JPH07504099A - Glaucoma treatment - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Glaucoma treatment The term glaucoma refers to a pathological condition of the eye that is due to increased intraocular pressure . Obstructed movement of aqueous humor often results in increased intraocular pressure. chronically Elevated intraocular pressure has a damaging effect on the optic nerve and retina, resulting in narrowed visual field. Not only that, but it is also possible that you may become blind.

Therefore, the search for active ingredients that can significantly reduce intraocular pressure is of great importance. It is considered that U.S. Patent No. 5,036,048 discloses angiotension describes H-II antagonists as drugs suitable for the treatment of glaucoma.

According to extensive pharmacological research, the formula (In the formula, X is When X is (Ia), the carboxy group is directly bonded to the cyclopentyl ring. Compounds represented by has been shown to be suitable. This effect can only be achieved by local administration of the active ingredient. Hana (also achieved by systemic administration).

Compounds of formula (I) and their salts can be prepared using the glucocorticoid model. When used to treat male white rats suffering from intraocular hypertension, the effect was surprisingly long-lasting. It was also found that there is a continuation.

The compounds of formula (I) or their salts have excellent ocular tolerance. This can be demonstrated in a rabbit eye test model. I can do it. For this purpose, eye drops containing different concentrations of the active ingredient are administered for a period of, for example, 5 days. It is administered to the conjunctival sac of Himalayan (pigmented) animals over a period of time. ophthalmological and ophthalmological Pathological examination revealed no local or systemic intolerance. Ta.

Another surprising effect is that compounds of formula (Ia) and their salts can be used locally It has a vasorelaxant effect on the eye, both when administered and when administered systemically, and therefore , can be used for the treatment of ocular vascular pain constitution.

Furthermore, the compounds of formula (Ia) and their salts are useful for the treatment of diabetic retinopathy. I can be there.

Compounds of formula (I) and their salts are disclosed in the patent publication No. 443983. As an angiotensin-II antagonist, in particular, in the patent application Example 16: [(S)-N-(1-carboxy-2-methylprob-1- yl)-N-pentanoyl-N-[2'-(IH-tetrazol-5-yl) -biphenyl-4-ylmedyl]-amine and Example 40: [N-(2-cal ruboxy-2,2-tetramethylene-ethyl)-N-pentanoyl-N-[2' -(IH-tetrazol-5-yl)-biphenyl-4-ylmethyl]-ami It is described in [

The present invention is useful for the treatment of glaucoma, increasing the movement of intraocular fluid, the aqueous humor (retina), and ocular spasticity. In the production of pharmaceutical compositions for the treatment of diabetic diathesis and diabetic retinopathy, the formula This invention relates to uses of the compounds (Ia) and their salts.

This application is for the treatment of glaucoma, increasing intraocular fluid movement (retinal), and treatment of painful diathesis of the eye. and a method for the treatment of diabetic retinopathy, the method comprising: a therapeutically effective amount of a compound of formula CI) or a pharmaceutically acceptable salt thereof. Including giving.

Compounds (1) and, where appropriate, their tautomers can be used as salts, especially pharmaceutical It may be in the form of a publicly acceptable vine salt. Compounds (I), for example, include at least Since it has one basic center, it can form acid addition salts. the latter is an inorganic strong acid such as a mineral acid, e.g. sulfuric acid, phosphoric acid or hydrohalic acid. with acids; substituted or unsubstituted, e.g. carboxylic acids, such as acetic acid, saturated or unsaturated dicarboxylic acids, such as Oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or Phthalic acid, hydroxycarboxylic acids such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid, amino acids such as asparagine acid or strong organic carboxylic acids such as glutamic acid or benzoic acid; Substituted or substituted, e.g. is an arylsulfonic acid such as methane- or p-+-luene-sulfonic acid. Any organic sulfonic acid can be used to generate the compound. The corresponding acid addition salts are , can be formed with any other basic center that may be present. moreover , Compounds (I) having an acidic 5-tetrazole group cannot form salts with bases. I can do it. Suitable salts with bases include, for example, alkali metal salts such as alkali metals. genus salts or alkaline earth metal salts, such as sodium salts, potassium salts or mag Metal salts such as nesium salts, or morpholine, thiomorpholine, piperidine , pyrrolidine, mono-, cy- or tri-lower alkylamines, such as ethyl Ru-1 tert-butyl, diethyl, diisopropyl, triethyl, tributyl mono- or dimethyl-propyl-amine; or mono-, di- or triethylamine; Droxy-lower alkylamines, such as mono-, di- or triethanol Salts with ammonia or organic amines such as amines. The corresponding internal salt also forms can be achieved.

