Polar C-1 esters of prostaglandins

The present invention provides a method of treating ocular hypertension which comprises applying to the eye an amount sufficient to treat ocular hypertension of a compound of formula (I) ##STR1## wherein the wavy line attachments indicate either alpha (.alpha.) or beta (.beta.) configuration; hatched lines indicate .alpha. configuration, solid triangles are used to indicate .beta. configuration; the dashed bonds represent a single bond or a double bond which can be in the cis or trans configuration; X is selected from the group consisting of O, NH, S and NR, where R is an aliphatic hydrocarbon group of about 1 to about 6 carbon atoms; Y is a polar functional group; one of R.sub.1 and R.sub.2 is .dbd.O, --OH or a --O(CO)R.sub.4 group, and the other one is --OH or a --O(CO)R.sub.4 group or R.sub.1 is .dbd.O and R.sub.2 is is H; R.sub.3 is --OH or --O(CO)R.sub.4, wherein R.sub.4 is a saturated or unsaturated acyclic hydrocarbon group having from 1 to about 20 carbon atoms, or --(CH.sub.2).sub.n R.sub.5 wherein n is 0-10, and R.sub.5 is an aliphatic ring from about 3 to about 7 carbon atoms, or an aromatic or heteroaromatic ring; or a pharmaceutically acceptable salt thereof. Also disclosed are pharmaceutical compositions including an effective amount of the compound of formula I or a pharmaceutically-acceptable salt thereof, in admixture with a nontoxic pharmaceutical carrier and ophthalmic solutions comprising a compound of formula I packaged for metered application. Finally, novel compounds according to Formula I are disclosed.

FIELD OF THE INVENTION 
The present invention relates to polar C-1 esters of prostaglandins. More 
particularly, the present invention concerns C-1 ester derivatives of 
naturally occurring and synthetic prostaglandins bearing polar groups in 
the alcohol portion. Such compounds are potent ocular hypotensives, and 
are particularly suitable for the management of glaucoma. Due to their 
increased water solubility, they can be readily formulated in aqueous 
ophthalmic solutions. 
BACKGROUND OF THE INVENTION 
Ocular hypotensive agents are useful in the treatment of a number of 
various ocular 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) 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 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 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 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 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% 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 
.beta.-adrenoreceptor antagonists have traditionally been the drugs of 
choice for treating glaucoma. 
Prostaglandins were earlier regarded as potent ocular hypertensives; 
however, evidence accumulated in the last decade shows that some 
protaglandins are highly effective ocular hypotensive agents and are 
ideally suited for the longterm medical management of glaucoma (see, for 
example, Bito, L. Z. Biological Protection with Prostaglandins Cohen, M. 
M., ed., Boca Raton, Fla., CRC Press Inc., 1985, pp. 231-252; and Bito, L. 
Z., Applied Pharmacology 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 PGF.sub.2.alpha., PGF.sub.1.alpha., 
PGE.sub.2, and certain lipid-soluble esters, such as C.sub.1 to C.sub.5 
alkyl esters, e.g. 1-isopropyl ester, of such compounds. 
In the U.S. Pat. No. 4,599,353 certain prostaglandins and their 
derivatives, in particular PGE.sub.2 and PGF.sub.2.alpha. and the C.sub.1 
to C.sub.5 alkyl esters of the latter compound, were reported to possess 
ocular hypotensive activity and were recommended for use in glaucoma 
management. It was suggested that the C.sub.1 to C.sub.5 alkyl esters of 
PGF.sub.2.alpha., such as its methyl and isopropyl esters, would be 
particularly advantageous due to their lipid-solubility which would permit 
more ready penetration through the cornea and would lower the effective 
amounts of these compounds. 
Although the precise mechanism is not yet known, recent experimental 
results indicate that the prostaglandin-induced reduction in intraocular 
pressure results from increased uveoscleral outflow [Nilsson et al., 
Invest. Ophthalmol. Vis. Sci. 28(suppl), 284 (1987)]. 
The isopropyl ester of PGF.sub.2.alpha. 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. Ophthalmol. 
105, 1036 (1987), and Siebold et al., Prodrug 5, 3 (1989)]. However, the 
use of PGF.sub.2.alpha. 1-isopropyl ester or other C-1 alkyl esters in the 
clinical practice, is considerably limited by formulation difficulties due 
to their hydrophobic nature. Their ophthalmic formulations can only be 
made with oily carriers, such as sterile anhydrous peanut oil. 
Also, whereas prostaglandins appear to be devoid of significant intraocular 
side effects, ocular surface (conjunctival) hyperemia and foreign-body 
sensation have been consistently associated with the topical ocular use of 
such compounds, in particular PGF.sub.2.alpha. and its prodrugs, e.g. its 
1-isopropyl ester, in humans. The clinical potential of prostaglandins in 
the management of conditions associated with increased ocular pressure, 
e.g. glaucoma, is greatly limited by these side effects. 
