NZ513111A

NZ513111A - Agent for treating visual cell function disorder

Info

Publication number: NZ513111A
Application number: NZ513111A
Authority: NZ
Inventors: Ryuji Ueno
Original assignee: R Tech Ueno Ltd
Priority date: 1998-12-24
Filing date: 1999-12-20
Publication date: 2003-10-31
Also published as: BR9917113A; AR022017A1; EP1140134A1; MXPA01006449A; NO20013146L; AU781049B2; CA2356382A1; KR20010099928A; CN1352565A; WO2000038703A1; CN1224420C; TW546145B; NO20013146D0; AU1690600A; JP2002542150A

Abstract

The present invention provides the use of a compound of formula I in the manufacture of a medicament for treating retinopathy and visual cell function disorder confirmed by ERG, wherein R1 to R24 are as defined in the specification.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 513111 513111 WO 00/38703 PCT/JP99/07161 DESCRIPTION AGENT FOR TREATING VISUAL CELL FUNCTION DISORDER TECHNICAL FIELD OF THE INVENTION The present invention relates to an agent for treating visual cell function 5 disorder. BACKGROUND OF THE INVENTION In the structure of the eye, retina is present in the eyeground and controls the function of the eye to recognize the presence or absence and shape of an object by the presence of a visual cell layer of retina. In recent years, patients with eye 10 diseases undergo objective test of retinal function by the determination of electroretinogram (hereinafter sometimes referred to merely as ERG) and the determination is utilized for the diagnosis of the condition. The ERG consists of a-wave, b-wave, c-wave and the like, and a-wave is considered to mainly reflect the function of visual cells, b-wave is considered to reflect the function of bipolar cell 15 layer (mainly Miiller cells) and c-wave is considered to reflect the function of retinal pigment epithelium. When the retinal function is damaged for some reason, it appears as changes in the peak latency and amplitude of each wave. For example, in the case of diabetic retinopathy, it is known that peak latency of each wave is extended from the early stage and the amplitude is attenuated; all waves are 2 0 attenuated and disappear in degenerative disease of retina, such as pigmentary retinal degeneration; and each wave becomes attenuated depending on the stages of disease in retinochoroidal disorder such as central retinal artery occlusion, central retinal vein thrombosis, fundus hypertonicus, retinal detachment and the like. While the b-wave and the like are originated from the source located more 2 5 toward the central side of the retina than the visual cell from which the a-wave is originated, when the light reaches the retina, the visual cell is first excited and the b-wave and the like are first generated when the excitement is transmitted to the retinal cells on the central side. Therefore, even when the source of origin is other than visual cell, the waves are under strong influence of the function of the visual 30 cell. In other words, when the function of visual cell is damaged, ERG components become abnormal even if the source of origin of the b-wave and the like is normal. Therefore, in ERG, a-wave is the most important component, and if changes in peak latency and amplitude of a wave, which are caused by the 1 10 25 damaged function of visual cell, can be suppressed or recovered, the visual cell function disorder is expected to be effectively treated. Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising" and the like, are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense, that is to say, in the sense of "including, but not limited to". The present inventor has conducted intensive studies and surprisingly found that interleukin 2 (hereinafter sometimes referred to simply as IL-2) miiibitor has superior improving effect on visual cell function disorder and exhibit superior therapeutic effect on the diseases associated with visual cell function disorder, which resulted in the completion of the present invention. Accordingly, the present invention provides the following. (1) The use, in the manufacture of a medicament for treating retinopathy, of a tricyclo compound (I) of the following formula SUMMARY OF TEE INVENTION OR17 OR16 wherein adjacent pairs of R1 and R2, R3 and R4, and R5 and R6 each independently 2 (followed by 2a) a) consist of two adjacent hydrogen atoms, wherein R2 is optionally alkyl, or b) form another bond optionally between carbon atoms binding with the members of said pairs ; R7 is hydrogen atom, hydroxy, protected hydroxy, or alkyloxy, or optionally form oxo with R1 ; R8 and R9 each independently show hydrogen atom or hydroxy; R10 is hydrogen atom, alkyl, alkyl substituted by one or more hydroxy, alkenyl, alkenyl substituted by one or more hydroxy or alkyl substituted by oxo ; X is oxo, (hydrogen atom, hydroxy), (hydrogen atom, hydrogen atom), or a group of the formula -CH2O-; Y is oxo, (hydrogen atom, hydroxy), (hydrogen atom, hydrogen atom), or a group of the formula N-NRnR12 or N-OR13 ; R11 and R12 each independently show hydrogen atom, alkyl, aiyl or tosyl; R13, R14, R15, R15, R17, R18, R19, R22 and R23 each independently show hydrogen atom or alkyl; R24 is a ring that is optionally substituted and optionally contain one or more hetero atom(s); and n is 1 or 2, wherein Y, R10 and R23 optionally show, together with the carbon atom they bind with, a saturated or unsaturated 