CA2128324A1 - Treatment of glaucoma - Google Patents
Treatment of glaucomaInfo
- Publication number
- CA2128324A1 CA2128324A1 CA002128324A CA2128324A CA2128324A1 CA 2128324 A1 CA2128324 A1 CA 2128324A1 CA 002128324 A CA002128324 A CA 002128324A CA 2128324 A CA2128324 A CA 2128324A CA 2128324 A1 CA2128324 A1 CA 2128324A1
- Authority
- CA
- Canada
- Prior art keywords
- treatment
- eye
- glaucoma
- constitutions
- retinal
- 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.)
- Abandoned
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
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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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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.
(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
,vo 93/15732 21 2 8 3 r~ ~1 pcI/uss3!ol43l Treatment of g!auc ma The term glaucoma cove,rs pathological symptoms of the eye that are attributable eo 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 op~ic nerve and the re~ina, which can result not only in a restricted field of vision but also in blindness.
~ccordingly, 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 phannacological studies have shown that the compounds of the formula CH2 CH)I\N/ COOH
CH2~ (I), wherein HN N
N=N
X is 5~ ~c/ (Ib) the carboxy group being linked direclly to the cyclopentyl rin~ in the case where X = (la~, and their salts are suitable to a surprising degree for reducing intra-ocular pressure. This effect is achieved not only by the topical adminis~ration of the active ingredient but also by its systemic administration.
The compounds of formula (I) and their salts were also found to have a surprisin_ly lono dura~ion of ac~ion when used in lhe treatmenl of male albino rats, in which intra ocular ~,~?,~3~ ~
Wo 93/15732 pcr/us93/ol4 hypertension had been produced, using the glucocor~icoid 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 ac~ive 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 examinadons revealed no local or systemic intolerances.
Another surprising effect is that the compounds of formula ~I) and their salts have a vaso-relaxing èffect on the eye, both when administered topically and when administered sy.~temically, and can accordingly be used in the treatment of vasospastic constitu~ions of the eye.
In addition, the compounds of formula (I) a ld the,r salts can be used in the trea~nent 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-1-yl)-N-pentanoyl-N-[2'-( I H-tetrazol-5-yl)-biphenyl-4-ylmethyl~-amine3 and 40 lN-(2-carboxy-2,2-tetra-methylene-ethyl)-N-pentanoyl-N-12'-( 1 H-tetrazol-5-yl)-biphenyl~-ylmethyl)-amine~ .
The present invention relates to the use of the compounds of formula (1) and their salts in the preparation of pharmaceu~ical compositions for the treatment of glaucoma, for increas-ing the movement of (retinal) intra-ocular fluid, being the aqueous humour, for the trea~ment of vasospastic constitutions of the eye and for the treatment of diabetic retino-pathy.
The present Application relates also to a method of treatin~ glaucoma, increasing the movement of (retinal) intra-ocular fluid, treatin~ vasospastic constitutions of the eye an treatin~ diabetic retinopathy, which method comprises administering to patients requiring such treatment a therapeutically effective amount of a compound of formula (I) or of a pharmaceu~ically acceptable salt thereof.
Compounds (1) and. where appropriate. their tautomers may be in the form of salls.
~'0 93/15732 212 ~3 3 2 ~ PCI/US93/01431 especially phaImaceutically 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 a~s unsubs-tituted or substitu~ed, for example halo-substituted, Cl-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 glu~nic acid, or such as benzoic acid, or with organic sulfonic acids, such as unsubstituted or substituted, for example halo-substituted, Cl-C4aLkanesulfonic or arylsulfonic acids, for example methane- or p-toluene-sulfonic aci5!"Corresponding acid addition salts can also be formed with any additional basic ~entre 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 aL~cali metal or aL~caline 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-t tributyl- or dimethyl-propyl-amine, or a mono-, di- or tri-hydroxy-lo~r alkylamine, for example mono-, di- or tri-ethanolamine.
Correspondin~ internal salts can also be formed.