The present application is for the treatment of glaucoma, increasing the movement of the aqueous humor (retinal) fluid.

A pharmaceutical composition for the treatment of ocular hypersensitivity and diabetic retinopathy, comprising: 1 Therapeutically effective amounts of a compound of formula (I) or a pharmaceutically acceptable salt thereof and ocular and systemic administration. It also relates to pharmaceutical compositions containing pharmaceutically acceptable formulation materials suitable for use in.

Corresponding ophthalmic compositions can be applied topically to the eye, in particular as solutions, ointments, gels or solid inserts. It is advantageous to administer. Such compositions contain the active ingredient, for example, about 0.0 In the range of 1 to about 10.0% by weight, preferably in the range of about 0.5 to 5.0% by weight Included in The unit dosage form of the active ingredient may be, for example, about 0.001 to about 5.0 wt. %, particularly from about 0.05 to about 2.0% by weight, preferably from about 0.1 to about 1.5% by weight. , and more particularly, from about 0.1 to about 1.0% by weight of active ingredient. Dosage of active ingredient depends on various factors such as dosage form, dosage requirements, age and/or individual conditions. You can change it.

Corresponding ophthalmic compositions contain the usual pharmaceutically acceptable excipients known to those skilled in the art or Additives, such as those of the following types, in particular tonicity agents, buffering agents, complexing agents, It is used with the addition of solubilizers and thickeners. Examples of such excipients and additives are , can be found in the PCT patent application with publication number WO91/15206. Ru. Such compositions can be prepared in a manner known per se, for example by combining the active ingredients with the corresponding prepared by mixing with excipients and/or additives to form the corresponding ophthalmic composition. will be built. The active ingredient is dissolved in ophthalmic solutions, especially sterile isotonic aqueous solutions, if necessary. , preferably in the form of eye drops buffered to the desired pH value.

Therefore, the present invention likewise provides compounds of formula (I) or pharmaceutically acceptable compounds thereof. The present invention relates to a systemically administrable pharmaceutical composition containing a salt as an active ingredient, and a method for producing the same.

Such pharmaceutical compositions can be administered enterally, such as orally, to warm-blooded animals, and also directly. For enteral or parenteral administration, the pharmaceutically active ingredient may be present on its own or in conventional pharmaceutical excipients. Consists of excipients. The pharmaceutical composition contains, for example, about 0.1% of the active ingredient. ~lOO%, preferably from about 1% to about 60%. Enteral or parenteral and ophthalmic Pharmaceutical compositions for administration to patients can be prepared, for example, in single units such as dragees, tablets, capsules or tablets. in single-dose form and in ampoule form. These compositions are known per se. by any conventional mixing, granulating, condensing, dissolving or lyophilizing method. Manufactured. For example, pharmaceutical compositions for oral administration combine the active ingredient with a solid carrier. Optionally, the resulting mixture is granulated and, if necessary, suitable excipients are added. After addition, the mixture or granules can be processed, if desired, to form tablet or dragee cores. to be accomplished.

