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WO1995013811A1 - Use of substituted thiazolidine derivatives in the treatment of raised intraocular pressure - Google Patents

Use of substituted thiazolidine derivatives in the treatment of raised intraocular pressure Download PDF

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Publication number
WO1995013811A1
WO1995013811A1 PCT/EP1994/003758 EP9403758W WO9513811A1 WO 1995013811 A1 WO1995013811 A1 WO 1995013811A1 EP 9403758 W EP9403758 W EP 9403758W WO 9513811 A1 WO9513811 A1 WO 9513811A1
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Prior art keywords
thiazolidine
phenyl
carboxy
alkyl
nitroxyethoxy
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PCT/EP1994/003758
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German (de)
French (fr)
Inventor
Jan Bron
Geert Jan Sterk
Hendrik Timmerman
Jan Fetze Van Der Werf
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Byk Nederland Bv
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Priority to AU81076/94A priority Critical patent/AU8107694A/en
Publication of WO1995013811A1 publication Critical patent/WO1995013811A1/en

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    • 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
    • A61K31/425—Thiazoles

Definitions

  • the invention relates to the new use of substituted thiazolidine derivatives for the manufacture of medicaments for the treatment of eye diseases.
  • W092 / 04337 known compounds are outstandingly suitable for the treatment of (pathologically increased) intraocular pressure.
  • the invention relates to the use of compounds of the formula I (see attached formula sheet), in which
  • R1 is hydrogen (H) or 1-4C-alkyl
  • R2 is hydrogen (H), 1-6C-alkyl, 4-8C-cycloalkyl, phenyl-1-3C-alkyl or a radical of the formula II (see attached formula sheet), in which
  • R9, R10 and R11 are the same or different and are hydrogen (H), 1-6C-alkyl, 1-6C-alkoxy, 4-8C-cycloalkyl, 4-8C-cycloalkoxy.
  • Halogen. Represent nitro, nitryloxy-2-6C-alkoxy, nitryloxy-4-8C-cycloalkoxy, nitryloxy1-2C-alkyl-4-8C-cycloalkyl-1-2C-alkoxy or a group of the formula -W-C0-Y-R12, in the
  • W is a bond or a group of the formula -OCHp-
  • Y represents an oxygen atom (0) or an imino group (NH) and R12 represents hydrogen (H), 1-4C-alkyl, 4-8C-cycloalkyl, nitryloxy-2-6C-alkyl or nitryloxy-4-8C-cycloalkyl,
  • R3 and R4 are hydrogen (H) or 1-4C-alkyl
  • R5 is hydrogen (H) or a group of the formula -CO-Z-R7, in which Z is an oxygen atom (0) or an imino group (NH) and
  • R7 hydrogen (H), 1-4C-alkyl, 4-8C-cycloalkyl, nitryloxy-2-6C-alkyl, nitryloxy-4-8C-cycloalkyl, nitryloxy-1-2C-alkyl-4-8C-cycloalkyl-1- 2C-alkyl or 4-nitryloxy-2,6-dioxabicyclo [3.3.0] oct-8-yl,
  • R6 is hydrogen (H) or a group of the formula -X-R8 in which
  • R8 represents 1-4C-alkyl, 4-8C-cycloalkyl, nitryloxy-2-6C-alkyl, nitryloxy-4-8C-cycloalkyl, phenyl or 1-4C-AI alkylphenyl,
  • 1-4C-Alkyl stands for straight-chain or branched AI kyl residues with 1 to 4 carbon atoms. Examples include the butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and especially the methyl radical.
  • 1-6C-Alkyl also includes straight-chain or branched alkyl radicals having 5 or 6 carbon atoms. Examples include the pentyl, isopentyl, neopentyl and hexyl radicals.
  • 4-8C-Cycloalkyl stands for cyclic alkyl radicals with 4 to 8 carbon atoms, that is for the cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl radical.
  • Phenyl-1-3C-alkyl stands for 1-3C-alkyl radicals which are substituted by a phenyl radical.
  • a phenyl radical for example, the phenyl propyl, the phenylethyl and the benzyl radical may be mentioned.
  • 1-6C-alkoxy radicals contain one of the 1-6C-alkyl radicals mentioned above. The methoxy and ethoxy radicals are preferred.
  • 4-8C-cycloalkoxy radicals contain one of the 4-8C-cycloalkyl radicals mentioned above.
  • the cyclopentyloxy and the cyclohexyloxy radical may be mentioned.
  • Halogen in the sense of the present invention is bromine, chlorine and fluorine.
  • Nitryloxy-2-6C-alkoxy radicals are straight-chain or branched 2-6C-alkoxy radicals to which a nitryloxy group (-O-NO 2 ) is attached.
  • Exemplary preferred nitryloxy-2-6C-alkoxy radicals are the 2-nitryloxyethoxy group (-OCH 2 CH 2 -O-NO 2 ), the 3-nitryloxypropoxy group (-O- (CH 2 ) 3 -O-NO 2 ), the 4th -Nitryloxybutoxyrios (-O- (CH 2 ) 4 -O-NO 2 ), the 2-nitryloxypropoxy group [-O-CH 2 -CH (CH 3 ) -O-NO 2 ] and the 2,2-dimethyl-3- nitryloxypropoxy group
  • Nitryloxy-4-8C-cycloalkoxy radicals are 4-8C-cycloalkoxy radicals to which a nitryloxy group is attached.
