, solutions, syrups and
elixirs etc. In such liquid compositions, one or more of the active
compound(s) is or are comprised in inert diluent(s) commonly used
in the art (for example, purified water, ethanol etc.). Besides
inert diluents, such compositions may also comprise adjuvants such
as wetting agents, suspending agents, sweetening agents, flavouring
agents, perfuming agents and preserving agents.
[0181] Other compositions for oral administration include spray
compositions which may be prepared by known methods and which
comprise one or more of the active compound(s). Spray compositions
may comprise additional substances other than inert diluents: e.g.
stabilizing agents such as sodium hydrogen sulfate, stabilizing
agents to give isotonicity, isotonic buffer such as sodium
chloride, sodium citrate, citric acid. For preparation of such
spray compositions, for example, the method described in the U.S.
Pat. Nos. 2,868,691 or 3,095,355 may be used.
[0182] Injections for parenteral administration include sterile
aqueous or non-aqueous solutions, suspensions and emulsions.
Aqueous solutions or suspensions include distilled water for
injection and physiological salt solution. Non-aqueous solutions or
suspensions include propylene glycol, polyethylene glycol, plant
oil such as olive oil, alcohol such as ethanol, POLYSOLBATE80
(registered trade mark) etc. Such compositions may comprise
additional diluents: e.g. preserving agents, wetting agents,
emulsifying agents, dispersing agents, stabilizing agent, assisting
agents such as assisting agents for dissolving (for example,
glutamic acid, asparaginic acid). They may be sterilized for
example, by filtration through a bacteria-retaining filter, by
incorporation of sterilizing agents in the compositions or by
irradiation. They may also be manufactured in the form of sterile
solid compositions and which can be dissolved in sterile water or
some other sterile diluents for injection immediately before
used.
[0183] Other compositions for parenteral administration include
liquids for external use, and endemic liniments, ointment,
suppositories and pessaries which comprise one or more of the
active compound(s) and may be prepared by know methods.
REFERENCE EXAMPLES AND EXAMPLES
[0184] The following reference examples and examples are intended
to illustrate, but not limit, the present invention. The solvents
in parentheses show the developing or eluting solvents and the
ratios of the solvents used are by volume in chromatographic
separations. NMR in the parentheses show measured solvents. In the
example, TBS is t-butyldimethylsilyl, THP is tetrahydropyranyl, Ac
is acetyl, EE is ethoxyethyl.
Reference Example 1
(4RS)-4-t-butyldimethylsilyloxy-5,5-propanoocta-1-yne
[0185] 350
[0186] To the mixture solution of (4RS)-5,5-propanoocta-1-yne-4-ol
(4.0 g) and imidazole (4.9 g) in dimethylformamide (50 ml) was
added t-butyldimethylsilylchloride (5.4 g) under cooling with ice.
The reaction mixture was stirred at 60.degree. C. for 7 hours. The
reaction mixture was quenched by addition of water, extracted with
ethyl acetate. The extract was washed with a saturated aqueous
solution of sodium chloride, dried over anhydrous magnesium sulfate
and concentrated. The residue was purified by column chromatography
on silica gel (hexane.fwdarw.hexane : ethyl acetate=10:1) to give
the title compound (6.8 g) having the following physical data.
[0187] TLC: Rf 0.64 (hexane); NMR (CDCl.sub.3): .delta.3.75 (1H, t,
J=5.8 Hz), 2.28 (1H, ddd, J=17, 5.0, 2.5 Hz), 2.16 (1H, ddd, J=17,
6.0, 2.5 Hz), 2.10-1.94 (1H, m), 1.92 (1H, t, J=2.5H 1.90-1.20 (9H,
m), 0.90 (3H, t, J=6.0 Hz), 0.89 (9H, s), 0.12 (3H, s), 0.07 (3H,
s).
Reference Example 2
(1E,4RS)-1-iodo-4-t-butyldimethylsilyloxy-5,5-propanoocta-1-ene
[0188] 351
[0189] To the mixture of the compound prepared in reference example
1 (3.0 g) and tributyltinhydride (3.7 ml) was added
azobisisobutylonitrile (35 mg). The mixture was stirred at
80.degree. C. for 1.5 hours. After the mixture was cooled to room
temperature, to the mixture was added dropwise iodine (4.1 g) in
dichloromethane (70 ml). The reaction mixture was stirred for 10
min. To the reaction mixture was added a saturated aqueous solution
of sodium thiosulfate, ethyl acetate and a saturated aqueous
solution of sodium chloride, stirred, filtered , and extracted. The
water layer was extracted with ethyl acetate. The organic layer was
washed with a saturated aqueous solution of sodium chloride, dried
over anhydrous magnesium sulfate and concentrated. The residue was
purified by column chromatography on silica gel (hexane) to give
the tittle compound (3.9 g) having the following physical data.
[0190] TLC: Rf 0.77 (hexane); NMR (CDCl.sub.3): .delta.6.49 (1H,
dt, J=14.5, 7.5 Hz), 5.97 (1H, d, J=14.5 Hz), 3.58 (1H, t, J=6.0
Hz), 2.20-1.20 (12H, m), 0.91 (3H, t, J=6.0 Hz), 0.91 (9H, s), 0.06
(3H, s), 0.05 (3H, s).
Reference Example 3
(5Z, 11.alpha.,
13E,16RS)-11,16-bis(t-butyldimethylsilyloxy)-9-oxo-17,17-p-
ropanoprosta-5,13-dienoic acid.cndot.methylester
[0191] 352
[0192] To a solution of
(1E,4RS)-1-iodo-4-t-butyldimethylsilyloxy-5,5-prop- anoocta-1-ene
(368 mg) in ether (6 ml) was added dropwise 1.7 M t-butyllithium in
pentane solution (1.06 ml) at -78.degree. C. After the mixture was
stirred for 45 min, to the mixture was added 0.25 M lithium
2-thienylcyanocuprate in tetrahydrofuran (4.33 ml). After the
mixture was stirred for 20 min at same temperature, to the mixture
was added dropwise a solution of
(5Z)-7-((3R)-3-t-butyldimethylsilyloxy-5-oxocyclopenta-1-en-
e)hepta-5-enoic acid.cndot.methylester (290 mg) in ether (4 ml).
The reaction mixture was warmed up to 0.degree. C. for 1 hour. The
reaction mixture was quenched by addition of a saturated aqueous
solution of sodium ammonium, extracted with ethyl acetate. The
extract was washed with a saturated aqueous solution of ammonium
chloride and a saturated aqueous solution of sodium chloride,
successively, dried overanhydrous magnesium sulfate and
concentrated. The residue was purified by column chromatography on
silica gel (hexane : ethyl acetate=25:1) to give the tittle
compound (332 mg) having the following physical data.
[0193] TLC: Rf 0.37 (hexane:ethyl acetate=10:1); NMR (CDCl.sub.3):
.delta.5.75-5.45 (1H, m), 5.45-5.20 (3H, m), 4.01 (1H, q, J=7.0
Hz), 3.66 (3H, s), 3.57 (1H, t, J=4.5 Hz), 2.60 (1H, dd, J=17.5,
6.5 Hz), 2.54-2.24 (3H, m), 2.30 (2H, t, J=7.0 Hz), 2.24-1.96 (6H,
m), 1.96-1.20 (12H, m), 0.95 (3H, m), 0.91 (9H, s), 0.88 (9H, s),
0.06 (3H, s), 0.05 (3H, s), 0.04 (3H, s), 0.03 (3H, s).
Reference Example 4
(4RS)-4-t-butyldimethylsilyloxy-5,5-propanoocta-1-ene
[0194] 353
[0195] To a solution of the compound prepared in reference example
2 (629 mg) in anhydrous ether (10 ml) was added dropwise 1.57 M
t-butyllithium in pentane solution (1.96 ml) at -78.degree. C. The
reaction mixture was stirred for 1 hour. The reaction mixture was
quenched by addition of a saturated aqueous solution of ammonium
chloride (20 ml), extracted with hexane (.times.2). The extract was
washed with a saturated aqueous solution of sodium chloride, dried
over anhydrous magnesium sulfate and concentrated. The residue was
purified by column chromatography on silica gel (hexane) to give
the tittle compound (434 mg) having the following physical
data.
[0196] TLC: Rf 0.75 (hexane); NMR (CDCl.sub.3): .delta.5.83 (1H,
ddt, J=17, 9.8, 7.4 Hz), 5.06-4.92 (2H, m), 3.59 (1H, dd, J=6.0,
4.6 Hz), 2.20-2.00 (2H, m), 2.00-1.20 (10H, m), 0.90 (3H, t, J=5.0
Hz), 0.83 (9H, s), 0.03 (6H, s).
Reference Example 5
(4RS)-4-t-butyldimethylsilyloxy-5,5-propanooctan-1-ol
[0197] 354
[0198] To a borane-tetrahydrofuran complex (2.3 ml, 1.0 M
tetrahydrofuran solution) was added dropwise cyclohexene (468
.mu.l) at 0.degree. C. under an atmosphere of argon. The mixture
was stirred for 1.5 hours. To the mixture was added dropwise a
solution of the compound prepared in reference example 4 (434 mg)
in tetrahydrofuran (10 ml) at 0.degree. C. The reaction mixture was
stirred for 30 min at same temperature, and stirred for 30 min at
room temperature. To the reaction was added 1N aqueous solution of
sodium hydroxide and 31% aqueous solution of hydroperoxide (3 ml).
The mixture was stirred at room temperature for 30 min. The
reaction mixture was quenched by addition of a saturated aqueous
solution of sodium thiosulfate (5 ml), extracted with ether. The
extract was washed with a saturated aqueous solution of sodium
thiosulfate and a saturated aqueous solution of sodium chloride,
successively, dried over anhydrous magnesium sulfate and
concentrated. The residue was purified by column chromatography on
silica gel (hexane.fwdarw.ethyl acetate) to give the tittle
compound (439 mg) having the following physical data.
[0199] TLC: Rf 0.52 (hexane:ethyl acetate=4:1); NMR (CDCl.sub.3):
.delta.3.61 (2H, t, J=6.2 Hz), 3.55 (1H, t, J=4.6 Hz), 2.18-1.20
(14H, m), 0.95-0.85 (12H, m), 0.05 (6H, s).
Reference Example 6
(4RS)-4-t-butyldimethylsilyloxy-1-iodo-5,5-propanooctane
[0200] 355
[0201] To a solution of the compound prepared in reference example
5 (430 mg) in anhydrous benzene (10 ml) was successively added
imidazole (243 mg), triphenylphosphine (936 mg) and iodine (726
mg). The reaction mixture was stirred for 15 min. The reaction
mixture was quenched by addition of a saturated aqueous solution of
sodium thiosulfate, extracted with benzene (.times.2). The extract
was washed with a saturated aqueous solution of sodium chloride
(.times.2), dried over anhydrous magnesium sulfate and
concentrated. The residue was purified by column chromatography on
silica gel (hexane) to give the tittle compound (553 mg) having the
following physical data.
[0202] TLC: Rf 0.63 (hexane); NMR (CDCl.sub.3): .delta.3.54 (1H, t,
J=5.0 Hz), 3.16 (2H, t, J=6.8 Hz), 2.17-1.22 (14H, m), 0.95-0.85
(12H, m), 0.09 (3H, s).
Reference Example 7
(3R,4R)-4-t-butyldimethylsilyloxy-2-methyliden-3-((4RS)-4-t-butyldimethyls-
ilyloxy-5,5-propanoocta-1-yne-1-yl)cyclopentanone
[0203] 356
[0204] To a solution of
(4RS)-t-butyldimethylsilyloxy-5,5-propanoocta-1-yn- e (730 mg) in
toluene (5 ml) was added dropwise 1.6 M n-butyllithium in hexane
solution (1.6 ml). After the mixture was stirred for 30 min, to the
mixture was added dropwise 0.95 M diethylaluminum chloride in
hexane solution (2.95 ml). After the mixture was stirred for 30
min, to the mixture was added dropwise a solution of
(4R)-2-(diethylaminomethyl)-4-t--
butyldimethylsilyloxy-2-cyclopenten-1-one (595 mg) in toluene (8
ml). The reaction mixture was stirred at room temperature for 15
min. The reaction mixture was quenched by addition of a saturated
aqueous solution of ammonium chloride and 2N aqueous solution of
hydrochloric acid, extracted with hexane. the extract was washed
with a saturated aqueous solution of sodium hydrogencarbonate,
dried over anhydrous magnesium sulfate and concentrated. The
residue was purified by column chromatography on silica gel (hexane
ethyl acetate=100:1) to give the tittle compound (364 mg) having
the following physical data.
[0205] TLC: Rf 0.77(hexane:ethyl acetate=10:1); NMR (CDCl.sub.3):
.delta.6.12 (1H, d, J=3.0 Hz), 5.53 (1H, d, J=3.0 Hz), 4.25 (1H,
m), 3.71 (1H, t, J=5.3 Hz), 3.50-3.40 (1H, m), 2.70 (1H, dd,
J=18.0, 6.4 Hz), 2.40-1.20 (13H, m), 0.95-0.82 (21H, m), 0.18-0.02
(12H, m).
Reference Example 8
(2R, 3R,
4R)-4-t-butyldimethylsilyloxy-2-((2Z)-7-(1-ethoxyethoxy)-hepta-2--
en-1-yl)-3-((4RS)-4-t-butyldimethylsilyloxy-5,5-propanoocta-1-yne-1-yl)
cyclopentanone
[0206] 357
[0207] To a solution of (1Z)-1-iodo-6-(1-ethoxyethoxy)hexa-1-ene
(537 mg) in ether (5 ml) was added dropwise 1.57 M t-butyllithium
in pentane solution (2.30 ml) at -78.degree. C. After the mixture
was stirred for 1.5 hours, to the mixture was added 0.25 M lithium
2-thienylcyanocuprate in tetrahydrofuran (8.00 ml). After the
mixture was stirred for 30 min at same temperature, to the mixture
was added dropwise a solution of the compound prepared in reference
example 7 (606 mg) in ether (10 ml). The reaction mixture was
warmed up to 0.degree. C. for 1 hour. The reaction mixture was
quenched by addition of a saturated aqueous solution of sodium
ammonium, extracted with hexane. The extract was washed with a
saturated aqueous solution of sodium chloride, dried over anhydrous
magnesium sulfate and concentrated. The residue was purified by
column chromatography on silica gel (hexane:ethyl
acetate=60:1.fwdarw.30:1) to give the tittle compound (585 mg)
having the following physical data.
[0208] TLC: Rf 0.57 (hexane:ethyl acetate=6:1); NMR (CDCl.sub.3):
.delta.5.57-5.28 (2H, m), 465 (1H, q, J=5.0 Hz), 4.32-4.03 (1H, m),
3.73-3.35 (5H, m), 2.74-2.60 (2H, m), 2.47-1.18 (28H, m), 0.96-0.80
(21H, m), 0.13-0.05 (12H, m).
Reference Example 9
(5Z, 1.alpha.,
16RS)-11,16-bis(t-butyldimethylsilyloxy)-9-oxo-17,17-propan-
oprosta-5-ene-13-yne-1-ol
[0209] 358
[0210] To a solution of the compound prepared in reference example
8 (643 mg) in methanol (14 ml) was added pyridinium
p-toluenesulfonate (24 mg) at 0.degree. C. The reaction mixture was
stirred at room temperature for 5 hours. The reaction mixture was
quenched by addition of a saturated aqueous solution of sodium
hydrogencarbonate, extracted with ethyl acetate. The extract was
washed with a saturated aqueous solution of sodium chloride, dried
over anhydrous magnesium sulfate and concentrated. The residue was
purified by column chromatography on silica gel (hexane:ethyl
acetate=10:1) to give the tittle compound (399 mg) having the
following physical data.
[0211] TLC: Rf 0.37 (hexane:ethyl acetate=4:1); NMR (CDCl.sub.3):
.delta.5.60-5.30 (2H, m), 4.32-4.22 (1H, m), 3.70 (1H, t, J=6.0
Hz), 3.64 (2H, t, J=7.0 Hz),2.72-2.60 (1H, m), 2.66 (1H, dd,
J=17.8, 66 Hz), 2.47-1.32 (23H, m), 0.95-0.83 (21H, m), 0.18-0.03
(12H, m).
Reference Example 10
(5Z, 11.alpha.,
16RS)-11,16-bis(t-butyldimethylsilyloxy)-9-oxo-17,17-propa-
noprosta-5-ene-13-ynoic acid.cndot.methylester
[0212] 359
[0213] To a solution of the compound prepared in reference example
9 (369 mg) in acetone (10 ml) was added dropwise Jones reagent (a
aqueous solution of chromium (VI) oxide and sulfuric acid, 2.0 M
containing as chromic acid, 1.0 ml) at -30.degree. C. The reaction
mixture was stirred for 1 hour. To the reaction mixture added
isopropyl alcohol (3 ml), diluted with water, extracted with ethyl
acetate. The extract was washed with a saturated aqueous solution
of sodium chloride, dried over anhydrous magnesium sulfate and
concentrated until the volume of 50 ml. To the residue solution was
added a solution of diazomethane in ether until the reaction
solution changed yellow color. The reaction mixture was
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (hexane:ethyl acetate=100:1) to
give the tittle compound (257 mg) having the following physical
data.
[0214] TLC: Rf 0.76 (hexane:ethyl acetate=4:1); NMR (CDCl.sub.3):
.delta.5.49-5.35 (2H, m), 4.32-4.22 (1H, m), 3.69 (1H, t, J=4.8
Hz), 3.66 (3H, s), 2.73-2.61 (12H, m), 2.44-1.32 (20H, m), 2.31
(2H, t, J=7.6 Hz), 0.95-0.82 (21H, m), 0.13-0.06 (12H, m).
Reference Example 11
(11.alpha., 13E,
16RS)-11,16-bis(t-butyldimethylsilyloxy)-9-oxo-17,17-prop-
anoprosta-13-ene-5-ynoic acid.cndot.methylester
[0215] 360
[0216] To a solution of
(1E,4RS)-1-iodo-4-t-butyldimethylsilyloxy-5,5-prop- anoocta-1-ene
(265 mg) in ether (2 ml) was added dropwise 1.7 M t-butyllithium in
pentane solution (0.83 ml) at -78.degree. C. After the mixture was
stirred for 1 hour, to the mixture was added 0.25 M lithium
2-thienylcyanocuprate in tetrahydrofuran (3.12 ml). After the
mixture was stirred for 20 min at same temperature, to the mixture
was added dropwise a solution of
(4R)-4-t-butyldimethylsilyloxy-2-cyclopenten-1-one (106 mg) in
tetrahydrofuran (4 ml). The reaction mixture was warmed up to
-20.degree. C. for 30 min. To the reaction mixture was added
dropwise a solution of 7-iodohepta-5-ynoic acid.cndot.methylester
(665 mg) in tetrahydrofuran (5 ml). The reaction mixture was
stirred for 3 hours. The reaction mixture was quenched by addition
of a saturated aqueous solution of ammonium chloride extracted with
hexane. The extract was washed with a saturated aqueous solution of
sodium chloride, dried over anhydrous magnesium sulfate and
concentrated. The residue was purified by column chromatography on
silica gel (hexane:ethyl acetate=50:1.fwdarw.20:1) to give the
tittle compound (44 mg) having the following physical data.
