Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
1~3!~132
PROSTAGLANDIN DERIVATIVES FOR THE TREATMENT OF
GLAUCOMA OR OCULAR HYPERTENSION
The invention is concerned with the use of prostaglandin
derivatives of PGA, PG8, PGD, PGE and PGF, in which the
omega chain has been modified with the common feature of
containing a ring structure, for the treatment of glaucoma
or ocular hypertension. The invention relates also to
ophthalmic compositions, containing an active amount of
these prostaglandin derivatives, and the manufacture of such
compositions.
Glaucoma is an eye disorder characterized by increased
intraocular pressure, excavation of the optic nerve head and
gradual loss of the visual field. An abnormally high intra-
ocular pressure is commonly known to be detrimental to the
eye, and there are elear indications that, in glaucoma
patients, this probably is the most important factor causing
degenerative changes in the retina. The pathophysiological
mechanism of open angle glaucoma is, however, still unknown.
Unless treated successfully glaucoma will lead to blindness
sooner or later, its course towards that stage is typically
slow with progressive loss of the vision.
The intraocular pressure, IOP (abbr. of intraocular ~ress-
ure) can be defined as according to the formula:
e (1)
where Pe is the episcleral venous pressure, generally
regarded as being around 9 mm Hg, F the flow of aqueous
humor, and R the resistanee to outflow of aqueous humor
through the trabecular meshwork and adjacent tissue into
Schlemm's canal.
-2- 1 33g 13 2
Besides passing through Schlemm's, canal aqueous humor might
also pass through the ciliary muscle into the suprachoroidal
space and finally leave the eye through sclera. This
uveoscleral route has been described for instance by Bill
(1975). The pressure gradient in this case is insignificant
compared to the gradient over the interior wall of Schlemm's
canal and adjacent tissue in the former case. The flow
limiting step along the uveoscleral route is assumed to be
the flow from the anterior chamber into the suprachoroidal
space.
A more complete formula is given by:
e (Ft ~ Fu) x R (2)
where Pe and R are defined as above, Ft is the total outflow
of aqueous humor and F is the fraction passing via the
uveoscleral route.
IOP in human beings is normally in the range of 12 - 22 mm
Hg. At higher values, for instance over 22 mm Hg, there is a
risk that the eye may be affected. In one particular form of
glaucoma, low tension glaucoma, damage may occur at intra-
ocular pressure levels otherwise regarded as physiologically
normal. The reason for this could be that the eye in these
individuals is unusually sensitive to pressure. The opposite
situation is also known, that some individuals may exhibit
an abnormally high intraocular pressure without any manifest
defects in the visual field or optic nerve head. Such
conditions are usually referred to as ocular hypertension.
Glaucoma treatments can be given by means of drugs, laser or
surgery. In drug treatment, the purpose is to lower either
the flow (F) or the resistance (R) which, according to
formula (1) above, will result in a reduced IOP; alterna-
tively to increase the flow via the uveoscleral route which
1339132
according to formula (2) also gives a reduced pressure.
Cholinergic agonists, for instance pilocarpine, reduce the
intraocular pressure mainly by increasing the outflow
through Schlemm's canal.
Prostaglandins, which recently have met an increasing
interest as IOP-lowering substances may be active in that
they will cause an increase in the uveoscleral outflow
(Crawford et al, 1987, and Nilsson et al, 1987). They do not
appear, however to have any effect on the formation of
aqueous humor or on the conventional outflow through
Schlemm's canal (Crawford et al, 1987).
The use of prostaglandins and their derivatives is described
for instance in US 4599353 and EP 87103714.9, and by Bito LZ
et al (1983), Camras CB et al (1981, 1987a, 1987b, 1988),
Giuffrè G (1985), Kaufman PL (1986), Kersetter JR et al
(1988), Lee P-Y et al (1988) and Villumsen J et al (1989).
With respect to the practical usefulness of some of the
previously described prostaglandins and derivatives, as
suitable drugs for treating glaucoma or ocular hypertension,
a limiting factor is their property of causing superficial
irritation and vasodilation in the conjunctiva. It is
probable, moreover, that prostaglandins have an irritant
effect on the sensory nerves of the cornea. Thus local side
effects will arise in the eye already when the amounts of
prostaglandin administered are quite small - that is,
already when the doses are lower than those that would be
desirable for achieving maximum pressure reduction. It has
thus been found, for instance, that for this reason it is
clinically impossible to use PGF2 -1-isopropyl ester in the
amount that would give maximum pressure reduction. Prosta-
glandins, being naturally occurring autacoids, are very
potent pharmacologically and affect both sensory nerves and
smooth muscle of the blood vessels. Since the effects caused
by administrations of PGF2a and its esters to the eye,
133913~
comprise in addition to pressure reduction also irritation
and hyperemia (increased blood flow), the doses currently
practicable in clinical tests are necessarily very low. The
irritation experienced when PGF2a or its esters are applied,
consists mainly in a feeling of grittiness or of having a
foreign body in one's eye, this being usually accompanied by
increased lacrimation.
We have now found that a solution to the problems discussed
above is the use of certain derivatives of prostaglandins A,
B, D, E and F, in which the omega chain has been modified
with the common feature of containing a ring structure, for
the treatment of glaucoma or ocular hypertension.