5 or 6-membered heterocyclic group containing nitrogen atom, sulfur atom and/or oxygen atom, the heterocyclic group being optionally substituted by one or more group(s) selected from the group consisting of alkyl, hydroxy, alkyloxy, benzyl, a group of the formula -CHaSefCeHs), and alkyl substituted by one or more hydroxy,. or a pharmaceutically acceptable salt thereof. (2) The use of (1), wherein the tricycle compound (I) is FK506. (3) The use of (1), wherein the retinopathy is ischemic retinopathy. intellectual property ofrcf of im.z 3 1 JUL 2003 RECEIVED 2a (followed by 2b) 10 15 20 25 (4) The use of (3), wherein the ischemic retinopathy is selected from a group consisting of diabetic retinopathy, fundus hypertonicus, central retinal artery occlusion, central retinal vein thrombosis, retinal peripheral vascular occlusion and retinopathy of prematurity. (5) The use of any of (1) to (4), which is in the form of a preparation for local administration to the eye. (6) Use of tricycle compound (I) for the production of a pharmaceutical composition for the treatment of retinopathy. (7) A use of (1), substantially as herein described with reference to Experimental Example 1. (8) A use of (6), substantially as herein described with reference to Experimental Example 1. (9) The use , , in the manufacture of a medicament for treating visual cell function disorder confirmed by ERG, of a trycyclo compound (I) of the following formula. OR17 OR16 (I) intellectual property office of n.z i. z 2b (followed by 2c) 3 1 JUL 2003 RECEIVED wherein adjacent pairs of R1 and R2, R3 and R4, and R5 and R6 each independently a) consist of two adjacent hydrogen atoms, wherein R2 is optionally alkyl, or b) form another bond optionally between carbon atoms binding with the , members of said pairs ; R7 is hydrogen atom, hydroxy, protected hydroxy, or alkyloxy, or optionally form oxo with R1 ; R8 and R9 each independently show hydrogen atom or hydroxy ; R10 is hydrogen atom, alkyl, alkyl substituted by one or more hydroxy, alkenyl, alkenyl substituted by one or more hydroxy or alkyl substituted by oxo ; X is oxo, (hydrogen atom, hydroxy), (hydrogen atom, hydrogen atom), or a group of the formula -CH2O-; Y is oxo, (hydrogen atom, hydroxy), (hydrogen atom, hydrogen atom), or a group of the formula N-NRnR12 or N-OR13 ; R11 and R12 each independently show hydrogen atom, alkyl, aiyl or tosyl; R13, R14, R15, R16, R17, R18, R19, R22 and R23 each independently show hydrogen atom or alkyl; R24 is a ring that is optionally substituted and optionally contain one or more hetero atom(s) ; and n is 1 or 2, wherein Y, R10 and R23 optionally show, together with the carbon atom they bind with, a saturated or unsaturated 5 or 6-membered heterocyclic group rnntaining nitrogen atom, sulfur atom and/or oxygen atom, the heterocyclic group being optionally substituted by one or more group(s) selected from the group consisting of alkyl, hydroxy, alkyloxy, benzyl, a group of the formula -CH2Se(C6H5), and alkyl substituted by one or more hydroxy, or a pharmaceutically acceptable salt thereof. intellectual property office of n.z 3 1 JUL 2003 RECEIVED 2c (followed by 2d) (10) The use of (9), wherein the tricycle compound (I) is FK506. (11) The use of (9), wherein the visual cell function disorder confirmed by ERG is retinopathy. (12) The use of (11), wherein the retinopathy is ischemic retinopathy. (13) The use of (12), wherein the ischemic retinopathy is selected from a group consisting of diabetic retinopathy, fundus hypertonicus, central retinal artery occlusion, central retinal vein thrombosis, retinal peripheral vascular occlusion and retinopathy of prematurity. (14) The use of any of (9) to (13), which is in the form of a preparation for local administration to the eye. (15) A use of (9), substantially as herein described with reference to Experimental Example 1. DETAILED DESCRIPTION OF THE INVENTION The IL-2 inhibitor to be used in the present invention has an IL-2 inhibitory activity. One example Intellectual property office of m.z 31 JUL 2003 RECEIVED WO 00/38703 PCT/JP99/07161 thereof is IL-2 production inhihitor. Other example is IL-2 signal transduction inhibitor. Preferable examples thereof include macrolide compounds such as FK506, Ascomycin derivative, Rapamydn derivative and the like and cyclosporins and the like. 5 Specific examples of macrolide compound include tricyclo compound (I) of the following formula and a pharmaceutically acceptable salt thereof. (i) OR17 OR16 wherein adjacent pairs of R1 and R2, R3 and R4, and R5 and R6 each independently a) consist of two adjacent hydrogen atoms, wherein R2 is optionally alkyl, or 10 b) form another bond optionally between carbon atoms binding with the members of said pairs ; R7 is hydrogen atom, hydroxy, protected hydroxy or alkyloxy, or may form oxo R8 and R9 each independently show hydrogen atom or hydroxy ; 15 R10 is hydrogen atom, alkyl, alkyl substituted by one or more hydroxy, alkenyl, alkenyl substituted by one or more hydroxy or alkyl substituted by oxo ; X is oxo, (hydrogen atom, hydroxy), (hydrogen atom, hydrogen atom), or a group of the formula -CH20- ; Y is oxo, (hydrogen atom, hydroxy), (hydrogen atom, hydrogen atom), or a group 20 of the formula N-NR11R12 or N-OR13 ; R11 and R12 each independently show hydrogen atom, alkyl, aiyl or tosyi; R13, R14, R15, R16, R17, R18, R19, R22 and R23 each independently show hydrogen atom or alkyl; 4 WO 00/38703 PCT /JP99/07161 R24 is a optionally substituted ring that may contain one or more hetero atom(s) ; and n is 1 or 2. In addition to the meaning noted above, Y, R10 and R23 may show, together 5 with the carbon atom they bind with, a saturated or unsaturated 5 or 6-membered heterocyclic group containing nitrogen atom, sulfur atom and/or oxygen atom, wherein the heterocyclic group may be substituted by one or more group(s) selected from alkyl, hydroxy, alkyloxy, benzyl, a group of the formula -CHaSefCeHs), and alkyl substituted by one or more hydroxy. 