CA1038294A

CA1038294A - Method and compositions for lowering intraocular pressure

Info

Publication number: CA1038294A
Application number: CA224,543A
Authority: CA
Inventors: Romano Deghenghi; Jean M. Ferland
Original assignee: American Home Products Corp
Current assignee: Wyeth LLC
Priority date: 1975-04-14
Filing date: 1975-04-14
Publication date: 1978-09-12

Abstract

METHOD AND COMPOSITIONS FOR LOWERING INTRAOCULAR PRESSURE

Abstract of the Disclosure Intraocular pressure is lowered in mammals by derivatives of 21-amino-3.beta.-hydroxy-14.beta.,21-oxido-20-nor-5.beta.,14.beta.-cholan-23-oic acid lactam or 3.beta.,14,23-trihydroxy-24-nor-5.beta.,14.beta.-chol-20(22)-en-21-oic acid .gamma.-lactone in which the hydrogen of the 3.beta.-hydroxyl is replaced with lower alkanoyl, hexosyl, HOCO(CH2)nCO- wherein n is an integer from one to three, y+?OCO(CH2)nCO- wherein Y+ is a pharmaceutically acceptable cation and n is an integer from one to three, R3N+ OSO2-wherein R3 is lower alkyl, or alanyl or a pharmaceutically acceptable acid addition salt thereof. Ophthalmic composition in which these derivatives are the active ingredient also are disclosed.

Description

AHP-6~164 Backqround of the Invention a)- ~leld of-lnvention ~his invention relates to a method for lowerlng intra-ocular pressure in mammals by administering derivatives of norcholanic acid and to compositions of such derivatives which are useful for this purpose. Since glaucoma results from the presence of excess intraocular pressure, the method and compo-sitions of this invention are usefui for treating glaucoma.
b) Prior Art Digitalis glycosides,such as digoxin, have been used for lowering intraocular pressure; however, accompany-ing toxic effects to the eye appear to preclude the develop-ment of these agents for the treatment of glaucoma (see, for example, W.H. Havener, "Ocular Pharmacology", 2nd ed., -C.V. Mosby Co., St. Louis, Mo., U.S.A., 1970, pp. 390-392~.
.... .
~ In view of this fact it is surprising that the -~ compounds of the present invention have been found to be ; effective for lowering intraocular pressure without e'liciting such toxic effects, even on prolonged administra- -tion. Furthermore, the active compounds of this invention have the desirable property of`possessing a longer half-life than most agents presently used for lowering intra-ocular pressure, for example, pilocarpine, epinephrine :~
or norepinephrine; hence, the method of this invention allows a more reasonable frequency of instillation of the active agent than that required by presently used thera-~- peutic methods.

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~038Z94 Still furthermore, although the generally accepted explanation f 0! the effectiveness of the digitatis glycosides for lowering intraocular press~re is due their ability to inhibit the actions of sodium-potassium activated adenosine triphosphatase, a necessary enzyme for aqueous humor formation,(see Havener,cited above), the compounds of the present invention have little or no effect on this enzyme.
: . SummarY of the Invention `` , Acc,ording to one aspect of this invention intraocular pres-sure is lowered in a mammal suffering from a glaucomatous condition by a method comprising administering to said mammal an ~ effective amount of a compound of formula I or 2 .
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in which Rl and R each are selected from the group consist-ing of lower alkanoyl, hexosyl, for example glucosyl, HOCO(CH2)nC0- wherein n is an integer from one to three, Y+ OCO(CH2)nC0- wherein Y+ is a pharmaceutically acceptable cation and n is an integer from one to three, R3N+ ~OS02- wherein R3 is lower alkyl, or alanyl or a pharmaceutTcally acceptable acid addition salt thereof.

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A further aspect of this invention involves an ophthalmic composition useful for lowering intraocular , 10 pressure comprising the norcholanic acid derivative of formu~a I or 2 and an ophthalmic carrier.
Detailed DescriPtion of the Invention ~ -3 The term "lower alkyl" as used herein contemplates ;~ straight chaih alkyl radicals containing from one to six carbon atoms and branched chain alkyl radicals containing three to four carbon atoms and includes methyl, ethyl ~- propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like.
The term "lower alkanoyl" as used herein contem-,. ,j .
~- plates both straight and branched chain alkanoyl radicals - 20 containing from two to six carbon atoms and includes acetyl, : :~ . - - ......................... ..
propionyl, hexanoyl and the like.