  • the 4-nitryloxycyclohexyloxy radical may be mentioned.
  • Nitryloxy-1-2C-alkyl-4-8C-cycloalkyl-1-2C-alkoxy radicals are 4-8C-cycloalkyl radicals which are bonded to a 1-2C-alkoxy radical and to which a nitryloxy-1-2C-alkyl radical is bound is.
  • An exemplary preferred nitryloxy-1-2C-alkyl-4-8C-cycloalkyl-1-2C-alkoxy radical is the nitroxymethyl - (trans) -cyclohexylmethoxy radical [-OCH 2 - (C 6 H 10 ) -CH 2 -O-NO 2 ].
  • Suitable pharmacologically acceptable salts for compounds of the formula I are preferably all acid addition salts with inorganic and organic acids commonly used in galenics. Suitable as such are water-soluble and water-insoluble acid addition salts with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, Nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) -benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenic acid, toluenic acid 3-hydroxy-2-naphthoic acid, the acids used in salt production - depending on whether it is a mono- or polybasic acid and which salt is desired - in an equimolar or a different quantity ratio.
  • acids
  • the compounds of the formula I are used in particular in the form of those medicaments which are suitable for the treatment of eye diseases.
  • suitable pharmaceutical formulations include, for example, emulsions, suspensions, ointments or solutions (e.g. eye drops) in which the active substance content is advantageously between 0.01 and 99%.
  • auxiliaries suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • solvents and other active ingredient carriers for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers or permeation promoters can be used.
  • the reduction in intraocular pressure in female New Zealand albino rabbits was determined using conventional methods.
  • the substances to be examined were dropped in 0.05% solution (50 ⁇ l) into one eye, while a solution of the

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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)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to the use of compounds of formula (I) wherein the substituents have the meanings shown in the description, and of the pharmacologically tolerated salts of the said compounds in the production of pharmaceutical agents for the treatment of pathologically raised intraocular pressure.

Description

Verwendung substuierter Thiazolidinderivate zur Behandlung von erhoehtem Augeninnendruck Use of substituted thiazolidine derivatives for the treatment of increased intraocular pressure
Anwendungsgebiet der Erfindung Field of application of the invention
Die Erfindung betrifft die neue Verwendung von substituierten Thiazolidinderivate zur Herstellung von Arzneimitteln für die Behandlung von Augenerkrankungen. The invention relates to the new use of substituted thiazolidine derivatives for the manufacture of medicaments for the treatment of eye diseases.
Bekannter technischer Hintergrund Known technical background
In der internationalen Patentanmeldung W092/04337 werden Nitratester beschrieben, die zur Behandlung cardiovaskulärer Erkrankungen eingesetzt werden sollen. - J.A. Nathanson [Journal of Pharmacology and Experimental Therapeutics 260, 956 (1992)] beschreibt die topische Anwendung von Nitrovasodilatoren (wie Nitroglyzerin oder Isosorbiddinitrat) am Auge zur Verringerung des Augeninnendruckes. International patent application W092 / 04337 describes nitrate esters which are to be used for the treatment of cardiovascular diseases. - YES. Nathanson [Journal of Pharmacology and Experimental Therapeutics 260, 956 (1992)] describes the topical application of nitrovasodilators (such as nitroglycerin or isosorbide dinitrate) to the eye to reduce the intraocular pressure.
Beschreibung der Erfindung Description of the invention
Es wurde nun gefunden, daß die unten näher beschriebenen, aus der It has now been found that those described in more detail below, from the
W092/04337 bekannten Verbindungen für die Behandlung des (krankhaft erhöhten) Augeninnendruckes in hervorragender Weise geeignet sind.  W092 / 04337 known compounds are outstandingly suitable for the treatment of (pathologically increased) intraocular pressure.
Gegenstand der Erfindung ist die Verwendung von Verbindungen der Formel I (siehe beiliegendes Formel blatt), worin The invention relates to the use of compounds of the formula I (see attached formula sheet), in which
R1 Wasserstoff (H) oder 1-4C-Alkyl bedeutet,  R1 is hydrogen (H) or 1-4C-alkyl,
