Use of angiostatic steroids in the manufacture of a medicament for controlling ocular hypertension.

PATENT OF INVENTION

No. 92 123

APPLICANT: ALCON LABORATORIES, INC. North American, Industrial, established at 6201 South Freeway, Fort Worth, Texas 76134-2099, United States of America.

EPÍGRAFE: ·· COMPOSITION PREPARATION PROCESS

TO CONTROL EYE HYPERTENSION WITH ANGIOSTATIC STEROIDS ”

INVENTORS: Abbot F.Clark.

Claim of right of priority under Article 4 of the Paris Convention of 20 March 1883.

United States of America on 31 October 1988 under number^? 264,918.

INPI Moo. 113 RF 1C732 q

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ALCON LABORATORIES PROCESS FOR

Η Ocular IPERTENSION

INC.

PREPARATION OF ANGIOSTATIC STEROID COMPOSITIONS

CONTROL THE

DESCRIPTIVE MEMORY

Light

The present invention relates to a process for the preparation of pharmaceutical compositions containing angiostatic steroids for use in the control of ocular hypertension and methods for their use in the treatment of ocular hypertension, including the control of primary open-angle qlaucoma-associated ocular hypertension.

Said process is comprised in said compositions of 0.00.3.3 percent by weight of a compound of the formula:

<img file="PT92123B_D0002.tif" />

wherein R1 is β-CH-, or β-CH3 Hc-; R1 is, for example, H or -Cl; R1 is, for example, = □ or -OH; R 'is H, CH', Cl or Fq R 'is H, OH, F, Cl, 4' r. · 'U

Br, CH3, phenyl, vinyl or allyl; R2 is H or CH3; R4 is H, OH, CH3, C (R).

F or ~ CH_?; R₁₀ H, OH, CH3, or R2 forms a second bond between the C-16 and C-17 positions; is -H or forms a double bond with R_J4; --H, -OH, -0, -Ό-P (0) (OH)₇ , or -0-C (-0) - (CH_OWhere t is an integer from 2 to 6; R 4 is H or forms a double bond with R_jr&gt;; R_J5 is ~ O or -OH; and, for example, R 4 with R 6 forms a cyclic phosphate as indicated by Formula II.

Invention Basics

Invention Field

This invention relates to methods and compositions for controlling ocular hypertension. Specifically, the invention is directed to pharmaceutical compositions comprising angiostatic steroids and methods of treatment comprising administering such compositions in the treatment of ocular hypertension, including the control of ocular hypertension associated with primary open-angle glaucoma.

Related Technique Description

Steroids that function to inhibit angiogenesis in the presence of heparin or specific heparin fragments are presented in Crum, et al., A New Class of Steroids Inhibits

First, Science, Vol. 230, pp 1375-1378 (December 20, 1985). The authors refer to these steroids as “angiostatic steroids. Included in the new class of steroids that have been found to be angiostatic are the dihydro and tetrahydro metabolites of cortisol and cortexolone. In a continuing study directed at testing a hypothesis regarding the mechanism by which steroids inhibit angiogenesis, heparin / angiostatic steroid compositions were found to lead to dissolution of the basal membrane supporting α. which attachment-dependent endotheliums are attached resulting in capillary involution; See, Ingber, et al., A Possible Mechanism has been Inhibition of Anxiety by Anqiostatic Steroids; Inducti.on of Cappilary Basement

Hembrane Dissolution, Endocrinology 118, pp. 1768-1775 (1886).

A group of tetrahydro steroids useful in inhibiting angiogenesis is set forth in International Patent Application No. PCT / US6S / 02139, Ariscoff, et al. (The Upjohn Company). The compounds are presented for use in the treatment of head injuries, vertebral (spine) injuries, septic or traumatic shock, stroke and hemorrhagic shock. In addition, the patent application discusses the usefulness of these compounds in embryonic implantation and in the treatment of cancer, arthritis and arteriosclerosis. The compounds are not presented for ophthalmic use.

