Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension

This invention relates a method for topical treatment of glaucoma or ocular hypertension by administration of an effective intraocular pressure reducing amount of a prostaglandin derivative of PGA, PGB, PGE and PGF, in which the omega chain contains a ring structure. The invention further relates to compositions comprising said prostaglandin derivatives in an ophthalmologically compatible carrier.

The invention is concerned with new prostaglandin derivatives of PGA, PGB, 
PGE and PGF, in which the omega chain has been modified with the common 
feature of containing a ring structure, and their use 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 intraocular pressure is commonly known to 
be detrimental to the eye, and there are clear 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 pressure) can be 
defined as according to the formula: 
EQU IOP=P.sub.e +F.times.R 
where P.sub.e is the episcleral venous pressure, generally regarded as 
being around 9 mm Hg, F the flow of aqueous humor, and R the resistance to 
outflow of aqueous humor through the trabecular meshwork and adjacent 
tissue into Schlemm's canal. 
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: 
EQU IOP=P.sub.e +(F.sub.t -F.sub.u).times.R 
where P.sub.e and R are defined as above, Ft is the total outflow of 
aqueous humor and F.sub.u 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 intraocular pressure levels otherwise regarded as 
physiologically normal. The reason for this could be that the eye is 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; alternatively to increase the flow via the uveoscleral route 
which 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 U.S. Pat. No. 4,599,353 (Bito), U.S. Pat. No. 4,883,819 (Bito), U.S. 
Pat. No. 4,952,581 (Bito), WO89/03384 (Stjernschantz), EP 170258 (Cooper), 
EP 253094 (Goh, Yasumasa), EP 308135 (Ueno, Ryuzo) and by Bito L. Z. et al 
(1983), Camras C. B. et al (1981, 1987a, 1987b, 1988), Giuffre G. (1985), 
Kaufman P. L. (1986), Kersetter J. R. 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 PGF.sub.2.alpha. -1-isopropyl ester in the amount that would give 
maximum pressure reduction. Prostaglandins, being naturally occurring 
autacoids, are vary potent pharmacologically and effect both sensory 
nerves and smooth muscle of the blood vessels. Since the effects caused by 
administrations of PGF.sub.2.alpha. and its esters to the eye, 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 PGF.sub.2.alpha. 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, 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 
##STR1## 
wherein A represents the alicyclic ring C.sub.8 -C.sub.12 and the bonds 
between the ring and the side chains represent the various isomers. In 
PGA, PGB, PGE and PGF A has the formula 
##STR2## 
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 occurring alpha chain, which is esterified to 
the structure 
##STR3## 
in which R.sub.1 is an alkyl group, preferably with 1-10 carbon, 
especially 1-6 atoms, for instance methyl, ethyl, propyl, isopropyl, 
butyl, isobutyl, neopentyl or benzyl or a derivative giving the final 
substance equivalent properties as a glaucoma agent. The chain could 
preferably be a C.sub.6 -C.sub.10 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: 
##STR4## 
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 carbon atoms, preferably more than 2 and less than 8 
atoms, and especially less than 5 atoms. The most efficient derivatives 
found so far has a chain with 3 atoms. The chain is optionally interrupted 
by preferably not more than two hetero atoms O, S, or N, the substituents 
on each carbon atom being H, alkyl groups, preferably lower alkyl groups 
with 1-5 carbon atoms, a carbonyl group, or a hydroxyl group, whereby the 
substituent on C.sub.15 preferably being a carbonyl group, or (R)--OH or 
(S)--OH: each chain D containing preferably not more than three hydroxyl 
groups or more than three carbonyl groups, 
R.sub.2 is a ring structure such as a phenyl group which is unsubstituted 
or has one or more substituents selected from C.sub.1 -C.sub.5 alkyl 
groups, C.sub.1 -C.sub.4 alkoxy groups, trifluoromethyl groups, C.sub.1 
-C.sub.3 aliphatic acylamino groups, nitro groups, halogen atoms, and an 
phenyl group; or an aromatic heterocyclic group having 5-6 ring atoms, 
like thiazol, imidazole, pyrrolidine, thiopene 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. Some examples 
on derivatives which were evaluated are the following (for structure 
information see Table I): 
(1) 16phenyl-17,18,19,20-tetranor-PGF.sub.2.alpha. -isopropylester 
(2) 17-phenyl-18,19,20-trinor-PGF.sub.2.alpha. -isopropylester 
(3) 15-dehydro-17-phenyl-18,19,20-PGF.sub.2.alpha. -isopropylester 
(4) 16-phenoxy-17,18,19,20-trinor-PGF.sub.2.alpha. -isopropylester 
(5) 17-phenyl-18,19,20-trinor PGE.sub.2 -isopropylester 
(6) 13,14-dihydro-17-phenyl-18,19,20-trinor-PGA.sub.2 -isopropylester 
(7) 15-(R)-17-phenyl-18,19,20-trinor-PGF.sub.2.alpha. -isopropylester 
(8) 16-[4-methoxy)-phenyl]-17,18,19,20-tetranor-PGF.sub.2.alpha. 