R2 Wasserstoff (H), 1-6C-Alkyl, 4-8C-Cycloalkyl, Phenyl-1-3C-alkyl oder einen Rest der Formel II (siehe beiliegendes Formelblatt) bedeutet, worin  R2 is hydrogen (H), 1-6C-alkyl, 4-8C-cycloalkyl, phenyl-1-3C-alkyl or a radical of the formula II (see attached formula sheet), in which
R9, R10 und R11 gleich oder verschieden sind und Wasserstoff (H), 1-6C- Alkyl, 1-6C-Alkoxy, 4-8C-Cycloalkyl, 4-8C-Cycloalkoxy. Halogen. Nitro, Nitryloxy-2-6C-alkoxy, Nitryloxy-4-8C-cycloalkoxy, Nitryloxy1-2C-alkyl-4-8C-cycloalkyl-1-2C-alkoxy oder eine Gruppe der Formel -W-C0-Y-R12 darstellen, in der R9, R10 and R11 are the same or different and are hydrogen (H), 1-6C-alkyl, 1-6C-alkoxy, 4-8C-cycloalkyl, 4-8C-cycloalkoxy. Halogen. Represent nitro, nitryloxy-2-6C-alkoxy, nitryloxy-4-8C-cycloalkoxy, nitryloxy1-2C-alkyl-4-8C-cycloalkyl-1-2C-alkoxy or a group of the formula -W-C0-Y-R12, in the
W eine Bindung oder eine Gruppe der Formel -OCHp-,  W is a bond or a group of the formula -OCHp-,
Y ein Sauerstoffatom (0) oder eine Iminogruppe (NH) und R12 Wasserstoff (H), 1-4C-Alkyl, 4-8C-Cycloalkyl, Nitryloxy- 2-6C-alkyl oder Nitryloxy-4-8C-cycloalkyl darstellt,  Y represents an oxygen atom (0) or an imino group (NH) and R12 represents hydrogen (H), 1-4C-alkyl, 4-8C-cycloalkyl, nitryloxy-2-6C-alkyl or nitryloxy-4-8C-cycloalkyl,
R3 und R4 Wasserstoff (H) oder 1-4C-Alkyl bedeuten, R3 and R4 are hydrogen (H) or 1-4C-alkyl,
R5 Wasserstoff (H) oder eine Gruppe der Formel -CO-Z-R7 bedeutet, in der Z ein Sauerstoffatom (0) oder eine Iminogruppe (NH) und  R5 is hydrogen (H) or a group of the formula -CO-Z-R7, in which Z is an oxygen atom (0) or an imino group (NH) and
R7 Wasserstoff (H), 1-4C-Alkyl, 4-8C-Cycloalkyl, Nitryloxy-2-6C-alkyl, Nitryloxy-4-8C-cycloalkyl, Nitryloxy-1-2C-alkyl-4-8C-cycloalkyl-1-2C-alkyl oder 4-Nitryloxy-2,6-dioxabicyclo[3.3.0]oct-8-yl bedeutet,  R7 hydrogen (H), 1-4C-alkyl, 4-8C-cycloalkyl, nitryloxy-2-6C-alkyl, nitryloxy-4-8C-cycloalkyl, nitryloxy-1-2C-alkyl-4-8C-cycloalkyl-1- 2C-alkyl or 4-nitryloxy-2,6-dioxabicyclo [3.3.0] oct-8-yl,
und and
R6 Wasserstoff (H) oder eine Gruppe der Formel -X-R8 bedeutet, in der  R6 is hydrogen (H) or a group of the formula -X-R8 in which
X Carbonyl (CO) oder Sulfonyl (SOJ und  X carbonyl (CO) or sulfonyl (SOJ and
R8 1-4C-Alkyl, 4-8C-Cycloalkyl, Nitryloxy-2-6C-alkyl, Nitryloxy-4- 8C-cycloalkyl, Phenyl oder 1-4C-AI kylphenyl darstellt,  R8 represents 1-4C-alkyl, 4-8C-cycloalkyl, nitryloxy-2-6C-alkyl, nitryloxy-4-8C-cycloalkyl, phenyl or 1-4C-AI alkylphenyl,
und ihren pharmakologisch verträglichen Salzen zur Herstellung von Arzneimitteln für die Behandlung des krankhaft erhöhten Augeninnendruckes. and their pharmacologically acceptable salts for the manufacture of medicaments for the treatment of pathologically increased intraocular pressure.
1-4C-Alkyl steht für geradkettige oder verzweigte AI kyl reste mit 1 bis 4 Kohlenstoffatomen. Beispielsweise seien genannt der Butyl-, iso-Butyl-, sec.-Butyl-, tert.-Butyl-, Propyl-, Isopropyl-, Ethyl- und insbesondere der Methylrest. 1-6C-Alkyl umfaßt außerdem geradkettige oder verzweigte AIkylreste mit 5 oder 6 Kohlenstoffatomen. Beispielsweise seien der Pentyl-, der Isopentyl-, der Neopentyl- und der Hexylrest genannt. 1-4C-Alkyl stands for straight-chain or branched AI kyl residues with 1 to 4 carbon atoms. Examples include the butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and especially the methyl radical. 1-6C-Alkyl also includes straight-chain or branched alkyl radicals having 5 or 6 carbon atoms. Examples include the pentyl, isopentyl, neopentyl and hexyl radicals.
4-8C-Cycloalkyl steht für cyclische AI kyl reste mit 4 bis 8 Kohlenstoffatomen, also für den Cyclobutyl-, Cyclopentyl-, Cyclohexyl-, Cycloheptyl- und Cyclooctylrest. 4-8C-Cycloalkyl stands for cyclic alkyl radicals with 4 to 8 carbon atoms, that is for the cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl radical.
Phenyl-1-3C-alkyl steht für 1-3C-Alkylreste, die durch einen Phenylrest substituiert sind. Beispielsweise seien der Phenyl propyl-, der Phenylethyl- und der Benzylrest genannt. 1-6C-Alkoxyreste enthalten neben dem Sauerstoffatom einen der vorstehend genannten 1-6C-Alkylreste. Bevorzugt sind der Methoxy- und der Ethoxyrest. Phenyl-1-3C-alkyl stands for 1-3C-alkyl radicals which are substituted by a phenyl radical. For example, the phenyl propyl, the phenylethyl and the benzyl radical may be mentioned. In addition to the oxygen atom, 1-6C-alkoxy radicals contain one of the 1-6C-alkyl radicals mentioned above. The methoxy and ethoxy radicals are preferred.