10 Preferable R24 is, for example, cyclo(C5-C7)alkyl optionally having suitable substituent, such as the following. (a) 3,4-dioxocyclohexyl; (b) 3-F^20-4-R21-cyclohexyl, wherein R20 is hydroxy, alkyloxy or -OCH2OCH2CH2OCH3, and 15 R21 is hydroxy, -OCN, alkyloxy, heteroaiyloxy having suitable substituent, -OCH2OCH2CH2OCH3, protected hydroxy, chloro, bromo, iodo, aminooxalyloxy, azide, p-tolyloxythiocarbonyloxy, or R25R26CHCOO-(wherein R25 is hydroxy optionally protected where desired or protected amino, and R26 is hydrogen atom or methyl, 20 or R20 and R21 in combination form an oxygen atom of epoxide ring) ; or (c) cyclopentyl wherein cyclopentyl is substituted by methoxymethyl, optionally protected hydroxymethyl where desired, acyloxymethyl (wherein acyl moiety is optionally quatemized dimethylamino or optionally esterified carboxy), one or more optionally protected amino and/or hydroxy, or 25 aminooxalyloxymethyl. Preferable example includes 2-formyl-cyclopentyl. The definition of each symbol used in the formula (I), specific examples thereof and preferable embodiments thereof are explained in detail in the following. "Lower" means that a group has 1 to 6 carbon atoms unless otherwise indicated. 3 0 Preferable examples of the alkyl moiety of "alkyl" and "alkyloxy" include linear or branched fatty hydrocarbon residue, such as lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, hexyl and the like). Preferable examples of "alkenyl" include linear or branched fatty hydrocarbon residue having one double bond, such as lower alkenyl (e.g., vinyl, propenyl (e.g., allyl and the like), butenyl, methylpropenyl, nyl and Preferable examples of "aiyF include phenyl, tolyl, xyfyl, cumenyl, mesityl, naphthyl and the like. Preferable examples of the protective group for "protected hydroxy" and "protected amino" include 1 -(loweralkylthio) (lower)alkyl such as lower alkylthiomethyl (e.g., methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, isobutylthiomethyl, hexylthiomethyl and the like), with more preference given to Cx - C4 alkylthiomethyl and most preference given to methylthiomethyl; tri-substituted silyl such as tri(lawer)alkylsilyl (e.g., trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyl dimethylsityl, tri-tert-butylsilyl and the like), and lower alkyldiaiylsifyl (e.g., methyldiphenylsilyl, ethyldiphenylsilyl, propyldiphenylsilyl, tert-butyldiphenylsilyl and the like, with more preference given to triJCi - C4)alkylsilyl and Cx - C4 alkyldiphenylsilyl, and most prefererence given to teA-butyl-dimethylsilyl, tert-butyldiphenylsilyl; acyl such as aliphatic acyl, aromatic acyl and aliphatic acyl substituted by aromatic group, which are derived from carboxylic acid, sulfonic acid and carbamic acid; and the like. The aliphatic acyl is exemplified by lower alkanoyl optionally having 1 or more suitable substituent(s) (e.g., carboxy) such as formyl, acetyl, propionyl, butyiyl, isobutyryl, valeryl, isovaleiyl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyry 1, carboxyhexanoyl and the cyclo(lower)alkyloxy(lower)alkanoyl optionally having 1 or more suitable substituent(s) (e.g., lower alkyl) such as cyclopropyloxyacetyl, cyclobutyloxypropionyl, cycloheptyloxybutyryl, mentyloxyacetyl, mentyloxypropionyl, mentyloxybutyryl, mentyloxypentanoyl, mentyloxyhexanoyl and the like, camphorsulfonyl. lower alkylcarbamoyi having one or more suitable substituent(s) such as carboxy or protected carboxy and the like, such as carboxy(lower)alkylcarbamoyl (e.g., carboxymethylcarbamoyl, carboxyethylcarbamoyl, carboxypropylcarbamoyl, carboxybutylcarbamoyl, carboxypentylcarbamoyl, carboxyhexylcarbamoyl) and the like. 11 like. WO 00/38703 PCT/JP99/07161 tri(lower)alkylsilyl(lower)alkyloxycarbonyl(lower)alkylcarbamoyl (e.g., trimethylsilylmethoxycarbonylethylcarbamoyl, trimethylsilylethoxycarbonylpropylcarbamqyl, triethylsilylethoxycarbonylpropylcarbamqyl, tert-butyl 5 dimethylsilylethoxycarbonylpropylcarbamoyl, trimethylsilylpropoxycarbonylbutylcarbamoyl). Aromatic acyl is exemplified by aroyl optionally having suitable substituent(s) (e.g., nitro), such as benzoyl, toluoyl, xyloyl, naphthoyl, nitrobenzoyl, dinitrobenzoyl, nitronaphthoyl and the like ; and 10 arenesulfonyl optionally having one or more suitable substituent(s) (e.g., halogen), such as benzenesulfonyl, toluenesulfonyl, jcylenesulfonyl, naphthalenesulfonyl, fluorobenzenesulfonyl, chlorobenzenesulfonyl, bromobenzenesulfonyl, iodobenzenesulfonyl and the like. The aliphatic acyl substituted by aromatic group may be, for example, 15 ar(lower)alkanoyl optionally having one or more suitable substituent(s) (e.g., lower alkyloxy or trihalo(lower)alkyl and the like), wherein specific examples are phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-phenylacelyl, 2-ethyl-2-trifluoromethyl-2-phenylacetyl, 2-trifluoromethyl-2-propoxy-2 -phenylacetyl and the like. 20 Of the above-mentiond acyl, more preferable acyl includes C2 - C4 alkanpyl optionally having carboxy, cyclo(C5 - C^alkylo^C! - C4)alkanqyl having two (CT -C4)alkyl in the cycloalkyl moiety, camphorsulfonyl, carboxy (Cx -G4)alkylcarbamoyl, trifC! - C4)allQrlsilyl(C1 - C4)alkyloxycarbonyl(Cx -C4)alkylcarbamoyl, benzoyl optionally having 1 or 2 nitro groups, and 2 5 benzenesulfonyl having halogen, phenyl(Cj - C4)alkanpyl having Cj - C4alkyloxy and trihalo(C! - C4)alkyl. Of these, most preferred are acetyl, carboxypropionyl, mentyloxyacetyl, camphorsulfonyl, benzoyl, nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl and the like. Preferable examples of the "heterocyclic group consisting of saturated or 3 0 unsaturated 5 or 6-membered ring having nitrogen atom, sulfur atom and/ or oxygen atom" are pyrolyl, tetrahydrofuiyl and the like. The "heteroaiyl optionally having a suitable substituent moiety" of the "hefceroaryloxy optionally having a suitable substituent" is that exemplified for R1 of WO 00/38703 PCT/JP99/07161 the compound of the formula I of EP-A-532,088, with preference given to 1-hydroxyethyIindol-5-yl. The disclosure is incorporated hereinto by reference. The tricyclo compound (I) and a pharmaceutically acceptable salt thereof to be used in the present invention have superior IL-2 inhibitory action and 5 immunosuppressive action, antibacterial action and other pharmacological activity, so that they are useful for the prophylaxis and treatment of rejection in organ or tissue transplantation, graft versus host reaction, autoimmune diseases, infectious diseases and the like, as noted, together with the production method thereof, in, for example, EP-A-184162, EP-A-323042, EP-A-423714, EP-A-427680, 10 EP-A-465426, EP-A-480623, EP-A-532088, EP-A-532089, EP-A-569337, EP-A-626385, W089/05303, W093/05058, W096/31514, W091/13889, W091/19495, W093/5059 and the like, all of these publications are hereby incorporated by reference. In particular, the compounds called FR900506 (=FK506), FR900520 15 (Ascomycin), FR900523 and FR900525 are produced by the genus Streptomyces, such as Streptomyces tsukubaerisis, No. 9993 (depository : National Institute of Bioscience and Human-Technology Agency of Industrial Science and Technology, the Ministry of International Trade and Industry, 1-3, Higashi 1-chome, Tsukuba-shi, Ibaraki-ken, Japan (formerly : Fermentation Research Institute, 2 0 Agency of Industrial Science and Technology, the Ministry of International Trade and Industry), date of deposit: October 5^1984, deposit number : FERM BP-927 or Streptomyces hygroscopicus subsp. Yakushimaensis, No. 7238 (depository : National Institute of Bioscience and Human-Technology Agency of Industrial Science and Technology, 1-3, Higashi 1-chome, Tsukuba-shi, Ibaraki-ken, Japan 25 (formerly : Fermentation Research Institute, Agency of Industrial Science and Technology, the Ministry of International Trade and Industry), date of deposit: January 12, 1985, deposit number : FERM BP-928 (EP-A-0184162), and the compound of the following formula, FK506 (general name : Tacrolimus) is a representative compound. 30 8 WO 00/38703 PCT/JP99/07161 HC CH30' ■ch2-ch=ch2 ICH36CH3 Chemical name : 17-altyl-1,14-dihydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl) -1 -methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos- 18-ene- Of the tricyclo compounds (I), more preferred is a compound wherein adjacent pairs of R3 and R4, and Rs and R6 each independently form another bond optionally between carbon atoms binding with the members of said pairs ; R9 is hydroxy; R10 is methyl, ethyl, propyl or allyl; X is (hydrogen atom, hydrogen atom) or oxo ; Y is oxo ; ... 15 R14, R15, R16, R17, R18, R19 and R22 each independently show methyl; R24 is 3-R20-4-R21 -cyclohexyl, wherein R^is hydroxy, alkyloxy or -OCH2OCH2CH2och3, and R21 is hydroxy,-OCN, alkyloxy, heteroaiyloxy having suitable substituent, -OCH2OCH2CH2OCH3, protected hydroxy, chloro, bromo, iodo, 20 aminooxalylaxy, azide, p-tolyloxythiocarbonyloxy 5 2,3,10,16-tetraone 10 R8 and R23 each independently show hydrogen atom ; or R25R26CHCOO- wherein R25 is optionally protected hydroxy as desired, or protected amino, and R26 is hydrogen atom or methyl), or R20 and R21 in combination form an oxygen atom of epoxide ring; and n is 1 or 2. WO 00/38703 PCT/JP99/07161 Particularly preferable tricyclo compound (I) include, besides FK506, Ascomycin derivatives such as halogenated derivative of 33-epi-chloro-33-desoxy Ascomycin described in Example 66a of EP-A-427,680 and the like. Other preferable ILr2 inhibitors (macrolide compounds) include 5 Rapamydn described in MERCK INDEX, 12 edition, No. 8288 and derivatives thereof. Preferable examples thereof indude O-substituted derivative described at page 1 of W095/16691, formula A, wherein the 40th hydroxy is -ORi (wherein Rj is hydroxyalkyl, hydroalkyloxyalkyl, acylaminoalkyl and aminoalkyl), such as 40-0-(2-hydroxy)ethyl Rapamycin, 40-0-(3-hydroxy)propyl Rapamydn, 40-0-[2-10 (2-hydraxy)ethoxy]ethyl Rapamycin and 40-0-(2-acetaminoethyl)-Rapamycin. These O-substituted derivatives can be produced by reacting, under appropriate conditions, Rapamycin (or dihydro or deoxo Rapamycin) and an organic