CA2020842A1 - Intraocular pressure reducing 9,11-diacyl prostaglandins - Google Patents

Abstract

INTRAOCULAR PRESSURE REDUCING 9,11-DIACYL
PROSTAGLANDINS
Abstract of the Invention Certain 9,11-diacyl prostaglandins and their use for lower-ing intraocular pressure are disclosed herein.

Description

2~ 2 INTRAOCULAR PRESSURE REDUCING 9,11-DIACYL
PROSTAGLANDINS
Back~rnund of the Invention The present invention relates to a means tor reducing or maintaining intraocular pressure. More particularly it relates to a ~ method and composition ~or reducin~ or maTnta~ning intraocular 7 pressure involving the administration ot a composition containing a 9,11-diacyl prosta~landin in an ophthalmically acceptable carrier.
The method and compositions ot the presen~ invention are . .
particularly usetul for the management ot ~laucoma, a disease of the eye characterized by increased intraocular pressure. On the basis of its etiolo~y, ~laucoma has been classified as primary or secondary. For exampl0, primary ~laucoma in adults, con~enital glaucoma, may be either chronic open-an~le or acute or chronic an~le-closure. Secondary ~laucoma results from pre-existin~
ocular diseases ~uch as uveitis, intraocular tumor or an enlar~ed 7 cataract.
The underlyin~ causes of primary ~laucoma are not yet well : . . . .
known. The increased intraocular tension is dus to obstruction of ii~
. ~
aqueous humor outflow. In chronic open-angle ~laucoma, the anterior chamber and its anatomic structures appear normal, but draina~e of the aqueous humor is impeded. In acute and chronic an~le-closure ~laucoma, the anterior chamber is shallow, the .~
filtration an~le is narrowed and the iris may obstruct the trabecular meshwork at the entrance to the canal of Schlemm.

; ~ -~ ~ :

; ~ ~
2 ~ L 2 ~ Dilation of the pupil may push the root of the iris forward against 2 the angle or may produce pupillary block and thus precipitate an ;
acute attack. Eyes with narrow anterior chamber an~les are predisposed to acute angle-closure ~laucoma attacks ot varying de~rees of severity.
Secondary glaucoma is caused by any interference with the 7 fiow 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 ~o escape by causing complete posterior synechia in iris bombe, and may plug the draina~e channel with exudates. Other common causes are intraocular tumors, enlarged cataracts, central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage. ~ -C~ nsidering all types to~ether, ~laucoma occurs in about 2% - -of all persons over the a~e of 40 and may be asymptomatic for -~-~
years before progressin~ to rap~d loss of vision. In cases wh~re surgery is not indicated, topical B-adrenoceptor antagonists have traditionally been the drugs of choice for treating glaucoma.
Carbon!1 esters of certain prosta~landins, have been reported to possess ocular hypotensive activity. However, prosta~landin ~ ~
ocular hypotenslves genarally suf~er from the disadvantage of ~ m inducin~ conJunctival hyperemia of varying severity and duration, smartin~, and foreign body sensation, as well as presentin~

.

2 ~

solubility problems in certain ophthalmically advantaQeous carriers.
This invention relates to derivatives of the known prostaglandins tormulated in a pharmaceutically acceptable vehicle, and ophthalmic use ot those prosta~landins. The present invention is advantageous with respect to the prior art by virtue of the reduction ot the a~orementioned undesirable side etfects with retention ot ocular hypotensive activity.
Summ~aLot the Inv~QIiQ~
In accordance with one aspect ot the present invention, lhere is provided a method ot treating ocular hypertension which comprises applyin~ to the eye an amount sutticient to treate ocular hypertension ot an 9,11-diacyl prosta~landin, the compounds of formula 1.