In a series of co-pending United States patent applications assigned to 
Allergan, Inc. prostaglandin esters with increased ocular hypotensive 
activity accompanied with no or substantially reduced side-effects are 
disclosed. The co-pending U.S. Ser. No. 386,835 (filed Jul. 27, 1989), 
relates to certain 11-acyl-prostaglandins, such as 11-pivaloyl, 11-acetyl, 
11-isobutyryl, 11-valeryl, and 11-isovaleryl PGF.sub.2.alpha.. Intraocular 
pressure reducing 15-acyl prostaglandins are disclosed in the co-pending 
application U.S. Ser. No. 357,394 (filed May 25, 1989). Similarly, 11,15- 
9,15- and 9,11 -diesters of prostaglandins, for example 11,15-dipivaloyl 
PGF.sub.2.alpha. are known to have ocular hypotensive activity. See the 
co-pending patent applications U.S. Ser. Nos. 385,645, 386,312 and 386,834 
(all filed Jul. 27, 1989). PGF 1-alcohols and their use as ocular 
hypotensives are disclosed in co-pending patent application U.S. Ser. No. 
07/538,204 (filed Jun. 14, 1990). Other prostaglandin derivatives for 
ocular use are, for example, disclosed in U.S. Ser. No. 07/611,029 (filed 
Nov. 9, 1990 ), U.S. Ser. No. 07/624,659 (filed Dec. 10, 1990) and U.S. 
Ser. No. 07/623,234 (filed Dec. 6, 1990). The disclosures of these patent 
applications are hereby expressly incorporated by reference. 
SUMMARY OF THE INVENTION 
Surprisingly, it has been found that water-soluble C-1 esters of 
prostaglandin compounds exhibit essentially the same ocular hypotensive 
activity as the 1-alkyl esters of the same parent compound, and cause 
significantly lower ocular surface hyperemia. These compounds differ from 
the known C-1 alkyl esters of prostaglandins in that they carry a polar 
group which dramatically increases their water-solubility. As a result, 
they can be readily formulated in water-based solutions which greatly 
facilitates their use in glaucoma management. 
In one aspect, the present invention relates to a method of treating ocular 
hypertension which comprises applying to the eye an amount sufficient to 
treat ocular hypertension of a compound of formula (I) 
##STR2## 
wherein the wavy line attachments indicate either alpha (.alpha.) or beta 
(.beta.) configuration; hatched lines indicate .alpha. configuration, 
solid triangles are used to indicate .beta. configuration; the dashed 
bonds represent a single bond or a double bond which can be in the cis or 
trans configuration; X is selected from the group consisting of O, S and 
NR, where R is hydrogen or an aliphatic hydrocarbon group of about 1 to 
about 6 carbon atoms; Y is a polar functional group; one of R.sub.1 and 
R.sub.2 is .dbd.O, --OH or a --O(CO)R.sub.4 group, and the other one is 
--OH or a --O(CO)R.sub.4 group or R.sub.1 is .dbd.O and R.sub.2 is H; 
R.sub.3 is --OH or --O(CO)R.sub.4, wherein R.sub.4 is a saturated or 
unsaturated acyclic hydrocarbon group having from 1 to about 20 carbon 
atoms, or --(CH.sub.2).sub.n R.sub.5 wherein n is 0-10, and R.sub.5 is an 
aliphatic ring from about 3 to about 7 carbon atoms, or an aromatic or 
heteroaromatic ring, wherein said heteroatom is O, S or N; or a 
pharmaceutically acceptable salt thereof. 
In another aspect, the present invention provides a method for increasing 
the water-solubility of prostaglandin compounds by converting them into 
their polar C-1 esters, as hereinabove defined. 
In a further aspect, the present invention relates to a pharmaceutical 
composition comprising an effective amount of a compound of formula (I) as 
hereinabove defined, or a pharmaceutically acceptable salt thereof. 
In a preferred embodiment, such pharmaceutical compositions are in the form 
of ophthalmic solutions for the treatment of ocular hypertension, 
comprising an amount sufficient to treat ocular hypertension of a compound 
of formula (I) as hereinabove defined, or a pharmaceutically acceptable 
salt thereof. 
The present invention further relates to pharmaceutical products comprising 
such ophthalmic solutions in a container adapted to dispense its contents 
in metered form. 
In another aspect, the present invention relates to new polar prostaglandin 
C-1 esters of the formula (I), in which the Y polar functional group is a 
lower hydroxyalkyl or aminoalkyl group which may be optionally substituted 
in the alkyl moiety, a carboxyl or aminocarbonyl group, or a --SO.sub.3 H 
or --PO.sub.3 H group, and the other symbols and substituents are as 
hereinabove defined, and pharmaceutically acceptable salts of these 
compounds. 