The prostaglandin derivatives have the general structure
alpha chain
12
\_~~ ~ omega chain
wherein A represents the alicyclic ring C8-C12 and the bonds
between the ring and the side chains represent the various
isomers. In PGA, PGB, PGD, PGE and PGF A has the formula
~ o OH O OH
~ OH OH
PGA PGB PGD PGE PGF
II . II IV V
The invention is based on the use of derivatives characterized
by their omega chain and various modifications of the alpha
chain is therefore possible still using the inventive
concept. The alpha chain could typically be the naturally
occuring alpha chain, which is esterified to the structure
~ /--\ COO Rl
-5- ~339 13~
in which Rl is an alkyl group, preferably with 1-10 carbon,
especially 1-6 atoms, for instance metyl, ethyl, propyl,
isopropyl, butyl, isobutyl, neopentyl or benzyl or a deriva-
tive giving the final substance equivalent properties as a
glaucoma agent. The chain could preferably be a C6-C10 chain
which might be saturated or unsaturated having one or more
double bonds, and allenes, or a triple bond and the chain
might contain one or more substituents such as alkyl groups,
alicyclic rings, or aromatic rings with or without hetero
atoms.
The omega chain is defined by the following formula:
(13) (14) (15-24)
C B C - D - R2
wherein
C is a carbon atom (the number is indicated within parenthesis)
B is a single bond, a double bond or a triple bond
D is a chain with 1-10, preferably 2-8, and especially 2-5,
and particularly 3 carbon atoms, optionally interrupted by
preferably not more than two hetero atoms (O,S, or N), the
substituent on each carbon atom being H, alkyl groups,
preferably lower alkyl groups within 1-5 carbon atoms, a
carbonyl group, or a hydroxyl group, whereby the substituent
on C15 preferably being a carbonyl group, or (R)-OH or
(S)-OH; each chain D containing preferably not more than
three hydroxyl groups or not more than three carbonyl
groups,
R2 is a ring structure such as a phenyl group which is
unsubstituted or has at least one substituent selected from
Cl-C5 alkyl groups, Cl-C4 alkoxy groups, trifluoromethyl
groups, Cl-C3 aliphatic acylamino groups, nitro groups,
halogen atoms, and phenyl group; or an aromatic heterocyclic
group having 5-6 ring atoms, like thiazol, imidazole,
pyrrolidine, thiophene and oxazole; or a cycloalkane or a
cycloalkene with 3-7 carbon atoms in the ring, optionally
substituted with lower alkyl groups with 1-5 carbon atoms.
13~gl32
Some examples on derivatives which were evaluated are the
following (for structure information see Table I):
(1) 16-phenyl-l7rl8~l9~2o-tetranor-pGF2a-isopropylester
(2) 17-phenyl-l8~l9~2o-trinor-pGF2a-isopropylester
(3) 15-dehydro-17-phenyl-18~19~20-trinor-PGF2a-isopropylester
(4) 16-phenoxy-l7~l8~l9~2o-tetranor-pGF2a-isopropylester
(5) 17-phenyl-18,19,20-trinor-PGE2-isopropylester
(6) 13,14-dihydro-17-phenyl-18,19,20-trinor-PGA2-isopropylester
(7) 15-(R)-17-phenyl-18,19,20-trinor-PGF2a-isopropyleSter
(8) 16-[4-(methoxy)-phenyl]-17,18,19,20-tetranor-PGF2a-
isopropylester
(9) 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2a-isopropylester
(10) 18-phenyl-l9~2o-dinor-pGF2a-isopropylester
(20) l9-phenyl-20-nor-PGF2a-isopropylester
The most preferred derivatives at present are those in which
the omega chain of the prostaglandin has the 18,19,20-trinor
form, and especially the 17-phenyl analogs, such as the
15-(R)-, 15-dehydro and 13,14-dihydro-17-phenyl-18,19,20-
trinor forms. Such derivatives are represented by (3), (6),
(7) and (9) in the formulas given in Table I.
In the formula given above the most preferred structure at
present is accordingly obtained when the prostaglandin is a
derivative of PGA, PGD, PGE or PGF, especially of PGA2,
2' G 2 a d G 2a
i339132
B is a single bond or a double bond
D is a carbon chain with 2-5, especially 3 atoms; C15 having
a carbonyl or (S)-OH substituent and C16-Clg having lower
alkyl substituents, or preferably H
R2 is a phenyl ring optionally having substituents selected
among alkyl and alkoxy groups.
The invention thus relates to the use of certain derivatives
of PGA, PGB, PGD, PGE and PGF for the treatment of glaucoma
or ocular hypertension. Among these derivatives defined
above it has been found that some are irritating or otherwise
not optimal, and in certain cases not even useful due to
adverse effects and these are excluded in that the group of
prostaglandin derivatives defined above is limited to
therapeutically effective and physiologically acceptable
derivatives. So is for instance (1) 16-phenyl-17,18,19,20-
tetranor-PGF2a-isopropyl ester irritating while this can be
eliminated by substituting the phenyl ring with a methoxy
group giving formula (8) which represents a therapeutically
more useful compound,
The method for treating glaucoma or ocular hypertension
consists in contacting an effective intraocular pressure
reducing amount of a composition, as aforesaid, with the eye
in order to reduce the eye pessure and to maintain said
pressure on a reduced level. The composition contains
0.1-30 ~g, especially 1-10 ~g, per application of the active
substance i.e. a therapeutically active and physiologically
acceptable derivative from the group defined above; the
treatment may advantageously be carried out in that one drop
of the composition, corresponding to about 30 ~l, is admin-
istered about 1 to 2 times per day to the patient's eye.
This therapy is applicable both to human beings and to
animals.
The invention further relates to the use of therapeutically
active and physiologically acceptable prostaglandin deriva-
tives from the group defined above for the preparation of an
13~9132
ophthalmological composition for the treatment of glaucoma
or ocular hypertension.
The prostaglandin derivative is mixed with an ophthalmologi-
cally compatible vehicle known p~ se. The vehicle which may
be employed for preparing compositions of this invention
comprises aqueous solutions as e.g. physiological salines,
oil solutions or ointments. The vehicle furthermore may
contain ophthalmologically compatible preservatives such as
e.g. benzalkonium chloride, surfactants like e.g. poly-
sorbate 80, liposomes or polymers, for example methyl
cellulose, polyvinyl alcohol, polyvinyl pyrrolidone and
hyaluronic acid, these may be used for increasing the
viscosity. Furthermore, it is also possible to use soluble
or insoluble drug inserts when the drug is to be administered.
