EP0626846A1 - Traitement du glaucome - Google Patents

Traitement du glaucome

Info

Publication number
EP0626846A1
EP0626846A1 EP93906040A EP93906040A EP0626846A1 EP 0626846 A1 EP0626846 A1 EP 0626846A1 EP 93906040 A EP93906040 A EP 93906040A EP 93906040 A EP93906040 A EP 93906040A EP 0626846 A1 EP0626846 A1 EP 0626846A1
Authority
EP
European Patent Office
Prior art keywords
treatment
glaucoma
eye
intra
constitutions
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
EP93906040A
Other languages
German (de)
English (en)
Inventor
William Cash
Georg Mathis
Marc De Gasparo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Ciba Geigy AG
Ciba Vision 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, Ciba Vision AG filed Critical Ciba Geigy AG
Publication of EP0626846A1 publication Critical patent/EP0626846A1/fr
Ceased legal-status Critical Current

Links

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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole

Definitions

  • 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 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.
  • 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.
  • the compounds of formula (I) and their salts can be used in the treatment of diabetic retinopathy.
  • 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.
  • 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, 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 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
  • Corresponding acid addition salts can also be formed with any additional basic centre that may be present.
  • 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- Chamberically 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.
  • 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.
  • 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 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.
  • 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,
  • 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 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 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.
  • 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.
  • 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:
  • the constituents are introduced into water and dissolved.
  • 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.

Landscapes

  • 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)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne l'utilisation des composés de la formule (I), dans laquelle X représente (Ia) ou (Ib), le groupe carboxy étant lié directement au cycle cyclopentyle lorsque X = (Ia), ainsi que leurs sels dans la préparation de compositions pharmaceutiques utilisées dans le traitement du glaucome, afin d'accroître le mouvement de fluide intra-oculaire (rétinien), dans le traitement de constitutions angiospastiques de l'oeil, et dans le traitement de la rétinopathie diabétique, ainsi que des compositions ophtalmiques correspondantes.
EP93906040A 1992-02-17 1993-02-17 Traitement du glaucome Ceased EP0626846A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CH45992 1992-02-17
CH459/92 1992-02-17
PCT/US1993/001431 WO1993015732A1 (fr) 1992-02-17 1993-02-17 Traitement du glaucome

Publications (1)

Publication Number Publication Date
EP0626846A1 true EP0626846A1 (fr) 1994-12-07

Family

ID=4187501

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93906040A Ceased EP0626846A1 (fr) 1992-02-17 1993-02-17 Traitement du glaucome

Country Status (8)

Country Link
EP (1) EP0626846A1 (fr)
JP (1) JPH07504099A (fr)
AU (1) AU3722493A (fr)
CA (1) CA2128324A1 (fr)
IL (1) IL104755A0 (fr)
NO (1) NO942756D0 (fr)
WO (1) WO1993015732A1 (fr)
ZA (1) ZA931063B (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE300287T1 (de) * 1994-02-08 2005-08-15 Novartis Pharma Gmbh Behandlung von normaldruckglaukom mit valsartan
HUT76542A (en) * 1994-03-17 1997-09-29 Ciba Geigy Ag Use of valsartan for the preparation of pharmaceutical composition serving for the treatment of diabetic nephropathy
GB9613470D0 (en) 1996-06-27 1996-08-28 Ciba Geigy Ag Small solid oral dosage form
CA2307285C (fr) 1998-08-17 2009-03-31 Senju Pharmaceutical Co., Ltd. Medicaments preventifs/curatifs pour le glaucome
WO2000010605A2 (fr) * 1998-08-20 2000-03-02 Senju Pharmaceutical Co., Ltd. Prophylaxie ou remedes pour la perturbation circulatoire de l'oeil
ATE289204T1 (de) * 1999-04-28 2005-03-15 Takeda Pharmaceutical Arzneimittel zur vorbeugung / behandlung / inhibierung des fortschritts für einfache oder preproliferative retinopathie
TW200304812A (en) * 2002-03-08 2003-10-16 Sankyo Co An eye drop containing a tetrazole derivative
FR2878522B1 (fr) 2004-12-01 2008-04-18 Merck Sante Soc Par Actions Si Nouveaux inhibiteurs specifiques de la caspas-10

Family Cites Families (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
DE122007000050I1 (de) * 1990-02-19 2007-11-08 Novartis Ag Acylverbindungen
TW201738B (fr) * 1990-03-20 1993-03-11 Sanofi Co
FR2672891B1 (fr) * 1991-02-20 1994-02-18 Synthelabo Derives de 3-pyrazolones, leur preparation et leur application en therapeutique.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9315732A1 *

Also Published As

Publication number Publication date
NO942756L (no) 1994-07-22
JPH07504099A (ja) 1995-05-11
CA2128324A1 (fr) 1993-08-19
AU3722493A (en) 1993-09-03
IL104755A0 (en) 1993-06-10
ZA931063B (en) 1993-09-23
NO942756D0 (no) 1994-07-22
WO1993015732A1 (fr) 1993-08-19

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