4-8C-Cycloalkoxyreste enthalten neben dem Sauerstoffatom einen der vorstehend genannten 4-8C-Cycloalkylreste. Beispielsweise seien der Cyclopentyloxy- und der Cyclohexyloxyrest genannt. In addition to the oxygen atom, 4-8C-cycloalkoxy radicals contain one of the 4-8C-cycloalkyl radicals mentioned above. For example, the cyclopentyloxy and the cyclohexyloxy radical may be mentioned.
Halogen im Sinne der vorliegenden Erfindung ist Brom, Chlor und Fluor. Halogen in the sense of the present invention is bromine, chlorine and fluorine.
Nitryloxy-2-6C-alkoxyreste sind geradkettige oder verzweigte 2-6C-Alkoxyreste, an die eine Nitryloxygruppe (-O-NO2) gebunden ist. Als beispielhafte bevorzugte Nitryloxy-2-6C-alkoxyreste seien die 2-Nitryloxyethoxygruppe (-OCH2CH2-O-NO2), die 3-Nitryloxypropoxygruppe (-O-(CH2)3-O-NO2), die 4-Nitryloxybutoxygruppe (-O-(CH2)4-O-NO2), die 2-Nitryloxypropoxygruppe [-O-CH2-CH(CH3)-O-NO2] und die 2,2-Dimethyl-3-nitryloxypropoxygruppe Nitryloxy-2-6C-alkoxy radicals are straight-chain or branched 2-6C-alkoxy radicals to which a nitryloxy group (-O-NO 2 ) is attached. Exemplary preferred nitryloxy-2-6C-alkoxy radicals are the 2-nitryloxyethoxy group (-OCH 2 CH 2 -O-NO 2 ), the 3-nitryloxypropoxy group (-O- (CH 2 ) 3 -O-NO 2 ), the 4th -Nitryloxybutoxygruppe (-O- (CH 2 ) 4 -O-NO 2 ), the 2-nitryloxypropoxy group [-O-CH 2 -CH (CH 3 ) -O-NO 2 ] and the 2,2-dimethyl-3- nitryloxypropoxy group
[-O-CH2-C(CH3)2-CH2-O-NO2] genannt. [-O-CH 2 -C (CH 3 ) 2 -CH 2 -O-NO 2 ] called.
Nitryloxy-4-8C-cycloalkoxyreste sind 4-8C-Cycloalkoxyreste, an die eine Nitryloxygruppe gebunden ist. Beispielsweise sei der 4-Nitryloxycyclohexyloxyrest genannt. Nitryloxy-4-8C-cycloalkoxy radicals are 4-8C-cycloalkoxy radicals to which a nitryloxy group is attached. For example, the 4-nitryloxycyclohexyloxy radical may be mentioned.
Nitryloxy-1-2C-alkyl-4-8C-cycloalkyl-1-2C-alkoxyreste sind 4-8C-Cycloalkylreste, die einerseits an einen 1-2C-Alkoxyrest gebunden sind und an die andererseits ein Nitryloxy-l-2C-alkylrest gebunden ist. Ein beispielhafter bevorzugter Nitryloxy-l-2C-alkyl-4-8C-cycloalkyl-l-2C-alkoxyrest ist der Nitroxymethyl - (trans)-cyclohexylmethoxyrest [-OCH2-(C6H10)-CH2-O-NO2]. Nitryloxy-1-2C-alkyl-4-8C-cycloalkyl-1-2C-alkoxy radicals are 4-8C-cycloalkyl radicals which are bonded to a 1-2C-alkoxy radical and to which a nitryloxy-1-2C-alkyl radical is bound is. An exemplary preferred nitryloxy-1-2C-alkyl-4-8C-cycloalkyl-1-2C-alkoxy radical is the nitroxymethyl - (trans) -cyclohexylmethoxy radical [-OCH 2 - (C 6 H 10 ) -CH 2 -O-NO 2 ].
Der in 4-Stellung durch -ONO2 substituierte 2,6-Dioxabicyclo[3.3.0]oct-8-ylrest kann auch (zusammen mit Z = 0) als Isosorbidmononitratrest bezeichnet werden. The 2,6-dioxabicyclo [3.3.0] oct-8-yl residue substituted in the 4-position by -ONO 2 can also (together with Z = 0) be referred to as the isosorbide mononitrate residue.
Als pharmakologisch verträgliche Salze kommen für Verbindungen der Formel I bevorzugt alle Säureadditionssalze mit in der in der Galenik üblicherweise verwendeten anorganischen und organischen Säuren in Betracht. Als solche eignen sich wasserlösliche und wasserunlösliche Säureadditionssalze mit Säuren wie beispielsweise Salzsäure, Bromwasserstoffsäure, Phosphorsäure, Salpetersäure, Schwefelsäure, Essigsäure, Zitronensäure, D-Gluconsäure, Benzoesäure, 2-(4-Hydroxybenzoyl)-benzoesäure, Buttersäure, Sulfosalicylsäure, Maleinsäure, Laurinsäure, Äpfelsäure, Fumarsäure, Bernsteinsäure, Oxalsäure, Weinsäure, Embonsäure, Stearinsäure, Toluolsulfonsäure, Methansulfonsäure oder 3-Hydroxy-2-naphtoesäure, wobei die Säuren bei der Salzherstellung - je nachdem, ob es sich um eine ein- oder mehrbasige Säure handelt und je nachdem, welches Salz gewünscht wird - im äquimolaren oder einem davon abweichenden Mengenverhältnis eingesetzt werden. Suitable pharmacologically acceptable salts for compounds of the formula I are preferably all acid addition salts with inorganic and organic acids commonly used in galenics. Suitable as such are water-soluble and water-insoluble acid addition salts with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, Nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) -benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenic acid, toluenic acid 3-hydroxy-2-naphthoic acid, the acids used in salt production - depending on whether it is a mono- or polybasic acid and which salt is desired - in an equimolar or a different quantity ratio.