The invention is also related to ophthalmological compo-
sitions for topical treatment of glaucoma or ocular hyper-
tension which comprise an effective intra ocular pressure
reducing amount of a prostaglandin derivative as defined
above and an ophthalmologically compatible carrier, the
effective amount comprising a dose of about 0.1-30 lu in
about 10-50 ~u of the composition.
In the experiments carried out in this investigation the
active compound, in an amount, varying with potency of the
drug, from 30 ,ug to 300 ~g/ml was dissolved in a sterilized
aqueous solution (saline 0.9 ~) containing 0.5 % polysorbate-80
as solubilizing agent.
The invention is illustrated by means of the following
non-limitative examples.
Synthesis of prostaglandin derivatives
1~391~2
Example 1: Preparation of 16-phenyl-17,18,19,20-tetranor
PGF~a-isopropyl ester (1).
A 50 ml round bottom flask equipped with a magnetic stirring
bar was charged with 17.5 mg (0.04 mmol) 16-phenyl-17,18,19,20-
tetranor PGF2a (Cayman Chemical), 5 ml CH2Cl2,30.2 mg (0.23
mmol) diisopropylethylamine. This solution was stirred at
-10 ~C and 13.5 mg (0.07 mmol) of isopropyltriflate (freshly
prepared) was added. This solution was allowed to stand at
-10 ~C for 15 min and was then slowly warmed to room tempera-
ture. When the esterification was complete according to TLC
(usually after 3-4 h at room temperature) the solvent was
removed ln vacuo. The residue was diluted with 20 ml ethyl-
acetate, washed with 2xlO ml 5 % sodium hydrogencarbonate
and 2xlO ml 3 ~ citric acid. The organic layer was dried
over unhydrous sodium sulfate. The solvent was removed in
vacuo and the residue was purified by column chromatography
on silica gel-60 using ethyl acetate: aceton 2: 1 as eluent.
The title compound was obtained as a colourless oily substance
(71 % yield).
Nuclear Magnetic Resonance spectrum (CDC13)- ppm:
1.2 (6H d) 3,3 (lH q)
2.8 (2H d) 5.0 (lH m)
3.8 (lH m) 5.3-5.7 (4H m)
4.1 (lH t) 7.1-7.3 (5H m)
Example 2: Preparation of 17-phenyl-18,19,20- trinor PGF2a-
isopropyl ester (2).
A 50 ml round bottom flask equipped with a magnetic stirring
bar was charged whith 20 mg (0.05 mmol) 17-phenyl-18,19,20-
trinor PGF2a (Cayman Chemicals), 6 ml acetone, 39.2 mg (0.25
mmol) DBU and 42.5 mg (0.25 mmol) isopropyl iodide. The
solution was allowed to stand at room temperature for 24 h,
the solvent was removed in vacuo and the residue was diluted
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1990-09-18 *
13~9132
--io--
with 30 ml of ethyl acetate, washed twice with 10 ml 5 %
sodiumhydrogen carbonate and 10 ml 3 % citric acid. The
solvent was removed ln vacuo, and the crude product was
chromatographed on silica gel-60 using ethyl acetate:
acetone 2:1 as eluent. The title compound (2) was obtained
as an oily substance (65 % yield).
Nuclear Magnetic Resonance spectrum (CDC13)- ppm:
1.2 (6H d) 4.9 (lH m)
3.9 (lH m) 5.4-5.6 (4H m)
4.1 (lH t) 7.1-7.3 (5H m)
4.2 (lH m)
Example 3: Preparation of 15-dehydro-17-phenyl-18,19,20-
trinor PGF2a-isopropyl ester (3)
20.9 mg (0.092 mmol) DDQ was added to a solution of 10 mg
(0.023 mmol) 17-phenyl-18,19,20 trinor PGF2a-isopropyl ester
(2) in 8 ml dioxane. The reaction mixture immediately turned
brown, the reaction mixture was stirred at room temperature
for 24 h. The precipitate formed was filtered, washed with
10 ml ethyl acetate, the filtrate was diluted with 10 ml
ethylacetate washed with 2x10 ml water, 2x10 ml NaOH IM and
20 ml brine. The organic layer was dried on unhydrous sodium
sulfate and the solvent was removed in vacuo, the residue
was purified by column chromatography on silica gel using
ethyl acetate: ether 1:1 as eluent. The title compound (3)
was obtained as a colourless oily substance (76 % yield).
Nuclear Magnetic Reson~n~ spectrum (CDC13),- ppm:
1.2 (6H d) 5.4 (2H m)
4.0 (lH m) 6.2 (lH d)
4.2 (lH m) 6.7 (lH q)
5.0 (lH m) 7.1-7.3 (5H m)
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1990-09-18 *
33913~
Example 4: Preparation of 16-phenoxy-17,18,19,20 -tetranor
PGF2a-isopropyl ester(4)-
Following a procedure similar to that described in example 2
using 20 mg (0.051 mmol) 16-phenoxy-17,18,19,20 -tetranor
PGF2a (Cayman Chemicals). The crude product was purified by
column chromatography on silica gel-60 using ethyl acetate:
acetone 2:1 as eluent. The title compound (4) was an oily
substance (53.2 ~ yield).
Nuclear Magnetic Reso~anrP spectrum (CDCl3)- ppm:
1.2 (6H d) 5.4 (2H m)
3.9 (3H m) 5.7 (2H m)
4.2 (lH m) 6.9 (3H m)
4.5 (lH m) 7.3 (2H m)
5.0 (lH m)
Example 5: Preparation of 17-phenyl-18,19,20-trinor PGE2-
isopropyl ester (5).
