CA2356382A1 - Agent for treating visual cell function disorder - Google Patents
Agent for treating visual cell function disorder Download PDFInfo
- Publication number
- CA2356382A1 CA2356382A1 CA002356382A CA2356382A CA2356382A1 CA 2356382 A1 CA2356382 A1 CA 2356382A1 CA 002356382 A CA002356382 A CA 002356382A CA 2356382 A CA2356382 A CA 2356382A CA 2356382 A1 CA2356382 A1 CA 2356382A1
- Authority
- CA
- Canada
- Prior art keywords
- hydrogen atom
- hydroxy
- agent
- alkyl
- optionally
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 230000000007 visual effect Effects 0.000 title claims abstract description 29
- 230000003915 cell function Effects 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 22
- 239000003120 macrolide antibiotic agent Substances 0.000 claims abstract description 11
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 claims abstract description 10
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 claims abstract description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 40
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
- 208000017442 Retinal disease Diseases 0.000 claims description 14
- 206010038923 Retinopathy Diseases 0.000 claims description 13
- 108010045851 interleukin 2 inhibitor Proteins 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 10
- 230000000302 ischemic effect Effects 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 229930182912 cyclosporin Natural products 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
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- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
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- 238000000034 method Methods 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
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- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 2
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
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- 108010036941 Cyclosporins Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000005103 alkyl silyl group Chemical group 0.000 description 3
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- 125000004429 atom Chemical group 0.000 description 3
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- 239000003885 eye ointment Substances 0.000 description 3
- 230000002207 retinal effect Effects 0.000 description 3
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
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- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- 125000001589 carboacyl group Chemical group 0.000 description 2
- 201000005849 central retinal artery occlusion Diseases 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
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- 238000000855 fermentation Methods 0.000 description 2
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- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The present invention provides an agent for treating visual cell function disorder containing an interleukin inhibitor such as macrolide compound, particularly FK506.
Description
DESG~?I P.TIaN
AGE FOR TREATZrTG VISUAL CELL FUNCTION DISORDER
TECHNICAL FIELD OF THE INVENTION
The present invention relates to an agerit for treating visual cell function disorder.
In the structure of the eye, retina is prevent in the eyeground and controls the function of the eye to recognize the presence or absence and shape of an objet by the presence of a visual cell layer of retina. an recent years, patients with eye diseases undergo objective test of retinal function by the determination of electroret~nogram (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 Muller 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 ligk~t 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 3 0 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 ttie most important component, and if changes in peak latency and amplitude of a wave, which are caused by the WO 00138703 PCTl,IP99/07161 damaged function of visual cell, can be suppressed or recovered, the visual cell function disorder is expected to be effectively treated.
BUJY OF ~ IN«ENTION
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 th.e present invention.
Accordingly, the present invention proviides the following.
( 1 ) An agent for treating visual cell function clisorder comprising an interleukin 2 inhibitor as an active ingredient.
{2) The agent of (1), wherein the interleukin 2 inlhibitor is a macrolide compound or a cyclosporin.
_ _ _ _ _ .. _ _ _ _ _ . _ . _ . _ . ... .. . (3) The agent of (2), wherein the macrolide compound is a tricyclo compound (I) of the following formula Rz4 R6 Rzz Rz RS ~Y
R19 ~ R1~R7 (CHz)n O R3 ~~~23 N ~ R$ R4 O n 14 R18~C) ~ls 17 ~,..16 wherein adjacent pairs of Rl 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 2 0 members of said pairs ;
R7 is hydrogen atom, hydroxy, protected hydxoxy or alkyloxy, or may form oxo with Rl ;
R8 and R9 each independently show hydrogen atom or hydroxy ;
WO 00/3$703 PCTlJP99/07161 Rl° 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~iRl2 or N-ORls ;
Rll and R12 each independently show hydrogen atom, alkyl, aryl or tosyi ;
Ris, R14; RI5' R16, Rm, R~s, Rlg, R~ and R~ each independently show hydrogen atom or alkyl ;
R24 is an optionally substituted ring that may contain one or more hetero atoms} ; and nislor2.