[0217] TLC: Rf 0.36(hexane:ethyl acetate=9:1); NMR (CDCl.sub.3):
.delta.5.78-5.55 (1H, m), 5.40-5.23 (1H, m), 4.10-3.95 (1H, m),
3.66 (3H, s), 3.63-3.53 (1H, m), 2.80-2.50 (2H, m), 2.50-1.20 (22H,
m), 1.00-0.80 (3H, m), 0.91, 0.90 and 0.88 (18H, 3s), 0.09, 0.05
and 0.04 (12H, 3s).
Example 1
(5Z, 11.alpha.,
13E)-11,16-dihydroxy-9-oxo-17,17-propanoprosta-5,13-dienoi- c
acid.cndot.methylester
[0218] 361
[0219] To a solution of the compound prepared in reference example
3 (330 mg) in acetonitrile (7 ml) was added pyridine (3 ml) and 47%
a aqueous solution of hydrofluoric acid (6 ml). The reaction
mixture was stirred at room temperature for 5 hours. The reaction
mixture quenched by addition of water, extracted with ethyl
acetate. The extract was washed with a saturated aqueous solution
of sodium hydrogencarbonate and a saturated aqueous solution of
sodium chloride, successively, dried over anhydrous magnesium
sulfate and concentrated. The residue was purified by column
chromatography on silica gel (hexane:ethyl acetate=1:1) to give the
present invention each stereomer on 16-position less polar compound
(55 mg) and more polar compound (55 mg)
[0220] less polar
[0221] TLC: Rf 0.37 (hexane:ethyl acetate=2:3); NMR (CDCl.sub.3):
.delta.5.71 (1H, ddd, J=15.3, 7.6, 6.3 Hz), 5.54-5.26 (3H, m),
4.18-4.00 (1H, m), 3.67 (3H, s), 3.55 (1H, dd, J=10.0, 2.4 Hz),
2.75 (1H, ddd J=18.6, 7.2, 1.0 Hz), 2.85-2.65 (1H, br), 2.50-1.50
(19H, m), 2.32 (2H, t, J=7.5 Hz), 1.50-1.20 (3H, m), 0.94 (3H, t,
J=6.9 Hz).
[0222] more polar
[0223] TLC: Rf 0.29 (hexane:ethyl acetate=2:3); NMR (CDCl.sub.3):
.delta.5.69 (1H, ddd, J=15.4, 8.2, 5.4 Hz), 5.49-5.25 (3H, m),
4.12-3.98 (1H, m), 3.67 (3H, s), 3.65-3.20 (1H, br), 3.55 (1H, dd,
J=10.2, 2.4 Hz), 2.74 (1H, ddd, J=18.4, 7.4, 1.0 Hz), 2.50-1.50
(19H, m), 2.31 (2H, t, J=7.3 Hz), 1.50-1.20 (3H, m), 0.94 (3H, t,
J=6.9 Hz).
Example 1(1).about.1(2)
[0224] By the same procedure as provided in example 1, using the
compound prepared in reference example 10 or reference example 11,
compounds of the present invention having the following physical
data were obtained.
Example 1(1) (
5Z, 11.alpha.,
16RS)-11,16-dihydroxy-9-oxo-17,17-propanoprosta-5-ene-13-yn- oic
acid.cndot.methylester
[0225] 362
[0226] mixture
[0227] TLC: Rf 0.57 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.54-5.31 (2H, m), 4.39-4.27 (1 H, m), 3.70-3.63 (1H, m),
3.67 (3H, s), 3.40-3.30 (1H, brs), 2.75 (1H, dd, J=18.4, 7.2 Hz),
2.72-1.20 (24H, m), 0.93 (3H, t, J=7.0 Hz).
Example 1(2)
(11.alpha.,
13E)-11,16-dihydroxy-9-oxo-17,17-propanoprosta-13-ene-5-ynoic
acid.cndot.methylester
[0228] 363
[0229] less polar
[0230] TLC: Rf 0.33 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.80 (1H, ddd, J=15.4, 7.6, 6.2 Hz), 5.52 (1H, dd, J=15.4,
8.2 Hz), 4.22-4.06 (1H, m), 3.68 (3H, s), 3.59 (1H, dd, J=9.8, 2.8
Hz), 2.90-2.55 (3H, m), 2.50-1.20 (21H, m), 2.43 (2H, t, J=7.6 Hz),
0.94 (3H, t, J=6.8 Hz).
[0231] more polar
[0232] TLC: Rf 0.24 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.76 (1H, ddd, J=15.4, 8.2, 5.4 Hz), 5.46 (1H, dd, J=15.4,
8.6 Hz), 4.19-4.03 (1H, m), 3.68 (3H, s), 3.58 (1H, dd, J=10.0, 2.2
Hz) 2.90-2.55 (3H, m), 2.50-1.20 (21H, m), 2.43 (2H, t, J=7.4 Hz),
0.94 (3H, t, J=6.8 Hz).
Example 2
(5Z, 11.alpha.,
16RS)-11,16-dihydroxy-9-oxo-17,17-propanoprosta-5-enoic
acid.cndot.methylester
[0233] 364
[0234] By the same procedure as provided in reference example
-3.fwdarw.example 1, using the compound prepared in reference
example 6, compound of the present invention having the following
physical data was obtained. mixture
[0235] TLC: Rf 0.34 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.51-5.28 (2H, m), 4.28-4.16 (1H, m), 3.67 (3H, s),
3.55-3.50 (1H, m), 2.68 (1H, ddd, J=19, 7, 3 Hz), 2.50-1.20 (25H,
m), 2.33 (2H, t, J=7 Hz), 0.93 (3H, t, J=7 Hz).
Example 3.about.3(9)
[0236] By the same procedure as provided in reference example
1.fwdarw.reference example 2.fwdarw.reference example
3.fwdarw.example 1, using corresponding acetylene derivatives
instead of (4RS)-5,5-propanoocta-1-yne-4-ol as starting material in
reference example 1, compounds of the present invention having the
following physical data were obtained.
Example 3
(5Z, 11.alpha.,
13E)-11,16-dihydroxy-20-methyl-9-oxo-17,17-propanoprosta-5-
,13-dienoic acid.cndot.methylester
[0237] 365
[0238] less polar
[0239] TLC: Rf 0.32 (hexane:ethyl acetate=1:1); NMR (CDCl.sub.3):
.delta.5.71 (1H, ddd, J=15, 8, 6 Hz), 5.52-5.27 (3H, m), 4.17-4.03
(1H, m), 3.67 (3H, s), 3.54 (1H, dd, J=10, 2 Hz), 2.75 (1H, dd,
J=19, 8 Hz), 2.50-1.90 (9H, m), 2.30 (2H, t, J=7 Hz), 1.90-1.20
(14H, m), 0.90 (3H, t, J=7 Hz).
[0240] more polar
[0241] TLC: Rf 0.28 (hexane:ethyl acetate=1:1); NMR (CDCl.sub.3):
.delta.5.71 (1H, ddd, J=15, 8, 6 Hz), 5.50-5.27 (3H, m), 4.17-4.00
(1H, m), 3.66 (3H, s), 3.56 (1H, dd, J=10, 2 Hz), 2.74 (1H, dd,
J=17, 6 Hz), 2.48-1.20 (23H, m), 2.30 (2H, t, J=7 Hz), 0.92 (3H, t,
J=7 Hz).
Example 3(1)
(5Z, 11.alpha.,
13E)-11,16-dihydroxy-20-ethyl-9-oxo-17,17-propanoprosta-5,-
13-dienoic acid.cndot.methylester
[0242] 366
[0243] less polar
[0244] TLC: Rf 0.31 (hexane:ethyl acetate=1:1); NMR (CDCl.sub.3):
.delta.5.71 (1H, ddd, J=15, 8, 6 Hz), 5.52-5.27 (3H, m), 4.15-4.02
(1H, m), 3.67 (3H, s), 3.54 (1H, dd, J=10, 2 Hz), 2.75 (1H, dd,
J=19, 8 Hz), 2.50-1.90 (9H, m), 2.32 (2H, t, J=7 Hz), 1.90-1.20
(16H, m), 0.90 (3H, t, J=7 Hz).
[0245] more polar
[0246] TLC: Rf 0.27 (hexane:ethyl acetate=1:1); NMR (CDCl.sub.3):
.delta.5.72 (1H, ddd, J=15, 8, 6 Hz), 5.49-5.27 (3H, m), 4.12-3.99
(1H, m), 3.66 (3H, s), 3.55 (1H, dd, J=10, 2 Hz), 2.75 (1H, dd,
J=19, 8 Hz), 2.50-1.90 (9H, m), 2.33 (2H, t, J=7 Hz), 1.90-1.10
(16H, m), 0.90 (3H, t, J=7 Hz).
Example 3(2)
(5Z, 11.alpha., 13
E)-20-chloro-11,16-dihydroxy-9-oxo-17,17-propanoprosta--
5,13-dienoic acid.cndot.methylester
[0247] 367
[0248] less polar
[0249] TLC: Rf 0.24 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.70 (1H, ddd, J=15, 8, 6 Hz), 5.53-5.26 (3H, m), 4.17-4.03
(1H, m), 3.67 (3H, s), 3.59-3.53 (3H, m), 2.76 (1H, dd, J=18, 8
Hz), 2.50-1.45 (21H, m), 2.30 (2H, t, J=7 Hz).
[0250] more polar
[0251] TLC: Rf 0.18 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.70 (1H, ddd, J=15, 8, 6 Hz), 5.50-5.26 (3H, m), 4.17-4.00
(1H, m), 3.66 (3H, s), 3.59-3.53 (3H, m), 2.74 (1H, dd, J=19, 7
Hz), 2.50-1.50 (21H, m), 2.30 (2H, t, J=7 Hz).
Example 3(3)
(5Z, 11.alpha.,
13E)-11,16-dihydroxy-9-oxo-18-phenyl-17,17-propano-19,
20-dinorprosta-5,13-dienoic acid.cndot.methylester
[0252] 368
[0253] less polar
[0254] TLC: Rf 0.29 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.7.33-7.20 (5H, m), 5.70 (1H, ddd, J=15, 8, 6 Hz), 5.54-5.27
(3H, m), 4.18-4.03 (1H, m), 3.66 (3H, s), 3.57 (1H, dd, J=10, 2
Hz), 2.92 (1H, d, J=13 Hz), 2.76 (1H, dd, J=19, 7 Hz), 2.65 (1H, d,
J=13 Hz), 2.50-1.45 (17H, m), 2.30 (2H, t, J=7 Hz).
[0255] more polar
[0256] TLC: Rf 0.21 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.7.36-7.18 (5H, m), 5.70 (1H, ddd, J=15, 8, 6 Hz), 5.49-5.26
(3H, m), 4.18-3.99 (1H, m), 3.65 (3H, s), 3.57 (1H, dd, J=10, 2
Hz), 2.91 (1H, d, J=14 Hz), 2.73 (1H, dd, J=18, 7 Hz), 2.66 (1H, d,
J=14 Hz), 2.50-1.45 (17H, m), 2.30 (2H, t, J=7 Hz).
Example 3(4)
(5Z, 11.alpha.,
13E)-11,16-dihydroxy-9-oxo-17,17-propanoprosta-5,13,19-tri- enoic
acid.cndot.methylester
[0257] 369
[0258] less polar
[0259] TLC: Rf 0.44 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.95 (1H, ddt, J=17.0, 10.0, 7.4 Hz), 5.71 (1H, ddd, J=15.4,
7.7, 5.9 Hz), 5.60-5.25 (3H, m), 5.20-5.05 (2H, m), 4.16-4.02 (1H,
m), 3.67 (3H, s), 3.56 (1H, dd, J=9.6, 2.0 Hz), 2.76 (1H, ddd,
J=18.3, 7.3, 1.4 Hz), 2.50-1.55 (21H, m), 2.32 (2H, t, J=7.5
Hz).
[0260] more polar
[0261] TLC: Rf 0.34 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.95 (1H, ddt, J=17.2, 10.0, 7.4 Hz), 5.70 (1H, ddd,
J=15.4,7.6, 5.6 Hz), 5.57-5.25 (3H, m),5.20- 5.05 (2H, m),
4.14-3.98 (1H, m), 3.67 (3H, s), 3.56 (1H, dd, J=10.2, 2.3 Hz),
3.00-2.70 (1H, br), 2.74 (1H, ddd, J=18.2, 7.4,1.4 Hz), 2.50-1.55
(20H, m), 2.32 (2H, t, J=7.5 Hz).
Example 3(5)
(5Z, 11.alpha.,
13E)-11,16-dihydroxy-20-methyl-9-oxo-17,17-propanoprosta-5-
,13-diene-19-ynoic acid.cndot.methylester
[0262] 370
[0263] less polar
[0264] TLC: Rf 0.43 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.83-5.66 (1H, m), 5.55-5.25 (3H, m), 4.18-4.00 (1H, m),
3.75-3,60 (1H, m), 3.67 (3H, s), 2.75 (1H, ddd, J=18.4, 7.4, 1.4
Hz), 2.50-1.55 (21H, m), 2.32 (2H, t, J=7.4 Hz), 1.80 (3H, t, J=2.6
Hz).
[0265] more polar
[0266] TLC: Rf 0.33 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.72 (1H, ddd, J=15.0, 7.8, 5.8 Hz), 5.52-5.25 (3H, m),
4.15-3.98 (1H, m), 3.73-3.62 (1H, m), 3.67 (3H, s), 2.74 (1H, ddd,
J=18.4, 72, 1.4 Hz), 2.50-1.50 (21H, m), 2.32 (2H, t, J=7.2 Hz),
1.80 (3H, t, J=2.6 Hz).
Example 3(6)
(5Z,11.alpha.,
13E)-17,17-butano-11,16-dihydroxy-9-oxoprosta-5,13-dienoic
acid.cndot.methylester
[0267] 371
[0268] less polar
[0269] TLC: Rf 0.43 (hexane:ethyl acetate=2:3); NMR (CDCl.sub.3):
.delta.5.71 (1H, ddd, J=15.2, 7.9, 5.7 Hz), 5.54-5.25 (3H, m),
4.14-4.01 (1H, m), 3.67 (3H, s), 3.47 (1H, dd, J=10.2, 2.0 Hz),
2.75 (1H, ddd, J=18.4, 7.4, 1.0 Hz), 2.50-1.80 (10H, m), 2.32 (2H,
t, J=7.4 Hz), 1.80-1.50 (9H, m), 1.50-1.20 (6H, m), 0.90 (3H, t,
J=6.8 Hz).
[0270] more polar
[0271] TLC: Rf 0.34 (hexane:ethyl acetate=2:3); NMR (CDCl.sub.3):
.delta.5.67 (1H, ddd, J=15.2, 8.2, 5.2 Hz), 5.48-5.25 (3H, m),
4.12-3.96 (1H, m), 3.70-3.40 (1H, br), 3.67 (3H, s), 3.48 (1H, dd,
J=10.2, 2.0 Hz), 2.75 (1H, ddd, J=18.4, 7.6, 1.0 Hz), 2.50-1.80
(10H, m), 2.31 (2H, t, J=7.5 Hz), 1.80-1.50 (8H, m), 1.50-1.20 (6H,
m), 0.90 (3H, t, J=6.6 Hz).
Example 3(7)
(5Z,11.alpha.,
13E)-11,16-dihydroxy-9-oxo-17,17-pentanoprosta-5,13-dienoic
acid.cndot.methylester
[0272] 372
[0273] less polar
[0274] TLC: Rf 0.47 (hexane:ethyl acetate=2:3); NMR (CDCl.sub.3):
.delta.5.71 (1H, ddd, J=15.4, 8.0, 5.6 Hz), 5.53-5.25 (3H, m),
4.16-4.01 (1H, m), 3.67 (3H, s), 3.47 (1H, dd, J=10.6, 2.0 Hz),
2.75 (1H, ddd J=18.6, 7.4, 1.2 Hz), 2.50-2.00 (10H, m), 2.32 (2H,
t, J=7.4 Hz), 2.00-1.15 (17H, m), 0.91 (3H, t, J=6.5 Hz).
[0275] more polar
[0276] TLC: Rf 0.38 (hexane:ethyl acetate=2:3); NMR (CDCl.sub.3):
.delta.5.69 (1H, ddd, J=15.4, 8.0, 5.6 Hz), 5.48-5.25 (3H, m),
4.12-3.96 (1H, m), 3.67 (3H, s), 3.60-3.00 (1H, br), 3.47 (1H, dd,
J=10.5, 1.7 Hz), 2.73 (1H, ddd, J=18.4, 7.4, 1.0 Hz), 2.50-1.95
(10H, m), 2.31 (2H, t, J=7.4 Hz), 1.80-1.15 (16H, m), 0.91 (3H, t,
J=6.7 Hz).
Example 3(8)
(5Z, 11.alpha.,
13E)-18-cyclohexyl-11,16-dihydroxy-9-oxo-17,17-propano-19,
20-dinorprosta-5,13-dienoic acid.cndot.methylester
[0277] 373
[0278] less polar
[0279] TLC: Rf 0.40 (hexane:ethyl acetate=2:3); NMR (CDCl.sub.3):
.delta.5.74 (1H, ddd, J=15.2, 8.0, 6.0 Hz), 5.60-5.25 (3H, m),
4.18-4.02 (1H, m), 3.67 (3H, s), 3.67-3.56 (1H, m), 2.76 (1H, dd,
J=18.2, 7.8 Hz), 2.60-1.95 (13H, m), 2.33 (2H, t, J=7.6 Hz),
1.95-1.45 (12H, m), 1.45-0.8 (7H, m).
[0280] more polar
[0281] TLC: Rf 0.35 (hexane:ethyl acetate=2:3); NMR (CDCl.sub.3):
.delta.5.72 (1H, ddd, J=15.4, 8.2, 5.2 Hz), 5.50-5.25 (3H, m),
4.14-3.98 (1H, m), 3.67 (3H, s), 3.61 (1H, dd, J=10.2, 2.0 Hz),
3.49 (1H, br) 2.74 (1H, ddd, J=8.4, 7.4, 1.0 Hz), 2.60-1.95 (12H,
m), 2.32 (2H, t, J=7.6 Hz), 1.95-1.45 (12H, m), 1.45- 0.85 (7H,
m).
Example 3(9) (5Z, 11.alpha.,
13E)-11,16-dihydroxy-9-oxo-17,17-propano-20-n-
orprosta-5,13-dienoic acid.cndot.methylester
[0282] 374
[0283] less polar
[0284] TLC: Rf 0.35 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.71 (1H, ddd, J=15, 8, 6 Hz), 5.52-5.24 (3H, m), 4.15-4.03
(1H, m), 3.67 (3H, s), 3.56 (1H, dd, J=10,2 Hz),2.75 (1H, ddd,
J=19, 7, 1 Hz), 2.50-1.35 (19H, m), 2.34 (2H , t, J=7 Hz), 0.92
(3H, t, J=7 Hz).
