Difluoroprostaglandin derivatives and their use

A fluorine-containing prostaglandin derivative of the formula (1) (or a salt thereof) and a medicine containing it, particularly, a preventive or therapeutic medicine for an eye disease: ##STR1## wherein A is a vinylene group or the like, R.sup.1 is an aryloxyalkyl group or the like, R.sup.2 and R.sup.3 are hydrogen atoms or the like, and Z is OR.sup.4 (wherein OR.sup.4 is a hydrogen atom or an alkyl group) or the like.

The present invention relates to fluorine-containing prostaglandin 
derivatives having two fluorine atoms at the 15-position (or their salts) 
and medicines containing the compounds as an active ingredient, 
particularly, preventive or therapeutic medicines for eye diseases. 
The naturally occurring prostaglandins (PGs) are a class of biologically 
active substances synthesized in the body and cellular functions in 
various tissues of the body as local hormones having various biological 
activities. The PGs F, a group of naturally occurring PGs, are known to 
lower intraocular pressure when topically applied to the eye and are 
expected to find applications as therapeutic medicines for ocular 
hypertension or glaucoma (U.S. Pat. No. 4,599,353). However, they are 
irritant to the eye and have a problem of their inflammatory side effects 
such as congestion and damage to the cornea. Therefore, research for 
development of PGF derivatives which do not have such side effects is 
extensively conducted both at home and abroad. PGF derivatives having a 
cyclic structure in the .omega.-chain are also known. Shielnshantz et al. 
reported specific PGA, PGB, PGD, PGE and PGF derivatives modified by 
introduction of a cyclic structure are less irritant and congestive to the 
eye (Japanese Unexamined Patent Publication JP-A-8-109132). Ophthalmic 
compositions for local therapeutic medicines for glaucoma and ocular 
hypertension containing a chloprostenol or fluprostenol analog have been 
also reported (Japanese Unexamined Patent Publication JP-A-7-165703). 
Among the above-mentioned compounds disclosed in the literature, the 
compound 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF.sub.2.alpha. 
isopropyl ester (Latanoprost) has an excellent pharmacological effect, and 
ophthalmic solutions containing Latanoprost as an active ingredient are 
used for treatment of glaucoma and ocular hypertension at actual medical 
sites. Although Latanoprost is less irritant and congestive to the eye, 
there is still room for improvement in the melanogenesis-stimulating 
property and the duration of efficacy. In particular, Latanoprost 
stimulates melanogenesis, and its side effect of causing iridal 
pigmentation (A. Alm, et al, Ophthalmology, Vol. 102, No. 12, 1743-1752 
(1995)) remains a problem to be solve. 
For this reason, extensive research has been conducted both at home and 
abroad for development of long-lasting PGF derivatives having much the 
same biological activities as the naturally occurring one and few side 
effects. 
Meanwhile, Bezglov et al. reported 15-fluoro-15-deoxy PGF.sub.2.alpha., 
which is derived from naturally occurring PGF2.alpha. by introducing 
fluorine at the 15-position and retains the skeleton of its origin. 
15-Fluoro-15-deoxy-PGF.sub.2.alpha. is reported to have remarkable 
pharmacological actions such as the 100-fold greater contraction action 
and the 1000-fold relaxation action on smooth muscle in the respiratory 
system as compared with those of the naturally occurring PGF.sub.2.alpha. 
and the action on the smooth muscle in the digestive and circulatory 
systems comparable to that of the naturally occurring PGF.sub.2.alpha. 
(Izv. Akad. Nauk SSSR, Ser. Biol., 6,831 (1989)). However, no report has 
been made on any pharmacological actions of the compound on any eye 
disease, particularly on glaucoma. 
No prostaglandin F derivatives that have a fluorine atom at the 15-position 
have been known except 15-fluoro-15-deoxy-PGF.sub.2.alpha.. Especially, no 
report has been made on derivatives having two fluorine atoms at the 
15-position, 15,15-difluoro-15-deoxy PGs F.sub.2.alpha. per se or their 
synthesis. 
The present inventors synthesized 15,15-difluoro-15-deoxy-PGF.sub.2.alpha. 
and its novel derivatives and measured their biological activities to 
assess their usefulness as medicines. The present inventors also measured 
the biological activities of derivatives of 
15,15-difluoro-15-deoxy-PGF.sub.2.alpha. which have a substituted or 
unsubstituted aryloxy group on the .omega.-chain and are prepared by 
modifying the carboxyl group or the hydroxyl group of the prostaglandin to 
assess their usefulness as medicines. As a result, the present inventors 
have found that 15,15-difluoro-15-deoxy-PGF.sub.2.alpha. and its 
derivatives are superior to the known natural PGF.sub.2.alpha. in the 
effect of lowering intraocular pressure are scarcely irritant to the eye, 
scarcely affect the ocular tissues such as the cornea, the iris and the 
conjunctive, and have long-lasting efficacy. They are characterized in 
that they stimulates melanogenesis much less as well as in that their 
efficacy lasts longer than Latanoprost. 
The present invention relates to the compound 
15,15-difluoro-15-deoxy-PGF.sub.2.alpha. and its derivatives and their 
use as medicines, in particular, as medicines for eye diseases, and 
provides a fluorine-containing prostaglandin derivative of the following 
formula (1) or a salt thereof: 
##STR2## 
wherein A is an ethylene group, a vinylene group, an ethynylene group, 
--OCH.sub.2 -- or --SCH.sub.2 --, 
R.sup.1 is a substituted or unsubstituted C.sub.3-8 alkyl group, a 
substituted or unsubstituted C.sub.3-8 alkenyl group, a substituted or 
unsubstituted C.sub.3-8 alkynyl group, a substituted or unsubstituted 
C.sub.3-8 cycloalkyl group, a substituted or unsubstituted aralkyl group 
or a substituted or unsubstituted aryloxyalkyl group, 
each of R.sup.2 and R.sup.3 which are independent of each other, is a 
hydrogen atom or an acyl group, or forms a single bond together with Z, 
X is --CH.sub.2 --, --O-- or --S--, Z is --OR.sup.4, --NHCOR.sup.5, 
--NHSO.sub.2 R.sup.6 or --SR.sup.7, or forms a single bond together with 
R.sup.2 or R.sup.3, 
each of R.sup.4, R.sup.5, R.sup.6 and R.sup.7 which are independent of one 
another, is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl 
group, a cycloalkyl group, an aryl group or an aralkyl group, 
and a dual line consisting of solid and broken lines is a single bond, a 
cis-double bond or a trans-double bond, a medicine containing the above 
compound as an active ingredient; and a preventive or therapeutic medicine 
for an eye disease containing the above compound as an active ingredient. 
The fluorine-containing prostaglandin derivatives of the present invention 
may be the same as the naturally occurring type except for the two 
fluorine atoms at the 15-position (namely, compounds wherein A is a 
vinylene group, R.sup.1 is a n-pentyl group, both R.sup.2 and R.sup.3 are 
hydrogen atoms, X is --CH.sub.2 --, Z is --OH, and the dual line is a 
cis-double bond). However, among the fluorine-prostaglandin derivatives of 
the present invention, those having an .omega.-chain which is not of the 
naturally occurring type (namely, wherein A is a vinylene group, and 
R.sup.1 is a n-pentyl group) are preferred. In particular, those having 
wherein R.sup.1 is one of the above-mentioned groups except an alkyl group 
are preferred. 
In the present invention, the eye disease as the target for prevention or 
therapy is preferably glaucoma or ocular hypertension. 
In the following description, the term "lower" for an organic group 
corresponds to a carbon number of from 1 to 6. A preferred lower organic 
group is an organic group having from 1 to 4 carbon atoms. 
An "alkyl group" may be linear or branched, and unless otherwise noted, a 
lower alkyl group is preferred. Specific examples include a methyl group, 
an ethyl group, a propyl group, an isopropyl group, a butyl group, an 
isobutyl group, a sec-butyl group, a t-butyl group, a pentyl group and a 
hexyl group. 
An "alkenyl group" is preferably a lower alkenyl group, unless otherwise 
noted, and more preferably a linear or branched alkenyl group having from 
2 to 6 carbon atoms and one unsaturated group. Specific examples include a 
vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, a 
3-butenyl group, a 3-pentenyl group and a 4-hexenyl group. 
An "alkynyl group" is preferably a lower alkynyl group, unless otherwise 
noted, more preferably a linear or branched alkynyl group having from 2 to 
6 carbon atoms and one unsaturated group. Specific examples include a 
1-propynyl group, a 2-propynyl group, a 3-butynyl group, a 3-pentynyl 
group and a 4-hexynyl group. 
As an "alkoxy group", although a wide variety of common alkoxy groups may 
be used, a lower alkoxy group is preferred, and more preferred is a linear 
or branched alkoxy group having from 1 to 4 carbon atoms. Specific 
examples include a methoxy group, an ethoxy group, a propoxy group and a 
butoxy group. 
A "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or 
an iodine atom. 
An "aryl group" means a monovalent aromatic hydrocarbon group which may 
have a substituent (such as a lower alkyl group, a halogen atom, a 
haloalkyl group, a lower alkoxy group or a lower alkylamino group), 
preferably a phenyl group or its derivative. For example, a phenyl group, 
a tolyl group, a halophenyl group (such as a chlorophenyl group, a 
fluorophenyl group or a bromophenyl group), a dihalophenyl group (such as 
a dichlorophenyl group, a difluorophenyl group or a dibromophenyl group), 
a trihalophenyl group (such as a trichlorophenyl group, a trifluorophenyl 
group or a tribromophenyl group), a haloalkylphenyl group (such as a 
trifluoromethylphenyl group), an alkoxyphenyl group (such as a 
methoxyphenyl group or an ethoxyphenyl group), a dialkoxyphenyl group 
(such as a dimethoxyphenyl group or a diethoxyphenyl group) or a 
trialkoxyphenyl group (such as a trimethoxyphenyl group or a 
triethoxyphenyl group) may be mentioned. 
An "aralkyl group" means an aryl-substituted alkyl group, in which the aryl 
group as the substituent may be as described above, and the carbon number 
of the alkyl group is preferably from 1 to 4. Specific examples include a 
benzyl group, a benzhydryl group, a trityl group and a phenethyl group. 
A "cycloalkyl group" means an unsubstituted or substituted 3 to 8-membered 
cycloalkyl group, and when substituted, may have a lower alkyl group, a 
halogen atom or an alkoxy group as a substituent. For example, a 
cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl 
group, a cycloheptyl group, a methylcyclohexyl group, a 
dimethylcyclopentyl group, a dimethylcyclohexyl group, a chlorocyclohexyl 
group or a dichlorocyclohexyl group may be mentioned. 
A "haloalkyl group" means a lower haloalkyl group having at least one 
halogen atom. A fluoromethyl group, a difluoromethyl group, a 
trifluoromethyl group, a trifluoroethyl group, a pentafluoroethyl group, a 
chloromethyl group, a dichloromethyl group, a trichlromethyl group or a 
bromomethyl group may be mentioned. 
An "acyl group" means a monovalent or polyvalent group derived from a 
carboxylic acid by removing hydroxyl group(s) from all the carboxyl 
group(s). As the carboxylic acid, a saturated or unsaturated aliphatic 
carboxylic acid, a carbocyclic carboxylic acid or a heterocyclic 
carboxylic acid may be mentioned. As the carbocyclic carboxylic acid, a 
saturated or unsaturated alicyclic carboxylic acid or an aromatic 
caroboxylic acid may be mentioned. 
Among the fluorine-containing prostaglandin derivatives of the formula (1) 
(hereinafter referred to as the fluorine-containing prostaglandin 
derivatives (1)), the following compounds are preferred from the 
standpoint of biological activities and physical properties. 
As A, a vinylene group or an ethylene group is preferred, and the vinylene 
group induces cis- or trans-vinylene groups. A trans-vinylene group is 
particularly preferred. In the case of --OCH.sub.2 -- or --SCH.sub.2 --, 
the oxygen atom or the sulfur atom is preferably linked to the ring. 
As X, --CH.sub.2 -- is particularly preferred. 
The dual line consisting of solid and broken lines is preferably a 
cis-double bond. 
R.sup.1 is preferably an organic group corresponding to the .omega.-chain 
moiety of the naturally occurring PGF.sub.2.alpha. (when the rest is not 
of the naturally occurring type) or an organic group corresponding to the 
.omega.-chain moiety of any of various synthetic PGs F.sub.2.alpha.. Such 
organic groups include, for example, a C.sub.3-8 alkyl group, a C.sub.3-8 
alkenyl group, a C.sub.3-8 alkynyl group, a C.sub.3-8 cycloalkyl group, an 
aralkyl group, an aryloxy group having an aryl group such as a phenyl 
group, and such groups having various substituents. 
The alkyl group may have a cyclic organic group such as a cycloalkyl group 
as a substituent, and the alkenyl group and the alkynyl group may have a 
cyclic organic group such as an aryl group or a cycloalkyl group as a 
substituent. For example, R.sup.1 may be a cycloalkyl group-substituted 
alkyl group, a cycloalkyl group-substituted alkenyl group, or an aryl 
group-substituted alkenyl group. Further, it may be an organic group 
having an oxygen atom or a sulfur atom introduced to replace a carbon atom 
of a linear organic group such as an alkyl group, or an organic group 
having a cyclic organic group such as a cycloalkylene group or an arylene 
group introduced between two carbon atoms of a linear organic group. 
Further, a cycloalkyl group, an aralkyl group, an aryloxy group and an 
organic group having such a group as a substituent may have a linear 
organic group such as an alkyl group as a substituent on the ring moiety. 
