WO1993015732A1

WO1993015732A1 - Treatment of glaucoma

Info

Publication number: WO1993015732A1
Application number: PCT/US1993/001431
Authority: WO
Inventors: William Cash; Georg Mathis; Marc De Gasparo
Original assignee: Ciba Vision Ag, Hettlingen
Priority date: 1992-02-17
Filing date: 1993-02-17
Publication date: 1993-08-19
Also published as: ZA931063B; NO942756L; JPH07504099A; NO942756D0; AU3722493A; CA2128324A1; IL104755A0; EP0626846A1

Abstract

The present invention relates to the use of the compounds of formula (I), wherein X is (Ia), or X is (Ib), the carboxy group being linked directly to the cyclopentyl ring in the case where X = (Ia), and their salts in the preparation of pharmaceutical compositions for the treatment of glaucoma, for increasing the movement of (retinal)intra-ocular fluid, for the treatment of vasospastic constitutions of the eye and for the treatment of diabetic retinopathy, and also to corresponding ophthalmic compositions.

Description

Treatment of glaucoma

The term glaucoma covers pathological symptoms of the eye that are attributable to elevated intra-ocular pressure. Obstruction of the movement of aqueous humour often causes an increase in intra-ocular pressure. Chronically increased intra-ocular pressure has a damaging effect on the optic nerve and the retina, which can result not only in a restricted field of vision but also in blindness.

Accordingly, the search for active ingredients that are able significantly to reduce intra- ocular pressure is regarded as very important. U.S. Patent No. 5 036 048 describes angio- tensin-II antagonists as being suitable agents for the treatment of glaucoma.

Extensive pharmacological studies have shown that the compounds of the formula

(I), wherein

X is (lb), the carboxy group being linked directly

to the cyclopentyl ring in the case where X = ( ^■ and their salts are suitable to a surprising degree for reducing intra-ocuiar pressiire. This effect is achieved not only by the topical administration of the active ingredient but also by its systemic administration.

The compounds of formula (I) and their salts were also found to have a surprisingly long duration of action when used in the treatment of male albino rats, in which intra-ocular hypertension had been produced, using the glucocorticoid model.

The compounds of formula (I) or salts thereof are also distinguished by being extremely well tolerated by the eye, which can be demonstrated in a test model using rabbits' eyes. For that purpose, eye drops comprising the active ingredient in different concentrations are administered to the conjunctival sac of animals of the Himalaya type (pigmented), for example over a period of five days. Ophthalmological and ophthalmopathological examinations revealed no local or systemic intolerances.

Another surprising effect is that the compounds of formula (I) and their salts have a vaso-relaxing effect on the eye, both when administered topically and when administered systemically, and can accordingly be used in the treatment of vasospastic constitutions of the eye.

In addition, the compounds of formula (I) and their salts can be used in the treatment of diabetic retinopathy.

The compounds of formula (I) and their salts are described in the European Patent Applic¬ ation having the publication number 443 983 as angiotensin-II antagonists, in particular specifically in Examples 16 [(S)-N-(l-carboxy-2-methylprop-l-yl)-N-pentanoyl-N-[2'- ( lH-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine] and 40 fN-(2-carboxy-2.2-tetra- methylene-ethyl)-N-pentanoyl-N- f 2' -( 1 H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine] .

The present invention relates to the use of the compounds of formula (I) and their salts in the preparation of pharmaceutical compositions for the treatment of glaucoma, for increas¬ ing the movement of (retinal) intra-ocular fluid, being the aqueous humour, for the treatment of vasospastic constitutions of the eye and for the treatment of diabetic retino¬ pathy.

The present Application relates also to a method of treating glaucoma, increasing the movement of (retinal) intra-ocular fluid, treating vasospastic constitutions of the eye and treating diabetic retinopathy, which method comprises administering to patients requiring such treatment a therapeutically effective amount of a compound of formula (I) or of a pharmaceutically acceptable salt thereof.

Compounds (I) and, where appropriate, their tautomers may be in the form of salts. especially pharmaceutically acceptable salts. Because compounds (I) have, for example, at least one basic centre, they can form acid addition salts. The latter are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, a phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as unsubs- tituted or substituted, for example halo-substituted, C₁-C₄alkanecarboxylic acids, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxy- carboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, or such as benzoic acid, or with organic sulfonic acids, such as unsubstituted or substituted, for example halo-substituted, C_rC₄alkanesulfonic or arylsulfonic acids, for example methane- or p-toluene-suifonic acid. Corresponding acid addition salts can also be formed with any additional basic centre that may be present. Furthermore, compounds (I), having the acidic 5-tetrazolyl group, can form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thio- morpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl-propyl-amine, or a mono-, di- or tri-hydroxy-lower alkylamine, for example mono-, di- or tri-ethanolamine. Corresponding internal salts can also be formed.