The present Application relates also to pharmaceulical compositions for the treatment of olaucoma, for increasin~ the movement of (retinal) fluid~ for the treatment of vasospastic constitutions of the eye and for the treatment of diabetic retinopathy, comprising a thera-peudcally effective amount of a compound of formula (1) or of a pharmaceu~icallyacceptable salt thereof, and a pharrnaceutically acceptable formulation agent suitable for ophthalmic and f~)r systemic use.
Corresponding ophthalmic 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 lhe active inoredient, 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 weioht. Unit dose forms ot ~he aclive ingredient comprise? for example, from approximately 0.001 to approximately 5.0 % by wei~ht, especially from approximately 0.05 to approximately 2.0 % by weioht, preferably from approximately 0.1 lo approximately 1.5 % by weioht, more especiallv from approximately 0.1 to approx-WO 93/lS732 P~US93/014 2 ~ 3 32 ~
imately 1.0 % by weight, of active ingredient. The dose of the active ingredient may depend on various factors, such as mode of admir~istration, requirement, age and/or individual condi~ion.
There are used for corresponding ophthalmic compositions customary pha~naceutically acceptable excipients or additives known tO the person skilled in the ar~, for example those of the type mentioned below, especially with the addition of isotonising agents, buffers, complexing age~ts, solubilisers and thickeners. Examples of such excipients and additives can be found in the PCT Patent Application having the publication number WO 91115206.
Such compositions are prepared in a manner known per ser for example by mixing the active ingredient with the corresponding excipients andlor additives to form corresponding o.phthalmic composidons. The active ingredient is preferably administered in the form of eye drops, ~eing dissolved especially in a sterile, aqueous isotonic solution which, if necessary. is buffered to the desired pH value.
Accordingly, the invendon relates likewise to systemically administrable pharmaceutical compositions that comprise a compound of formula (I) or a pharmaceudcally acceptable salt thereof as active ingredie!lt, and to a process for the preparation thereof.
Those pharmaceudcal compositions are for enteral, such as oral, and also recta~ or parenteral administration to warm-blooded anirnals, the pharmacological active ingredient being comprised on itS own or together with customary pharmaceutical excipients. The pharmaceutical composi~ions comprise, for example, approximately from 0.1 % to 100 %, preferably from approximately 1 % to approximately 60 %, of the active ingredient.
Pharrnaceutical compositions for enteral or parenteral and also for ocular administration are, for example, compositions in unit dose forms, such as dragées, tablets, capsules or suppositories, and also ampoules. Ihose composi~ions are prepared in a manner known se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes. For example, phannaceu~ical compositions for oral adminis-tration can be obtained by combining the active ingredient with solid camers, optionally ~ranulating a resulting mixture and, if desired, processing the mixture or granules, if necessary after the addi~ion of suitable excipients, to ~orm tablets or dragée cores.
Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose prepara~ions and/or calcium phosphates, for exarnple tri-calcium phosphate or calcium hydrogen phosphate, also binders, such as starch pastes ,1vO 9~/15732 2 1 2 8 3 2 ~ Pcr/US93/01~31 using, for example, com, 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 polyvin~lpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate. Excipients are especia ~ flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragée cores are pro~ided 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 dio~ide, or coating solutions in suitable organic solvents or solvent mL~tures, or, for the production of enteric coatings, solutions of suitable cellulose prepar-ations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
Col,ourings or pigments may be added to the tablets or dragée coaungs, for example for identification purposes or to indicate t' ~ferent doses of active ingredient.
Fur~her orally ac; listrable pharmac ~ compositions include dry-f~lled capsules consisting of geL3~ n, and also soft, s~ ' capsules consisting of gelatin and a plasticiser, such as glycerol or sorbitol. The dry- .~d capsules may contain the active ingredient in tne form of granules, for example in .mixture with fillers, such as laeto~e, binders, such as S~ -~hes, and/or glidants, such as lalc or magnesium stearate, and or nally st. bilisers.
In ~ capsules, the active ingredien~ is preferably dissolved or suspes d in suitaole liq~.s, such as fatty oils, p raffin oil or liquid polyethylene glycols, ~ 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 glycqls and paraffin hydrocarbons.