c R~ ~ ~:
~ COA
~ ' ' .~
C
O ' ' 1 1 ` ~.
- In tormula 1, the dashed bond represents a sin~le bond or a double ~o bond which can be in the cis or trans confi~uration; A is -OH, or a 2~ 2 pharmaceutieally aceeptable salt thereof or -OR1 where R1 is lower alkyl; the two R groups ara independently an acyclic hydroearbon, saturatod or unsaturated, havin~ from 1 to 20 earbon atoms, or R is -(CH2)nR2 where n is 0-10 and R2 is an aliphatie hy-droearbon ring or an aromatie or heteroaromatie ring.
In aeeordancs w~th another aspeet of the present ~nvention, there is provided an ophthalrnically acceptable eomposition for reducin~ ocular hypertension whieh eomprises at laast one 9,11-di-aeyl prosta~landin deseribed above, present in an ophthalmieally ~ ;
aeceptable exeipient 10r topieal applieation to the surfaee ot the eye. Sueh an exeipient ~s one whieh does not have a deleterious or untoward effeet on the eye when used in normal treatment ;
regimens.
Further features and advanta~es of the present inventionwill become apparent from the detailed description of the inv~n-tion, taken to~ether with the illustrative examples.
De~ailed Descrietion of the Invention It has been discovered that certain prosta~landins low~r intraoeular pressure in man and other mammals whenl applied topically to the eye. Althou~h the precise mechanism is not y~t known, prosta~landins appear to increase aqueous humor outflow to restore a normotensive or hypotensive state. However, topical application of prosta~landins ~enerally causes side effects such as 1 6758 ;~

2~2~2 t conjunctival hyperemia, smarting and forei~n body sensation which ran~e in degree trom undes~rable to unacceptable, dependin~ upon the particular patient and dosa~e necessary to produce a sufficient pressure regulating effect.ln accordance with one aspect of the present invention, there has been provided a method for treatin~
ocular hypertension which comprises administering to the e~e a 7 compound of formula 1. It has further been dTscovered that these . esters which may be more effective than PGF2a both in terms of de~ree and duration of activity. In addition, animals treated with ~o formulations comprisin~ these esters experience si~nificantly reduced adverse side e~fects, notably ocular surface hyperemia, 12 compared to that reported for i~GF2aand PGF2a-1-isopropyl ester.
- In the foregoin~ illustration, as well as those provided hereinafter, wavy llne attachments indicate either the alpha (a) or beta (B) confi~uration. The dotted lines on bonds between carbons 5 -and 6 (C-5), betwesn carbons 13 and 14 (C-13), and between car-~7 bons 17 and 18 (C-17) indicate a sin~le or double bond which can be in the cis or trans confi~uration. If two solid lines are used at C-5, C-13, or C-17, it indicates a specific confi~uration for that double bond. Ratched lines used at position C-9, C-11 and C-15 indicate the a confi~uration. If one were to draw the B confi~uration, a solid trian~ular lin~ would be used at any of these three positions.

-The naturally occurrin~ stereochemistry o~ PGF2a includes the C-9, C-11 and C-15 position hydroxyl groups in the c~ confi~ura-tion. In the compositions of the present inv~ntion, however, esters of prosta~landins havin~ the C-9 or C-11 or C-15 hydroxyl group in the ~ con~iguration are also contemplated.
The 9,11-diacyl prosta~landins suitable for use In this invention can comprise any ot a variety of acyl substituents at the ~ -9 and 11 positions~ As per formulas 1, either R group can be an aliphatic acyclic hydrocarbon having from one to twenty carbon ~o atoms, inclusive. Preferably each R ~roup has from on~ to ten ~
Il carbon atoms. Most preferably each R ~roup is the same and is me- ~ -12 ~hyl, ethyl, propyl, butyl, pentyl, or an isomeric form thereof. The prefered isomer~c forms are the isopropyl, butyl, isobutyl, and 4 t-butyl isomers.
~Iternat~vely each R ~roup can comprise a cyclic component.
,. In particular, either R ~roup can be (CH2)nR2 where n is 0-10 and ;

17 R2 iS a saturated or unsaturated rin~, preferably a saturated ring havin~ from three to seven carbon atoms, ~nclusive, or an aromatic or h-teroaromatic ring of 5 to 7 carbon atoms, and havin~ oxy~en, nitrogen or sulfur in the case of a heteroaromatic rin~. Preferably n is 0-4.
~2 In all formulat~ons provided herein broken line attachments ~ -to the cyclopsntane rin~ indicate substituents in ths a confi~ura~

~ :

2~8~2 ~ion. Thickened solid line attachments to the cyclopentane ring indicate substituents ~n the B configuration. For instance, PGFB
compounds have the same structure as the above PGFa compounds, except that the hydroxyl at the C-9 position is ~n the B configura~
tion. Also, the broken line attachment ot the hydroxyl ~roup to the C-15 carbon atom si~nifies the a configuration; therefore, compounds with the epi confi~uration for the hydroxyl group at C-15 are designated by using 15B and if there is no indication of the B configuration, the contiguration is the a form.
The preferred compounds of this invention are those which have the followin~ structures. ~ ~-O ' ~