In addition to the meaning noted above, Y, Rl° and R23 may show, together _ . ___ with.the earbQnvatom. they.bind vaith, a saturated or unsaturated 5 or b-membered . . .
heterocyclic group containing nitrogen atom, sulfur atom and/or oxygen atom, the heterocyclic group being optionally substituted by one or more gxoup(s) selected from alkyl, hydroxy, alkyloxy, benzyl, a group oif the formula -CH2Se(C6H5), and alkyl substituted by one or more hydroxy, or a pharmaceutically acceptable salt thereof.
2 0 (4) The agent of (2) or (3), wherein the macrolide; compound is FK506.
(5) The agent of any of (1) to (4), which is used for the treatment of retinopathy.
(6) The agent of (5), wherein the retinopathy is iachemic retinopathy.
(7) The agent of (6), wherein the ischemic retino~pathy is diabetic retinopathy.
(8} The agent of any of ( 1) to (?), which is in the form of a preparation for local 2 5 administration to the eye.
(9) 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.
( 10) Use of an interleukin 2 inhibitor for the production of a pharmaceutical 30 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 Ilr2 inhibitory activity. One example thereof is IIr2 production inhibitor. Other exannple is IL-2 signal transduction inhibitor. Preferable examples thereof include rnacrolide compounds such as FK506, Ascomycin derivative, Rapamycin derivative and the like and cyclosporins and the like.
Specific examples of macrolide compound include tricycio compound (I) of the following formula. and a pharmaceutically acceptable salt thereof.
R2 ~ R6 Rzz R2 RS Y
R19 R1/ 'R7 to (CI-Iz~l 0 ~R23 N ~ s Ra 0 R Dla (I) ~" 15 '~R
Y . R's--~ ._~O /. _ _._...._. ._... _ . . _ ..
17 ~!"~16 wherein adjacent pairs of Rl 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 aikyloxy, or may form oxo With Rl ;
R$ and R9 each independently show hydrogen atom or hydroxy ;
Rl° 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-NRllRia or N-ORla ;
Rl l and R12 each independently show hydrogen atom, alkyl, aryl or tosyl ;
Ri3, R14, R15, R16, Rm, R18, Rls, Rzz and R23 each independently show hydrogen atom or alkyl ;
AGE FOR TREATZrTG VISUAL CELL FUNCTION DISORDER
TECHNICAL FIELD OF THE INVENTION
The present invention relates to an agerit for treating visual cell function disorder.
In the structure of the eye, retina is prevent in the eyeground and controls the function of the eye to recognize the presence or absence and shape of an objet by the presence of a visual cell layer of retina. an recent years, patients with eye diseases undergo objective test of retinal function by the determination of electroret~nogram (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 Muller 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 ligk~t 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 3 0 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 ttie most important component, and if changes in peak latency and amplitude of a wave, which are caused by the WO 00138703 PCTl,IP99/07161 damaged function of visual cell, can be suppressed or recovered, the visual cell function disorder is expected to be effectively treated.
BUJY OF ~ IN«ENTION
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 th.e present invention.
Accordingly, the present invention proviides the following.
( 1 ) An agent for treating visual cell function clisorder comprising an interleukin 2 inhibitor as an active ingredient.
{2) The agent of (1), wherein the interleukin 2 inlhibitor is a macrolide compound or a cyclosporin.
_ _ _ _ _ .. _ _ _ _ _ . _ . _ . _ . ... .. . (3) The agent of (2), wherein the macrolide compound is a tricyclo compound (I) of the following formula Rz4 R6 Rzz Rz RS ~Y
R19 ~ R1~R7 (CHz)n O R3 ~~~23 N ~ R$ R4 O n 14 R18~C) ~ls 17 ~,..16 wherein adjacent pairs of Rl 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 2 0 members of said pairs ;
R7 is hydrogen atom, hydroxy, protected hydxoxy or alkyloxy, or may form oxo with Rl ;
R8 and R9 each independently show hydrogen atom or hydroxy ;
WO 00/3$703 PCTlJP99/07161 Rl° 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~iRl2 or N-ORls ;
Rll and R12 each independently show hydrogen atom, alkyl, aryl or tosyi ;
Ris, R14; RI5' R16, Rm, R~s, Rlg, R~ and R~ each independently show hydrogen atom or alkyl ;
R24 is an optionally substituted ring that may contain one or more hetero atoms} ; and nislor2.