Tetrahydrocortiso1 (THF) has been presented for its use to lower intraocular pressure (IOP) of rabbits rendered hypertensive with dexamethasone. alone, or with dexamethasone / 5-beta-dihydrochloride; see Southren, et al. Intraocular Effect of a Topically Applied Metabolite Cortisol:

3-alpha., 5-beta-tetrahydrocortisol, Investigative Ophthalmol Diggy and Visual Science, Vol. 23 (May, 1937). The authors suggest that THF may be useful as an antig1aucoma agent. European Patent Application Publication No. 250,033, Southren, et al., Discloses THF-containing pharmaceutical compositions and a method for using these compositions for controlling eye pressure. THF has been presented as an antagonist steroid in Folkman, et al., Anqiostatic Steroids, Ann. Surg., Vol. 206, No. 3 (1937) in which it is suggested that angiostatic steroids may potentially be used for dominated diseases; by abnormal vascularization, including diabetic retinopathy, neovascular glaucoma, and retro1enticular fibroplasia.

by a graph that steroid-induced tetrahydrocortexone1Brief Description of the Drawing A single drawing is shown illustrating the IOP which lowers the efficacy of (THS) on rabbits with ocular hypertension.

Summary of the invention comprising useful for, particularly, primary.

This invention is directed to angiostatic steroid compositions and steroid metabolites controlling ocular hypertension, and the compositions are useful in the treatment of open angle glaucoma.

Further the invention includes methods for controlling ocular hypertension by topically administering compositions herein.

Detailed Description of Preferred Presentations

The development of blood vessels for the purpose of viable support tissue is known as angiogenesis. Agents that inhibit angiogenesis are known by a number of terms such as angiostatic, angiolitic or anthiotropic agents. For purposes of this specification, the term angiostatic agent means compounds that may be used to inhibit angiogenesis.

The angiostatic agents of the present invention are steroids or steroid metabolites. As used herein, the term angiostatic steroids means steroids and steroid metabolites that inhibit angiogenesis. The present invention is based on the discovery that angiostatic steroids can be used is&gt;

to control eye hypertension. In particular, the agents may be used for the treatment of primary open angle qlaucoma.

Agents that may be used in accordance with the present invention comprise angiostatic steroids. Angiostatic steroids that may be used will typically comprise the angiostatic steroids in PCT / US31 / 02189 having the following formula:

<img file="PT92123B_D0003.tif" />

-DC (= 0) (C₁-Ç_go, wherein R1 is fl-CH-, or fl-CUr-JL

R1 is H or -Cl;

R1 is H, = O, -OH, -0-C1 -C4 alkyl,

-OC (= O) ARIL, -OC (= O) N (R) ^, or -OC (00) 0R-., Where ARYL is thienyl, pyrrolyl, or pyridyl and each is optionally substituted with one. said or two alkyl, furyl, halves (C 1) groups at 1 chi 1, or ARYL is - (CH_? ) wherein phenyl is 0 to 2 and the phenyl ring is optionally substituted with those selected from chloro, fluoro, bromo, guppo;

at 1 chi (C -C_T) (C1 -C4) alkoxy, thioalkoxy (C1 -C4), C1, C-, F, C-, -WH

R is hydrogen, (C1 -C4) alkyl, and -NHCOCH, e or phenyl and each R may be the same or different, and R? â € ƒâ € ƒâ € ƒis ARYL as defined herein, or (C1 -C10) at 1µl;

or

<td colspan="2">where R '_no and R, taken positions C-9 and C-11; or</td><td>together are</td><td>oxygen</td><td> &lt; -0-)</td><td>1iqando</td>

<td>in</td><td>that Rn&gt; and R, taken in</td><td>set form</td><td>a duo</td><td>1 igation</td><td>en t.rie</td>

<td>at</td><td>positions C-9 and 0-11;</td><td></td><td></td><td></td><td></td>

<td>or</td><td>R_O is uF and R_T is β-ΟΗ;</td><td></td><td></td><td></td><td></td>