For parenteral administration there are suitable especially aqueous solutions of an active ingredient in water-soluble form, for exarnple in the form of a water-soluble salt, and also suspensions of the active ingredient, such as corresponding oily injection suspensions, there bei~ ;? used suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oll. or synlhetic fatty acid esters, for example ethyl oleate or triglycerides, or WO 93/15732 P~/US93/014~
21~832~
aqueous injection suspensions that comprise viscosi~-increasing substances, for example sodiurn 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 andlor individual condi~ion.
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 pharrnaceutical compositions for the treatment of glaucoma, for increasing the movement of (retinal) intra-ocular fluid, for the treatment of vasospæ~ic constitutions of the eye and for the treatment of diabetic retino-pathy.
~e following E~xamples 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-yl)-N-pentanoyl-N-~2' -( lH-tetrazol-5-yl)-biphenyl-4-ylmethyl~-amine, can be made up as follows:
Composition:
1) aclive in~redient 20.00 mg NaOH.lN 86.00 mg benzalkonium chloride 0.l0 m~
disodium ethylenediamine tetraacetate 0.50 mg sorbitol 10.00 mg Na2HPO~-2H2o 9.91 mg K2HPO4 0.44 mg water (purity: pro inj.j ad 1.00 ml 2) active in~redient 20.00 mg NaOH.lN 86.00 mg Macrogol 400 20.00 mg benza!konium chloride 0.10 rng ~o 93/15732 ~ ~L 2 ~ PCr/US93/01431 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 d~isodium 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 wa~r and dissolved.
Formulation Examples 4 and 5 for eve drops:
Vehicle:
Na2HPO4-12 H2O 3.58 g NaCI 0.29 g H2O 100 ml Active ingredient:
N-(2-carboxy-2,2-tetramethylene-ethyl)-N-pentanoyl-N-~2' -~ l H-tetrazol-5-yl~-biphenyl-4-ylmethyl~-amine 4) 5 % active ingredient solution:
vehicle 0.995 ml NaOH 2N 0.015 ml active inaredient (5 %) 50 ml ~H = 6.0 WO 93/15732 PCr/US93/014 2 1~83~ 8-5) 0.5 % active ingredient solu~ion:
vehicle 0.9 ml ac~ive ingredient (5 ~o) 0.1 ml pH=7.0 A compound of forrnula (I) or a pharmaceutically acceptable salt thereof can be processed in an analogous marmer, fvr example as described in the above Examples.
~ccordingly, 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 phannacological studies have shown that the compounds of the formula CH2 CH)I\N/ COOH
CH2~ (I), wherein HN N
N=N
X is 5~ ~c/ (Ib) the carboxy group being linked direclly to the cyclopentyl rin~ in the case where X = (la~, and their salts are suitable to a surprising degree for reducing intra-ocular pressure. This effect is achieved not only by the topical adminis~ration of the active ingredient but also by its systemic administration.
The compounds of formula (I) and their salts were also found to have a surprisin_ly lono dura~ion of ac~ion when used in lhe treatmenl of male albino rats, in which intra ocular ~,~?,~3~ ~
Wo 93/15732 pcr/us93/ol4 hypertension had been produced, using the glucocor~icoid 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 ac~ive 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 examinadons revealed no local or systemic intolerances.
Another surprising effect is that the compounds of formula ~I) and their salts have a vaso-relaxing èffect on the eye, both when administered topically and when administered sy.~temically, and can accordingly be used in the treatment of vasospastic constitu~ions of the eye.
In addition, the compounds of formula (I) a ld the,r salts can be used in the trea~nent 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-1-yl)-N-pentanoyl-N-[2'-( I H-tetrazol-5-yl)-biphenyl-4-ylmethyl~-amine3 and 40 lN-(2-carboxy-2,2-tetra-methylene-ethyl)-N-pentanoyl-N-12'-( 1 H-tetrazol-5-yl)-biphenyl~-ylmethyl)-amine~ .