R
C~ OH

, ' ~ ~ ': . :

, :

-2 ~ 2 ~ 2 :
8 '~

R~ ~O, ., ~
~` W~co~ ~"'' ~ ' '"'' r~ oY~~\
~ ~OH
O

CO~

R ~ ~ , ; ~ I~ OH , ;~ ~ Wlthin this preferred group, the most preferred compounds are those~ where both R ~roups are the same and are methyl, isopro~
. , pyl, butyl, isobutyl, and L-butyl ~ ~ ' 7 Where A is -OH the qoid oan be converted to a salt O X~
' wh-re~X*is the anion component o~ any of a variety of pharmaceutica ly acceptable salts A pharmaceutically acceptable ~ ' ~ , ~ ;,,, .,, ~ , .
O salt may be prepared for any compound in this disclosure havin~ a '~
;funotion11ity oapable of formin~ suoh a salt, in particular, the ' '''-carboxylio~aoid~ group :at C1 f :the 9,11 -diacyl prosta~landins dis-olosed hereln ~A pharmaoeuiically acceptable salt is any salt which ~ ;
retains th'e~aa~vity of the parent compound and does not ~mput iany ;

1 67~8 .: ~

:: : .

2 ~ 2 deleterious or undcsirable effect on the subJect to which It is administered and in the context in which it is administered. ~;
A pharmac~utically acceptable ~alt of an acid may be derived from an organic or ~norganic base. Such a sal~ may b~ a mono- or polyvalent ion. Of particular interest are the inorganic ions, sodium, potassium, calcium, magnesium and zinc. Or~anic 7 ammonium salts may be made with amines, such as mono-, di-, and trialkyl amines or ethanol-amines. Salts may also be formed with caffeine, tromethamine and similar molecules.
In another aspect, this invention relates to a composition which can be applled topically to the eye to lower intraocular pressure. This compos~tion comprises one or more of the foregoin~ I
9,11-diacyl prosta~landins therein. The composition may comprise any of a variety of ophthalmically acceptable carriers as will be known to those skilled in the art of ocular dru~ delive~ ;. A ;~ preferred method of application would be topically, in a :~ 17 pharmaceutically acceptable topical formulation. Such a carrier may be comprised of a saline and/or deter~ent, containin~
pharmaceutically required or advanta~eous adjuvants, alon~ with an effective dose of the int~aocular pressuré reducing'dru~. ~2~ In accordance with a pref0rred embodiment of the present ~ ~;
n Tnvention, the carrier comprises a solution havin~ polysorbate 80 -:;
1 OmM TRIS in the ran~e of from about 0.05-1.0% by wei~ht, and preferably about 0.1%, which is particularly suited for 1 6758 ;
.. .

2~2Q~2 administration in the form of a liquid eye drop. This carrier may additionally compriss pharmaceutically advantageous adjuvants such as a preservative, antibiotic/antimycotic agents, pH bu~fers or osmotic balancers. In a pre~erred embodiment of the present invention, the intraocular pressure-reducing agent comprisos a . derivative of PGF2a, preferably one or a combination of the 9,1 1 -diacetyl, 9,1 1 -diisobutyryl, 9,1 1 -isovaleryl or . 9,11-dipivaloyl derivatives of PGF2a.
The optimal concentration of the prostaglandin derivative is o a function of a variety of factors, such as desired frequency of application and duration of effect, level of adverse side effects and 12 considerations implicated by the chemical nature of the carrier. In general, however, concentrations are contemplated within the range of from about 0.0001% to 1%, preferably from 0.001% to 0.1% by ~ ~
weight in relation to the pharmaceutically acce~ltable carrier.;'?''~. '' . The followin~ examples are set out to illustrate, but not limit, the scope of this invention. All temperatures are in degrees centi~rade.

