Ocular Tension Lowering Agent Okulares Hypotonikum Réducteur De Tension Oculaire

Europäisches Patentamt *EP001110551B1* (19) European Patent Office

Office européen des brevets (11) EP 1 110 551 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.7: A61K 31/4178, A61K 31/4174, of the grant of the patent: A61K 31/5377, A61P 27/06 12.05.2004 Bulletin 2004/20 // (A61K31/5377, 31:4178), (21) Application number: 01102527.7 (A61K31/5377, 31:4174)

(22) Date of filing: 16.03.1995

(54) Ocular tension lowering agent Okulares Hypotonikum Réducteur de tension oculaire

(84) Designated Contracting States: (72) Inventors: AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL • Hosokawa, Tsunemichi, PT SE Sankyo Company Limited Tokyo 140-8710 (JP) (30) Priority: 16.03.1994 JP 4540494 • Yokoyama, Tomihisa, Sankyo Company Limited Tokyo 140-8710 (JP) (43) Date of publication of application: • Yanagisawa, Hiroaki, Sankyo Company Limited 27.06.2001 Bulletin 2001/26 Tokyo 140-8710 (JP)

(62) Document number(s) of the earlier application(s) in (74) Representative: Gibson, Christian John Robert accordance with Art. 76 EPC: MARKS & CLERK, 95912428.0 / 0 795 326 57/60 Lincoln’s Inn Fields London WC2A 3LS (GB) (73) Proprietor: Sankyo Company Limited Chuo-ku, Tokyo 103-8426 (JP) (56) References cited: EP-A- 0 603 001 WO-A-91/15206 WO-A-95/21609 US-A- 5 219 856

Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 110 551 B1

Printed by Jouve, 75001 PARIS (FR) EP 1 110 551 B1

Description

[Technological field]

5 [0001] The present invention relates to an excellent ocular tension lowering agent and/or a glaucoma therapeutic agent for eye drops and/or relates to their uses as an ocular tension lowering agent and/or a glaucoma therapeutic agent for eye drops.

[Technological background] 10 [0002] Hitherto, the use of an angiotensin II inhibitor for the purpose of lowering ocular tension has been described in reports. However, there are a few cases where the effect has been certified in actual experiment, and only oral use of the inhibitor has been described. [0003] On the other hand, if the inhibitor is used only for the purpose of lowering ocular tension, its local application 15 may be preferable because of less adverse reactions and in fact has been desired so far. It has been disclosed in International Publication WO 91/15206 that angiotensin II inhibitors (in particular, DUP-753 shown by the following formula) can be locally applied by dropping in the eyes for the therapy of ocular hypertension.

35 [0004] However, in order to use the inhibitor as eye drops, the effect of administering the inhibitor as eye drops in the invention disclosed in the aforesaid International Publication was not enough to use the inhibitor as a medicament. [0005] US-A-5219856 also discloses angiotensin II inhibitors for use in the treatment of ocular hypertension and glaucoma, although they are structurally more remote from the compounds used in the present invention than those 40 disclosed in International Publication WO 91/15206. [0006] Though after the Priority Date of the present invention, G. A. Mathis et al. of CIBA Vision Ophtha reported that eye application of angiotensin II inhibitors, CGP 48933 and CGP 49870, showed ocular tension lowering activity, in the annual meeting of "The Association for Research in Vision and Ophthalmology" held in Florida from 1st to 6th, May, 1994; and the abstracts including this report were published under date of 15th, March, 1994. 45 [0007] Also after the priority date of the present invention, EP-A-603001 and EP-A-573218 were published disclosing injectible compositions in which the active components are some of the compounds used in the novel use of the present invention.

[Process of Invention] 50 [0008] For a long time, the present inventors studied eagerly a novel ocular tension lowering agent and/or a glaucoma therapeutic agent for eye drops and/or their uses as an ocular tension lowering agent and/or a glaucoma therapeutic agent for eye drops, and in addition a method of medical treatment administering the agent to mammals with ocular hypertension and/or glaucoma diseases. Our study resulted in finding that our novel compositions showed an excellent 55 ocular tension lowering and/or a glaucoma therapeutic effect even by its local application such as dropping in the eyes without adverse reactions, and in completion of the present invention.

2 EP 1 110 551 B1

[Constitution of Invention]

[0009] In a first aspect of the present invention, there is provided the use of a compound of general formula (I):

20 wherein R1 represents an alkyl group having from 1 to 6 carbon atoms; R2 represents a group of a formula -C(R6)(R7)(R8) wherein R6 represents a hydroxyl group and R7 and R8 are the same or different and each represents 25 an alkyl group having from 1 to 6 carbon atoms; R3 represents a carboxyl group; and R4 represents a carboxyl group, a carboxycarbonyl group or tetrazol-5-yl group; or a pharmacologically acceptable salt, ester or other derivative thereof, in the manufacture of a medicament suitable for local application to the eyes for use in combination with a β-blocker for the treatment of ocular hypertension and/ 30 or glaucoma. [0010] In a second aspect of the present invention, there is provided a medicament formulated as eye drops suitable for local application to the eyes comprising an effective amount of a compound of general formula (I), as defined above, or a pharmacologically acceptable salt ester or other derivative thereof and an effective amount of a β-blocker for use in the treatment of ocular hypertension and/or glaucoma. 35 [0011] Among the aforesaid compounds of formula (I) capable of being used in the manufacture of a medicament suitable for local application to the eyes for the medical treatment of ocular hypertension and/or glaucoma diseases in accordance with the invention, and/or in a medicament formulated as eye drops suitable for local application to the eyes for use in the treatment of ocular tension and/or glaucoma, the preferred compounds are those in which:

40 (1) R1 represents an alkyl group containing 1 to 4 carbon atoms; (2) R1 represents an alkyl group containing 2 to 4 carbon atoms; (3) R2 represents a group of formula: -C(R6)(R7)(R8) (wherein R6 represents a hydroxyl group, and R7 and R8 are the same or different and each represents an alkyl group containing 1 to 4 carbon atoms; (4) R7 and R8 are the same or different and each represents an alkyl group containing 1 or 2 carbon atoms; 45 (5) R2 represents a 1-hydroxy-1-methylethyl group; (6) R4 represents a tetrazol-5-yl group; (7) R1 represents an alkyl group having from 1 to 6 carbon atoms; R2 represents a group of formula: -C(R6)(R7)(R8) (wherein R6 represents a hydroxyl group; and R7 and R8 are the same or different and each represents an alkyl group having from 1 to 6 carbon atoms); R3 represents a carboxyl group; and R4 represents a 50 tetrazol-5-yl group; (8) R1 represents an alkyl group having from 1 to 6 carbon atoms; R2 represents a group of formula: -C(R6)(R7)(R8) (wherein R6 represents a hydroxyl group; and R7 and R8 are the same or different and each represents an alkyl group containing 1 to 4 carbon atoms); R3 represents a carboxyl group; and R4 represents a carboxyl group or a tetrazol-5-yl group; 55 (9) R1 represents an alkyl group having from 1 to 6 carbon atoms; R2 represents a group of formula: -C(R6)(R7)(R8) (wherein R6 represents a hydroxyl group; and R7 and R8 are the same or different and each represents an alkyl group containing 1 to 4 carbon atoms); R3 represents a carboxyl group; and R4 represents a tetrazol-5-yl group;