DETAILED DESCRIPTION OF THE INVENTION 
The present invention relates to polar C-1 esters of prostaglandins. 
Prostaglandins can be described as derivatives of prostanoic acid which has 
the following structural formula: 
##STR3## 
Various types of prostaglandins are known, depending on the structure and 
substituents carried on the alicyclic ring of the prostanoic acid 
skeleton. Further classification is based on the number of unsaturated 
bonds in the side chains indicated by numerical subscripts after the 
generic type of prostaglandin [e.g., prostaglandin E.sub.1 (PGE.sub.1), 
prostaglandin E.sub.2 (PGE.sub.2)], and on the configuration of the 
substituents on the alicyclic ring indicated by .alpha. or .beta. [e.g. 
prostaglandin F.sub.2.alpha. (PGF.sub.2.alpha.)]. 
The prostaglandin derivatives according to the present invention are 
encompassed by the formula (I) 
##STR4## 
wherein the wavy line attachments indicate either alpha (.alpha.) or beta 
(.beta.) configuration; hatched lines indicate .alpha. configuration, 
solid triangles are used to indicate .beta. configuration; the dashed 
bonds represent a single bond or a double bond which can be in the cis or 
trans configuration; X is selected from the group consisting of O, S and 
NR, where R is hydrogen or an aliphatic hydrocarbon group of about 1 to 
about 6 carbon atoms; Y is a polar functional group; one of R.sub.1 and 
R.sub.2 is .dbd.O, --OH or a --O(CO)R.sub.4 group, and the other one is 
--OH or a --O(CO)R.sub.4 group or R.sub.1 is .dbd.O and R.sub.2 is H; 
R.sub.3 is --OH or --O(CO)R.sub.4, wherein R.sub.4 is a saturated or 
unsaturated acyclic hydrocarbon group having from 1 to about 20 carbon 
atoms, or --(CH.sub.2).sub.n R.sub.5 wherein n is 0-10, and R.sub.5 is an 
aliphatic ring from about 3 to about 7 carbon atoms, or an aromatic or 
heteroaromatic ring wherein said heteroatom is O, S or N; or a 
pharmaceutically acceptable salt thereof. 
The above formula includes C-1 polar esters of prostaglandins of the F, D, 
E, A and B series. A preferred group of the compounds of the present 
invention is encompassed by the following formula (II) 
##STR5## 
wherein R.sub.1 /R.sub.2 is --OH/--OH, .dbd.O/--OH, --OH/.dbd.O (the --OH 
groups may be esterified) and the other symbols and substituents are as 
defined hereinabove. This definition includes PGF, PGE, and PGD 
derivatives. 
Particularly preferred are the PGF.sub.2.alpha. derivatives of the formula 
(III) 
##STR6## 
and their 9- and/or 11- and/or 15-esters. 
In all of the above formulae, as well as in those provided hereinafter, the 
dotted lines on bonds between carbons 5 and 6 (C-5), between carbons 13 
and 14 (C-13), between carbons 8 and 12 (C-8), between carbons 10 and 11 
(C-10) and between carbons 17 and 18 (C-17) indicate a single or a double 
bond which can be in the cis or trans configuration. If two solid lines 
are used that indicates a specific configuration for that double bond. 
Hatched lines at positions C-9, C-11 and C-15 indicate the .alpha. 
configuration. If one were to draw the .beta. configuration, a solid 
triangular line would be used. 
The naturally occurring stereochemistry of PGF.sub.2.alpha. includes the 
C-9, C-11, and C-15 hydroxyl groups in the .alpha. configuration. In the 
compounds used in accorance with the present invention, however, 
prostaglandins having the C-9 or C-11 or C-15 substituents in .beta. 
configuration are also contemplated. As hereinabove mentioned, in all 
formulas provided herein broken line attachments to the cyclopentane ring 
indicate substituents in the .alpha. configuration. Thickened solid line 
attachments to the cyclopentane ring indicate substituents in the .alpha. 
configuration. For instance, 9.beta.-PGF compounds have the same structure 
as PGF.sub..alpha. compounds, except that the hydroxyl at the C-9 position 
is in the .beta. configuration. Also, the broken line attachment of the 
hydroxyl group or other substituent to the C-11 and C-15 carbon atoms 
signifies the .beta. configuration; therefore, compounds with the epi 
configuration for the hydroxyl group at C-15 are designated by using 
15.beta. and if there is no indication of the .beta. configuration, the 
configuration is assumed .alpha.. 