[0285] more polar
[0286] TLC: Rf 0.26 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.71 (1H, ddd, J=15, 8, 6 Hz), 5.48-5.26 (3H, m), 4.12-3.99
(1H, m), 3.66 (3H, s), 3.56 (1H, dd, J=10, 2 Hz), 2.73 (1H, ddd,
J=19, 7, 1 Hz), 2.48-1.47 (19H, m), 2.34 (2H , t, J=7 Hz), 0.92
(3H, t, J=7 Hz).
Example 4
(5Z, 11.alpha.,
13E)-11,16-dihydroxy-9-oxo-17,17-propanoprosta-5,13-dienoi- c
acid
[0287] 375
[0288] To the mixture of the less polar compound prepared in
example 1 (55 mg) in ethanol (0.4 ml) and phosphate buffer (pH 7.4,
4 ml) was added PLE (pig liver esterase, 20 .mu.l) at room
temperature. The reaction mixture was stirred for 3 hours. The
reaction mixture was quenched by addition of a saturated aqueous
solution of ammonium sulfate, extracted with ethyl acetate. The
extract was washed with 1N aqueous solution of hydrochloric acid
and a saturated aqueous solution of sodium chloride, successively,
dried over anhydrous magnesium sulfate and concentrated. The
residue was purified by column chromatography on silica gel
(hexane:ethyl acetate=1:1.fwdarw.ethyl acetate) to give the present
invention compound (33 mg) having the following physical data. By
the same procedure as provided in the above method, using the more
polar compound prepared in example 1, compound (29 mg) of the
present invention having the following physical data were
obtained.
[0289] less polar
[0290] TLC: Rf 0.41 (ethyl acetate:hexane:acetic acid=16:8:1); NMR
(CDCl.sub.3): .delta.5.74 (1H, dt, J=15.0, 6.0 Hz), 5.55-5.25 (3H,
m), 4.08 (1H, q, J=7.5 Hz), 3.64 (1H, dd, J=10.5, 2.5 Hz), 2.75
(1H, dd, J=18.0, 7.5 Hz), 2.50-2.20 (7H, m), 2.20-1.20 (18H, m),
0.94 (3H, t, J=7.0 Hz).
[0291] more polar
[0292] TLC: Rf 0.36 (ethyl acetate:hexane:acetic acid=16:8:1); NMR
(CDCl.sub.3): .delta.5.71 (1H, ddd, J=14.0, 8.0, 6.0 Hz), 5.54-5.30
(3H, m), 4.05 (1H, q, J=8.5 Hz), 3.61 (1H, dd, J=10.0, 2.5 Hz),
2.74 (1H, dd, J=19.0, 8.0 Hz), 2.50-2.20 (7H, m), 2.20-1.20 (18H,
m), 0.95 (3H, t, J=6.5 Hz).
Example 4(1).about.4(13)
[0293] By the same procedure as provided in example 4, using the
compound prepared in example 3-3(9), example 2 or example
1(1)-1(2), compounds of the present invention having the following
physical data were obtained.
Example 4(1)
(5Z, 11.alpha.,
13E)-11,16-dihydroxy-20-methyl-9-oxo-17,17-propanoprosta-5-
,13-dienoic acid
[0294] 376
[0295] less polar
[0296] TLC: Rf 0.74 (ethyl acetate:acetic acid=50:1); NMR
(CDCl.sub.3): .delta.5.72 (1H, dt, J=16, 7 Hz), 5.52-5.31 (3H, m),
5.10-4.50 (3H, brs), 4.14-4.01 (1H, m), 3.60 (1H, dd, J=16, 2 Hz),
2.74 (1H, dd, J=18, 7 Hz), 2.45-1.15 (25H, m), 0.90 (3H, t, J=7
Hz).
[0297] more polar
[0298] TLC: Rf 0.67 (ethyl acetate:acetic acid=50:1); NMR
(CDCl.sub.3): .delta.5.90-4.80 (7H, m), 4.10-3.98 (1H, m), 3.56
(1H, d, J=9 Hz), 2.72 (1H, dd, J=18, 7 Hz), 2.47-1.15 (23H, m),
2.30 (2H, t, J=7 Hz), 0.90 (3H, t, J=7 Hz).
Example 4(2)
(5Z, 11.alpha.,
13E)-11,16-dihydroxy-20-ethyl-9-oxo-17,17-propanoprosta-5,-
13-dienoic acid
[0299] 377
[0300] less polar
[0301] TLC: Rf 0.80 (ethyl acetate:acetic acid=50:1); NMR
(CDCl.sub.3): .delta.5.72 (1H, dt, J=15, 7 Hz), 5.52-5.31 (3H, m),
5.60-4.40 (3H, brs), 4.14-4.01 (1H, m), 3.60 (1H, dd, J=11, 2 Hz),
2.74 (1H, dd, J=18, 8 Hz), 2.45-1.18 (25H, m), 2.34 (2H, t, J=7
Hz), 0.90 (3H, t, J=7 Hz).
[0302] more polar
[0303] TLC: Rf 0.73 (ethyl acetate:acetic acid=50:1); NMR
(CDCl.sub.3): .delta.5.76-5.61 (1H, m), 5.49-5.32 (3H, m),
4.80-4.20 (3H, brs), 4.11-3.98 (1H, m), 3.59 (1H, dd, J=10, 1 Hz),
2.73 (1H, dd, J=18, 8 Hz), 2.45-1.15 (25H, m), 2.35 (2H, t, J=7
Hz), 0.90 (3H, t, J=7 Hz).
Example 4(3)
(5Z, 11 .alpha.,
13E)-20-chloro-11,16-dihydroxy-9-oxo-17,17-propanoprosta--
5,13-dienoic acid
[0304] 378
[0305] less polar
[0306] TLC: Rf 0.50 (ethyl acetate:acetic acid, 50:1) NMR
(CDCl.sub.3): .delta.5.80-5.65 (1H, m), 5.54-5.38 (3H, m),
4.20-3.00 (3H, br), 4.17-4.02 (1H, m), 3.63 (1H, dd, J=10, 2 Hz),
3.56 (2H, t, J=6.2 Hz), 2.76 (1H, dd, J=17.8, 6.8 Hz), 2.46-1.48 (2
3H, m).
[0307] more polar
[0308] TLC: Rf 0.44 (ethyl acetate:acetic acid=50:1); NMR
(CDCl.sub.3): .delta.5.68 (1H, ddd, J=15, 7, 5 Hz), 5.50-5.29 (3H,
m), 4.80-4.00 (3H, br), 4.12-3.99 (1H, m), 3.63-3.53 (3H, m), 2.74
(1H, dd, J=18, 7 Hz), 2.45-1.50 (21H, m), 2.30 (2H, t, J=7 Hz).
Example 4(4)
(5Z, 11.alpha.,
13E)-11,16-dihydroxy-9-oxo-18-phenyl-17,17-propano-19,
20-dinorprosta-5,13-dienoic acid
[0309] 379
[0310] less polar
[0311] TLC: Rf 0.52 (ethyl acetate: acetic acid=50 1); NMR
(CDCl.sub.3): .delta.7.37-7.18 (5H, m), 5.72 (1H, ddd, J=15, 7, 6
Hz), 5.54-5.40 (3H, m), 4.14-4.01 (1H, m), 3.67 (1H, dd, J=10,2
Hz), 3.50-2.90 (3H brs), 2.90 (1H, d, J=14 Hz), 2.75 (1H, dd, J=19,
8 Hz), 2.66 (1H, d, J=14 Hz), 2.47-1.45 (17H, m), 2.31 (2H, t, J=7
Hz).
[0312] more polar
[0313] TLC: Rf 0.43 (ethyl acetate:acetic acid=50 1); NMR
(CDCl.sub.3): .delta.7.37-7.18 (5H, m), 5.67 (1H, ddd, J=15, 8, 6
Hz), 5.49-5.28 (3H, m), 5.20-4.60 (3H, brs), 4.18-3.98 (1H, m),
3.62 (1H, brd, J=10 Hz), 2.87 (1H, d, J=14 Hz), 2.73 (1H, dd, J=18,
8 Hz), 2.65 (1H, d, J=14 Hz), 2.45-1.42 (19H, m).
Example 4(5)
(5Z, 11.alpha., 13E)-11,16-dihydroxy-9-oxo-17,17-propanoprosta-5,
13-19-trienoic acid
[0314] 380
[0315] less polar
[0316] TLC: Rf 0.28 (hexane:ethyl acetate:acetic acid=1:2:0.03);
NMR (CDCl.sub.3): .delta.5.94 (1H, ddt, J=17.0, 10.0, 7.4 Hz), 5.72
(1H, ddd, J=15.0, 7.8, 6.2 Hz), 5.60-5.30 (3H, m), 5.20-5.05 (2H,
m), 5.00-4.00 (3H, br), 4.16-4.00 (1H, m), 3.63 (1H, dd, J=10.2,
2.4 Hz), 2.75 (1H, ddd, J=18.2, 7.4, 1.0 Hz), 2.50-1.60 (21H,
m).
[0317] more polar
[0318] TLC: Rf 0.21 (hexane:ethyl acetate: acetic acid=1:2:0.03);
NMR (CDCl.sub.3): .delta.5.94 (1H, ddt, J=17.2, 10.2, 7.2 Hz), 5.66
(1H, ddd, J=15.2, 8.0, 5.6 Hz), 5.53-5.25 (3H, m), 5.30-4.50 (3H,
br), 5.20-5.00 (2H, m), 4.12-3.96 (1H, m), 3.58 (1H, dd, J=10.2,1.8
Hz), 2.72 (1H, dd, J=18.2, 7.2 Hz) 2.50-1.60 (21H, m).
Example 4(6)
(5Z, 11.alpha.,
13E)-11,16-dihydroxy-20-methyl-9-oxo-17,17-propanoprosta-5-
,13-diene-19-ynoic acid
[0319] 381
[0320] less polar
[0321] TLC: Rf 0.26 (hexane:ethyl acetate:acetic acid=1:2:0.03);
NMR (CDCl.sub.3): .delta.5.84-5.66 (1H, m), 5.56-5.32 (3H, m),
4.80-3.60 (3H, br), 4.18-4.00 (1H, m), 3.77 (1H, dd, J=10.0, 2.6
Hz), 2.76 (1H, ddd, J=18.4, 7.4, 1.0 Hz), 2.50-1.60 (21H, m), 1.81
(3H, t, J=2.5 Hz).
[0322] more polar
[0323] TLC: Rf 0.20 (hexane:ethyl acetate:acetic acid=1:2:0.03);
NMR (CDCl.sub.3): .delta.5.71 (1H, ddd, J=15.0, 7.6, 5.8 Hz),
5.52-5.28 (3H, m), 5.30-4.20 (3H, br), 4.13-3.95 (1H, m), 3.72 (1H,
dd, J=10.2, 2.2 Hz), 2.74 (1H, ddd, J=18.4, 7.4,1.0 Hz), 2.50-1.60
(21H, m), 1.81 (3H, t, J=2.5 Hz).
Example 4(7)
(5Z, 11.alpha.,
13E)-17,17-butano-11,16-dihydroxy-9-oxoprosta-5,13-dienoic acid
[0324] 382
[0325] less polar
[0326] TLC: Rf 0.33 (hexane:ethyl acetate:acetic acid=2:3:0.05);
NMR (CDCl.sub.3): .delta.5.82-5.65 (1H, m), 5.55-5.30 (3H, m),
5.40-4.60 (3H, br), 4.16-3.98 (1H, m), 3.55 (1H, dd, J=10.6, 2.0
Hz), 2.75 (1H, dd, J=18.0, 7.0 Hz), 2.50-1.90 (11H, m), 1.80-1.10
(14H, m), 0.90 (3H, t, J=6.4 Hz).
[0327] more polar
[0328] TLC: Rf 0.26 (hexane:ethyl acetate:acetic acid=2:3:0.05);
NMR (CDCl.sub.3): .delta.5.75-5.57 (1H, m), 5.50-5.30 (3H, m),
5.80-4.80 (3H, br), 4.12-3.94 (1H, m), 3.51 (1H, d, J=9.4 Hz), 2.73
(1H, dd, J=18.0, 7.0 Hz), 2.50-1.95 (11H, m), 1.80-1.10 (14H,
m),0.90 (3H, t, J=6.4 Hz).
Example 4(8) (5Z, 11.alpha.,
13E)-11,16-dihydroxy-9-oxo-17,17-pentanoprost- a-5,13-dienoic
acid
[0329] 383
[0330] less polar
[0331] TLC: Rf 0.35 (hexane ethyl acetate:acetic acid 2:3:0.05);
NMR (CDCl.sub.3): .delta.5.81-5.63 (1H, m), 5.55-5.30 (3H, m),
5.40-4.50 (3H, br), 4.15-3.98 (1H, m), 3.53 (1H, d, J=10.2 Hz),
2.75 (1H, dd, J=18.2, 7.0 Hz) 2.50-1.90 (11H, m), 1.80-1.10 (16H,
m), 0.90 (3H, t, J=6.4 Hz).
[0332] more polar
[0333] TLC: Rf 0.28 (hexane:ethyl acetate:acetic acid=2:3:0.05);
NMR (CDCl.sub.3): .delta.5.75-5.57 (1H, m), 5.50-5.30 (3H, m),
5.80-5.00 (3H, br), 4.11-3.95 (1H, m), 3.50 (1H, d, J=10.0 Hz),
2.73 (1H, dd, J=18.4, 7.0 Hz) 2.50-1.90 (11H, m), 1.80-1.10 (16H,
m), 0.90 (3H, t, J=6.4 Hz).
Example 4(9)
(5Z, 11.alpha.,
13E)-18-cyclohexyl-11,16-dihydroxy-9-oxo-17,17-propano-19,
20-dinorprosta-5,13-dienoic acid
[0334] 384
[0335] less polar
[0336] TLC: Rf 0.36 (hexane:ethyl acetate:acetic acid=1:2:0.03);
NMR (CDCl.sub.3): .delta.5.75 (1H, ddd, J=15.2, 7.4, 6.0 Hz),
5.55-5.30 (3H, m), 5.40-4.40 (3H, br), 4.17-4.02 (1H, m), 3.68 (1H,
dd, J=10.2, 2.2 Hz), 2.76 (1H, dd, J=18.2, 7.0 Hz), 2.50-1.90 (14H,
m), 1.90-1.40 (11H, m), 1.40-0.80 (7H, m).
[0337] more polar
[0338] TLC: Rf 0.26 (hexane:ethyl acetate:acetic acid=1:2:0.03);
NMR (CDCl.sub.3): .delta.5.73 (1H, ddd, J=15.0, 7.7, 6.1 Hz),
5.55-5.30 (3H, m), 4.80-3.60 (3H, br), 4.15-3.98 (1H, m), 3.66 (1H,
dd, J=10.2, 2.0 Hz), 2.74 (1H, dd, J=18.2, 6.8 Hz), 2.50-1.90 (14H,
m), 1.90-1.40 (11H, m), 1.40-0.80 (7H, m).
Example 4(10)
(5Z, 11.alpha.,
13E)-11,16-dihydroxy-9-oxo-17,17-propano-20-norprosta-5,13-
-dienoic acid
[0339] 385
[0340] less polar
[0341] TLC: Rf 0.43 (ethyl acetate:acetic acid=50:1); NMR
(CDCl.sub.3): .delta.5.73 (1H, ddd, J=16, 8, 7 Hz), 5.53-5.38 (3H,
m), 4.90-4.10 (3H, brs), 4.14-4.02 (1H, m), 3.63 (1H, dd, J=10, 3
Hz), 2.75 (1H, ddd, J=19, 8,1 Hz), 2.45-1.30 (19H, m), 2.33 (2H, t,
J=7 Hz), 0.92 (3H, t, J=7 Hz).
[0342] more polar
[0343] TLC: Rf 0.39 (ethyl acetate:acetic acid=50:1); NMR
(CDCl.sub.3): .delta.5.71 (1H, ddd, J=15, 8, 6 Hz), 5.49-5.29 (3H,
m), 5.20-4.40 (3H, brs), 4.11-3.98 (1H, m), 3.60 (1H, dd, J=1Q, 2
Hz), 2.73 (1H, ddd, J=18, 7, 1 Hz), 2.45-1.35 (19H, m), 2.33 (2H,
t, J=7 Hz), 0.92 (3H, t, J=7 Hz).
Example 4(11)
(5Z, 11.alpha.,
16RS)-11,16-dihydroxy-9-oxo-17,17-propanoprosta-5-enoic acid
[0344] 386
[0345] mixture
[0346] TLC: Rf 0.62 (ethyl acetate:acetic acid=50:1); NMR
(CDCl.sub.3): .delta.5.50-5.20 (2H, m), 5.20-4.60 (3H, brs),
4.20-4.10 (1H, m), 3.58-3.52 (1H, m), 2.75-2.61 (1H, dd, J=18, 7
Hz), 2.50-1.20 (25H, m), 2.32 (2H, t, J=7 Hz), 0.92 (3H, t, J=7
Hz).
Example 4(12)
(5Z, 11.alpha.,
16RS)-11,16-dihydroxy-9-oxo-17,17-propanoprosta-5-ene-13-y- noic
acid
[0347] 387
[0348] mixture
[0349] TLC: Rf 0.45 (ethyl acetate acetic acid=50:1); NMR
(CDCl.sub.3): .delta.6.00-5.20 (3H, brs), 5.50-5.30 (2H, m),
4.37-4.21(1H, m), 3.75-3.65 (1H, m), 2.73 (1H, dd, J=18.2, 6.6 Hz),
2.70-1.20 (23H, m), 0.93 (3H, t, J=7.0 Hz).
Example 4(13)
(11.alpha.,
13E)-11,16-dihydroxy-9-oxo-17,17-propanoprosta-13-ene-5-ynoic
acid
[0350] 388
[0351] less polar
[0352] TLC: Rf 0.30 (hexane ethyl:acetate:acetic acid=1:3:0.04);
NMR (CDCl.sub.3): .delta.5.83 (1H, dt, J=15.4, 6.8 Hz), 5.48 (1H,
dd, J=15.4, 8.2 Hz), 5.50-4.50 (3H, br), 4.22-4.05 (1H, m), 3.60
(1H, dd, J=10.0, 2.4 Hz), 2.88-2.62 (3H, m), 2.49 (2H, t, J=7.1
Hz), 2.40-1.20 (19H, m), 0.94 (3H, t, J=6.7 Hz).
[0353] more polar
[0354] TLC: Rf 0.25 (hexane:ethyl acetate:acetic acid=1:3:0.04);
NMR (CDCl.sub.3): .delta.6.00-4.80 (3H, br), 5.71 (1H, ddd, J=15.0,
9.2, 4.4 Hz), 5.41 (1H, dd, J=15.0, 8.5 Hz), 4.20-4.03 (1H, m),
3.61 (1H, d, J=10.0 Hz), 2.88-2.65 (3H, m), 2.50 (2H, t, J=7.0 Hz),
2.40-1.20 (19H, m), 0.94 (3H, t, J=6.7 Hz).