Die Anwendung der Verbindungen der Formel I erfolgt insbesondere in Form solcher Arzneimittel, wie sie für die Behandlung von Augenerkrankungen geeignet sind. Für die Herstellung der Arzneimittel werden die Verbindungen der Formel I und/oder ihre pharmakologisch verträglichen Salze (= Wirkstoffe) vorzugsweise mit geeigneten pharmazeutischen Hilfsstoffen vermischt und zu geeigneten Arznei formulierungen weiterverarbeitet. Als geeignete Arzneiformulierungen seien beispielsweise Emulsionen, Suspensionen, Salben oder Lösungen (z.B. Augentropfen) genannt, in denen der Wirkstoffgehalt vorteilhafterweise zwischen 0,01 und 99 % beträgt. The compounds of the formula I are used in particular in the form of those medicaments which are suitable for the treatment of eye diseases. For the preparation of the medicaments, the compounds of the formula I and / or their pharmacologically tolerable salts (= active ingredients) are preferably mixed with suitable pharmaceutical auxiliaries and processed further to form suitable medicament formulations. Suitable pharmaceutical formulations include, for example, emulsions, suspensions, ointments or solutions (e.g. eye drops) in which the active substance content is advantageously between 0.01 and 99%.
Welche Hilfsstoffe für die gewünschten Arznei formulierungen geeignet sind, ist dem Fachmann aufgrund seines Fachwissens geläufig. Neben Lösemitteln und anderen Wirkstoffträgem können beispielsweise Antioxidantien, Dispergiermittel, Emulgatoren, Konservierungsmittel, Lösungsvermittler oder Permeationspromotoren verwendet werden. The person skilled in the art is familiar with the auxiliaries suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge. In addition to solvents and other active ingredient carriers, for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers or permeation promoters can be used.
Hervorzuhebende, erfindungsgemäß verwendbare Verbindungen der Formel I sind in den Ansprüchen genannt. Besonders hervorzuheben sind hierbei solche Verbindungen, die systemisch nur eine geringe Wirksamkeit am Herz und/oder Kreislauf zeigen. Compounds of the formula I which can be used according to the invention are mentioned in the claims. Particularly noteworthy here are those compounds which have only a low cardiac and / or circulatory activity systemically.
Die Verbindungen der Formel I sind aus der W092/04337 bekannt. Biologische Untersuchungen The compounds of formula I are known from WO92 / 04337. Biological studies
Die Verringerung des Augeninnendrucks wurde bei weiblichen Neuseeland-Albinokaninchen nach üblichen Methoden ermittelt. The reduction in intraocular pressure in female New Zealand albino rabbits was determined using conventional methods.
Die zu untersuchenden Substanzen wurden in 0,05 %iger Lösung (50 μl ) in das eine Auge getropft, während in das andere Auge eine Lösung der The substances to be examined were dropped in 0.05% solution (50 μl) into one eye, while a solution of the
Kontroll Substanz getropft wurde. Control substance was dropped.
Durch die Substanz 4-Carboxy-2-[3-(2-nitroxyethoxy)phenyl]thiazolidin wird eine Senkung des Augeninnendruckes um 15,4 % erzielt. The substance 4-carboxy-2- [3- (2-nitroxyethoxy) phenyl] thiazolidine reduces the intraocular pressure by 15.4%.
Figure imgf000008_0001
Figure imgf000008_0001

Claims

Patentansprüche claims
1. Verwendung von Verbindungen der Formel I,
Figure imgf000009_0001
1. Use of compounds of the formula I,
Figure imgf000009_0001
worin wherein
R1 Wasserstoff (H) oder 1-4C-Alkyl bedeutet,  R1 is hydrogen (H) or 1-4C-alkyl,
R2 Wasserstoff (H), 1-6C-Alkyl, 4-8C-Cycloalkyl, Phenyl-1-3C-alkyl oder einen Rest der Formel II  R2 is hydrogen (H), 1-6C-alkyl, 4-8C-cycloalkyl, phenyl-1-3C-alkyl or a radical of the formula II
Figure imgf000009_0002
bedeutet,
Figure imgf000009_0002
means
worin  wherein
