U.S. patent application number 12/848597 was filed with the patent office on 2010-11-25 for method for treating abdominal discomfort.
This patent application is currently assigned to SUCAMPO AG. Invention is credited to Sachiko KUNO, Ryuji UENO.
Application Number | 20100298424 12/848597 |
Document ID | / |
Family ID | 32717850 |
Filed Date | 2010-11-25 |
United States Patent
Application |
20100298424 |
Kind Code |
A1 |
UENO; Ryuji ; et
al. |
November 25, 2010 |
METHOD FOR TREATING ABDOMINAL DISCOMFORT
Abstract
Disclosed is a novel use of a chloride channel opener,
especially a prostaglandin compound for the treatment of abdominal
discomfort. Further disclosed is a novel use of a chloride channel
opener, especially a prostaglandin compound for the treatment of
functional gastrointestinal disorders.
Inventors: |
UENO; Ryuji; (Potomac,
MD) ; KUNO; Sachiko; (Potomac, MD) |
Correspondence
Address: |
SUGHRUE MION, PLLC
2100 PENNSYLVANIA AVENUE, N.W., SUITE 800
WASHINGTON
DC
20037
US
|
Assignee: |
SUCAMPO AG
ZUG
CH
|
Family ID: |
32717850 |
Appl. No.: |
12/848597 |
Filed: |
August 2, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10745689 |
Dec 29, 2003 |
7795312 |
|
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12848597 |
|
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60436462 |
Dec 27, 2002 |
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60436463 |
Dec 27, 2002 |
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Current U.S.
Class: |
514/456 ;
514/573 |
Current CPC
Class: |
A61P 1/10 20180101; A61P
1/00 20180101; A61K 31/557 20130101; C07C 57/56 20130101; A61K
31/5585 20130101; A61P 1/14 20180101; A61K 31/5575 20130101; A61P
1/04 20180101; A61P 43/00 20180101 |
Class at
Publication: |
514/456 ;
514/573 |
International
Class: |
A61K 31/352 20060101
A61K031/352; A61K 31/19 20060101 A61K031/19; A61P 1/00 20060101
A61P001/00 |
Claims
1. A method for treating functional gastrointestinal disorders in a
mammalian subject, which comprises administration of an effective
amount of a chloride channel opener to the subject.
2. The method as described in claim 1, wherein said chloride
channel opener is a ClC channel opener.
3. The method as described in claim 2, wherein said ClC channel
opener is a ClC-2 channel opener.
4. The method as described in claim 1, wherein said chloride
channel opener is a prostaglandin compound.
5. The method as described in claim 4, wherein said prostaglandin
compound is a compound as shown by the following general formula
(I) ##STR00008## wherein L, M and N are hydrogen atom, hydroxy,
halogen atom, lower alkyl, hydroxy(lower)alkyl, lower alkanoyloxy
or oxo, wherein at least one of L and M is a group other than
hydrogen, and the five-membered ring may have at least one double
bond; A is --CH.sub.3, or --CH.sub.2OH, --COCH.sub.2OH, --COOH or a
functional derivative thereof; B is single bond,
--CH.sub.2--CH.sub.2--, --CH.dbd.CH--, --C.ident.C--,
--CH.sub.2--CH.sub.2--CH.sub.2--, --CH.dbd.CH--CH.sub.2--,
--CH.sub.2--CH.dbd.CH--, --C.ident.C--CH.sub.2-- or
--CH.sub.2--C.ident.C--; Z is ##STR00009## or single bond wherein
R.sub.4 and R.sub.5 are hydrogen, hydroxy, halogen, lower alkyl,
lower alkoxy or hydroxy(lower)alkyl, wherein R.sub.4 and R.sub.5
are not hydroxy and lower alkoxy at the same time; R.sub.1 is a
saturated or unsaturated bivalent lower or medium aliphatic
hydrocarbon residue, which is unsubstituted or substituted with
halogen, alkyl, hydroxy, oxo, aryl or heterocyclic group, and at
least one of carbon atom in the aliphatic hydrocarbon is optionally
substituted by oxygen, nitrogen or sulfur; and Ra is a saturated or
unsaturated lower or medium aliphatic hydrocarbon residue, which is
unsubstituted or substituted with halogen, oxo, hydroxy, lower
alkyl, lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl,
cyclo(lower)alkyloxy, aryl, aryloxy, heterocyclic group or
heterocyclic-oxy group; lower alkoxy; lower alkanoyloxy;
cyclo(lower)alkyl; cyclo(lower)alkyloxy; aryl; aryloxy;
heterocyclic group; heterocyclic-oxy.
6. The method as described in claim 4, wherein said prostaglandin
compound is a 16-mono or dihalogen-prostaglandin compound.
7. The method as described in claim 4, wherein said prostaglandin
compound is a 13,14-dihydro-16-mono or dihalogen-prostaglandin
compound.
8. The method as described in claim 4, wherein said prostaglandin
compound is a 13,14-dihydro-15-keto-16-mono or
dihalogen-prostaglandin compound.
9. The method as described in claim 4, wherein said prostaglandin
compound is a 13,14-dihydro-16-mono or difluoro-prostaglandin
compound.
10. The method as described in claim 4, wherein said prostaglandin
compound is a 13,14-dihydro-15-keto-16-mono or
difluoro-prostaglandin compound.
11. The method as described in claim 4, wherein said prostaglandin
compound is a 13,14-dihydro-16-mono or dihalogen-prostaglandin E
compound.
12. The method as described in claim 4, wherein said prostaglandin
compound is a 13,14-dihydro-15-keto-16-mono or
dihalogen-prostaglandin E compound.
13. The method as described in claim 4, wherein said prostaglandin
compound is a 13,14-dihydro-16,16-difluoro-prostaglandin E.sub.1
compound.
14. The method as described in claim 4, wherein said prostaglandin
compound is a 13,14-dihydro-15-keto-16,16-difluoro-prostaglandin
E.sub.1 compound or
13,14-dihydro-15-keto-16,16-difluoro-18-methyl-prostaglandin
E.sub.1 compound.