3 EP 1 110 551 B1

(10) R1 represents an alkyl group having from 1 to 6 carbon atoms; R2 represents a group of formula: -C(R6)(R7)(R8) (wherein R6 represents a hydroxyl group; and R7 and R8 are the same or different and each represents an alkyl group containing 1 or 2 carbon atoms); R3 represents a carboxyl group; and R4 represents a carboxyl or tetrazol-5-yl group; 5 (11) R1 represents an alkyl group having from 1 to 6 carbon atoms; R2 represents a group of formula: -C(R6)(R7)(R8) (wherein R6 represents a hydroxyl group; and R7 and R8 are the same or different and each represents an alkyl group containing 1 or 2 carbon atoms); R3 represents a carboxyl group; and R4 represents a tetrazol-5-yl group; (12) R1 represents an alkyl group containing 2 to 4 carbon atoms; R2 represents a group of formula: 10 -C(R6)(R7)(R8) (wherein R6 represents a hydroxyl group; and R7 and R8 are the same or different and each represents an alkyl group having from 1 to 6 carbon atoms); R3 represents a carboxyl group; and R4 represents a carboxyl group or a tetrazol-5-yl group; (13) R1 represents an alkyl group containing 2 to 4 carbon atoms; R2 represents a group of formula: -C(R6)(R7)(R8) (wherein R6 represents a hydroxyl group; and R7 and R8 are the same or different and each rep- 15 resents an alkyl group having from 1 to 6 carbon atoms); R3 represents a carboxyl group; and R4 represents a tetrazol-5-yl group; (14) R1 represents an alkyl group containing 2 to 4 carbon atoms; R2 represents a group of formula: -C(R6)(R7)(R8) (wherein R6 represents a hydroxyl group; and R7 and R8 are the same or different and each represents an alkyl group containing 1 to 4 carbon atoms); R3 represents a carboxyl group; and R4 represents a 20 carboxyl group or a tetrazol-5-yl group; (15) R1 represents an alkyl group containing 2 to 4 carbon atoms; R2 represents a group of formula: -C(R6)(R7)(R8) (wherein R6 represents a hydroxyl group; and R7 and R8 are the same or different and each represents an alkyl group containing 1 to 4 carbon atoms); R3 represents a carboxyl group; and R4 represents a tetrazol-5-yl group; 25 (16) R1 represents an alkyl group containing 2 to 4 carbon atoms: R2 represents a group of formula: -C(R6)(R7)(R8) (wherein R6 represents a hydroxyl group; and R7 and R8 are the same or different and each represents an alkyl group containing 1 or 2 carbon atoms); R3 represents a carboxyl group; and R4 represents a carboxyl group or a tetrazol-5-yl group; (17) R1 represents an alkyl group containing 2 to 4 carbon atoms; R2 represents a group of formula: 30 -C(R6)(R7)(R8) (wherein R6 represents a hydroxyl group; and R7 and R8 are the same or different and each represents an alkyl group containing 1 or 2 carbon atoms); R3 represents a carboxyl group; and R4 represents a tetrazol-5-yl group; (18) A compound having the following formula:

55 or (19) A compound having the following formula:

4 EP 1 110 551 B1

15 [0012] In the above general formula (I): [0013] In the definition of R1,R7and R8, the alkyl group having from 1 to 6 carbon atoms is a straight or branched chain alkyl group containing 1 to 6 carbon atoms such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methyl- 20 pentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl; and preferably a straight or branched chain alkyl group containing 1 to 4 carbon atoms. More preferably, R1 signifies a straight or branched chain alkyl group containing 2 to 4 carbon atoms and the term alkyl group used in the definition of R7 and R8 signifies a straight chain alkyl group containing 1 or 2 carbon atoms. 25 [0014] The term "pharmacologically acceptable salt" signifies the salts which may be produced from a compound of general formula (I) used in the present invention. As such salts there come especially into consideration: a metal salt such as an alkaline metal salt (e.g., sodium salt, potassium salt and lithium salt), an alkaline earth metal salt (e.g., calcium salt and magnesium salt), aluminium salt or iron salt; an amine salt such as an inorganic salt (e.g., ammonium salt) or an organic salt (e.g., tert-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, alkyl phenylg- 30 lycinate salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-ben- zylphenethylamine salt, piperazine salt, tetramethylammonium salt and tris(hydroxymethyl)aminomethane salt); an inorganic acid salt such as a hydrohalic acid salt (e.g., hydrochloric acid salt, hydrobromic acid salt and hydroiodic acid salt), nitric acid, sulfuric acid or phosphoric acid; an organic acid salt such as a lower alkanesulfonic acid (e.g., meth- 35 anesulfonic acid salt, trifluoromethanesulfonic acid salt and ethanesulfonic acid salt), an arylsulfonic acid (e.g., ben- zenesulfonic acid salt and p-toluenesulfonic acid salt), an acetic acid salt, a malic acid salt, a fumaric acid salt, a succinic acid salt, a citric acid salt, a tartaric acid salt, an oxalic acid salt and a maleic acid salt; and an amino acid salt (e.g., glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt and aspartic acid salt). [0015] When the compounds of formula (I) used in the invention are allowed to stand in the atmosphere or recrys- 40 tallized, they sometimes form a hydrate compound based upon absorbing water or hydrating. The present invention also covers such a salt. [0016] The term "esters or other derivatives" signifies such derivatives that, where the compounds of formula (I) used in the present invention have at least one hydroxyl group, can be derived by modifying with a "conventional protecting group" or a "protecting group capable of cleaving by biological methods such as an enzymatic reaction in vivo"; and/ 45 or that, where the compounds of formula (I) used in the present invention have at least one carboxyl group or carboxycarbonyl group, can be derived by modifying with a "conventional protecting group" or with a "protecting group capable of cleaving by biological methods such as an enzymatic reaction in vivo", or the said term signifies an amide of the said carboxyl group or the said carboxycarbonyl group. [0017] The term "conventional protecting group" signifies a protecting group capable of being removed by chemical 50 methods such as reduction or hydrolysis. As the "conventional protecting group" of a "hydroxyl group" there comes into consideration: an "aliphatic acyl group" which signifies an "alkylcarbonyl group" such as, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, hep- 55 tadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, eicosanoyl or heneicosa- noyl, a "carboxylated alkylcarbonyl group" such as succinoyl, glutaroyl or adipoyl, a "halogeno-lower alkylcarbonyl group" such as chloroacetyl, dichloroacetyl, trichloroacetyl or trifluoroacetyl, a "lower alkoxy-lower alkylcarbonyl group" such as methoxyacetyl, or an "unsaturated alkylcarbonyl group" such as (E)-2-methyl-2-butenoyl, and preferably an

5 EP 1 110 551 B1

"alkylcarbonyl group"; an "aromatic acyl group" which signifies for example, an "arylcarbonyl group" such as benzoyl, α-naphthoyl or β-naphthoyl, a "halogenoarylcarbonyl group" such as 2-bromobenzoyl or 4-chlorobenzoyl, a "lower alkylated arylcarbonyl group" such as 2,4,6-trimethylbenzoyl or 4-toluoyl, a "lower alkoxylated arylcarbonyl group" such as 4-anisoyl, a "carboxylated arylcarbonyl group" such as 2-carboxybenzoyl, 3-carboxybenzoyl or 4-carboxybenzoyl, 5 a "nitrated arylcarbonyl group" such as 4-nitrobenzoyl or 2-nitrobenzoyl, a "lower alkoxycarbonylated arylcarbonyl group" such as 2-(methoxycarbonyl)benzoyl, or an "arylated arylcarbonyl group" such as 4-phenylbenzoyl, and preferably an "arylcarbonyl group"; a "tetrahydropyranyl or tetrahydrothiopyranyl group" such as tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl or 4-methoxytetrahydrothi- opyran-4-yl; a "tetrahydrofuranyl or tetrahydrothiofuranyl group" such as tetrahydrofuran-2-yl or tetrahydrothiofuran- 10 2-yl; a "silyl group" such as a tri(lower alkyl)silyl group (e.g. trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyld- imethylsilyl, methyldiisopropylsilyl, methyldi-tert-butylsilyl and triisopropylsilyl) or a tri(lower alkyl)silyl group substituted by 1 or 2 aryl groups (e.g diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl); an "alkoxymethyl group" such as a lower alkoxymethyl group (e.g. methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and tert-butoxymethyl), a lower alkoxylated alkoxyme- 15 thyl group (e.g. 2-methoxyethoxymethyl) or a halogeno-lower alkoxymethyl group (e.g. 2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methy); a substituted ethyl group such as a lower alkoxylated ethyl group (e.g. 1-ethoxyethyl and 1-(isopropoxy)ethyl) or a halogenated ethyl group (e.g. 2,2,2-trichloroethyl); an "aralkyl group" which signifies an alkyl group having from 1 to 6 carbon atoms substituted by 1 to 3 aryl groups such as benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, 6-phenylhexyl, α-naphthyldiphenylmethyl or 20 9-anthrylmethyl, or an alkyl group having from 1 to 6 carbon atoms substituted by 1 to 3 aryl groups, which are substituted by lower alkyl, lower alkoxy, nitro, halogen, cyano and/or alkoxycarbonyl, such as 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis(2-nitrophenyl)methyl, piperonyl or 4-methoxycarbonylbenzyl, preferably an "aralkyl group" in which the alkyl group has 1 to 4 carbon atoms, and more 25 preferably an alkyl group containing 1 to 4 carbon atoms substituted by 1 or 2 aryl groups; an "alkoxycarbonyl group" such as a lower alkoxycarbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and isobutoxycar- bonyl) or a lower alkoxycarbonyl group substituted by halogen or tri(lower alkyl)silyl (e.g. 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl); an "alkenyloxycarbonyl group" such as vinyloxycarbonyl or allyloxycarbonyl; and an "aralkyloxycarbonyl group" which may optionally be substituted by 1 or 2 lower alkoxy or nitro groups such as 30 benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl or 4-nitrobenzyloxycarbonyl. [0018] As the "conventional protecting group" of a "carboxyl group or carboxycarbonyl group" there come especially into consideration: the aforesaid alkyl group having from 1 to 6 carbon atoms; a "lower alkenyl group" which signifies a straight or branched chain alkenyl group containing 2 to 6 carbon atoms such as ethenyl, 1-propenyl, 2-propenyl, 35 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl, and preferably a straight or branched chain alkenyl group containing 3 40 to 5 carbon atoms; a "lower alkynyl group" which signifies a straight or branched chain alkynyl group containing 2 to 6 carbon atoms such as ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl, 2-ethyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 2-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl- 3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl or 5-hexynyl, and preferably a 45 straight or branched chain alkynyl group containing 3 to 5 carbon atoms, a "halogeno-lower alkyl group" such as 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluor- obutyl, 6-iodohexyl or 2,2-dibromoethyl; a hydroxy- "lower alkyl group" such as 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl or 4-hydroxybutyl; an "aliphatic acyl-lower alkyl group" such as acetylmethyl; the aforesaid "aralkyl group"; and the aforesaid "silyl group". 50 [0019] The term "protecting group capable of cleaving by biological methods such as an enzymatic reaction in vivo" signifies a protecting group capable of cleaving by biological methods such as an enzymatic reaction in vivo to produce a free acid or its salt. In order to determine whether a compound is such a derivative or not, one can administer the compound orally or intravenously to an experimental animal such as a rat or mouse followed by examining the body fluids of the animal to detect and determine an original compound or pharmacologically acceptable salt. 55 [0020] As the "protecting group capable of cleaving by biological methods such as an enzymatic reaction in vivo" of a hydroxyl group there come into consideration, for example, a "1-(acyloxy)-lower alkyl group" such as a "1-(aliphatic acyloxy)-lower alkyl group" (e.g. formyloxymethyl, acetoxymethyl, dimethylaminoacetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl,