Suitable carriers are in particular sugars such as lactose, sucrose, mannitol or sorbitol, cellulose formulations and/or calcium phosphates, e.g. Fillers such as acid tricalcium cum or calcium hydrogen phosphate; e.g. Starch paste made from sorghum, wheat, rice or potato starch, gelatin , gum tragacanth, methylcellulose and/or polyvinylpyrrolidone, binders such as; and, if desired, the starches mentioned above, and also carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar or alginic acid or alginic acid )・Disintegrants such as its salts such as lium. Excipients include flow control agents and Also lubricants such as silicic acid, talc, stearic acid or magnesium stearate or their salts such as calcium, and/or polyethylene glycol. Ru. The dragee core is provided with a suitable, optionally intestinal coating, inter alia beer gum, talc, polyvinylpyrrolidone, polyethylene glycol and/or a concentrated sugar solution, which may contain titanium dioxide, a suitable organic solvent or solvent. Coating solutions in vehicle mixtures or cellulose acetate phthalate to make intestinal coatings. a suitable cellulose, such as hydroxypropyl methyl cellulose or A solution of the base formulation is used. Colorants or pigments may be used, for example, for identification purposes or may be added to the tablet or dragee coating to indicate different doses of active ingredient. .

Additionally, orally administrable pharmaceutical compositions include dry-filled capsules of gelatin. cells, and seals made of gelatin and plasticizers such as glycerol or sorbitol. Contains soft capsules.

The dry-filled capsules contain the active ingredient in the form of granules, for example lactose. fillers such as, binders such as starches and/or talc or stearic acid May contain a lubricant such as magnesium, and optionally a stabilizer. . In soft capsules, the active ingredients can be added in fatty oils, paraffin oil, or liquid polyester. Preferably dissolved or suspended in a suitable liquid such as tyrene glycols, as well as stabilizers may be added to them.

Suitable rectally administrable pharmaceutical compositions include, for example, a combination of an active ingredient and a suppository base. The pressure side consists of Suitable pressure bases include, for example, natural or synthetic triglycerides. compounds, paraffinic hydrocarbons, polyethylene glycols, and higher alkano These are the rules. Also available are gelatin rectal capsules containing a combination of active ingredients and carriers. Cells may also be used. Suitable bases include, for example, liquid triglycerides, polyethylene These are lene glycols and paraffin hydrocarbons.

For parenteral administration, suitable, especially effective, water-soluble forms, such as water-soluble salts, Aqueous solutions or corresponding oily injectable suspensions of the ingredients, including oils and fats, e.g. Sesame oil, synthetic fatty acid esters such as ethyl oleate or triglyceride oleaginous injectable suspensions in which a suitable lipophilic solvent or vehicle is used, such as or thickening substances, such as sodium carboxymethylcellulose, sorbyl and/or dextran and, if desired, also stabilizers. There are suspensions of active ingredients such as liquid suspensions.

The dosage of the active ingredient depends on the mode of administration, the species of warm-blooded animal, the age and/or the individual condition. Which may vary depending on various factors.

This application applies to the treatment of glaucoma, the increase of intraocular fluid movement (retinal), and the treatment of painful diathesis of the eye. 2 Compounds of formula (I) in the manufacture of pharmaceutical compositions for the treatment of diabetic retinopathy The present invention also relates to uses of pharmaceutically acceptable salts thereof.

The following examples illustrate the invention described above but in no way limit its scope. It's not meant to be.

Formulation Examples 1.2 and 3: 20 mg of active ingredient, e.g. ruboxy-2-methylprob-1-yl)-N-pentanoyl-N-[2'- (LH-tetrazol-5-yl)-biphenyl-4-ylmethylcoamine A solution containing can be prepared as follows.