15. The method as described in claim 4, wherein said functional
gastrointestinal disorders comprise irritable bowel syndrome and/or
functional dyspepsia.
16. The method as described in claim 4, which comprises systemic
administration 1-4 times per day or continuous administration at
the amount of 0.01-100 .mu.g per day.
17. The method as described in claim 4, wherein the administration
is at the amount of 0.1-10 .mu.g/kg per day.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation of U.S. application Ser. No.
10/745,689 filed Dec. 29, 2003, which claims the benefit of
provisional application Nos. 60/436,462 and 60/436,463 both filed
Dec. 27, 2002, the contents of all of which are incorporated herein
by reference in their entireties.
TECHNICAL FIELD
[0002] The present invention relates to a method for treating
abdominal discomfort with a chloride channel opener, especially, a
prostaglandin compound.
[0003] Further, the present invention relates to a method for
treating functional gastrointestinal disorders with a chloride
channel opener, especially, a prostaglandin compound.
BACKGROUND ART
[0004] Abdominal indefinite complaint or abdominal discomfort is
most often experienced in our daily lives, and it includes
heartburn, nausea, emesis, anorexia, epigastric pain, abdominal
bloating, chronic abdominal pain, abdominal discomfort, abnormal
bowel movement such as constipation and diarrhea and the like.
Various disorders may cause abdominal discomfort. It is also known
that abdominal discomfort may also occur as a side effect of drug,
medication or surgical procedure. However, it is not yet known as
to the drug that may be used for safely and effectively treating
abdominal discomfort.
[0005] Patients having functional gastrointestinal disorders often
report abdominal discomfort. Functional gastrointestinal disorders
are characterized by chronic or recurrent gastrointestinal symptoms
which are not explained by any organic, i.e. structural or
biochemical, abnormality. In general, functional disorders should
be distinguished from morphological or organic disorders in which
the organ structures have been abnormally changed. An organic
disorder may accompany functional abnormality of organs but it is
surely possible to diagnose if there is any underlying organic
abnormality.
[0006] Stress may affect on various organs in various ways, and the
typical example of such organs is gastrointestinal tract. The
interaction among stress-brain-gastrointestinal organ is called
brain-gut axis, and now a days, it draws great interest of the art.
In the field of clinical medicine, a group of functional disorders
in which the brain-gut axis plays a central role of the pathology
is called functional gastrointestinal disorders.
[0007] Typical examples of functional gastrointestinal disorders
include irritable bowel syndrome (IBS) and functional dyspepsia
(FD). These terms are not used for exclusively determining the
nature of separate disorders but most commonly used for expressing
various overlapping symptoms manifested in the upper and lower
gastrointestinal tracts.
[0008] IBS is an archetype disorder of functional gastrointestinal
disorders with no underlying organic abnormality. IBS patient
reports continued lower gastrointestinal symptoms such as abnormal
bowel movement, abdominal pain, abdominal bloating and abdominal
discomfort, as well as upper gastrointestinal symptoms such as
epigastric pain, hypochondriac pain, nausea, anorexia, borborygmus,
vomiting, belching and heartburn.
[0009] FD patient has no underlying organic disorder such as ulcer
and reports continued upper gastrointestinal tract symptoms such as
abdominal pain, nausea, anorexia and slow digestion. The term
"dyspepsia" means chronic or repetitious pain or discomfort mainly
occurring in epigastric region. Up to 60% of the dyspepsia patients
have no underlying organic disorder and are diagnosed as FD.
[0010] As explained above, functional gastrointestinal disorders
are a group of disorders in which the gastrointestinal symptoms
continue for a long period or by repeating a period of
recrudescence and palliation without clear organic abnormalities.
No systematic method has been established for treating such
disorder.
[0011] Prostaglandins (hereinafter, referred to as PG(s)) are
members of class of organic carboxylic acids, which are contained
in tissues or organs of human or other mammals, and exhibit a wide
range of physiological activity. PGs found in nature (primary PGs)
generally have a prostanoic acid skeleton as shown in the formula
(A):
##STR00001##
On the other hand, some of synthetic analogues of primary PGs have
modified skeletons. The primary PGs are classified to PGAs, PGBs,
PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs according to the
structure of the five-membered ring moiety, and further classified
into the following three types by the number and position of the
unsaturated bond at the carbon chain moiety: Subscript 1:
13,14-unsaturated-15-OH Subscript 2: 5,6- and
13,14-diunsaturated-15-OH Subscript 3: 5,6-, 13,14-, and
17,18-triunsaturated-15-OH.
[0012] Further, the PGFs are classified, according to the
configuration of the hydroxyl group at the 9-position, into .alpha.
type (the hydroxyl group is of an .alpha.-configuration) and .beta.
type (the hydroxyl group is of a .beta.-configuration).
[0013] PGE.sub.1 and PGE.sub.2 and PGE.sub.3 are known to have
vasodilation, hypotension, gastric secretion decreasing, intestinal
tract movement enhancement, uterine contraction, diuretic,
bronchodilation and anti ulcer activities. PGF.sub.1.alpha.,
PGF.sub.2.alpha. and PGF.sub.3.alpha. have been known to have
hypertension, vasoconstriction, intestinal tract movement
enhancement, uterine contraction, lutein body atrophy and
bronchoconstriction activities.
[0014] The present inventor already found that prostaglandin
compounds open chloride channels, especially ClC channels, more
especially ClC-2 channel (WO 03/030912, this reference is herein
incorporated by reference).
[0015] However, it is not known how chloride channel openers and/or
prostaglandin compounds act on abdominal discomfort, or the
functional gastrointestinal disorders.
DISCLOSURE OF THE INVENTION
[0016] The present inventor has conducted intensive studies and
found that a chloride channel opener, especially prostaglandin
compound have a significant effect on abdominal discomfort,
especially, on functional gastrointestinal disorders such as IBS
and FD, which resulted in the completion of the present
invention.
[0017] Namely, the present invention relates to a method for
treating abdominal discomfort in a mammalian subject, which
comprises administration of an effective amount of a chloride
channel opener, especially ClC channel opener, more especially
ClC-2 channel opener such as prostaglandin compound to the
subject.