The present Application relates also to pharmaceutical compositions for the treatment of glaucoma, for increasing the movement of (retinal) fluid, for the treatment of vasospastic constitutions of the eye and for the treatment of diabetic retinopathy, comprising a thera- peutically effective amount of a compound of formula (I) or of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable formulation agent suitable for ophthalmic and for systemic use.

Corresponding ophthalmic compositions are advantageously administered topically to the eye, especially in the form of a solution, an ointmen , a gel or a solid insert. Such compositions comprise the active ingredient, for ex _ pie, in a range of from approx¬ imately 0.01 to approximately 10.0 % by weight, preferably from approximately 0.5 to approximately 5.0 % by weight. Unit dose forms of the active ingredient comprise, for example, from approximately 0.001 to approximately 5.0 % by weight, especially from approximately 0.05 to approximately 2.0 % by weight, preferably from approximately 0.1 to approximately 1.5 % by weight, more especially from approximately 0.1 to approx- imately 1.0 % by weight, of active ingredient. The dose of the active ingredient may depend on various factors, such as mode of administration, requirement, age and/or individual condition.

There are used for corresponding ophthalmic compositions customary pharmaceutically acceptable excipients or additives known to the person skilled in the art, for example those of the type mentioned below, especially with the addition of isotonising agents, buffers, complexing agents, solubilisers and thickeners. Examples of such excipients and additives can be found in the PCT Patent Application having the publication number WO 91/15206. Such compositions are prepared in a manner known per se, for example by mixing the active ingredient with the corresponding excipients and/or additives to form corresponding ophthalmic compositions. The active ingredient is preferably administered in the form of eye drops, being dissolved especially in a sterile, aqueous isotonic solution which, if necessary, is buffered to the desired pH value.

Accordingly, the invention relates likewise to systemically administrable pharmaceutical compositions that comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient, and to a process for the preparation thereof.

Those pharmaceutical compositions are for enteral, such as oral, and also rectal or parenteral administration to warm-blooded animals, the pharmacological active ingredient being comprised on its own or together with customary pharmaceutical excipients. The pharmaceutical compositions comprise, for example, approximately from 0.1 % to 100 %, preferably from approximately 1 % to approximately 60 %, of the active ingredient. Pharmaceutical compositions for enteral or parenteral and also for ocular administration are, for example, compositions in unit dose forms, such as dragdes, tablets, capsules or suppositories, and also ampoules. Those compositions are prepared in a manner known p_er se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes. For example, pharmaceutical compositions for oral adminis¬ tration can be obtained by combining the active ingredient with solid carriers, optionally granulating a resulting mixture and, if desired, processing the mixture or granules, if necessary after the addition of suitable excipients, to form tablets or dragέe cores.

Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tri- calcium phosphate or calcium hydrogen phosphate, also binders, such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatin, gum tragacanth, methyl- cellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, such as the above- mentioned starches, also carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate. Excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and or polyethylene glycol. Dragέe cores are provided with suitable, optionally enteric, coatings, there being used, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the production of enteric coatings, solutions of suitable cellulose prepar¬ ations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Colourings or pigments may be added to the tablets or dragέe coatings, for example for identification purposes or to indicate different doses of active ingredient.

Further orally administrable pharmaceutical compositions include dry-filled capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and optionally stabilisers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilisers may likewise be added.

Suitable rectally administrable pharmaceutical compositions are, for example, suppositories that consist of a combination of the active ingredient and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols and higher alkanols. It is also possible to use gelatin rectal capsules that comprise a combination of the active ingredient and a base material. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols and paraffin hydrocarbons.

For parenteral administration there are suitable especially aqueous solutions of an active ingredient in water-soluble form, for example in the form of a water-soluble salt, and also suspensions of the active ingredient, such as corresponding oily injection suspensions, there being used suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions that comprise viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, also stabilisers.

The dose of the active ingredient may depend on various factors, such as the mode of administration, species of warm-blooded animal, age and/or individual condition.

