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WO1993015717A1 - Compositions de traitement du glaucome - Google Patents

Compositions de traitement du glaucome Download PDF

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Publication number
WO1993015717A1
WO1993015717A1 PCT/US1993/001432 US9301432W WO9315717A1 WO 1993015717 A1 WO1993015717 A1 WO 1993015717A1 US 9301432 W US9301432 W US 9301432W WO 9315717 A1 WO9315717 A1 WO 9315717A1
Authority
WO
WIPO (PCT)
Prior art keywords
treatment
hydroxy
tetrazol
butyl
ylmethyl
Prior art date
Application number
PCT/US1993/001432
Other languages
English (en)
Inventor
Peter Herold
William Cash
Georg Mathis
Marc De Gasparo
Original Assignee
Ciba-Geigy Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ciba-Geigy Ag filed Critical Ciba-Geigy Ag
Publication of WO1993015717A1 publication Critical patent/WO1993015717A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim

Definitions

  • compositions for the treatment of glaucoma are provided.
  • 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.
  • U.S. Patent No. 5 036 048 describes angio- tensin-II antagonists as being suitable agents for the treatment of glaucoma.
  • the compound of formula (I) and its salts can be used in the treatment of diabetic retinopathy.
  • the present invention relates to the use of the compound 2,6-di-n-butyl-4-hydroxy-5-(2'- tetrazol-5-ylbiphenyl-4-ylmethyl)-pyrimidine or a pharmaceutically acceptable salt thereof in the preparation of pharmaceutical compositions for the treatment of glaucoma, for increasing the flow 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 flow 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 2,6-di-n-butyl-4-hydroxy- (2'-tetrazol- 5-ylbiphenyl-4-ylmethyl)-pyrimidine or of a pharmaceutically acceptable salt thereof.
  • Compound (I) may be in the form of a proton tautomer. Accordingly, hereinbefore and hereinafter, compound (I) is to be understood as being also the corresponding tautomeric form, where appropriate.
  • Compound (I) and, where appropriate, its tautomers may be in the form of salts, especially pharmaceutically acceptable salts.
  • compound (I) has, for example, at least one basic centre, it can form acid addition salts.
  • the latter are formed, for example, with strong inorganic acid' , such as mineral acids, for example sulfuric acid, a phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as unsubstituted or substituted, for example halo-substituted, C 1 -C 4 alkanecarboxylic 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 hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, or such as be
  • Corresponding acid addition salts can also be formed with any additional basic centre that may be present.
  • compound (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, thiomorpholine, piperidine, pyrrol- idine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diiso- propyl-, 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.
  • An especially preferred salt of compound (I) is the choline salt of the formula
  • the present Application relates also to that salt, its preparation and use and also to pharmaceutical compositions comprising that salt.
  • the salt (IA) is distinguished from the free acid of formula (I) and from other salts in that it exhibits surprisingly advantageous physical properties.
  • the choline salt (I) in question has advant ⁇ ageous physical properties, such as an unexpectedly high degree of water-solubility, and it also exhibits significantly better solubility in other polar solvents. Accordingly, this salt is far more suitable for use in a pharmaceutical composition and also exhibits favourable storage stability.
  • the choline salt (IA) is a potent angiotensin-II antagonist and can accordingly be used, for example, as an active ingredient in antihypertensives which are used, for example, in the treatment of high blood pressure and cardiac insufficiency.
  • the invention accordingly relates to the use of the choline salt of formula (IA) and its tautomers in the preparation of corresponding medicaments and in the therapeutic treatment of high blood pressure and cardiac insufficiency.
  • the preparation of corresponding medicaments includes also the commercial formulation of the active substances.
  • the choline salt (IA) can be used for treating glaucoma and for increasing the flow of (retinal) intra-ocular fluid and, equally, for treating vasospastic constitutions of the eye and diabetic retinopathy.
  • the present Application accordingly relates also to the use of the choline salt of the free acid of formula (I) for treating glaucoma and for increasing the flow of (retinal) fluid or to a method of treating glaucoma and increasing the flow of intra-ocular fluid, and also of treating vasospastic constitutions of the eye and diabetic retinopathy, which method comprises administering to patients requiring such treatment a therapeutically effective amount of choline salt of 2,6-di-n-butyl-4-hydroxy-5-(2'- tetrazol-5-ylbiphenyl-4-ylmethyl)-pyrimidine.
  • the invention relates also to a process for the preparation of the choline salt of compound (I), which process comprises reacting the free acid (I) with choline and isolating the choline salt (IA).
  • the reaction is carried out in a manner known ** >er se, for example in the absence, or generally in the presence, of a suitable solvent or diluent or a mixture thereof, the operation being effected, as required, with cooling, at room temperature or with heating, for example in a temperature range of approximately from -80°C up to the boiling temperature of the reaction medium, especially from approximately -10° to approximately +200°C, preferably at room temperature, and, if necessary, in a closed vessel, under pressure, in an inert gas atmosphere and/or under anhydrous conditions.