[0018] The present invention further relates to a pharmaceutical
composition for treating abdominal discomfort in a mammalian
subject, which comprises an effective amount of a chloride channel
opener, especially ClC channel opener, more especially ClC-2
channel opener such as prostaglandin compound.
[0019] Further more, the present invention relates to a use of a
chloride channel opener, especially ClC channel opener, more
especially ClC-2 channel opener such as prostaglandin compound for
manufacturing a pharmaceutical composition for treating abdominal
discomfort in a mammalian subject.
[0020] Another embodiment of the present invention relates to a
method for treating functional gastrointestinal disorders in a
mammalian subject, which comprises administration of an effective
amount of a chloride channel opener, especially ClC channel opener,
more especially ClC-2 channel opener such as prostaglandin compound
to the subject.
[0021] The present invention further relates to a pharmaceutical
composition for treating functional gastrointestinal disorders in a
mammalian subject, which comprises an effective amount of a
chloride channel opener, especially ClC channel opener, more
especially ClC-2 channel opener such as prostaglandin compound.
[0022] Further more, the present invention relates to a use of a
chloride channel opener, especially ClC channel opener, more
especially ClC-2 channel opener such as prostaglandin compound for
manufacturing a pharmaceutical composition for treating functional
gastrointestinal disorders in a mammalian subject.
DETAILED DESCRIPTION OF THE INVENTION
[0023] The chloride channel opener used in the present invention is
not particularly limited and may be any compound as far as it has a
chloride channel opening activity. The chloride channel opening
activity may be confirmed by measuring the increase of chloride-ion
flows through a chloride channel in a cell membrane from inside to
outside of the cell or in the opposite direction. For instance, it
is possible to carry out a screening for a compound having chloride
channel opening activity by using a known assay strategy such as
the patch clamp. Preferred chloride channel opener is a ClC channel
opener, especially a ClC-2 channel opener.
[0024] Examples of compounds having the opening activity of a ClC-2
channel include cyclooxygenase inhibitor, nonsteroidal
anti-inflammatory agent (e.g. ibuprofen and ebselen), protein
kinase A, oleic acid, elaidic acid, arachidonic acid, cell growth
factor (e.g., TGF.alpha. (transforming growth factor-.alpha.) and
KGF (keratinocyte growth factor)), benzimidazole derivative and
prostaglandin compound. Preferred compound of the present invention
is a prostaglandin compound.
[0025] The nomenclature of the prostaglandin compounds used herein
is based on the numbering system of the prostanoic acid represented
in the above formula (A).
[0026] The formula (A) shows a basic skeleton of the C-20 carbon
atoms, but the present invention is not limited to those having the
same number of carbon atoms. In the formula (A), the numbering of
the carbon atoms which constitute the basic skeleton of the PG
compounds starts at the carboxylic acid (numbered 1), and carbon
atoms in the .alpha.-chain are numbered 2 to 7 towards the
five-membered ring, those in the ring are 8 to 12, and those in the
.omega.-chain are 13 to 20. When the number of carbon atoms is
decreased in the .alpha.-chain, the number is deleted in the order
starting from position 2; and when the number of carbon atoms is
increased in the .alpha.-chain, compounds are named as substitution
compounds having respective substituents at position 2 in place of
the carboxy group (C-1). Similarly, when the number of carbon atoms
is decreased in the .omega.-chain, the number is deleted in the
order starting from position 20; and when the number of carbon
atoms is increased in the .omega.-chain, the carbon atoms beyond
position 20 are named as substituents. Stereochemistry of the
compounds is the same as that of the above formula (A) unless
otherwise specified.
[0027] In general, each of the terms PGD, PGE and PGF represents a
PG compound having hydroxy groups at positions 9 and/or 11, but in
the present specification, these terms also include those having
substituents other than the hydroxy group at positions 9 and/or 11.
Such compounds are referred to as 9-dehydroxy-9-substituted-PG
compounds or 11-dehydroxy-11-substituted-PG compounds. A PG
compound having hydrogen in place of the hydroxy group is simply
named as 9- or 11-dehydroxy-PG compound.
[0028] As stated above, the nomenclature of the PG compounds is
based on the prostanoic acid skeleton. However, in case the
compound has a similar partial structure as a prostaglandin, the
abbreviation of "PG" may be used. Thus, a PG compound of which
.alpha.-chain is extended by two carbon atoms, that is, having 9
carbon atoms in the .alpha.-chain is named as
2-decarboxy-2-(2-carboxyethyl)-PG compound. Similarly, a PG
compound having 11 carbon atoms in the .alpha.-chain is named as
2-decarboxy-2-(4-carboxybutyl)-PG compound. Further, a PG compound
of which .omega.-chain is extended by two carbon atoms, that is,
having 10 carbon atoms in the .omega.-chain is named as 20-ethyl-PG
compound. These compounds, however, may also be named according to
the IUPAC nomenclatures.
[0029] Examples of the analogs (including substituted derivatives)
or derivatives include a PG compound of which carboxy group at the
end of .alpha.-chain is esterified; compound of which .alpha.-chain
is extended; physiologically acceptable salt thereof; a compound
having a double bond at 2-3 position or a triple bond at position
5-6, a compound having substituent(s) at position 3, 5, 6, 16, 17,
18, 19 and/or 20; and a compound having lower alkyl or a hydroxy
(lower) alkyl group at position 9 and/or 11 in place of the hydroxy
group.
[0030] According to the present invention, preferred substituents
at position 3, 17, 18 and/or 19 include alkyl having 1-4 carbon
atoms, especially methyl and ethyl. Preferred substituents at
position 16 include lower alkyl such as methyl and ethyl, hydroxy,
halogen atoms such as chlorine and fluorine, and aryloxy such as
trifluoromethylphenoxy. Preferred substituents at position 17
include lower alkyl such as methyl and ethyl, hydroxy, halogen
atoms such as chlorine and fluorine, aryloxy such as
trifluoromethylphenoxy. Preferred substituents at position 20
include saturated or unsaturated lower alkyl such as C1-4 alkyl,
lower alkoxy such as C1-4 alkoxy, and lower alkoxy alkyl such as
C1-4 alkoxy-C1-4 alkyl. Preferred substituents at position 5
include halogen atoms such as chlorine and fluorine. Preferred
substituents at position 6 include an oxo group forming a carbonyl
group. Stereochemistry of PGs having hydroxy, lower alkyl or
hydroxy(lower)alkyl substituent at position 9 and/or 11 may be
.alpha., .beta. or a mixture thereof.