In all of the above groups preferred are compounds in which the Y polar 
functional group is a lower hydroxyalkyl or aminoalkyl group which may be 
optionally substituted in the alkyl moiety, a carboxyl or aminocarbonyl 
group, or a --SO.sub.3 H or --PO.sub.3 H group, and the other symbols and 
substituents are as hereinabove defined, and pharmaceutically acceptable 
salts of these compounds. Particularly preferred are such derivatives of 
PGF.sub.2.alpha. compounds. The optional substituents of the "alkyl" 
moiety include, for example, hydroxyl, nitro, chloro, fluoro, etc., and 
other substituents which do not affect the therapeutic utility of the 
prostaglandin derivatives of this invention. 
In the substituent definitions, the "aliphatic hydrocarbon groups" have 
from 1 to about 6, most preferably 1 to about 4 carbon atoms. The 
aliphatic hydrocarbon groups may be straight or branched chained, 
saturated or unsaturated, such as straight or branched chained alkyl, 
alkenyl, alkynyl groups. Typical representatives of the alkyl groups 
include, for example, methyl, ethyl, n- and isopropyl, n-, sec-, iso- and 
tert-butyl, n- and isopentyl, n- and neohexyl, etc. groups. Typical 
alkenyl and alkynyl groups are vinyl, allyl, propenyl, ethynyl and 
propargyl. 
The definition of R.sub.4 may include a cyclic component, 
--(CH.sub.2).sub.n R.sub.5, wherein n is 0-10, R.sub.5 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, R.sub.5 preferably is a monoaromatic, e.g., phenyl, and 
the heteroaromatic rings, which are also preferably monoaromatic, have 
oxygen, nitrogen or sulfur as a heteroatom and most preferably the 
heteroatom is sulfur, as in R.sub.5 is thienyl. Preferably n is 0-4. 
In the definition of Y, the term "polar functional group" is used in the 
broadest sense and includes any groups comprising elements with different 
electronegativities and therefore having covalent bonds of polar nature. 
The most preferred compounds are those PGF.sub.2.alpha. derivatives in 
which Y is a lower hydroxyalkyl or aminoalkyl group which may be 
optionally substituted in the alkyl moiety, a carboxyl or aminocarbonyl 
group, or a --SO.sub.3 H or --PO.sub.3 H group. 
The term "lower alkyl" alone or in combination with other moieties refers 
to alkyl groups having from one to about 6 carbon atoms. Preferred are the 
alkyl groups containing 1 to about 4, more preferably, 1 to 2 carbon 
atoms. 
Particularly preferred are the following compounds: 
PGF.sub.2.alpha. 1-(2-hydroxy)ethyl ester, 
PGF.sub.2.alpha. 1-aminocarbonylmethyl ester, and 
PGF.sub.2.alpha. 1-glycolamide. 
The compounds of the present invention can be prepared by methods known in 
the art. The synthesis of PGF.sub.2.alpha. 1-(2-hydroxy)ethyl ester and 
PGF.sub.2.alpha. 1-aminocarbonylmethyl ester is illustrated in the 
Examples and in the synthesis described in FIG. 1, where the reagents and 
reaction conditions employed are as follows: 
Reaction a: ICH.sub.2 CH.sub.2 OH, iPr.sub.2 NEt, DMF, 70.degree. C., 3 
hours; 
Reaction b: ICH.sub.2 CONH.sub.2, iPr.sub.2 NEt, DMF, 25.degree. C., 16 
hours. 
Other compounds of formula (I) can be made in an analogous manner or by 
other reactions well known in organic chemistry. 
A pharmaceutically acceptable salt is any salt which 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. Of particular interest are the acid addition 
salts of the amine compounds of the present invention. Within this group, 
ophthalmically acceptable salts are those which do not impart any 
deleterious or undesirable effect when applied to the eye. 
Pharmaceutical compositions may be prepared by combining a therapeutically 
effective amount of at least one compound according to the present 
invention, or a 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 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 vehicle. The pH of such 
ophthalmic solutions should preferably be maintained between 6.5 and 7.2 
with an appropriate buffer system, a substantially neutral pH being 
preferred. The formulations may also contain conventional, 
pharmaceutically acceptable preservatives, stabilizers and surfactants. 
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 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 opthalmically 
acceptable tonicity adjustor. 
Various buffers and means for adjusting pH may be used 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 
hydroxytoluene. 
Other excipient components which may be included in the ophthalmic 
preparations are chelating agents. The preferred chelating agent is 
edentate disodium, although other chelating agents may also be used in 
place or in conjunction with it. 
The ingredients are usually used in the following amounts: 
______________________________________ 
Ingredient Amount (% w/v) 
______________________________________ 
active ingredient about 0.001-5 
preservative 0-0.10 
vehicle 0-40 
tonicity adjustor 0-10 
buffer 0.01-10 
pH adjustor q.s. pH 4.5-7.5 
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. 
Especially preservative-free solutions are often 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 .mu.l.