Preearation ~f PGF2,~5-t-butyldimethylsilyl ether 21 PGF2a(69.6 m~, 0.197 mmol) and 1-butaneboronic acid (22 u mg, 0.22 mmol) were heated under reflux in dichloromethane (1 ml) -u for 20 min. under ar~on. The solvent was removed under reduced pressure and the residue was kept under high vaeuum tor 2 hours.
The residue from th0 preeeeding step was taken up in dry dichloromethane (0.5 ml) and eooled to 0. 2,6-Lutidin~ (69 111, 0.59 mmol) and t-bu~yldimethylsilyl tritluoromethanesulfonate (113 ~
0.49 mmol) were added with stirring. The iec bath was r~moved and ~ the solution was stirred at 25 ~or 2 hours. New bateh~s o~
7 2,6-lutidine and t-butyldimethylsilyl trifluoro-methanesulfonate were added and stirring was eontinued for a turther 5 hours. The reaetion mixture was diluted with diehloromethane and was washed with 10% citrie aeid and brine.
The or~anic layer was dried over anhydrous sodium sulfate and coneentrated inyaeuo. The residual oil was dissolved in methanol (1 ml) and s~irred for 2 hours at 25. Evaporation of solvent gave - the crude P6F2 1 5-t-butyldimethylsilyl ether.
" 1 H NMR (300 MHz, CDC13): ~O.Ol (3H, s), 0.02(3H, s), 0.86 ~6 (12H, large sin~let with si~nals underneath), 1.2-2.4 (20H, m), 3.97 , (1H, distorted quintet, J.4 Hz), 4.05 (1H, q, Js6.2 Hz), 4.19 (1H, t, J~4.5 Hz), 5.3-5.4 (2H, m), 5.40 and 5.52 ppm (2H, ABX, J.15.4, 8.4 -- and 5.9 Hz). !

- Preearation of 9.11-acetyl PGF2a ; ~ ;
The crude silyl ether prepared in Example 1 above was - -treated at 0 with pyridine (0.75 ml), acetic anhydride (~9 1ll, 0.89 ' ': `

2 ~ 2 mmol) and 4-dirnethylaminopyridine (2 mg, 0.16 mmol). The solution was stirred at 0 for 3 hours. Th~ solvents were removed in vacuQ and the r~sidue was taken up in ~thyl acetate. The organic phase was washed with 10% citric acid and brine, dried over anhydrous magnesium sul~at~ and concentrated to ~ive ~ ht yellow oil. Purification by silica gel column chromato~raphy (30%
ethyl ac~tate in hexan~s with 0.5% acetic acid as elu~nt) gave the 9,11 -diacetyl PGF2a 1 5-t butyldim~thylsilyl ether.
Thè diacetyl silyl eth~r (80 m~, 0.144 mmol) was stirred vi~ourously in 80% aqueous acetic acid (1 ml) at 25 for 14 hours.
The solvents were evaporat~d ~n ~acUQ to leav~ a colorless oil .
which was purified by column chromoto~raphy (silica gel, 35-40%
- ethyl acetate in hexanes with 0.5% acetic acid) to ~ive the 9,11-di-- acetyl ~GF2-Seectral Data:
1 H NMR (300 MHz, CDC13): ~0.85 (3H, t, J.6 Hz), 1.2-2.3 - (12H, m), 2.01 (3H, s), 2.06 (3H, s), 2.30 (2H, t, J~6.3 Hz), 2.45-2.6 (2H, m), 4.15 (1H, q, J~6 Hz), 4.89 (1H, dt, J~8, 4.5 Hz), 5.10 (1H, t, J-4.5 Hz), 5.3-5.4 (2H, ti~ht AB), 5.52 and 5.6 ppm (2H, ABX J=15, 7.7 and 5.8 Hz).
3C NMR (75 MHz, CDC13): ~13.96, 21.06, 21.17 22.56, 24.41, 24.48, 24.96, 26.22, 31.67, 32.90, 36.85, 38.88, 47.89, 51.91, 72.26, 74.05, 77.85, 127.98, 129.88, 129.93, 135.38, 170.53, 170.85 and 177.55 ppm.
IR (film): 2400-3600, 2930, 2860,1710,1430, 1370,1250, ' 1040, 1025, 970, g15 and 735 cm 1.
MS (El on 15-trimethylsilyl other mcthyl ester): mlz 524 ' (1.4, M~), 393(26), 333(100), 332(17), 314(12), 1~9(13), 117(13), 75(15) and 73(33).
7 ~Is~eL~
~a ~ rud0 silyl ~thsr pr~par~d in Exampls 1 was trea~sd at 0 with pyridin~ (0.7 ml), isobutyric anhydrid~ (135 ~I, 0.81 mmol) and 4-dim~thylaminopyridino (2 m~, 0.02 mmol). The solution was 12 stirr~d at 25 for 16 hours. Solv~nts worl3 r~moved in xa~Qand th~ residue was taken up in ethyl acetate. Th~ or~anic phas~ was washed with 10% ~!itric acid and brine~ dried ovor anhydrous maynesium sulfat~ and concentrated to give a li~ht yellow oil.
,. Purification by flash chromato~raphy (SiO2, 20% ethyl acetate/hex-17 ane) ~ave 9,11-diisobutyryl PGF2a15-t-butyldimethylsilyl e~hsr.
The diisobutyryl silyl ether (89 m~, 0.128 mmolJ was stirred vigorously in 80% aquéous acetic acid (0.3 ml) at 25 for 18 hours. Th~ solvcnts w~rs 0vaporatsd in va~uo leavin~ a colorlcss oil which was purifi~d via column chromato~raphy producin~ tho 9,11-diisobutYrYI PGF2 SPQCtCal Datgl:
2 1 H NMR (300 MHZ, CDCI3): ~ 0.85 (3H, t,J~6 HZ), 1.11 (6H, dd, J~2.8, 7.1 Hz) 1.16 ~6H d,J~7 Hz), 1.2-2.3 (1811, m), 2.4-2.6 (2H, m), 2.29 (2H, t, J-6.5 Hz~, 4.16 (1H, distort~d q, J,14 Hz), ~.92 (1H, ddd, J~4, 7.5 and 9 HZ), 5.13 (1H, ~, J-4.5 HZ), 5.3-5.45 (2H, ti~ht AB) and 5.55-5.65 ppm (2H, t;~ht AB). ~ .
7 1 3C NMR (75 MHZ, CDCI3): ~ 13.98, 18.76, 18.87, 22.55, :
24.42, 24.95, 26.16, 31.67, 32.80, 33.86, 34.22, 36.89, 39.05. 48.32, 9 5~.27, 72.21, 73.74, 127.96, 129.89, 129.94, 134.97, 176.34, 176.84 and 177.27 ppm.
IR (film): 2400-3600, 2960, 2920, 2860, 1710, 1455, 1382, ~2 1332, 1290, 1250, 1190, 1150, 1070, 1010, 965, 915, 845 and 730 " cm-1.
- MS (El on 15-trimethylsilyl ether methyl ester): m/z 581 (1, M+), 4.J1 (17), 334(26), 333(100), 332~12), 199(13), 145(12), 6 75(16), 73(37) and 71(23).