  • the present Application relates also to pharmaceutical compositions for the treatment of glaucoma and for increasing the flow of (retinal) fluid, and also for the treatment of vaso ⁇ spastic constitutions of the eye and diabetic retinopathy, comprising a therapeutically effective amount of compound (I) or of a pharmaceutically acceptable salt thereof, especially the choline salt thereof, and a pharmaceutically acceptable formulation agent suitable for ophthalmic use.
  • compositions are advantageously administered topically to the eye, especially in the form of a solution, an ointment, a gel or a solid insert.
  • Such compositions comprise the active ingredient, for example, 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.
  • 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.
  • 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.
  • 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.
  • 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 drag ⁇ es, tablets, capsules or suppositories, and also ampoules.
  • Those compositions are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes.
  • 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 drag ⁇ e 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.
  • 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
  • binders such as starch pastes using, for example, corn
  • 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.
  • Drag ⁇ e 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 org ⁇ . c 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 drag ⁇ e coatings, for example for identification purposes or to indicate different doses of active ingredient.
  • 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.
  • 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.
  • aqueous solutions of an active ingredient in water-soluble form for example in the form of a water-soluble salt
  • suspensions of the active ingredient such as corresponding oily injection suspensions
  • 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.
  • 19 g of a 45 % solution of choline in methanol are diluted with 200 ml of ethanol.
  • 30 g of 2,6-di-n-butyl-4-hydroxy-5-(2'-tetrazol-5-ylbiphenyl-4-ylmethyl)-pyrimidine are then added in one portion, with stirring.
  • the resulting solution is filtered until clear and then concentrated by evaporation under a water-jet vacuum at 40°C.
  • the residue is dissolved under reflux in 200 ml of acetonitrile and the solution is filtered while hot and slowly cooled first to room temperature and then to 0°C, with stirring.
  • the crystals are isolated by filtration, washed three times with 50 ml of ice-cold acetonitrile each time and then dried in vacuo at 80°C to constant weight to give the choline salt of 2,6-di-n-butyl- 4-hydroxy-5-(2'-tetrazol-5-ylbiphenyl-4-ylmethyl)-pyrimidine in the form of white needles. M.p. 183-184°C.
  • Formulation Example 1 Tablets, each comprising 50 mg of active ingredient, for example the choline salt of 2,6-di-(n-butyl)-4-hydroxy-5-(2'-tetrazol-5-ylbiphenyl-4-ylmethyl)- pyrimidine, can be prepared as follows:
  • composition for 10 000 tablets: active ingredient 500.0 g lactose 500.0 g potato starch 352.0 g gelatin 8.0 g talc 60.0 g magnesium stearate 10.0 g silica (highly dispersed) 20.0 g ethanol q.s.
  • the active ingredient is mixed with the lactose and 292 g of potato starch and the mixture is moistened with an alcoholic solution of the gelatin and granulated through a sieve. After drying, the remainder of the potato starch, the talc, the magnesium stearate and the highly dispersed silica are admixed and the mixture is compressed to form tablets each weighing 145.0 mg and comprising 50.0 mg of active ingredient; if desired, the tablets can be provided with dividing notches for finer adaptation of the dose.
  • Formulation Example 2 Film-coated tablets, each comprising 100 mg of active ingredient, for example the choline salt of 2,6-di-(n-butyl)-4-hydroxy-5-(2'-tetrazol-5-ylbiphenyl- 4-ylmethyl)-pyrimidine, can be prepared as follows:
  • composition for 1000 tablets: active ingredient 100.00 g lactose 100.00 g corn starch 70.00 g talc 8.50 g calcium stearate 1.50 g hydroxypropylmethylcellulose 2.36 g shellac 0.64 g water q.s. dichloromethane q.s.
  • the active ingredient, the lactose and 40 g of the corn starch are mixed and moistened with a paste, prepared from 15 g of corn starch and water (with heating), and granulated.
  • the granules are dried, and the remainder of the corn starch, the talc and the calcium stearate are added and mixed with the granules.
  • the mixture is compressed to form tablets (weight: 280 mg) which are film-coated with a solution of the hydroxypropylmethyl ⁇ cellulose and the shellac in dichloromethane (final weight of the film-coated tablet: 283 mg).
  • a solution, comprising 20 mg of active ingredient, for example the choline salt of 2,6-di-(n-butyl)-4-hydroxy-5-(2'-tetrazol-5-ylbiphenyl-4-ylmethyl)- pyrimidine, can be prepared as follows:
  • Macrogol 400 benzalkonium chloride disodium ethylenediamine tetraacetate sorbitol
  • the constituents are introduced into water and dissolved.
  • the compound 2,6-di-n-butyl-4-hydroxy-5-(2'-tetrazol-5-ylbiphenyl-4-ylmethyl)- pyrimidine or a pharmaceutically acceptable salt thereof being different from the choline salt can be processed in an analogous manner, for example as described in the above Formulation Examples.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation du composé 2,6-di-n-butyle-4-hydroxy-5-(2'-tétrazole-5-ylbiphényle-4-ylméthyle)-pyrimidine ainsi que de ses sels dans la préparation de compositions pharmaceutiques utilisées dans le traitement du glaucome, afin d'accroître l'écoulement de fluide intra-oculaire (rétinien), dans le traitement de constitutions angiospastiques de l'÷il, et dans le traitement de la rétinopathie diabétique, ainsi que des compositions pharmaceutiques correspondantes et le nouveau sel de choline.
PCT/US1993/001432 1992-02-17 1993-02-17 Compositions de traitement du glaucome WO1993015717A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH46192 1992-02-17
CH461/92-2 1992-02-17