<td>or</td><td>R_O is u-Cl and R is β-Cl;</td><td></td><td></td><td></td><td></td>

<td>and F</td><td>&lt;is H, CH1, Cl or F;</td><td></td><td></td><td></td><td></td>

<td>R ^ u</td><td>is Η, 0H, F, Cl, Br, CH</td><td>,, phenyl, vinyl</td><td>or allyl</td><td></td><td></td>

<td>^R6</td><td>is H or CH2;</td><td></td><td></td><td></td><td></td>

<td>^R9</td><td>is Η, 0H, CH ,, F or CH_</td><td> 1</td><td></td><td></td><td></td>

1Θ

H, OH, CH, or

R form one. second link between a;

positions C-16 and C-17;

-H or forms a double bond with R

Rj- is H, -OH, = 0,

-0-P (0) &lt;0H),., Or -0-C (= 0&gt; - &lt;CH₇ &gt; _tC00H where t is an integer from 2 to 6;

R1 is H or forms a double bond with R2;

R, cr is 00 or -OH;

oe R_no- with R 2 forms an x ​​· if 1V cyclic phosphate as indicated by

Formula II; where R &lt;? and Rp or wherein R is as defined above;

du -0-C (= 0) is -ΌΗ, OC (^ O) -R₁₁, —0P (0) - (0H), which t

- (CH₇)_tC00H at Y- (CHnJ -X- (CH „) -SO ^ H, an integer -Y of (CH„&gt; -X - (CH „) -NR ,, R ,, 2 ρ, 2 q 16 17 or

-Z (CH 3,), wherein Y is a bond or -0; Y is a -0-, du

-S-; each of X and X is a bond, -CONCR ^) -,

-Ν (β'ιθ) ΟΟ-, -0-, -3-, -3 (0) -, or -SCO) -; R4 is hydrogen or (C1 -C4) alkyl; each of R 1 and R 4 is a lower alkyl group of 1 to 4 carbon atoms optionally substituted by a hydroxyl or R 1 and R 2 taken together with the L 1 / nitrogen atom to which each of them is. is attached form a monocyclic heterocyclic selected from pyrrolidine, piperidino, morpholino, thiomorpholino, piperazine or N-lower alkyl) piperino wherein alkyl has from 1 to 4 carbon atoms; n is an integer from 4 to 9; m is an integer from 1 to 5; an integer from 2 to 9; q is an integer from 1 to 5;

Z is a bond or -0-; r is an integer from 2 to 9; and D is one of the following:

(1) -R₁₉-CH_OWhere R is -S-, -SCO) -, -SCD) ^ -,

-S0_ON (R_O^) -, or N (R₀₀ ) S0₇-; and R1, θ is hydrogen or (C1 -C4) lower alkyl; provided that the total number of carbon atoms in R ^_ft and &lt;CH_r,) is not more than 10; or (2) -C0-C00H; or (3) CONCR.-,₁ Wherein R1 is H and R1 is H, CH-, -CH-, COOH, -CH-, CH-, COOH, -CH-, ΟΗ, CH-, SH, -CH-, CH-, SCH2 or -CH-, Ph-OH wherein Ph-OH is p-hydroxyphenyl;

or R₇₁ is CHt and R1 is H;

or R- | and R-η, - taken together are -CH-.CH-.CH -, -;

or -NCR-.j) CHC R -.-.) COOH taken together is -NHCH-.CONHCH-.COOH; and pharmaceutically acceptable salts thereof;

with the proviso that except for the compound wherein R3 is -CH3, R3, and R3 taken together form a double bond between positions 9 and 11, R3 and R6 are hydrogen, R3 -, and R ^g taken together form a double bond between positions 4 and 5, F α is α-F, R ^ is R-CH-, Rj α is α-OH, R ^ -, and R-j are e. R_Q-, is -0P C 0) - C0H-,) - ,, is = 0 only when Rcom R ^^^weapon Cyclic phosphate described above.