R9, R10 und R11 gleich oder verschieden sind und Wasserstoff (H), 1-6C- Alkyl, 1-6C-Alkoxy, 4-8C-Cycloalkyl, 4-8C-Cycloalkoxy, Halogen, Nitro, Nitryloxy-2-6C-alkoxy, Nlitryloxy-4-8C-cycloalkoxy, Nitryloxyl-2C-alkyl-4-8C-cycloalkyl-1-2C-alkoxy oder eine Gruppe der Formel -W-CO-Y-R12 darstellen,  R9, R10 and R11 are the same or different and are hydrogen (H), 1-6C-alkyl, 1-6C-alkoxy, 4-8C-cycloalkyl, 4-8C-cycloalkoxy, halogen, nitro, nitryloxy-2-6C-alkoxy Represent nitryloxy-4-8C-cycloalkoxy, nitryloxyl-2C-alkyl-4-8C-cycloalkyl-1-2C-alkoxy or a group of the formula -W-CO-Y-R12,
in der W eine Bindung oder eine Gruppe der Formel -OCH2-, in the W is a bond or a group of the formula -OCH 2 -,
Y ein Sauerstoffatom (0) oder eine Iminogruppe (NH) und R12 Wasserstoff (H), 1-4C-Alkyl, 4-8C-Cycloalkyl, Nitryloxy-2-6C- alkyl oder Nitryloxy-4-8C-cycloalkyl darstellt,  Y represents an oxygen atom (0) or an imino group (NH) and R12 represents hydrogen (H), 1-4C-alkyl, 4-8C-cycloalkyl, nitryloxy-2-6C-alkyl or nitryloxy-4-8C-cycloalkyl,
R3 und R4 Wasserstoff (H) oder 1-4C-Alkyl bedeuten, R3 and R4 are hydrogen (H) or 1-4C-alkyl,
R5 Wasserstoff (H) oder eine Gruppe der Formel -CO-Z-R7 bedeutet, in der Z ein Sauerstoffatom (0) oder eine Iminogruppe (NH) und  R5 is hydrogen (H) or a group of the formula -CO-Z-R7, in which Z is an oxygen atom (0) or an imino group (NH) and
R7 Wasserstoff (H), 1-4C-Alkyl, 4-8C-Cycloalkyl, Nitryloxy-2-6C-alkyl, Nitryloxy-4-8C-cycloalkyl, Nitryloxy-1-2C-alkyl-4-8C-cycloalkyl-1- 2C-alkyl oder 4-Nitryloxy-2,6-dioxabicyclo[3.3.0]oct-8-yl bedeutet, und  R7 hydrogen (H), 1-4C-alkyl, 4-8C-cycloalkyl, nitryloxy-2-6C-alkyl, nitryloxy-4-8C-cycloalkyl, nitryloxy-1-2C-alkyl-4-8C-cycloalkyl-1- 2C-alkyl or 4-nitryloxy-2,6-dioxabicyclo [3.3.0] oct-8-yl, and
R6 Wasserstoff (H) oder eine Gruppe der Formel -X-R8 bedeutet, in der  R6 is hydrogen (H) or a group of the formula -X-R8 in which
X Carbonyl (CO) oder Sulfonyl (SO2) und X carbonyl (CO) or sulfonyl (SO 2 ) and
R8 1-4C-Alkyl, 4-8C-Cycloalkyl, Nitryloxy-2-6C-alkyl, Nitryloxy-4- 8C-cycloalkyl, Phenyl oder 1-4C-Alkylphenyl darstellt,  R8 represents 1-4C-alkyl, 4-8C-cycloalkyl, nitryloxy-2-6C-alkyl, nitryloxy-4-8C-cycloalkyl, phenyl or 1-4C-alkylphenyl,
und ihren pharmakologisch verträglichen Salzen zur Herstellung von Arzneimitteln für die Behandlung des krankhaft erhöhten Augeninnendruckes. and their pharmacologically acceptable salts for the manufacture of medicaments for the treatment of pathologically increased intraocular pressure.
2. Verwendung nach Anspruch 1 einer Verbindung der Formel I nach Anspruch 1 oder ihres pharmakologisch verträglichen Salzes zur Herstellung von Arzneimitteln für die Behandlung des krankhaft erhöhten Augeninnendruckes, wobei die Verbindung der Formel I ausgewählt ist aus der Gruppe bestehend aus 2. Use according to claim 1 of a compound of formula I according to claim 1 or its pharmacologically acceptable salt for the manufacture of medicaments for the treatment of abnormally elevated intraocular pressure, the compound of formula I being selected from the group consisting of
2-Butyl-N-(4-methylbenzolsulphonyl)-4-[(5-nitroxyisosorbid)carbonyl]thiazolidin, 2-butyl-N- (4-methylbenzenesulphonyl) -4 - [(5-nitroxyisosorbide) carbonyl] thiazolidine,
N-Benzoyl-4-[(5-nitroxyisosorbid)carbonyl]-2-butylthiazolidin,  N-benzoyl-4 - [(5-nitroxyisosorbide) carbonyl] -2-butylthiazolidine,
N-Benzoyl-2-butyl-5,5-dimethyl-4-[(5-nitroxyisosorbid)carbonyl]thiazolidin, N-benzoyl-2-butyl-5,5-dimethyl-4 - [(5-nitroxyisosorbide) carbonyl] thiazolidine,
2-Butyl-5,5-dimethyl-N-(4-methylbenzolsulphonyl)-4-[(5-nitroxyisosorbid)-carbonyl]thiazolidin, 2-butyl-5,5-dimethyl-N- (4-methylbenzenesulphonyl) -4 - [(5-nitroxyisosorbide) carbonyl] thiazolidine,
4-Carboxy-2-{4-[(2-nitroxyethyl)aminocarbonyl]phenyl)thiazolidin,  4-carboxy-2- {4 - [(2-nitroxyethyl) aminocarbonyl] phenyl) thiazolidine,
N-Acetyl-2-(2-carboxyphenyl)-4-[(2-nitroxyethyl)aminocarbonyl]thiazolidin, N-acetyl-2- (2-carboxyphenyl) -4 - [(2-nitroxyethyl) aminocarbonyl] thiazolidine,