[0031] Further, the above analogs or derivatives may be compounds
having an alkoxy, cycloalkyl, cycloalkyloxy, phenoxy or phenyl
group at the end of the .omega.-chain where the chain is shorter
than the primary PGs.
[0032] A preferred compounds used in the present invention is
represented by the formula (I):
##STR00002##
[0033] wherein L, M and N are hydrogen, hydroxy, halogen, lower
alkyl, hydroxy(lower)alkyl, lower alkanoyloxy or oxo, wherein at
least one of L and M is a group other than hydrogen, and the
five-membered ring may have at least one double bond;
[0034] A is --CH.sub.3, or --CH.sub.2OH, --COCH.sub.2OH, --COOH or
a functional derivative thereof;
[0035] B is single bond, --CH.sub.2--CH.sub.2--, --CH.dbd.CH--,
--CH.sub.2--CH.sub.2--CH.sub.2--, --CH.dbd.CH--CH.sub.2--,
--CH.sub.2--CH.dbd.CH--, --C.ident.C--CH.sub.2-- or
--CH.sub.2--C.ident.C--;
[0036] Z is
##STR00003##
or single bond
[0037] wherein R.sub.4 and R.sub.5 are hydrogen, hydroxy, halogen,
lower alkyl, lower alkoxy or hydroxy(lower)alkyl, wherein R.sub.4
and R.sub.5 are not hydroxy and lower alkoxy at the same time;
[0038] R.sub.1 is a saturated or unsaturated bivalent lower or
medium aliphatic hydrocarbon residue, which is unsubstituted or
substituted with halogen, alkyl, hydroxy, oxo, aryl or heterocyclic
group, and at least one of carbon atom in the aliphatic hydrocarbon
is optionally substituted by oxygen, nitrogen or sulfur; and
[0039] Ra is a saturated or unsaturated lower or medium aliphatic
hydrocarbon residue, which is unsubstituted or substituted with
halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower
alkanoyloxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl,
aryloxy, heterocyclic group or hetrocyclic-oxy group; lower alkoxy;
lower alkanoyloxy; cyclo(lower)alkyl; cyclo(lower)alkyloxy; aryl;
aryloxy; heterocyclic group; heterocyclic-oxy group.
[0040] A preferred compound used in the present invention is
represented by the formula (II):
##STR00004##
[0041] wherein L and M are hydrogen, hydroxy, halogen, lower alkyl,
hydroxy(lower)alkyl, lower alkanoyloxy or oxo, wherein at least one
of L and M is a group other than hydrogen, and the five-membered
ring may have one or more double bonds;
[0042] A is --CH.sub.3, or --CH.sub.2OH, --COCH.sub.2OH, --COOH or
a functional derivative thereof;
[0043] B is single bond, --CH.sub.2--CH.sub.2--, --CH.dbd.CH--,
--C.ident.C--, --CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.dbd.CH--CH.sub.2--, --CH.sub.2--CH.dbd.CH--,
--C.ident.C--CH.sub.2-- or --CH.sub.2--C.ident.C--;
[0044] Z is
##STR00005##
or single bond
[0045] wherein R.sub.4 and R.sub.5 are hydrogen, hydroxy, halogen,
lower alkyl, lower alkoxy or hydroxy(lower)alkyl, wherein R.sub.4
and R.sub.5 are not hydroxy and lower alkoxy at the same time;
[0046] X.sub.1 and X.sub.2 are hydrogen, lower alkyl, or
halogen;
[0047] R.sub.1 is a saturated or unsaturated bivalent lower or
medium aliphatic hydrocarbon residue, which is unsubstituted or
substituted with halogen, alkyl, hydroxy, oxo, aryl or heterocyclic
group, and at least one of carbon atom in the aliphatic hydrocarbon
is optionally substituted by oxygen, nitrogen or sulfur;
[0048] R.sub.2 is a single bond or lower alkylene; and
[0049] R.sub.3 is lower alkyl, lower alkoxy, lower alkanoyloxy,
cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy,
heterocyclic group or heterocyclic-oxy group.
[0050] In the above formula, the term "unsaturated" in the
definitions for R.sub.1 and Ra is intended to include at least one
or more double bonds and/or triple bonds that are isolatedly,
separately or serially present between carbon atoms of the main
and/or side chains. According to the usual nomenclature, an
unsaturated bond between two serial positions is represented by
denoting the lower number of the two positions, and an unsaturated
bond between two distal positions is represented by denoting both
of the positions.
[0051] The term "lower or medium aliphatic hydrocarbon" refers to a
straight or branched chain hydrocarbon group having 1 to 14 carbon
atoms (for a side chain, 1 to 3 carbon atoms are preferable) and
preferably 1 to 10, especially 1 to 8 carbon atoms.
[0052] The term "halogen atom" covers fluorine, chlorine, bromine
and iodine.
[0053] The term "lower" throughout the specification is intended to
include a group having 1 to 6 carbon atoms unless otherwise
specified.
[0054] The term "lower alkyl" refers to a straight or branched
chain saturated hydrocarbon group containing 1 to 6 carbon atoms
and includes, for example, methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, t-butyl, pentyl and hexyl.
[0055] The term "lower alkylene" refers to a straight or branched
chain bivalent saturated hydrocarbon group containing 1 to 6 carbon
atoms and includes, for example, methylene, ethylene, propylene,
isopropylene, butylene, isobutylene, t-butylene, pentylene and
hexylene.
The term "lower alkoxy" refers to a group of lower alkyl-O--,
wherein lower alkyl is as defined above.
[0056] The term "hydroxy(lower)alkyl" refers to a lower alkyl as
defined above which is substituted with at least one hydroxy group
such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and
1-methyl-1-hydroxyethyl.