The term "pharmacologically acceptable cation"

contemplates the cation from a suitable n~tal, ammonia or ; 3mine `~ which are known to be acceptable to a living host. Especi; 311y ~ ~ ~p~er-red metal cations are those derived from the alkali n letaIs, e.g., ..
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, sodium, lithium, and potassium, and from the alkaline earth metals, e.g., magnesium, calcium, strontium, and barium, although the cationic form of other metals, e.g., aluminum, zinc, iron, and silver, are within the scope of this invention. Pharmacologically acceptable amines can be ~ derived from primary, secondary, or tertiary amines.
; Examples of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropyl-amine, N-methylhexylamine and the like. The "pharmaceutically acceptable cation" containing salts are prepared by a variety of known methods. A convenient method involves neutralizing the acid from which it is derived with one equivalent of ' an appropriate base, for example, sodium or potassium bicarbonate, in an appropriate solvent, for example, methanol-water t2:1), and evaporating the resulting mixture.
-~ The"pharmaceutically acceptable acid addition salts"of formula I or 2 in which Rl and R2 are alanyl, respectively, are prepared by reacting the compound of formula I or 2 with ~.
substantially one equivalent or preferably with an excess of ~20 the appropriate acid in an organic solvent, for example, ether, tetrahydrofuran or an ethanol-ether mtxture. These salts, when administered to mammals, possess the same pharmacologic activities as tha corresponding compound of formula I or 2 in which Rl and R2 are alanyl, respectively.
- For many reasons it is preferable to administer the salts rather than the "free" alanate. Among the acids suitable for this purpose are hydrochloric, sulfuric, phosphoric, acetic, maleic and tartaric acids.

.

The compounds of formula I in which R is lower alkanoyl, hemisuccinoyl or hexosyl~ are described by J.M. Ferland and Y. Lefebvre, U.S. Patent No. 3,462,413, issued August 19, 1969. See also J.M. Ferland et al., Can. J. Chem., 49, 2676 (1971).

The compounds of formula 2 in which Rl is lower ; alkanoyl or hexo~y l r are described by Y. Lefebvre and J.M. Ferland in U.S. Patent No. 3,398,138, issued r~ August 20, 1968. See also, J.M. Ferland, Can. J. Chem., ~
` 10 52, 1652 (1974). ~ .

~i The compounds of formula I or 2 in which Rl and :~ 2 ;?~ R respectively are HOCO(CH2)nCO- are prepared by reacting ~ the corresponding compound of formula I or _ in which RI is ; hydrogen with an appropriate lower alkanoic anhydride ;
r and pyridine in the same manner as described for the ~ -preparation of the compound of formula I in which R is hemi- - -succinoyl (U.S. Patent No. 3,462,413, cited above). When .-~- ~ ~ prepared in this manner the compound of formula 2 in which ,A ~: 2 R is hemisuccinoyl, 3~,14,23-trihydroxy-24-nor-5~,14~-chol-20(22)-en-21-oic acid l-lactone 3-hemisuccinate, has ~ m.p. 198 - 199C.

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The compounds of formula I or 2 in which Rl and R2 respectively are R N OS02- in which R3 is lower alkyl are ~repared by the reacting the corresponding free alcohol, i.e., thP corresponding compound of formula I or 2 in which Rl and R2 are hydrogen, with the appropriate tri(lower)alkylamine -sulfur trioxide complex in an inert solvent. An example follows:
To a solution of 3~,14,23-trihydroxy-24-nor-5~,-14~-chol-20(22)-en-21-oic acid ~-lactone (1.6 9), described in U.S. Patent No. 3,389,138, cited above, in dry tetrahydro-furan (16 ml), a solution of triethylamine - sulfur trioxide `3 complex (0.8 9) in dry tetrahydrofuran (24 ml) is added : ~ .
dropwise. The solution is stirred at 20-24C for 40 minutes.