Substituents in R.sup.1 include, in addition to the above-mentioned 
substituents, a halogen atom, an oxygen atom-containing substituent, a 
sulfur atom-containing substituent, a nitrogen atom-containing 
substituent, and others. 
When R.sup.1 is a linear substituted or unsubstituted group, a linear 
C.sub.5-6 alkyl group, a linear C.sub.5-6 alkenyl group and a linear 
C.sub.5-6 alkynyl group and such groups substituted with one or two methyl 
group are particularly preferred. Specific linear groups as R.sup.1 
include the following groups. Among them, preferred are a n-pentyl group, 
a 2-methylhexyl group, a 1-methyl-3-pentynyl group, a 1-methyl-3-hexynyl 
group, and a 1,1-dimethyl-3-hexynyl group. 
A n-propyl group, a n-butyl group, a n-pentyl group, a n-hexyl group, a 
n-heptyl group, a n-octyl group, a n-decyl group, a 1-methylpentyl group, 
a 1,1-dimethylpentyl group, a 1-methylhexyl group, a 2-methylpentyl group, 
a 2-methylhexyl group, a 3-pentenyl group, a 1-methyl-3-pentenyl group, a 
1-methyl-3-hexenyl group, a 1,1-dimethyl-3-pentenyl group, a 
1,1-dimethyl-3-hexenyl group, a 2-methyl-3-pentenyl group, a 
2-methyl-3-hexenyl group, a 3-pentynyl group, a 1-methyl-3-pentynyl group, 
a 1-methyl-3-hexynyl group, a 2-methyl-3-pentynyl group, a 
2-methyl-3-hexynyl group, a 1,1-dimethyl-3-pentynyl group, and a 
1,1-dimethyl-3-hexynyl group. 
The substituted or unsubstituted cycloalkyl group as R.sup.1 is preferably 
a C.sub.3-8 cycloalkyl group, or such a cycloalkyl group substituted by at 
least one lower alkyl group. Particularly preferred is an unsubstituted 
cyclopentyl group, an unsubstituted cyclohexyl group, a C.sub.1-4 alkyl 
group-substituted cyclopentyl group, or a C.sub.1-4 alkyl 
group-substituted cyclohexyl group. 
The substituted or unsubstituted aralkyl group as R.sup.1 is preferably an 
aralkyl group which contains, for example, a benzene ring, a furan ring, a 
thiophene ring or a naphthalene ring and may be substituted by, for 
example, a halogen atom, a haloalkyl group, an alkoxy group or a hydroxyl 
group. The carbon number of the alkyl moiety (i.e. the alkylene group) of 
the aralkyl group is preferably from 1 to 4. A particularly preferred 
aralkyl group is a C.sub.1-2 alkyl group substituted with a phenyl group 
or a C.sub.1-2 alkyl group substituted with a phenyl group substituted 
with one or two lower alkyl groups. 
Specifically, a phenylmethyl group, a 2-phenylethyl group, a 
3-methylphenylmethyl group, a 2-(3-methylphenyl)ethyl group, a 
3-trifluoromethylphenylmethyl group, a 2-(3-trifluoromethylphenyl)ethyl 
group, a 3-chlorophenylmethyl group, a 2-(3-chlorophenyl)ethyl group, a 
2-(3,5-dichlorophenyl)ethyl group and a 2-(3,4-dichlorophenyl)ethyl group 
are preferred. 
The substituted or unsubstituted aryloxyalkyl group as R.sup.1 is 
preferably an aryloxyalkyl group which contains, for example, a benzene 
ring, a furan ring, a thiophene ring or a naphthalene ring and may have, 
for example, a halogen atom, a haloalkyl group, an alkoxy group or a 
hydroxyl group as a substituent on the aryl moiety. The aryl moiety is 
preferably a phenyl group which is not substituted or substituted with 
from 1 to 3 halogen atoms or haloalkyl groups. The carbon number of the 
alkyl moiety substituted with an aryloxy group is preferably from 1 to 3. 
Specific preferred aryloxyalkyl groups as a phenoxymethyl group, a 
3-chlorophenoxymethyl group, a 3-fluorophenoxymethyl group, a 
3-trifluoromethylphenoxymethyl group, a 3,5-dichlorophenoxymethyl group, a 
3,4-dichlorophenoxymethyl group, a 3,5-difluorophenoxymethyl group, a 
3,4-difluorophenoxymethyl group, a 3,5-bis(trifluoromethyl)phenoxymethyl 
group and a 3,4-bis(trifluoromethyl)phenoxymethyl group. 
As R.sup.1, in addition to those described above, a C.sub.1-4 alkyl group 
substituted by the above-mentioned cycloalkyl group is preferred as a type 
of substituted alkyl group. As such a cycloalkyl group, a cyclopentyl 
group or a cyclohexyl group is preferred, and as such an alkyl group, a 
C.sub.1-2 alkyl group is preferred. Specific examples include a 
cyclopentylmethyl group, a 2-cyclopentylethyl group and a cyclohexylmethyl 
group. 
As R.sup.1, more preferred are the above-mentioned substituted or 
unsubstituted aryloxyalkyl groups. Among them, a substituted or 
unsubstituted phenoxymethyl group such as a phenoxymethyl group, a 
3-chlorophenoxymethyl group, a 3,5-dichlorophenoxymethyl group or a 
3,4-dichlorophenoxymethyl group is preferred. 
Each of R.sup.2 and R.sup.3 which are independent of each other, is a 
hydrogen atom or an acyl group, or forms a single bond as described later. 
It is preferred that both R.sup.2 and R.sup.3 are hydrogen atoms, or that 
either R.sup.2 or R.sup.3 is an acyl group and the other is a hydrogen 
atom. When only one of them is an acyl group, it is preferred that R.sup.2 
is an acyl group. Compounds wherein at least one of R.sup.2 and R.sup.3 is 
an acyl group are useful as prodrugs because they hydrolyze in vivo to 
biologically active compounds. As the acyl group, a C.sub.2-20 acyl group, 
particularly, an aliphatic hydrocarbon type C.sub.2-20 acyl group is 
preferred. In particular, fluorine-containing prostaglandin derivatives 
wherein either R.sup.2 or R.sup.3 is an aliphatic linear hydrocarbon type 
acyl group having a carbon number of at least 4 are useful as prodrugs 
having improved lipid solubility. 
Z is --OR.sup.4, --NHCOR.sup.5, --NHSO.sub.2 R.sup.6, --SR.sup.7 or 
represents a single bond together with R.sup.2 or R.sup.3, which means 
cyclization of a compound wherein Z is OH and either R.sup.2 or R.sup.3 is 
a hydrogen atom (a compound having a carboxyl group at the end of the 
.alpha.-chain and a hydroxyl group either at the 9-position or at the 
11-position) by esterification of the carboxyl group and the hydroxyl 
group to form an ester bond between the end of the .alpha.-chain and the 
9- or 11-position. Such cyclic compounds having an ester bond hydrolyze in 
vivo into biologically active compounds, and therefore are useful as 
prodrugs. 
As R.sup.4 -R.sup.7 in the groups represented by --OR.sup.4, --NHCOR.sup.5, 
--NHSO.sub.2 R.sup.6 and --SR.sup.7, a hydrogen atom, an alkyl group, an 
alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group and an 
aralkyl group may be mentioned. The alkyl group, the alkenyl group, the 
alkynyl group and the alkyl moiety of the aralkyl group may be linear or 
branched and may have various substituents such as halogen atoms. The 
cycloalkyl group, the aryl group and the aralkyl group may have an alkyl 
group or other substituents on the ring. As such substituents, the 
substituents described above for R.sup.1 may be mentioned. 
The alkyl group, the alkenyl group and the alkynyl group as R.sup.4 
-R.sup.7 preferably have a carbon number of at most 20, particularly, at 
most 8. Specific examples of these linear hydrocarbon groups include the 
following groups. As the alkyl group, a methyl group, an ethyl group, a 
n-propyl group, an isopropyl group, a n-butyl group, a n-pentyl group, a 
n-hexyl group, a n-heptyl group, a n-octyl group, a n-decyl group, a 
1-methylpentyl group, a 1,1-dimethylpentyl group, a 1-methylhexyl group, a 
2-methylpentyl group and 2-methylhexyl group may be mentioned. 
As the alkenyl group, an allyl group, a 2-butenyl group, a 3-pentenyl 
group, 1-methyl-3-pentenyl group, 1-methyl-3-hexenyl group, 
1,1-dimethyl-3-pentenyl group and a 1,1-dimethyl-3-hexenyl group may be 
mentioned. 
As the alkenyl group, a propargyl group, a 3-pentynyl group, a 
1-methyl-3-pentynyl group, a 1-methyl-3-hexynyl group, a 
1,1-dimethyl-3-pentynyl group and a 1,1-dimethyl-3-hexynyl group may be 
mentioned. 
As the substituted alkyl group, a halogen atom-substituted alkyl group or a 
cycloalkyl group-substituted alkyl group may be mentioned. The carbon 
number of the halogen atom-substituted alkyl group is preferably at most 
6, and the carbon number of the alkyl moiety of the cycloalkyl 
group-substituted alkyl group is preferably from 1 to 2. As the halogen 
atom-substituted alkyl group, for example, a trifluoromethyl group or a 
pentafluoroethyl group may be mentioned. As the cycloalkyl 
group-substituted alkyl group, for example, a cyclobutylmethyl group, a 
cyclopentylmethyl group or a cyclohexylmethyl group may be mentioned. 
The carbon number of the cycloalkyl group is preferably at most 10. 
Specific examples include a cyclopropyl group, a cyclobutyl group, a 
cyclopentyl group, a cyclohexyl group, a 2,2-dimethylcyclopropyl group, a 
3-cyclopentenyl group, a 3-cyclohexynyl group and a cyclooctanyl group. 
As the aryl group, a substituted or unsubstituted phenyl group is 
preferred. As the substituent, an alkyl group (preferably having a carbon 
number of at most 4), a halomethyl group, a halogen atom, an alkoxy group, 
an acyl group, an acylamino group or a nitro group is preferred. Specific 
examples of the aryl group include a phenyl group, a 4-methylphenyl group, 
a 4-(t-butyl)phenyl group, a 3-trifluoromethylphenyl group, a 
4-trifluoromethylphenyl group, a 4-chlorophenyl group, a 4-acetylphenyl 
group, a 4-benzoylphenyl group, a 4-acetylaminophenyl group, a 
4-benzoylaminophenyl group, a 3-nitrophenyl group and a 4-nitrophenyl 
group. 
As the aralkyl group, an aralkyl group consisting of an alkyl moiety having 
a carbon number of at most 4 (preferably a carbon number of 1 or 2) and a 
phenyl group is preferred. The phenyl group may be substituted with an 
alkyl group (preferably having a carbon number of at most 4), a halomethyl 
group, a halogen atom, an alkoxy group, an acyl group, an acylamino group, 
a nitro group or the like. The alkyl moiety of the aralkyl group may be 
branched. Specific examples include: 
a benzyl group, a phenethyl group, a diphenylmethyl group, a 
3-methylphenylmethyl group, a 3-chlorophenylmethyl group, a 
3-fluoromethylphenylmethyl group, a 3-bromophenylmethyl group, a 
3-trifluoromethylphenylmethyl group, a 1-(3-methylphenyl)ethyl group, a 
1-(3-chlorophenyl)ethyl group, a 1-(3-trifluoromethylphenyl)ethyl group, a 
1-(3-fluorophenyl)ethyl group, a 1-(3-bromophenyl)ethyl group, a 
2-(3-methylphenyl)ethyl group, a 2-(3-chlorophenyl)ethyl group, a 
2-(3-trifluoromethylphenyl)ethyl group, a 2-(3-fluorophenyl)ethyl group, a 
2-(3-bromophenyl)ethyl group, a 1-methyl-2-(3-methylphenyl)ethyl group, a 
1-methyl-2-(3-chlorophenyl)ethyl group, a 
1-methyl-2-(3-trifluoromethylphenyl)ethyl group, a 
1-methyl-2-(3-fluorophenyl)ethyl group and a 
1-methyl-2-(3-bromophenyl)ethyl group. 
Each of R.sup.4 -R.sup.7 is preferably a substituted or unsubstituted 
alkyl, cycloalkyl or aralkyl group. As the substituent, a halogen atom or 
an alkyl group having a carbon number of at most 4 which is bonded to a 
ring is preferred. Particularly preferred R.sup.4 -R.sup.7 are alkyl 
groups, and a haloalkyl is particularly preferred as R.sup.6. 
Z is preferably a group represented by --OR.sup.4. R.sup.4 in Z is 
preferably a hydrogen atom or a C.sub.1-20 hydrocarbon group such as an 
alkyl group, a cycloalkyl group or an aralkyl group. Compounds wherein 
R.sup.4 is a hydrocarbon group are useful as prodrugs because they 
hydrolyze in vivo into biologically active compounds. It is possible to 
improve the lipid solubility of compounds by proper selection of 
hydrocarbon groups. As Z, particularly preferred are a hydroxyl group, a 
methoxy group, an ethoxy group, an isopropoxy group, an isobutoxy group, a 
cyclohexyloxy group and a benzyloxy group. 
A fluorine-containing prostaglandin derivative of the present invention 
having an acidic group such as a carboxy group, for example like those 
wherein Z is a hydroxyl group, may take the form of a salt with a base. 