[0057] The term "lower alkanoyloxy" refers to a group represented
by the formula RCO--O--, wherein RCO-- is an acyl group formed by
oxidation of a lower alkyl group as defined above, such as
acetyl.
[0058] The term "cyclo(lower)alkyl" refers to a cyclic group formed
by cyclization of a lower alkyl group as defined above but contains
three or more carbon atoms, and includes, for example, cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl.
[0059] The term "cyclo(lower)alkyloxy" refers to the group of
cyclo(lower)alkyl-O--, wherein cyclo(lower)alkyl is as defined
above.
[0060] The term "aryl" may include unsubstituted or substituted
aromatic hydrocarbon rings (preferably monocyclic groups), for
example, phenyl, tolyl, xylyl. Examples of the substituents are
halogen atom and halo(lower)alkyl, wherein halogen atom and lower
alkyl are as defined above.
[0061] The term "aryloxy" refers to a group represented by the
formula ArO--, wherein Ar is aryl as defined above.
The term "heterocyclic group" may include mono- to tri-cyclic,
preferably monocyclic heterocyclic group which is 5 to 14,
preferably 5 to 10 membered ring having optionally substituted
carbon atom and 1 to 4, preferably 1 to 3 of 1 or 2 type of hetero
atoms selected from nitrogen atom, oxygen atom and sulfur atom.
Examples of the heterocyclic group include furyl, thienyl,
pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
imidazolyl, pyrazolyl, furazanyl, pyranyl, pyridyl, pyridazinyl,
pyrimidyl, pyrazinyl, 2-pyrrolinyl, pyrrolidinyl, 2-imidazolinyl,
imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidino,
piperazinyl, morpholino, indolyl, benzothienyl, quinolyl,
isoquinolyl, purinyl, quinazolinyl, carbazolyl, acridinyl,
phenanthridinyl, benzimidazolyl, benzimidazolinyl, benzothiazolyl,
phenothiazinyl. Examples of the substituent in this case include
halogen, and halogen substituted lower alkyl group, wherein halogen
atom and lower alkyl group are as described above.
[0062] The term "heterocyclic-oxy group" means a group represented
by the formula HcO--, wherein Hc is a heterocyclic group as
described above.
[0063] The term "functional derivative" of A includes salts
(preferably pharmaceutically acceptable salts), ethers, esters and
amides.
[0064] Suitable "pharmaceutically acceptable salts" include
conventionally used non-toxic salts, for example a salt with an
inorganic base such as an alkali metal salt (such as sodium salt
and potassium salt), an alkaline earth metal salt (such as calcium
salt, and magnesium salt), an ammonium salt; or a salt with an
organic base, for example, an amine salt (such as methylamine salt,
dimethylamine salt, cyclohexylamine salt, benzylamine salt,
piperidine salt, ethylenediamine salt, ethanolamine salt,
diethanolamine salt, triethanolamine salt,
tris(hydroxymethylamino)ethane salt, monomethyl-monoethanolamine
salt, procaine salt and caffeine salt), a basic amino acid salt
(such as arginine salt and lysine salt), tetraalkyl ammonium salt
and the like. These salts may be prepared by a conventional
process, for example from the corresponding acid and base or by
salt interchange.
[0065] Examples of the ethers include alkyl ethers, for example,
lower alkyl ethers such as methyl ether, ethyl ether, propyl ether,
isopropyl ether, butyl ether, isobutyl ether, t-butyl ether, pentyl
ether and 1-cyclopropyl ethyl ether; and medium or higher alkyl
ethers such as octyl ether, diethylhexyl ether, lauryl ether and
cetyl ether; unsaturated ethers such as oleyl ether and linolenyl
ether; lower alkenyl ethers such as vinyl ether, allyl ether; lower
alkynyl ethers such as ethynyl ether and propynyl ether;
hydroxy(lower)alkyl ethers such as hydroxyethyl ether and
hydroxyisopropyl ether; lower alkoxy (lower)alkyl ethers such as
methoxymethyl ether and 1-methoxyethyl ether; optionally
substituted aryl ethers such as phenyl ether, tosyl ether,
t-butylphenyl ether, salicyl ether, 3,4-di-methoxyphenyl ether and
benzamidophenyl ether; and aryl(lower)alkyl ethers such as benzyl
ether, trityl ether and benzhydryl ether.
[0066] Examples of the esters include aliphatic esters, for
example, lower alkyl esters such as methyl ester, ethyl ester,
propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl
ester, pentyl ester and 1-cyclopropylethyl ester; lower alkenyl
esters such as vinyl ester and allyl ester; lower alkynyl esters
such as ethynyl ester and propynyl ester; hydroxy(lower)alkyl ester
such as hydroxyethyl ester; lower alkoxy (lower) alkyl esters such
as methoxymethyl ester and 1-methoxyethyl ester; and optionally
substituted aryl esters such as, for example, phenyl ester, tolyl
ester, t-butylphenyl ester, salicyl ester, 3,4-di-methoxyphenyl
ester and benzamidophenyl ester; and aryl(lower)alkyl ester such as
benzyl ester, trityl ester and benzhydryl ester.
[0067] The amide of A mean a group represented by the formula
--CONR'R'', wherein each of R' and R'' is hydrogen, lower alkyl,
aryl, alkyl- or aryl-sulfonyl, lower alkenyl and lower alkynyl, and
include for example lower alkyl amides such as methylamide,
ethylamide, dimethylamide and diethylamide; arylamides such as
anilide and toluidide; and alkyl- or aryl-sulfonylamides such as
methylsulfonylamide, ethylsulfonyl-amide and
tolylsulfonylamide.
[0068] Preferred examples of L and M include hydroxy and oxo, and
especially, M is hydroxy and L is oxo which has a 5-membered ring
structure of, so called, PGE type.
Preferred example of A is --COOH, its pharmaceutically acceptable
salt, ester or amide thereof.
[0069] Preferred example of X.sub.1 and X.sub.2 is fluorine, so
called 16,16-difluoro type.