6 EP 1 110 551 B1

1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypro- pyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxy- butyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl and 1-pival- 5 oyloxyhexyl); a "1-(cycloalkylcarbonyloxy)-lower alkyl group" (e.g. cyclopentylcarbonyloxymethyl, cyclohexylcarbony- loxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cy- clohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl and 1-cyclohexylcarbonyloxybutyl), a "1-(aromatic acyloxy)-lower alkyl group" (e.g. benzoyloxymethyl) or the like; a "1-(alkoxycarbonyloxy)alkyl group" such as methoxycar- bonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbo- 10 nyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, cyclopentyloxycarbonyloxymethyl, hexy- loxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl, 1-(propoxycarbonyloxy) ethyl, 1-(isopropoxycarbonyloxy)ethyl, 1-(butoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy) ethyl, 1-(tert-butoxycarbonyloxy)ethyl, 1-(pentyloxycarbonyloxy) ethyl, 1-(hexyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)propyl, 1-(cyclohexyloxycarbonyloxy)propyl, 1-(cyclopentyloxy- 15 carbonyloxy)butyl, 1-(cyclohexyloxycarbonyloxy)butyl, 1-(cyclohexyloxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)propyl, 1-(methoxycarbonyloxy)propyl, 1-(ethoxycarbonyloxy)propyl, 1-(propoxycarbonyloxy)propyl, 1-(isopropoxycarbonyloxy)propyl, 1-(butoxycarbonyloxy)propyl, 1-(isobutoxycarbonyloxy)propyl, 1-(pentyloxycarbonyloxy)propyl, 1-(hexyloxycarbonyloxy)propy, 1-(methoxycarbonyloxy)butyl, 1-(ethoxycarbonyloxy)butyl, 1-(propoxycarbonyloxy)butyl, 1-(isopropoxycarbonyloxy)butyl, 1-(butoxycarbonyloxy)butyl, 1-(isobutoxycarbonyloxy)butyl, 1-(methoxycarbonyloxy) 20 pentyl, 1-(ethoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy)hexyl or 1-(ethoxycarbonyloxy)hexyl; a "2-oxo-1,3-dioxolenylmethyl group" such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl] methyl, [5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-fluorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-chlorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, (2-oxo-1,3-dioxolen-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxolen- 4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-isopropyl-2-oxo- 25 1,3-dioxolen-4-yl)methyl or (5-butyl-2-oxo-1,3-dioxolen-4-yl)methyl; a "phthalidyl group" such as phthalidyl, dimethyl- phthalidyl or dimethoxyphthalidyl; the aforesaid "aliphatic acyl group"; the aforesaid "aromatic acyl group"; a "half ester salt residue of succinic acid"; "an amino acid residue capable of forming an ester"; a carbamoyl group; a carbamoyl group substituted by 1 or 2 lower alkyl groups; a "1-(acyloxy)alkyloxycarbonyl group" such as pivaloyloxymethyloxy- carbonyl; and preferably a "2-oxo-1,3-dioxolenylmethyl group", "phthalidyl group", "aliphatic acyl group" or "aromatic 30 acyl group". [0021] As the "protecting group capable of cleaving by biological methods such as an enzymatic reaction in vivo" of a "carboxyl group or carboxycarbonyl group" there come especially into consideration: an "alkoxy-lower alkyl group" such as a lower alkoxy-lower alkyl group (e.g. methoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy) ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxyme- 35 thyl, n-butoxymethyl and tert-butoxymethyl); a lower alkoxylated lower alkoxy-lower alkyl group (e.g. 2-methoxyethoxymethyl); an "aryloxy-lower alkyl group" (e.g. phenoxymethyl); a halogenated lower alkoxy-lower alkyl group (e. g. 2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl) or the like; a "lower alkoxycarbonyl-lower alkyl group" such as methoxycarbonylmethyl; a "cyano-lower alkyl group" such as cyanomethyl or 2-cyanoethyl; a "lower alkylthi- omethyl group" such as methylthiomethyl or ethylthiomethyl; an "arylthiomethyl group" such as phenylthiomethyl or 40 naphthylthiomethyl; a "lower alkylsulfonyl-lower alkyl group which may optionally be substituted by halogen" such as 2-methanesulfonylethyl or 2-trifluoromethanesulfonylethyl; an "arylsulfonyl-lower alkyl group" such as 2-benzenesul- fonylethyl or 2-toluenesulfonylethyl; the aforesaid "1-(acyloxy)-lower alkyl group"; the aforesaid "phthalidyl group"; the foresaid "aryl group"; the aforesaid "lower alkyl group"; a "carboxylalkyl group" such as carboxymethyl; an "amino acid residue capable of forming an amide" such as phenylalanine; and preferably an "alkoxy-lower alkyl group", a "1-(acy- 45 loxy)-lower alkyl group", a "phthalidyl group", a "lower alkyl group" or an "amino acid residue capable of forming an amide". [0022] The compounds comprised in the composition in accordance with the present invention can exist in the form of various stereoisomers due to the presence of an asymmetric carbon atom having R- or S-configuration in the mol- ecule. But the present invention covers both the individual isomers and mixtures thereof. 50 [0023] All compounds of formula (I) of the present invention, which are ocular tension lowering agents and/or glaucoma therapeutic agents for eye drops, which are submitted to the use as a ocular tension lowering agent and/or a glaucoma therapeutic agent for eye drops and which are used in a method of medical treatment of ocular hypertension and/or glaucoma diseases, are known and can be synthesized following the procedure disclosed in, for example, (1) Japanese Patent Kokai Application No. Hei 5-78328, (2) Japanese Patent Kokai Application No. Hei 6-49036, (3) EP 55 245637A, (4) EP 253310A, (5) EP 291969A, (6) EP 323841A, (7) EP 324377A, (8) EP 380959A, (9) EP 392317A, (10) EP 399731A, (11) EP 399732A, (12) EP 400835A, (13) EP 400974A, (14) EP 401030A, (15) EP 403158A, (16) EP 403159A, (17) EP 407102A, (18) EP 407342A, (19) EP 409332A, (20) EP 411507A, (21) EP 411766A, (22) EP 412594A, (23) EP 412848A, (24) EP 415886A, (25) EP 419048A, (26) EP 420237A, (27) EP 424317A, (28) EP