radical bound with leaving group (e.g., RX wherein R is an organic radical desirable as O-substituent, such as alkyl, allyl and benzyl moiety, and X is a leaving group such 15 as CC13C(NH)0 and CF3S03)). The conditions are: when X is CC13C(NH)0, acidic or neutral conditions, such as in the presence of trifluoromethanesulfonic acid, camphorsulfonic add, p-toiuenesulfonic add or their corresponding pyridinium or substituted pyridinium salt, and when X is CF3S03, in the presence of a base such as pyridine, substituted pyridine, diisopropylethylamine and 20 pentamethylpiperidine. The most preferable Rapamycin derivative is 40-0-(2-hydroxy)ethyl Rapamycin as disdosed in W094/09010, which is hereby incorporated into the specification by reference. The phajmaceutically acceptable salt of tricyclo compound (I), Rapamycin and derivatives thereof are nontoxic and pharmaceutically acceptable 25 conventional salts, which are exemplified by salts with inorganic or organic base such as alkali metal salt (e.g., sodium salt, potassium salt and the like), alkaline earth metal salt (e.g., caldum salt, magnesium salt and the like), ammonium salt, and amine salt (e.g., triethylamine salt, N-ben^l-N-methylamine salt and the like). In the IL-2 inhibitor of the present invention, particularly macrolide 30 compound, one or more pairs of stereoisomers, such as optical isomers and geometric isomers, may be included due to conformer or asymmetric carbon atom and double bond. Such conformers and isomers are also encompassed in the present invention. In addition, macrolide compounds can form solvates, which 10 WO 00/38703 PCT/JP99/07161 case is also encompassed in the present invention. Preferable solvate is exemplified by hydrates and ethanolates. Other IL-2 inhibitors are known from MERCK INDEX, 12th ed., No. 2821, US Patent Nos. 4,117,118,4,215,199,4,288,431,4,388,307, Helv. Chim. Acta, 60, 5 1568 (1977) and 65,1655 (1982) and Transplant Proc. 17, 1362 (1985) and the like. Specifically, they are cyclosporins such as cyclosporin A, B, C, D, E, F and G and derivatives thereof. Particularly preferred is cyclosporin A. These are hereby incorporated into the specification by reference. The tricyclo compound (I), pharmaceutically acceptable salt thereof, 10 cyclosporins and derivatives thereof can be classified as "IL-2 production inhibitor" that inhibit production of IL-2. Rapamycin and derivative thereof can be classified as IL-2 signal transduction inhibitor" that inhibit transmission of ILr2 signal. In the present invention, visual cell function disorder means the state 15 where visual cell of retina is suffering from disorder in the function for a certain reason, which can be specifically confirmed by the variation of peak latency or amplitude of a-wave in ERG as compared to those in the normal state. Inasmuch as the visual cell function disorder is caused by various retinal disorders such as degenerative retinopathy, retinochoroidal disorders and the like, the agent of the 20 present invention for the treatment of visual cell function disorder can be used for treating retinopathy. In particular, the agent for treating visual cell function disorder of the present invention has superior action of improving visual cell function disorder, as is evident from the experimental example to be mentioned later, in ischemic retinopathy models, and can be used for the treatment of 25 ischemic retinopathy. The ischemic retinopathy is caused by various reasons. For example, retinovascular diseases are caused by systemic disease, such as diabetes, hypertension and arteriosclerosis, and are exemplified by diabetic retinopathy, fundus hypertonicus, as well as local vascular disorders in retina, such as central retinal artery occlusion, central retinal vein thrombosis, retinal 30 peripheral vascular occlusion, retinopathy of prematurity and the like. The treatment in the context of the present invention includes any management such as prevention, treatment, alleviation of symptom, reduction of symptoms, prevention of progression and the like. 11 The interleukin 2 inhibitor to be used in the present invention can be used as a pharmaceutical agent for human and animals, and can be administered systemically or locally by oral administration, intravenous administration (inclusive of transfusion), subcutaneous administration, rectal or vaginal 5 administration, administration to local site of the eye (inclusive of eye ointment). In consideration of systemic influence, significant expression of the effect and the like, it is particularly preferably used in the form for local administration to the eye. The dose of the interleukin 2 inhibitor varies depending on the kind, age, body weight of the administration object such as human and animal, condition to 10 be treated, desired therapeutic effect, administration route, treatment method, treatment period and the like. Generally, when it is administered systemically, the dose is about 0.0001 - 1000 mg, preferably 0.001 - 500 mg, which is given in a single dose or 2 to 4 doses a day or in a sustained manner. When it is administered locally to the eye, a preparation containing the active ingredient in a 15 proportion of 0.001 - 10.0 w/v%, preferably 0.005 - 5.0 w/v%, is applied several times a day per eye, preferably instilled or applied 1 to 6 times a day. According to the present invention, an