" Prspar~on of 9 11-diisolvalQrxl PGF2a Crude silyl sth6r (~52.5 m~, 0.112 mmol) prepared as per Example 1 was 1reated at 0 with pyridins (0.7 ml), isovaleric 2~ chlorid~ (34 ~î, 0.28 mmol) and 4-dim~thylaminopyridine (1.21 mg, 0.01 mmol). The solution was stirred at 0 for 6 hours. Then solvents w~re remov~d in vacuQand ~he residue was taken up in 2 ~ 2 ethyl acetat~ (5 ml). The organic phas~ was wash~d with 2 X 5 ml water, tollowed by brina and then dried over anhydrous sodium ~ sul~at~ and concsntratsd kL~L~ Puri~ication by flash 4 chromatography yielded the 9,11-diisovaleryl PGF2a 15-t-butyldimethylsilyl Hther.
Combined diisovalerate silyl ether batches as prepared abova (63 m~) wers stirred vi~orously in 80% aqu~ous acetic acid (1 ml) at 25 for 16 hours. Th~ solv~nts w~r0 ~vaporated i~va~uo and taken up in 5 ml ethyl ac~tate. Tha ethyl acetate solutlon was th~n ~o washed with 2 x 7 ml water ~ollow~d by 7 ml of brine. The ethyl acetats layer was dried over sodium sulfate and concentrated to yield th~ crude diisovaleryl derivative. It was purifi6d furth~r by revers~ phas~ thin layer chromato~raphy (7:1 CH2CI2, MeOH; 7:3 OH, H2O) to ~iv~ the 9,11-diisovaleryl PGF2.
Sesctral D ata:
. 1 H NMR (300 MHz, CDC13): ~ 0.87 (3H, partially hidden t, J=6 Hz), 0.93 (6H d, J=6.5 Hz), 0.97 (6H, d, J=6.5 Hz), 1.2-2.35 (20H m), 2.31 (2H, t, J=5.2 Hz), 2.5-2.6 (2H, m), 4.22 (1H, m), 4.96 (1H, m), 5.19 (1H, t, Js4.s Hz), 5.3-5.5 (2H, m), 5.55-5.65 ppm (2H, ti~ht AB).
3C NMR (75 MHz, CDC13): ~ 14.02, 22.35, 22.57, 24.37, 24.4S, 25.01, 25.53, 25.77, 25.89, 26.09, 31.68, 32.69, 3~.98, 39.21, 43.47, 43.69, 48.29, 52.13, 72.26, 73.81, 77.21, 77.54, 127.9~, 129,83, 129.91, 134.74, 172.54, 172.84 and 176.68 ppm.