7 EP 1 110 551 B1

425211A, (29) EP 425921A, (30) EP 426021A, (31) EP 427463A, (32) EP 429257A, (33) EP 430300A, (34) EP 430709A, (35) EP 432737A, (36) EP 434038A, (37) EP 434249A, (38) EP 435827A, (39) EP 437103A, (40) EP 438869A, (41) EP 442473A, (42) EP 443568A, (43) EP 443983A, (44) EP 445811A, (45) EP 446062A, (46) EP 447342A, (47) EP 449699A, (48) EP 450566A, (49) EP 453210A, (50) EP 454511A, (51) EP 455423A, (52) EP 5 456442A, (53) EP 456510A, (54) EP 459136A, (55) EP 461039A, (56) EP 461040A, (57) EP 465323A, (58) EP 465368A, (59) EP 467207A, (60) EP 467715A, (61) EP 468372A, (62) EP 468470A, (63) EP 470543A, (64) EP 470794A, (65) EP 470795A, (66) EP 475206A, (67) EP 475898A, (68) EP 479479A, (69) EP 480204A, (70) EP 480659A, (71) EP 481448A, (72) EP 481614A, (73) EP 483683A, (74) EP 485929A, (75) EP 487252A, (76) EP 487745A, (77) EP 488532A, (78) EP 490587A, (79) EP 490820A, (80) EP 495626A, (81) EP 495627A, (82) EP 10 497121A, (83) EP 497150A, (84) EP 497516A, (85) EP 503162A, (86) EP 510812A, (87) US 4340598, (88) US 4355042, (89) US 4820843, (90) US 4870186, (91) US 4874867, (92) US 4880804, (93) US 4916129, (94) US 5015651, (95) US 5039814, (96) US 5041552, (97) US 5043349, (98) US 5045540, (99) US 5049565, (100) US 5053329, (101) US 5057522, (102) US 5064825, (103) US 5066586, (104) US 5081127, (105) US 5087634, (106) US 5087702, (107) US 5093346, (108) US 5098920, (109) US 5100897, (110) US 5102880, (111) US 5104891, (112) US 5126342, (113) 15 US 5128327, (114) US 5128356, (115) US 5130318, (116) US 5130439, (117) US 5137906, (118) US 5138069, (119) WO 8906233, (120) WO 9100277, (121) WO 9100281, (122) WO 9107404, (123) WO 9111909, (124) WO 9111999, (125) WO 9112001, (126) WO 9112002, (127) WO 9113063, (128) WO 9114367, (129) WO 9114679, (130) WO 9115206, (131) WO 9115209, (132) WO 9115479, (133) WO 9115479, (134) WO 9116313, (135) WO 9117148, (136) WO 9118888, (137) WO 9119697, (138) WO 9119715, (139) WO 9200067, (140) WO 9200068, (141) WO 9200285, 20 (142) WO 9200977, (143) WO 9202257, (144) WO 9202508, (145) WO 9202510, (146) WO 9204335, (147) WO 9204343, (148) WO 9205161, (149) WO 9206081, (150) WO 9207852, (151) WO 9210179, (152) WO 9210180, (153) WO 9210181, (154) WO 9210182, (155) WO 9210183, (156) WO 9210184, (157) WO 9210185, (158) WO 9210186, (159) WO 9210187, (160) WO 9210188 and (161) WO 9211255; preferably Japanese Patent Kokai Application No. Hei 5-78328 and 6-49036. 25 [0024] The "esters and other derivatives" of a carboxyl group and/or a carboxycarbonyl group can be prepared from the corresponding carboxylic acid salts or free carboxylic acids as follows: [0025] where the said protecting reaction is alkylation, it is conducted in accordance with one of following methods:

Method 1 30 [0026] The method is to react a compound of general formula (I) having at least one carboxyl group and/or one carboxycarbonyl group with a compound of general formula: R11-X in a solvent in the presence of a base, normally, at a temperature of -20°C to 120°C (preferably 0°C to 80°C) for a period of 0.5 to 10 hours. [0027] In the above formula, 35 R11 represents a residue of the corresponding esters or other derivatives; and X represents a group capable of leaving as a nucleophilic group. Examples of such groups include, for example, a halogen atom such as chlorine, bromine or iodine; a lower alkanesulfonyloxy groups such as methanesulfonyloxy or ethanesulfonyloxy; halogeno-lower alkanesulfonyloxy groups such as trifluoromethanesulfonyloxy or pentafluoroethanesulfonyloxy; and arylsulfonyloxy groups such as benzenesulfonyloxy, p-toluenesulfonyloxy or p-nitrobenze- 40 nesulfonyloxy. [0028] As the compounds having a general formula: R11-X there come into consideration, for example: aliphatic acyloxymethyl halides such as acetoxymethyl chloride, pivaloyloxymethyl bromide or pivaloyloxymethyl chloride; lower alkoxycarbonyloxyalkyl halides such as ethoxycarbonyloxymethyl chloride, isopropoxycarbonyloxymethyl chloride, 1-(ethoxycarbonyloxy)ethyl chloride or 1-(ethoxycarbonyloxy)ethyl iodide; phthalidyl halides; and (5-methyl-2-oxo- 45 1,3-dioxolen-4-yl)methyl halides. [0029] There is no particular limitation upon the nature of the solvent used, provided that it has no adverse effect upon the reaction and can dissolve the starting material at some extent. Examples of preferred solvents include: aliphatic hydrocarbons such as hexane or heptane; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlo- 50 robenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol diemthyl ether; ketones such as acetone, methyl ethyl ketone or methyl isobutyl ketone; nitriles such as acetonitrile; and amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphoric triamide. [0030] There is no particular limitation upon the nature of the base used, provided that it can be used as a base in 55 normal reaction. Examples of preferred bases include: inorganic bases such as alkaline metal carbonates (e.g. sodium carbonate, potassium carbonate and lithium carbonate), alkaline metal hydrogencarbonates (e.g. sodium hydrogencarbonate, potassium hydrogencarbonate and lithium hydrogencarbonate), alkaline metal hydrides (e.g. lithium hydride, sodium hydride and potassium hydride), alkaline metal hydroxides (e.g. sodium hydroxide, potassium hydroxide,

8 EP 1 110 551 B1

barium hydroxide and lithium hydroxide), or alkaline metal fluorides (e.g. sodium fluoride and potassium fluoride); alkaline metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide or lithium methoxide; organic bases such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimeth- 5 ylamino)pyridine, 2,6-di(tert-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane or 1,8-diazabicyclo[5.4.0]undec-7-ene; and organic metal bases such as butyllithium, lithium diisopropylamide or lithium bis(trimethylsilyl)amide.

Method 2 10 [0031] This method is to react a compound of general formula (I) having at least one carboxyl group and/or one carboxycarbonyl group with a compound of general formula: R11-OH (in which R11 is as defined above) in a solvent in the presence or absence of a base under the influence of a condensing agent. [0032] There is no particular limitation upon the nature of the solvent used, provided that it has no adverse effect 15 upon the reaction and can dissolve the starting material at some extent. Examples of preferred solvents include: aliphatic hydrocarbons such as hexane or heptane; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; nitriles 20 such as acetonitrile or isobutyronitrile; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphoric triamide. [0033] There is no particular limitation upon the nature of the base used, provided that it can be used as a base in normal reaction. Examples of preferred bases include: organic bases such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 25 4-(N,N-dimethylamino)pyridine, 2,6-di(tert-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline and N,N-diethylaniline. [0034] As the condensing agents to be used there come into consideration:

