Note: Descriptions are shown in the official language in which they were submitted.
WO 95/1996.1 PCT/US95/00288
EP2-RECEPTOR AGONISTS AS AGENTS FOR LOVVERING
INTRAOCULAR PRESSURE
Field of the Invention
The present invention relates to the use of EP2 receptor
agonists to lower the intraocular pressure of mammals and
thus are useful in treating glaucoma. In particular, (~) trans-
2-[-4(1-hydroxyhexyl) phenyl]-5-oxocyclopentaneheptanoic-
acid, and ester and unsaturated derivatives thereof, are
effective for the management of glaucoma.
Background of the Invention
Ocular hypotensive. agents are useful in the treatment of
a number of various e~cular hypertensive conditions, such as
post-surgical and post-laser trabeculectomy ocular
hypertensive episodes, glaucoma, and as presurgical adjuncts.
Glaucoma is a disease of the eye characterized by
increased intraocular pressure. On the basis of its etiology,
glaucoma has been classified as primary or secondary. For
example, primary glaucoma in adults (congenital glaucoma)
2 5 may be either open-angle or acute or chronic angle-closure.
Secondary glaucoma results from pre-existing ocular diseases -
such as uveitis, intraocular tumor or an enlarged cataract.
The underlying causes of primary glaucoma are not yet
3 0 known. The increased intraocular tension is due to the
obstruction of aqueous humor outflow. In chronic open-angle
glaucoma, the anterior chamber and its anatomic structures
. appear normal, but drainage of the aqueous humor is impeded.
In acute or chronic angle-closure glaucoma, the anterior
. 3 5 chamber is shallow, the filtration angle is narrowed, and the
iris may obstruct the trabecular meshwork at the entrance of
the canal of Schlemm. Dilation of the pupil may push the root
218169
W0951199G4 ~ , PCTlUS95100288
2
of the iris forward against the angle, and may produce
pupillary block and thus precipitate an acute attack. Eyes with
narrow anterior chamber angles are predisposed to acute
angle-closure glaucoma attacks of various degrees of severity.
'
Secondary glaucoma is caused by any interference with
the flow of aqueous humor from the posterior chamber into '
the anterior chamber and subsequently, into the canal of
Schlemm. Inflammatory disease of the anterior segment may
1 0 prevent aqueous escape by causing complete posterior
synechia in iris bombe and may plug the drainage channel
with exudates. Other common causes are intraocular tumors,
enlarged cataracts, central retinal vein occlusion, trauma to the
eye, operative procedures and intraocular hemorrhage.
Considering all types together, glaucoma occurs in about
2°l0 of all persons over the age of 40 and may be asymptotic for
years before progressing to rapid loss of vision. In cases
where surgery is not indicated, topical ~i-adrenoreceptor
2 0 antagonists have traditionally been the drugs of choice for
treating glaucoma.
Prostaglandins were earlier regarded as potent ocular
hypertensives; however, ev idence accumulated in the last two
decades shows that some prostaglandins are highly effective
ocular hypotensive agents and are ideally suited for the long-
term medical management of glaucoma. (See, for example,
Starr, M.S. Ex~E_ye Res. 1971, 11, pp. 170-177; Bito, L. Z.
Biological Protection with Prosta~landins Cohen, M. M., ed.,
3 0 Boca Raton, Fla, CRC PressInc., 1985, pp. 231-252; and Bito, L.
Z., Applied Pharmacolog y in the Medical Treatment of
Glaucomas Drance, S. M. and Neufeld, A. H. eds., New York,
Grune & Stratton, 1984, pp. 477-505). Such prostaglandins _
include PGF2a, PGFla, P GE2, and certain lipid-soluble esters,
such as C1 to Cg alkyl esters,
e.g. 1-isopropyl ester, of
such '
compounds.