4-Ethoxycarbonyl-2-{4-[(2-nitroxyethl)aminocarbonyl]phenyl}thiazoldin,4-ethoxycarbonyl-2- {4 - [(2-nitroxyethl) aminocarbonyl] phenyl} thiazoldin,
N-Acetyl-2-phenyl-4-[(2-nitroxyethyl)aminocarbonyl]thiazolidin, N-acetyl-2-phenyl-4 - [(2-nitroxyethyl) aminocarbonyl] thiazolidine,
4-Carboxy-2-(2-[(2-nitroxyethyl)aminocarbonylmethoxy]phenyl}thiazolidin, 4-carboxy-2- (2 - [(2-nitroxyethyl) aminocarbonylmethoxy] phenyl} thiazolidine,
4-Carboxy-2-{3-methoxy-4-[(2-nitroxyethyl)aminocarbonylmethoxyjphenyl}-thiazolidin, 4-Ethoxycarbonyl-2-([3-methoxy-4-(2-nitroxyethyl)aminocarbonylmetnoxy]phenyljthiazolidin, 4-carboxy-2- {3-methoxy-4 - [(2-nitroxyethyl) aminocarbonylmethoxyjphenyl} thiazolidine, 4-ethoxycarbonyl-2 - ([3-methoxy-4- (2-nitroxyethyl) aminocarbonylmetnoxy] phenyljthiazolidine,
4-Carboxy-2-[3-ethoxy-2-(2-nitroxyethoxy)phenyl]thiazolidin,  4-carboxy-2- [3-ethoxy-2- (2-nitroxyethoxy) phenyl] thiazolidine,
4-Carboxy-2-[4-(2-nitroxyethoxy)phenyl]thiazolidin, 4-carboxy-2- [4- (2-nitroxyethoxy) phenyl] thiazolidine,
4-Carboxy-2-[3-methoxy-2-(2-nitroxyethoxy)phenyl]thiazolidin, 4-carboxy-2- [3-methoxy-2- (2-nitroxyethoxy) phenyl] thiazolidine,
4-Carboxy-2-[5-methoxy-2-(2-nitroxyethoxy)phenyl]thiazolidin, 4-carboxy-2- [5-methoxy-2- (2-nitroxyethoxy) phenyl] thiazolidine,
4-Carboxy-2-[2-(2-nitroxyethoxy)phenyl]thiazolidin, 4-carboxy-2- [2- (2-nitroxyethoxy) phenyl] thiazolidine,
N-Acetyl-4-carboxy-2-[2-(2-nitroxyethoxy)phenyl]thiazolidin, N-acetyl-4-carboxy-2- [2- (2-nitroxyethoxy) phenyl] thiazolidine,
4-Carboxy-2-[3-(2-nitroxyethoxy)phenyl]thiazolidin, 4-carboxy-2- [3- (2-nitroxyethoxy) phenyl] thiazolidine,
2-[3-(2-Nitroxyethoxy)phenyl]thiazolidin, 2- [3- (2-nitroxyethoxy) phenyl] thiazolidine,
4-Carboxy-2-[3,5-dinitro-2-(2-nitroxyethoxy)phenyl]thiazolidin,  4-carboxy-2- [3,5-dinitro-2- (2-nitroxyethoxy) phenyl] thiazolidine,
4-Carboxy-2-[5-nitro-2-(2-nitroxyethoxy)phenyl]thiazolidin, 4-carboxy-2- [5-nitro-2- (2-nitroxyethoxy) phenyl] thiazolidine,
N-Acetyl-2-(2-phenylethyl)-4-[(4-nitroxymethylcyclohexyl)methoxycarbonyl]thiazolidin, N-acetyl-2- (2-phenylethyl) -4 - [(4-nitroxymethylcyclohexyl) methoxycarbonyl] thiazolidine,
2-[3-Brom-5-methoxy-4-(2-nitroxyethoxy)phenyl]-4-carboxythiazolidin, 2- [3-bromo-5-methoxy-4- (2-nitroxyethoxy) phenyl] -4-carboxythiazolidine,
4-Carboxy-2-{4-[(2-nitroxyethyl)aminocarbonylmethoxy]phenyl]thiazolidin,4-carboxy-2- {4 - [(2-nitroxyethyl) aminocarbonylmethoxy] phenyl] thiazolidine,
4-Carboxy-2-[5-chlor-2-(2-nitroxyethoxy)phenyl]thiazolidin, 4-carboxy-2- [5-chloro-2- (2-nitroxyethoxy) phenyl] thiazolidine,
4-Carboxy-5,5-dimethyl-2-[(2-nitroxyethoxy)phenyl]thiazolidin,  4-carboxy-5,5-dimethyl-2 - [(2-nitroxyethoxy) phenyl] thiazolidine,
2-[(2-Nitroxyethoxy)phenyl]thiazolidin,  2 - [(2-nitroxyethoxy) phenyl] thiazolidine,
4-Ethoxycarbonyl-2-[2-(2-nitroxyethoxy)phenyl]thiazolidin,  4-ethoxycarbonyl-2- [2- (2-nitroxyethoxy) phenyl] thiazolidine,
4-Carboxy-2-(2-{[4-nitroxymethyl-(trans)-cyclohexyl]methoxy)phenyl)thiazolidin,  4-carboxy-2- (2 - {[4-nitroxymethyl- (trans) -cyclohexyl] methoxy) phenyl) thiazolidine,
4-Carboxy-2-[2-(2,2-dimethyl-3-nitroxypro.poxy)phenyl]thiazolidin,  4-carboxy-2- [2- (2,2-dimethyl-3-nitroxypro.poxy) phenyl] thiazolidine,
4-Carboxy-N-(2,2-dimethyl-3-nitroxypropionyl)-2-phenylthiazolidin, 4-carboxy-N- (2,2-dimethyl-3-nitroxypropionyl) -2-phenylthiazolidine,
4-Carboxy-2-[2-(3-nitroxypropoxy)phenyl]thiazolidin, 4-carboxy-2- [2- (3-nitroxypropoxy) phenyl] thiazolidine,
4-Carboxyl-N-(2,2-dimethyl-3-nitroxypropionyl)-2-phenylthiazolidin, 4-carboxyl-N- (2,2-dimethyl-3-nitroxypropionyl) -2-phenylthiazolidine,
4-Carboxy-2-[2-(4-nitroxybutoxy)phenyl]thiazolidin, 4-carboxy-2- [2- (4-nitroxybutoxy) phenyl] thiazolidine,
4-Carboxy-2-[3-nitro-4-(2-nitroxyethoxy)phenyl]thiazolidin und 4-carboxy-2- [3-nitro-4- (2-nitroxyethoxy) phenyl] thiazolidine and
4-Carboxy-2-[2-(2-nitroxypropoxy)phenyl]thiazolidin. 4-carboxy-2- [2- (2-nitroxypropoxy) phenyl] thiazolidine.