(1) A combination of phosphates such as diphenylphosphoryl azide or diethyl cyanophosphate and the aforesaid 30 base; (2) Carbodiimides such as 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide or 1-ethyl-3-(3-dimethylami- nopropyl)carbodiimide; (3) A combination of the aforesaid carbodiimides and the aforesaid bases; (4) A combination of the aforesaid carbodiimides and N-hydroxy derivatives such as N-hydroxysuccinimide, 1-hy- 35 droxybenzotriazole or N-hydroxy-5-norbornene-2,3-dicarboximide; (5) A combination of disulfides such as 2,2'-dipyridyl disulfide or 2,2'-dibenzothiazolyl disulfide and phosphines such as triphenylphosphine or tributylphosphine; (6) Carbonates such as N,N'-disuccinimidyl carbonate, di-2-pyridyl carbonate or S,S'-bis(1-phenyl-1H-tetrazol- 5-yl) dithiocarbonate; 40 (7) Phosphinic chlorides such as N,N'-bis(2-oxo-3-oxazolidinyl)phosphinic chloride; (8) Oxalates such as N,N'-disuccinimidyl oxalate, N,N'-diphthalimide oxalate, N,N'-bis(5-norbornene-2,3-dicarbo- xyimidyl) oxalate, 1,1'-bis(benzotriazolyl) oxalate, 1,1'-bis(6-trifluoromethylbenzotriazolyl) oxalate; (9) A combination of the aforesaid phosphines and azodicarboxylates or azodicarboxyamides such as diethyl azodi- carboxylate or 1,1'-(azodicarbonyl)dipiperidine; 45 (10) A combination of the aforesaid phosphines and the aforesaid bases; (11) N-lower alkyl-5-arylisoxazolium-3'-sulfonates such as N-ethyl-5-phenylisoxazolium-3'-sulfonate; (12) Diheteroaryl diselenides such as di-2-pyridyl diselenide; (13) Arylsulfonyl triazolides such as p-nitrobenzenesulfonyl triazolide; (14) 2-Halogeno-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide; 50 (15) Imidazoles such as 1,1'-oxalyldiimidazole or N,N'-carbonyldiimidazole; (16) 3-Lower alkyl-2-halobenzothiazolium fluoroborates such as 3-ethyl-2-chlorobenzothiazolium fluoroborate; (17) 3-Lower alkylbenzothiazole-2-selones such as 3-methylbenzothiazole-2-selone; (18) Phosphates such as phenyl dichlorophosphate or polyphosphate; (19) Halogenosulfonyl isocyanates such as chlorosulfonyl isocyanate; 55 (20) Halogenosilanes such as trimethylsilyl chloride or triethylsilyl chloride; (21) A combination of lower alkanesulfonyl halides such as methanesulfonyl chloride and the bases shown below; (22) N,N,N',N'-tetra(lower alkyl)halogenoformamidium chlorides such as N,N,N',N'-tetramethylchloroformamidium chloride; and preferably carbodiimides or a combination of phosphines and azodicarboxylates or azodicarboxya-

9 EP 1 110 551 B1

mides.

[0035] The reaction can also be carried out using a catalytic amount of 4-(N,N-dimethylamino)pyridine or 4-pyrrolidinopyridine together with other bases. In order to conduct effectively the reaction, dehydrating agents such as molecular 5 sieves; quaternary ammonium salts such as benzyltriethylammonium chloride or tetrabutylammonium chloride; crown ethers such as dibenzo-18-crown-6; acid-capturing agents such as 3,4-dihydro-2H-pyrido[1,2-α]pyrimidin-2-one or the like can be added to the reaction mixture. [0036] The reaction is carried out at a temperature of from - 20°C to 80°C, preferably 0°C to room temperature. [0037] The time required for the reaction varies mainly depending upon the reaction temperature as well as upon 10 the nature of the starting material, the reagent and the solvent used, but the reaction is normally completed within a period of 10 minutes to 3 days, preferably 30 minutes to 1 day.

Method 3

15 [0038] The method is to react a compound of general formula (I) having at least one carboxyl group and/or one carboxycarbonyl group with the corresponding alcohol such as methanol, ethanol, propanol or butanol in a solvent in the presence of an acid catalyst. [0039] There is no particular limitation upon the nature of the solvent used, provided that it has no adverse effect upon the reaction and can dissolve the starting material at some extent. Examples of preferred solvents include: the 20 same alcohol as the reagent used; aliphatic hydrocarbons such as hexane or heptane; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; and preferably the same alcohol as the reagent used. [0040] There is no particular limitation upon the nature of the acid catalyst used, provided that it can be used as an 25 acid catalyst in normal reaction. Examples of preferred acid catalysts include: Bronsted acid such as inorganic acids (e.g. hydrogen chloride, hydrobromic acid, sulfuric acid, perchloric acid and phosphoric acid) or organic acids (e.g. acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid and trifluoromethanesulfonic acid); Lewis acids such as boron trichloride, boron trifluoride or boron tribromide; and acidic ion-exchange resin. 30 [0041] The reaction is carried out at a temperature of from 0°C to 100°C, preferably 20°C to 60°C. [0042] The time required for the reaction varies mainly depending upon the reaction temperature as well as upon the nature of the starting material, the reagent and the solvent used, but the reaction is normally completed within a period of from 1 to 24 hours.

35 Method 4

[0043] The method is to react a compound of general formula (I) having at least one carboxyl group and/or one carboxycarbonyl group with (1) a halogenating agent (for example, phosphorus pentachloride, thionyl chloride, oxalyl chloride and the like) at near room temperature for a period of 30 minutes to 5 hours to produce an acid halide, or with 40 (2) chloroformates such as methyl chloroformate or ethyl chloroformates (e.g. methyl chloroformate and ethyl chloroformate) in the presence of an organic base such as triethylamine to produce a mixed acid anhydride, and then reacting the product with the corresponding alcohol in an inert solvent in the presence of a base (e.g. triethylamine) at a temperature of from -10°C to 150°C (preferably at near room temeperature) for a period of from 10 minutes to 15 hours (preferably 30 minutes to 10 hours). 45 [0044] There is no particular limitation upon the nature of the inert solvent used, provided that it has no adverse effect upon the reaction and can dissolve the starting material to some extent. Examples of preferred solvent include: aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane or chloroform; esters such as ethyl acetate or propyl acetate; ethers such as ether, tetrahydrofuran, dioxane or dimethoxyethane; and nitriles such as acetonitrile. 50 Method 5

[0045] The method is to react a compound of general formula (I) having at least one carboxyl group and/or one carboxycarbonyl group with a diazoalkane such as diazomethane or diazoethane (generally an ether solution of dia- 55 zoalkane) at near room temperature (depending on the reaction system, if necessary, upon heating).

10 EP 1 110 551 B1

Method 6

[0046] Furthermore, where the protecting reaction is lower alkylation, it can be conducted by reacting a compound of general formula (I) having at least one carboxyl group and/or one 5 carboxycarbonyl group with a dialkyl sulfate such as dimethyl sulfate or diethyl sulfate by conventional means in the presence of a similar base to that described in Method 1. [0047] After completion of the reaction, the desired compound can be recovered from the reaction mixture by conventional means. [0048] An example of such technique comprises: neutralizing properly the reaction mixture; or filtering off where 10 insoluble materials exist; adding water and a water-immiscible solvent such as ethyl acetate; washing the organic phase with water; separating the organic phase comprising the desired compound; drying over anhydrous magnesium sulfate or the like; and finally distilling off the solvent. [0049] If necessary, the compounds thus obtained can be further separated and purified by conventional means, for example, recrystallization, reprecipitation or by the proper combination of conventional means for separating and pu- 15 rifying organic compounds, for example, absorption chromatography through a carrier such as silica gel, alumina or Florisil (magnesium-silica gel) and partition chromatography through a carrier such as Cephadex LH-20 (a product of Pharmacia Inc.), Amberlite XAD-11 (a product of Rohm & Haas Co.) or Diaion HP-20 (a product of Mitsubishi Kasei Co.) by eluting using an apropriate eluting solution. [0050] The reaction for preparing the salt of carboxylic acid: 20 (1) In the case of metal salts of a carboxylic acid, the desired metal salts can be prepared by reacting a compound of general formula (I) having at least one carboxyl group and/or one carboxycarbonyl group with the hydroxides, carbonates or the like of the said metal in an aqueous solvent. 25 Examples.of the aqueous solvents used include: water; alcohols such as methanol or ethanol; acetone; a mixture of water and one or more of these organic solvents; and preferably a mixture of a hydrophilic organic solvent and water. The reaction can usually be conducted at near room temperature, if necessary, upon heating. (2) In the case of amine salts of a carboxylic acid, 30 the desired amine salts can be prepared by reacting a compound of general formula (I) having at least one carboxyl group and/or one carboxycarbonyl group with the corresponding amine in a solvent by conventional means. Examples of the solvents used include: water; alcohols such as methanol or ethanol; ethers such as tetrahydrofuran; nitriles such as acetonitrile; a mixture of water and one or more of these solvents; and preferably alcohols. 35 (3) In the case of amino acid salts of a carboxylic acid, the desired amino acid salts can be prepared by reacting a compound of general formula (I) having at least one free carboxyl group with the corresponding amino acid in an aqueous solvent. Examples of the aqueous solvents used include: water; alcohols such as methanol or ethanol; ethers such as tetrahydrofuran; and a mixture of water and one or more of these solvents. 40 The reaction can usually be conducted upon heating, preferably at a temperature of from 50°C to 60°C.