Following a procedure similar to that described in example 2
using 10 mg (0.026 mmol) 17-phenyl-18,19,20- trinor PGE2
(Cayman Chemicals). The crude product was purified by column
chromatography on silica gel-60 using ether as eluent. The
title compound (5) was an oily substance (38.9 % yield).
Nuclear Magnetic Resonance spectrum (CDCl3~- ppm:
1.2 (6H d) 5.3 (2H m)
3.9-4.1 (2H m) 5.6 (2H m)
4.9 (lH m) 7.2 (5H m)
Example 6: Preparation of 13,14-dihydro-17-phenyl-18,19,20-
trinor PGA2-isopropyl ester (6).
Following a procedure similar to that described in example 2
using 10 mg (0.026 mmol) 13,14-dihydro-17-phenyl PGA2
Al,-PS/pb
lC90-09-18 *
-12- i3 3g 13~
(Cayman Chemicals). The crude product was chromatographed on
silica gel-60 using ether as eluent. The title compound (6)
W2.S an oily substance (48 % yield).
NLLclear Magnetic Resonance spectrum (CDCl3)- ppm:
1.2 (6H d) 5.4 (2H m)
4.3 (lH m) 7.3 (5H m)
5.0 (lH m)
Example 7: Preparation of 15-(R)-17-phenyl-18,1g,20-trinor
PGF a-isopropyl ester (7). (Table II)
7.1 Preparation of 1-(S)-2-oxa-3-oxo-6-(R)-(3-oxo-5-phenyl-
-1-trans-pentenyl)-7-(R)-(4-phenylbenzoyloxy)-cis-bicyclo
[3,3,0] octane (13).
___________________________________________________________
18 g (0.05 mol) alcohol (11), 32 g (0.15 mol) DCC, 39.1 g
(0.5 mol) DMS~ (newly distilled from CaH2) and 30 ml DME
were charged to a 200 ml flask under nitrogen. 0.49 g
(0.005 mol) of orthophosphoric acid was added in one portion,
and an exothermic reaction occured. The reaction mixture was
stirred mechanically at room temperature for 2h, and the
resultant precipitate was filtered and washed with DME. The
filtrate (12) can be used directly for Emmon condensation
reaction.
To a suspension of 1.2 g (0.04 mol) NaH (80 % washed with
n-pentane to remove mineral oil) in 100 ml DME under nitrogen
was added dropwise 12.3 g (0.048 mol) dimethyl-2-oxo-
4-phenylbutyl-phosphonate in 30 ml DME. The mixture was
stirred mechanically for lh at room temperature, then cooled
to -10 ~C and a solution of the crude aldehyde (12) was
added in dropwise. After 15 min at 0 ~C and lh at room
temperature the reaction mixture was neutralized with
glacial acetic acid, the solvent was removed under vacuum,
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1990-09-18 *
-13- ~ 3391 32
and to the residue was added 100 ml ethyl acetate, washed
with 50 ml water and 50 ml brine. The organic layer was
dried over unhydrous sodium sulfate. The solvent was removed
ln vacuo
and the resulting white precipitate filtered and washed with
cold ether. The title compound (13) was obtained as a
crystalline substance mp 134.5-135.5 (53 % yield).
7.2 Preparation of 1-(S)-2-oxa-3Oxo-6-(R)-[3-(R,S)-
hydroxy-5-phenyl-1-trans-pentenyl]-7-(R)-(4-phenylbenzoyloxy)
cis-bicyclo [3,3,0]octane (14).
____________________________________________________________
10 g (0.021 mol) enone (13) and 3.1 g (0,008 mol) cerous-
chloride heptahydrate in 50 ml methanol and 20 ml CH2Cl2
were charged to a 200 ml round bottom flask equipped with a
magnetic stirring bar and was cooled to -78 ~C under nitrogen.
0.476 g (0.012 mol) of sodium borohydride was added in small
portions, after 30 min the reaction mixture was quenched by
addition of saturuted NH4Cl, and extracted with 2x50 ml
ethyl acetate. The extracts were dried and concentrated to
leave a colourless oil (98 % yield).
7.3 Preparation of 1-(S)-2-oxa-3-oxo-6-(R)-[3-(R,S)-hydroxy-
5-phenyl-1-trans-pentenyl]-7-(R)-hydroxy-cis-bicyclo-[3,3,0]
octane (15).
____________________________________________________________
To a solution of 9.8 g (0.02 mol) lactone (14) in 100 ml
absolute methanol was added 1.7 (0.012 mol) potassium
carbonate. The mixture was stirred with a magnetic bar, at
room temperature. After 3 h the mixture was neutralized with
40 ml HCl 1 M, and extracted with 2x50 ml ethyl acetate. The
extracts were then dried on unhydrous sodium sulfate and
concentrated. The crude product was chromatographed on
silica gel using ethyl acetate: acetone as eluent. The title
compound (15) was obtained as an oily substance (85
yield).
AL-PS/pb
1990-09-18 *
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1339132
7.4 Preparation of 1-(S)-2-oxa-3-hydroxy-6-(R)-[3-(R,S)-
hydroxy-5-phenyl-l-trans-pentenyl]-7-(R)-hydroxy-cis-
bicyclo[3,3,0] octane (16).
_________________________________________________________
To a solution of 3g(0.011 mol) lactone (15) in 60 ml un-
hydrous THF, stirred magnetically and cooled to -78 ~C,
4.5 g (0.0315 mol) DIBAL-H in toluene was added dropwise.
After 2h the reaction mixture was quenched by addition of 75
ml methanol. The mixture was filtered,the filtrate was con-
centrated in vacuo and the residue was chromatographed on
silica gel-60 using ethyl acetate: acetone 1:1 as eluent.
The title compound (16) was obtained as a semisolid sub-
stance (78 % yield).
7.5 Preparation of 15-(R,S)-17-phenyl-18,19,20-trinor
PGF2a(17).