[0070] Preferred R.sub.1 is a hydrocarbon residue containing 1-10
carbon atoms, preferably 6-10 carbon atoms. Further, at least one
carbon atom in the aliphatic hydrocarbon is optionally substituted
by oxygen, nitrogen or sulfur. Examples of R.sub.1 include, for
example, the following groups:
[0071]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
[0072] --CH.sub.2--CH.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2--,
[0073] --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.dbd.CH--,
[0074] --CH.sub.2--C.ident.C--CH.sub.2--CH.sub.2--CH.sub.2--,
[0075] --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
[0076] --CH.sub.2--CH.dbd.CH--CH.sub.2--O--CH.sub.2--,
[0077] --CH.sub.2--C.ident.C--CH.sub.2--O--CH.sub.2--,
[0078]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.su-
b.2--,
[0079]
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
[0080]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.dbd.CH--,
[0081]
--CH.sub.2--C.ident.C--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
[0082]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH(CH.sub.3)--C-
H.sub.2--,
[0083]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
[0084]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.su-
b.2--CH.sub.2--,
[0085]
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.s-
ub.2--,
[0086]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.db-
d.CH--,
[0087]
--CH.sub.2--C.ident.C--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.s-
ub.2--, and
[0088]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH(CH-
.sub.3)--CH.sub.2--.
[0089] Preferred Ra is a hydrocarbon containing 1-10 carbon atoms,
more preferably, 1-8 carbon atoms. Ra may have one or two side
chains having one carbon atom.
[0090] The configuration of the ring and the .alpha.- and/or
.omega. chains in the above formula (I) and (II) may be the same as
or different from that of the primary PGs. However, the present
invention also includes a mixture of a compound having a primary
type configuration and a compound of non-primary type
configuration.
[0091] In the present invention, the PG compound which is dihydro
between 13 and 14, and keto (.dbd.O) at 15 position may be in the
keto-hemiacetal equilibrium by formation of a hemiacetal between
hydroxy at position, 11 and keto at position 15.
[0092] For example, it has been revealed that when both of X.sub.1
and X.sub.2 are halogen atoms, especially, fluorine atoms, the
compound contains a tautomeric isomer, bicyclic compound.
[0093] If such tautomeric isomers as above are present, the
proportion of both tautomeric isomers varies with the structure of
the rest of the molecule or the kind of the substituent present.
Sometimes one isomer may predominantly be present in comparison
with the other. However, it is to be appreciated that the present
invention includes both isomers.
[0094] Further, the 15-keto-PG compounds used in the invention
include the bicyclic compound and analogs or derivatives
thereof.
[0095] The bicyclic compound is represented by the formula
(III)
##STR00006##
[0096] wherein, A is --CH.sub.3, or --CH.sub.2OH, --COCH.sub.2OH,
--COON or a functional derivative thereof;
[0097] X.sub.1' and X.sub.2' are hydrogen, lower alkyl, or
halogen;
[0098] Y is
##STR00007##
[0099] wherein R.sub.4' and R.sub.5' are hydrogen, hydroxy,
halogen, lower alkyl, lower alkoxy or hydroxy(lower)alkyl, wherein
R.sub.4' and R.sub.5' are not hydroxy and lower alkoxy at the same
time.
[0100] R.sub.1 is a saturated or unsaturated divalent lower or
medium aliphatic hydrocarbon residue, which is unsubstituted or
substituted with halogen, alkyl, hydroxy, oxo, aryl or heterocyclic
group, and at least one of carbon atom in the aliphatic hydrocarbon
is optionally substituted by oxygen, nitrogen or sulfur; and
[0101] R.sub.2' is a saturated or unsaturated lower or medium
aliphatic hydrocarbon residue, which is unsubstituted or
substituted with halogen, oxo, hydroxy, lower alkyl, lower alkoxy,
lower alkanoyloxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl,
aryloxy, heterocyclic group or hetrocyclic-oxy group; lower alkoxy;
lower alkanoyloxy; cyclo(lower)alkyl; cyclo(lower)alkyloxy; aryl;
aryloxy; heterocyclic group; heterocyclic-oxy group.
[0102] R.sub.3' is hydrogen, lower alkyl, cyclo(lower)alkyl, aryl
or heterocyclic group.
[0103] Furthermore, while the compounds used in the invention may
be represented by a formula or name based on keto-type regardless
of the presence or absence of the isomers, it is to be noted that
such structure or name does not intend to exclude the hemiacetal
type compound.
[0104] In the present invention, any of isomers such as the
individual tautomeric isomers, the mixture thereof, or optical
isomers, the mixture thereof, a racemic mixture, and other steric
isomers may be used in the same purpose.
[0105] Some of the compounds used in the present invention may be
prepared by the method disclosed in U.S. Pat. Nos. 5,073,569,
5,166,174, 5,221,763, 5,212,324, 5,739,161 and 6,242,485 (these
cited references are herein incorporated by reference).
[0106] The term "chloride or ClC or ClC-2 channel opener" used
herein includes the compound which activates, promotes or modulates
the Cl.sup.- current, Cl.sup.- secretion or Cl.sup.- transport by
opening chloride or ClC or ClC-2 channel
[0107] According to the present invention a mammalian subject may
be treated by the instant invention by administering the compound
used in the present invention. The subject may be any mammalian
subject including a human. The compound may be applied systemically
or topically. Usually, the compound may be administered by oral
administration, intravenous injection (including infusion),
subcutaneous injection, intra rectal administration, intra vaginal
administration, transdermal administration and the like. The dose
may vary depending on the strain of the animal, age, body weight,
symptom to be treated, desired therapeutic effect, administration
route, term of treatment and the like. A satisfactory effect can be
obtained by systemic administration 1-4 times per day or continuous
administration at the amount of 0.001-1000 .mu.g/kg per day, more
preferably 0.01-100 .mu.g/kg, most preferably 0.1-10 .mu.g/kg.
[0108] A typical treatment regimen entails administering to a human
patient a composition containing from about 18 to about 30 .mu.g of
active ingredient according to the invention from one to three
times daily, with about 24 .mu.g two times per day being preferred.
The composition for the oral administration may be administered
with or without food and/or water.