Similarly, when a compound of the present invention has a basic group such 
as an amino group, it may take the form of a salt with an acid. Salts with 
bases include alkali metal salts such as sodium salts and potassium salts, 
alkaline earth metal salts such as calcium salts and magnesium salts and 
ammonium salts such as unsubstituted ammonium salts and alkyl-substituted 
ammonium salts. Salts with acids include inorganic acid salts such as 
hydrochlorides, sulfates and phosphates and organic acid salts such as 
acetates, oxalates, citrates, succinates and p-toluenesulfonates. 
The fluorine-containing prostaglandin derivatives of the present invention 
can be synthesized by a process similar to a general process for producing 
prostaglandin F.sub.2.alpha.. For example, first of all, the .omega.-chain 
is introduced into the starting material, a Corey lactone, and the 
resulting enone is converted by fluorination into an 
.omega.-chain-containing Corey lactone having two fluorine atoms at the 
15-position. Subsequent reduction of the lactone is to a lactol followed 
by introduction of the .alpha.-chain unit by the Wittig reaction, and, if 
necessary, acylation or of a hydroxyl group or removal of the protecting 
group for a hydroxyl group, gives fluorine-containing prostaglandin 
derivatives of the present invention. The introduction of the 
.alpha.-chain unit may be followed by conversion of a carboxyl group into 
an ester, an acyl amide, a sulfonamide or a thioester and, if necessary, 
removal of the protecting group for a hydroxyl group or acylation of a 
hydroxyl group to produce fluorine-containing prostaglandin derivatives of 
the present invention. 
Specifically speaking, the fluorine-containing prostaglandin derivatives 
(1) can be prepared, for example, by a process comprising fluorination of 
a ketone (2) having an .omega.-chain to give an .omega.-chain-containing 
Corey lactone (3) having two fluorine atoms at the 15-position, reduction 
of the lactone (3) to a lactol (4) and reaction of the lactol (4) with a 
phosphorane (5) to introduce an .alpha.-chain unit. The phosphorane (5) is 
obtainable from a phosphonium salt (6). Because it is not necessary for 
the starting compound to have the same configuration as the resulting 
fluorine-containing prostaglandin derivative (1), the following formulae 
(2) to (4) do not specify the configurations of the substituents bonded to 
the cyclopentane rings. In the formulae (5) and (6), R.sup.8 is a 
substituted or unsubstituted alkyl group, a substituted or unsubstituted 
aryl group, a substituted or unsubstituted aralkyl group or a dialkylamino 
group, and Y is a halogen atom such as a chlorine atom, a bromine atom or 
an iodine atom. 
##STR3## 
The ketones shown above are known compound except those having specific 
substituents as R.sup.1. The novel ketones having specific substituents as 
R.sup.1 can be prepared by a process similar to that for the other known 
ketones. For example, these ketones can be prepared by reaction of a 
dialkyl 3-substituted-2-oxopropylphosphonate with a Corey lactone having a 
formyl group. 
The conversion of a ketone into an .omega.-chain-containing Corey lactone 
having two fluorine atoms at the 15-position by fluorination can be 
achieved by various known fluorination processes, for example, by using 
various nucleophilic fluorinating agents in inert solvents. 
When a ketone as the starting material has a functional group liable to 
fluorinate during the fluorination, it is preferred to preliminarily 
protect the functional group by a protecting group. For example, when 
R.sup.3 is a hydrogen atom, R.sup.3 is preferably protected by a 
protecting group during the fluorination of the carbonyl group at the 
15-position and then the protection group is removed. 
The protecting groups include, for example, a triorganosilyl group, an acyl 
group, an alkyl group, an aralkyl group and a cyclic ether group. An acyl 
group to protect a hydroxyl group at the 11-position of a ketone used as 
the starting material may be the same as or different from the acyl group 
as R.sup.3 of a fluorine-containing prostaglandin derivative (1). A 
fluorine-containing prostaglandin derivative (1) having an acyl group 
which is different from the acyl group used as the protecting group can be 
obtained by removing the protecting group and then introducing a different 
acyl group. 
The triorganosilyl group is a group having three organic groups such as 
alkyl groups, aryl groups, aralkyl groups or alkoxy groups bonded to a 
silicon atom. Particularly preferred is a triorganosilyl group having 
three groups of at least one kind selected from the group consisting of 
lower alkyl groups and aryl groups. Specifically, a t-butyldimethylsilyl 
group, a t-butyldiphenylsilyl group, a triethylsilyl group, a 
triphenylsilyl group or a triisopropylsilyl group may, for example, be 
preferred. 
As the acyl group, an acetyl group, a trifluoroacetyl group, a pivaloyl 
group, a benzoyl group or a p-phenylbenzoyl group is preferred, and as the 
cyclic ether group, a tetrahydropyranyl group or a tetrahydrofuranyl group 
is preferred. As the alkyl group or the aralkyl group which may have a 
substituent, an alkoxyalkyl group such as a methoxymethyl group, a 
1-ethoxyethyl group or a 2-methoxyethoxymethyl group as well as a benzyl 
group, a methoxybenzyl group or a trityl group may, for example, be 
mentioned. 
The protecting group for a hydroxyl group as mentioned above, can be 
converted to a hydroxyl group by a conventional method. For example, it 
can readily be converted to a hydroxyl group by methods disclosed in 
publications e.g. "Shinjikken Kagaku Koza 14 Syntheses and Reactions of 
Organic Compounds (I), (II) and (V)", published by Maruzen, and 
"Protective Groups in Organic Synthesis" written by T. W. Greene, 
published by J. Wiley & Sons. 
The process for fluorination of a ketone having a carbonyl group at the 
15-position as the starting material to an .omega.-chain-containing Corey 
lactone having two fluorine atoms at the 15-position uses a fluorinating 
agent. The fluorination is preferably carried out in an inert solvent and 
may be conducted in the presence of a base. The reaction temperature for 
the fluorination is usually from -150 to +100.degree. C., preferably from 
-80 to +60.degree. C. A fluorinating agent is used usually in an amount of 
from 0.5 to 20 parts by weight, preferably from 1 to 5 parts by weight, 
per part by weight of the substrate, a ketone as the starting material. 
The fluorinating agent used in the process for fluorinating a ketone 
having a carbonyl group at the 15-position as the starting material to an 
.omega.-chain-containing Corey lactone having two fluorine atoms at the 
15-position is not particularly limited, and known or common nucleophilic 
fluorinating agents may be employed. For example, nucleophilic 
fluorinating agents disclosed in publications such as "Fluorine Chemistry" 
written by Tomoya Kitazume, Takashi Ishihara and Takeo Taguchi and 
published by Kodansha Scientific, may be used. 
Specifically, dialkylaminosulfur trifluoride derivatives, 
tetrafluorophenylphophorane, fluoroalkylamine agents such as 
diethylamine-chlorotrifluoroethene adducts and 
diethylamine-hexafluoropropene adducts, hydrogen fluoride-amine complexes 
such as HF-pyridine and HF-triethylamine, silicon tetrafluoride, sulfur 
tetrafluoride, metal fluorides such as potassium fluoride, cesium fluoride 
and silver fluoride, and ammonium salts and phosphonium salts such as 
tetrabutylammonium fluoride, tetraethylammonium fluoride and 
tetrabutylphosphonium fluoride may, for example, be mentioned. 
A carbonyl group can directly be fluorinated by using these nucleophilic 
fluorinating agents. A carbonyl group may be fluorinated after conversion 
of a ketone into its derivative such as an oxime, a hydrazone, a 
thioacetal or a diazo compound in order to improve its reactivity or 
inhibit side reactions. For example, the process of Olah et al. (Synlett 
1990, 594, Synlett 1994, 425), the process of Katzenellenbogen et al. (J. 
Org. Chem. 51, 3508 (1986)), the process of Hiyama et al. (Synlett 1991, 
909) and the process of Fujisawa et al. (J. Fluorine Chem. 71, 9 (1995)) 
are applicable. 
Fluorination of a carbonyl group by a nucleophilic fluorinating agent is 
preferred in view of yield and selectivity. Dialkylaminosulfur trifluoride 
derivatives are particularly preferred as the nucleophilic fluorinating 
agent for fluorination, and specifically, morpholinosulfur trifluoride, 
piperidinosulfur trifluoride, diethylaminosulfur trifluoride, 
dimethylaminosulfur trifluoride and the like are preferred. As the inert 
solvent, a halogen-containing solvent, an etherial solvent, a hydrocarbon 
solvent, an ester solvent, a polar solvent, a mixture thereof is 
preferred. An inert solvent is used usually in an amount of from 2 to 500 
parts by weight, preferably from 5 to 100 parts by weight, per part by 
weight of a ketone. 
Preferable halogen-containing solvents are methylene chloride, chloroform, 
1,2-dichloroethane, carbon tetrachloride, chlorobenzene and 
dichloropentafluoropropanes. 
Preferable etherial solvents are diethyl ether, tetrahydrofuran THF!, 
1,4-dioxane, dimethoxyethane, diglyme and t-butyl methyl ether. 
Preferable hydrocarbon solvents are hexane, toluene, benzene, pentane, 
xylene and petroleum ether. 
Preferable ester solvents are ethyl acetate and butyl acetate. 
Preferable polar solvents are dimethyl sulfoxide, hexamethylphosphoramide 
HMPA!, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMPU!, 
1,3-dimethyl-2-imidazolidinone DMI! and 
N,N,N',N'-tetramethylethylenediamine TMEDA! (in the square brackets are 
abbreviations). 
Particularly preferred solvents are methylene chloride, chloroform, 
1,2-dichloroethane and toluene. 
As the base used for the fluorination, amines such as tertiary amines and 
aromatic amines and salts of alkali metals and alkaline earth metals are 
preferred. Specifically, triethylamine, diisopropylethylamine, pyridine, 
2,6-lutidine, dimethylaminopyridine, sodium carbonate, potassium 
carbonate, sodium hydrogencarbonate and potassium hydrogencarbonate may be 
mentioned. 
The lactone obtained by the above-mentioned fluorination is reduced to a 
lactol. For the reduction, a reducing agent is usually used in an inert 
solvent. For example, methods disclosed in publications such as 
"Shinjikken Kagaku Koza 15 Oxidation and reduction (II)" published by 
Maruzen and "Jikken Kagaku Koza 26 Organic Syntheses VIII, asymmetric 
synthesis, reduction, sugar and labeled compounds, fourth edition" 
published by Maruzen may be used. In the reduction, a reducing agent is 
used usually in amount of from 0.01 to 50 equivalents, preferably from 1 
to 20 equivalents, per equivalent of a lactone. The reaction temperature 
is preferably from -150.degree. to +100.degree. C., particularly 
preferably from -80.degree. to 0.degree. C. 
As reducing agents, diisobutylaluminum hydride DIBAH!, dialkylaluminum 
alkoxides, lithium aluminum hydride, tributyltin hydride, triphenyltin 
hydride, triethylsilane, trichlorosilane, dimethylphenylsilane, 
diphenylsilane, sodium borohydride, sodium trimethoxyborohydride, lithium 
tri(s-butyl)borohydride, potassium tri(s-butyl)borohydride, lithium 
triethylborohydride, lithium trisiamylborohydride, potassium 
trisiamylborohydride, zinc borohydride, calcium borohydride, lithium 
trialkoxyaluminum hydrides, sodium bis(2-methoxyethoxy)aluminum hydride, 
diborane, disiamylborane, thexylborane and 9-borabiscyclo3.3.1!nonane may 
be mentioned. Diisobutylaluminum hydride DIBAH!, sodium 
bis(2-methoxyethoxy)aluminum hydride, disiamylborane and lithium 
tri(s-butyl)borohydride are preferred. 
As the inert solvent used for the reduction, an etherial solvent, a 
hydrocarbon solvent, a polar solvent or a mixture thereof is preferred. 
Specific examples of the etherial solvent, the hydrocarbon solvent and the 
polar solvent are the etherial solvents, hydrocarbon solvents and polar 
solvents specifically described above for the fluorination. Above all, 
diethyl ether, THF, t-butyl methyl ether and toluene are particularly 
preferred. The configuration of the lactol produced by the reduction is 
not particularly limited. 
As described above, a phosphorane is produced from the corresponding 
phosphonium salt in an inert solvent in the presence of a base. The 
resulting phosphorane is not usually isolated and directly used for the 
Wittig reaction with a lactol. For production of a phosphorane from the 
corresponding phosphonium salt, methods disclosed in publications such as 
"Shinjikken Kagaku Koza 14 Syntheses and reactions of organic compounds 
(I)" published by Maruzen, and "Jikken Kagaku Koza 19 Organic Synthesis I, 
hydrocarbons and halogen compounds, fourth edition" published by Maruzen 
and the method of Schaaf et al. (J. Med. Chem. 22, 1340 (1979)) may, for 
example, be employed. 
Z in the phosphorane or the phosphonium salt is usually a hydroxyl group 
(namely, OR.sup.4 wherein R.sup.4 is a hydrogen atom) although it may be 
any of those described above for Z. In such a case, the reaction of the 
phosphorane with lactol gives a fluorine-containing prostaglandin 
derivative wherein Z is a hydroxyl group. In order to obtain a 
fluorine-containing prostaglandin derivative wherein Z is not a hydroxyl 
group, it is preferred to convert Z of a fluorine-containing prostaglandin 
derivative from a hydroxyl group to a different group. A 
fluorine-containing prostaglandin derivative wherein Z is not a hydroxyl 
group can be prepared from a phosphorane or its precursor having a group 
other than a hydroxyl group as Z. 