W095/1996.t ~ ~ PCTlUS95100288
3
In the United States Patent No. 4,599,353 certain
prostaglandins, in particular PGE2 and-PGF2a and the C1 to CS
alkyl esters of the latter compound, were reported to possess
ocular hypotensive activity and were recommended for use in
glaucoma management.
Although the precise mechanism is not yet known,
recent experimental resvults indicate that the prostaglandin-
induced reduction in intraocular pressure results from
increased uveoscleral outflow [Nilsson et al., I n v a s t .
Ophthalmol. Vis Scs ~$(suppI), 284 (1987)].
The isopropyl ester of PGF2a has been shown to have
significantly greater hypotensive potency than the parent
compound, which was attributed to its more effective
penetration through the cornea. In 1987 this compound was
described as "the most potent ocular hypotensive agent ever
reported." [See, for example, Bito, L. Z., Arch. Onhthalmol ~,
1036 (1987), and Siebold et al., Prodrue ~, 3 (1989)].
Whereas prostaglandins appear to be devoid of
significant intraocular side effects, ocular surface
(conjunctival) hyperemia and foreign-body sensation have
2 5 been consistently associated with the topical ocular use of such
compounds, in particular PGF2a and its prodrugs, e.g. its (-
isopropyl ester, in humans. The clinical potential of
prostaglandins in the management of conditions associated
with increased ocular pressure, e.g. glaucoma, is greatly
3 0 limited by these side effects.
Certain phenyl and phenoxy mono, tri and tetra nor
prostaglandins and their 1-esters are disclosed in European
. Patent Application 0,364,417 as useful in the treatment of
3 5 glaucoma or ocular hypertension.
CA 02181569 2005-02-22
WO 9$!19964 PCT/US95l00288
4
Finally, certain EP2-receptor agonists are disclosed in
Nials et al, Cardiovascular Drug Reviews, Vol. 11, No. 2, pp.
165-179, Coleman et al, Comprehensive Medicinal Chemistry,
Vol. 3, pp. 643-714, 1990 and Woodward et al, Prostaglandins.,
pp. 371-383, 1993.
Summary of the Tnvention
We have found that certain EP2-receptor agonists are
potent ocular hypotens~ve agents. We have further found that
traps-2-[-4(1-hydroxyhexyl) phenyl]-5-
oxocyclopentaneheptanoicacid, and ester and unsaturated
derivatives thereof, are especially useful in the treatment of
glaucoma and surprisingly, cause no or significantly lower
ocular surface hyperemia than the other compounds that are
useful in lowering intraocular pressure, e.g. PGF2a and lower
alkyl esters thereof.
W 0 95119964 PCT/US95/00288
S
The present invention relates to methods of treating
ocular hypertension which comprises administering an
effective amount of a compound represented by the formula I
,O
OR
OH
wherein, the wavy bands indicate the a or (3 configuration, R is
a saturated or unsaturated acyclic hydrocarbon group having
1 0 from I to about 20 carbon atoms, or -(CH2)mR 1 wherein m is
0-10, and RI is an aliphatic ring having from about 3 to about
7 carbon atoms, or an aryl or heteroaryl ring having from
about 4 to about 10 carbon atoms, e.g. R1 may be cyclohexyl,
phenyl, thienyl, pyridyl or furanyl, or a pharmaceutically
1 5 acceptable salt thereof and the dashed bond represents either
a single or double bond which may be in the cis or trans
position. Preferably R1 is lower alkyl.
More preferably the method of the present invention
20 comprises administering a compound represented by the
formula II
WO 95/1996.1 ~ ~ ~ ~ ~ ~ ~ ~ PCTlUS95100288
., ° 6
OR2
OH
wherein R2 is a lower alkyl radical and the other symbols are
as defined above.
In a further aspect, the present invention relates to
pharmaceutical compositions comprising a therapeutically
effective amount of a compound of formulae (I) or (II)
wherein the symbols have the above meanings, or a
pharmaceutically acceptable salt thereof in admixture with a
non-toxic, pharmaceutically acceptable liquid vehicle.