The present invention relates to the use of the compounds of formula (1) and their salts in the preparation of pharmaceu~ical compositions for the treatment of glaucoma, for increas-ing the movement of (retinal) intra-ocular fluid, being the aqueous humour, for the trea~ment of vasospastic constitutions of the eye and for the treatment of diabetic retino-pathy.
The present Application relates also to a method of treatin~ glaucoma, increasing the movement of (retinal) intra-ocular fluid, treatin~ vasospastic constitutions of the eye an treatin~ diabetic retinopathy, which method comprises administering to patients requiring such treatment a therapeutically effective amount of a compound of formula (I) or of a pharmaceu~ically acceptable salt thereof.
Compounds (1) and. where appropriate. their tautomers may be in the form of salls.
~'0 93/15732 212 ~3 3 2 ~ PCI/US93/01431 especially phaImaceutically 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 a~s unsubs-tituted or substitu~ed, for example halo-substituted, Cl-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 glu~nic acid, or such as benzoic acid, or with organic sulfonic acids, such as unsubstituted or substituted, for example halo-substituted, Cl-C4aLkanesulfonic or arylsulfonic acids, for example methane- or p-toluene-sulfonic aci5!"Corresponding acid addition salts can also be formed with any additional basic ~entre 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 aL~cali metal or aL~caline 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-t tributyl- or dimethyl-propyl-amine, or a mono-, di- or tri-hydroxy-lo~r alkylamine, for example mono-, di- or tri-ethanolamine.
Correspondin~ internal salts can also be formed.
The present Application relates also to pharmaceulical compositions for the treatment of olaucoma, for increasin~ the movement of (retinal) fluid~ for the treatment of vasospastic constitutions of the eye and for the treatment of diabetic retinopathy, comprising a thera-peudcally effective amount of a compound of formula (1) or of a pharmaceu~icallyacceptable salt thereof, and a pharrnaceutically acceptable formulation agent suitable for ophthalmic and f~)r systemic use.
Corresponding ophthalmic 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 lhe active inoredient, 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 weioht. Unit dose forms ot ~he aclive ingredient comprise? for example, from approximately 0.001 to approximately 5.0 % by wei~ht, especially from approximately 0.05 to approximately 2.0 % by weioht, preferably from approximately 0.1 lo approximately 1.5 % by weioht, more especiallv from approximately 0.1 to approx-WO 93/lS732 P~US93/014 2 ~ 3 32 ~
imately 1.0 % by weight, of active ingredient. The dose of the active ingredient may depend on various factors, such as mode of admir~istration, requirement, age and/or individual condi~ion.
There are used for corresponding ophthalmic compositions customary pha~naceutically acceptable excipients or additives known tO the person skilled in the ar~, for example those of the type mentioned below, especially with the addition of isotonising agents, buffers, complexing age~ts, solubilisers and thickeners. Examples of such excipients and additives can be found in the PCT Patent Application having the publication number WO 91115206.
Such compositions are prepared in a manner known per ser for example by mixing the active ingredient with the corresponding excipients andlor additives to form corresponding o.phthalmic composidons. The active ingredient is preferably administered in the form of eye drops, ~eing dissolved especially in a sterile, aqueous isotonic solution which, if necessary. is buffered to the desired pH value.
Accordingly, the invendon relates likewise to systemically administrable pharmaceutical compositions that comprise a compound of formula (I) or a pharmaceudcally acceptable salt thereof as active ingredie!lt, and to a process for the preparation thereof.
Those pharmaceudcal compositions are for enteral, such as oral, and also recta~ or parenteral administration to warm-blooded anirnals, the pharmacological active ingredient being comprised on itS own or together with customary pharmaceutical excipients. The pharmaceutical composi~ions comprise, for example, approximately from 0.1 % to 100 %, preferably from approximately 1 % to approximately 60 %, of the active ingredient.
Pharrnaceutical compositions for enteral or parenteral and also for ocular administration are, for example, compositions in unit dose forms, such as dragées, tablets, capsules or suppositories, and also ampoules. Ihose composi~ions are prepared in a manner known se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes. For example, phannaceu~ical compositions for oral adminis-tration can be obtained by combining the active ingredient with solid camers, optionally ~ranulating a resulting mixture and, if desired, processing the mixture or granules, if necessary after the addi~ion of suitable excipients, to ~orm tablets or dragée cores.
Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose prepara~ions and/or calcium phosphates, for exarnple tri-calcium phosphate or calcium hydrogen phosphate, also binders, such as starch pastes ,1vO 9~/15732 2 1 2 8 3 2 ~ Pcr/US93/01~31 using, for example, com, 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 polyvin~lpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate. Excipients are especia ~ flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragée cores are pro~ided 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 dio~ide, or coating solutions in suitable organic solvents or solvent mL~tures, or, for the production of enteric coatings, solutions of suitable cellulose prepar-ations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
Col,ourings or pigments may be added to the tablets or dragée coaungs, for example for identification purposes or to indicate t' ~ferent doses of active ingredient.
Fur~her orally ac; listrable pharmac ~ compositions include dry-f~lled capsules consisting of geL3~ n, and also soft, s~ ' capsules consisting of gelatin and a plasticiser, such as glycerol or sorbitol. The dry- .~d capsules may contain the active ingredient in tne form of granules, for example in .mixture with fillers, such as laeto~e, binders, such as S~ -~hes, and/or glidants, such as lalc or magnesium stearate, and or nally st. bilisers.
In ~ capsules, the active ingredien~ is preferably dissolved or suspes d in suitaole liq~.s, such as fatty oils, p raffin oil or liquid polyethylene glycols, ~ 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 glycqls and paraffin hydrocarbons.
For parenteral administration there are suitable especially aqueous solutions of an active ingredient in water-soluble form, for exarnple in the form of a water-soluble salt, and also suspensions of the active ingredient, such as corresponding oily injection suspensions, there bei~ ;? used suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oll. or synlhetic fatty acid esters, for example ethyl oleate or triglycerides, or WO 93/15732 P~/US93/014~
21~832~
aqueous injection suspensions that comprise viscosi~-increasing substances, for example sodiurn 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 andlor individual condi~ion.
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 pharrnaceutical compositions for the treatment of glaucoma, for increasing the movement of (retinal) intra-ocular fluid, for the treatment of vasospæ~ic constitutions of the eye and for the treatment of diabetic retino-pathy.
~e following E~xamples 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-yl)-N-pentanoyl-N-~2' -( lH-tetrazol-5-yl)-biphenyl-4-ylmethyl~-amine, can be made up as follows:
Composition:
1) aclive in~redient 20.00 mg NaOH.lN 86.00 mg benzalkonium chloride 0.l0 m~
disodium ethylenediamine tetraacetate 0.50 mg sorbitol 10.00 mg Na2HPO~-2H2o 9.91 mg K2HPO4 0.44 mg water (purity: pro inj.j ad 1.00 ml 2) active in~redient 20.00 mg NaOH.lN 86.00 mg Macrogol 400 20.00 mg benza!konium chloride 0.10 rng ~o 93/15732 ~ ~L 2 ~ PCr/US93/01431 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 d~isodium 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 wa~r and dissolved.
Formulation Examples 4 and 5 for eve drops:
Vehicle:
Na2HPO4-12 H2O 3.58 g NaCI 0.29 g H2O 100 ml Active ingredient:
N-(2-carboxy-2,2-tetramethylene-ethyl)-N-pentanoyl-N-~2' -~ l H-tetrazol-5-yl~-biphenyl-4-ylmethyl~-amine 4) 5 % active ingredient solution:
vehicle 0.995 ml NaOH 2N 0.015 ml active inaredient (5 %) 50 ml ~H = 6.0 WO 93/15732 PCr/US93/014 2 1~83~ 8-5) 0.5 % active ingredient solu~ion:
vehicle 0.9 ml ac~ive ingredient (5 ~o) 0.1 ml pH=7.0 A compound of forrnula (I) or a pharmaceutically acceptable salt thereof can be processed in an analogous marmer, fvr example as described in the above Examples.