______________________________________________________
2.5 g (25 mmol) sodium methyl sulfinylmethide in DMS0
(freshly prepared from sodium anhydride and DMS0) was added
dropwise to a solution of 5.6 g (12.6 mmol) 4-caboxybutyl
triphenyl-phosphonium bromide in 12 ml DMS0. To the resultant
red solution of the ylide was added dropwise a solution of
the 1.2 g (4.2 mmol) hemiacetal (16) in 13 ml DMS0, and the
mixture was stirred for lh. The reaction mixture was diluted
with 10 g ice and 10 ml water and extracted with 2x50 ml
ethyl acetate, whereafter the aqueous layer was cooled,
acidified with HCl 1 M and extracted with ethyl acetate, and
then the organic layer was dried and concentrated. The
resulting crude product was a colourless substance. The
purity of the title compound (17) was estimated by TLC on
silica gel using ethyl acetate: acetone: acetic acid 1:1:0.2
v/v/v as eluent.
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1990-09-18 *
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7.6 Preparation of 15-(R)-17-phenyl-18,19,20- trinor PGF2a-
isopropyl ester (7).
____________________________________________________________
The crude product (17) was esterified following a procedure
similar to that described in example 2 the product was
purified by column chromatography on silica gel-60 using
ethyl acetate as eluent and the resulting mixture of C15
epimeric alcohol were separated.
The title compound (7) was obtained as a colourless oily
substance (46 % yield).
Nuclear Magnetic Resonance spectrum (CDC13),- ppm:
1.2 (6H m) 5 4 (2H m)
3.9 (lH m) 5.6 (2H m)
4.15 (2H m) 7.2 (5H m)
4.95 (lH m)
Example 8: Preparation of 16-[4-(methoxy)phenyl]-17,18,19,20-
tetranor PGF2 -isopropyl ester (8).
Following a procedure similar to that described in example 7
with modified step 7-2, the aldehyde 12 described in step
7-2 was reacted with dimethyl-2-oxo-3-[4-(methoxy)phenyl]-
propylphosphonate and was purified by column chromatography
on silica gel-60 using ethyl acetate: toluene 1:1 as eluent.
A colourless oily substance was obtained (57 % yield).
The title compound 16-[4-(methoxy)phenyl]-17,18,19,20-
-tetranor PGF2a-isopropyl ester (8) was obtained as an oily
substance, and purified by column chromatography on silica
gel-60 using ethyl acetate as eluent (46 % yield).
-16- 1339132
Nuclear Magnetic Resonance spectrum (CDC13)- ppm:
1.2 (6H d) 5.0 (lH m)
2.8 (2H d) 5.4 (2H m)
3.75 (3H S) 5.6 (2H m)
3.9 (lH m) 6.8 (2H d)
4.15 (lH m) 7.2 (2H d)
4.3 (lH m)
Example 9: Preparation of 13,14-dihydro-17-phenyl-18,19,20-
trinor PGF2a-isopropyl ester (9).
Following a procedure similar to that described in example
7, with minor modification, 5 g (0.018 mol) enone (13) in
100 ml THF was reduced using 2.03 g 10 % pd/c under hydrogen
atmosphere. After completion of the reaction (as determined
by TLC on silica gel using ethylacetate: toluene 1:1 as
eluent) the mixture was filtered on celite. The filtrate was
concentrated in vacuo and an oily substance was obtained
(86 % yield).
The final product 13,14-dihydro-17-phenyl-18,19,20-trinor
PGF2a-isopropyl ester containing a mixture of C15 epimeric
alcohols were separated by preparative liquid chromatography
using 40 % CH3CN in water v/v as eluent.
Nuclear Magnetic Renonance spectrum (CDCl3)- ppm:
1.2 (6H d) 5.0 (lH m)
3.6 (lH m) 5.4 (2H m)
3.9 (lH m) 7.2 (5H m)
4.15 (lH m)
Example 10: Preparation of 18-phenyl-19,20-trinor PGF2a-
isopropyl ester (10).
-17- 1339132
Following a procedure similar to that described in example
(7) with modified step 7-2. The aldehyde (12) described in
7-2 was reacted with dimethyl-2-oxo-5-phenyl pentyl phos-
phonate gave a crystalline substance trans-enone lactone
(67 % yield).
The final product 18-phenyl-19,20-dinor PGF2a-isopropyl
ester (10) was purified by column chromatography on silica
gel-60 using ethyl acetate as eluent gave a colourless oil
(41 % yield).
1.2 (6H d) 5.0 (lH m)
3.95 (lH m) 5.4 (2H m)
4.10 (lH m) 5.6 (2H q)
4.20 (lH m) 7.2 (5H m)
Example 11: Preparation of l9-phenyl-20-nor-PGF2a-isopropyl
ester (20).
Following a procedure similar to that described in example
(7) with modified step (7-2).
The aldehyde (12) described in (7-2) was reacted with
dimethyl-2-oxo-6-phenyl-hexylphosphonate gave a colourless
oil trans-enone lactone (56 % yield).
The final product l9-phenyl-20-nor-PGF2a-isopropyl ester
(20) was a colourless oil, and was purified by column
chromatography on silica gel-60 using ethyl acetate as
eluent (30 % yield).
Nuclear Magnetic Resonance spectrum (CDC13)-ppm:
1.2 (6H d) 5.0 (lH m)
2.6 (2H t) 5.4 (2H m)
3.9 (lH m) 5.5 (2H t)
4.1 (lH m) 7.2 (5H m)
4.2 (lH m)
-18- 1339132
Studies of eye pressure lowering effect and adverse reactions
The intraocular pressure (IOP) was determined in animals
with a pneumatonometer (Digilab Modular One , Bio Rad),
specially calibrated for the eye of the particular species.