PCT/EP1994/003758 1993-11-17 1994-11-12 Use of substituted thiazolidine derivatives in the treatment of raised intraocular pressure WO1995013811A1 (en)

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US6110945A (en) * 1998-06-03 2000-08-29 Celltech Therapeutics Limited Aromatic amine derivatives
US6274577B1 (en) 1998-09-30 2001-08-14 Celltech Therapeutics Limited Benzodiazepines
US6319922B1 (en) 1998-11-23 2001-11-20 Celltech Therapeutics Limited Propanoic acid derivatives
US6329362B1 (en) 1998-03-16 2001-12-11 Celltech Therapeutics Limited Cinnamic acid derivatives
US6329372B1 (en) 1998-01-27 2001-12-11 Celltech Therapeutics Limited Phenylalanine derivatives
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US6329372B1 (en) 1998-01-27 2001-12-11 Celltech Therapeutics Limited Phenylalanine derivatives
US6555562B1 (en) 1998-02-26 2003-04-29 Celltech R&D Limited Phenylalanine derivatives
US6329362B1 (en) 1998-03-16 2001-12-11 Celltech Therapeutics Limited Cinnamic acid derivatives
US6521626B1 (en) 1998-03-24 2003-02-18 Celltech R&D Limited Thiocarboxamide derivatives
US6362204B1 (en) 1998-05-22 2002-03-26 Celltech Therapeutics, Ltd Phenylalanine derivatives
US6110945A (en) * 1998-06-03 2000-08-29 Celltech Therapeutics Limited Aromatic amine derivatives
US6369229B1 (en) 1998-06-03 2002-04-09 Celltech Therapeutics, Limited Pyridylalanine derivatives
US6465471B1 (en) 1998-07-03 2002-10-15 Celltech Therapeutics Limited Cinnamic acid derivatives
WO2000009106A2 (en) * 1998-08-14 2000-02-24 Gpi Nil Holdings, Inc. Carboxylic acids and isosteres of heterocyclic ring compounds having multiple heteroatoms for vision and memory disorders
WO2000009106A3 (en) * 1998-08-14 2000-10-12 Guilford Pharm Inc Carboxylic acids and isosteres of heterocyclic ring compounds having multiple heteroatoms for vision and memory disorders
US6348463B1 (en) 1998-09-28 2002-02-19 Celltech Therapeutics Limited Phenylalanine derivatives
US6677339B2 (en) 1998-09-28 2004-01-13 Celltech R & D Limited Phenylalanine derivatives
US6274577B1 (en) 1998-09-30 2001-08-14 Celltech Therapeutics Limited Benzodiazepines
US6319922B1 (en) 1998-11-23 2001-11-20 Celltech Therapeutics Limited Propanoic acid derivatives
US6953798B1 (en) 1998-11-30 2005-10-11 Celltech R&D Limited β-alanine derivates
US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
US6534513B1 (en) 1999-09-29 2003-03-18 Celltech R&D Limited Phenylalkanoic acid derivatives
US6455539B2 (en) 1999-12-23 2002-09-24 Celltech R&D Limited Squaric acid derivates
US6610700B2 (en) 2000-04-17 2003-08-26 Celltech R & D Limited Enamine derivatives
US6545013B2 (en) 2000-05-30 2003-04-08 Celltech R&D Limited 2,7-naphthyridine derivatives
US6403608B1 (en) 2000-05-30 2002-06-11 Celltech R&D, Ltd. 3-Substituted isoquinolin-1-yl derivatives
US6740654B2 (en) 2000-07-07 2004-05-25 Celltech R & D Limited Squaric acid derivatives
US6469025B1 (en) 2000-08-02 2002-10-22 Celltech R&D Ltd. 3-substituted isoquinolin-1-yl derivatives
US20100183629A1 (en) * 2006-07-25 2010-07-22 Alcon Research, Ltd. Antagonists of endothelial differentiation gene subfamily 3 (edg-3, s1p3) receptors for prevention and treatment of ocular disorders

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