Example 5
(5Z, 11.alpha., 13E)-17,17-propano-19,
20-methano-11,16-dihydroxy-9-oxopro- sta-5,13-dienoic
acid.cndot.methylester
[0355] 389
[0356] By the same procedure as provided in example 1, using the
protected compound by TBS provided by the same procedure in
reference example 1, reference example 2 or reference example 3,
compounds of the present invention having the following physical
data were obtained.
[0357] less polar
[0358] TLC: Rf 0.48 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.73 (1H, ddd, J=15.2, 7.8, 5.8 Hz), 5.54-5.26 (3H, m),
4.17-4.01 (1H, m), 3.74-3.63 (1H, m), 3.67 (3H, s), 2.75 (1H, ddd,
J=18.4, 7.6, 1.0 Hz), 2.50-1.60 (19H, m), 2.32 (2H, t, J=7.6 Hz),
1.54 (1H, dd, J=14.0, 6.8 Hz), 1.34 (1H, dd, J=14.0, 6.4 Hz),
0.90-0.68 (1H, m), 0.55-0.44 (2H, m), 0.16-0.05 (2H, m).
[0359] more polar
[0360] TLC: Rf 0.38 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.70 (1H, ddd, J=15.4,8.2, 5.6 Hz), 5.50-5.25 (3H, m),
4.14-3.98 (1H, m), 3.74-3.62 (1H, m), 3.67 (3H, s), 3.34 (1H, br),
2.74 (1H, ddd, J=18.4, 7.4,1.0 Hz), 2.50-1.60 (18H, m), 2.31 (2H,
t, J=7.4 Hz), 1.53 (1H, dd, J=4.0, 6.8 Hz), 1.36 (1H, dd, J=14.0,
6.4 Hz), 0.90-0.68 (1H, m), 0.56-0.45 (2H, m), 0.16-0.06 (2H,
m).
Example 5(1).about.5(7)
[0361] By the same procedure as provided in example 5, compounds of
the present invention having the following physical data were
obtained.
Example 5(1) (5Z, 11.alpha.,
13E)-17,17-propano-20,20-methylene-11,16-dihy-
droxy-9-oxoprosta-5,13-dienoic acid.cndot.methylester
[0362] 390
[0363] less polar
[0364] TLC: Rf 0.49 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.86 (1H, ddt, J=17.0, 10.4, 6.5 Hz), 5.71 (1H, ddd, J=15.2,
7.8, 5.8 Hz), 5.55-5.25 (3H, m), 5.10-4.90 (2H, m), 4.18-4.01 (1H,
m), 3.67 (3H, s), 3.57 (1H, dd, J=10.0, 2.6 Hz), 2.76 (1H, ddd,
J=18.4, 7.4, 1.0 Hz), 2.50-1.40 (23H, m), 2.32 (2H, t, J=7.4
Hz).
[0365] more polar
[0366] TLC: Rf 0.40 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.86 (1H, ddt, J=17.2, 10.2, 6.4 Hz), 5.71 (1H, ddd, J=15.2,
8.0, 5.8 Hz), 5.50-5.25 (3H, m), 5.10-4.90 (2H, m), 4.14-3.98 (1H,
m), 3.67 (3H, s), 3.57 (1H, dd, J=10.2, 2.4 Hz), 3.02 (1H, br),
2.74 (1H, ddd, J=18.4, 7.4, 1.0 Hz), 2.50-1.40 (22H, m), 2.32 (2H,
t, J=7.5 Hz).
Example 5(2)
(5Z, 11.alpha.,
13E)-17,17-propano-20-methoxy-11,16-dihydroxy-9-oxoprosta--
5,13-dienoic acid.cndot.methylester
[0367] 391
[0368] less polar
[0369] TLC: Rf 0.25 (hexane:ethyl acetate=1:3); NMR (CDCl.sub.3):
.delta.5.71 (1H, ddd, J=15.4, 7.4, 6.4 Hz), 5.55-5.25 (3H, m),
4.16-4.00 (1H, m), 3.67 (3H, s), 3.57 (1H, dd, J=9.6, 2.6 Hz),
3.48-3.30 (2H, m,), 3.35 (3H, s), 2.75 (1H, ddd, J=18.4, 8.0, 1.0
Hz), 2.70 (1H, br), 2.50-1.45 (22H, m), 2.32 (2H, t, J=7.5 Hz).
[0370] more polar
[0371] TLC: Rf 0.17 (hexane:ethyl acetate=1:3); NMR (CDCl.sub.3):
.delta.5.69 (1H, ddd, J=15.2, 8.4, 5.6 Hz), 5.50-5.25 (3H, m),
4.13-3.98 (1H, m), 3.67 (3H, s), 3.56 (1H, dd, J=10.0, 2.2 Hz),
3.46-3.32 (2H, m), 3.35 (3H, s), 2.74 (1H, ddd, J=18.4, 7.4, 1.0
Hz), 2.50-1.45 (23H, m), 2.31 (2H, t, J=7.3 Hz).
Example 5(3)
(5Z, 11.alpha.,
13E)-17,17-propano-20-fluoro-11,16-dihydroxy-9-oxoprosta-5-
,13-dienoic acid.cndot.methylester
[0372] 392
[0373] less polar
[0374] TLC: Rf 0.31 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.71 (1H, ddd, J=15.4, 7.6, 5.8 Hz), 5.55-5.25 (3H, m), 4.47
(2H, dt, J=47.0, 5.2 Hz), 4.17-4.02 (1H, m), 3.67 (3H, s), 3.58
(1H, dd, J=10.0, 2.4 Hz), 2.76 (1H, ddd, J=18.6, 7.4,1.2 Hz),
2.50-1.40 (23H, m), 2.32 (2H, t, J=7.3 Hz).
[0375] more polar
[0376] TLC: Rf 0.24 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.70 (1H, ddd, J=15.4, 8.2, 5.8 Hz), 5.52-5.25 (3H, m), 4.47
(2H, dt, J=46.8, 5.8 Hz), 4.14-3.98 (1H, m), 3.67 (3H, s), 3.58
(1H, dd, J=10.2, 2.2 Hz), 3.06 (1H, br), 2.74 (1H, ddd, J=18.4,
7.4, 1.0 Hz), 2.50-1.40 (22H, m), 2.32 (2H, t, J=7.5 Hz).
Example 5(4)
(5Z, 11.alpha.,
13E)-17,17-propano-19-methyl-11,16-dihydroxy-9-oxoprosta-5-
,13-dienoic acid.cndot.methylester
[0377] 393
[0378] less polar
[0379] TLC: Rf 0.45 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.73 (1H, ddd, J=15.2, 8.0, 6.0 Hz), 5.50-5.25 (3H, m),
4.17-4.02 (1H, m), 3.70-3.58 (1H, m), 3.67 (3H, s), 2.76 (1H, ddd,
J=18.4, 7.6, 1.0 Hz), 2.50-1.60 (20H, m), 2.33 (2H, t, J=7.4 Hz),
1.56 (1H, dd, J=4.2, 6.8 Hz), 1.33 (1H, dd, J=14.2, 6.2 Hz), 0.92
(6H, d, J=6.6 Hz).
[0380] more polar
[0381] TLC: Rf 0.35 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.72 (1H, ddd, J=15.2, 8.2, 5.8 Hz), 5.50-5.25 (3H, m),
4.14-3.98 (1H, m), 3.70-3.59 (1H, m), 3.67 (3H, s), 3.24 (1H, br),
2.74 (1H, ddd, J=18.4, 7.6, 1.0 Hz), 2.50-1.60 (19H, m), 2.32 (2H,
t, J=7.4 Hz), 1.56 (1H, dd, J=14.2, 6.8 Hz), 1.34 (1H, dd, J=14.2,
6.4 Hz), 0.92 (6H, d, J=6.6 Hz).
Example 5(5)
(5Z, 11.alpha.,
13E)-17,17-propano-11,16-dihydroxy-9-oxo-20-norprosta-5,13-
,18-trienoic acid.cndot.methylester
[0382] 394
[0383] less polar
[0384] TLC: Rf 0.30 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.95 (1H, dd, J=17.2, 10.7 Hz), 5.69 (1H, ddd, J=15.2, 7.6,
6.0 Hz), 5.49-5.29 (3H, m), 5.22 (1H, dd, J=10.7, 1.8 Hz), 5.15
(1H, dd, J=17.2, 1.8 Hz), 4.13-4.01 (1H, m), 3.67 (3H, s), 3.60
(1H, dd, J=10.0, 2.3 Hz), 2.74 (1H, ddd, J=18.4, 7.4, 1.2 Hz),
2.45-1.60 (19H, m), 2.30 (2H, t, J=7.0 Hz).
[0385] more polar
[0386] TLC: Rf 0.22 (hexane:ethyl acetate=1:2); NMR (CDCl.sub.3):
.delta.5.94 (1H, dd, J=17.0, 10.8 Hz), 5.67 (1H, ddd, J=15.2, 8.4,
5.8 Hz), 5.45-5.29 (3H, m), 5.23 (1H, dd, J=10.8, 1.6 Hz), 5.15
(1H, dd, J=17.0, 1.8 Hz), 4.13-3.97 (1H, m), 3.66 (3H, s), 3.59
(1H, dd, J=10.4, 2.2 Hz), 2.73 (1H, dd, J=18.2, 7.2 Hz), 2.44-1.60
(19H, m), 2.30 (2H, t, J=6.9 Hz).
Example 5(6)
(5Z, 11.alpha., 13E)-17,17-propano-11,16-dihydroxy-9-oxo-19,
20-dinorprosta-5,13-dienoic acid.cndot.methylester
[0387] 395
[0388] more polar
[0389] TLC: Rf 0.30 (hexane:ethyl acetate=1:3); NMR (CDCl.sub.3):
.delta.5.71 (1H, ddd, J=5, 8, 6Hz), 5.55-5.25 (3H, m), 4.18-4.02
(1H, m), 3.67 (3H, s), 3.56 (1H, dd, J=10, 2Hz), 2.73 (1H, ddd,
J=19, 7, 1 Hz), 2.50-1.60 (21H, m), 1.15 (3H, s).
Example 5(7)
(5Z, 11.alpha., 13E)-17,17-propano-11,16-dihydroxy-9-oxo-18,19,
20-trinorprosta-5,13-dienoic acid.cndot.methylester
[0390] 396
[0391] more polar
[0392] TLC: Rf 0.25 (hexane ethyl acetate=1:3); NMR (CDCl.sub.3):
.delta.5.70 (1H, ddd, J=15, 8, 6Hz), 5.54-5.26 (3H, m), 4.17-4.00
(1H, m), 3.66 (3H, s), 3.62-3.50 (1H, m), 2.74 (1H, ddd, J=18, 7, 1
Hz), 2.60-1.60 (22H, m).
Example 6
(5Z, 11.alpha., 13E)-17,17-propano-19, 20-methano-11
,16-dihydroxy-9-oxoprosta-5,13-dienoic acid
[0393] 397
[0394] By the same procedure as provided in example 4, using each
obtained the compound prepared in example 5, compounds of the
present invention having the following physical data were
obtained.
[0395] less polar
[0396] TLC: Rf 0.31 (hexane:ethyl acetate:acteic acid=1:2:0.03);
NMR (CDCl.sub.3): .delta.5.83-5.66 (1H, m), 5.60-5.30 (3H, m),
5.40-4.20 (3H, br), 4.17-4.00 (1H, m), 3.77 (1H, dd, J=10.4, 2.2
Hz), 2.75 (1H, dd, J=18.4, 7.6 Hz), 2.50-1.60 (19H, m), 1.53 (1H,
dd, J=14.2, 6.7 Hz), 1.35 (1H, dd, J=14.2, 6.4 Hz), 0.95-0.65 (1H,
m), 0.60-0.45 (2H, m), 0.20-0.05 (2H, m).
[0397] more polar
[0398] TLC: Rf 0.26 (hexane:ethyl acetate:acteic acid=1:2:0.03);
NMR (CDCl.sub.3): .delta.6.00-4.00 (3H, br), 5.70 (1H, ddd, J=15.4,
7.8, 5.6 Hz), 5.50-5.25 (3H, m), 4.14-3.96 (1H, m), 3.73 (1H, dd,
J=10.0, 2.0 Hz), 2.74 (1H, dd, J=18.4, 7.6 Hz), 2.50-1.60 (19H, m),
1.50 (1H, dd, J=14.2, 6.8 Hz), 1.37 (1H, dd, J=14.2, 6.3 Hz),
0.90-0.70 (1H, m), 0.60-0.45 (2H, m), 0.17-0.05 (2H, m).
Example 6(1).about.6(8)
[0399] By the same procedure as provided in example 6, compounds of
the present invention having the following physical data were
obtained.
Example 6(1)
(5Z, 11.alpha.,
13E)-17,17-propano-20,20-methylene-11,16-dihydroxy-9-oxopr-
osta-5,13-dienoic acid
[0400] 398
[0401] less polar
[0402] TLC: Rf 0.32 (hexane:ethyl acetate:acteic acid=1:2:0.03);
NMR (CDCl.sub.3): .delta.5.86 (1H, ddt, J=17.0, 10.2, 6.8 Hz),
5.80-5.64 (1H, m), 5.55-5.30 (3H, m), 5.10-4.90 (2H, m), 5.00-4.00
(3H, br), 4.16-4.00 (1H, m), 3.64 (1H, dd, J=10.2, 2.4 Hz), 2.75
(1H, dd, J=18.4, 7.4 Hz), 2.50-1.40 (23H, m).
[0403] more polar
[0404] TLC: Rf 0.27 (hexane:ethyl acetate:acteic acid=1:2:0.03);
NMR (CDCl.sub.3): .delta.5.86 (1H, ddt, J=17.0, 10.2, 6.4 Hz),
5.78-5.60 (1H, m), 5.60-4.40 (3H, br), 5.55-5.25 (3H, m), 5.10-4.90
(2H, m), 4.12-3.96 (1H, m), 3.61 (1H, dd, J=10.2, 1.8 Hz), 2.74
(1H, dd, J=18.6, 7.4 Hz), 2.50-1.40 (23H, m).
Example 6(2)
(5Z, 11.alpha.,
13E)-17,17-propano-20-methoxy-11,16-dihydroxy-9-oxoprosta--
5,13-dienoic acid
[0405] 399
[0406] less polar
[0407] TLC: Rf 0.36 (ethyl acetate:acteic acid 100:1); NMR
(CDCl.sub.3): .delta.5.72 (1H, dt, J=15.2, 6.6 Hz), 5.55-5.25 (3H,
m), 5.60-4.40 (3H, br), 4.16-4.00 (1H, m), 3.61 (1H, dd, J=9.6, 2.2
Hz), 3.48-3.38 (2H, m), 3.37 (3H, s), 2.75 (1H, dd, J=18.2, 7.4
Hz), 2.50-1.40 (23H, m).
[0408] more polar
[0409] TLC: Rf 0.27 (ethyl acetate:acteic acid=100:1); NMR
(CDCl.sub.3) .delta.5.68 (1H, ddd, J=15.2, 8.0, 5.0 Hz), 5.50-5.20
(3H, m), 5.40-4.20 (3H, br), 4.13-3.97 (1H, m), 3.56 (1H, dd,
J=10.4, 2.0 Hz), 3.55-3.35 (2H, m), 3.38 (3H, s), 2.75 (1H, dd,
J=18.2, 7.4 Hz), 2.50-1.40 (23H, m).
Example 6(3) (5Z, 11.alpha.,
13E)-17,17-propano-20-fluoro-11,16-dihydroxy--
9-oxoprosta-5,13-dienoic acid
[0410] 400
[0411] less polar
[0412] TLC: Rf 0.30 (hexane:ethyl acetate:acetic acid=1:3:0.04);
NMR (CDCl.sub.3): .delta.5.72 (1H, ddd, J=15.5, 7.0, 6.0 Hz), 5.48
(1H, dd, J=15.5, 8.5 Hz), 5.46-5.36 (2H, m), 5.20-3.80 (3H, br),
4.55-4.48 and 4.46-4.38 (2H, m), 4.12-4.04 (1H, m), 3.64 (1H, dd,
J=10.5, 2.0 Hz), 2.75 (1H, ddd, J=18.5, 7.5, 1.0 Hz), 2.43-2.26
(6H, m), 2.21 (1H, dd, J=18.5, 10.0 Hz), 2.15-1.95 (6H, m),
1.95-1.63 (9H, m), 1.57-1.48 (1H, m).
[0413] more polar
[0414] TLC: Rf 0.23 (hexane:ethyl acetate:acteic acid=1:3:0.04);
NMR (CDCl.sub.3): .delta.5.68 (1H, ddd, J=15.5, 8.0, 5.5 Hz), 5.46
(1H, dd, J=15.5, 8.5 Hz), 5.50-4.50 (3H, br), 5.45-5.33 (2H, m),
4.55-4.48 and 4.46-4.38 (2H, m), 4.10-4.02 (1H, m), 3.61 (1H, dd,
J=10.5, 2.0 Hz), 2.73 (1H, dd, J=18.0, 7.0 Hz), 2.43-2.25 (6H, m),
2.20 (1H, dd, J=18.0, 10.0 Hz), 2.15-1.95 (6H, m), 1.95-1.62 (9H,
m), 1.57-1.48 (1H, m).
Example 6(4)
(5Z, 11.alpha.,
13E)-17,17-propano-19-methyl-11,16-dihydroxy-9-oxoprosta-5-
,13-dienoic acid
[0415] 401
[0416] less polar
[0417] TLC: Rf 0.31 (hexane:ethyl acetate:acteic acid=1:2:0.03);
NMR (CDCl.sub.3): .delta.5.75 (1H, dt, J=15.2, 6.4 Hz), 5.55-5.30
(3H, m), 5.40-4.40 (3H, br), 4.17-4.00 (1H, m), 3.70 (1H, dd,
J=10.2, 2.0 Hz), 2.76 (1H, ddd, J=18.6, 7.4, 1.0 Hz), 2.50-1.50
(20H, m), 1.55 (1H, dd, J=14.2, 6.8 Hz), 1.33 (1H, dd, J=14.2, 6.2
Hz), 0.92 (6H, d, J=6.6 Hz).
[0418] more polar
[0419] TLC: Rf 0.24 (hexane:ethyl acetate:acetic acid=1:2:0.03);
NMR (CDCl.sub.3): .delta.5.72 (1H, ddd, J=15.2, 8.0, 5.8 Hz),
5.55-5.25 (3H, m), 5.20-4.20 (3H, br), 4.14-3.98 (1H, m), 3.68 (1H,
dd, J=10.0, 2.0 Hz), 2.74 (1H, ddd, J=18.0, 7.2, 1.0 Hz), 2.50-1.50
(20H, m), 1.55 (1H, dd, J=14.2, 7.2 Hz), 1.33 (1H, dd, J=14.2, 6.4
Hz), 0.92 (6H, d, J=6.4 Hz).