[0051] The esters or other derivatives of a hydroxyl group can be produced from the corresponding compound as follows. [0052] It is conducted in accordance with one of following methods: 45 Method A

[0053] The method is to react a compound of general formula (I) having at least one hydroxyl group with 1 to 4 equivalents (preferably 2 to 3 equivalents) of a compound of formula; R12-X' or R12-O-R12, wherein R12 represents. 50 an acyl group, in a solvent in the presence or absence of a base. [0054] In the above formulae, R12 represents the corresponding residue of esters or other derivatives; and X' represents a leaving group. There is no particular limitation upon the nature of the leaving group, provided that it is generally capable of leaving as a nucleophilic group. Examples of preferred leaving groups include: a halogen atom 55 such as chlorine, bromine or iodine; a lower alkoxycarbonyloxy group such as methoxycarbonyloxy or ethoxycarbonyloxy; a halogenated alkylcarbonyloxy group such as chloroacetyloxy, dichloroacetyloxy, trichloroacetyloxy or trifluor- oacetyloxy; a lower alkanesulfonyloxy group such as methanesulfonyloxy or ethanesulfonyloxy; a halogeno-lower alkanesulfonyloxy group such as trifluoromethanesulfonyloxy or pentafluoroethanesulfonyloxy; an arylsulfonyloxy group

11 EP 1 110 551 B1

such as benzenesulfonyloxy, p-toluenesulfonyloxy or p-nitrobenzenesulfonyloxy; and more preferably a halogen atom, a halogeno-lower alkanesulfonyloxy or arylsulfonyloxy group. [0055] As examples of a compound having general formula: R12-X there come into consideration: acyl halides such as aliphatic acyl halides (e.g. acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride and hexanoyl chloride), 5 lower alkoxycarbonyl halides (e.g. methoxycarbonyl chloride, methoxycarbonyl bromide, ethoxycarbonyl chloride, pro- poxycarbonyl chloride, butoxycarbonyl chloride and hexyloxycarbonyl chloride) or arylcarbonyl halides (e.g. benzoyl chloride, benzoyl bromide and naphthoyl chloride); silyl halides such as trimethylsilyl chloride or triethylsilyl bromide; aralkyl halides such as benzyl chloride or benzyl bromide; and carbonyloxy-lower alkyl halides such as pivaloyloxymethyl chloride or ethoxycarbonyloxymethyl chloride. 10 [0056] As examples of a compound having general formula: R12-O-R12 there come into consideration: aliphatic carboxylic acid anhydrides such as acetic anhydride, propionic anhydride, valeric anhydride or hexanoic anhydride and mixed acid anhydrides such as acetic formic anhydride. [0057] There is no particular limitation upon the nature of the solvent used, provided that it has no adverse effect upon the reation and can dissolve the starting material to some extent. Examples of preferred solvents include: aliphatic 15 hydrocarbons such as hexane or heptane; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; nitriles such as acetonitrile or isobutyronitrile; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, 20 N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphoric triamide. [0058] There is no particular limitation upon the nature of the base used, provided that it can be used as a base in normal reaction. Examples of preferred bases include: organic bases such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(tert-buyl)-4-methylpyridine, quinoline, N,N-dimethylaniline or N,N-diethyl- 25 aniline. [0059] The reaction can also be carried out using a catalytic amount of 4-(N,N-dimethylamino)pyridine or 4-pyrro- lidopyridine together with other bases. In order to conduct effectively the reaction, quaternary ammonium salts such as benzyltriethylammonium chloride or tetrabutylammonium chloride; crown ethers such as dibenzo-18-crown-6 or the like can be added to the reaction mixture. 30 [0060] The reaction is normally carried out at a temperature of -20°C to reflux temperature of the solvent used, preferably 0°C to reflux temperature of the solvent used. [0061] The time required for the reaction varies mainly depending upon the reaction temperature as well as the nature of the starting material, the base and the solvent used, but the reaction is generally completed within a period of 10 minutes to 3 days, preferably 1 to 6 hours. 35 Method B

[0062] The method is to react a compound of general formula (I) having at least one hydroxyl group with a compound of general formula: R12-OH, wherein R12 signifies an acyl group, and, in the above formula, R12 is as defined above, 40 in a solvent in the presence or absence of a base under the influence of the aforesaid "condensing agent". [0063] The solvent to be used is the same one as those used in Method 2. [0064] The base to be used is the same one as those used in Method A. [0065] The reaction is carried out at a temperature of -20°C to 80°C, preferably 0°C to room temperature. [0066] The time required for the reaction varies mainly depending upon the reaction temperature as well as the 45 nature of the starting material, the base and the solvent used, but the reaction is generally complete within a period of 10 minutes to 3 days, preferably 30 minutes to 1 day.

Method C

50 [0067] The method is to react a compound of general formula (I) having at least one hydroxyl group with a compound of general formula: R12-OH, wherein R12 signifies an acyl group and, in the above formula, R12 is as defined above, in a solvent in the presence of dialkyl halogenated phosphate such as diethyl chlorophosphate and a base. [0068] The solvent to be used is the same one as those used in Method 3. [0069] The base to be used is the same one as those used in Method A. 55 [0070] The reaction is carried out at a temperature of 0°C to reflux temperature of the solvent used, preferably room temperature to 50°C. [0071] The time required for the reaction varies mainly depending upon the reaction temperature as well as the nature of the starting material, the reagent and the solvent used, but the reaction is generally completed within a period

12 EP 1 110 551 B1

of 10 minutes to 3 days, preferably 30 minutes to 1 day.

Method D:

5 [0072] The method is to react a compound of general formula (I) having at least one hydroxyl group, in case of lower alkylation, with dialkyl sulfates such as dimethyl sulfate or diethyl sulfate in the presence of a base. [0073] The base used is preferably alkali metal hydrides such as sodium hydride, potassium hydride or lithium hydride. [0074] The reaction is carried out at a temperature of 0°C to 120°C (preferably 20°Cto80°C) and completed within 10 a period of 1 to 24 hours (preferably 1 to 16 hours). [0075] After completion of the reaction, the desired compound can be recovered from the reaction mixture by conventional means. One example of such technique include: neutralizing appropriately the reaction mixture; or filtering off where insoluble materials exist; adding water and a water-immiscible organic solvent such as ethyl acetate; separating the organic phase comprising the desired compound after washing; drying over anhydrous magnesium sulfate 15 or the like; and finally distilling off the solvent. [0076] The desired compound thus obtained can be separated and purified by conventional means, for example, recrystallization, reprecipitation or by proper combination of conventional means for separating and purifying organic compounds, for example, absorption chromatography through a carrier such as silica gel, alumina or Florisil (magnesium-silica gel) and partition chromatography through a carrier such as Cephadex LH-20 (a product of Pharmacia Inc.), 20 Amberlite XAD-11 (a product of Rohm & Haas Co.) or Diaion HP-20 (a product of Mitsubishi Kasei Co.).

[Effect of Invention]

[Experimental method] 25 [0077] New Zealand white rabbits each weighing 2 to 3 kg were used. [0078] According to the method reported by Kurihara et al. [Ophthalmologic Pharmacology 4, 62-64, (1990)], an ocular hypertension model was prepared to examine the ocular tension lowering effect of the test compounds. After general anaesthesia with urethane, the ocular tension of the test rabbit was determined by use of a tonometer (Alcon 30 Applanation Pneumatonography). [0079] After a local anaesthetic was applied to the rabbit eye by dropping, 0.1 ml of 5% sodium chloride solution was injected into the vitreous body through a 30-gauge injection needle. At the time, 30 minutes after injection, when ocular hypertension was confirmed, 50ml of a sample solution was applied by dropping. Then, the ocular tension was determined over 2 hours at intervals of 30 minutes. 35 [Result]

[0080] The area (AUC) between the ocular tension curve obtained from the control group (without drug application) and that obtained from the drug application group, and the maximum value of the lowered ocular tension were calculated 40 to regard as the indices of ocular tension lowering effect. [0081] As can be seen in Table 1, the compositions containing compounds of forumal (I) used in the present invention showed an excellent ocular hypertension improving effect.