In a still further aspect, the present invention relates to
certain (t) trans-2-[-4(1-hydroxyhexyl) phenyl]-5-oxocyclo-
1 S pentaneheptanoicacid, and ester and unsaturated derivatives
thereof, of the above formulae, wherein the substituents and
symbols are as defined hereinabove, or a pharmaceutically
acceptable salt of such compounds.
W0 95It9964 PCT/US95100288
Detailed Description of the Invention
The present invention relates to the use of (t) traps-2-[-
4(1-hydroxyhexyl) phenyl]-5-oxocyclopentaneheptanoic- acid,
' S and ester and unsaturated derivatives thereof, as ocular
hypotensives. These therapeutic agents are represented by
compounds having the formula I
n
OR
OH
as defined above. The preferred compounds used in
accordance with the present invention are encompassed by the
following structural formula II
WO 95/19964 ~ ~ PCT/US95I00288
8
.O . ~,
OR2
OH
wherein R2 is a lower alkyl radical.
In all of the above formulae,as well
as in
those
provided
hereinafter, the straight lines Where there
represent bonds. is
no symbol for the atoms between the bonds,the appropriate
carbon-containing inferred. For example
radical is to be in
formula I, the radical between cyclopentylring and the
the
OR
O
radical is a polymethylene (CH2) radical, i.e. a hexylenyl
radical. The dotted lines on the bond between carbons 5 and 6
(C-5), indicate a single or a double bond which can be in the
cis or trans configuration. The radical adjacent the double
bond is a CH radical. If two solid lines are used that indicates a
specific configuration for that double bond. Hatched lines at
positions C-9 and C-I1 indicate the a configuration. If one
2 0 were to draw the (3 configuration, a solid triangular line would
be used.
W0 95119961 PCT/U595/00288
9
In the compounds used in accordance with the present
invention, compounds having the C-9 or C-11 substituents in
the a or (i configuration are contemplated. As hereinabove
mentioned, in all formulas provided herein broken line
attachments to the cyclopentane ring indicate substituents in
the a configuration. Thickened solid line attachments to the
cyclopentane ring indicate substituents in the (i configuration.
For the purpose of this invention, unless further
limited,
the term "alkyl" refers
to alkyl groups having
from one to ten
carbon atoms and includes
"lower alkyl" radicals
having from
one to five carbon atoms, the term "cycloalkyl" refers
to
cycloalkyl groups having
from three to seven carbon
atoms,
the term "aryl" refers to aryl groups having from four to
ten
carbon atoms. The term "saturated or unsaturated acyclic
hydrocarbon group" i s used to refer to straight or branched
chain, saturated or unsaturated hydrocarbon groups having
from one to about 6, preferably one to about 4 carbon
atoms.
Such groups include alkyl, alkenyl and alkynyl groups
of
2 0 appropriate lengths, and preferably are alkyl, e.g. methyl,
ethyl, propyl, butyl, pentyl, or hexyl, or an isomeric
form
thereof.
'The definition of R may include a cyclic component,
-(CH~)I"R1, wherein m is 0-10, RZ is an aliphatic ring from
about 3 to about 7 carbon atoms, or an aromatic or
heteroaromatic ring. The "aliphatic ring" may be saturated or
unsaturated, and preferably is a saturated ring having 3-7
carbon atoms, inclusive. As an aromatic ring, Rl preferably is
3 0 phenyl, and the heteroaromatic rings have oxygen, nitrogen or
sulfur as a heteroatom, i.e., Rl may be thienyl, furanyl, pyridyl,
etc. Preferably m is 0-4.
Preferred representatives of the compounds within the
3 5 scope of the present invention are (~) trans-2-[-4(1-
hydroxyhexyl)phenyl]-5-oxocyclopentaneheptanoicacid,
WO 951199G.i ~ ~ ~ ~ ~ ~ ~ - ' - PCTlUS95100288
unsaturated derivatives thereof, and lower alkyl esters of
Lhese compounds.