Conversion of a phosphonium salt wherein Z is --NHCOR.sup.5 or --NHSO.sub.2 
R.sup.6 to a phosphorane is sometimes accompanied by replacement of the 
hydrogen atom bonded to the nitrogen atom in --NHCOR.sup.5 or --NHSO.sub.2 
R.sup.6 by a metal ion. Consequently, in such a case, the product of the 
Wittig reaction of the resulting phosphorane with a lactol also has a 
metal ion at the corresponding site. The metal ion is attributed to the 
metal ion (specifically, an alkali metal ion or an alkaline earth metal 
ion) in the base used for conversion of a phosphonium salt into a 
phosphorane. The metal ion can eventually be replaced by a hydrogen atom 
through hydrolysis or other processes. 
Examples of the phosphonium salts include, for example, the following 
compounds. These phosphonium salts yield the corresponding phosphoranes. 
(4-Carboxybutyl)triphenylphosphonium bromide; 
(4-carboxy-3-oxabutyl)triphenylphosphonium bromide; 
4-(N-methanesulfonyl)carbamoylbutyl!triphenylphosphonium bromide; 
4-(N-benzoyl)carbamoylbutyl!triphenylphosphonium bromide; 
(4-carboxybutyl)tri(o-tolyl)phosphonium bromide; 
(4-carboxybutyl)tri(m-tolyl)phosphonium bromide; and 
(4-carboxybutyl)tri(p-tolyl)phosphonium bromide. 
A phosphorane is used usually in an amount of from 0.1 to 20 equivalents, 
preferably from 1 to 10 equivalents, per equivalent of a lactol. The 
reaction of a lactol with a phosphorane is classified as the so-called 
Wittig reaction. Ordinary conditions for the Wittig reaction are 
applicable to the reaction of a lactol with a phosphorane according to the 
present invention. In particular, it is preferred to carry out the 
reaction under basic conditions in an inert solvent. The reaction 
temperature is usually from -150 to +200.degree. C., preferably from 
-80.degree. to +100.degree. C. 
A base is used usually in an amount of from 1 to 20 equivalents, preferably 
from 2 to 10 equivalents, per equivalent of a lactol. A base of the proper 
kind should be used in view of the acidity of the hydrogen atom bonded to 
the carbon atom at the .alpha.-position based on the phosphorus atom of a 
phosphonium salt as the precursor of a phosphorane and the stability of 
the resulting phosphorane. Such a base can be selected, for example, from 
the following bases. 
Sodium hydroxide, potassium hydroxide, sodium carbonate, potassium 
carbonate, sodium methoxide, sodium ethoxide, triethylamine, 
diisopropylethylamine, pyridine, N-methylmorpholine, 
1,5-diazabicyclo4.3.0!non-5-ene, 1,8-diazabicyclo5.4.0!undec-7-ene, 
potassium t-butoxide, lithium amide, sodium amide, potassium amide, 
lithium diisopropylamide, lithium diethylamide, lithium dicyclohexylamide, 
lithium isopropylcyclohexylamide, lithium 2,2,6,6-tetramethylpiperidine, 
lithium bis(trimethylsilyl)amide, sodium diethylamide, sodium 
bis(trimethylsilyl)amide, potassium 3-aminopropylamide, potassium 
bis(trimethylsilyl)amide, lithium hydride, sodium hydride, potassium 
hydride, sodium methylsulfinylmethylide, n-butyllithium, s-butyllithium, 
t-butyllithium, methyllithium, phenyllithium, lithium naphthalenide, 
lithium biphenylide and tritylsodium. 
Among these bases, potassium carbonate, potassium t-butoxide, lithium 
amide, sodium amide, potassium amide, lithium diisopropylamide, lithium 
diethylamide, lithium dicyclohexylamide, lithium isopropylcyclohexylamide, 
lithium 2,2,6,6-tetramethylpiperidine, lithium bis(trimethylsilyl)amide, 
sodium diethylamide, sodium bis(trimethylsilyl)amide, potassium 
3-aminopropylamide, potassium bis(trimethylsilyl)amide and sodium 
methylsulfinylmethylide are preferred. Potassium t-butoxide, sodium 
bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide and sodium 
methylsulfinylmethylide are particularly preferred. 
As the inert solvent, an etherial solvent, a hydrocarbon solvent, a polar 
solvent, an aqueous solvent, an alcoholic solvent or a solvent mixture 
thereof is preferred. An inert solvent is used usually in an amount of 
from 5 to 1000 parts by weight, preferably from 10 to 100 parts by weight, 
per part by weight of a lactol. As specific examples of the etherial 
solvent, the hydrocarbon solvent and the polar solvent, the etherial 
solvents, the hydrocarbon solvents and the polar solvents specifically 
described above for the fluorination are preferred. As the aqueous 
solvent, water or a solvent mixture of water with an alcoholic solvent is 
preferred. As the alcoholic solvent, methanol, ethanol, t-butanol and 
t-amyl alcohol are preferred. Particularly preferred solvents are diethyl 
ether, THF, 1,2-dimethoxyethane, t-butyl methyl ether and toluene. 
Z of the resulting fluorine-containing prostaglandin derivative can be 
converted into a different kind of Z, if necessary. For example, a 
fluorine-containing prostaglandin derivative wherein Z is a hydroxyl group 
can optionally be converted into an ester, a salt of a carboxylic acid, an 
acyl amide, sulfonamide or a thioester by a conventional method. 
For esterification of Z, ordinary methods such as methods disclosed in 
publications such as "Shinjikken Kagaku Koza 14 Syntheses and reactions of 
organic compounds (II)" published by Maruzen may be used. Esterification 
by condensation with an alcohol or a phenol, esterification with an 
O-alkylating agent, esterification by use of an alkene or an alkyne, 
esterification with a dialkyl sulfate or a halogenated hydrocarbon may be 
mentioned. 
For conversion into an acyl amide or a sulfonamide, the method of 
Tithereley et al. (J. Chem. Soc. 85, 1673 (1904)), the method of Lynch et 
al. (Can. J. Chem. 50, 2143 (1972)), the method of Davidson et al. (J. Am. 
Chem. Soc. 80, 376 (1958)) and the like can be used. Alternatively, 
conversion of a carboxylic acid into an acid halide or a reactive ester 
followed by condensation with an amide or a sulfonamide or reaction of a 
carboxylic acid with an amine to produce an amide followed by acylation or 
sulfonylation may be employed. 
For conversion of Z into a thioester, methods described in publications 
such as "Shinjikken Kagaku Koza 14 Syntheses and reactions of organic 
compounds (III)" published by Maruzen and "protective Groups in Organic 
Syntheses" written by T. W. Greene and published by J. Wiley & Sons may be 
employed. For example, a process comprising conversion of a carboxylic 
acid is converted into an acid halide or a reactive ester and then reacted 
with a thiol may be employed. 
Specific examples of the compound of the formula (I) are given below, and, 
however, the compound is not limited to these specific examples. 
15-Deoxy-15,15-difluoroprostaglandin F.sub.2.alpha., 
15-deoxy-15,15-difluoroprostaglandin F.sub.2.alpha. methyl ester, 
15-deoxy-15,15-difluoroprostaglandin F.sub.2.alpha. ethyl ester, 
15-deoxy-15,15-difluoroprostaglandin F.sub.2.alpha. isopropyl ester, 
16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprosta 
glandin F.sub.2.alpha. methyl ester, 
16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprosta 
glandin F.sub.2.alpha. ethyl ester, 
16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprosta 
glandin F.sub.2.alpha. isopropyl ester, 
16-(3,4-dichlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprosta 
glandin F.sub.2.alpha. methyl ester, 
16-(3,4-dichlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprosta 
glandin F.sub.2.alpha. ethyl ester, 
16-(3,4-dichlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprosta 
glandin F.sub.2.alpha. isopropyl ester, 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglan 
din F.sub.2.alpha. methyl ester, 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglan 
din F.sub.2.alpha. ethyl ester, 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglan 
din F.sub.2.alpha. isopropyl ester, 
16-(3-trifluoromethylphenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorp 
rostaglandin F.sub.2.alpha. methyl ester, 
16-(3-trifluoromethylphenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorp 
rostaglandin F.sub.2.alpha. ethyl ester, 
16-(3-trifluoromethylphenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorp 
rostaglandin F.sub.2.alpha. isopropyl ester, 
16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin 
F.sub.2.alpha. methyl ester, 
16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin 
F.sub.2.alpha. ethyl ester, 
16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin 
F.sub.2.alpha. isopropyl ester, 
17-phenyl-15-deoxy-15,15-difluoro-18,19,20-trinorprostaglandin 
F.sub.2.alpha. methyl ester, 
17-phenyl-15-deoxy-15,15-difluoro-18,19,20-trinorprostaglandin 
F.sub.2.alpha. ethyl ester, 
17-phenyl-15-deoxy-15,15-difluoro-18,19,20-trinorprostaglandin 
F.sub.2.alpha. isopropyl ester, 
15-deoxy-15,15-difluoro-13,14-dihydroprostaglandin F.sub.2.alpha. methyl 
ester, 
15-deoxy-15,15-difluoro-13,14-dihydroprostaglandin F.sub.2.alpha. ethyl 
ester, 
15-deoxy-15,15-difluoro-13,14-dihydroprostaglandin F.sub.2.alpha. 
isopropyl ester, 
16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20- 
tetranorprostaglandin F.sub.2.alpha. methyl ester, 
16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20- 
tetranorprostaglandin F.sub.2.alpha. ethyl ester, 
16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20- 
tetranorprostaglandin F.sub.2.alpha. isopropyl ester, 
16-(3,4-dichlorophenoxy)-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20- 
tetranorprostaglandin F.sub.2.alpha. methyl ester, 
16-(3,4-dichlorophenoxy)-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20- 
tetranorprostaglandin F.sub.2.alpha. ethyl ester, 
16-(3,4-dichlorophenoxy)-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20- 
tetranorprostaglandin F.sub.2.alpha. isopropyl ester; 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetr 
anorprostaglandin F.sub.2.alpha. methyl ester, 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetr 
anorprostaglandin F.sub.2.alpha. ethyl ester, 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetr 
anorprostaglandin F.sub.2.alpha. isopropyl ester, 
16-(3-trifluoromethylphenoxy)-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,1 
9,20-tetranorprostaglandin F.sub.2.alpha. methyl ester, 
16-(3-trifluoromethylphenoxy)-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,1 
9,20-tetranorprostaglandin F.sub.2.alpha. ethyl ester, 
16-(3-trifluoromethylphenoxy)-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,1 
9,20-tetranorprostaglandin F.sub.2.alpha. isopropyl ester; 
16-phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranorprosta 
glandin F.sub.2.alpha. methyl ester, 
16-phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranorprosta 
glandin F.sub.2.alpha. ethyl ester, 
16-phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranorprosta 
glandin F.sub.2.alpha. isopropyl ester, 
17-phenyl-15-deoxy-15,15-difluoro-13,14-dihydro-18,19,20-trinorprostaglandi 
n F.sub.2.alpha. methyl ester, 
17-phenyl-15-deoxy-15,15-difluoro-13,14-dihydro-18,19,20-trinorprostaglandi 
n F.sub.2.alpha. ethyl ester, 
17-phenyl-15-deoxy-15,15-difluoro-13,14-dihydro-18,19,20-trinorprostaglandi 
n F.sub.2.alpha. isopropyl ester; 
15-deoxy-15,15-difluoro-3-oxaprostaglandin F.sub.2.alpha., 
15-deoxy-15,15-difluoro-3-oxaprostaglandin F.sub.2.alpha. methyl ester, 
15-deoxy-15,15-difluoro-3-oxaprostaglandin F.sub.2.alpha. ethyl ester, 
15-deoxy-15,15-difluoro-3-oxaprostaglandin F.sub.2.alpha. isopropyl ester, 
16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor 
prostaglandin F.sub.2.alpha. methyl ester, 
16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor 
prostaglandin F.sub.2.alpha. ethyl ester, 
16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor 
prostaglandin F.sub.2.alpha. isopropyl ester, 
16-(3,4-dichlorophenoxy)-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor 
prostaglandin F.sub.2.alpha. methyl ester, 
16-(3,4-dichlorophenoxy)-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor 
prostaglandin F.sub.2.alpha. ethyl ester, 
16-(3,4-dichlorophenoxy)-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor 
prostaglandin F.sub.2.alpha. isopropyl ester, 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranorpros 
taglandin F.sub.2.alpha. methyl ester, 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranorpros 
taglandin F.sub.2.alpha. ethyl ester, 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranorpros 
taglandin F.sub.2.alpha. isopropyl ester; 
16-(3-trifluoromethylphenoxy)-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tet 
ranorprostaglandin F.sub.2.alpha. methyl ester, 
16-(3-trifluoromethylphenoxy)-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tet 
ranorprostaglandin F.sub.2.alpha. ethyl ester, 
16-(3-trifluoromethylphenoxy)-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tet 
ranorprostaglandin F.sub.2.alpha. isopropyl ester, 
16-phenoxy-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranorprostaglandin 
F.sub.2.alpha. methyl ester, 
16-phenoxy-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranorprostaglandin 
F.sub.2.alpha. ethyl ester, 
16-phenoxy-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranorprostaglandin 
F.sub.2.alpha. isopropyl ester; 
17-phenyl-15-deoxy-15,15-difluoro-3-oxa-18,19,20-trinorprostaglandin 