interleukin 2 inhibitor, which is an active ingredient, can be administered alone or in combination with other pharmacologically active components. When administered after formulating a 2 0 preparation, it can be administered as a preparation produced by a conventional method. The dosage form may be, for example, eye drop, eye ointment, powder, k granule, tablet, capsule, injection, ointment and the like, with particular preference given to eye drop and eye ointment Such preparation can be produced according to a conventional method. Of such preparations, an oral 2 5 preparation is preferably a solid solution preparation produced in the same manner as in the preparation of EP-A-0240773. When an eye drop is desired, an eye drop as described in EP-A-0406791 is preferable. When desired, additives generally used for eye drop such as isotonizing agent (e.g., sodium chloride), buffer (e.g., boric acid, phosphoric acid-sodium hydrogen, sodium dihydrogenphosphate 30 and the like), preservative (e.g., benzalkonium chloride, benzetonium chloride, chlorobutanol and the like), tackifier [e.g., sugar (lactose, mannitol, maltose sugar and the like), hyaluronic acid (sodium hyaluronate, potassium hyaluronate and the like), a salt thereof, mucopolysaccharide (chondroitin sulfate and the like), 12 IPONZ 3 1 jui. £.ii03 WO 00/38703 PCT/JP99/07161 sodium pofyacrylate, vinyl carboxy polymer, crosslinked polyacrylate, and the like] may be added. These are hereby incorporated into the specification by reference. The present invention is explained in more detail in the following by way of Examples, to which the present invention is not limited. Experimental Example 1 Effect on changes in ERG of rats with retinal ischemia An ischemic state was induced by lighting the retinal blood vessel of rat and reperfusion to make ischemic retinopathy model in rat, with which the effect on changes in retinal potential was tested. 10 (1) Test animal Long Evans colored rats (male, 7- or 8-week-old when received: body weight 200 - 250 g) were prebred for 8 days and the animals free of abnormality in general conditions, such as body weight, were used for the test. (2) Test substance and administration method 15 As the active ingredient in the present invention, FK506 was used and the following 0.1% eye drop (suspension) was used as a test drug. Test drug Suspension having the following composition which was prepared in the same manner as in EP-A-0406791 (Example 6) 20 FK506 1.0 mg polyvinyl alcohol 7.0 mg disoclium hydrogenphosphate 12 hydrate 0.05 mg sodium-dihydrogenphosphate 2 hydrate 0.76 mg phosphoric acid appropriate amount 25 sodium hydroxide appropriate amount sodium chloride 8.56 mg benzalkonium chloride 0.1 mg injectable water appropriate amount 30 Total amount 1 ml As the control, the base agent of an eye drop without the active ingredient was used. The test drug was instilled to the eye by 10 [il/eye using a micropipette 13 WO 00/38703 PCT/JP99/0716I 3 times a day (8 : 00,13 : 00,18 : 00) from day 1 to day 7 of the test. The control agent was also administered by instillation in the same manner. (1) preparation of ischemic retinopathy model At day 8 of the test, the rats were anesthetized by intraperitoneal 5 administration of diazepam (0.625 mg/kg), and pentobarbital (20 mg/kg) and a part of periorbita was removed from the side. A pedicle consisting of optic nerve, ophthalmic arteiy and ophthalmic vein was removed and the whole pedicle was ligated to cause ischemia. The ischemia was continued for 45 minutes and reperfused by releasing the ligation. 10 (2) ERG determination The apparatus and parameter were standarized by the following. "Standard for Clinical Electroretinography" (International Standardization Committee) Apparatus: 15 The Electrophysiologic Personal Interfaced Computer-2000 (LKC Technologies Incorporated) ERG determination parameter: amplifier high pass filter : 500 Hz 20 low pass filter : 0.3 Hz notch filter : off amplitude : 50 nV/division (maximum 1500 |iV) time : 20 ms/ division (maximum 2500 ms) cornea electrode 25 impedance : 10 to 20 K£2 optical stimulation single flash : 15 ms intensity : 2.289 cd. s.m"2 ganzfeld 30 filter: none ERG was determined with the lapse of time before and after ischemia under the above-mentioned conditions. (3) results Taking the ERG before ischemia as 100%, the ratio thereto of the peak 3 5 latency of the a-wave after reperfusion was determined. It disappeared immediately after reperfusion. Hie results are shown in Table 1. 14 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 00/38703 PCT/JP99/07161 Table 1 Administration group (n) a-wave peak latency (% average ±SD) 60 min after reperfusion 90 min after reperfusion 120 min after reperfusion Control drug (8) 195.6±53.5 190.8 ±55.3 191.9 ±60.4 Test drug (8) 137.1 ±47.1* 141.6+44.8* 134.4 ±31.6* * P<0.05 (comparison to control drug by ANOVA detection) 5 The a-wave peak latency disappeared immediately after reperfusion, but peak latency was prolonged with the lapse of time thereafter. As is evident from Table 1, the test drug administration group significantly suppressed the prolongation of the a-wave peak latency as compared to the control drug group. 10 This application is based on application No. 60/113,939 filed in United States of America, the content of which is incorporated hereinto by reference. 15 CLAIMS