Example 6(5)
(5Z, 11.alpha.,
13E)-17,17-propano-11,16-dihydroxy-9-oxo-20-norprosta-5,13-
,18-trienoic acid
[0420] 402
[0421] less polar
[0422] TLC: Rf 0.36 (ethyl acetate:acteic acid 50:1); NMR
(CDCl.sub.3): .delta.5.93 (1H, dd, J=17.2, 10.6 Hz), 5.70 (1H, ddd,
J=15.2, 7.2, 5.8 Hz), 5.49-5.38 (3H, m), 5.24 (1H, dd, J=10.6, 1.4
Hz), 5.16 (1H, dd, J=17.2,1.4 Hz), 4.20-3.20 (3H, br), 4.13-4.00
(1H, m), 3.68 (1H, dd, J=10.4, 2.4 Hz), 2.74 (1H, ddd, J=18.4, 7.4,
1.2 Hz), 2.43-1.60 (19H, m).
[0423] more polar
[0424] TLC: Rf 0.32 (ethyl acetate:acteic acid=50:1); NMR
(CDCl.sub.3): .delta.5.93 (1H, dd, J=17.2, 10.6 Hz), 5.65 (1H, ddd,
J=15.2, 8.2, 5.6 Hz), 5.28-5.15 (3H, m), 5.25 (1H, dd, J=10.6, 1.4
Hz), 5.16 (1H, dd, J=17.2,1.4 Hz), 5.10-4.10 (3H, br), 4.08-3.95
(1H, m), 3.63 (1H, dd, J=10.6, 2.0 Hz), 2.70 (1H, ddd, J=19.2, 7.6,
1.1 Hz), 2.42-1.60 (19H, m).
Example 6(6)
(5Z, 11.alpha.,
13Z)-17,17-propano-11,16-dihydroxy-9-oxoprosta-5,13-dienoi- c
acid
[0425] 403
[0426] less polar
[0427] TLC: Rf 0.49 (hexane:ethyl acetate:acteic acid=1:2:0.03);
NMR (CDCl.sub.3): .delta.6.00-4.00 (3H, br), 5.67 (1H, dt, J=5, 11
Hz), 5.46 (1H, t, J=11 Hz), 5.43-5.33 (2H, m), 4.08-4.00 (1H, m),
3.61 (1H, dd, J=10, 2 Hz), 2.83-2.72 (2H, m), 2.40-2.25 (3H, m),
2.33 (2H, t, J=7.5 Hz), 2.25 (1H, dd, J=19, 9.5 Hz), 2.15-2.03 (4H,
m), 2.03-1.63 (8H, m), 1.60-1.53 (1H, m), 1.43-1.25 (3H, m), 0.95
(3H, t, J=7 Hz).
[0428] more polar
[0429] TLC: Rf 0.45 (hexane:ethyl acetate:acteic acid=1:2:0.03);
NMR (CDCl.sub.3): .delta.5.69 (1H, dt, J=11, 8 Hz), 5.47-5.35 (3H,
m), 5.00-3.00 (3H, br), 4.10-4.03 (1H, m), 3.64 (1H, dd, J=7, 3
Hz), 2.84-2.73 (2H, m), 2.43-1.95 (9H, m), 2.33 (2H, t, J=7 Hz),
2.26 (1H, dd, J=18.5, 9.5 Hz), 1.92-1.55 (7H, m), 1.45-1.30 (3H,
m), 0.95 (3H, t, J=7 Hz).
Example 6(7)
(5Z, 11.alpha., 13E)-17,17-propano-11 ,16-dihydroxy-9-oxo-19,
20-dinorprosta-5,13-dienoic acid
[0430] 404
[0431] more polar
[0432] TLC: Rf 0.19 (hexane:ethyl acetate:acteic acid=1:3:0.04);
NMR (CDCl.sub.3): .delta.6.00-4.00 (3H, br), 5.71 (1H, ddd, J=15,
8, 6 Hz), 5.55-5.30 (3H, m), 4.15-3.95 (1H, m), 3.60 (1H, dd, J=10,
2 Hz), 2.73 (1H, ddd, J=18, 7, 1 Hz), 2.50-1.60 (19H, m), 1.15 (3H,
s).
Example 6(8)
(5Z, 11.alpha., 13E)-17,17-propano-11,16-dihydroxy-9-oxo-18,19,
20-trinorprosta-5,13-dienoic acid
[0433] 405
[0434] more polar
[0435] TLC: Rf 0.16 (hexane:ethyl acetate:acteic acid=1:3:0.04);
NMR (CDCl.sub.3): .delta.6.00-4.00 (3H, br), 5.70 (1H, ddd, J=15,
8, 6Hz), 5.53-5.28 (3H, m), 4.13-3.96 (1H, m), 3.65-3.55 (1H, m),
2.74 (1H, ddd, J=18, 7, 1Hz), 2.60-1.60 (20H, m).
Reference Example 12
(5Z, 13E)-17,17-propano-16-hydroxy-9-oxoprosta-5,10,13-trienoic
acid.cndot.methylester
[0436] 406
[0437] To a solution of the compound prepared in example 1 (more
polar; 95 mg) in THF (5 ml) was added copper chloride (40 mg) and
1N aqueous solution of hydrochloric acid (5 ml). The reaction
mixture was stirred at 60.degree. C. for 4 hours. The reaction
mixture was quenched by addition of a saturated aqueous solution of
sodium hydrogencarbonate, extracted with ethyl acetate. The extract
was washed with a saturated aqueous solution of sodium chloride,
dried over anhydrous magnesium sulfate and concentrated. To the
residue was dissolved into diethyl ether (5 ml) was added a
solution of diazomethane in diethyl ether until the reaction
solution became yellow color. The reaction mixture was concentrated
with under reduced pressure. The residue was purified by column
chromatography on silica gel (hexane-ethyl acetate) to give the
tittle compound (65 mg) having the following physical data.
[0438] TLC: Rf 0.68 (hexane:ethyl acetate=1:1). NMR (CDCl.sub.3):
.delta.7.49 (1H, dd, J=6.0, 2.8 Hz), 6.16 (1H, dd, J=6.0, 2.2 Hz),
5.67-5.24 (4H, m), 3.67 (3H, s), 3.54 (1H, dd, J=9.8, 2.8 Hz),
3.25-3.19 (1H, m), 2.30-1.25 (20H, m), 2.32 (2H, t, J=6.8 Hz), 0.92
(3H, t, J=7.0 Hz).
Reference Example 13
(5Z,
13E)-17,17-propano-16-t-butyldimethylsilyloxy-9-oxoprosta-5,10,13-tri-
enoic acid.cndot.methylester
[0439] 407
[0440] To a solution of the compound prepared in reference example
12 (60 mg) and 2,6-lutidine (116 .mu.l) in anhydrous
dichloromethane (5 ml) was added dropwise trifluoromethanesulfonic
acid t-butyldimethylsilylester (190 .mu.l) at 0.degree. C. under an
atmosphere of argon. The reaction mixture was stirred at 0.degree.
C. for 2 hours. The reaction mixture was quenched by addition of a
saturated aqueous solution of sodium hydrogencarbonate, extracted
with hexane (.times.2). The extract was washed with a saturated
aqueous solution of sodium chloride, dried over anhydrous magnesium
sulfate and concentrated. The residue was purified by column
chromatography on silica gel (hexane-ethyl acetate) to give the
title compound (44 mg) having the following physical data.
[0441] TLC: Rf 0.53 (hexane:ethyl acetate=4:1).
Reference Example 14
(5Z,
13E)-17,17-propano-16-t-butyldimethylsilyloxy-9-oxoprosta-5,13-dienoi-
c acid.cndot.methylester
[0442] 408
[0443] To a suspension of lithium aluminum hydride (48 mg) in
anhydrous THF (1 ml) was added a suspension of copper iodide (I)
(190 mg) in THF-HMPA (1:1, 2 ml) at -78.degree. C. under an
atmosphere of argon. The mixture was stirred at same temperature
for 30 min. To the mixture was added dropwise a solution of the
compound prepared in reference example 13 (43 mg) in anhydrous THF
(2 ml). The reaction mixture was stirred at same temperature for 30
min. To the reaction mixture was added a saturated aqueous solution
of sodium ammonium, warmed up at room temperature, filtered. The
precipitate was washed with ether. The water layer of the filtrate
was extracted with ether. The extract was washed with a saturated
aqueous solution of sodium chloride, dried over anhydrous magnesium
sulfate and concentrated. The residue was purified by column
chromatography on silica gel (hexane-ethyl acetate) to give the
title compound (25 mg) having the following physical data.
[0444] Rf 0.41 (hexane:ethyl acetate=4:1); NMR (CDCl.sub.3):
.delta.5.60-5.25 (4H, m), 3.66 (3H, s), 3.57 (1H, m), 2.50-1.20
(24H, m), 2.30 (2H, t, J=6.8 Hz), 0.98-0.85 (12H, m), 0.03 (6H,
s).
Example 7
(5Z, 13E)-17,17-propano-16-hydroxy-9-oxoprosta-5,13-dienoic acid
methylester
[0445] 409
[0446] By the same procedure as provided in example 1, using the
compound prepared in reference example 14, compounds of the present
invention having the following physical data were obtained.
[0447] less polar
[0448] TLC: Rf 0.81 (hexane ethyl acetate=1:1); NMR (CDCl.sub.3):
.delta.5.58-5.33 (4H, m), 3.67 (3H, s), 3.51 (1H, dd, j=10.2, 2.6
Hz), 2.56-1.24 (25H, m), 2.33 (2H, t, J=7.6 Hz), 0.94 (3H, t, J=7.0
Hz).
[0449] more polar
[0450] TLC: Rf 0.76(hexane:ethyl acetate=1:1); NMR (CDCl.sub.3):
.delta.5.70-5.25 (4H, m), 3.67 (3H, s), 3.53 (1H, dd, J=10.0, 2.4
Hz), 2.58-1.22 (25H, m), 2.32 (2H, t, J-7.6 Hz), 0.94 (3H, t, J=6.8
Hz).
Example 8
(5Z, 13E)-17,17-propano-16-hydroxy-9-oxoprosta-5,13-dienoic
acid
[0451] 410
[0452] By the same procedure as provided in example 4, using the
compound prepared in example 7, compounds of the present invention
having the following physical data were obtained.
[0453] less polar
[0454] TLC: Rf 0.74 (hexane:ethyl acetate:acteic acid=100:100:1);
NMR (CDCl.sub.3): .delta.5.58-5.37 (4H, m), 5.40-3.40 (2H, br),
3.60 (1H, dd, J=10.2, 2.2 Hz), 2.53-1.20 (24H, m), 2.30 (2H, t,
J=6.8 Hz), 0.93 (3H, t, J=6.8 Hz).
[0455] more polar
[0456] TLC: Rf 0.71 (hexane:ethyl acetate:acteic acid=100:100:1);
NMR (CDCl.sub.3): .delta.5.62-5.37 (4H, m), 5.60-3.20 (2H, br),
3.64-3.53 (1H, m), 2.55-1.20 (24H, m), 2.30 (2H, t, J=6.8 Hz), 0.94
(3H, t, J=6.8 Hz).
Example 9
(5Z, 11
.alpha.,13E)-17,17-propano-11-methoxy-16-hydroxy-9-oxoprosta-5,13--
dienoic acid.cndot.methylester
[0457] 411
[0458] To a solution of the compound prepared in example 1 (more
polar; 78 mg) in ether (5 ml) was added silica gel (kiesel gel)
(4.7 g). To the mixture was added dropwise a solution of
diazomethane in ether under cooling with ice. The suspension was
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (kiesel gel 7734, 20 g,
hexane:ethyl acetate=5:1.fwdarw.3:1) to give the present invention
compound (more polar: 45 mg) having the following physical
data.
[0459] more polar
[0460] Rf 0.57 (hexane:ethyl acetate=1:1); NMR (CDCl.sub.3):
.delta.5.67 (1H, ddd, J=15.4, 7.6, 5.8 Hz), 5.51 (1H, dd, J=15.4,
7.8 Hz), 5.50-5.26 (2H, m), 3.77-3.63 (1H, m), 3.67 (3H, s), 3.53
(1H, dd, J=10.2, 2.4 Hz), 3.37 (3H, s), 2.76 (1H, ddd, J=18.6, 7.2,
1.2 Hz), 2.54 (1H, dt, J=11.8, 7.8 Hz), 2.45-1.20 (21H, m), 2.31
(2H, t, J=7.5 Hz), 0.94 (3H, t, J=6.9 Hz).
[0461] By the same reaction as provided in above method, using the
less polar compound prepared in example 1, compound (less polar: 47
mg) of the present invention having the following physical data was
obtained.
[0462] less polar
[0463] Rf 0.66 (hexane:ethyl acetate=1:1); NMR (CDCl.sub.3):
.delta.5.74-5.26 (4H, m), 3.78-3.65 (1H, m), 3.67 (3H, s), 3.54
(1H, dd, J=10.0, 2.4 Hz), 3.38 (3H, s), 2.77 (1H, ddd, J=18.4, 7.0,
1.0 Hz), 2.55 (1H, dt, J=11.6, 7.4 Hz), 2.40-1.20 (21H, m), 2.32
(2H, t, J=7.4 Hz), 0.94 (3H, t, J=6.9 Hz).
Example 9(1).about.9(4)
[0464] By the same procedure as provided in example 9, compounds of
the present invention having the following physical data were
obtained.
Example 9(1)
(5Z, 11.alpha.,
13E)-17,17-propano-11-methoxy-16-hydroxy-9-oxo-19-methylpr-
osta-5,13-dienoic acid.cndot.methylester
[0465] 412
[0466] more polar
[0467] TLC: Rf 0.72 (hexane:ethyl acetate 1:1); NMR (CDCl.sub.3):
.delta.5.79-5.25 (4H, m), 3.77-3.60 (2H, m), 3.66 (3H, S), 3.37
(3H, s), 2.76 (1H, ddd, J=18.4, 7.6, 1.2 Hz), 2.61-1.20 (21H, m),
2.33 (2H, t, J=6.9 Hz), 0.93 (3H, d, J=1.0 Hz), 0.90 (3H, d, J=1.0
Hz).
Example 9(2)
(5Z, 11.alpha., 13E)-17,17-propano-11-methoxy-16-hydroxy-9-oxo-19,
20-methanoprosta-5,13-dienoic acid.cndot.methylester
[0468] 413
[0469] more polar
[0470] TLC: Rf 0.63 (hexane:ethyl acetate=1:1); NMR (CDCl.sub.3):
.delta.5.77-5.23 (4H, m), 3.76-3.64 (2H, m), 3.66 (3H, S), 3.37
(3H, s), 2.76 (1H, ddd, J=18.4, 7.0,1.2 Hz), 2.61-1.23 (20H, m),
2.33 (2H, t, J=6.9 Hz), 0.90-0.70 (1H, m), 0.55-0.45 (2H, m),
0.15-0.05 (2H, m).
Example 9(3)
(5Z, 11.alpha.,
13E)-17,17-propano-11-methoxy-16-hydroxy-9-oxo-20-norprost-
a-5,13-dienoic acid.cndot.methylester
[0471] 414
[0472] more polar
[0473] TLC: Rf 0.56 (hexane:ethyl acetate=1:1); NMR (CDCl.sub.3):
.delta.5.75-5.27 (4H, m), 3.76-3.64 (1H, m), 3.66 (3H, s), 3.54
(1H, dd, J=10.0, 2.4 Hz), 3.37 (3H, s), 2.76 (1H, ddd, J=18.4,
7.0,1.2 Hz), 2.60-1.35 (20H, m), 2.31 (2H, t, J=6.8 Hz), 0.92 (3H,
t, J=7.2 Hz).
Example 9(4)
(5Z, 11.alpha.,
13E)-17,17-propano-11-methoxy-16-hydroxy-9-oxoprosta-5,13,-
19-trienoic acid.cndot.methylester
[0474] 415
[0475] more polar
[0476] TLC: Rf 0.53 (hexane:ethyl acetate=1:1); NMR (CDCl.sub.3):
.delta.6.03-5.81 (1H, m), 5.75-5.23 (4H, m), 5.15-5.06 (2H, m),
3.76-3.64 (1H, m), 3.54 (1H, dd, J=10.4, 2.2 Hz), 3.37 (3H, s),
2.76 (1H, ddd, J=18.4, 7.0, 1.4 Hz), 2.60-1.50 (20H, m), 2.31 (2H,
t, J=6.9 Hz).
Example 10
(5Z, 11.alpha.,
13E)-17,17-propano-11-methoxy-16-hydroxy-9-oxoprosta-5,13-- dienoic
acid
[0477] 416
[0478] By the same procedure as provided in example 4, using the
compound prepared in example 9 (less polar or more polar),
compounds of the present invention having the following physical
data were obtained.
[0479] less polar
[0480] TLC: Rf 0.40 (hexane:ethyl acetate: methanol=1:1:0.02); NMR
(CDCl.sub.3): .delta.5.66 (1H, ddd, J=15.4, 7.6, 5.4 Hz), 5.50 (1H,
dd, J=15.4, 7.2 Hz), 5.50-5.30 (2H, m), 4.50-2.50 (2H, br),
3.78-3.63 (1H, m), 3.63 (1H, dd, J=10.4, 2.4 Hz), 3.38 (3H, s),
2.77 (1H, ddd, J=18.2, 7.0, 1.0 Hz), 2.51 (1H, dt, J=11.4, 7.8 Hz),
2.40-1.20 (20H, m), 2.34 (2H, t, J=6.8 Hz), 0.94 (3H, t, J=6.7
Hz).
[0481] more polar
[0482] TLC: Rf 0.36 (hexane:ethyl acetate :methanol=1:1:0.02); NMR
(CDCl.sub.3): .delta.5.69 (1H, ddd, J=15.4, 6.6, 6.0 Hz), 5.54 (1H,
dd, J=15.4, 7.2 Hz), 5.50-5.30 (2H, m), 5.00-3.00 (2H, br),
3.77-3.63 (1H, m), 3.60 (1H, dd, J=10.0, 2.4 Hz), 3.37 (3H, s),
2.77 (1H, ddd, J=18.2, 7.2, 1.2 Hz), 2.53 (1H, dt, J=11.2, 7.8 Hz),
2.42-1.20 (20H, m), 2.34 (2H, t, J=7.1 Hz), 0.94 (3H, t, J=6.8
Hz).
Example 10(1).about.10(4)
[0483] By the same procedure as provided in example 10, compounds
of the present invention having the following physical data were
obtained.
Example 10(1)
(5Z, 11.alpha., 13E)-17,
17-propano-11-methoxy-16-hydroxy-19-methyl-9-oxop- rosta-5,
13-dienoic acid
[0484] 417
[0485] more polar
[0486] TLC: Rf 0.28 (hexane:ethyl acetate=1:1); NMR
(CDCl.sub.3):.delta.5.78-5.28 (4H, m), 5.00-4.00 (2H, br),
3.77-3.64 (2H, m), 3.37 (3H, s), 2.77 (1H, dd, J=18.4, 7.4 Hz),
2.60-1.22 (20H, m), 2.34 (2H, t, J=6.9 Hz), 0.93 (3H, d, J=1.2 Hz),
0.90 (3H, d, J=1.0 Hz).