The cornea was anaesthetized with 1-2 drops of oxibuprocain
before each IOP measurement. In healthy human volunteers IOP
was measured with applanation tonometry or with an air puff
tonometer (Keeler pulsair). For applanation tonometry either
a pneumatonometer (Digilab) or Goldmann's applanation
tonometer mounted on a slit lamp microscope was used. The
cornea was anaesthetized with oxibuprocain before each
measurement with applanation tonometry. No local anaesthesia
was employed before measurement with the pulsair tonometer.
The ocular discomfort after application of the test substances
was evaluated in cats. The behaviour of cats
after topical application of the test drug was followed and
ocular discomfort was graded on a scale from O to 3, O
indicating complete absence of any signs of discomfort, and
3 indicating maximal irritation as obvious from complete lid
closure.
Conjunctival hyperemia after topical application of the test
substances was evaluated in rabbits. The conjunctiva at the
insertion of the superior rectus muscle of the eye was
inspected or photographed with regular intervals and the
degree of hyperemia was later evaluated from the color
photographs in a blind manner. Conjunctival hyperemia was
evaluated on a scale from O to 4, O indicating complete
absence of any hyperemia, and 4 indicating marked hyperemia
with conjunctival chemosis.
For determination of the effects on the intraocular pressure,
primarily monkeys (cynomolgus) were employed. The reason for
this is that the monkey eye is highly reminiscent of the
human eye and therefor, generally, drug effects are readily
extrapolated to the human eye. However, the disadvantage of
-19- 1339132
using the monkey eye as a model is that the conjunctiva in
this species is pigmented making it impossible to evaluate
conjunctival hyperemia and furthermore, the monkey eye is
relatively insensitive to irritation. Therefore, the cat
eye, being very sensitive to prostaglandins was used for
evaluating ocular discomfort and the rabbit eye with pro-
nounced tendency to hyperemic reactions was used for evalu-
ating conjunctival and episcleral hyperemia.
It is evident from Table III that modification of the omega
chain of the prostaglandin skeleton introduced new and
unexpected features to the prostaglandins with respect to
ocular irritation (discomfort). Particularly 17-phenyl,18,19,20-
trinor-PGF2a-IE and analogs were unique in exhibiting a
complete loss of ocular irritation with retained IOP lowering
effect in monkeys. Whereas the 17-phenyl,18,19,20-trinor-
PGF2a derivatives were extremely well tolerated, 16-phenyl-
-17,18,19,20-tetranor-PGF2 -IE caused clear ocular discomfort
although to a lesser degree than PGF2a-IE or 15-propionate-
PGE2-IE (Table III). However, substituting a hydrogen atom
in the phenyl ring with a methoxy group having electron
donating properties rendered the molecule practically free
of ocular irritating effect, Table III. It is also evident
from Table III that 18-phenyl-19,20,-dinor-PGF2aIE, 19-phenyl-
-20-nor-PGF2a-IE as well as 17-phenyl-18,19,20-trinor-PGE2-IE
and 13,14-dihydro-17-phenyl-18,19,20-trinor-PGA2-IE, had no
or very little irritating effect in the eye of cats. This
indicates that the invention not only is valid for 16-, and
17-tetra- and trinor analogs of PGF2a but for a range of
omega chain modified and ring substituted analogs of PGF2a
(as exemplified with 16-phenyl-17,18,19,20-tetranor-PGF2a-IE
to 19-phenyl-20-nor-PGF2 -IE), and more importantly even for
different members of the prostaglandin family such as PGE2
and PGA2 modified in an analogous way (Table III). Thus,
modifying the omega chain and substituting a carbon atom in
the chain with a ring structure introduces completely new,
unexpected and advantageous qualities to naturally occuring
-20- 1 3391 32
prostaglandins in that the irritating effect in the conjunc-
tiva and cornea is abolished. In the case of 16-phenyl-
-17,18,19,20-tetranor-PGF2 -IE exhibiting some irritating
effect substituting a hydrogen atom in the ring structure
with e.g. a methoxy group attenuates or abolishes the
irritating effect.
In addition to the lack of ocular discomfort the omega chain
modified analogs also exhibited an advantage over naturally
occuring prostalgandins in that they caused considerably
less conjunctival hyperemia as studied in the rabbit eye
(Table IV). Particularly, 15-dehydro-17-phenyl-18,19,20-
trinor-PGF2a-IE,13,14-dihydro-17-phenyl-18,19,20-trinor-
-PGF2a-IE, and 13,14-dihydro-17-phenyl-18,19,20-trinor
PGA2-IE were adventageous in this respect. Also 18-phenyl-
-19,20-dinor-PGF2a-IE and 19-phenyl-20-nor-PGF2a-IE induced
very little conjunctival hyperemia (TablelV).
The intraocular pressure lowering effect of omega chain
modified and riny-substituted prostaglandin analogs is
demonstrated in Table V. It can be seen that particularly
16-phenyl-tetranor and 17-phenyl-trinor prostaglandin
analogs significantly reduced IOP in animal eyes (Table V).
In all but two series of experiments cynomolgus monkeys were
used. It is of particular interest to note that 17-phenyl-
18,19,20-trinor PGF2a-derivatives exhibiting no ocular
irritation and only modest conjunctival/episcleral hyperemia
significantly lowered IOP in primates. It should furthermore
be observed that both 16-phenyl-17,18,19,20-tetranor-PGFa-IE,
18-phenyl-l9~2o-dinor-pGF2a-IE and 19-phenyl-20-nor-PGFa-IE
reduced the intraocular pressure, thus, modification of the
omega chain and substituting a carbon atom in the chain with
a ring structure do not render the molecule inactive with
respect to the effect on the intraocular pressure.