[0109] The compound may preferably be formulated in a
pharmaceutical composition suitable for administration in a
conventional manner. The composition may be those suitable for oral
administration, injection or perfusion as well as it may be an
external agent, suppository or pessary.
[0110] The composition of the present invention may further contain
physiologically acceptable additives. Said additives may include
the ingredients used with the present compounds such as excipient,
diluent, filler, resolvent, lubricant, adjuvant, binder,
disintegrator, coating agent, cupsulating agent, ointment base,
suppository base, aerozoling agent, emulsifier, dispersing agent,
suspending agent, thickener, tonicity agent, buffering agent,
soothing agent, preservative, antioxidant, corrigent, flavor,
colorant, a functional material such as cyclodextrin and
biodegradable polymer, stabilizer. The additives are well known to
the art and may be selected from those described in general
reference books of pharmaceutics.
[0111] The amount of the above-defined compound in the composition
of the invention may vary depending on the formulation of the
composition, and may generally be 0.00001-10.0 wt %, more
preferably 0.0001-1.0 wt %, most preferably 0.001-0.1%.
[0112] Examples of solid compositions for oral administration
include tablets, troches, sublingual tablets, capsules, pills,
powders, granules and the like. The solid composition may be
prepared by mixing one or more active ingredients with at least one
inactive diluent. The composition may further contain additives
other than the inactive diluents, for example, a lubricant, a
disintegrator and a stabilizer. Tablets and pills may be coated
with an enteric or gastroenteric film, if necessary. They may be
covered with two or more layers. They may also be adsorbed to a
sustained release material, or microcapsulated. Additionally, the
compositions may be capsulated by means of an easily degradable
material such gelatin. They may be further dissolved in an
appropriate solvent such as fatty acid or its mono, di or
triglyceride to be a soft capsule. Sublingual tablet may be used in
need of fast-acting property.
[0113] Examples of liquid compositions for oral administration
include emulsions, solutions, suspensions, syrups and elixirs and
the like. Said composition may further contain a conventionally
used inactive diluents e.g. purified water or ethyl alcohol. The
composition may contain additives other than the inactive diluents
such as adjuvant e.g. wetting agents and suspending agents,
sweeteners, flavors, fragrance and preservatives.
[0114] The composition of the present invention may be in the form
of spraying composition, which contains one or more active
ingredients and may be prepared according to a known method.
[0115] Examples of the injectable compositions of the present
invention for parenteral administration include sterile aqueous or
non-aqueous solutions, suspensions and emulsions. Diluents for the
aqueous solution or suspension may include, for example, distilled
water for injection, physiological saline and Ringer's
solution.
[0116] Non-aqueous diluents for solution and suspension may
include, for example, propylene glycol, polyethylene glycol,
vegetable oils such as olive oil, alcohols such as ethanol and
polysorbate. The composition may further comprise additives such as
preservatives, wetting agents, emulsifying agents, dispersing
agents and the like. They may be sterilized by filtration through,
e.g. a bacteria-retaining filter, compounding with a sterilizer, or
by means of gas or radioisotope irradiation sterilization. The
injectable composition may also be provided as a sterilized powder
composition to be dissolved in a sterilized solvent for injection
before use.
[0117] The present external agent includes all the external
preparations used in the fields of dermatology and otolaryngology,
which includes ointment, cream, lotion and spray.
[0118] Another form of the present invention is suppository or
pessary, which may be prepared by mixing active ingredients into a
conventional base such as cacao butter that softens at body
temperature, and nonionic surfactants having suitable softening
temperatures may be used to improve absorbability.
[0119] The term "treatment" used herein includes any means of
control such as prevention, care, relief of the condition,
attenuation of the condition and arrest of progression.
[0120] The term "abdominal discomfort" used herein includes any
abdominal discomfort involved or being associated with any type of
condition and/or diseases, or caused by drugs, medications or
surgical procedures.
[0121] In the present specification and/claims, "treatment of
abdominal discomfort" or "treating abdominal discomfort" includes
to relieve or to eliminate the abdominal discomfort. In addition,
"treatment of functional gastrointestinal disorder" or "treating
functional gastrointestinal disorder" covers to relieve or to
eliminate abdominal discomfort which is associated with functional
gastrointestinal disorders.
[0122] One of the typical disorders being accompanied by abdominal
discomfort includes functional gastrointestinal disorders. Examples
of the functional gastrointestinal disorders include irritable
bowel syndrome and functional dyspepsia.
[0123] The pharmaceutical composition of the present invention may
further contain other pharmacological ingredients as far as they do
not contradict the purpose of the present invention.
[0124] The further details of the present invention will follow
with reference to test examples, which, however, are not intended
to limit the present invention.
Example 1
Methods
[0125] Patients with irritable bowel syndrome (IBS) were randomly
allocated to the following two treatment groups. [0126] Group 1:
Test substance (13,14-dihydro-15-keto-16,16-difluoro-PGE.sub.1) 48
.mu.g total (24 .mu.g/breakfast+24 .mu.g/dinner) [0127] Group 2:
Matching placebo (placebo/breakfast+placebo/dinner)
[0128] Each group underwent two weeks washout period and then began
to administer oral test substance (capsules) or placebo (capsules)
daily for 4 weeks. Test substance or placebo was taken two times a
day (b.i.d) at breakfast with food and at least 8 ounces of water
and at dinner with food and at least 8 ounces of water. Patients
were asked to evaluate abdominal discomfort upon waking in the
morning, using a 5-point scale (Score: 0=absent, 1=mild,
2=moderate, 3=severe, 4=very severe) at 4 weeks after the
initiation of the treatments.
[0129] (Results)
[0130] As shown in Table 1, test substance of this invention
significantly improved the abdominal discomfort in the patients
with IBS.
TABLE-US-00001 TABLE 1 Effect of test substance on abdominal
discomfort in patients with IBS Abdominal discomfort score, Mean
.+-. SD (N) Week Placebo Test Substance Baseline 2.31 .+-. 0.788
(26) 2.25 .+-. 0.803 (32) Week 4 2.19 .+-. 0.895 (26) 1.48 .+-.