Example 10(2)
(5Z, 11.alpha., 3E)-17, 17-propano-11-methoxy-16-hydroxy-9-oxo-19,
20-methanoprosta-5, 13-dienoic acid
[0487] 418
[0488] more polar
[0489] TLC: Rf 0.29 (hexane ethyl acetate=1:1); NMR
(CDCl.sub.3):.delta.5.80-5.30 (4H, m), 3.79-3.64 (2H, m), 3.38 (3H,
s), 2.77 (1H, dd, J=18.2, 7.2 Hz), 2.59-1.10 (23H, m), 0.95-0.70
(1H, m), 0.55-0.45 (2H, m), 0.15-0.05 (2H, m).
Example 10(3)
(5Z, 11.alpha., 13E)-17,
17-propano-11-methoxy-16-hydroxy-9-oxo-20-norpros- ta-5, 13-dienoic
acid
[0490] 419
[0491] more polar
[0492] TLC: Rf 0.27 (hexane:ethyl acetate=1:1); NMR (CDCl.sub.3):
.delta.5.78-5.30 (4H, m), 3.76-3.58 (2H, m), 3.60-2.60 (2H, br),
3.37 (3H, s), 2.77 (1H, ddd, J=18.4, 7.0, 1.4 Hz), 2.60-1.32 (19H,
m), 2.33 (2H, t, J=7.0 Hz), 0.92 (3H, t, J=7.4 Hz).
Example 10(4)
(5Z, 11.alpha., 13E)-17,
17-propano-11-methoxy-16-hydroxy-9-oxoprosta-5, 13, 19-trienoic
acid
[0493] 420
[0494] more polar
[0495] TLC: Rf 0.25 (hexane ethyl acetate=1:1); NMR (CDCl.sub.3):
.delta.6.03-5.82 (1H, m), 5.77-5.30 (4H, m), 5.17-5.07 (2H, m),
4.40-1.40 (2H, br), 3.76-3.59 (2H, m), 3.37 (3H, s), 2.77 (1H, ddd,
J=18.4, 7.2, 1.2 Hz), 2.59-1.60 (19H, m), 2.33 (2H, t, J=7.0
Hz).
Reference Example 15
(5Z, 11.alpha., 13E)-17, 17-propano-11,
16-bis(t-butyldimethylsilyloxy)-9,- 9-methyleneprosta-5, 13-dienoic
acid.cndot. methylester
[0496] 421
[0497] To a stirred suspension of zinc powder (2.875 g) in THF (25
ml) was added dropwise dibromomethane (1.01 ml) at room temperature
under an atmosphere of argon. After the reaction mixture cooled at
-40.degree. C. , to the mixture was slowly added dropwise titanium
tetrachloride (1.13 ml). The mixture was stirred at 5.degree. C.
for 3 days, Nozaki-Lombardo reagent was obtained as a grayish
suspension.
[0498] To a stirred solution of the compound prepared in reference
example 3 (150 mg) in dichloromethane (3 ml) was added the aboved
obtained Nozaki-Lombardo reagent (3 ml) at 0.degree. C. The
reaction mixture was stirred at room temperature for 1.5 hours. The
reaction mixture was quenched by addition of ice and a saturated
aqueous solution of sodium hydrogencarbonate, extracted with ether
(.times.3). The extract was washed with water (.times.2), a
saturated aqueous solution of sodium chloride, successively, dried
over anhydrous magnesium sulfate and concentrated. The residue was
purified by column chromatography on silica gel (Merck Kiesel gel
7734, 20 ml, ethyl acetate:hexane=1:40) to give the tittle compound
(120 mg) as a colorless oil having the following physical data.
[0499] TLC: Rf 0.47 (ethyl acetate:hexane=1:20); NMR (CDCl.sub.3):
.delta.5.65-5.15 (4H, m), 4.88 (1H, brs), 4.83 (1H, brs), 3.77 (1H.
q, J=7.5 Hz), 3.66 (3H, s), 3.56 (1H, t, J=5.0 Hz), 2.60 (1H, dd,
J=16.5, 7.0 Hz), 2.40-1.15 (23H, m), 0.90 (9H, s), 0.87 (9H, s),
1.00-0.80 (3H, m,), 0.05 (6H, s), 0.02 (6H, s).
Example 11
(5Z, 11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9,9-methyleneprosta-5- , 13-dienoic acid.phi.
methylester
[0500] 422
[0501] By the same procedure as provided in example 1, using the
compound prepared in reference example 15, compounds of the present
invention having the following physical data were obtained.
[0502] less polar
[0503] TLC: Rf 0.39 (ethyl acetate:hexane=1:2); NMR (CDCl.sub.3):
.delta.5.70-5.30 (4H, m), 4.96 (1H, brs), 4.88 (1H, brs), 3.83 (1H,
q, J=7.5 Hz), 3.67 (3H, s), 3.52 (1H, dd, J=10.0, 2.0 Hz), 2.76
(1H, dd, J=16.0, 7.0 Hz), 2.40-1.20 (25H, m), 0.93 (3H, t, J=7.0
Hz).
[0504] more polar
[0505] TLC: Rf 0.33 (ethyl acetate:hexane=1:2); NMR (CDCl.sub.3):
.delta.5.70-5.30 (4H, m), 4.95 (1H, brs), 4.88 (1H, brs), 3.82 (1H,
q, J=7.0 Hz), 3.70 (3H, s), 3.53 (1H, dd, J=10.0, 2.5 Hz), 2.75
(1H, dd, J=16.0, 7.0 Hz), 2.40-1.20 (25H, m), 0.94 (3H, t, J=7.0
Hz).
Example 12
(5Z, 11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9,9-methyleneprosta-5- , 13-dienoic acid
[0506] 423
[0507] By the same procedure as provided in example 4, using the
compound prepared in example 11, compounds of the present invention
having the following physical data were obtained.
[0508] less polar
[0509] TLC: Rf 0.52 (ethyl acetate:hexane:acetic acid=9:10:1); NMR
(CDCl.sub.3): .delta.5.70-5.30 (4H, m), 4.96 (1H, brs), 4.89 (1H,
brs), 3.82 (1H, q, J=8.5 Hz), 3.61 (1H, dd, J=10, 2.5 Hz), 2.74
(1H, dd, J=15.5, 7.0 Hz), 2.40-1.20 (25H, m), 0.93 (3H, t, J=7.0
Hz).
[0510] more polar
[0511] TLC: Rf 0.52 (ethyl acetate:hexane:acetic acid 9:10:1); NMR
(CDCl.sub.3): .delta.5.70-5.20 (4H, m), 4.95 (1H, brs), 4.88 (1H,
brs), 3.81 (1H, q, J=6.5 Hz), 3.59 (1H, dd, J=10, 2.5 Hz), 2.73
(1H, dd, J=16.0, 7.0 Hz), 2.40-1.20 (25H, m), 0.94 (3H, t, J=7.0
Hz).
Example 13
(5Z, 11.alpha., 13E)-17, 17-propano-11, 16-dihydroxy-9-oxoprosta-5,
13-dienoic acid amide
[0512] 424
[0513] To a stirred solution of the compound prepared in example 4
(less polar; 42 mg) in dichloromethane (1 ml) was added
triethylamine (81 ml) and isobutyl chloroformate (60 ml) at
0.degree. C. After the mixture was stirred for 30 min, to the
mixture was added ammonia in water solution (0.5 ml). The reaction
mixture was stirred for 10 min. The reaction mixture was quenched
by addition of 1N aqueous solution of hydrochloric acid, extracted
with ethyl acetate (.times.3). The extract was washed with water
(.times.2), 1N aqueous solution of hydrochloric acid (.times.2) and
a saturated aqueous solution of sodium chloride, successively,
dried over anhydrous magnesium sulfate and concentrated. The
residue was purified by column chromatography on silica gel (Merck
Kiesel gel 7734, 5 ml, ethyl
acetate:hexane=3:2.fwdarw.MeOH:CHCl.sub.3=1:- 19.fwdarw.1:9) to
give the present invention compound (32 mg) as a pale yellow oil
having the following physical data.
[0514] less polar
[0515] TLC: Rf 0.52 (methanol:chloroform=1:9); NMR (CDCl.sub.3):
.delta.5.90-5.20 (6H, m), 4.10 (1H, q, J=9.0 Hz), 3.55 (1H, d,
J=8.0 Hz), 2.73 (1H, dd, J=11.0, 7.5 Hz), 2.75-2.55 (1H, m),
2.55-1.20 (24m), 0.94 (3H, t, J=6.5 Hz).
[0516] By the same procedure as provided in above example, using
the compound prepared in example 4 (more polar), compound of the
present invention having the following physical data was
obtained.
[0517] more polar
[0518] TLC: Rf 0.52 (methanol:chloroform=1:9); NMR (CDCl.sub.3):
.delta.5.90-5.60 (2H, m), 5.60-5.20 (4H, m), 4.07 (1H, q, J=8.5
Hz), 3.55 (1H, dd, J=10.0, 2.0 Hz), 3.04 (1H, brs), 2.74 (1H, ddd,
J=18.0, 7.0, 1.0 Hz), 2.75-2.50 (1H, m), 2.50-1.20 (23H, m), 0.94
(3H, t, J=7.0 Hz).
Reference Example 16
(5Z, 9.alpha., 11.alpha., 13E)-17, 17-propano-11,
16-bis(t-butyldimethylsi- lyloxy)-9-hydroxy-prosta-5, 13-dienoic
acid.cndot.methylester
[0519] 425
[0520] To a solution of (5Z, 11.alpha., 13E)-17, 17-propano-11,
16-bis(t-butyldimethylsilyloxy)-9-oxoprosta-5, 13-dienoic
acid.cndot.methylester (740 mg, the compound prepared in reference
example 3) in THF (20 ml) was added dropwise L-Selectride (1.76 ml;
1.0 M in THF solution) at -78.degree. C. under an atmosphere of
argon. After the mixture was stirred at same temperature for 30
min, to the solution was added dropwise a 30% aqueous solution of
hydroperoxide (1 ml) at same temperature. The reaction mixture was
warmed up to 0.degree. C. The reaction mixture was quenched by
addition of 2N aqueous solution of hydrochloric acid (1 ml),
extracted with ethyl acetate. The extract was washed with water and
a saturated aqueous solution of sodium chloride, successively,
dried over anhydrous magnesium sulfate and concentrated. The
residue was purified by column chromatography on silica gel (Merck
Kiesel gel 7734, 30 g, hexane:ethyl acetate=9 1) to give the title
compound (558 mg) as a pale yellow oil having the following
physical data.
[0521] TLC: Rf 0.35 (hexane:ethyl acetate=9:1); NMR (CDCl.sub.3):
.delta.5.60-5.10 (4H, m), 4.15-3.90 (2H, m), 3.66 (3H, s), 3.55
(1H, t, J=5 Hz), 2.70-2.50 (1H, m), 2.40-1.20 (24H, m), 1.00-0.80
(21H, m), 0.10-0.00 (12H, m).
Reference Example 17
(5Z, 9.alpha., 11.alpha., 13E)-17, 17-propano-11,
16-bis(t-butyldimethylsi- lyloxy)-9-acetyloxy-prosta-5, 13-dienoic
acid methylester
[0522] 426
[0523] To a solution of the compound prepared in reference example
16 (518 mg) in pyridine (1 ml) was added acetic anhydride (0.15 ml)
and dimethylaminopyridine (catalytic amount). The reaction mixture
was stirred at room temperature overnight. The reaction mixture was
quenched by addition of water, extracted with ethyl acetate. The
extract was washed with dilute hydrochloric acid, water and a
saturated aqueous solution of sodium chloride, successively, dried,
filtered, and concentrated to give the title compound having the
following physical data.
[0524] TLC: Rf 0.42 (hexane:ethyl acetate=91).
Reference Example 18
(5Z, 9.alpha., 11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9-acetyloxy- -prosta-5, 13-dienoic
acid.cndot.methylester
[0525] 427
[0526] To a solution of the compound prepared in reference example
17 in acetonitrile (10 ml) was added dropwise 48% aqueous solution
of hydrofluoric acid (0.5 ml) under cooling with ice. The reaction
mixture was stirred at room temperature for 1.5 hours. The reaction
mixture was quenched by addition of a saturated aqueous solution of
sodium hydrogencarbonate, extracted with ethyl acetate. The extract
was washed with a saturated aqueous solution of sodium
hydrogencarbonate and a saturated aqueous solution of sodium
chloride, successively, dried over anhydrous magnesium sulfate and
concentrated. The residue was purified by Lobar column
chromatography (size B, hexane:ethyl acetate=2:3) to give the title
two compounds (less polar; 142 mg, more polar; 148 mg) having the
following physical data.
[0527] less polar
[0528] TLC: Rf 0.30 (hexane:ethyl acetate=1:1); NMR (CDCl.sub.3)
:.delta.5.66 (1H, ddd, J=15.0, 7.8, 6.0 Hz), 5.45-5.30 (3H, m),
5.15-5.05 (1H, m), 4.00-3.85 (1H, m), 3.67 (3H, s), 3.55 (1H, dd,
J=10.0, 2.4 Hz), 2.58-2.40 (1H, m), 2.40-1.30 (23H, m), 2.31 (2H,
t, J=7.4 Hz), 2.06 (3H, s), 0.94 (3H, t, J=7.2 Hz).
[0529] more polar
[0530] TLC: Rf 0.23 (hexane:ethyl acetate 1:1); NMR (CDCl.sub.3):
.delta.5.65 (1H, ddd, J=14.8, 8.0, 6.2 Hz), 5.43-5.25 (3H, m),
5.15-5.05 (1H, m), 3.95-3.82 (1H, m), 3.67 (3H, s), 3.55 (1H, dd,
J=10.0, 2.4 Hz), 2.60-2.40 (1H, m), 2.40-1.20 (23H, m), 2.30 (2H,
t, J=7.4 Hz), 2.06 (3H, s), 0.94 (3H, t, J=6.7 Hz).
Reference Example 19
(5Z, 9.alpha., 11.alpha., 13E)-17, 17-propano-11,
16-bis(2-tetrahydropyran- yloxy)-9-acetyloxy-prosta-5, 13-dienoic
acid methylester
[0531] 428
[0532] To a stirred solution of the compound prepared in reference
example 18 (less polar; 64 mg) in dichloromethane (1 ml) was added
dihydropyran (400 ml) and PPTS (pyridinium p-toluenesulfonate; 4
mg) at room temperature under an atmosphere of argon. The reaction
mixture was stirred at room temperature for 6 hours. The reaction
mixture was quenched by addition of water and a saturated aqueous
solution of sodium hydrogencarbonate, extracted with ethyl acetate
(.times.3). The extract was washed with water (.times.2) and a
saturated aqueous solution of sodium chloride, successively, dried
over anhydrous magnesium sulfate and concentrated. The residue was
purified by column chromatography on silica gel (Fuji Silysia
BW-300 20 ml, ethyl acetate:hexane=1:7.fwdarw.1:5) to give the
title compound (77.5 mg) as a colorless oil having the following
physical data.
[0533] TLC: Rf 0.37 (ethyl acetate:hexane=1:4); NMR (CDCl.sub.3):
.delta.5.85-5.45 (1H, m), 5.45-5.20 (3H, m), 5.10-4.98 (1H, m),
4.75-4.55 (2H, m), 4.05-3.70 (3H, m), 3.67 (3H, s), 3.65-3.38 (3H,
m), 2.60-1.20 (36H, m), 2.04 (3H, s), 1.00-0.85 (3H, m).
Reference Example 20
(5Z, 9.alpha., 11.alpha., 13E)-17, 17-propano-11,
16-bis(2-tetrahydropyran- yloxy)-9-hydroxy-prosta-5, 13-dienoic
acid.cndot.methylester
[0534] 429
[0535] To a stirred solution of the compound prepared in reference
example 19 (77 mg) in methanol (2 ml) was added potassium carbonate
(15 mg) at room temperature under an atmosphere of argon. The
reaction mixture was stirred at room temperature for 1 day. The
reaction mixture was quenched by addition of water and 1 N aqueous
solution of hydrochloric acid, extracted with ethyl acetate
(.times.3). The extract was washed with water (.times.2) and a
saturated aqueous solution of sodium chloride, successively, dried
over anhydrous magnesium sulfate and concentrated. The residue was
purified by column chromatography on silica gel (Merck 7734, 20 ml,
ethyl acetate:hexane=1:4.fwdarw.1:3) to give the title compound (70
mg) as a colorless oil having the following physical data.
[0536] TLC: Rf 0.39 (ethyl acetate:hexane=1:2); NMR (CDCl.sub.3):
.delta.5.75 (4H, m), 4.75-4.55 (2H, m), 4.20-3.75 (4H, m), 3.67
(3H, s), 3.62-3.38 (3H, m), 2.60-1.20 (34H, m), 2.32 (2H, t, J=7.5
Hz), 0.93 (3H, t, J=7.5 Hz).
Reference Example 21
(5Z, 9.beta., 11.alpha., 13E)-17, 17-propano-11,
16-bis(2-tetrahydropyrany- loxy)-9-fluoro-prosta-5, 13-dienoic
acid.cndot.methylester
[0537] 430
[0538] To a stirred solution of the compound prepared in reference
example 20 (70 mg) in dichloromethane (2 ml) was added DAST (20 ml,
diethylaminosulfur trifluoride) at -78.degree. C. under an
atmosphere of argon. The reaction mixture was stirred for 20 min.
The reaction mixture was quenched by addition of water and a
saturated aqueous solution of sodium hydrogencarbonate, extracted
with ethyl acetate (.times.3). The extract was washed with water
(.times.2) and a saturated aqueous solution of sodium chloride,
successively, dried over anhydrous magnesium sulfate and
concentrated. The residue was purified by column chromatography on
silica gel (Fuji Silysia BW-300 20 ml, ethyl acetate:hexane=1:10)
to give the title compound (36 mg) as a colorless oil having the
following physical data.
[0539] TLC: Rf 0.46 (ethyl acetate:hexane=1:5); NMR (CDCl.sub.3):
.delta.5.90-5.20 (4H, m), 4.75-4.55 (2H, m), 4.40-3.75 (3H, m),
3.67 (3H, s), 3.67-3.40 (3H, m), 2.60-1.20 (35H, m), 2.32 (2H, t,
J=7.5 Hz), 0.93 (3H, t, J=6.5 Hz).
Example 14
(5Z, 9.beta., 11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9-fluoro-pro- sta-5, 13-dienoic
acid.cndot.methylester
[0540] 431
[0541] To a stirred mixture of the compound prepared in reference
example 21 (36 mg) in THF (1 ml) and water (0.5 ml) was added
acetic acid (2 ml) at room temperature. The reaction mixture was
stirred at 45.degree. C. The reaction mixture was quenched by
addition of water, extracted with ethyl acetate (.times.3). The
extract was washed with water (.times.2) and a saturated aqueous
solution of sodium chloride, successively, dried over anhydrous
magnesium sulfate and concentrated. The residue was purified by
column chromatography on silica gel (Merck 7734, 20 ml, ethyl
acetate:hexane=1:2.fwdarw.1:1) and (Merck Lobar prepackaged column
size A, ethyl acetate:hexane=2:1) to give the present invention
compound (12 mg) having the following physical data.