`i The resu!ting precipitate is collected and crystallized from ~-` methylene chloride-acetone to give 3~,14,23-trihydroxy-~ 24-nor-5~,143-chol-20(22)-en-21-oic acid ~lactone 3-tri-;~ ethylammonium sulfate, m.p. 196-198C.

The compounds of formula I or 2 in which Rl and R respectively are alanyl are prepared by reacting the corresponding free alcohol with a N-protected derivative - 20 of alanine acid chloride, for example, N-phthalyl-DL-alanine acid chloride, in the presence of an acid ~ ~ .

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acceptor, preferably pyridine. An example follows:
To a stirred solution at 0C of 38,14,23-tri- 1 hydroxy-24-nor-5~,143-chol-20t22)-en-21-oic acid ~lactone (1.2 9), described in U.S. Patent No. 3,389,138 cited ~
above, in pyridine (24 ml), N-phthalyl-DL-alanine acid ~ -;s chloride (2.4 9) is added. The solution is slowly warmed to room temperature t20 - 24C) and then stirred overnight. The solution is poured into ice-wate~r. The ;: resulting solid is collected, washed and dissolved in chloroform. The organic solution is washed with water, dried and evaporated to give 3~-~N-phthalyl-DL-aJanyl~
~i 14,23-dihydroxy-24-nor-5~,143-chol-20(22)-en-21-oic acid , . ` '',.
~-lactone-~ A solution of the latter compound (2.3 9) in :.,~ , .ethanol (20 ml) and hydrazine hydrate in ethanol (0.2 M, ~-27 ml) is heated at reflux for one and a balf hours. After evaporatTon of most of the ethanol, water is added to the residue and the solid collected. The solid is washed with water and dissolved in chloroform. The organic solution is washed ~; 20 with water and acetic acid solution (5~). The acidic extracts are rendered neutral with sodium bicarbonate solution.
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The resulting solid is collected, washed with water and dissolved in chloroform. The chloroform solution is dried and evaporated to dryness to give a solid which on crystalliz---' ation from methylene chloride-ether gives 3~,14,23-trihydroxy-`~ 24-nor-53,14~-chol-20(22)-en-21-oic acid l~lactone 3-alanate, ' -,?

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~W8Z94 m.p. 218 - 221C. The corresponding hydrochloric acid addition salt of the latter compound has m.p. 249 - 251C after recrystallization from methanol-methylene chloride-hexane.
The ability of the compounds of formula I or 2 of this invention to lower intraocular pressure is demonstrated by standard pharmacological tests. For example, those described by M.E. Langham and D.D. Carmel, J. Pharmacol. Exp. Therap., 163, 369 (1968) and by B. Fortenbèrry, et al., Proc. Soc. Exp. Biol. Med., 131, 637 (-1969) and references therein.
In practising the method of this invention for lowering the intraocular pressure in a mammal, an intra-ocular pressure-lowering amount of the compound of formula I or 2 - ~ -is administered to said animal. Generally the most desirable ~ results are obtained by admintstering topically to the eye a ~- `
-~ pharmaceutical composition in which the compound of formula I
or 2 is the active ingredient. Convenient topical compositlons for this purpose are those in the form-of-:~ topical ophthalmlc solutions~or ointments. -The ~

~ 20 active ingredient also is administered topically by - means of a hydrophilic contact lens previously soaked in a solution of the active ingredient. Alternatively the active ingredient is administered in the form of a solution by subconjunctival or retrobulbar injection.
A typical composition for topical application, for example, is a solution having concentrations ranging from 0.1 .~ , .

fo 20 mg, preferably 0.5 to 10 mg, of the compound of formula I

or 2, per millilitre of a pharmaceutically acceptable liquid ,..j carrier, preferably distilled water rendered isotonic by the addition thereto of sodium chloride, together with the ~, addition of phenyl mercuric acetate, 0.02 to 0.002 mg/ml, as a preservative. Compounds of formula I or 2 which are especially suitable for preparing the aforementioned topical _ g _ , ~ . ~ ' ` .