F.sub.2.alpha. methyl ester, 
17-phenyl-15-deoxy-15,15-difluoro-3-oxa-18,19,20-trinorprostaglandin 
F.sub.2.alpha. ethyl ester, 
17-phenyl-15-deoxy-15,15-difluoro-3-oxa-18,19,20-trinorprostaglandin 
F.sub.2.alpha. isopropyl ester, 
15-deoxy-15,15-difluoro-9-pivaloylprostaglandin F.sub.2.alpha. methyl 
ester, 
15-deoxy-15,15-difluoro-9-pivaloylprostaglandin F.sub.2.alpha. ethyl 
ester, 
15-deoxy-15,15-difluoro-9-pivaloylprostaglandin F.sub.2.alpha. isopropyl 
ester; 
16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tet 
ranorprostaglandin F.sub.2.alpha. methyl ester, 
16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tet 
ranorprostaglandin F.sub.2.alpha. ethyl ester, 
16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tet 
ranorprostaglandin F.sub.2.alpha. isopropyl ester, 
16-(3,4-dichlorophenoxy)-15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tet 
ranorprostaglandin F.sub.2.alpha. methyl ester, 
16-(3,4-dichlorophenoxy)-15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tet 
ranorprostaglandin F.sub.2.alpha. ethyl ester, 
16-(3,4-dichlorophenoxy)-15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tet 
ranorprostaglandin F.sub.2.alpha. isopropyl ester; 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tetrano 
rprostaglandin F.sub.2.alpha. methyl ester, 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tetrano 
rprostaglandin F.sub.2.alpha. ethyl ester, 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tetrano 
rprostaglandin F.sub.2.alpha. isopropyl ester, 
16-(3-trifluoromethylphenoxy)-15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,2 
0-tetranorprostaglandin F.sub.2.alpha. methyl ester, 
16-(3-trifluoromethylphenoxy)-15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,2 
0-tetranorprostaglandin F.sub.2.alpha. ethyl ester, 
16-(3-trifluoromethylphenoxy)-15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,2 
0-tetranorprostaglandin F.sub.2.alpha. isopropyl ester; 
16-phenoxy-15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tetranorprostagla 
ndin F.sub.2.alpha. methyl ester, 
16-phenoxy-15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tetranorprostagla 
ndin F.sub.2.alpha. ethyl ester, 
16-phenoxy-15-deoxy-15,15-difluoro-9-pivaloyl-17,18,19,20-tetranorprostagla 
ndin F.sub.2.alpha. isopropyl ester, 
17-phenyl-15-deoxy-15,15-difluoro-9-pivaloyl-18,19,20-trinorprostaglandin 
F.sub.2.alpha. methyl ester, 
17-phenyl-15-deoxy-15,15-difluoro-9-pivaloyl-18,19,20-trinorprostaglandin 
F.sub.2.alpha. ethyl ester, 
17-phenyl-15-deoxy-15,15-difluoro-9-pivaloyl-18,19,20-trinorprostaglandin 
F.sub.2.alpha. isopropyl ester; 
15-deoxy-15,15-difluoro-11-pivaloylprostaglandin F.sub.2.alpha. methyl 
ester, 
15-deoxy-15,15-difluoro-11-pivaloylprostaglandin F.sub.2.alpha. ethyl 
ester, 
15-deoxy-15,15-difluoro-11-pivaloylprostaglandin F.sub.2.alpha. isopropyl 
ester, 
16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20-te 
tranorprostaglandin F.sub.2.alpha. methyl ester, 
16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20-te 
tranorprostaglandin F.sub.2.alpha. ethyl ester, 
16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20-te 
tranorprostaglandin F.sub.2.alpha. isopropyl ester; 
16-(3,4-dichlorophenoxy)-15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20-te 
tranorprostaglandin F.sub.2.alpha. methyl ester, 
16-(3,4-dichlorophenoxy)-15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20-te 
tranorprostaglandin F.sub.2.alpha. ethyl ester, 
16-(3,4-dichlorophenoxy)-15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20-te 
tranorprostaglandin F.sub.2.alpha. isopropyl ester, 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20-tetran 
orprostaglandin F.sub.2.alpha. methyl ester, 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20-tetran 
orprostaglandin F.sub.2.alpha. ethyl ester, 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20-tetran 
orprostaglandin F.sub.2.alpha. isopropyl ester; 
16-(3-trifluoromethylphenoxy)-15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19, 
20-tetranorprostaglandin F.sub.2.alpha. methyl ester, 
16-(3-trifluoromethylphenoxy)-15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19, 
20-tetranorprostaglandin F.sub.2.alpha. ethyl ester, 
16-(3-trifluoromethylphenoxy)-15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19, 
20-tetranorprostaglandin F.sub.2.alpha. isopropyl ester, 
16-phenoxy-15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20-tetranorprostagl 
andin F.sub.2.alpha. methyl ester, 
16-phenoxy-15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20-tetranorprostagl 
andin F.sub.2.alpha. ethyl ester, 
16-phenoxy-15-deoxy-15,15-difluoro-11-pivaloyl-17,18,19,20-tetranorprostagl 
andin F.sub.2.alpha. isopropyl ester; 
17-phenyl-15-deoxy-15,15-difluoro-11-pivaloyl-18,19,20-trinorprostaglandin 
F.sub.2.alpha. methyl ester, 
17-phenyl-15-deoxy-15,15-difluoro-11-pivaloyl-18,19,20-trinorprostaglandin 
F.sub.2.alpha. ethyl ester, 
17-phenyl-15-deoxy-15,15-difluoro-11-pivaloyl-18,19,20-trinorprostaglandin 
F.sub.2.alpha. isopropyl ester, 
15-deoxy-15,15-difluoroprostaglandin F.sub.2.alpha. 1,9-lactone, 
15-deoxy-15,15-difluoroprostaglandin F.sub.2.alpha. 1,11-lactone, 
16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprosta 
glandin F.sub.2.alpha. 1,9-lactone; 
16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprosta 
glandin F.sub.2.alpha. 1,11-lactone, 
16-(3,4-dichlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprosta 
glandin F.sub.2.alpha. 1,9-lactone, 
16-(3,4-dichlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprosta 
glandin F.sub.2.alpha. 1,11-lactone, 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglan 
din F.sub.2.alpha. 1,9-lactone, 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglan 
din F.sub.2.alpha. 1,11-lactone, 
16-(3-trifluoromethylphenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorp 
rostaglandin F.sub.2.alpha. 1,9-lactone; 
16-(3-trifluoromethylphenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorp 
rostaglandin F.sub.2.alpha. 1,11-lactone, 
16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin 
F.sub.2.alpha. 1,9-lactone, 
16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin 
F.sub.2.alpha. 1,11-lactone, 
17-phenyl-15-deoxy-15,15-difluoro-18,19,20-trinorprostaglandin 
F.sub.2.alpha. 1,9-lactone, 
17-phenyl-15-deoxy-15,15-difluoro-18,19,20-trinorprostaglandin 
F.sub.2.alpha. 1,11-lactone; 
16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprosta 
glandin F.sub.2.alpha., 
16-(3,4-dichlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprosta 
glandin F.sub.2.alpha., 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglan 
din F.sub.2.alpha., 
16-(3-trifluoromethylphenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorp 
rostaglandin F.sub.2.alpha. ; 
16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin 
F.sub.2.alpha., 
17-phenyl-15-deoxy-15,15-difluoro-18,19,20-trinorprostaglandin 
F.sub.2.alpha., 
15-deoxy-15,15-difluoro-13,14-dihydroprostaglandin F.sub.2.alpha., 
16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20- 
tetranorprostaglandin F.sub.2.alpha., 
16-(3,4-dichlorophenoxy)-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20- 
tetranorprostaglandin F.sub.2.alpha. ; 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetr 
anorprostaglandin F.sub.2.alpha., 
16-(3-trifluoromethylphenoxy)-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,1 
9,20-tetranorprostaglandin F.sub.2.alpha., 
16-phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranorprosta 
glandin F.sub.2.alpha., 
17-phenyl-15-deoxy-15,15-difluoro-13,14-dihydro-18,19,20-trinorprostaglandi 
n F.sub.2.alpha., 
15-deoxy-15,15-difluoro-3-oxa-prostaglandin F.sub.2.alpha., 
16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor 
prostaglandin F.sub.2.alpha. ; 
16-(3,4-dichlorophenoxy)-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranor 
prostaglandin F.sub.2.alpha., 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-3-oxa-17,18,19,20-tetranorpros 
taglandin F.sub.2.alpha., 
16-(3-trifluoromethylphenoxy)-15-deoxy-15,15-difluoro-13,14-dihydro-3-oxa-1 
7,18,19,20-tetranorprostaglandin F.sub.2.alpha., 
16-phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-3-oxa-17,18,19,20-tetranor 
prostaglandin F.sub.2.alpha., 
17-phenyl-15-deoxy-15,15-difluoro-13,14-dihydro-3-oxa-18,19,20-trinorprosta 
glandin F.sub.2.alpha. ; 
N-methanesulfonyl-15-deoxy-15,15-difluoroprostaglandin F.sub.2.alpha. 
carboxamide, 
N-methanesulfonyl-16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19 
,20-tetranorprostaglandin F.sub.2.alpha. carboxamide, 
N-methanesulfonyl-16-(3,4-dichlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19 
,20-tetranorprostaglandin F.sub.2.alpha. carboxamide, 
N-methanesulfonyl-16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20- 
tetranorprostaglandin F.sub.2.alpha. carboxamide, 
N-methanesulfonyl-16-(3-trifluoromethylphenoxy)-15-deoxy-15,15-difluoro-17, 
18,19,20-tetranorprostaglandin F.sub.2.alpha. carboxamide, 
N-methanesulfonyl-16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranorpr 
ostaglandin F.sub.2.alpha. carboxamide, and 
N-methanesulfonyl-17-phenyl-15-deoxy-15,15-difluoro-18,19,20-trinorprostagl 
andin F.sub.2.alpha. carboxamide. 
The fluorine-containing prostaglandin derivative of the formula (I) has 
asymmetric carbon atoms in its structure and thus has various 
stereoisomers and optical isomers. The fluorine-containing prostaglandin 
derivatives of the present invention include all of such stereoisomers, 
optical isomers and their mixtures. 
The compounds of the present invention (the fluorine-containing 
prostaglandin derivatives and their salts) are superior to known naturally 
occurring PGF.sub.2.alpha. in the effect of lowering intraocular 
pressure. They hardly irritate the eye and have very little effect on the 
ocular tissues such as the cornea, the iris and the conjunctiva. Further, 
they are unlikely to decompose through metabolic processes such as 
hydrolysis and oxidation and stable in the body. They also easily 
penetrate the cornea and are easily absorbed by the eye. For these 
reasons, they are very useful as medicines. In addition, they solve the 
problem of the stimulation of melanogenesis by conventional 
PGF.sub.2.alpha. derivatives and are compounds which hardly stimulate 
melanogenesis. Therefore, the medicine of the present invention is 
effective as a therapeutic agent, particularly for glaucoma or ocular 
hypertension. 
The medicine of the present invention is a pharmaceutical containing the 
compound of the present invention as an active ingredient and typically 
applied to the eye, for example, in drops. As its dosage forms, external 
preparations such as eye drops and ophthalmic ointments and injections are 
mentioned, and the compounds of the present invention are formulated by 
using common techniques. For example, in the case of eye drops, 
isotonicities such as sodium chloride and concentrated glycerine, 
buffering agents such as sodium phosphate and sodium acetate, surfactants 
such as polyoxyethylene sorbitane monoolate (hereinafter referred to as 
polysorbate 80), polyoxyl 40 stearate and polyoxyethylene hydrogenated 
castor oil, stabilizers such as sodium citrate and sodium edetate and 
antiseptics such as benzalkonium chloride and paraben are optionally used 
to prepare the medicine of the present invention. The pH should be within 
a range acceptable for ocular medicines and is preferably from 4 to 8. 
Although the dose depends on the condition and the age of the patient and 
the dosage form, in the case of an ophthalmic solution, it is applied to 
the eye at a concentration of 0.0001 to 1% (w/v), preferably from 0.0005 
to 0.5% (w/v) once or a couple of times a day. 
Now, the present invention will be described in further detail with 
reference to Examples. However, the present invention is by no means 
restricted to such specific Examples. In Examples 1 to 21, compounds of 
the present invention were prepared. Example 22 illustrates formulations 
of the medicines of the present invention, and in Example 23, a 
pharmacological tests of medicines of the present invention are presented.

EXAMPLE 1 
Preparation of 
(1S,5R,6R,7R)-2-oxa-7-benzoyloxy-6-(1E)-4-(3-chlorophenoxy)-3-oxo-1-buten 
yl!bicyclo3.3.0!octan-3-one 
To a solution of 26.5 g of dimethyl 
2-oxo-3-(3-chlorophenoxy)propylphosphonate in THF (260 ml), 3.39 g of 
lithium chloride and 10.9 ml of triethylamine were added under cooling 
with ice. After 15 minutes of stirring, a solution of 18.1 g of 
(1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo3.3.0!octan-3-one in 
methylene chloride (65 ml) was added. After 1 hour of stirring at 
0.degree. C., the reaction solution was poured into a 1/1 mixture of 
saturated aqueous ammonium chloride/ethyl acetate, and the resulting 
mixture was allowed to separeate. The aqueous layer was extracted with 
ethyl acetate, and the combined organic layer was dried and concentrated. 
The concentrate was purified by silica gel column chromatography 
(hexane/ethyl acetate 1/3-2/1) to obtain 19.8 g of the above-identified 
compound. 