1. The use, in the manufacture of a medicament for treating retinopathy, of a tricyclo compound (I) of the following formula wherein adjacent pairs of R1 and R2, R3 and R4, and R5 and R6 each independently a) consist of two adjacent hydrogen atoms, wherein R? is optionally alkyl, or b) form another bond optionally between carbon atoms binding with the members of said pairs ; R7 is hydrogen atom, hydroxy, protected hydroxy, or alkyloxy, or optionally form oxo with R1; R8 and R9 each independently show hydrogen atom or hydroxy; Ri0 is hydrogen atom, alkyl, alkyl substituted by one or more hydroxy, alkenyl, alkenyl substituted by one or more hydroxy or alkyl substituted by oxo ; OR17 OR16 (i) " ( i INTELLECTUAL PROPERTY OFRCE OF N.Z 16 31 JUL 2003 RECEIVED 10 X is oxo, (hydrogen atom, hydroxy), (hydrogen atom, hydrogen atom), or a group of the formula -CH2O-; Y is oxo, (hydrogen atom, hydroxy), (hydrogen atom, hydrogen atom), or a group of the formula N-NRUR12 or N-OR13 ; R11 and R12 each independently show hydrogen atom, alkyl, aiyl or tosyl; R13, R14, R15, R16, R17, R18, R19, R22 and R23 each independently show hydrogen atom or alkyl; R24 is a ring that is optionally substituted and optionally contain one or more hetero atom(s); and n is 1 or 2, wherein Y, R10 and R23 optionally show, together with the carbon atom they bind with, a saturated or unsaturated 5 or 6-membered heterocyclic group containing nitrogen atom, sulfur atom and/or oxygen atom, the heterocyclic group being optionally substituted by one or more group(s) selected from the group consisting of alkyl, hydroxy, alkyloxy, ben2yl, a group of the formula -CHaSefGsHs), and alkyl substituted by one or more hydroxy, 20 or a pharmaceutically acceptable salt thereof.