solutTons are those in which the Rl or R2, respectively, is HOCO(CH2)nC0- wherein n is t~o, R N -52- whereTn R3 is ethyl, or alanyl. ~esides distilled water other acceptable 11quid carrlers may be used; for example, tower mo1ecular -~ polyethylene glycols, for instance, 1.3-butylene glycol, ~ dtethylene glycol, dipropylene glycol and glycerol. In - instances where the compound of formula I or 2 is not sufficiently soluble in the vehicle, suspending agents are added to the formulation; for example, polyvinyl alcohol, polyvinylpyrrol7done or methylcellulose.
The compositions for topical application, such as those described above, are applied dropwise to the eye with i the frequency of instillation being individualized, usually from once daily to eight times daily or according to instructi~ons of a physician. The effective dosage usually ranges from 0.1 to 20 mg, preferably 0.5 to 5 mg, of the active ingredient per administration. Daily doses usually range from 0.1 to 100 mg, preferably I to 20 mg.
- The ingredients of the above compositions may be compounded as ophthalmic ointments. For example, the finely ~ milled active ingredient, together with a suitable preservative, and other usual adjuvants, are mixed with an acceptable j ointment base, for example, white petrolatum, wax, glyceryl monostearate or spermaceti, until a uniform distribution and :7 desired dosage form is obtained. Practical concentrations of the active ingredient in these ointments range from .
~, 0.1 to 20 mg per gram, preferably 0.5 to 10 mg per gram.Such oTntments are applied to the eye from one to eight times dai!y as required or as directed by a phvsician. Frequencv ' '1 1 0 . ~ .

~038294 of application is reduced as a decrease in intraocular pressure is noted.
Additional compositions suitable for topical ophthalmic use are described by D.L. Deardorff in - "Remington's Pharmaceutical Science", A. Osol, et al., Eds., 14th ed., Mack Publishing Company, Easton, Penn., U.S.A., 1970, pp. 1545-1577. 'Specific examples of formulation are given hereinafter. -For subconjuctival or retrobulbar injection,the compounds of formula I or 2 are dissolved or suspended in x suitable sterile liquid carriers such as distilled water, - lower molecular polyethylene glycolsj described above, or oils of synthetic, animal, petroleum or vegetable origin, for - example, soybean'oil, sesame oil, mineral oil or propylene glycol. The usual preservatives and other ingredients used for pharmaceutical preparations for parenteral dosage forms -'~
~ may also be incorporated. The concentration of the active '~ - agent in these preparations for injectable use is selected to provide a generally useful composition. A typical composition would ordinarily constitute from about 0.1 to 2% by we7ght, of the compound of formula I or 2 in a suitable sterile liquid carrier. ' -' When utilizing the compounds of formula I or 2 '-~ ....... . .
as injectable compositions for lowering intraocular .. . .
pressure the dosage may range from 0.05 to 10 mg, ~ preferably 0.1 to 1.0 mg per administration. Generally, x the injectable dose is given once a day or as directed bya physt_ian, the object being to keep the intraocular '~1 pressure at an'acceptable level.
' 30 The following examples will illustrate further ~' tnis invention.

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,' `~`` AHP-6464 ~ 1038Z94 ~ EXAMPLE I
rj The percentages in this example of composittons - for topical use refer to percent weight by volume.
`i a) Sterile ITquid composition containing Per cent ~`
21-amino-3~-hydroxy-14~,21-oxido-20-nor-5~,14~-cholan-23-oic acid lactam 3-hemisuccinate sodium salt 0.5 ~
chlorbutanol 0.5 -sodium bisulfite 0.3 , i~ boric acid 0.8 -~
~ sodium borate - O.6 - water, q.s. ad 100 ml.
b) Sterile liquld composition contalnlng Per cent 21-amino-3~-hydroxy-14~,21-oxido-20-nor-53,14~-- cholan-23-oic acid lactam 3-hemisuccinate sodium salt I.o --~
- phenyl mercuric acetate 0.002 :
sodium bisulfite 0.3 ~sodium hydroxide or hydrochlor7c acid to pH 7.2 - 7.6 - water, q.s. ad 100 ml.
- In the foregoing compositions (a) and ~b) of this ~ - example, the antioxidant, sodium bisutfite, may be varied in concentration from 0.3 to 0.03 per cent. The preservatives - chlorbutanol and phenyl mercuric acetate, as well as the -~ antioxidant, may be replaced by any preservative or anti-~ oxidant suitable for ophthalmic use. Such preservatives -~ and antioxidants are described in "Remington's Pharmaceutical Science", A. Osol, et al., Eds., 14th ~d., Mack Publishing Co., Easton, Penn.,U.S.A., 1970, pp. 1316-1319. Other suitable buffers, ;~ in place of sodium hydroxide and hydrochloric acld, and boric acid .~ .
-la- -''' . .
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103t~294 and sodium borate used above, may be substituted. Such suitable buffers are described also in the foregoing text, pp. 1553-1555.