.sup.1 H NMR(CDCl.sub.3); .delta. 2.2-2.9(m,6H),4.67(s,2H),5.09(m,1H), 
5.34(m,1H),6.56(d,J=15.9 Hz,1H),6.73-6.97(m,4H),7.18 
(m,1H),7.44(m,2H),7.58(m,1H),7.97(m,2H). 
EXAMPLE 2 
Preparation of 
(1S,5R,6R,7R)-2-oxa-7-benzoyloxy-6-(1E)-3,3-difluoro-4-(3-chlorophenoxy)- 
1-butenyl!bicyclo3.3.0!octan-3-one 
To a solution of 5.00 g of the enone prepared in Example 1 in methylene 
chloride (150 ml), 19.8 g of morpholinosulfur trifluoride was added at 
0.degree. C. The resulting mixture was stirred at room temperature for 180 
hours, then poured into saturated aqueous sodium bicarbonate and extracted 
with ethyl acetate. The extract was purified by silica gel column 
chromatography (hexane/ethyl acetate 2/1) to obtain 3.47 g of the 
above-identified compound. 
.sup.1 H NMR(CDCl.sub.3): .delta. 2.2-3.0(m,6H),4.13(m,2H),5.09(m,1H), 
5.30(m,1H),5.87(dt,J=15.6,11.2 Hz,1H),6.15(m,1H),6.72 
(m,1H),6.84(m,1H),6.97(m,1H),7.18(m,1H),7.41(m,2H),7.55 (m,1H),7.96(m,2H). 
.sup.19 F NMR(CDCl.sub.3): -104.1(m). 
EXAMPLE 3 
Preparation of 
(1S,5R,6R,7R)-2-oxa-7-hydroxy-6-(1E)-3,3-difluoro-4-(3-chlorophenoxy)-1-b 
utenyl!bicyclo3.3.0!octan-3-one 
3.47 g of the fluoride prepared in Example 2 was dissolved in 40 ml of 
methanol, and 645 mg of potassium carbonate was added. The mixture was 
stirred at room temperature for 3 hours. After the pH was adjusted to 
about 7 with acetic acid, water was added, and the mixture was extracted 
with ethyl acetate. The extract was purified by silica gel column 
chromatography (hexane/ethyl acetate 1/2-2/3) to obtain 2.69 g of the 
above-identified compound. 
.sup.1 H NMR(CDCl.sub.3): .delta. 2.0-2.8(m,6H),4.09-4.21(m,3H), 
4.95(m,1H),5.84(dt,J=15.6,11.2 Hz,1H),6.07(m,1H),6.81 
(m,1H),6.91(m,1H),7.01(m,1H),7.23(m,1H). .sup.19 F NMR(CDCl.sub.3): 
-103.7(m). 
EXAMPLE 4 
Preparation of 
(1S,5R,6R,7R)-2-oxa-3,7-dihydroxy-6-(1E)-3,3-difluoro-4-(3-chlorophenoxy) 
-1-butenyl!bicyclo3.3.0!octane 
To a solution of 1.57 g of 
(1S,5R,6R,7R)-2-oxa-7-hydroxy-6-(1E)-3,3-difluoro-4-(3-chlorophenoxy)-1-b 
utenyl!bicyclo3.3.0!octan-3-one prepared in Example 3 in THF (50 ml), a 
toluene solution (1M, 17.5 ml) of diisobutylaluminum hydride was added at 
-78.degree. C., and the mixture was stirred for 30 minutes. Water (20 ml) 
and 1N hydrochloric acid (40 ml) were added, and the mixture was extracted 
with ethyl acetate. The extract was purified by silica gel column 
chromatography (hexane/ethyl acetate 1/1-3/2) to obtain 1.26 g of the 
above-identified compound. 
.sup.1 H NMR(CDCl.sub.3): .delta. 2.0-2.6(m,6H),2.89-3.10(m,1H), 
3.98(m,1H),4.18(m,2H),4.66(m,1H),5.57-5.67(m,1H),5.79 
(m,1H),6.11(m,1H),6.81(m,1H),6.92(m,1H),6.99(m,1H), 7.22(m,1H). .sup.19 F 
NMR(CDCl.sub.3): -103.4(m). 
EXAMPLE 5 
Preparation of 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostagla 
ndin F.sub.2.alpha. isopropyl ester 
To a solution of 6.21 g of 4-carboxybutyltriphenylphosphonium bromide in 
THF (80 ml), a toluene solution (0.5M, 56 ml) of potassium 
bis(trimethylsilyl)amide was added, and the mixture was stirred at room 
temperature for 30 minutes. A solution of 1.26 g of the lactol prepared in 
Example 4 in THF (30 ml) was added at -20.degree. C., and the mixture was 
stirred at room temperature for 1 hour. Water was added to terminate the 
reaction, and the reaction mixture was washed with diethyl ether. The 
aqueous layer was acidified and then extracted with ethyl acetate. The 
extract was dried, and then the solvent was evaporated off to obtain 1.56 
g of a crude carboxylic acid. 
To a solution of 1.56 g of the carboxylic acid thus obtained in acetone (14 
ml), 4.28 g of 1,8-diazabicyclo5.4.0!undec-7-ene and 5.38 g of 
2-iodopropane were added, and the mixture was stirred for 17 hours. The 
reaction mixture was diluted with ethyl acetate, then washed with 
saturated aqueous sodium chloride, 3% aqueous citric acid and aqueous 
sodium bicarbonate, dried and concentrated. The concentrate was purified 
by silica gel column chromatography (hexane/ethyl acetate 1/1) to obtain 
0.91 g of the above-identified compound. 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.22(d,J=6.4 Hz,6H),1.6-2.8(m,14H), 
4.03(m,1H),4.18(t,J=11.7 Hz,2H),4.21(m,1H),4.99(m,1H), 
5.38(m,1H),5.78(dt,J=15.6,11.2 Hz,1H),6.10(m,1H),6.81 
(m,1H),6.92(m,1H),6.98(m,1H),7.21(m,1H). .sup.19 F NMR(CDCl.sub.3): 
-103.3(m). 
EXAMPLE 6 
Preparation of 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostagla 
ndin F.sub.2.alpha. 
To a solution of 440 mg of 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostagla 
ndin F.sub.2.alpha. isopropyl ester prepared in Example 5 in ethanol (13 
ml), 0.2N aqueous sodium hydroxide (11.3 ml) was added, and the mixture 
was stirred at room temperature for 22 hours. The reaction solution was 
poured into saturated aqueous sodium bicarbonate and washed with toluene. 
The reaction solution was adjusted to pH 1 with 2N hydrochloric acid and 
then extracted with ethyl acetate. The extract was dried and concentrated 
to obtain 423 mg of the above-identified compound. 
.sup.1 H NMR(CDCl.sub.3): .delta. 
1.6-2.5(m,14H),4.04(m,1H),4.14-4.20(m,3H),5.38(m,2H),5.78(dt,J=15.6,11.2 
Hz,1H),6.09 (m,1H),6.81(m,1H),6.92(m,1H),6.98(m,1H),7.21(m,1H). .sup.19 F 
NMR(CDCl.sub.3): -103.4(m). 
EXAMPLE 7 
Preparation of 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostagla 
ndin F.sub.2.alpha. ethyl ester 
To a solution of 200 mg of 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostagla 
ndin F.sub.2.alpha. prepared in Example 6 in acetone (2 ml), 275 mg of 
1,8-diazabicyclo5.4.0!undec-7-ene and 316 mg of iodoethane were added, 
and the resulting reaction solution was stirred for 5 hours. The reaction 
solution was diluted with ethyl acetate, then washed with saturated 
aqueous sodium chloride, 3% aqueous citric acid and aqueous sodium 
bicarbonate, dried and concentrated. The concentrate was purified by 
silica gel column chromatography (hexane/ethyl acetate 1/1) to obtain 82 
mg of the above-identified compound. 
.sup.1 H NMR(CDCl.sub.3); .delta. 1.25(t,J=7.3 Hz,3H),1.6-2.6(m,14H), 
4.04(m,1H),4.12(q,J=7.3 Hz,2H),4.15-4.21(m,3H),5.39(m,2H), 
5.78(dt,J=15.6,11.2 Hz,1H),6.11(m,1H),6.81(m,1H),6.92 
(m,1H),6.99(m,1H),7.22(m,1H). .sup.19 F NMR(CDCl.sub.3): -103.4(m). 
EXAMPLE 8 
Preparation of 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostagla 
ndin F.sub.2.alpha. methyl ester 
To a solution of 221 mg of 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostagla 
ndin F.sub.2.alpha. in a solvent mixture of methanol (1 ml) and benzene (4 
ml), trimethylsilyldiazomethane (10% hexane solution, 2.5 ml) was added, 
and the resulting reaction solution was stirred for 30 minutes. Acetic 
acid was added dropwise to terminate the reaction, and the reaction 
solution was concentrated. The concentrate was purified by silica gel 
column chromatography (hexane/ethyl acetate 1/1) to obtain 65 mg of the 
above-identified compound. 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.6-2.5(m,14H),3.66(s,3H),4.04(m,1H), 
4.15-4.21(m,3H),5.39(m,2H),5.78(dt,J=15.6,11.2 Hz,1H), 
6.11(m,1H),6.81(m,11H),6.92(m,1H),6.99(m,1H),7.22(m,1H). .sup.19 F 
NMR(CDCl.sub.3): -103.4(m). 
EXAMPLE 9 
Preparation of 
16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin 
F.sub.2.alpha. isopropyl ester 
The above-identified compound was prepared in the same manners as in 
Examples 1 to 5 using 
(1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo3.3.0!octan-3-one and 
dimethyl 2-oxo-3-phenoxypropylphosphonate. 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.22(d,J=6.4 Hz,6H),1.59(m,1H),1.66 
(m,2H),1.83(m,1H),2.0-2.4(m,7H),2.47(m,1H),4.02(m,1H), 4.19(t,J=11.5 
Hz,2H),4.19(m,1H),4.99(m,1H),5.38(m,2H),5.80 (dt,J=15.6,11.2 
Hz,1H),6.10(m,1H),6.91(m,2H),7.00(m,1H), 7.30(m,2H). .sup.19 F 
NMR(CDCl.sub.3): -103.7(m). 
The following compounds were prepared in the respective steps in the 
present Example. 
(1S,5R,6R,7R)-2-oxa-7-benzoyloxy-6-(1E)-4-phenoxy-3-oxo-1-butenyl!bicyclo 
3.3.0!octan-3-one 
.sup.1 H NMR(CDCl.sub.3): .delta. 2.29(ddd,J=15.6,4.9,0.2 Hz,1H), 
2.45-2.51(m,1H),2.60(dt,J=15.6,6.6 Hz,1H),2.83-2.95(m,3H), 
4.67(s,2H),5.08(td,J=4.6,1.7 Hz,1H),5.31(m,1H),6.60(dd, J=15.6,1.0 
Hz,1H),6.84-6.87(m,2H),6.91(dd,J=15.6, 7.8 Hz,1H),6.98(t,J=7.3 
Hz,1H),7.25-7.29(m,2H),744 (t,J=7.3 Hz,2H),7.58(dt,J=7.3,1.2 
Hz,1H),7.97(dd,J=8.3, 1.2 Hz,2H). 
(1S,5R,6R,7R)-2-oxa-7-benzoyloxy-6-(1E)-3,3-difluoro-4-phenoxy-1-butenyl!b 
icyclo3.3.0!octan-3-one 
.sup.1 H NMR(CDCl.sub.3): .delta. 2.2-2.9(m,6H),4.17(t,J=11.5 Hz,2H), 
5.09(m,1H),5.29(m,1H),5.89(dt,J=15.6,11.0 Hz,1H),6.15 (m,1H),6.85(d,J=7.8 
Hz,2H),6.99(t,J=7.3 Hz,1H),7.27(m,2H), 7.41(m,2H),7.55(t,J=7.3 
Hz,1H),7.97(d,J=7.3 Hz,2H). .sup.19 F NMR(CDCl.sub.3): -104.0(m). 
(1S,5R,6R,7R)-2-oxa-7-hydroxy-6-(1E)-3,3-difluoro-4-phenoxy-1-butenyl!bicy 
clo3.3.0!octan-3-one 
.sup.1 H NMR(CDCl.sub.3): .delta. 2.0-2.8(m,6H),4.09(m,1H),4.20(t, J=11.5 
Hz,2H),4.94(m,1H),5.84(dt,J=15.6,11.2 Hz,1H),6.07 (m,1H),6.91(d,J=7.8 
Hz,2H),7.02(t,J=7.3 Hz,1H),7.31(m,2H). .sup.19 F NMR(CDCl.sub.3): 
-103.6(m). 
(1S,5R,6R,7R)-2-oxa-3,7-dihydroxy-6-(1E)-3,3-difluoro-4-phenoxy-1-butenyl! 
bicyclo3.3.0!octane 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.8-2.9(m,6H),3.96(m,1H),4.19 (t,J=11.5 
Hz,2H),4.60-4.71(m,1H),5.56-5.65(m,1H),5.82 (m,1H),6.11(m,1H),6.91(d,J=8.3 
Hz,2H),7.00(m,1H),7.30 (t,J=7.8 Hz,2H). .sup.19 F NMR(CDCl.sub.3): 
-103(m). 
EXAMPLE 10 
Preparation of 
16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin 
F.sub.2.alpha. 
The above-identified compound was prepared in the same manner as in Example 
6 using 
16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin 
F.sub.2.alpha. isopropyl ester prepared in Example 9. 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.60(m,1H),1.67(m,2H),1.83(m,1H), 
2.0-2.5(m,8H),2.47(m,1H),4.03(m,1H),4.18(t,J=11.7 Hz,2H), 
4.18(m,1H),5.36(m,2H),5.80(dt,J=15.8,10.5 Hz,1H),6.09 
(m,1H),6.91(m,2H),6.99(m,1H),7.29(m,2H). .sup.19 F NMR(CDCl.sub.3): 
-103.7(m). 