MS (El Ofl 15-trimethylsilyl ~ther m~thyl ester): m/z ' 608(0.7, M+) 435(11), 423(11), 334(20), 333(76), 332~14), 319(18), 314(10), 199(18), 167(22), 159(19), 149(53), 129(16), 113(11), 99(13), 91(11), 85(41), 83(173, 81(21), 77(31), 75(35), 7~,(13), 73(80), 71 (37), 70(16), 69(29), 58(10), 57(100), 56(1 1) snd 55(31 ).
Tho ~oregoin~ prcedurcs can be modined to produce all the 9,11 diacyl PGF2a compounds of this inv~ntion as will be ~ appreciated by on~ of skill in the art.

,0 EXAMPLE 5 Intra~ular Press~e Reduc j~ Effect in ~.
Exporimental quantitias of the dosi~natod 9,11-diacyl prosta~landins pr6parad in accordance with tha procedurs of Exampl~ 1 4 wer~ tasted as follows. The resultin~ 9,11-diacyl PGF2a wer~ added to a polysorbate oarrier in amounts to produce a ~ 0.01%, 0.1% or 1% solut~on of each ~st~r. A ~roup o~ 8 experimental 17 rabbits was trsatsd by administarin~ approximately one drop of each solution ~o the surfaca of the eye, and intraocular pressure was measured by applanation pneumatonom~try (Model 30 RT
manufactur~d by Di~ilab) at the tima of administration and at 21 int6rvals of 2, 3, 4, 6, B or 10 hours thereafter. The followin~ data ~ were obtained:
~ .
TABLE I

2 ~

INTRAOCULAR PRESSURE DECREASES AT PREDETERMINED TiMES (HR) AFTER PROSTAGLANDIN ADMINISTRATION
Compound PG Dose/l. Time IHour R0duction in IOP (mrn H~!
4 6 ~L lQ
7 PBF2a~ isopropylO.01% ~ ~ 1.3 5.82 3.52 2 92 ~stor 0.1% . , 3.21 ~,72 10.12 10 o2 ' g,1 1-diacetyl 0.01% 2.62 3.42 3.6 5.7 PGF2a 0.1% 2.3 2.71 4.62 3.71 " 9,11-diisobutyryl 0.01% 3.12 3.62 1.81 0.1 PGF2a 0.1% 0 0.9 0 1.52 1.1 0.7 ~5 ; ~ - ~
" 9,11-diisovaleryl 0.1% 1.9 4.82 4.72 4.72 3.
7 F~F
2a :
9,11-dipivaloyl 0.1% 2.3 2.1 li.5 0 PGF2aC 1.0% 0.3 3.7 4.21 5.72 5.52 3.21 ,0 . . .
Pqrcent Animal Exhibiting Ocular Surface Hyeercmia 27i ,~, 3 4 6 8 10 2a 1-isopropylo.o1%1oo! 100 100 100 ~ 1.0% 100 100 100 100 100 87.5 2, :
9,11-diacetyl 0.01%100 100 100 20 27 PGF2a~ 0.1% 100 100 100 100 - -.

... , .; .. . .

2 ~ 2 9,11-diiso 0.01%100100 87.5 37.5 - -butyryl PGF2a 0.1%100 100 100 100 37.5 0 , 9,11-diisovaleryl 0.1%100 100 100 100 62.5 , PGF2a 9,11-dipTvaloyl 0.1% 0 0 0 0 7 PGF2 1.0%63 63 63 63 0 0 , 1 - p c 0.05; 2 - p ~0.01 ~o Alihou~h this invention has been described in terms of c~rtain preferred embodim~nts, o~h6r embodim~nts tha~ ars apparent to those of ordinary skill in the art ars also within the scope of this invention. Thsse embodiments are set out to illus-trata the invention, not to limit it.