[0542] less polar
[0543] TLC: Rf 0.54 (ethyl acetate:hexane=1:1); NMR (CDCl.sub.3):
.delta.5.80-5.40 (4H, m), 4.95-4.55 (1H, m), 4.20-4.00 (1H, m),
3.67 (3H, s), 3.54 (1H, dd, J=10.0, 2.5 Hz), 2.40-1.20 (24H, m),
2.33 (2H, t, J=7.5 Hz), 0.94 (3H, t, J=7.0 Hz).
[0544] By the same procedure as provided in reference example 19,
20 21 and example 14, using the compound prepared in reference
example 18 (more polar), compound of the present invention having
the following physical data was obtained.
[0545] more polar
[0546] TLC: Rf 0.48 (ethyl acetate:hexane=1:1); NMR (CDCl.sub.3):
.delta.5.80-5.30 (4H, m), 4.95-4.55 (1H, m), 4.20-4.00 (1H, m),
3.67 (3H, s), 3.53 (1H, dd, J=10.0, 2.0 Hz), 3.00-1.20 (24H, m),
2.32 (2H, t, J=7.5 Hz), 0.94 (3H, t, J=6.5 Hz).
Example 15
(5Z, 9.beta., 11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9-fluoro-pro- sta-5, 13-dienoic acid
[0547] 432
[0548] To a stirred solution of the compound prepared in example 14
(10 mg) in methanol (1 ml) was added 2N aqueous solution of sodium
hydroxide (0.3 ml) at room temperature under an atmosphere of
argon. The reaction mixture was stirred for 2 hours. The reaction
mixture was quenched by addition of water and 1N aqueous solution
of hydrochloric acid, extracted with ethyl acetate (.times.3). The
extract was washed with water (.times.2) and a saturated aqueous
solution of sodium chloride, successively, dried over anhydrous
magnesium sulfate and concentrated to give the present invention
compound (10 mg) as a colorless oil having the following physical
data.
[0549] less polar
[0550] TLC: Rf 0.38 (ethyl acetate:hexane=3:1); NMR (CDCl.sub.3):
.delta.5.80-5.30 (4H, m), 5.00-4.60 (1H, m), 4.20-4.00 (1H, m),
3.62 (1H, dd, J=10.0, 2.0 Hz), 2.34 (2H, t, J=6.5 Hz), 2.40-1.20
(24H, m), 0.94 (3H, t, J=6.5 Hz).
[0551] By the same procedure as provided in example 15, using the
compound prepared in example 14 (more polar), compound of the
present invention having the following physical data was
obtained.
[0552] more polar
[0553] TLC: Rf 0.35 (ethyl acetate:hexane=3:1); NMR (CDCl.sub.3):
.delta.5.80-5.30 (4H, m), 5.00-4.80 (1H, m), 4.20-4.00 (1H, m),
3.59 (1H, d, J=10.5 Hz), 2.35 (2H, t, J=7.0 Hz), 2.40-1.20 (24H,
m), 0.94 (3H, t, J=6.5 Hz).
Reference Example 22
(5Z, 9.alpha., 11.alpha., 13E)-17, 17-propano-11,
16-bis(t-butyldimethylsi- lyloxy)-9-acetyloxy-20-norprosta-5,
13-dienoic acid.cndot.methylester
[0554] 433
[0555] To a stirred solution of (5Z, 9.alpha., 11.alpha., 13E)-17,
17-propano-11, 16-dihydroxy-9-acetyloxy-20-norprosta-5, 13-dienoic
acid.cndot.methylester (119 mg; more polar; the compound prepared
in same method by reference example 18) in dichloromethane (2 ml)
was added 2,6-lutidine (0.26 ml) and trifluoromethanesulfonic acid
t-butyldimethylsilylester (0.26 ml) at 0.degree. C. under an
atmosphere of argon. The reaction mixture was stirred at 0.degree.
C. for 3 hours. The reaction mixture was quenched by addition of
water, extracted with ethyl acetate (.times.3). The extract was
washed with 0.1 N aqueous solution of hydrochloric acid (.times.2),
water and a saturated aqueous solution of sodium chloride,
successively, dried over anhydrous magnesium sulfate and
concentrated to give the tittle compound (211 mg) as a colorless
oil having the following physical data.
[0556] TLC: Rf 0.45 (ethyl acetate:hexane=1:8); NMR
(CDCl.sub.3):.delta.5.70-5.45 (1H, m), 5.32 (1H, t, J=4.5 Hz),
5.25-5.05 (1H, m), 5.05-4.95 (1H, m), 3.90-3.70 (1H, m), 3.6 (3H,
s), 358 (1H, t, J=5.0 Hz), 2.50-1.35 (21H, m), 2.29 (2H, t, J=7.5
Hz), 2.04 (3H, s), 1.00-0.80 (3H, m), 0.91 (9H, s), 0.86 (9H, s),
0.06 (3H, s), 0.05 (3H, s), 0.01 (6H, s).
Reference Example 23
(5Z, 9.alpha., 11.alpha., 13E)-17, 17-propano-11,
16-bis(t-butyldimethylsi- lyloxy)-9-hydroxy-20-norprosta-5,
13-dienoic acid.cndot.methylester
[0557] 434
[0558] To a stirred solution of the compound prepared in reference
example 22 (211 mg) in methanol (3 ml) was added potassium
carbonate (60 mg) under an atmosphere of argon. The reaction
mixture was stirred at room temperature for 1 day. The reaction
mixture was quenched by addition of water and 1 N aqueous solution
of hydrochloric acid, extracted with ethyl acetate (.times.3). The
extract was washed with water (.times.2) and a saturated aqueous
solution of sodium chloride, successively, dried over anhydrous
magnesium sulfate and concentrated. The residue was purified by
column chromatography on silica gel (Merck 7734, 20 ml, ethyl
acetate:hexane=1:8) to give the title compound (161 mg) as a
colorless oil having the following physical data.
[0559] TLC: Rf 0.35 (ethyl acetate:hexane=1:8); NMR (CDCl.sub.3):
.delta.5.60-5.15 (4H, m), 4.20-4.00 (1H, m), 4.00-3.95 (1H, m),
3.66 (3H, s), 3.57 (1H, t, J=5.0 Hz), 2.61 (1H, d, J=9.0 Hz),
2.42-1.35 (20H, m), 2.31 (2H, t, J=7.5 Hz), 1.00-0.80 (3H, m), 0.90
(9H, s), 0.87 (9H, s,), 0.07 (3H, s), 0.05 (3H, s), 0.04 (6H,
s).
Reference Example 24
(5Z, 9.alpha., 11.alpha., 13E)-17, 17-propano-11,
16-bis(t-butyldimethylsi- lyloxy)-9-tosyloxy-20-norprosta-5,
13-dienoic acid.cndot.methylester
[0560] 435
[0561] To a stirred solution of the compound prepared in reference
example 23 (161 mg) in pyridine (1 ml) was added tosyl chloride
(102 mg) at 0.degree. C. under an atmosphere of argon. The reaction
mixture was stirred at room temperature for 9 hours. the reaction
mixture was quenched by addition of water, extracted with ethyl
acetate (.times.3). The extract was washed with a saturated aqueous
solution of sodium hydrogencarbonate (.times.2), water and a
saturated aqueous solution of sodium chloride, successively, dried
over anhydrous magnesium sulfate and concentrated to give the title
compound (194 mg) having the following physical data.
[0562] TLC: Rf 0.64 (ethyl acetate:hexane=1:9).
Reference Example 25
(5Z, 9.beta., 11.alpha., 13E)-17, 17-propano-11,
16-bis(t-butyldimethylsil- yloxy)-9-chloro-20-norprosta-5,
13-dienoic acid.cndot.methylester
[0563] 436
[0564] To a stirred solution of tetrabutylammonium chloride (742
mg) was added dropwise a solution of the compound prepared in
reference example 24 (194 mg) in toluene (4 ml) under an atmosphere
of argon. The reaction mixture was stirred at 40.degree. C. for 12
hours. The reaction solution was changed to white suspension. The
reaction mixture was quenched by addition of water, extracted with
ethyl acetate (.times.3). The extract was washed with water
(.times.2), a saturated aqueous solution of sodium
hydrogencarbonate (.times.2) and a saturated aqueous solution of
sodium chloride, successively, dried over anhydrous magnesium
sulfate and concentrated to give the title compound (95 mg) having
the following physical data.
[0565] TLC: Rf 0.67 (ethyl acetate:hexane=1:8).
Example 16
(5Z, 9.beta., 11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9-chloro-20-- norprosta-5, 13-dienoic
acid.cndot.methylester
[0566] 437
[0567] By the same procedure as provided in example 14, using the
compound prepared in reference example 25, compound of the present
invention having the following physical data was obtained.
[0568] more polar
[0569] TLC: Rf 0.49 (ethyl acetate:hexane=1:1); NMR (CDCl.sub.3):
.delta.5.60 (1H, ddd, J=15, 8, 6 Hz), 5.50-5.33 (3H, m), 4.20-3.95
(2H, m), 3.67 (3H, s), 3.53 (1H, dd, J=10.5, 2.5 Hz), 2.32 (2H, t,
J=7.0 Hz), 2.40-1.50 (21H, m), 1.45 (1H, sept, J=7.0 Hz), 0.91 (3H,
t, J=7.5 Hz).
Example 16(1).about.16(6)
[0570] By the same procedure as provided in example 16, using the
compound prepared in reference example 22, 23, 24, 25 or example
16, compounds of the present invention having the following
physical data were obtained.
Example 16(1)
(5Z, 9.beta., 11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9-chloropros- ta-5, 13, 19-trienoic
acid.cndot.methylester
[0571] 438
[0572] more polar
[0573] TLC: Rf 0.49 (ethyl acetate:hexane=1:1); NMR (CDCl.sub.3):
67 6.06-5.83 (1H, m), 5.67-5.23 (4H, m), 5.20-5.04 (2H, m),
4.20-3.95 (2H, m), 3.67 (3H, s), 3.53 (1H, dd, J=10.0, 2.5 Hz),
2.60-1.50 (22H, m), 2.32 (2H, t, J=8.0 Hz).
Example 16(2)
(5Z, 9.beta., 11.alpha., 13E)-17, 17-propano-19, 20-methano-11,
16-dihydroxy-9-chloroprosta-5, 13-dienoic
acid.cndot.methylester
[0574] 439
[0575] more polar
[0576] TLC: Rf 0.25 (hexane:ethyl acetate=2:1); NMR (CDCl.sub.3):
.delta.5.61 (1H, ddd, J=15.4, 7.8, 5.4 Hz), 5.52-5.35 (3H, m),
4.18-3.94 (2H, m), 3.67 (3H, s), 3.67 (1H, dd, J=10.0, 2.2 Hz),
2.40-1.60 (20H, m), 2.33 (2H, t, J=7.4 Hz), 1.52 (1H, dd, J=14.4,
6.6 Hz), 1.35 (1H, dd, J=14.4, 6.2 Hz), 0.90-0.68 (1H, m),
0.55-0.45 (2H, m), 0.15-0.05 (2H, m).
Example 16(3)
(5Z, 9.beta., 11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9-chloro-19-- methylprosta-5, 13-dienoic
acid.cndot.methylester
[0577] 440
[0578] more polar
[0579] TLC: Rf 0.32 (hexane:ethyl acetate=2:1); NMR (CDCl.sub.3):
.delta.5.62 (1H, ddd, J=15.4, 7.8, 5.4 Hz), 5.52-5.35 (3H, m),
4.18-3.94 (2H, m), 3.67 (3H, s), 3.61 (1H, dd, J=10.4, 2.2 Hz),
2.40-1.60 (21H, m), 2.33 (2H, t, J=7.4 Hz), 1.55 (1H, dd, J=14.2,
6.6 Hz), 1.33 (1H, dd, J=14.2 6.6 Hz), 0.918 (3H, d, J=6.6 Hz),
0.915 (3H, d, J=6.6 Hz).
Example 16(4)
(5Z, 9.beta., 11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9-chloropros- ta-5, 13-dienoic
acid.cndot.methylester
[0580] 441
[0581] less polar
[0582] TLC: Rf 0.29 (hexane:ethyl acetate=2:1); NMR (CDCl.sub.3):
.delta.5.61 (1H, ddd, J=15.4, 7.6, 5.8 Hz), 5.55-5.35 (3H, m),
4.20-3.95 (2H, m), 3.68 (3H, s), 3.53 (1H, dd, J=9.8, 2.2 Hz),
2.40-1.20 (24H, m), 2.33 (2H, t, J=7.6 Hz), 0.94 (3H, t, J=6.8
Hz).
[0583] more polar
[0584] TLC: Rf 0.26 (hexane:ethyl acetate=2:1); NMR (CDCl.sub.3):
.delta.5.58 (1H, ddd, J=15.0, 8.2, 5.6 Hz), 5.50-5.32 (3H, m),
4.18-3.95 (2H, m), 3.67 (3H, s), 3.53 (1H, dd, J=10.4, 2.2 Hz),
2.76 (1H, br), 2.40-1.20 (23H, m), 2.33 (2H, t, J=7.3 Hz), 0.94
(3H, t, J=6.8 Hz).
Example 16(5)
(5Z, 9.beta., 11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9-chloro-19, 20-dinorprosta-5, 13-dienoic
acid.cndot.methylester
[0585] 442
[0586] more polar
[0587] TLC: Rf 0.30 (hexane:ethyl acetate=1:1); NMR (CDCl.sub.3):
.delta.5.59 (1H, ddd, J=15, 8, 6Hz), 5.47-5.30 (3H, m), 4.18-3.95
(2H, m), 3.67 (3H, s), 3.53 (1H, dd, J=10, 2Hz), 2.40-1.55 (22H,
m), 1.14 (3H, s).
Example 16(6)
(5Z, 9.beta., 11 .alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9-chloro-18- , 19, 20-trinorprosta-5, 13-dienoic
acid.cndot.methylester
[0588] 443
[0589] more polar
[0590] TLC: Rf 0.26 (hexane:ethyl acetate=1:1); NMR (CDCl.sub.3):
.delta.5.60 (1H, ddd, J=15, 8, 6Hz), 5.49-5.31 (3H, m), 4.19-3.95
(2H, m), 3.67 (3H, s), 3.62-3.48 (1H, m), 2.60-1.60 (23H, m).
Example 17
(5Z, 9.beta., 11.alpha., 13E)-17, 17-propano-11 ,
16-dihydroxy-9-chloro-20- -norprosta-5, 13-dienoic acid
[0591] 444
[0592] By the same procedure as provided in example 15, using the
compound prepared in example 16, compound of the present invention
having the following physical data was obtained.
[0593] more polar
[0594] TLC: Rf 0.44 (ethyl acetate:hexane:acetic acid=6:3:0.1); NMR
(CDCl.sub.3): .delta.5.80-5.35 (4H, m), 4.20-4.00 (2H, m), 3.59
(1H, dd, J=10.5, 2.5 Hz), 2.36 (2H, t, J=7.0 Hz), 2.40-1.60 (19H,
m), 1.45 (1H, sept, J=7.5 Hz), 0.92 (3H, t, J=7.5 Hz).
Example 17(1).about.17(6)
[0595] By the same procedure as provided in example 17, using the
compound prepared in example 16(1)-16(6), compounds of the present
invention having the following physical data were obtained.
Example 17(1)
(5Z, 9.beta., 11.alpha., 13E)-17, 17-propano-11 ,
16-dihydroxy-9-chloropro- sta-5, 13, 19-trienoic acid
[0596] 445
[0597] more polar
[0598] TLC: Rf 0.44 (ethyl acetate:hexane:acetic acid=6:3:0.1); NMR
(CDCl.sub.3): 67 6.95 (1H, ddt, J=17.0, 10.0, 2.0 Hz), 5.70-5.32
(4H, m), 5.20-5.00 (2H, m), 4.20-4.00 (2H, m), 3.59 (1H, dd,
J=10.0, 2.0 Hz), 2.36 (2H, t, J=7.0 Hz), 2.40-1.60 (20H, m).
Example 17(2)
(5Z, 9.beta., 11.alpha., 13E)-17, 17-propano-19, 20-methano-11,
16-dihydroxy-9-chloroprosta-5, 13-dienoic acid
[0599] 446
[0600] more polar
[0601] TLC: Rf 0.31 (hexane:ethyl acetate:acetic acid=3:2:0.05);
NMR (CDCl.sub.3): .delta.5.60 (1H, ddd, J=15.4, 7.6, 5.4 Hz),
5.55-5.35 (3H, m), 4.20-3.98 (2H, m), 4.20-3.00 (3H, br), 3.71 (1H,
dd, J=10.4, 2.2 Hz), 2.40-1.60 (18H, m), 2.36 (2H, t, J=6.9 Hz),
1.51 (1H, dd, J=14.2, 6.8 Hz), 1.37 (1H, dd, J=14.2, 6.2 Hz),
0.90-0.65 (1H, m), 0.57-0.45 (2H, m), 0.15-0.05 (2H, m).
Example 17(3)
(5Z, 9.beta., 11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9-chloro-19-- methylprosta-5, 13-dienoic acid
[0602] 447
[0603] more polar
[0604] TLC: Rf 0.34 (hexane:ethyl acetate:acetic acid=3:2:0.05);
NMR (CDCl.sub.3): 67 5.60 (1H, ddd, J=15.4, 8.2, 5.6 Hz), 5.55-5.35
(3H, m), 4.20-3.98 (2H, m), 4.20-3.00 (3H, br), 3.65 (1H, dd,
J=10.2, 2.2 Hz), 2.40-1.65 (19H, m), 2.36 (2H, t, J=7.1 Hz), 1.55
(1H, dd, J=14.2, 6.6 Hz), 1.33 (1H, dd, J=14.2, 6.2 Hz), 0.92 (3H,
d, J=6.6 Hz), 0.91 (3H, d, J=6.6 Hz).
Example 17(4)
(5Z, 9.beta., 11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9-chloropros- ta-5, 13-dienoic acid
[0605] 448
[0606] less polar
[0607] TLC: Rf 0.33 (hexane:ethyl acetate:acetic acid=3:2:0.05);
NMR (CDCl.sub.3): .delta.5.60 (1H, ddd, J=15.4, 7.8, 5.6 Hz),
5.55-5.37 (3H, m), 4.20-4.00 (2H, m), 4.20-3.00 (3H, br), 3.60 (1H,
dd, J=10.0, 2.2 Hz), 2.40-1.20 (22H, m), 2.35 (2H, t, J=6.9 Hz),
0.94 (3H, t, J=6.8 Hz).
[0608] more polar
[0609] TLC: Rf 0.31 (hexane:ethyl acetate:acetic acid=3:2:0.05);
NMR (CDCl.sub.3): .delta.5.58 (1H, ddd, J=15.4, 7.6, 5.4 Hz),
5.55-5.35 (3H, m), 4.20-4.00 (2H, m), 4.00-3.00 (3H, br), 3.57 (1H,
dd, J=10.2, 2.2 Hz), 2.40-1.20 (22H, m), 2.36 (2H, t, J=6.9 Hz),
0.94 (3H, t, J=6.8 Hz).