EXAMPLE 11 
Preparation of 
16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin 
F.sub.2.alpha. ethyl ester 
The above-identified compound was prepared in the same manner as in Example 
7 using 
16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin 
F.sub.2.alpha. prepared in Example 10. 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.25(t,J=7.2 Hz,3H),1.55-1.75(m,3H), 
1.85(m,1H),2.05-2.50(m,8H),4.01(m,1H),4.12(q,J=7.2 Hz,2H), 4.20(t,J=11.7 
Hz,2H),4.21(m,1H),5.38(m,2H),5.81(dt,J=11.1, 15.7 
Hz,1H),6.10(ddt,J=2.0,9.1,15.7 Hz,1H),6.91(m,2H),7.00 (m,1H),7.30(m,2H). 
.sup.19 F NMR(CDCl.sub.3): -103.3(m). 
EXAMPLE 12 
Preparation of 
16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin 
F.sub.2.alpha. methyl ester 
The above-identified compound was prepared in the same manner as in Example 
8 using 
16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin 
F.sub.2.alpha. prepared in Example 10. 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.60(m,1H),1.67(m,2H),1.84(m,1H), 
2.0-2.4(m,8H),2.47(m,1H),3.66(s,3H),4.02(m,1H),4.20 (t,J=12.0 
Hz,2H),4.20(m,1H),5.38(m,2H),5.80(dt,J=16.4, 10.8 
Hz,1H),6.10(m,1H),6.91(m,2H),7.00(m,1H),7.30(m,2H). .sup.19 F 
NMR(CDCl.sub.3): -103.7(m). 
EXAMPLE 13 
Preparation of 
16-(3,5-dichlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprost 
aglandin F.sub.2.alpha. isopropyl ester 
The above-identified compound was prepared in the same manners as in 
Examples 1 to 5 using 
(1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo3.3.0!octan-3-one and 
dimethyl 2-oxo-3-(3,5-dichlorophenoxy)propylphosphonate. 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.23(d,J=6.1 Hz,6H),1.6-2.5(m,12H), 
4.03(m,1H),4.17(t,J=11.4 Hz,2H),4.22(m,1H),5.00(m,1H),5.39 (t,J=5.0 
Hz,2H),5.76(m,1H),6.11(m,1H),6.83(d,J=1.8 Hz,2H), 7.02(t,J=1.8 Hz,1H). 
.sup.19 F NMR(CDCl.sub.3): -103.5(m). 
The following compounds were prepared in the respective steps in the 
present Example. 
(1S,5R,6R,7R)-2-oxa-7-benzoyloxy-6-(1E)-4-(3,5-dichlorophenoxy)-3-oxo-1-bu 
tenyl!bicyclo3.3.0!octan-3-one 
.sup.1 H NMR(CDCl.sub.3): .delta. 2.31(ddd,J=15.6,4.9,2.0 Hz,1H),2.51 
(m,1H),2.65(dt,J=15.6,6.5 Hz,1H),2.87-2.98(m,3H),4.67 
(s,2H),5.11(dt,J=6.5,2.0 Hz,1H),5.35(m,1H),6.54(d, J=16.1 
Hz,1H),6.77(d,J=2.0 Hz,2H),6.92(dd,J=16.1,7.8 Hz,1H), 6.99(t,J=2.0 
Hz,1H),7.45(m,2H),7.60(m,1H),7.98(m,2H). 
(1S,5R,6R,7R)-2-oxa-7-benzoyloxy-6-(1E)-3,3-difluoro-4-(3,5-dichlorophenox 
y)-1-butenyl!bicyclo3.3.0!octan-3-one 
.sup.1 H NMR(CDCl.sub.3): .delta. 2.2-2.9(m,6H),4.12(m,2H),5.08(m,1H), 
5.31(q,J=6.1 Hz,1H),5.85(m,1H),6.14(dd,J=15.9,7.6 Hz,1H), 6.76(d,J=1.7 
Hz,2H),6.98(t,J=1.7 Hz,1H),7.4-7.6(m,3H), 7.94(m,2H). .sup.19 F 
NMR(CDCl.sub.3): -104(m). 
(1S,5R,6R,7R)-2-oxa-7-hydroxy-6-(1E)-3,3-difluoro-4-(3,5-dichlorophenoxy)- 
1-butenyl!bicyclo3.3.0!octan-3-one 
.sup.1 H NMR(CDCl.sub.3): .delta. 2.04(m,1H),2.4-2.9(m,5H),4.08(dt, 
J=6.1,6.4 Hz,1H),4.15(t,J=11.5 Hz,2H),4.95(dt,J=4.4,2.4 Hz, 
1H),5.79(dt,J=15.9,11.2 Hz,1H),6.06(ddt,J=15.9,8.0,1.0 Hz, 
1H),6.81(d,J=1.7 Hz,2H),7.00(t,J=1.7 Hz,1H). .sup.19 F NMR(CDCl.sub.3): 
-103(m). 
(1S,5R,6R,7R)-2-oxa-3,7-dihydroxy-6-(1E)-3,3-difluoro-4-(3,5-dichloropheno 
xy)-1-butenyl!bicyclo3.3.0!octane 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.8-2.9(m,6H),3.97(m,1H),4.15(t, J=12.2 
Hz,2H),4.65(m,1H),5.55-5.65(m,1H),5.77(m,1H),6.07 
(m,1H),6.82(m,2H),7.01(m,1H). .sup.19 F NMR(CDCl.sub.3): -103.5(m). 
EXAMPLE 14 
Preparation of 
(1S,5R,6R,7R)-2-oxa-7-benzoyloxy-6-4-(3-chlorophenoxy)-13-oxobutyl!bicycl 
o3.3.0!octan-3-one 
5% Pd-C (580 mg) was suspended in a solution of 4.08 g of the enone 
prepared in Example 1 in ethyl acetate (80 ml), and the suspension was 
stirred under a hydrogen atmosphere at room temperature for 2 hours. The 
reaction mixture was filtered through Celite and then concentrated. The 
concentrate was purified by silica gel column chromatography (hexane/ethyl 
acetate 1/1) to obtain 3.89 g of the above-identified compound. 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.68(m,1H),1.81(m,1H),2.13(m,1H), 
2.35-2.52(m,3H),2.68(m,1H),2.78-2.95(m,3H),4.56(s,2H), 5.10(dt,J=1.0,6.0 
Hz,1H),5.20(ddd,J=2.9,3.3,6.0 Hz,1H),6.74 
(m,1H),6.85(m,1H),6.97(m,1H),7.19(m,1H),7.43(m,2H),7.55 (m,1H),7.97(m,2H). 
EXAMPLE 15 
Preparation of 16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-13, 
14-dihydro-17,18,19,20-tetranorprostaglandin F.sub.2.alpha. isopropyl 
ester 
The above-identified compound was prepared in the same manners as in 
Examples 2 to 5 using the ketone prepared in Example 14. 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.22(d,J=6.4 Hz,6H),1.43(m,2H), 
1.65-1.75(m,4H),1.9-2.5(m,10H),3.95(m,1H),4.10(m,2H),4.20 
(m,1H),5.00(m,1H),5.41(m,2H),6.82(m,1H),6.93(m,1H),6.99 (m,1H),7.22(m,1H). 
.sup.19 F NMR(CDCl.sub.3): -105.7(m). 
The following compounds were prepared in the respective steps in the 
present Example. 
(1S,5R,6R,7R)-2-oxa-7-benzoyloxy-6-3,3-difluoro-4-(3-chlorophenoxy)butyl!b 
icyclo3.3.0!octan-3-one 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.68(m,2H),2.2-2.5(m,6H),2.72(m,1H), 
2.94(dd,J=18.3,10.7 Hz,1H),4.11(t,J=11.5 Hz,2H),5.12(dt, J=5.7,1.0 
Hz,1H),5.27(m,1H),6.78(ddd,J=5.9,2.5,1.7 Hz,1H), 6.90(t,J=2.2 
Hz,1H),7.01(m,1H),7.21(t,J=8.1 Hz,1H),7.44 (t,J=7.7 
Hz,2H),7.54(m,1H),7.99(m,2H). .sup.19 F NMR(CDCl.sub.3): -106.1(m). 
(1S,5R,6R,7R)-2-oxa-7-hydroxy-6-3,3-difluoro-4-(3-chlorophenoxy)butyl!bicy 
clo3.3.0!octan-3-one 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.55-1.68(m,2H),1.89(m,1H), 
2.1-2.6(m,6H),2.85(dd,J=18.8,11.2 Hz,1H),4.05(m,1H), 
4.10(m,2H),4.98(ddd,J=7.1,6.8,2.2 Hz,1H),6.81(ddd,J=8.3, 1.7,1.0 
Hz,1H),6.92(t,J=2.2 Hz,1H),7.01(m,1H),7.23(t, J=8.3 Hz,1H). .sup.19 F 
NMR(CDCl.sub.3): -106.0(m). 
EXAMPLE 16 
Preparation of 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tet 
ranorprostaglandin F.sub.2.alpha. 
The above-identified compound was prepared in the same manner as in Example 
6 using 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tet 
ranorprostaglandin F.sub.2.alpha. isopropyl ester prepared in Example 15. 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.41(m,2H),1.65-2.40(m,14H),3.95 
(m,1H),4.10(t,J=11.6 Hz,2H),4.17(m,1H),5.40(m,2H),6.81 
(m,1H),6.92(m,1H),7.00(m,1H),7.22(m,1H). .sup.19 F NMR(CDCl.sub.3): 
-105.8(m). 
EXAMPLE 17 
Preparation of 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tet 
ranorprostaglandin F.sub.2.alpha. methyl ester 
The above-identified compound was prepared in the same manner as in Example 
8 using 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tet 
ranorprostaglandin F.sub.2.alpha. prepared in Example 16. 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.42(m,2H),1.7-2.4(m,14H),3.67 
(s,3H),3.95(m,1H),4.11(t,J=11.5 Hz,2H),4.20(m,1H),5.41 
(m,2H),6.81(m,1H),6.93(m,1H),7.00(m,1H),7.23(m,1H). .sup.19 F 
NMR(CDCl.sub.3): -105.8(m). 
EXAMPLE 18 
Preparation of 
16-phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranorprost 
aglandin F.sub.2.alpha. isopropyl ester 
The above-identified compound was prepared in the same manners as in 
Examples 1, 14, 2, 3, 4 and 5 using 
(1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo3.3.0!octan-3-one and 
dimethyl 2-oxo-3-phenoxy-propylphosphonate. 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.23(d,J=6.4 Hz,6H),1.4-2.5(m,18H), 
3.95(m,1H),4.10-4.94(m,3H),5.00(m,1H),5.42(m,2H),6.92 
(m,2H),7.01(m,1H),7.31(m,2H). .sup.19 F NMR(CDCl.sub.3): -105.7(m). 
The following compounds were prepared in the respective steps in the 
present Example. 
(1S,5R,6R,7R)-2-oxa-7-benzoyloxy-6-(4-phenoxy-3-oxobutyl)bicyclo3.3.0!octa 
n-3-one 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.74(m,2H),2.13(m,1H),2.32-2.52 
(m,3H),2.66(m,1H),2.80-2.93(m,3H),4.57(s,2H),5.09(m,1H), 
5.20(m,1H),6.85(d,J=7.8 Hz,2H),6.99(t,J=7.3 Hz,1H),7.28 
(m,2H),7.43(m,2H),7.55(t,J=7.3 Hz,1H),7.98(d,J=7.3 Hz,2H). 
(1S,5R,6R,7R)-2-oxa-7-benzoyloxy-6-(3,3-difluoro-4-phenoxybutyl)bicyclo3.3 
.0!octan-3-one 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.67(m,2H),2.18-2.54(m,6H),2.72 
(m,1H),2.94(dd,J=18.3,10.5 Hz,1H),4.13(t,J=11.5 Hz,2H),5.11 
(m,1H),5.26(m,1H),6.89(d,J=7.8 Hz,2H),7.01(t,J=7.3 Hz,1H), 
7.30(m,2H),7.44(m,2H),7.56(m,1H),7.99(d,J=7.3 Hz,2H). .sup.19 F 
NMR(CDCl.sub.3): -105.9(m). 
(1S,5R,6R,7R)-2-oxa-7-hydroxy-6-(3,3-difluoro-4-phenoxybutyl)bicyclo3.3.0! 
octan-3-one 
.sup.1 H NMR(CDCl.sub.3); .delta. 1.47-1.68(m,2H),1.89(m,1H),2.0-2.2 
(m,3H),2.32(dt,J=15.1,5.9 Hz,1H),2.51-2.60(m,2H),2.84(dd, J=18.8,11.0 
Hz,1H),4.09(m,1H),4.13(t,J=11.5 Hz,2H),4.98 (m,1H),6.92(d,J=8.3 
Hz,2H),7.02(t,J=7.3 Hz,1H),7.32(t, J=7.8 Hz,2H). .sup.19 F 
NMR(CDCl.sub.3): -105.9(m). 
(1S,5R,6R,7R)-2-oxa-3,7-dihydroxy-6-(3,3-difluoro-4-phenoxybutyl)bicyclo3. 