1.029** (31) Test substance:
13,14-dihydro-15-keto-16,16-difluoro-PGE.sub.1 **p < 0.01 (van
Elteren test stratified by center)
Example 2
Methods
[0131] Patients with occasional constipation were randomly
allocated to the following two treatment groups. [0132] Group 1:
Test substance (13,14-dihydro-15-keto-16,16-difluoro-PGE1) 48 .mu.g
total (24 .mu.g/breakfast+24 .mu.g/dinner) [0133] Group 2: Matching
placebo (placebo/breakfast+placebo/dinner)
[0134] Each group underwent two weeks washout period and then began
to administer oral test substance (capsules) or placebo (capsules)
daily for 4 weeks. During the washout period, the patient's bowel
habit was documented to confirm the existence of constipation.
Constipation is defined as, on average, less than three spontaneous
bowel movements per week. All existing laxative medication was
withdrawn at the start of the washout period and the patients were
instructed not to change their diet or lifestyle during the
study.
[0135] Test substance or placebo was taken orally for a total
treatment period of 4 weeks; it was taken two times a day (b.i.d)
at breakfast with food and at least 8 ounces of water and at dinner
with food and at least 8 ounces of water.
[0136] The patients were asked to evaluate abdominal discomfort
upon waking in the morning, using a 5-point scale (Score: 0=absent,
1=mild, 2=moderate, 3=severe, 4=very severe) at 2 and 4 weeks after
the initiation of the treatments.
[0137] (Results)
[0138] As shown in Table 2, test substance of this invention
significantly improved the abdominal discomfort in patients with
constipation.
TABLE-US-00002 TABLE 2 Effect of test substance on abdominal
discomfort in patients with constipation Abdominal discomfort
score, Mean .+-. SD (N) Placebo Test Substance Week 2 1.41 .+-.
1.035 (122) 1.09 .+-. 1.047* (116) Week 3 1.64 .+-. 1.114 (122)
1.27 .+-. 1.057* (117) Week 4 1.52 .+-. 1.038 (122) 1.22 .+-.
1.060* (117) Test substance:
13,14-dihydro-15-keto-16,16-difluoro-PGE.sub.1 *p < 0.05 (van
Elteren test stratified by center)
Example 3
Methods
[0139] Patients with irritable bowel syndrome (IBS) were randomly
allocated to the following two treatment groups. [0140] Group 1:
Test substance (13,14-dihydro-15-keto-16,16-difluoro-PGE.sub.1) 48
.mu.g total (24 .mu.g/breakfast+24 .mu.g/dinner) [0141] Group 2:
Matching placebo (placebo/breakfast+placebo/dinner)
[0142] Each group underwent two weeks washout period and then began
to administer oral test substance (capsules) or placebo (capsules)
daily for 4 weeks. Test substance or placebo was taken two times a
day (b.i.d) at breakfast with food and at least 8 ounces of water
and at dinner with food and at least 8 ounces of water. The
patients were asked to evaluate abdominal bloating upon waking in
the morning, using a 5-point scale (Score: 0=absent, 1=mild,
2=moderate, 3=severe, 4=very severe) at 4 weeks after the
initiation of the treatments.
[0143] (Results)
[0144] As shown in Table 3, test substance of this invention
significantly improved the abdominal bloating in patients with
IBS.
TABLE-US-00003 TABLE 3 Effect of test substance on abdominal
bloating in patients with IBS Abdominal bloating score, Mean .+-.
SD (N) Week Placebo Test Substance Baseline 2.46 .+-. 0.859 (26)
2.50 .+-. 0.916 (32) Week 4 2.42 .+-. 0.945 (26) 1.74 .+-. 0.999**
(31) Test substance: 13,14-dihydro-15-keto-16,16-difluoro-PGE.sub.1
**p < 0.01 (van Elteren test stratified by center)
Example 4
Methods
[0145] Patients with irritable bowel syndrome (IBS) exhibiting
dyschezia were randomly allocated to the following two treatment
groups. [0146] Group 1: Test substance
(13,14-dihydro-15-keto-16,16-difluoro-PGE.sub.1) 48 .mu.g total (24
.mu.g/breakfast+24 .mu.g/dinner) [0147] Group 2: Matching placebo
(placebo/breakfast+placebo/dinner)
[0148] Each group underwent two weeks washout period and then began
to administer oral test substance (capsules) or placebo (capsules)
daily for 4 weeks. Test substance or placebo was taken two times a
day (b.i.d) at breakfast with food and at least 8 ounces of water
and at dinner with food and at least 8 ounces of water. After 3
consecutive days of not having spontaneous bowel movement, the
investigator could prescribe to the patient 10 mg bisacodyl
suppository as a rescue medication. If this was not effective,
Fleet.RTM. enema could be used. During the study period, each
patient documented bowel activity. A spontaneous bowel movement was
defined as any bowel movement, except for that occurred within 24
hours after the rescue medication. Frequency of spontaneous bowel
movements at Baseline, Weeks 1, 2, 3 and 4 were analyzed.
[0149] (Results)
[0150] As shown in Table 4, test substance of this invention
significantly improved the spontaneous bowel movement frequency in
patients with IBS exhibiting dyschezia.
TABLE-US-00004 TABLE 4 Effect of test substance on spontaneous
bowel movement frequency rates in patients with IBS exhibiting
dischezia Spontaneous Bowel Movement Frequency Rates, Mean .+-. SD
(N) Week Placebo Test Substance Baseline 1.85 .+-. 2.310 (26) 1.43
.+-. 0.773 (32) Week 1 3.58 .+-. 2.887 (26) 6.50 .+-. 4.108** (32)
Week 2 2.84 .+-. 2.481 (26) 5.58 .+-. 4.003** (32) Week 3 2.30 .+-.
2.170 (26) 5.93 .+-. 4.775** (32) Week 4 2.21 .+-. 2.399 (26) 5.17
.+-. 4.333* (32) Test substance:
13,14-dihydro-15-keto-16,16-difluoro-PGE.sub.1 *p < 0.05, **p
< 0.01 (van Elteren test stratified by center)
* * * * *