The following compound m~~y be used in the
5 pharmaceutical compositions , and the methods of treatment of
., .
the present invention are''(+_) trans-2-[-4(1-hydroxyhexyl)
phenyl]-5-oxocyclopentaneheptanoicacid.
A pharmaceutically acceptable salt is any salt which
10 retains the activity of the parent compound and does not
impart any deleterious or undesirable effect on the subject to
whom it is administered and in the context in which it is
administered. Such salts are those formed with
pharmaceutically acceptable canons, e.g., alkali metals, alkali
earth metals, etc.
Pharmaceutical compositions may be prepared by
combining a therapeutically effective amount of at least one
compound according to the present invention, or a
2 0 pharmaceutically acceptable salt thereof, as an active
ingredient, with conventional ophthalmically acceptable
pharmaceutical excipients, and by preparation of unit dosage
forms suitable for topical ocular use. The therapeutically
efficient amount typically is between about 0.0001 and about
2 5 5% (w/v), preferably about 0.001 to about 1.0% (w/v) in liquid
formulations.
For ophthalmic application, preferably solutions are
prepared using a physiological saline solution as a major
3 0 vehicle. The pH of such ophthalmic solutions should
preferably be maintained between 4.5 and 8.0 with an
appropriate buffer system, a neutral pH being preferred but
not essential. The formulations may also contain conventional,
pharmaceutically acceptable preservatives, stabilizers and
3 5 surfactants.
CA 02181569 2005-02-22
WO 95/19964 PCTIUS95/00288
11
Preferred preservatives that may be used in the
pharmaceutical compositions of the present invention include,
but are not limited to, benzalkonium chloride, chlorobutanol,
thimerosal, phenylmercuric acetate and phenylmercuric
nitrate. A preferred surfactant is, for example, Tween 80.
Likewise, various preferred vehicles may be used in the
ophthalmic preparations of the present invention. These
vehicles include, but are not limited to, polyvinyl alcohol,
povidone, hydroxypropyl methyl cellulose, poloxamers,
carboxymethyl cellulose, hydroxyethyl cellulose cyclodextrin
and purified water.
Tonicity adjustors may be added as needed or
convenient. They include, but are not limited to, salts,
particularly sodium chloride, potassium chloride, mannitol and
glycerin, or any other suitable ophthalmically acceptable
tonicity adjustor.
Various buffers and means for adjusting pH may be used
2 0 so long as the resulting preparation is ophthalmically
acceptable. Accordingly, buffers include acetate buffers,
citrate buffers, phosphate buffers and borate buffers. Acids or
bases may be used to adjust the pH of these formulations as
needed.
In a similar vein, an ophthalmically acceptable
antioxidant for use in the present invention includes, but is not
limited to, sodium metabisulfite, sodium thiosulfate,
acetylcysteine, butylated hydroxyanisole and butylated
3 0 hydroxytoluene. '
Other excipient components which may be included in
the ophthalmic preparations are chelating agents. The
preferred chelatiz~g agent is edentate disodium, although other
3 5 chelating agents may also be used in place of or in conjunction
with it.
* Trade-mark
WO 951199G.~ ~" ~, PCTIUS95100288
12
The ingredients are usually used in the following
amounts:
>~gredient Amount f% w/vl
active ingredientabout 0.001-5
preservative 0-0.10
vehicle 0-40 --
tonicity adjustor0-1,0:;
buffer 0.01-10
pH adjustor q.s. pH 4.5-8.0
antioxidant as needed
surfactant as needed
purified water as needed to make
100%
The actual dose of the active compounds of the present
invention depends on the specific compound, and on the
condition to be treated; the selection of the appropriate dose is
well within the knowledge of the skilled artisan.
The ophthalmic formulations of the present invention
are conveniently packaged in forms suitable for metered
application, such as in containers equipped with a dropper, to
facilitate application to the eye. Containers suitable for
dropwise application are usually made of suitable inert, non-
toxic plastic material, and generally contain between about 0.5
and about 15 ml solution. One package may contain one or
more unit doses.
Especially preservative-free solutions are often
2 0 formulated in non-resealable containers containing up to about
ten, preferably up to about five units doses, where a typical
unit dose is from one to about 8 drops, preferably one to about
3 drops. The volume of one drop usually is about 20-35 p 1.
2 5 The invention is further illustrated by the following non-
Iimiting Examples.
W0 95l199G4 PCT1U595/00288
13
Exam In a 1
(~) TRANS-2-[-4(1-HYDROXYHEXYL) PHENYL]-5
OXOCYCLO- PENTANEHEPTANOICACID AND LOWER
S ALKS'L ESTERS THEREOF
The above acid compound is well known and may be
purchased or synthesized by methods known in the art. The
lower alkyl esters of this compound may be made by the
esterification procedures described in the various patent
applications described in the Background of the Invention.
Intraocular pressure was measured by
pneumatonometry in normal monkeys. Studies were
performed in conscious animals trained to accept
pneumatonometry. The compound of Example 1 was
2 0 administered topically to one eye in a 25 p l volume drop, the
contralateral eye received vehicle as a control. Statistical
analysis was by Student's paired t test.
The intraocular pressure results are summarized in
2 5 Table 1.
35
W095/199G-t ~ ~ PCT/US95100288
14
TABLE 1. EFFECT OF (~) TRANS-2-[-4(1-
HYDROXYHEXYL) PHENYL]-S-OXOCYCLO PENTANE
HEPTANOIC ACID, 0.1%, B.LD. ON THE INTRAOCULAR '
PRESSURE OF NORMAL MONKEYS
TIME(HR) RELATIVE TO NET CHANGE IN
FIRST DOSE PRESSURE(MMHg~
0
2 -1.17
4 -2.0
6 -1.50
24 -0.67
1 26 -1.0
5
28 -1.83
30 -1.50
48 -1.50
50 -2.33
2 52 -1.50
0
54 -1.50
72 -2.33
74 -2.17
76 -2.33
2 78 -2.0
S
96 -1.83
98 -2.0
100 -2.0
102 -2.0
(all changes in intraocular pressure are significant p < 0.01 according
to Students t test)
Example 3
3 5 Intraocular Pressure Reduction After Laser Treatment
Intraocular pressure reduction was also achieved in laser-
induced ocular hypertensive monkeys. Ocular hypertension
was induced by photocoagulating the trabecular meshwork by
circumferential argon laser treatment.
45
CA 02181569 2005-02-22
WO 95/19964 PCTNS95100288
TABLE 2. EFFECT OF A SINGLE DOSE (0.1%) OF TRANS-
2-[-4(1-HYDROXYHEXYL)PHENYL]-5-OXO-
5 CYCLOPENTANEHEPTANOIC ACID ON OCULAR PRESSURE
ON LASER-INDUCED OCULAR HYPERTENSIVE MONKEYS
TIME (HR) RELATIVE CHANGE IN INTRA-
TO FIRST DOSE OCULAR PRESSURE (MMHg)
10 0 0
1 -4.5
2 -6.0**
4 -4.7**
6 -4.5
* p < 0.05
** p < 0.01 (Students t test)
xa ple 4
2 0 Determination of EPZ Receptor Activity
E P 2 receptor activity may be measured in accordance
with the procedure disclosed in Woodward et al,
Prostaglandins, pp. 371-383, 1993.
The foregoing description details specific methods and
compositions that can be employed to practice the present
invention, and represents the best mode contemplated.
3 0 However, it is apparent from one of ordinary skill in the art
that different pharmaceutical compositions may be prepared
and used with substantially the same results. That is other
EP2-receptor agonists, such as 19R(OH)PGE2, butaprost, etc.
will effectively lower intraocular pressure in animals and are
3 5 within the broad scope of the present invention.