3.0!octane 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.4-2.5(m,10H),3.95(m,1H),4.12(t, J=11.5 
Hz,2H),4.68(m,1H),5.54-5.67(m,1H),6.92(d,J=7.8 Hz, 2H),7.01(t,J=7.3 
Hz,1H),7.31(t,J=7.8 Hz,2H). .sup.19 F NMR(CDCl.sub.3): -105.6(m). 
EXAMPLE 19 
Preparation of 
16-phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranorprost 
aglandin F.sub.2.alpha. 
The above-identified compound was prepared in the same manner as in Example 
6 using 
16-phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranorprost 
aglandin F.sub.2.alpha. isopropyl ester prepared in Example 18. 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.4-2.4(m,18H),3.96(m,1H),4.12(t, J=11.7 
Hz,2H),4.17(m,1H),5.40(m,2H),6.92(m,2H),7.00(m,1H), 7.30(m,2H). .sup.19 F 
NMR(CDCl.sub.3): -105.7(m). 
EXAMPLE 20 
Preparation of 
16-phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranorprost 
aglandin F.sub.2.alpha. ethyl ester 
The above-identified compound was prepared in the same manner as in Example 
7 using 
16-phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranorprost 
aglandin F.sub.2.alpha. prepared in Example 19. 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.25(t,J=7.3 Hz,3H),1.4-2.7(m,18H), 
3.95(m,1H),4.09-4.18(m,5H),5.41(m,2H),6.92(m,2H),7.00 (m,1H),7.30(m,2H). 
.sup.19 F NMR(CDCl.sub.3): -105.7(m). 
EXAMPLE 21 
Preparation of 
16-phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranorprost 
aglandin F.sub.2.alpha. methyl ester 
The above-identified compound was prepared in the same manner as in Example 
8 using 
16-phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranorprost 
aglandin F.sub.2.alpha. prepared in Example 19. 
.sup.1 H NMR(CDCl.sub.3): .delta. 1.4-2.6(m,18H),3.66(s,3H),3.95(m,1H), 
4.10-4.19(m,3H),5.41(m,2H),5.76(m,1H),6.92(m,2H),7.00 (m,1H),7.31(m,2H). 
.sup.19 F NMR(CDCl.sub.3): -105.7(m). 
EXAMPLE 22 (FORMULATION EXAMPLE) 
Typical formulations of an ophthalmic solution and an ophthalmic ointment 
containing 
16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin 
F.sub.2.alpha. methyl ester (hereinafter referred to as Compound A) 
prepared in Example 12 are given below. 
1) Ophthalmic Solution 100 ml 
______________________________________ 
Compound A 10 mg 
Concentrated glycerine 
2500 mg 
Polysorbate 80 2000 mg 
Sodium dihydrogenphosphate dihydrate 
200 mg 
Sterilized pure water appropriate amount 
1N hydrochloric acid or 1N sodium hydroxide 
appropriate amount 
pH 6.0 
______________________________________ 
Based on the above formulation, 0.001% (w/v), 0.005% (w/v), 0.05% (w/v) and 
0.1% (w/v) ophthalmic solutions can be prepared by varying the amount of 
compound A and optionally varying the amounts of the additives. 
Moreover, based on the above-formulation, 0.001% (w/v), 0.005% (w/v), 0.01% 
(w/v), 0.05% (w/v) and 0.1% (w/v) ophthalmic solutions of 
16-(3-chlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostagla 
ndin F.sub.2.alpha. methyl ester (hereinafter referred to as Compound B) 
prepared in Example 8, 
16-phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranorprost 
aglandin F.sub.2.alpha. methyl ester (hereinafter referred to as Compound 
C) prepared in Example 21 and 
16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin 
F.sub.2.alpha. isopropyl ester (hereinafter referred to as Compound D) 
prepared in Example 9 can be prepared by using compounds B, C and D 
instead of compound A and optionally varying the amounts of the additives. 
2) Ophthalmic Ointment 100 g 
______________________________________ 
Compound A 0.1 g 
Liquid paraffin 20 g 
White soft paraffin 
77.9 g 
Purified lanolin 2 g 
______________________________________ 
Based on the above formulation, similar opthalmic ointments can be prepared 
by using compounds Br C and D instead of compound A. 
The formulation of a ophthalmic solution containing Latanoprost which was 
used as a comparative compound is shown below. 
______________________________________ 
Ophthalmic solution 100 ml 
______________________________________ 
Latanoprost 10 mg 
Concentrated glycerine 
2500 mg 
Polysorbate 80 2000 mg 
Sodium dihydrogenphosphate dihydrate 
200 mg 
Sterilized pure water appropriate amount 
1N hydrochloric acid or 1N sodium hydroxide 
appropriate amount 
pH 6.0 
______________________________________ 
Based on the above formulation, a 0.1% (w/v) ophthalmic solution of 
Latanoprost can be prepared by varying the amount of Latanoprost and 
optionally varying the amounts of the additives. 
EXAMPLE 23 (PHARMACOLOGICAL TESTS) 
The effects of compounds of the present invention on intraocular pressure 
and melanogenesis were investigated to find their usefulness as medicines 
for an ocular disease. Eye irritations caused by them were assessed in 
accordance with the method of Fukui et al. ("Gendai-no-rinsho", Vol. 4, 
277-289 (1970)), and they were found to be irritant to the eye as little 
as Latanoprost. 
1) Effects on Intraocular Pressure 
The effects of single application and two-week repeated application of 
compounds of the present invention to the eye were studied in accordance 
with the method disclosed in a report of a study on the effect of the 
tromethamine salt and the isopropyl ester of PGF.sub.2.alpha. on 
intraocular pressure in crab-eating macaques (Exp. Eye Res., 61, 677-683 
(1995)). 
(a) Single Application Test 
(Method) 
Crab-eating macaques weighing from 2.5 to 7.5 kg (3-10 years old) were used 
in the test. The intraocular pressures were measured just before and 4, 6 
and 8 hours after application of the test compounds under ketamine 
anesthasia (5-10 mg/kg, intramuscular administration) by means of an 
air-puff applanation tonometer. 
(Results) 
Table 1 shows the resulting changes in intraocular pressure with time after 
application of 20 .mu.l of 0.01% (w/v) and 0.1% (w/v) ophthalmic solutions 
containing compounds A, B, C or D, in relation to the initial intraocular 
pressure (the intraocular pressure just before application). The results 
of application of 0.01% (w/v) and 0.1% (w/v) ophthalmic solutions 
containing Latanoprost, which is known as a therapeutic agent for glaucoma 
are also shown in Table 1. In the square brackets are the numbers of 
subjects. 
TABLE 1 
______________________________________ 
Change in ocular pressure 
after application (mmHg) 
4 hours 6 hours 8 hours 
______________________________________ 
Compound A 
(0.01%) 7! -1.7 -2.3 -2.3 
(0.1%) 8! -2.6 -3.0 -3.1 
Compound B 
(0.01%) 10! -0.9 -1.0 -1.0 
(0.1%) 9! -1.3 -1.4 -2.0 
Compound C 
(0.01%) 9! -0.6 -1.2 -2.0 
(0.1%) 9! -1.0 -0.4 -2.0 
Compound D 
(0.01%) 12! -0.1 -0.8 -1.3 
(0.1%) 12! -0.8 -1.6 -2.3 
Latanoprost 
(0.01%) 5! -0.4 -1.2 -0.6 
(0.1%) 8! -0.8 -1.3 -0.8 
______________________________________ 
As is evident from Table 1, the intraocular pressure had already started to 
decrease 4 hours after the application of compounds of the present 
invention and was still decreasing even 8 hours after the application. 
Compound A lowered the intraocular pressure twice as much as Latanoprost 
did 6 hours after application, and about 4 times as much 8 hours after 
application. 
This proves that the compound of the present invention has a long-lasting 
effect of lowering intraocular pressure. 
(b) Two-week Repeated Application Test 
(Method) 
Crab-eating macaques weighing from 2.4 to 5.6 kg (3 to 8 years old) were 
used in the test. A 20 .mu.l of a test ophthalmic solution was applied to 
one of the eyes of each macaque, and an equal volume of the corresponding 
vehicle solution (which was of the same formulation as the ophthalmic 
solution containing the test compound but did not contain the test 
compound) was applied to the other eye once a day for 14 consecutive days. 
The intraocular pressure was measured under ketamine anesthasia (5-10 
mg/kg, intramuscular administration) by means of an air-puff applanation 
tonometer. 
(Results) 
Table 2 illustrates the resulting difference in intraocular pressure 
between the right and left eyes (the intraocular pressure of an eye 
treated with an ophthalmic solution containing a test compound)--(the 
intraocular pressure of an eye treated with the corresponding vehicle 
solution)! 6 hours after application of a 0.01% (w/v) or 0.1% (w/v) 
ophthalmic solution containing compound D or a 0.1% (w/v) ophthalmic 
solution containing compound A or B on the 1st, 3rd, 7th, 10th and 14th 
days. The results of application of a 0.1% (w/v) ophthalmic solution 
containing Latanoprost, which is known as a therapeutic medicine for 
glaucoma are also shown in Table 2. In the square brackets are the numbers 
of subjects. 
TABLE 2 
__________________________________________________________________________ 
Difference in intraocular pressure 
between the right and left eyes (mmHg) 
(Intraocular pressure of the eye treated with test 
compound) - 
(Intraocular pressure of the eye treated with vehicle 
solution)! 
1st day 
3rd day 
7th day 
10th day 
14th day 
__________________________________________________________________________ 
Compound A 
(0.1%) 
7! 
-0.5 
-2.7 -3.4 
-3.3 -2.6 
Compound B 
(0.1%) 
7! 
-0.5 
-2.5 -3.2 
-2.8 -1.9 
Compound D 
(0.01%) 
7! 
-2.1 
-2.8 -3.0 
-2.2 -1.9 
(0.1%) 
7! 
-1.6 
-4.4 -3.9 
-2.7 -2.4 
Latanoprost 
(0.1%) 
7! 
-0.6 
-2.1 -1.7 
-0.7 -0.3 
__________________________________________________________________________ 
As is evident from Table 2, the intraocular pressure had remarkably 
decreased since the 3rd day from the start of the application of compounds 
of the present invention and kept low till the 14th day. Compound D 
lowered intraocular pressure about 2 to 8 times as much as Latanoprost 
did. When the intraocular pressures were measured, no turbid cornea, 
abnormal conjunctiva vessels, conjunctivoma or secretions were observed. 
This proves that the compound of the present invention has an excellent 
effect of lowering intraocular pressure. 
2) Effects on Melanogenesis 
The effect of compounds of the present invention on melanogenesis was 
investigated by using B16 pigment cells in accordance with a report of a 
study on the effect of pyrroloquinoline quinone on expression of mRNA of 
tyrosinase, which is involved in melanogenesis (Life Sci., 56, 1707-1713 
(1995)). 
(Method) 
To a B16 pigment cell culture (2.times.10.sup.3 cells/ml) preincubated at 
37.degree. C. under 5% CO.sub.2 for 24 hours, a test compound was added, 
and the culture was incubated at 37.degree. C. under 5% CO.sub.2 for 48 
hours. After renewal of the culture medium and addition of the test 
compound, the cell culture was incubated at 37.degree. C. under 5% 
CO.sub.2 for another 48 hours. The B16 pigment cells were separated from 
the culture medium and dissolved in a 0.1N sodium hydroxide-10% triton-X 
mixed solution, and the absorbances of the culture medium and the cell 
solution (wavelength 415 nm) were measured. 
The gross amounts of melanin in the culture medium and the cell solution 
were determined from a calibration chart prepared by using synthetic 
melanin standard solutions. The amount of protein in the culture medium 
was measured, and the melanin content was given by the following equation 
and represented in relation to the amount of melanin in the absence of the 
test compound. 
##EQU1## 
A.sub.c : Absorbance of the culture medium in the absence of a test 
compound 
B.sub.c : Absorbance of cell solution in the absence of a test compound 
P.sub.c : The amount of protein in a cell solution in the absence of a test 
compound 
A.sub.s : Absorbance of the culture medium in the presence of a test 
compound 
B.sub.s : Absorbance of the cell solution in the presence of a test 
compound 
P.sub.s : The amount of protein in the cell solution in the presence of a 
test compound 
(Results) 
Table 3 illustrates the effect of addition of the free forms (carboxylic 
acids) of Compounds A, B and C on melanogenesis by B16 pigment cells. The 
results of addition of the free form (a carboxylic acid) of Latanoprost, 
which is known as a therapeutic medicine for glaucoma are also shown in 
Table 3. The free form of Compound D is the same as that of Compound A. 
TABLE 3 
______________________________________ 
Concentration 
1 .mu.M 10 .mu.M 
100 .mu.M 
______________________________________ 
Compound A 102% 113% 111% 
Compound B 110% 122% 107% 
Compound C 107% 116% 127% 
Latanoprost 109% 136% 224% 
______________________________________ 
As is evident from Table 3, compounds of the present invention did not have 
much effect and, the melanin contents in the presence of 100 .mu.M of them 
were only about 1.1 to 1.3 times higher than that in the absence of them. 
On the other hand, when Latanoprost was added at concentrations of 10 
.mu.M and 100 .mu.M, the melanin contents were about 1.4 times and about 
2.2 times, respectively, higher than that in its absence. 
This proves that compounds of the present invention have little effect on 
melanogenesis and do not cause iridal pigmentation when applied 
repeatedly. 
The results of the pharmacological tests clearly indicate that the 
compounds of the present invention are useful as long-lasting therapeutic 
medicines for glaucoma, are hardly irritant to the eye and have little 
effect on melanogenesis.