-isopropylester 
(9) 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF.sub.2.alpha. 
-isopropylester 
(10) 18-phenyl-19,20-dinor-PGF.sub.2.alpha. -isopropylester 
(20) 19-phenyl-20-nor-PGF.sub.2.alpha. -isopropylester 
(112) 20-phenyl-PGF.sub.2.alpha. -isopropyl ester 
(113) 20-(4-phenylbutyl)-PGF.sub.2.alpha. -isopropyl ester 
(114) 17-(2-thiophene)-18,19,20-trinor-PGF.sub.2.alpha. -isopropyl ester 
(115) 17-(3-thiophene)-18,19,20-trinor-PGF.sub.2.alpha. -isopropyl ester 
(116 and 117) 17-R,S-methyl-17-phenyl-18,19,20-trinor-PGF.sub.2.alpha. 
-isopropyl ester 
(118) 17-(4-trifluoromethyl phenyl)-18,19,20-trinor-PGF.sub.2.alpha. 
-isopropyl ester 
(119) 13,14-dihydro-15-dehydro-17-phenyl-18,19,20-trinor-PGF.sub.2.alpha. 
-isopropylester 
(120) 17-(4-methylphenyl)-18,19,20-trinor-PGF.sub.2.alpha. -isopropyl ester 
(121) 17-(2-methylphenyl)-18,19,20-trinor-PGF.sub.2.alpha. -isopropyl ester 
(122) 17-(4-fluorophenyl)-18,19,20-trinor-PGF.sub.2.alpha. -isopropyl ester 
(123) 20-(methylenephenyl)-PGF.sub.2.alpha. -isopropyl ester 
(124) 17-naphthyl-18,19,20-trinor-PGF.sub.2.alpha. -isopropyl ester 
(125) 17-cyclohexyl-18,19,20-trinor-PGF.sub.2.alpha. -isopropyl ester 
(126) 17-(4-methoxyphenyl)-18,19,20-trinor-PGF.sub.2.alpha. -isopropyl 
ester 
(127) 17-(3-methoxyphenyl)-18,19,20-trinor-PGF.sub.2.alpha. -isopropyl 
ester 
(128) 15-cyclohexyl-16,17,18,19,20-pentanor-PGF.sub.2.alpha. 
-isopropylester 
The isopropyl esters have been synthesized in the examples given in this 
patent application but it should be noticed that the substances disclosed 
comprises any alkyl ester of the prostaglandin derivatives, preferably 
with 1-10 carbon atoms and especially with 1-6 atoms, for instance methyl, 
ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl or benzyl esters. 
The most preferred new 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 analogues, 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. 
These new derivatives are in general terms described as 
17-phenyl-18,19,20-trinor-PGF.sub.2.alpha. -alkyl esters, especially lower 
alkyl esters with 1-6 carbon atoms, for instance methyl, ethyl, propyl, 
isopropyl, butyl, isobutyl, neopentyl or benzyl esters. 
In the formula given above the most preferred structure at present is 
obtained when the prostaglandin is a derivative of PGA.sub.2, PGE.sub.2, 
and PGF.sub.2.alpha., 
B is a single bond or a double bond, 
D is a carbon chain with 2-5, especially 3 atoms; C.sub.15 having a 
carbonyl or (S)--OH substituent and C.sub.16 -C.sub.19 having lower alkyl 
substituents, or preferably H, 
R.sub.2 is a phenyl ring, optionally having substituents selected among 
alkyl and alkyoxy groups. 
The invention thus relates to the use of certain derivatives of PGA, PGB, 
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, that is 
intraocular pressure or hypertension lowering, and physiologically 
acceptable derivatives. So is for instance (1) 
16-phenyl-17,18,19,20-tetranor-PGF.sub.2.alpha. -isopropylester 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 comprises 
contacting an effective intraocular pressure reducing amount of a 
composition, as aforesaid, with the eye in order to reduce the eye 
pressure and to maintain said pressure on a reduced level. The composition 
contains about 0.1-30 .mu.g, especially 1-10 .mu.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 .mu.l, is administered about 1 to 2 times per 
day to the patients eye. This therapy is applicable both to human beings 
and to animals. 
The prostaglandin derivative is mixed with an opthalmologically compatible 
vehicle known per 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 opthalmologically compatible preservatives such as e.g. 
benzalkonium chloride, surfactants like e.g. polysorbate 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 opthamological compositions for topical 
treatment of glaucoma or ocular hypertension which comprise an effective 
intraocular pressure reducing amount of a prostaglandin derivative as 
defined above and an opthalmologically compatible carrier, the effective 
amount comprises a dose of about 0.1-30.mu. in about 10-50 .mu.g of the 
composition. 
In the experiments carried out in this invention the active compound, in an 
amount, varying with the potency of the drug, from 30 .mu.g to 300 
.mu.g/ml was dissolved in a sterilized aqueous solution (saline 0.9%) 
containing 0.5% polysorbate-80 as solubilizing agent.