Claims (6)
What is claimed is:
1. The use of a compound of formula (I) (I), wherein X is (Ia) or (Ib), the carboxy group being linked directly to the cyclopentyl ring in the case where X = (Ia), 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. The use of the compound (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-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.
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'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-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 administrable 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) intraocular 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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH459/92-4 | 1992-02-17 | ||
| CH45992 | 1992-02-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2128324A1 true CA2128324A1 (en) | 1993-08-19 |
Family
ID=4187501
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002128324A Abandoned CA2128324A1 (en) | 1992-02-17 | 1993-02-17 | Treatment of glaucoma |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0626846A1 (en) |
| JP (1) | JPH07504099A (en) |
| AU (1) | AU3722493A (en) |
| CA (1) | CA2128324A1 (en) |
| IL (1) | IL104755A0 (en) |
| NO (1) | NO942756L (en) |
| WO (1) | WO1993015732A1 (en) |
| ZA (1) | ZA931063B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995021609A1 (en) * | 1994-02-08 | 1995-08-17 | Ciba-Geigy Ag | Treatment of normotensive glaucoma with angiotensin ii antagonists |
| CA2184712A1 (en) * | 1994-03-17 | 1995-09-21 | Marc De Gasparo | Treatment of diabetic nephropathy with valsartan |
| GB9613470D0 (en) | 1996-06-27 | 1996-08-28 | Ciba Geigy Ag | Small solid oral dosage form |
| EP1459742B9 (en) | 1998-08-17 | 2012-05-02 | Senju Pharmaceutical Co., Ltd. | Agent for prophylaxis and treatment of asthenopia and pseudomyopia |
| WO2000010605A2 (en) * | 1998-08-20 | 2000-03-02 | Senju Pharmaceutical Co., Ltd. | Preventives or remedies for eye circulatory failure |
| BR0010084A (en) * | 1999-04-28 | 2002-01-15 | Takeda Chemical Industries Ltd | Pharmaceutical composition, processes to prevent, treat or inhibit the development of simple retinopathy or proliferative retinopathy, and to increase retinal potential or mammalian retinal edema, and, use of a compound |
| TW200304812A (en) * | 2002-03-08 | 2003-10-16 | Sankyo Co | An eye drop containing a tetrazole derivative |
| FR2878522B1 (en) * | 2004-12-01 | 2008-04-18 | Merck Sante Soc Par Actions Si | NEW SPECIFIC INHIBITORS OF CASPAS-10 |
Family Cites Families (4)
| 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 |
| ATE134624T1 (en) * | 1990-02-19 | 1996-03-15 | Ciba Geigy Ag | ACYL COMPOUNDS |
| IE910913A1 (en) * | 1990-03-20 | 1991-09-25 | Sanofi Sa | N-substituted heterocyclic derivates, their preparation¹and pharmaceutical compositions containing them |
| FR2672891B1 (en) * | 1991-02-20 | 1994-02-18 | Synthelabo | DERIVATIVES OF 3-PYRAZOLONES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION. |
-
1993
- 1993-02-16 IL IL104755A patent/IL104755A0/en unknown
- 1993-02-16 ZA ZA931063A patent/ZA931063B/en unknown
- 1993-02-17 CA CA002128324A patent/CA2128324A1/en not_active Abandoned
- 1993-02-17 WO PCT/US1993/001431 patent/WO1993015732A1/en not_active Application Discontinuation
- 1993-02-17 JP JP5514345A patent/JPH07504099A/en active Pending
- 1993-02-17 EP EP93906040A patent/EP0626846A1/en not_active Ceased
- 1993-02-17 AU AU37224/93A patent/AU3722493A/en not_active Abandoned
-
1994
- 1994-07-22 NO NO942756A patent/NO942756L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0626846A1 (en) | 1994-12-07 |
| WO1993015732A1 (en) | 1993-08-19 |
| ZA931063B (en) | 1993-09-23 |
| AU3722493A (en) | 1993-09-03 |
| NO942756D0 (en) | 1994-07-22 |
| NO942756L (en) | 1994-07-22 |
| JPH07504099A (en) | 1995-05-11 |
| IL104755A0 (en) | 1993-06-10 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |