AU781049B2

AU781049B2 - Agent for treating visual cell function disorder

Info

Publication number: AU781049B2
Application number: AU16906/00A
Authority: AU
Inventors: Ryuji Ueno
Original assignee: Sucampo GmbH
Current assignee: Sucampo GmbH
Priority date: 1998-12-24
Filing date: 1999-12-20
Publication date: 2005-05-05
Anticipated expiration: 2019-12-20
Also published as: NZ513111A; WO2000038703A1; JP2002542150A; EP1140134A1; KR20010099928A; MXPA01006449A; CN1224420C; AR022017A1; BR9917113A; NO20013146L; AU1690600A; CN1352565A; CA2356382A1; NO20013146D0; TW546145B

Description

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 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 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 layer (mainly Miller 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 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 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 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 WO 00/38703 PCT/JP99/07161 damaged function of visual cell, can be suppressed or recovered, the visual cell function disorder is expected to be effectively treated.

SUMMARY OF THE INVENTION The present inventor has conducted intensive studies and surprisingly found that interleukin 2 (hereinafter sometimes referred to simply as IL-2) inhibitor 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.

An agent for treating visual cell function disorder comprising an interleukin 2 inhibitor as an active ingredient.

The agent of wherein the interleukin 2 inhibitor is a macrolide compound or a cyclosporin.

The agent of wherein the macrolide compound is a tricyclo compound of the following formula R24,

R

6

R

2 RS R-- RI9 RI R7 1 C H 2 n 0 R

R-

N I R8 R4 0 RI4 x (I) R9 R18

OR

17 OR16 wherein adjacent pairs of R 1 and R 2

R

3 and R 4 and R 5 and R 6 each independently a) consist of two adjacent hydrogen atoms, wherein R 2 is optionally alkyl, or b) form another bond optionally between carbon atoms binding with the members of said pairs

R

7 is hydrogen atom, hydroxy, protected hydroxy or alkyloxy, or may form oxo with R

R

8 and R 9 each independently show hydrogen atom or hydroxy WO 00/38703 PCT/JP99/07161

R'

1 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 of the formula N-NR"R 1 2 or N-OR 13 R" and R 12 each independently show hydrogen atom, alkyl, aryl or tosyl

R

1 3

R

1 4

R

15

R

1 6

R

1 7

R

18

R

1 9

R

2 and R 23 each independently show hydrogen atom or alkyl

R

24 is an 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, R' 1 and R 23 may 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 alkyl, hydroxy, alkyloxy, benzyl, a group of the formula -CH 2 Se(C 6 Hs), and alkyl substituted by one or more hydroxy, or a pharmaceutically acceptable salt thereof.

The agent of or wherein the macrolide compound is FK506.

The agent of any of to which is used for the treatment of retinopathy.

The agent of wherein the retinopathy is ischemic retinopathy.

The agent of wherein the ischemic retinopathy is diabetic retinopathy.

The agent of any of to which is in the form of a preparation for local administration to the eye.

A method for treating visual cell function disorder, comprising administering an effective amount of an interleukin 2 inhibitor to a subject in need of the treatment of visual cell function disorder.

Use of an interleukin 2 inhibitor for the production of a pharmaceutical composition for the treatment of visual cell function disorder.

DETAILED DESCRIPTION OF THE INVENTION The IL-2 inhibitor to be used in the present invention is not particularly limited and may be any as long as it has an IL-2 inhibitory activity. One example WO 00/38703 PCT/JP99/07161 thereof is IL-2 production inhibitor. Other example is IL-2 signal transduction inhibitor. Preferable examples thereof include macrolide compounds such as FK506, Ascomycin derivative, Rapamycin derivative and the like and cyclosporins and the like.

Specific examples of macrolide compound include tricyclo compound of the following formula and a pharmaceutically acceptable salt thereof.

R24 6 R22

R

Rt Y 0 R 4 X

(I)

R9

R'

8 0

OR

17

OR

16 wherein adjacent pairs of R 1 and R 2

R

3 and R 4 and R and R 6 each independently a) consist of two adjacent hydrogen atoms, wherein R 2 is optionally alkyl, or b) form another bond optionally between carbon atoms binding with the members of said pairs

R

7 is hydrogen atom, hydroxy, protected hydroxy or alkyloxy, or may form oxo with R'

R

8 and R 9 each independently show hydrogen atom or hydroxy

R'

1 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 of the formula N-NRI1R 12 or N-OR 13

R

11 and R 12 each independently show hydrogen atom, alkyl, aryl or tosyl

R

1 3

R

14

R

15

R

16

R

17

R

18

R

19

R

2 2 and R 23 each independently show hydrogen atom or alkyl WO 00/38703 PCT/JP99/07161

R

2 4 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, R 1 0 and R 23 may 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, wherein the heterocyclic group may be substituted by one or more group(s) selected from alkyl, hydroxy, alkyloxy, benzyl, a group of the formula -CH 2 Se(C 6

H

5 and alkyl substituted by one or more hydroxy.

Preferable R 24 is, for example, cyclo(C 5

-C

7 )alkyl optionally having suitable substituent, such as the following.

3,4-dioxocyclohexyl 3-R 20 -4-R 2 -cyclohexyl, wherein R 20 is hydroxy, alkyloxy or -OCH20CH 2

CH

2

OCH

3 and

R

2 1 is hydroxy, -OCN, alkyloxy, heteroaryloxy having suitable substituent, 2

CH

2 0CH 3 protected hydroxy, chloro, bromo, iodo, aminooxalyloxy, azide, p-tolyloxythiocarbonyloxy, or R 2 5

R

26

CHCOO-

(wherein R 25 is hydroxy optionally protected where desired or protected amino, and R 26 is hydrogen atom or methyl, or R 20 and R 2 1 in combination form an oxygen atom of epoxide ring) or cyclopentyl wherein cyclopentyl is substituted by methoxymethyl, optionally protected hydroxymethyl where desired, acyloxymethyl (wherein acyl moiety is optionally quaternized dimethylamino or optionally esterified carboxy), one or more optionally protected amino and/or hydroxy, or aminooxalyloxymethyl. Preferable example includes 2-formyl-cyclopentyl.

The definition of each symbol used in the formula 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.

Preferable examples of the alkyl moiety of "alkyl" and "alkyloxy" include linear or branched fatty hydrocarbon residue, such as lower alkyl methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, hexyl and the like).

Preferable examples of"alkenyl" include linear or branched fatty 3-05: 3:05PM:DAVIE-S COLLISON CAVE 9/1 9/ 12 hydrocarbon residue having one double bond, such as lower alkenyl,(e.g., vinyl, propenyl, allyl and the like), butenyl, methyipropenyl, pententyl, hexenyl and the like.

Preferable examples of "aryl" include phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl and the like.

Preferable examples of the protective group for "protected hydroxy" and "protected amnino" include l-(loweralkythio)(lower)alkyl such as lower aLkyitbiomethyl methylthiomethyl, ethylthiomethyl, propylthioxnethyl, isopropylthiomnethyl, butyithiornethyl, isobutylthiomethyl, hexylthiomethyl and the like), with more preference given to C 1

-C

4 alkylthiomethyl and most preference given to methylthiomethyl; tri-substituted silyl such as tri(lower)alkylsilyl trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyl dimethylsilyl, tri-tert-butylsilyl and the like), and lower alkyldiarylsilyl inethyldiphenylsilyl, ethyiliphenylsilyl, propyldiphenylsilyl, tertbutyldiphenylsilyl and the like, with more prcference given to tni(C 1

-C

4 )alkylsilyl and Cj-

C

4 alkyldiphenylsilyl, and most preference given to tert-butyl-dimethylsilyl, tertbutyldiphenylsilyl; 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) carboxy) such as formyl, acetyl, propionyl, butyryl, isobutyryl, valryl isvalryl pialolhexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl, cabxhx*y an h ie cyclo(lower)alkyloxy(lower)alkanoyl optionally having I Or more suitable substituent(s) lower alkyl) such as cylcopropyloxyacetyl, cyc]lobutyloxypropionyl, cycloheptyloxybutyryl, mentyloxyacetyl, mentyloxypropionyl, mentyloxybutyryl, mentyloxypentanoyl, mentyloxyhexanoyl and the like, caruphorsulfonyl; lower alkylcarbamnoyl having one or more suitable substituent(s) such as carboxy or protected carboxy and the like, such as carboxy(lower)alkylcarbamoyl carboxyinethylcarbamoyl, carboxyethylcarbainoyl, carboxypropylcarbamoyl, carboxybutylcarbamoyl, carboxypentylcarbamoyl, carboxyhexylcarbamoyl) and -6- COMS IDNo. SBMI-011586>45 Received by IP Australia: Time 15:16 Date 2005-03-10 WO 00/38703 WO 0038703PCTIJP99O7 161 triflower)alkylsilyl(lower)alkyloxycarbonylalower)alkylcarbamoyl trimethylsilylrnethoxycarbonylethylcarbamoyl, trimethylsilylethoxycarbonylpropylcarbamoyl, triethylsilylethoxycarbonylpropylcarbamoyl, tert-butyl diinethylsilylethoxycarbonylpropylcarbamoyl, trimethylsilylpropoxycarbonylbutylcarbamoyl).

Aromatic acyl is exemplified by aroyl optionally having suitable substituent(s) nitro), such as benzoyl, toluoyl, xyloyl, naphthoyl, nitrobenzoyl, dinitrobeazoyl, nitronaphthoyl and the like and arenesulfonyl optionally having one or more suitable substituent(s) halogen), such as benzenesulfonyl, toluenesulfonyl, xylenesulfonyl, naphthalenesulfonyl, fluorobenzenesulfonyl, chlorobenzenesulfonyl, bromobenzenesulfonyl, iodobenzenesulfonyl and the like.

The aliphatic acyl substituted by aromatic group may be, for example, ar(lower)alkanoyl optionally having one or more suitable substituent(s) lower alkyloxy or trihaloolower)alcyl and the like), wherein specific examples are phenylacetyl, phenyipropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2phenylacetyl, 2-ethyl-2-trifiuoromethyl-2-phenylacetyl, 2-trifiuoromethyl-2propoxy-2-phenylacetyl and the like.

Of the above-mentiond acyl, more preferable acyl includes C, C 4 alkanoyl optionally having carboxy, cyclO(C 5

C

6 )alkyloxy(Cj C4)alkcanoyl having two (CI C4)alkyl in the cycloalkyl moiety, camphorsulfonyl, carboxy (C 1

C

4 )alkylcarbamoyl, tri(C 1

C

4 )alkylsiy(Cj C 4 )alkyloxycarbony(Cj

C

4 )alkylcarbamnoyl, benzoyl optionally having 1 or 2 nitro groups, and benzenesulfonyl having halogen, phenyl(C I C 4 )alkanoyl having C 1

C

4 alkyloxy and trihalo(CI C 4 )alkyl. Of these, most preferred are acetyl, carboxypropionyl, mentyloxyacetyl, camphorsulfonyl, benzoyl, nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl, 2-trifluoromethyl-2-methoxy-2-phenylacetyI and the like.

Preferable examples of the "heterocyclic group consisting of saturated or unsaturated 5 or 6-membered ring having nitrogen atom, sulfur atom and/or oxygen atom" are pyrolyl, tetrahydrofiuyl and the like.

The "heteroaryl optionally having a suitable substituent moiety" of the "heteroaryloxy optionally having a suitable substituent" is that exemplified for R' of WO 00/38703 PCT/JP99/07161 the compound of the formula I of EP-A-532,088, with preference given to 1- The disclosure is incorporated hereinto by reference.

The tricyclo compound and a pharmaceutically acceptable salt thereof to be used in the present invention have superior IL-2 inhibitory action and 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, EP-A-465426, EP-A-480623, EP-A-532088, EP-A-532089, EP-A-569337, EP-A- 626385, W089/05303, W093/05058, WO96/31514, 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 (Ascomycin), FR900523 and FR900525 are produced by the genus Streptomyces, such as Streptomyces tsukubaensis, 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, 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 (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.

WO 00/38703 WO 0038703PCT/JP99/07161

CH

3 0- CM 3

CM

3 0

H

ICH 2 -CH=CH2 0

CH

3 C3 OH CH 3 0

CH

3

CH

3 Chemical name 17-allyl- 1, 14-dihydroxy- 12-[2-(4-hydroxy-3methoxycyclohexyl)- 1 -methylvinyl]-23,25-dimethoxy- 13,19,21,27tetramethyl- 1 1,28-dioxa-4-azatricyclo[22.3. 1 .0 4 9 octacos- 18-ene- 2,3,1O,16-tetraone Of the tricyclo compounds more preferred is a compound wherein adjacent pairs of R 3 and W 4 and R 5 and R 6 each independently form another bond optionally between carbon atoms binding with the members of said pairs;

R

8 and R 23 each independently show hydrogen atom;

R

9 is hydroxy

R

10 is methyl, ethyl, propyl or allyl; X is (hydrogen atom, hydrogen atom) or oxo; Y is oxo R1 4

R

15 R1 6 R1 7

R'

8 R1 9 and R 22 each independently show methyl

R

24 is 3-R 20 -4-R 2 -cyclohexyl, wherein R 20 is hydroxy, alkyloxy or -OCH 2

OCH

2

CH

2

OCH

3 and

R

2 is hydroxy,-OCN, alkyloxy, heteroaryloxy having suitable substituent,

-OCH

2

OCH

2

CH

2

OCH

3 protected hydroxy, chloro, bromo, iodo, aminooxalyloxy, azide, p-tolyloxythiocarbonyloxy or R 25

R

26 CHCOO- wherein R 25 is optionally protected hydroxy as desired, or protected amino, and R 26 is hydrogen atom or methyl), or R 20 and R 2 1 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 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 IL-2 inhibitors (macrolide compounds) include Rapamycin described in MERCK INDEX, 12 edition, No. 8288 and derivatives thereof. Preferable examples thereof include O-substituted derivative described at page 1 of W095/16691, formula A, wherein the 40 h hydroxy is -OR 1 (wherein

R

1 is hydroxyalkyl, hydroalkyloxyalkyl, acylaminoalkyl and aminoalkyl), such as 40-O-(2-hydroxy)ethyl Rapamycin, 40-O-(3-hydroxy)propyl Rapamycin, 40-0-[2- (2-hydroxy)ethoxy]ethyl Rapamycin and 40-O-(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 RX wherein R is an organic radical desirable as Osubstituent, such as alkyl, allyl and benzyl moiety, and X is a leaving group such as CCl 3 C(NH)O and CF 3

SO

3 The conditions are: when X is CCl 3 C(NH)O, acidic or neutral conditions, such as in the presence of trifluoromethanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid or their corresponding pyridinium or substituted pyridinium salt, and when X is CF 3

SO

3 in the presence of a base such as pyridine, substituted pyridine, diisopropylethylamine and pentamethylpiperidine. The most preferable Rapamycin derivative is 40-O-(2hydroxy)ethyl Rapamycin as disclosed in W094/09010, which is hereby incorporated into the specification by reference.

The pharmaceutically acceptable salt of tricyclo compound Rapamycin and derivatives thereof are nontoxic and pharmaceutically acceptable conventional salts, which are exemplified by salts with inorganic or organic base such as alkali metal salt sodium salt, potassium salt and the like), alkaline earth metal salt calcium salt, magnesium salt and the like), ammonium salt, and amine salt triethylamine salt, N-benzyl-N-methylamine salt and the like).

In the IL-2 inhibitor of the present invention, particularly macrolide 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 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, 12 h ed., No. 2821, US Patent Nos. 4,117,118, 4,215,199, 4,288,431, 4,388,307, Helv. Chim. Acta, 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 pharmaceutically acceptable salt thereof, 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 IL-2 signal.

In the present invention, visual cell function disorder means the state 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 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 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 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.

WO 00/38703 PCT/JP99/07161 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 virginal 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 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 proportion of 0.001 10.0 w/v/o, preferably 0.005 5.0 w/v/o, 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 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, 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 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 sodium chloride), buffer boric acid, phosphoric acid-sodium hydrogen, sodium dihydrogenphosphate and the like), preservative benzalkonium chloride, benzetonium chloride, chlorobutanol and the like), tackifier 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), WO 00/38703 PCT/JP99/07161 sodium polyacrylate, 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.

Examples Experimental Example 1 Effect on changes in ERG of rats with retinal ischemia An ischemic state was induced by ligating 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.

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.

Test substance and administration method 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) FK506 1.0 mg polyvinyl alcohol 7.0 mg disodium hydrogenphosphate 12 hydrate 0.05 mg sodium dihydrogenphosphate 2 hydrate 0.76 mg phosphoric acid appropriate amount sodium hydroxide appropriate amount sodium chloride 8.56 mg benzalkonium chloride 0.1 mg injectable water appropriate amount 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 l/eye using a micropipette WO 00/38703 PCT/JP99/07161 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.

preparation of ischemic retinopathy model At day 8 of the test, the rats were anesthetized by intraperitoneal 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 artery 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.

ERG determination The apparatus and parameter were standarized by the following.

"Standard for Clinical Electroretinography" (International Standardization Committee) Apparatus The Electrophysiologic Personal Interfaced Computer-2000 (LKC Technologies Incorporated) ERG determination parameter amplifier high pass filter 500 Hz low pass filter 0.3 Hz notch filter off amplitude 50 pV/division (maximum 1500 pV) time 20 ms/division (maximum 2500 ms) cornea electrode impedance 10 to 20 KQ optical stimulation single flash 15 ms intensity 2.289 cd. s.m 2 ganzfeld filter none ERG was determined with the lapse of time before and after ischemia under the above-mentioned conditions.

results Taking the ERG before ischemia as 100%, the ratio thereto of the peak latency of the a-wave after reperfusion was determined. It disappeared immediately after reperfusion. The results are shown in Table 1.

P)o.npjScXJ39988r do.-IMlPlA2 Table 1 Administration group a-wave peak latency average SD) min after 90 min after 120 min after reperfusion reperfusion reperfusion Control Drug 195.6 53.5 190.8+ 55.3 191.9 60.4 Test Drug 137.1± 47.1* 141.6 44.8* 134.4 31.6 *P<0.05 (comparison to control drug by ANOVA detection) 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.

This application is based on application No. 60/113,939 filed in United States of 10 America, the content of which is incorporated hereinto by reference.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form or suggestion that that prior art forms part of the 20 common general knowledge in Australia.

It would be appreciated by a person skilled in the art the numerous variations and/or modifications may be made to the invention as shown the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Claims

3-05: 3:05PM:DAVIE-S COLLISON CAVE #1/1 10/ is P.WAVJPoWA P=&40C3W3 THE CLAIMS DEFINING =H INVENTION ARE AS FOLLOWS: 1. Use of a tricyclo compound of the following fornula R2 ReR 2 2 Z (CH- 2 )n R 0 N R R1 00 wherein adjacent pairs of R' and R 2 R' and and R5 and R 6 each independently consist of two adjacent hydrogen atoms, wherein R 2 is optionally alkyl, or 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 10 R'; R 8 and R9 each independently show hydrogen atom or hydroxy; R'o 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 -CH 2 O-; Y is oxo, (hydrogen atom, hydroxy), (hydrogen atom, hydrogen atom), or a group of the formula N-NR' 'R 1 2 or N-OR'1 3 R' and R'2 each independently show hydrogen atom, alkyl, aryl or tosyl; R1 3 R1 4 R1 5 R1 6 R1 7 R1 8 R19, R 22 and R 23 each independently show hydrogen atom or alkyl; R2 4 is a ring that. is optionally substituted and optionally contain one or more hetero atom(s); and n is 1 or 2, -16- COMS ID No: SBMI-01158645 Received by IP Australia: Time 15:16 Date 2005-03-10 3-05; 3:05PM:DAVIES COLLISON CAVE 11/ Il F.10PERVJglc6U00644mimd4alhl<9 wherein Y, R' and R 23 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 -CH 2 Se(C 6 Hs), and alkyl substituted by one or more hydroxy, or a pharmaceutically acceptable salt thereof, for the production of a pharmaceutical composition for the local treatment of the eye for visual cell function disorder. 2. The use of claim 1, wherein the tricyclo compound is FK506. 3. The use of claim 1 or claim 2, wherein the visual cell function disorder is S retinopathy. The use of claim 3, wherein the retinopathy is ischemic retinopathy. The use of claim 4, wherein the ischemic retinopathy is diabetic retinopathy. 20 6. A method for treating visual cell function disorder, comprising administering an effective amount of a tricyclo compound of the following formula R 24 R e R 2 2 R (CH2)n R 1 9 R R7 R' 0 N N R' 4 RZ 0 R'S 0 o x R OR7 OR 6 (I) -17- COMS ID No: SBMI-01158645 Received by IP Australia: Time 15:16 Date 2005-03-10 3-05; 3:05PM:DAVIES COLLISON CAVE 12/ 1E r.<ilPeiualPcM d(ishimns ooiK«) wherein adjacent pairs of R' and R 2 R' and R 4 and R 5 and R 6 each independently consist of two adjacent hydrogen atoms, wherein R 2 is optionally alkyl, or form another bond optionally between carbon atoms binding with the members of said pairs; R' is hydrogen atom, hydroxy, protected hydroxy, or alkyloxy, or optionally form oxo with R'; R 8 and R 9 each independently show hydrogen atom or hydroxy; R1 0 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 -CHzO-; Y is oxo, (hydrogen atom, hydroxy), (hydrogen atom, hydrogen atom), or a group of the formula N-NR'"R 2 or N-OR 3 S: R" 1 and R 12 each independently show hydrogen atom, alkyl, aryl or tosyl; R' 3 R 1 4 R 15 R 16 R 17 R' 1 R 19 R 22 and R 23 each independently show hydrogen atom or alkyl; 24 R is a ring that is optionally substituted and optionally contain one or more hetero atom(s); and is 1 or 2, 20 wherein Y, R 1 0 and R 23 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 -CH 2 Se(C6Hs), and 25 alkyl substituted by one or more hydroxy, or a pharmaceutically acceptable salt thereof, to a subject in need of the treatment of visual cell function disorder, wherein the tricyclo compound is in the form of a preparation for local administration to the eye.
7. The use of claim 1, substantially as hereinbefore described with reference to the Examples. -18- COMS ID No: SBMI-01158645 Received by IP Australia: Time 15:16 Date 2005-03-10 3-05: 3:05PM:DAVIES COLLISON CAVE 13/ 1E Pno|VC\0190C40 catrunraoo.IU)M
8. The use of claim 1, wherein the pharmaceutical composition is in the form of eye drop.
9. The method of claim 6, substantially as hereinbefore described with reference to the Examples. An agent when used in the local treatment of the eye for visual cell function disorder, comprising a tricyclo compound of the following formula R2 R R22 2 (CH 2 )n R I R' R R1 0 SR4 R 23 Ra R16 0 o R OR R' (1) wherein adjacent pairs of R and R 2 R 3 and R 4 and R5 and R5 each independently consist of two adjacent hydrogen atoms, wherein R 2 is optionally alkyl, or form another bond optionally between carbon atoms binding with the members of said pairs; 0000 R' is hydrogen atom, hydroxy, protected hydroxy, or alkyloxy, or optionally form oxo with 15 R'; R i and R 9 each independently show hydrogen atom or hydroxy; R' 0 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 -CH 2 0-; Y is oxo, (hydrogen atom, hydroxy), (hydrogen atom, hydrogen atom), or a group of the formula N-NR' 1 or N-OR 3 -19- COMS ID No: SBMI-01158645 Received by IP Australia: Time 15:16 Date 2005-03-10 3-05: 3:05PM:DAVIE-S COLLISON CAVE #1/l 1 4/ Ile R" and R 1 2 each independently show hydrogen atom, alkyl, aryl or tosyl; R'3, R"14, R1 5 R1 6 R1 7 R's, R1 9 R 22 and W3~ each independently show hydrogen atom or alkyl; R2 is a ring that is optionally substituted and optionally contain one or more hetero atom(s); and n is 1 or 2, wherein Y, R1 0 and R 23 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 -CH 2 S(C 6 5 and alkyl substituted by one or more hydroxy, or a pharmaceutically acceptable salt thereof.
11. The agent when used of claim 10, substantially as hereinbefore described with reference to the Examples. DTDths10da SuapoA be. yDATE OLISN CV Paen Atony.o h plcn *00 COMS ID No: SBMI-01158645 Received by IP Australia: Time 15:16 Date 2005-03-10