Except for the compounds of Formula I are compound 3.11 (3,17,4,21-tetrahydro: i-5-pregnane-2 '-one (the 3-alpha, 5-beta; 5-alpha; 3-beta, 5-alpha; and 3-beta, 5-beta of tetrahydrocortiso1) wherein:

R._ç is = 0; R,. is OH; lo 10

R is CH-; R_. is β OH; R_O is H;

R is H; R1 is a or (3 OH; R1 is H;

10 14

R · is u or PH; F:_ç is H; R is H; R_The is H and is OH.

Unless otherwise specified, all substituent groups attached The cyclopenta phenanthrene moiety of Formula I may be in the alpha or beta position. Additionally, the foregoing structures include all pharmaceutically acceptable salts of the aniostatic steroids.

Preferred anglostatic steroids are:

<img file="PT92123B_D0004.tif" />

H

Tetrahydrocortexolone (THF) and its pharmaceutically acceptable salts;

<img file="PT92123B_D0005.tif" />

OH

4,9 (11) -pregnadien 17a, 21-diol-3,20-dione and its pharmaceutically acceptable salts;

<img file="PT92123B_D0006.tif" />

6a-fluoro-17a, 2'-dihydro-i-15yl-methyl-prequin-4,9 (11) diene-3,20-dione and its pharmaceutically acceptable salts.

Without wishing to be bound by any theory, it is believed that anthiostatic steroids of the type previously described act to control intraocular pressure by inhibiting the accumulation or stimulation of dissolution of amorphous extracellular material in the trabecular network of the eye. The presence of this amorphous extracellular material alters the integrity of the healthy traboular network and is a symptom associated with primary open-angle glaucoma (GAAF '). The reason why this amorphous extracellular material forms in the trabecular network of people suffering from GGAP is not well understood. However, amorphous extracellular material has been found to consist generally of glycosaminoglycans (GAGs) and basement membrane material; see, Ophthalmoloqy. Vol. 90, No.7 (July 1993); Mayo Clin Proc, Vol. 61, pp 59-67 (Jan.1968); and Pediat, Neurosis. Vol. 12, pp. 240-251 (1995-96).

When these materials form in the trabecular meshwork, aqueous humor, usually present in the anterior chamber of the eye, cannot leave this chamber through its normal pathway (the trabecular meshwork) at its normal rate. Thus, a normal volume of aqueous humor is produced by the ciliary processes of the eye and is introduced into the anterior chamber, but exits through the abnormally slow trabecular meshwork. This results in the formation of inner eye pressure, ocular hypertension, which can give rise to pressure on the optic nerve. The ocular hypertension thus generated can lead to blindness due to optic nerve damage.

it's on a

Many methods for the treatment of primary open angle glaucoma and coronary artery disease. Eye hypertension focuses on blocking the production of aqueous humor by the eye. However, aqueous humor is the primary source of augmentation to the tissues of the eye, particularly the cornea and creatine, which are not maintained by the blood supply. Thus, it is not desirable to deprive these tissues of the necessary irrigation and nutrition provided by aqueous humor - it is desirable to strive hard for a way out.

normal aqueous humor maintaining the normal integrity of the trabecular network. This is achieved in accordance with the present invention by the administration of aniostatic steroids.

The aniostatic steroids presented herein are believed to function in the trabecular network in a manner similar to that indicated by Ingber, et al. , in which angiostatic steroids are shown to lead to dissolution of the supporting basement membrane using a chick embryo neovascularization model; Encocrinoloqy, 119, pp. 1763-1775 (1986). Angiostatic steroids of the present invention are believed to prevent the accumulation, or promote dissolution of, ex trace 1u materials. 1 Amorphous air in the trabecular meshwork inhibiting the formation of basement membrane and qicosicosaminoids. Thus, by preventing the development of these materials or promoting their dissolution, the normal integrity of the trabecular meshwork is maintained and aqueous humor flows through the trabecular meshwork at a normal rate. Consequently, intraocular pressure of the eye is controlled.