Claims (22)

1. A method of treating ocular hypertension which comprises applying to the eye in an ophthalmically acceptable excipient an amount sufficient to treat ocular hypertension of the compound:
wherein the dashed bond represents a single bond, or a double bond which can being the cis or trans configuration; A is -OH, or a pharmaceutically acceptable salt thereof or -OR1 where R1 is lower alkyl; the two R groups are independently an acyclic hydrocarbon, saturated or unsaturated, having from 1 to 20 carbon atoms, or R is -(CH2)nR2 where n is 0-10 and R2 is an aliphatic hy-drocarbon ring, an aromatic or a heteroaromatic ring.

2. The method of claim 1 wherein the R groups are the same and are methyl, ethyl, propyl, butyl, pentyl or an isomeric form thereof.

3. The method of claim 2 where the C-5 and C-13 bonds are cis and trans double bonds respectively, the C-17 bond is a sin-gle bond, and the C-9, C-11 and C-15 substituents are in the .alpha. con-figuration the compound having the following formula:

4. The method of claim 3 where the R groups are meth-yl, the diacetyl compound.

5. The method of claim 3 where the R groups are -CH(CH3)2, the diisobutyryl compound.

6. The method of claim 3 where the R groups are -CH2CH(CH3)2, the diisovaleryl compound.

7. The method of claim 3 where the R groups are -C(CH3)3, the dipivaloyl compound.

8. The method of claim 1 where C-5 and C-17 are cis double bonds, C-13 a trans double bond, and the substituents at C-

9, C-11 and C-15 are in the .alpha. configuration, the compound of the following formula.

9. The method of claim 8 wherein the R groups are the same and are methyl, ethyl, propyl, butyl, pentyl or an isomeric form thereof.

10. The method of claim 1 where the C-5 and C-17 bonds are single bonds, the C-13 bond is a trans double bond, and the sub-stituents at C-9, C-11 and C-15 are in the a configuration, the compound of the following formula.

11. The method of claim 10 wherein the R groups are the same and are methyl, ethyl, propyl, butyl, pentyl or an isomeric form thereof.

12. An ophthalmically acceptable composition for reducing ocular hypertension which comprises an ophthalmically acceptable excipient and at least one compound of the formula:
wherein the dashed bond represents a single bond, or a double bond which can be in the cis or trans configuration; A is -OH, or a pharmaceutically acceptable salt thereof or -OR1 where R1 is lower alkyl; the two is groups are independently an acyclic hydrocarbon, saturated or unsaturated, having from 1 to 20 carbon atoms, or R is -(CH2)nR2 where n is 0-10 and R is an aliphatic hy-drocarbon ring, an aromatic or a heteroaromatic ring.

13. The composition of claim 12 wherein the R groups are the same and are methyl, ethyl, propyl, butyl, pentyl or an iso-meric form thereof.

14. The composition of claim 13 where the C-5 and C-13 bonds are cis and trans double bonds respectively, the C-17 bond is a single bond, and the substituents at C-9, C-11 and C-15 are in the a configuration, the compound having the following formula.

15. The composition of claim 14 where the R groups are methyl, the diacetyl compound.

16. The composition of claim 14 where the R groups are -CH(CH3)2.

17. The composition of claim 14 where the R groups are -CH2CH(CH3)2, the diisovaleryl compound.

18. The composition of claim 14 where the R groups are -C(CH3)3, the dipivaloyl compound.

19. The composition of claim 12 where C-5 and C-17 bonds are cis double bonds, C-13 is a trans double bond, and the substituents at C-9, C-11 and C-15 are in the .alpha. configuration, the compound of the following formula.

20. The composition of claim 19 wherein the R groups are the same and are methyl, ethyl, propyl, butyl, pentyl or an iso-meric form thereof.

21. The composition of claim 12 where the C-6 bond and the C-17 bond are single bonds, C-13 is a trans double bond, and the substituents at C-9, C-11 and C-15 are in the .alpha. configuration, the compound of the following formula.

22. The composition of claim 20 wherein the R groups are the same and are methyl, ethyl, propyl, butyl, pentyl or an iso-meric form thereof.