Similar compositions for topical use may be prepared containing any of the other compounds of formula I or 2 disclosed herein.

' 3~,14,23-Trihydroxy-24-nor-5~,19~-chol-20(22)-en-21-oic acid l~lactone 3-hemisuccinate (20 9) is dissolved in 980 ml of distilled water containing 2.07 9 of sodium hydroxide, the solution is made isotonic by addition of sodium chloride or sodium citrate or glucose, a preservative such as 0.1 percent weight by volume of methylparaban and 0.015 psrcent weight by volume of propylparaban or 0.5 percent weight by volume of chlorbutanol is added, The- ` -~
.~ .
solution is made up to 1000 ml with distilled water, -. sterilized by autoclaving or sterile filtration, and filled into 2 ml ampoules or vials, to make a solution for ~-~f parenteral administration containing 20 mg/ml of the active 5~ 20 ~ ingredient.
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~b) In the same manner, but using 0.5 9 of 3f3,14, 23-;~ - trihydroxy-24-nor-53,19~-chol-20(22)-en-21-oic 2-lactone : - - - . ' ~.:
Y 3-hemisuccinate, a solution for parenteral administration - ~
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3 containing 0.5 mg/ml of the active ingredienf is obtained and is filled into 2 ml ampoules or vials.

~¢ (c) 3~,14,23-trihydroxy-24-nor-5~,19~-chol-20(22)-en-21-oic acid ~~lactone 3-hemisuccinate (20 9) is suspended in f .!

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965 9 of sesame oil and 15 9 of benzyl alcohol by means of a mechanical blender. The suspension is filled into Z ml ampoules or vials. After autoclaving, a suspension containing

2~ of the active ingredient by weight is obtained for parenteral admin;stration.
td) Again in the same manner, but using 0.225 9, 0~45 9, 2.5 g, or 10.0 9 of 3~,14,23-trihydroxy-24-nor-5~,19~-chol-20(22)-en-21-oic acid ~-lactone 3-he~isuccinate sodium salt, without additives or preservatives, -::
solutions for parenteral administration for pharmacological purposes containing 0.225 mg/ml, 0.45 mg/ml, 2~5 mg/ml, and 10.0 mg/ml of the active ingredient are obtained, respectively.

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Claims

We claim:

1. A topical ophthalmic composition comprising a topical ophthalmic carrier and a compound of formula 1 or in which R1 and R2 each are selected from the group consist-ing of lower alkanoyl, hexosyl, HOCO(CH2)mCO- wherein n is an integer from one to three, Y+ -OCO(CH2)nCO- wherein Y+ is a pharmaceutically acceptable cation and n is an integer from one to three, R3N+ -OSO2- wherein R3 is lower alkyl, or alanyl or a pharmaceutically acceptable acid addition salt thereof, the compound of formula 1 or 2 being present in a concentration ranging from 0.1 to 20 mg per ml of liquid carrier or from 0.1 to 20 mg per gram of an ointment base carrier.

2. The ophthalmic composition of Claim I in which the carrier is a liquid carrier and the compound of formula I or 2 is present in a concentration ranging from 0.1 to 20 mg per ml.

3. The ophthalmic composition of Claim 1 in which the carrier is an ophthalmic ointment base and the compound of formula I or 2 is present in a concentration ranging from 0.1 to 20 mg per gram.

4. The ophthalmic composition of Claim 1 in which the compound of formula I is the compound of formula I in which R1 is HOCO(CH2)nCO- wherein n is two, R3N+?OSO2- wherein R3 is ethyl,or alanyl.

5. The ophthalmic composition of Claim 1 in which the compound of formula 2 is the compound of formula 2 in which R1 is HOCO(2H2)nCO- wherein n is two, R3N+ ?OSO2- wherein R3 is ethyl or alanyl.