Angiostatic steroids of the present invention may be incorporated into various formulations for administration to the eye. For example, topical formulations may be used which may include pharmaceutically acceptable preservatives, surfactants, viscosity enhancers, buffers, sodium chloride and water to form sterile aqueous ophthalmic solutions and suspensions. In order to prepare sterile ophthalmic unquent formulations, an angiostatic steroid is combined with a preservative in an appropriate carrier such as mineral oil, liquid lanolin or white petrolatum. Sterile ophthalmic gel formulations comprising the angiostatic steroids of the present invention may be prepared by suspending an angiostatic steroid on a hydrophilic base prepared from a combination of, for example, Carbopol-940 (a carboxyvinyl polymer supplied by

BF Goodrich Company) according to published formulations for analog ophthalmic preparations. Condoms and tonicity agents may also be incorporated into such gel formulations.

The specific type of formulations selected will depend upon a number of factors, such as the angiostatic steroid or salt thereof to be used, and the frequency of dosing. Solutions, aqueous suspensions, ointments and topical ophthalmic gels are the preferred dosage forms. The angiostatic steroid will normally be contained in these formulations in an amount ranging from about 0.005 to about 2.0 weight percent (p.7). Preferably the concentrations range from about 0.05 to about 1.0 ρ „Z. Thus, for topical administration, these formulations are administered to the eye surface one to four times daily, depending on the routine decision of the experienced clinician. .

Example 1

The following formulation illustrates a topical ophthalmic composition which may be used in accordance with the present invention.

<td colspan="2">Component</td><td>P. Z</td>

<td>THS</td><td></td><td>0.005 to 2.0</td>

<td>T i 1 oxa po 1</td><td></td><td>0.01 to 0.05</td>

<td>Chloride of</td><td>BenzaIconio</td><td> 0,0 1</td>

<td>Chloride of</td><td>Sodium</td><td>0, B</td>

<td>Edetate of</td><td>Disodium</td><td> 0,0 1</td>

NaDH / HCl pH 7.4

Purified Water 1 ml

It has been found that ocular hypertension can be triggered in young rabbits by topical application of a potent glucocorticoid; to see. Experimental Eye Research. 27: 567 (1778); Investigative Qphta1mo1oqy and Visual Science, 26: 1073 (1785); or by a combination of glucocorticoid and cortisol dihydrocortisol metabolite; see, Investigative Qphtalmology and Visual Science, Vol. 26 (March, 1785). It has also been found that ocular injections of glucocorticoids also induce ocular hypertension in rabbits; see, J. Ocular Pharmacology, 3: 185-187 (1787). This eye-injected rabbit model was used to test the effect of the angiostatic steroid tetrahydrocortexolone (THS) on ocular hypertension. New Zealand red rabbits weighing approximately 1 kg were given weekly injections of Subtenon dexamethasone acetate and 5- (5-dihydrocortisol) in two quadrants of each eye (approximately 1 mg dexamethasone acetate and 5 (5-dihyd. tiso 1 / kg body weight / week) Intraocular pressures were measured weekly with the application of an Alcon pneumotonometer Each group contained 4-5 animals. After two weeks of steroid treatment, IOP was increased by 5 mmz'Hg. Half of the animals were then injected with Subtenon THS (approximately 3 mg / kg body weight / week) in addition to 1 mg / kg body weight / week of dexamethasone / 5- [5-dihydrocortisol]. The other half continued to receive dexamethasone / 5- (5-dihydrocortisol injections of approximately 1 mg / kg body weight / week).

Fig. 1 illustrates the effect of IOP drop caused by the angiostatic steroid, THS, in rabbits with glucocorticoid-induced ocular hypertension described above. The plots indicate mean IOP data of the animals over a four week period. After four weeks, the group receiving THS in addition to dexamethasone / 5R-dihydrocortisol (Q - ΕΞ -) had a decrease of approximately 4 mm Hg in the IOP compared with the control group (-Q-0-). which received dexamethasone acetate / SB-dihydrocortisol. These results indicate that the angiostatic steroid, THS, is effective in lowering intraocular pressure in rabbits with steroid induced ocular hypertension.

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