Example 17(5)
(5Z, 9.beta., 11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9-chloro-19, 20-dinorprosta-5, 13-dienoic acid
[0610] 449
[0611] more polar
[0612] TLC: Rf 0.32 (hexane:ethyl acetate:acetic acid=2:3:0.04);
NMR (CDCl.sub.3): .delta.5.60 (1H, ddd, J=15, 8, 6Hz), 5.55-5.35
(3H, m), 4.20-4.00 (2H, m), 4.00-3.00 (3H, br), 3.57 (1H, dd, J=10,
2Hz), 2.40-1.50 (201.14 (3H, s).
Example 17(6)
(5Z, 9.beta., 11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9-chloro-18, 19, 20-trinorprosta-5, 13-dienoic
acid
[0613] 450
[0614] more polar
[0615] TLC: Rf 0.25 (hexane:ethyl acetate:acetic acid 2:3:0.04);
NMR (CDCl.sub.3): .delta.5.59 (1H, ddd, J=15, 8, 6Hz), 5.54-5.33
(3H, m), 4.20-3.98 (2H, m), 4.00-3.00 (3H, br), 3.62-3.50 (1H, m),
2.60-1.55 (21H, m).
Reference Example 26
(5Z, 9.beta., 11.alpha., 13E)-17, 17-propano-11,
16-bis(t-butyldimethylsil- yloxy)-9-formyloxy-prosta-5, 13-dienoic
acid.cndot.methylester
[0616] 451
[0617] To a stirred solution of the compound prepared in reference
example 16 (330 mg) in THF (1.5 ml) was added formic acid (25 ml)
and triphenylphosphine (160 mg) under an atmosphere of argon. To
the mixture was added dropwise DEAD (0.1 ml;
diethylazodicarboxylate) at 0.degree. C. The reaction mixture was
stirred for 30 min. The reaction mixture was quenched by addition
of water, extracted with ethyl acetate (.times.3). The extract was
washed with water (.times.2) and a saturated aqueous solution of
sodium chloride, successively, dried over anhydrous magnesium
sulfate and concentrated. The residue was purified by column
chromatography on silica gel (Merck 7734, 15 ml, ethyl
acetate:hexane=0:1.fwdarw.1:20) to give the title compound (20 mg)
as a yellow oil having the following physical data.
[0618] TLC: Rf 0.56 (ethyl acetate:hexane=1:8); NMR (CDCl.sub.3):
.delta.7.99 (1H, s), 5.65-5.17 (4H, m), 5.04-4.90 (1H, m), 3.94
(1H, q, J=7.5 Hz), 3.66 (3H, s), 3.56 (1H, t, J=5.5 Hz), 2.30
(2H,t, J=7.5 Hz), 2.40-1.20 (23H, m), 0.91 and 0.90 (9H, each-s),
0.86 (9H, s), 1.00-0.80 (3H, m), 0.06 (3H, s), 0.05 (3H, s), 0.01
(6H, s).
Reference Example 27
(5Z, 9.beta., 11.alpha., 13E)-17, 17-propano-11,
16-bis(t-butyldimethylsil- yloxy)-9-hydroxy-prosta-5, 13-dienoic
acid.cndot.methylester
[0619] 452
[0620] To a stirred solution of the compound prepared in reference
example 26 (20 mg) in methanol (1 ml) was added ammonia in water
solution (0.1 ml) at room temperature under an atmosphere of argon.
The reaction mixture was stirred for 30 min. the reaction mixture
was quenched by addition of a saturated aqueous solution of
ammonium chloride, extracted with ethyl acetate. The extract was
washed with water (.times.2) and a saturated aqueous solution of
sodium chloride, successively, dried over anhydrous magnesium
sulfate and concentrated. The residue was purified by column
chromatography on silica gel (Merck 7734, 15 ml, ethyl
acetate:hexane=1:8.fwdarw.1:4) to give the title compound (15 mg)
as a colorless oil having the following physical data.
[0621] TLC: Rf 0.18 (ethyl acetate:hexane=1:8); NMR (CDCl.sub.3):
.delta.5.62-5.18 (4H, m), 4.10-3.90 (2H, m), 3.67 (3H, s), 3.55
(1H, t, J=5.5 Hz), 2.32 (2H, t, J=8.0 Hz), 2.40-1.20 (23H, m),
1.00-0.80 (3H, m), 0.90 and 0.89 (9H, each-s), 0.86 (9H, s), 0.06
(3H, s), 0.04 (3H, s), 0.01 (6H, s).
Reference Example 28
(5Z, 9.beta., 11.alpha., 13E)-17, 17-propano-11,
16-bis(t-butyldimethylsil- yloxy)-9-tosyloxy-prosta-5, 13-dienoic
acid.cndot.methylester
[0622] 453
[0623] By the same procedure as provided in reference example 24,
using the compound prepared in reference example 27, title compound
having the following physical data was obtained.
[0624] TLC: Rf 0.47(ethyl acetate:hexane=61).
Reference Example 29
(5Z, 9.alpha., 11.alpha., 13E)-17, 17-propano-11,
16-bis(t-butyldimethylsi- lyloxy)-9-chloro-prosta-5, 13-dienoic
acid.cndot.methylester
[0625] 454
[0626] By the same procedure as provided in reference example 25,
using the compound prepared in reference example .sup.28,title
compound having the following physical data was obtained.
[0627] TLC: Rf 0.45(ethyl acetate:hexane=1:20); NMR (CDCl.sub.3):
67 5.72-5.10 (4H, m), 4.35-4.25 (1H, m), 3.95-3.75 (1H, m), 3.66
(3H, s), 3.57 (1H, t, J=5.5 Hz), 2.54 (2H, ddd, J=15.0, 9.0, 6.0
Hz), 2.50-1.20 (21H, m), 2.31 (2H, t, J=8.0 Hz), 1.00-0.80 (3H, m),
0.91 and 0.90 (9H, each s), 0.86 (9H, s), 0.10-0.00 (6H, m), 0.01
(6H, s).
Example 18
(5Z, 9.alpha., 11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9-chloro-pr- osta-5, 13-dienoic
acid.cndot.methylester
[0628] 455
[0629] By the same procedure as provided in example 1, using the
compound prepared in reference example 25, compound of the present
invention having the following physical data was obtained.
[0630] less polar
[0631] TLC: Rf 0.56(ethyl acetate:hexane=1:1); NMR (CDCl.sub.3):
.delta.5.66 (1H, ddd, J=15.5, 8.0, 6.0 Hz), 5.50-5.30 (3H, m), 4.38
(1H, t, J=5.0 Hz), 4.10-3.90 (1H, m), 3.67 (3H, s), 3.56 (1 H, dd,
J=10.0, 2.0 Hz), 2.70-1.20 (22H, m), 2.33 (2H, t, J=8.0 Hz), 0.94
(3H, t, J=7.0 Hz).
[0632] more polar
[0633] TLC: Rf 0.47(ethyl acetate:hexane=1:1); NMR (CDCl.sub.3)
.delta.5.66 (1H, ddd, J=15.5, 8.0, 5.5 Hz), 5.50-5.30 (3H, m), 4.38
(1H, t, J=5.0 Hz), 3.98 (1H, ddd, J=9.0, 6.0, 2.5 Hz), 3.67 (3H,
s), 3.56 (1H, dd, J=10.0, 2.0 Hz), 2.70-1.20 (22H, m), 2.32 (2H, t,
J=7.5 Hz), 0.94 (3H, t, J=7.0 Hz).
Example 19
(5Z, 9.alpha., 11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9-chloro-pr- osta-5, 13-dienoic acid
[0634] 456
[0635] By the same procedure as provided in example 15, using the
compound prepared in example 18, compound of the present invention
having the following physical data was obtained.
[0636] less polar
[0637] TLC: Rf 0.47 (ethyl acetate:hexane=2:1); NMR (CDCl.sub.3):
67 5.75-5.30 (4H, m), 4.44 (1H, t, J=4.5 Hz), 3.97 (1H, ddd, J=9.0,
6.0, 3.5 Hz), 3.68 (1H, dd, J=10.0, 2.0 Hz), 2.70-1.20 (22H, m),
2.34 (2H, t, J=6.5 Hz), 0.94 (3H, t, J=6.5 Hz).
[0638] more polar
[0639] TLC: Rf 0.47 (ethyl acetate:hexane=2:1); NMR (CDCl.sub.3):
.delta.5.67 (1H, dt, J=15.5, 6.5 Hz), 5.60-5.30 (3H, m), 4.42 (1H,
t, J=5.0 Hz), 4.03 (1H, ddd, J=9.0, 6.0, 3.0 Hz), 3.66 (1H, dd,
J=9.5, 2.5 Hz) 2.70-1.20 (22H, m), 2.34 (2H, t, J=7.0 Hz), 0.94
(3H, t, J=6.5 Hz).
Reference Example 30
(5Z, 8Z, 11.alpha., 13E)-17, 17-propano-11,
16-bis(t-butyldimethylsilyloxy- )-9-acetyloxy-prosta-5,8,
13-trienoic acid.cndot.methylester
[0640] 457
[0641] To a solution of (1 E,
4RS)-1-iodo-4-t-butyldimethylsilyloxy-5,5-pr- opanoocta-1-ene (407
mg) in an hydrous ether (3 ml) was added dropwise t-butyllithium
(1.21 ml; 1.7 M pentane solution) at -78.degree. C. After the
mixture was stirred for 60 min, to the mixture was added dropwise
lithium 2-thienylcyanocuprate (4.8 ml; 0.25 M tetrahydrofuran
solution) at same temperature. After the mixture was stirred for 20
min, to the mixture was added dropwise a solution of
(5Z)-7-((3R)-3-t-butyldimethylsi- lyloxy-5-oxocyclopenta-1-ene (234
mg) in ether (4 ml). After the mixture was warmed up to -20.degree.
C. for 45 min, to the mixture was added acetic anhydride (1.88 ml).
The reaction mixture was stirred at 0.degree. C. for 30 min. The
reaction mixture was quenched by addition of a saturated aqueous
solution of ammonium chloride, extracted with hexane. The extract
was washed with a saturated aqueous solution of sodium chloride,
dried over anhydrous magnesium sulfate and concentrated. The
residue was purified by column chromatography on silica gel (Wako
gel C-200, 40 ml, hexane:ethyl acetate=1:0.fwdarw.50:1.fwdarw.20:1)
to give the title compound (324 mg) having the following physical
data.
[0642] TLC: Rf 0.50 (hexane:ethyl acetate=9:1); NMR (CDCl.sub.3):
.delta.5.70-5.45 (1H, m), 5.45-5.15 (3H, m), 4.14-4.02 (1H, m),
3.66 (3H, s), 3.55 (1H, t, J=5.1 Hz), 3.05-2.92 (1H, m), 2.99-2.68
(2H, m), 2.60-2.30 (2H, m), 2.30 (2H, t, J=7.6 Hz), 2.20-1.20 (16H,
m), 2.13 (3H, s), 1.00-0.90 (21H, m), 0.10-0.00 (12H, m).
Example 20
(5Z, 8Z, 11.alpha., 13E)-17, 17-propano-11,
16-dihydroxy-9-acetyloxy-prost- a-5,8, 13-trienoic
acid.cndot.methylester
[0643] 458
[0644] By the same procedure as provided in example 1, using the
compound prepared in reference example 30, compounds of the present
invention having the following physical data were obtained.
[0645] less polar
[0646] TLC: Rf 0.44 (hexane:ethyl acetate=1:1); NMR (CDCl.sub.3):
67 5.63 (1H, ddd, J=15.4, 7.4, 6.0 Hz), 5.50-5.25 (3H, m),
4.18-4.02 (1H, m), 3.67 (3H, s), 3.52 (1H, dd, J=9.6, 2.4 Hz),
3.10-3.00 (1H, m), 3.00-2.72 (2H, m), 2.66-2.40 (2H, m), 2.40-1.20
(18H, m), 2.32 (2 H, t, J=7.2 Hz), 2.16 (3H, s), 0.93 (3H, t, J=6.8
Hz).
[0647] more polar
[0648] TLC: Rf 0.39 (hexane:ethyl acetate=1:1); NMR (CDCl.sub.3):
.delta.5.62 (1H, ddd, J=15.4, 7.8, 6.2 Hz), 5.50-5.25 (3H, m),
4.18-4.02 (1H, m), 3.67 (3H, s), 3.52 (1H, dd, J=9.6, 2.2 Hz),
3.10-3.00 (1H, m), 2.98-2.72 (2H, m), 2.66-2.40 (2H, m), 2.40-1.20
(18H, m), 2.31 (2 H, t, J=7.4 Hz), 2.16 (3H, s), 0.93 (3H, t, J=6.9
Hz).
Reference Example 31
(5Z, 11.alpha., 13E)-17, 17-propano-11,
16-bis(t-butyldimethylsilyloxy)-1,- 9-dihydroxy-prosta-5,
13-diene
[0649] 459
[0650] To a solution of the compound prepared in reference example
3 (174 mg) in THF (3 ml) was added dropwise DIBAL (1.16 ml; 0.95 M
hexane solution) at -78.degree. C. The reaction mixture was stirred
at 0.degree. C. for 30 min, and stirred at room temperature for 30
min. To the reaction mixture was added dropwise a saturated aqueous
solution of sodium sulfate (0.3 ml), diluted with ether. The
mixture was stirred at room temperature for 30 min. the reaction
mixture was dried over anhydrous magnesium sulfate and concentrated
to give the title compound (160 mg) having the following physical
data.
[0651] TLC: Rf 0.40 (9.alpha.-OH form) and 0.24 (9.beta.-OH form)
(hexane:ethyl acetate=3:1).
Reference Example 32
(5Z, 11.alpha., 13E)-17, 17-propano-1, 11,
16-tris(t-butyldimethylsilyloxy- )-9-hydroxy-prosta-5, 13-diene
[0652] 460
[0653] To a solution of the compound prepared in reference example
31 (160 mg) and pyridine (44 ml) in dichloromethane (3 ml) was
added TBSCI (45 mg; t-butyldimethylsilyl chloride) under cooling
with ice. The reaction mixture was stirred at room temperature for
overnight. To the reaction mixture was added pyridine (50 ml) and
TBSCI (50 mg). The reaction mixture was stirred at room temperature
for 3 hours. The reaction mixture was quenched by addition of a
saturated aqueous solution of sodium hydrogencarbonate, extracted
with hexane. The extract was dried over anhydrous magnesium sulfate
and concentrated. The residue was purified by column chromatography
on silica gel (Merck 7734, 20 g, hexane:ethyl
acetate=1:0.fwdarw.20:1.fwdarw.10:1) to give the title compound
(total 142 mg) having the following physical data.
[0654] TLC: Rf 0.62 (9.alpha.-OH form) and 0.46 (9.beta.-OH form)
(hexane:ethyl acetate=9:1);
[0655] NMR (CDCl.sub.3): .delta.5.60-5.15 (4H, m), 4.10-3.90 (2H,
m), 3.65-3.45 (3H, m), 2.40-1.20 (24H, m), 1.00-0.90 (30H, m),
0.10-0.00 (18H, m).
Reference Example 33
(5Z, 11.alpha., 13E)-17, 17-propano-1 , 11 ,
16-tris(t-butyldimethylsilylo- xy)-9-oxo-prosta-5, 13-diene
[0656] 461
[0657] To a solution of oxalyl chloride (33 ml) in dichloromethane
(0.5 ml) was added dropwise dimethylsulfoxide (55 ml) at
-78.degree. C. After the mixture was stirred for 10 min, to the
mixture was added dropwise a solution of the compound prepared in
reference example 32 (140 mg) in dichloromethane (3 ml). After the
mixture was warmed up to -40.degree. C. for 1 hour, to the mixture
added dropwise triethylamine (0.22 ml). The reaction mixture was
warmed up to -10.degree. C. for 1 hour. The reaction mixture was
quenched by addition of water and 2N aqueous solution of
hydrochloric acid (0.7 ml), extracted with hexane. The extract was
washed with a saturated aqueous solution of sodium chloride, dried
over anhydrous magnesium sulfate and concentrated. The residue was
purified by column chromatography on silica gel (Wako gel C-200, 15
g, hexane:ethyl acetate=1:0.fwdarw.30:1) to give the title compound
(112 mg) having the following physical data.
[0658] TLC: Rf 0.80 (hexane:ethyl acetate=9:1); NMR (CDCl.sub.3):
67 5.70-5.20 (4H, m), 4.05-3.90 (1H, m), 3.59 (2H, t, J=6.3 Hz),
3.58-3.50 (1H, m), 2.65-1.20 (24H, m), 1.00-0.90 (30H, m),
0.10-0.00 (18H, m).
Example 21
(5Z, 11.alpha., 13E)-17, 17-propano-11, 16-dihydroxy-9-oxoprosta-5,
13-diene-1-ol
[0659] 462
[0660] By the same procedure as provided in example 1, using the
compound prepared in reference example 33, compounds of the present
invention having the following physical data were obtained.
[0661] less polar
[0662] TLC: Rf 0.40 (hexane:ethyl acetate:methanol=1:3 0.04);
[0663] NMR (CDCl.sub.3): .delta.5.76 (1H, dt, J=5.2, 7.0 Hz), 5.45
(1H, dd, J=15.2, 7.8 Hz), 5.50-5.20 (2H, m), 4.12-3.98 (1H, m),
3.70-3.59 (2H, m), 3.50 (1H, dd, J=10.4, 2.6 Hz), 2.74 (1H, ddd,
J=18.2, 7.2, 1.0 Hz), 2.55-1.20 (26H, m), 0.94 (3H, t, J=7.4
Hz).
[0664] more polar
[0665] TLC: Rf 0.37 (hexane:ethyl acetate:methanol=1:3:0.04); NMR
(CDCl.sub.3): .delta.5.71 (1H, ddd, J=15.4, 8.2, 5.8 Hz), 5.50-5.20
(3H, m), 4.10-3.95 (1H, m), 3.64 (2H, t, J=6.4 Hz), 3.56 (1H, dd,
J=10.2, 2.4 Hz), 2.73 (1H, ddd, J=18.0, 7.6, 1.0 Hz), 2.50-1.20
(26H, m), 0.94 (3H, t, J=6.8 Hz).
Formulation Example
Formulation example 1
[0666] The following compounds were admixed in conventional method,
dried, added microcrystalline cellulose, mixed until homogeneous
and punched out to obtain 100 tablets each containing 30 .mu.g of
active ingredient.
16 The solution of (5Z, 11.alpha., 13E)-11,16-dihydroxy-9-o-
xo-17,17- 10 mL propanoprosta-5,13-dienoic acid (3 mg) in ethanol
Magnesium stearate 100 mg silicon dioxide 20 mg talc 10 mg
Carboxymethylcellulose calcium 200 mg Microcrystalline cellulose
5.0 g
* * * * *