The present Application relates also to the use of a compound of formula (I) or a pharma¬ ceutically acceptable salt thereof in the preparation of pharmaceutical compositions for the treatment of glaucoma, for increasing the movement of (retinal) intra-ocular fluid, for the treatment of vasospastic constitutions of the eye and for the treatment of diabetic retino¬ pathy.

The following Examples illustrate the invention described above; they are not, however, intended to limit the scope thereof in any way.

Formulation Examples 1, 2 and 3: A solution, comprising 20 mg of active ingredient, for example (S)-N-( 1 -carboxy-2-methylprop- 1 -y I)-N-pentanoyl-N- [2' -( 1 H-tetrazol-5-yl)- biphenyl-4-ylmethyl]-amine, can be made up as follows:

Composition:

1) active ingredient

NaOH.lN benzalkonium chloride disodium ethylenediamine tetraacetate sorbitol

Na₂HPO₂.2H₂O

K₂HPO₄ water (purity: pro inj.) ad

2) active ingredient

NaOH.lN

Macrogol 400 benzalkonium chloride

disodium ethylenediamine tetraacetate 0.50 mg sorbitol 6.00 mg

Na₂HPO₂.2H₂O 9.73 mg

K₂HPO₄ 0.43 mg water (purity: pro inj.) ad 1.00 ml

3) active ingredient 20.00 mg

NaOH.lN 86.00 mg

Polyoxyl 35 castor oil 4.00 mg benzalkonium chloride 0.10 mg disodium ethylenediamine tetraacetate 0.50 mg sorbitol 6.00 mg

Na₂HPO₂.2H₂O 9.91 mg

K₂HPO₄ 0.44 mg water (purity: pro inj.) ad 1.00 ml

For this purpose, the constituents are introduced into water and dissolved.

Formulation Examples 4 and 5 for eve drops: Vehicle:

Na₂HPO₄.12 H₂O 3.58 g

NaCl 0.29 g

H₂O 100 ml

Active ingredient:

N-(2-carboxy-2,2-tetramethylene-ethyl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)-biphenyl-

4-ylmethyl]-amine

4)

5)

A compound of formula (I) or a pharmaceutically acceptable salt thereof can be processed in an analogous manner, for example as described in the above Examples.

Claims

What is claimed is:

1. The use of a compound of formula (I)

(I), wherein

X is (lb), the carboxy group being linked directly to

the cyclopentyl ring in the case where X = (la), or a pharmaceutically acceptable salt thereof in the preparation of pharmaceutical compositions for the treatment of glaucoma, for increasing the movement of (retinal) intra-ocular fluid, for the treatment of vasospastic constitutions of the eye and for the treatment of diabetic retinopathy.

2. Th? use of the compound (S)-N-(l-carboxy-2-methylprop-l-yl)-N-pentanoyl-N-[2'- (11 . - razol-5-yl)-biphenyl-4-ylmethyl]-amine or a pharmaceutically acceptable salt theiv \ in the preparation of pharmaceutical compositions for the treatment of glaucoma, for increasing the movement of (retinal) intra-ocular fluid, for the treatment of vasospastic constitutions of the eye and for the treatment of diabetic retinopathy.

3. The use of the compound N-(2-carboxy-2,2-tetramethylene-ethyl)-N-pentanoyl-N-[2'- (lH-tetrazol-5-yl)-biphenyl-4-ylmemyl]-amine or a pharmaceutically acceptable salt thereof in the preparation of pharmaceutical compositions for the treatment of glaucoma, for increasing the movement of (retinal) intra-ocular fluid, for the treatment of vasospastic constitutions of the eye and for the treatment of diabetic retinopathy.

4. An ophthalmic composition for the treatment of glaucoma, for increasing the movement of (retinal) intra-ocular fluid, for the treatment of vasospastic constitutions of the eye and for the treatment of diabetic retinopathy, comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 or of a pharmaceutically acceptable salt thereof.

5. A systemically adminisurable composition for the treatment of glaucoma, for increasing the movement of (retinal) intra-ocular fluid, for the treatment of vasospastic constitutions of the eye and for the treatment of diabetic retinopathy, comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 or of a pharmaceut¬ ically acceptable salt thereof.

6. A method of treating hypertension, cardiac insufficiency and glaucoma, increasing the movement of (retinal) intra-ocular fluid, treating vasospastic constitutions of the eye and treating diabetic retinopathy, which method comprises administering to patients requiring such treatment a therapeutically effective amount of a compound of formula (I) according to claim 1 or of a pharmaceutically acceptable salt thereof.