2. The use of claim 1, wherein the tricycle compound (I) is FK506.

3. The use of claim 1, wherein the retinopathy is ischemic retinopathy. 15 25 30

4. The use of claim 3, wherein the ischemic retinopathy is selected from a group consisting of diabetic retinopathy, fundus hypertonicus, central retinal artery occlusion, central retinal vein thrombosis, retinal peripheral vascular occlusion and retinopathy of prematurity. 17 intellectual property ofrce of n.z 3 I JUL 2003 RECEIVED

5. The use of any of claim 1 to claim 4, which is in the form of a preparation for local administration to the eye.

6. Use of tricycle compound (I) for the production of a pharmaceutical composition for the treatment of retinopathy.

7. A use of claim 1, substantially as herein described with reference to Experimental Example 1.

8. A use of claim 6, substantially as herein described with reference to Experimental Example 1.

9. The use , in the manufacture of a medicament for treating visual cell function disorder confirmed by ERG, of a trycyclo compound (I) of the following formula. wherein adjacent pairs of R1 and R2, R3 and R4, and R5 and R6 parh independently a) consist of two adjacent hydrogen atoms, wherein R2 is optionally alkyi, or R R22 R2 (I) OR17 OR16 18 intellectual property office of n.z 3 i JUL 2003 RECEIVED b) form another bond optionally between carbon atoms binding with the , members of said pairs ; . R7 is hydrogen atom, hydroxy, protected hydroxy, or alkyloxy, or optionally form oxo with R1; R8 and R9 each independently show hydrogen atom or hydroxy; R10 is hydrogen atom, alkyl, alkyl substituted by one or more hydroxy, alkenyl, alkenyl substituted by one or more hydroxy or alkyl substituted by oxo ; X is oxo, (hydrogen atom, hydroxy), (hydrogen atom, hydrogen atom), or a group of the formula -CH2O-; Y is oxo, (hydrogen atom, hydroxy), (hydrogen atom, hydrogen atom), or a group of the formula N-NRnR12 or N-OR13 ; R11 and R12 each independently show hydrogen atom, alkyl, aiyl or tosyl; R13, R14, R15, R16, R17, R18, R19, R22 and R23 each independently show hydrogen atom or alkyl; R24 is a ring that is optionally substituted and optionally contain one or more hetero atom(s); and n is 1 or 2, wherein Y, R10 and R23 optionally show, together with the carbon atom they bind with, a saturated or unsaturated 5 or 6-membered heterocyclic group containing nitrogen atom, sulfur atom and/or oxygen atom, the heterocyclic group being optionally substituted by one or more group(s) selected from the group consisting of alkyl, hydroxy, alkyloxy, benzyl, a group of the formula -CH2Se(C6H5), and alkyl substituted by one or more hydroxy, or a pharmaceutically acceptable salt thereof. 19

10. The use of claim 9, wherein the tricycle compound (I) is FK506.

11. The use of claim 9, wherein the visual cell function disorder 5 confirmed by ERG is retinopathy.

12. The use of claim 11, wherein the retinopathy is ischemic retinopathy. 10

13. The use of claim 12, wherein the ischemic retinopathy is selected from a group consisting of diabetic retinopathy, fundus hypertonicus, central retinal artery occlusion, central retinal vein thrombosis, retinal peripheral vascular occlusion and retinopathy of prematurity. 15

14. The use of any of claim 9 to claim 13, which is in the form of a preparation for local administration to the eye.

15. A use of claim 9, substantially as herein described with reference to Experimental Example 1. 20 intellectual property" ofrce of n.z 31 JUL 2003 RECEIVED </div>