13 EP 1 110 551 B1

14 EP 1 110 551 B1

[Possible utility in industry]

[0082] As mentioned above, since the novel compositions for eye drops of the present invention have an excellent ocular tension lowering activity and no toxicity, the compositions are useful as an ocular tension lowering agent and/ 5 or as a glaucoma therapeutic agent. [0083] Additionally, since the novel compositions for eye drops of the present invention have an excellent ocular tension lowering activity and no toxicity, use of the compositions as an ocular tension lowering agent and/or as a glaucoma therapeutic agent is advantageous. [0084] In addition to the above, since the novel compositions for eye drops of the present invention have an excellent 10 ocular tension lowering activity and no toxicity, administration of the compositions to mammalians for the therapy of ocular hypertension and/or glaucoma is useful. [0085] When the compositions of the present invention are desired to be administered, these may be administered in drug composition forms for ophthalmologic use which are suitable for local application to the eyes such as solutions, suspensions, gels, ointments and solid inserts. 15 [0086] These drug compositions can contain from the lowest limit of 0.01%, preferably from 0.1%, to the highest limit of 10%, preferably to 5%, of the active ingredient. [0087] In addition to the compound of formula (I), the compositions of the present invention contain a β-blocker such as timolol maleate. The compositions of the present invention may also contain a parasympathomimetic agent such as pilocarpine. 20 [0088] Any non-toxic inorganic or organic carrier for pharmaceutical use can preferably be mixed to form the drug preparation containing the active composition. [0089] As typical pharmaceutically acceptable carriers, there may be mentioned: water; a mixed solvent of water with a water-miscible solvent such as a lower alkanol or aralkanol; a vegetable oil; a polyalkyleneglycol; a jelly which is based on petroleum; ethylcellulose; ethyl oleate; carboxymethylcellulose; polyvinylpyrrolidone; isopropyl myristate; 25 and other pharmaceutically acceptable carriers which can be used preferably. The pharmaceutical preparation can contain non-toxic additives including emulsifiers, antiseptics, wetting agents and vehicles; for example, polyethyleneg- lycol 200, 300, 400 and 600; carbowax 1000, 1500, 4000, 6000 and 10000; p-hydroxybenzoates such as methyl p- hydroxybenzoate and propyl p-hydroxybenzoate; quaternary ammonium compounds which are known to have a bac- tericidal effect and no toxity in use (e.g. benzethonium chloride and benzalkonium chloride); antibacterial drugs such 30 as phenyl mercurate; thimerosal; methylparabene; propylparabene; benzyl alcohol; phenylethanol; buffer components such as sodium chloride, sodium borate, sodium acetate; buffer substances of gluconic acid type; sorbitan monolaurate; triethanolamine; polyoxyethylenesorbitan monopalmitate; dioctylsodium sulfosuccinate; monothioglycerol; thiosorbitol; ethylenediamine tetraacetate. [0090] Suitable vehicles for ophthalmological use can be employed as a carrier substance for the present invention: 35 As the carriers, there may be mentioned: standard phosphate buffer vehicles (e.g. sodium phosphate buffers, and potassium phosphate buffers); isotonic borate vehicles; isotonic sodium chloride vehicles; and isotonic sodium borate vehicles. [0091] Alternatively, the drug preparation may be used in the form of solid inserts which can remain in a nearly perfect form after administration, or of bio-degradable inserts which can dissolve in tear fluid or disintegrate by any other 40 mechanism. [0092] In general, the active ingredient of the present invention can be used at a dose of from the lowest limit of about 0.001 mg, preferably from about 0.01 mg, to the highest limit of about 50 mg, preferably to about 20 mg, per kg. Depending upon the daily dosage required, administration may be carried out by single dose or divided doses. Unit administration may be also possible. 45 The Reference example shown below will explain the present invention more concretely.

[Reference example 1]

4-(1-Hydroxy-1-methyethyl)-2-propyl-1-[4-(2-tetrazol-5-yl)benzyl]imidazole-5-carboxylic acid 50 [0093] To 10 ml N,N-dimethylacetamide solution containing 1.00 g of ethyl 5-(1-hydroxy-1-methylethyl)-2-propylim- idazole-4-carboxylate, 0.20 g of 55% sodium hydride in oil was added. [0094] After stirring the reaction mixture for 30 minutes at room temperature, 20 ml N,N-dimethylacetamide solution containing 1.95 g of 4-(2-trityltetrazol-5-yl)benzyl bromide was added dropwise to the reaction mixture. 55 [0095] The reaction mixture was stirred for 2 hours at room temperature, then ethyl acetate and water were added to it and the ethyl acetate layer separated. The extracted solution was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off under a reduced pressure. The residue was subjected to silica gel column chromatography in which the solvent system was hexane-ethyl acetate (1:1) to obtain 1.51 g of crystalline ethyl

15 EP 1 110 551 B1

4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-(2-trityltetrazol-5-yl)benzyl]imidazole-5-carboxylate. m.p.: 187-189°C NMR spectrum (CDCl3)δ ppm: 0.98 (3H, t, J=7.5Hz), 1.20 (3H, t, J=7.5Hz), 1.68 (6H, s), 1.65-1.78 (2H, m), 2.66 (2H, t, J=8Hz), 4.24 (2H, 5 q, J=7.5Hz), 5.53 (2H, s), 5.78 (1H, s), 7.04 (2H, d, J=8Hz), 7.17-7.41 (15H, m), 8.13 (2H, d, J=8Hz) [0096] In a mixed solution of 15 ml of acetic acid with 5 ml of water, 1.40 g of the compound obtained above was dissolved. The solution was stirred for 3.5 hours at 60°C, then cooled, and the precipitate was filtered off. A small amount of the remaining acetic acid and water were distilled off by azeotropy with toluene. The residue was subjected to silica gel column chromatography in which the solvent system was methanol-methylene chloride (1:4) to obtain 0.78 10 g of gummy ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-(2-tetrazol-5-yl)benzyl]imidazole-5-carboxylate. [0097] In 12 ml of dioxane solution containing 0.78 g of the said compound, 11 ml of water containing 0.486 g of lithium hydroxide monohydrate was added, and stirred at room temperature for 4.5 hours. Dioxane was distilled off under a reduced pressure. To the remaining water solution, 11.6 ml of 1N hydrochloric acid was added. Sodium chloride was further added to it to salt out. The target compound was extracted with ethyl acetate. The extracted solution was 15 dried over anhydrous magnesium sulfate and the solvent was distilled off under a reduced pressure to obtain a crystalline residue. After filtering with isopropyl ether, 0.41 g of the target compound was obtained. m.p.: 194-196°C NMR spectrum (DMSO-d6)δ ppm: 0.89 (3H, t, J=7.5Hz), 1.58 (6H, s), 1.62 (2H, sextet, J=7.5Hz), 2.63 (2H, t, J=8Hz), 5.71 (2H, s), 7.18 (2H, 20 d, J=8.5Hz), 8.00 (2H, d, J=8.5Hz)

Claims

25 1. The use of a compound of general formula (I):

wherein:

45 R1 represents an alkyl group having from 1 to 6 carbon atoms; R2 represents a group of a formula -C(R6)(R7) (R8) wherein R6 represents a hydroxyl group and R7 and R8 are the same or different and each represents an alkyl group having from 1 to 6 carbon atoms;

R3 represents a carboxyl group; and 50 R4 represents a carboxyl group, a carboxycarbonyl group or tetrazol-5-yl group;

or a pharmacologically acceptable salt ester or other derivative thereof, in the manufacture of a medicament suitable for local application to the eyes for use in combination with a β-blocker for the treatment of ocular hypertension 55 and/or glaucoma.

2. The use according to claim 1 of a compound of formula (1) wherein R1 represents an alkyl group containing 2 to 4 carbon atoms.

16 EP 1 110 551 B1

3. The use according to claim 2 of a compound of formula (I) wherein R2 represents a group of a formula -C(R6)(R7) (R8) wherein R6 represents a hydroxyl group, and R7 and R8 are the same or different and each represents an alkyl group containing 1 to 4 carbon atoms.