-21-
1339132
Furthermore, it should be observed that substituting a
hydrogen on the ring structure of 16-phenyl,17,18,19,20-
-tetranor-PGF2a-IE with a methoxy group eliminated much of
the ocular irritating effect preserving most of the intra-
ocular pressure lowering effect. Thus, omega chain modified
and ring substituted prostaglandin analogs reduce IOP
effectively in animals. It is further demonstrated in
Table V that 16-phenoxy-17,18,19,10-tetranor-PGF2a-IE
effectively lowers the intraocular pressure as studied in
cats. Thus, substituting carbon 17 in the omega chain with a
hetero atom, in this case oxygen, does not render the
molecule inactive with respect to the effect on IOP.
It is noteworthy that most of the 17-phenyl,18,19,20-trinor-
prostaglandin analogs had poor intraocular pressure lowering
effect in cats, even at high doses. It is to be observed
that the doses at which compounds were used presented in
Table III are lower than those e.g. in Table V. Doses
presented in Table III should be explicitly compared with
those of the naturally occuring prostaglandins in the same
table. The same is true for Table IV. It is clear that with
increasing dose side effects may increase. However, the
doses of prostaglandin derivatives used in monkeys are
comparatively similar to those used in human volunteers,
(Table VI) being practically free of side effects.
The effect of some omega chain modified prostaglandin
analogs, more specifically 17-phenyl-18,19,20-trinor-PGF2a-IE,
15-dehydro-17-phenyl-18,19,20-trinor-PGF2a-IE, 15-(R)-17-
phenyl-18,19,20-trinor-PGF2 -IE, 13,14-dihydro-17-phenyl-
18,19,20-trinor-PGF2a-IE, and 18-phenyl-19-20-dinor-PGF2 -IE
on the intraocular pressure of healthy human volunteers is
demonstrated in Table VI. All compounds significantly
reduced the intraocular pressure. It is particularly sig-
nificant in this respect that none of the compounds had any
significant irritating effect (ocular discomfort) and that
13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2a-IE and 15-
dehydro-17-phenyl-18,19,20-trinor-PGF2a-IE caused very
-22-
1~9132
little if any conjunctival/episcleral hyperemia in man.
Thus, omega chain modified, and ring substituted prostaglandin
analogs seem to be unique in that these compounds reduce IOP
without causing significant ocular side effects such as
hyperemia and discomfort.
The present invention thus describes a group of compounds
exhibiting the unique property of causing insignificant
ocular side effects while retaining the intraocular pressure
lowering effect. From the foregoing it is evident that the
crucial modification of the molecule is a ring structure in
the omega chain. Furthermore, substituents in the ring
structure and/or in the omega chain may be introduced in
certain molecules still exhibiting some side-effects in the
eye. Hetero atoms may also be introduced into the ring
substituted omega chain. Presently, particularly 17-phenyl-
18,19,20-trinor-PGF2 -derivatives seem very promising for
therapeutic use in glaucoma. From the scientific literature
it is evident that PGE2 and PGA2 or their esters lower IOP
in the monkey (see Bito et al, 1989). Clinical studies with
PGE2 have also been performed demonstrating IOP-lowering
effect in man (Flach and Eliason (1988)). Thus, the analogy
with PGF2a and its esters lowering IOP in the primate eye is
logic. It is most reasonable to assume that other prosta-
glandins with modified omega chain exhibit essentially the
same properties as PGF2a with modified omega chain, i.e. IOP
lowering effect without side effects.
- 22a - 13 39132
Supplementary Disclosure
Example 12: Preparation of 13,14-dihydro-15-dehydro-17-
phenyl-18,19,20-trinor PGF?~isopropyl ester
13,14-dihydro-17-phenyl-18,19,20-trinor PGF2~ isopropyl
ester contains three hydroxyl groups (on C9, C11 and
C15). Therefore selective oxidation with pyridinium
chlorochromate was impossible, and the use of a proper
protective group is necessary. The C1s-dehydro PG
analogue was synthesised from the appropriate C1-alkyl
ester by initial protection of the C9 and C11 hydroxyl
groups with 2 mol. excess phenylboronic acid (Tethr.
Lett. 31(1975) 2647-2650). The formation of the cyclic
boronate proceeds rapidly at room temperature in the
presence of activated molecular sieve to give the cyclic
9,11-boronate ester. Oxidation with pyridinium
chlorochromate adsorbed on alumina proceeds very smoothly
to give the protected C1s-keto ester, which was
deprotected and isolated by column chromatography on
silica gel.
13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2~isopropyl
ester (265 mg, 0.61 mmol) in dichloromethane (1 ml) was
added to a solution of phenylboronic acid (149 mg, 1,22
mmol) in dichloromethane (3 ml) in the presence of
activated molecular sieve 4A. The solution was allowed
to stand at room temperature for 30 min. to form the
9,11-boronate carboxylate ester. The boronate ester was
directly treated with pyridinium chlorochromate (262 mg,
1,22mmol) adsorbed on alumina (1,3 g). The mixture was
then allowed to stand at room temperature for 4 h (TLC
monitoring). The mixture was diluted with ether (20 ml),
whereafter the solid was filtered and washed with 3x10 ml
portions of ether. The combined filtrate was evaporated.
The residue was then diluted with ethyl acetate (30 ml)
and washed with sodium hydroxide 0,5 N (3x10 ml) and
water (20 ml). The organic layer was dried over (Na2SO4),
_~ ? ~
1~39132
- 22b -
and concentrated in vacuo. The residue was dissolved in
THF (10 ml) followed by addition of H202 (0,5 ml) to
remove the protecting group. Ethyl acetate
i339132
(30 ml) was added and the mixture was washed with brine
(10 ml). The organic layer was dried over sodium sulfate,
concentrated and subjected to flash column chromatography
(silicagel, ether) which gave the desired product as a
colourless oil. Yield = 53 ~.