composition; Active ingredient 20.00mg NaOH, IN S6.00mg Benzalkonium chloride 0.10mg Disodium ethylenediaminetetraacetate 0.50mg Sorbitol 1. O, O Omg Naz HPO2,2H209,91mgK2 HPO40,44mg Water (purity: injection purity) total 1.00ml 1 active ingredient 20.00mg NaOH, IN S6.00mg Macrogol 400 20.00mg Benzalkonium Chloride 0. tomg Disodium ethylenediaminetetraacetate 0.50mg sorbitol 6. OOm g Nag HPO2,2H209,73mgK28PO40,43mg Water (purity: injection purity) total 1.00ml 1 active ingredient 20.00mg NaOH, IN S6.00mg Polyoxyl 35 Castor Oil 4.00mg Benzalkonium Chloride 0.10mg Ethylenediaminetetraacetic acid disodium 0.50mg Sorbitol 6.00m g Na2HPO2,2H209,91+ngK 2HP O40, 44mg Total of 1.00 ml of water (purity: injection purity) For this purpose, add the ingredients to the water and dissolved.

Formulation Examples 4 and 5 for eye drops: Vehicle: Na-HPO4,2Hi O3, 58g Active ingredients: N-(2-carboxy-2,2-tetramethylene-ethyl)-N-pentanoyl -N-[2'-(IH-tetrazol-5-yl)-biphenyl-4-ylme Chill]-amine 4) 5% active ingredient solution Vehicle 0.995m1 NaOH2N O, 015m1 Active ingredient (5%) 50ml pH=6.0 5) 0.5% active ingredient solution Vehicle 0.9ml Active ingredient (5%) 0.1ml p) (=7.0 A compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared by analogous methods, e.g. It can be processed as described in the embodiments above.

Continuation of front page (81) Designated countries EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE) , 0A (BP, BJ, CF, CG, CI, CM, GA, GN, ML, MR, SN, TD.

TG), AU, BB, BG, BR, CA, CZ, FI.

HU, JP, KP, KR, I, MG, MN, MW, NO, NZ , PL, RO, RU, SD, SK, UA, US (72) Inventor Dogi Jasparo, Marx Switzerland 2842 Ross Maison Ru Nisplanche (No. groundless)

Claims (6)

[Claims] 1. Treatment of glaucoma, increasing intraocular fluid movement (retinal), treatment of eye spasm and sugar Formula (I) in the manufacture of a pharmaceutical composition for the treatment of urinary retinopathy ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, X is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Ia) or ▲ Mathematical formulas, chemical formulas, tables, etc. etc. ▼ (Ib), and the carboxy group is when X is (Ia), directly bonded to the cyclopentyl ring) or its pharmaceutically acceptable Uses of tolerable salt. 2. Treatment of glaucoma, increasing intraocular fluid movement (retinal), treatment of eye spasm and sugar (S)-N-(1-carboxylic acid) in the manufacture of a pharmaceutical composition for the treatment of urinary retinopathy. ruboxy-2-methylbrob-1-yl)-N-bentanoyl-N-[2'-( 1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine or Pharmaceutically acceptable uses of its salts. 3. Treatment of glaucoma, increasing intraocular fluid movement (retinal), treatment of eye spasm and sugar N-(2-carboxy -2,2-tetramethylene-ethyl)-1N-pentanoyl-N-[2'-(1H -tetrazol-5-yl)monobiphenyl-4-ylmethyl]monoamine or pharmaceutical acceptable uses of the salt. 4. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof Treatment of glaucoma, increasing (retinal) intraocular fluid movement, spasmodic bodies of the eye, including in therapeutically effective amounts. Ophthalmic composition for quality treatment and treatment of diabetic retinopathy. 5. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof Treatment of glaucoma, increasing (retinal) intraocular fluid movement, spasmodic bodies of the eye, including in therapeutically effective amounts. A systemically administrable composition for the treatment of diabetic retinopathy and diabetic retinopathy. 6. Treatment of hypertension, heart failure and glaucoma, increased (retinal) intraocular fluid movement, eye spasms A method of treating diabetic retinopathy and diabetic retinopathy, the method of treating such treatment. The compound of formula (I) according to claim 1 or its pharmaceutically acceptable A method characterized in that the method comprises administering a therapeutically effective amount of a salt.