Publications (1)

Publication Number Publication Date
WO1993015717A1 true WO1993015717A1 (fr) 1993-08-19

Family

ID=4187547

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/001432 WO1993015717A1 (fr) 1992-02-17 1993-02-17 Compositions de traitement du glaucome

Country Status (4)

Country Link
AU (1) AU3722593A (fr)
IL (1) IL104756A0 (fr)
WO (1) WO1993015717A1 (fr)
ZA (1) ZA931062B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996008476A1 (fr) * 1994-09-17 1996-03-21 Boryung Pharmaceutical Co., Ltd. Derives de pyrimidinone
WO2006058592A1 (fr) * 2004-12-01 2006-06-08 Merck Patent Gmbh Nouveaux inhibiteurs specifiques de la caspase-10
WO2007045407A2 (fr) * 2005-10-18 2007-04-26 Artmed S.R.L. Compositions nutraceutiques et pharmaceutiques contenant de la choline et pouvant servir d'adjuvants dans la prevention et le traitement des retinopathies et du glaucome

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0424317A2 (fr) * 1989-10-19 1991-04-24 Ciba-Geigy Ag Pyrimidines
US5036048A (en) * 1986-03-07 1991-07-30 Schering Corporation Angiotensin II receptor blockers as antiglaucoma agents
WO1991015209A1 (fr) * 1990-03-30 1991-10-17 Merck & Co., Inc. Pyrimidines, pyrimidinones et pyridopyrimidines substitues
EP0465323A1 (fr) * 1990-07-02 1992-01-08 Laboratoires Upsa Dérivés de pyrimidine antagonistes des récepteurs à l'angiotensine II, leurs procédés de préparation et compositions pharmaceutiques les contenant

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5036048A (en) * 1986-03-07 1991-07-30 Schering Corporation Angiotensin II receptor blockers as antiglaucoma agents
EP0424317A2 (fr) * 1989-10-19 1991-04-24 Ciba-Geigy Ag Pyrimidines
WO1991015209A1 (fr) * 1990-03-30 1991-10-17 Merck & Co., Inc. Pyrimidines, pyrimidinones et pyridopyrimidines substitues
EP0465323A1 (fr) * 1990-07-02 1992-01-08 Laboratoires Upsa Dérivés de pyrimidine antagonistes des récepteurs à l'angiotensine II, leurs procédés de préparation et compositions pharmaceutiques les contenant

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996008476A1 (fr) * 1994-09-17 1996-03-21 Boryung Pharmaceutical Co., Ltd. Derives de pyrimidinone
US5869476A (en) * 1994-09-17 1999-02-09 Boryung Pharmaceutical Co., Ltd. Pyrimidinone derivatives
CN1115337C (zh) * 1994-09-17 2003-07-23 保宁制药株式会社 嘧啶酮衍生物
WO2006058592A1 (fr) * 2004-12-01 2006-06-08 Merck Patent Gmbh Nouveaux inhibiteurs specifiques de la caspase-10
US7829721B2 (en) 2004-12-01 2010-11-09 Merck Patent Gmbh Specific caspase-10 inhibitors
WO2007045407A2 (fr) * 2005-10-18 2007-04-26 Artmed S.R.L. Compositions nutraceutiques et pharmaceutiques contenant de la choline et pouvant servir d'adjuvants dans la prevention et le traitement des retinopathies et du glaucome
WO2007045407A3 (fr) * 2005-10-18 2007-07-26 Artmed S R L Compositions nutraceutiques et pharmaceutiques contenant de la choline et pouvant servir d'adjuvants dans la prevention et le traitement des retinopathies et du glaucome

Also Published As

Publication number Publication date
ZA931062B (en) 1993-08-17
AU3722593A (en) 1993-09-03
IL104756A0 (en) 1993-06-10

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