Rf = 0,46 (silicagel, EtOAc)
H-NMR (CDC13/TMS): ~ = 1,2 (d,6H), 2,3 (t,4H), 2,5 (t,2H),
2,7 (t,2H), 2,9 (t,2H), 3,8 (m,lH), 4,2 (m,lH), 5,0 (m,lH),
5,4 (m,2H), 7,2 (m,5H)
AL-PS/pb
1990-09-18 *
133Y13~
21 ,~
The results from an experiment in which the substance 13,14-
dihydrc-15-dehydro-17-phenyl-18,19,20-trinor-P~2~-
isopropylester, from Example 12, was administered in two
healthy volunteers whereby each person received one drop of a
test formulation containing 5 ~g of the active substance
immediately after the intraocular pressure had been measure at
time Oh. The contralateral control eye received only the
vehicle. The pressure was then measured after 4, 7 and 9 hours
and the following results measured with a pulsair tonometer
were obtained. All the results are given in mmHg.
Person Eye Time after administration
Oh 4h 7h 9h
1 Exp 13.4 12.3 11.0 11.9
Contr 13.9 12.2 12.5 13.4
2 Exp 14.0 12.6 12.3 11.2
Contr 12.3 13.0 13.2 lZ.O
These results show that the substance indeed reduces the
intraocular pressure although the starting pressures (at Oh)
in these specific examples were very low. Most strikingly,
there were no side effects observed in any of the persons,
neither conjunctival hyperemia nor superficial ocular
irritation in the form of grittiness or foreign body feeLing.
TABLE I . i 3 ~ 9 13 2
~ cooc~(C~,~, ~, ~ \ ~cooc~(C~I,),
o~ \ <~3
o. 2
OH CooC~(C~ COOCH(CH,)
HO J ~ ~~ 1~\--/ \~~/ ~>
3 4
o
~J~~==, cooCH(CH,), ~, ~ COCCH(CH,~
O
OH O~- cooC~1[C~ ~,
~ ~ C H( C H ,~ O C H,
H 8
c-cc H ( c H ~ )?
,uo ~
o~
24
133913~
TABLE II.
O
11 12- 13 14
0/'~ ( Ch
,
16 17
cooc ~c~
, ~/ C:~oCH(CH,~
.. ~ /
C~
7 2
Reagents: a) DCC/DMSO/DME
b) NaH/ dimethyl-2-oxo-4-phenylbutyl phosphonate/DME
c) CeC13.7H20~NaBH4/ CH30H/ -78
d) K2CO /CH~8H
e) Dlba~/-7c" C
f) NaCH~SOCH3/
(4-carboxybutyl)-triphenylphosphonium bromide/DMSO
g) DBU/iprI/acetone
1339132
Table III. Irritative effect of naturally occuring prosta-
glandins (PGF2a, PGD2 and PGE2), and omega chain modified
analogs applied as isopropylester on the cat eye. The
avarage degree of discomfort was evaluated during 60 min
after topical application of the respective test drug. The
numbers within paranthesis refer to Table I.
Dose Degree of
Substance (~g) occular irritation
PGF2a-isopropylester (-IE) 1 3.0 + 0.0
15-propionate-PGE2-IE 0.1-1 3.0 + 0.0
15-propionate-PGD2-IE 1 1.3 + 0.2
17-phenyl-18,19,20-
trinor-PGF2a-IE (2) 1-5 0
15-dehydro-17-phenyl-
18,19,20-trinor-
PGF2 -IE (3) 5 0
15-(R)-17-phenyl-
18,19,20-trinor-PGF2a-IE (7) 1-5 0
13,14-dihydro-17-phenyl-
18,19,20-trinor-PGF2a-IE (9) 1 0
17-phenyl-18,19,20-
trinor-PGE2-IE (5) 0.3 0
13,14-dihydro-17-phenyl-
18,19,20-trinor-PGA2-IE (6) 1 0
16-phenyl-17,18,19,20-
tetranor-PGF2 -IE (1) 1 2.2 + 0.3
16-[4-(methoxy)-phenyl]-
17,18,19,20-tetranor-
2a (8) 1 0.2 + 0.1
18-phenyl-19,20-dinor-
2a (10) 1 0.7 + 0.1
henyl-2o-nor-pGF2a-IE (20) 1 0.5 + 0.1
16-phenoxy-17,18,19,20-
tetranor-PGF2a-IE (4) 5 0.3 + 0.2
-26-
13~9132
Table IV. Degree of conjunctival hyperemia in the rabbit
eye after application of naturally occuring prostaglandins
(PGF2a, and PGE2), and omega chain modified analogs applied
as isopropylesters.
Substance Dose Degree of
(,ug) hyperemia
PGF2a-isopropylester (-IE) 0.1 2.8 + 0.2
15-propionate-PGE2-IE 0.5 2.7 + 0.3
16-phenyl-17,18,19,20-
tetranor-PGF2 -IE (1) 0.5 1.3 + 0.9
17-phenyl-18,19,20-trinor-
2a (2) 0.5 2.0 + 0.3
15-dehydro-17-phenyl-
18,19,20-trinor-PGF2a-IE (3) 0.5 0.7 + 0-3
15-(R)-17-phenyl-18,19,20-
2a ( ) 2.0 + 0.0
13,14-dihydro-17-phenyl-
18~19~20-trinor-PGF2a-IE (9) 0.5 1.3 + 0.3
17-phenyl-18,19,20-trinor-
PGE2-IE (5) 0-5 2.7 + 0.2
13,14-dihydro-17-phenyl-
18,19,20-trinor-PGA2-IE (6) 0.5 0.3 + 0.3
18-phenyl-19,20-dinor-
2a (10) 0.5 0.3 + 0.2
19-phenyl-20-nor-PGF2a-IE (20) 0.5 0.2 + 0.2
16-phenoxy-17,18,19,20-
tetranor-PGF2a-IE (4) 0.5 2.3 + 0.3
i33~ 132
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28
1'339132
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-30-
1339132
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