5 4. The use according to claim 3 a compound of formula (I) wherein R2 represents a group of a formula -C(R6)(R7) (R8) wherein R6 represents a hydroxyl group, and R7 and R8 are the same or different and each represents an alkyl group containing 1 or 2 carbon atoms.

5. The use according to any one of claims 1 to 4 of a compound of formula (I) wherein R4 represents a carboxyl group 10 or a tetrazol-5-yl group.

6. The use according to claim 5 of a compound of formula (I), wherein R4 represents a tetrazol-5-yl group.

7. The use according to any one of claims 1 to 6 of a compound having the following formula: 15

or a pharmacologically acceptable salt, ester or other derivative thereof.

45 8. The use according to claim 7 of a compound having the following formula:

17 EP 1 110 551 B1

15 or a pharmacologically acceptable salt, ester or other derivative thereof.

9. The use according to any one of claims 1 to 8 wherein said β-blocker is timolol maleate.

10. The use according to any one of claims 1 to 9 wherein the medicament is formulated as eye drops. 20 11. A medicament formulated as eye drops suitable for local application to the eyes comprising an effective amount of a compound of general formula (I) as defined in any one of claims 1 to 8, or a pharmacologically acceptable salt, ester or other derivative thereof and an effective amount of a β-blocker for use in the treatment of ocular hypertension and/or glaucoma. 25 12. The medicament according to claim 11 wherein said β-blocker is timolol maleate.

Patentansprüche 30 1. Verwendung einer Verbindung der allgemeinen Formel (I):

worin:

50 R1 eine Alkylgruppe mit 1 bis 6 Kohlenstoffatomen darstellt,

R2 eine Gruppe der Formel -C(R6)(R7)(R8) darstellt, worin R6 eine Hydroxygruppe darstellt, und R7 und R8 gleich oder unterschiedlich sind und jeweils eine Alkylgruppe mit 1 bis 6 Kohlenstoffatomen darstellen,

55 R3 eine Carboxylgruppe darstellt, und

R4 eine Carboxylgruppe, eine Carboxycarbonylgruppe oder eine Tetrazol-5-ylgruppe darstellt,

18 EP 1 110 551 B1

oder eines pharmakologisch geeigneten Salzes, Esters oder anderen Derivats davon bei der Herstellung eines Arzneimittels, das für die lokale Anwendung auf die Augen zur Verwendung in Kombination mit einem β-Blocker zur Behandlung von Augenüberdruck und/oder Glaukom geeignet ist.

5 2. Verwendung nach Anspruch 1 einer Verbindung der Formel (I), worin R1 eine Alkylgruppe darstellt, die 2 bis 4 Kohlenstoffatome enthält.

3. Verwendung nach Anspruch 2 einer Verbindung der Formel (I), worin R2 eine Gruppe der Formel -C(R6)(R7)(R8) darstellt, worin R6 eine Hydroxygruppe darstellt, und R7 und R8 gleich oder unterschiedlich sind und jeweils eine 10 Alkylgruppe mit 1 bis 4 Kohlenstoffatomen darstellen.

4. Verwendung nach Anspruch 3 einer Verbindung der Formel (I), worin R2 eine Gruppe der Formel -C(R6)(R7)(R8) darstellt, worin R6 eine Hydroxygruppe darstellt, und R7 und R8 gleich oder unterschiedlich sind und jeweils eine Alkylgruppe mit 1 oder 2 Kohlenstoffatomen darstellen. 15 5. Verwendung nach einem der Ansprüche 1 bis 4 einer Verbindung der Formel (I), worin R4 eine Carboxylgruppe oder eine Tetrazol-5-ylgruppe darstellt.

6. Verwendung nach Anspruch 5 einer Verbindung der Formel (I), worin R4 eine Tetrazol-5-ylgruppe darstellt. 20 7. Verwendung nach einem der Ansprüche 1 bis 6 einer Verbindung der folgenden Formel:

oder eines pharmakologisch geeignetes Salzes, Esters oder eines anderen Derivats davon. 50 8. Verwendung nach Anspruch 7 einer Verbindung der folgenden Formel:

19 EP 1 110 551 B1

15 oder eines pharmakologisch geeigneten Salzes, Esters oder eines anderen Derivats davon.

9. Verwendung nach einem der Ansprüche 1 bis 8, wobei der β-Blocker Timololmaleat ist.

20 10. Verwendung nach einem der Ansprüche 1 bis 9, wobei das Arzneimittel als Augentropfen formuliert ist.

11. Arzneimittel, formuliert als Augentropfen, welches für die lokale Anwendung auf die Augen geeignet ist, welches eine wirksame Menge einer Verbindung der allgemeinen Formel (I) wie in einem der Ansprüche 1 bis 8 definiert oder ein pharmakologisch geeignetes Salz, Ester oder anderes Derivat davon sowie eine wirksame Menge eines 25 β-Blockers umfasst, für die Verwendung bei der Behandlung von Augenüberdruck und/oder Glaukom.

12. Arzneimittel nach Anspruch 11, wobei der β-Blocker Timololmaleat ist.

30 Revendications

1. Utilisation d'un composé de formule générale (I) :

dans laquelle : 50 R1 représente un groupe alkyle contenant de 1 à 6 atomes de carbone ; R2 représente un groupe ayant la formule -C(R6)(R7)(R8) dans laquelle R6 représente un groupe hydroxyle et R7 et R8 sont les mêmes ou différents et représentent chacun un groupe alkyle contenant de 1 à 6 atomes de carbone ; 55 R3 représente un groupe carboxyle ; et R4 représente un groupe carboxyle, un groupe carboxycarbonyle ou un groupe tétrazol-5-yle ;

ou un sel pharmaceutiquement acceptable, un ester ou un autre dérivé de ceux-ci, dans la fabrication d'un

20 EP 1 110 551 B1

médicament adéquat pour l'application locale sur les yeux destiné à être employé en association avec un β-bloquant pour le traitement de l'hypertension oculaire et/ou du glaucome.

2. Utilisation selon la revendication 1 d'un composé de formule (1) dans laquelle R1 représente un groupe alkyle 5 contenant de 2 à 4 atomes de carbone.

3. Utilisation selon la revendication 2 d'un composé de formule (1) dans laquelle R2 représente un groupe ayant la formule -C(R6)(R7)(R8) dans laquelle R6 représente un groupe hydroxyle et R7 et R8 sont les mêmes ou différents et représentent chacun un groupe alkyle contenant de 1 à 4 atomes de carbone. 10 4. Utilisation selon la revendication 3 d'un composé de formule (1) dans laquelle R2 représente un groupe ayant la formule -C(R6)(R7)(R8) dans laquelle R6 représente un groupe hydroxyle et R7 et R8 sont les mêmes ou différents et représentent chacun un groupe alkyle contenant de 1 à 2 atomes de carbone.

15 5. Utilisation selon l'une quelconque des revendications 1 à 4 d'un composé de formule (1) dans laquelle R4 repré- sente un groupe carboxyle ou un groupe tétrazol-5-yle.

6. Utilisation selon la revendication 5 d'un composé de formule (1) dans laquelle R4 représente un groupe tétrazol- 5-yle. 20 7. Utilisation selon l'une quelconque des revendications 1 à 6 d'un composé ayant la formule suivante :

50 ou un sel pharmaceutiquement acceptable, un ester ou un autre dérivé de ceux-ci.

8. Utilisation selon la revendication 7 d'un composé ayant la formule :

21 EP 1 110 551 B1

15 ou un sel pharmaceutiquement acceptable, un ester ou un autre dérivé de ceux-ci.

9. Utilisation selon l'une quelconque des revendications 1 à 8 dans laquelle le β-bloquant est le maléate de timolol.

20 10. Utilisation selon l'une quelconque des revendications 1 à 9 dans laquelle le médicament est formulé sous la forme de gouttes oculaires.

11. Médicament formulé sous la forme de gouttes oculaires adéquates pour l'application locale sur les yeux compre- nant une quantité efficace d'un composé de formule générale (I) telle que définie dans l'une quelconque des re- 25 vendications 1 à 8, ou un sel pharmaceutiquement acceptable, un ester ou un autre dérivé de ceux-ci et une quantité efficace de β-bloquant pour utilisation dans le traitement de l'hypertension oculaire et/ou du glaucome.

12. Médicament selon la revendication 11 dans lequel ledit β-bloquant est le maléate de timolol.