In addition to the meaning noted above, Y, Rl° and R23 may show, together _ . ___ with.the earbQnvatom. they.bind vaith, a saturated or unsaturated 5 or b-membered . . .
heterocyclic group containing nitrogen atom, sulfur atom and/or oxygen atom, the heterocyclic group being optionally substituted by one or more gxoup(s) selected from alkyl, hydroxy, alkyloxy, benzyl, a group oif the formula -CH2Se(C6H5), and alkyl substituted by one or more hydroxy, or a pharmaceutically acceptable salt thereof.
2 0 (4) The agent of (2) or (3), wherein the macrolide; compound is FK506.
(5) The agent of any of (1) to (4), which is used for the treatment of retinopathy.
(6) The agent of (5), wherein the retinopathy is iachemic retinopathy.
(7) The agent of (6), wherein the ischemic retino~pathy is diabetic retinopathy.
(8} The agent of any of ( 1) to (?), which is in the form of a preparation for local 2 5 administration to the eye.
(9) 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.
( 10) Use of an interleukin 2 inhibitor for the production of a pharmaceutical 30 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 Ilr2 inhibitory activity. One example thereof is IIr2 production inhibitor. Other exannple is IL-2 signal transduction inhibitor. Preferable examples thereof include rnacrolide compounds such as FK506, Ascomycin derivative, Rapamycin derivative and the like and cyclosporins and the like.
Specific examples of macrolide compound include tricycio compound (I) of the following formula. and a pharmaceutically acceptable salt thereof.
R2 ~ R6 Rzz R2 RS Y
R19 R1/ 'R7 to (CI-Iz~l 0 ~R23 N ~ s Ra 0 R Dla (I) ~" 15 '~R
Y . R's--~ ._~O /. _ _._...._. ._... _ . . _ ..
17 ~!"~16 wherein adjacent pairs of Rl 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 aikyloxy, or may form oxo With Rl ;
R$ and R9 each independently show hydrogen atom or hydroxy ;
Rl° 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-NRllRia or N-ORla ;
Rl l and R12 each independently show hydrogen atom, alkyl, aryl or tosyl ;
Ri3, R14, R15, R16, Rm, R18, Rls, Rzz and R23 each independently show hydrogen atom or alkyl ;
WO OOI38703 PCT/JP991071b1 R24 is a optionally substituted ring that may contain one or more hetero atoms) ; and nis 1 or2.
In addition to the meaning noted above, 'Y, Rl° and R23 may show, together with the carbon atom they bind with, a saturated or unsaturated 5 or 6-membered heterocyclic group containing nitrogen atom, su:lfut° atom and/ or oxygen atom, wherein the heterocyclic group may be substituted by one or more groups) selected from alkyl, hydroxy, alkyloxy, benzyl, a group of the formula -CH2Se(C6H5), and alkyl substituted by one or more hydroxy.
Preferable R24 is, for example, cyclo(C5-C:~)alkyl optionally having suitable substituent, such as the following.
(a) 3,4-dioxocyclohexyl ;
(b) 3-R2°-4-R21-cyclohexyl, .____ . .._ . wherein_R?° is hydroxy, alkyloxy or -OCH.,OCH2CH20CH3, and R21 is hydroxy, -OCN, alkyloxy, heteroar~,rloxy having suitable substituent, -OCHZOCH2CH2OCH3, protected hydroxy, chloro, bromo, iodo, aminooxalyloxy; azide, p-tolyloxythiocarbonyloxy, or R25R26CHC00-(wherein R25 is hydroxy optionally protected where desired or protected amino, and R26 is hydrogen atom or methyl, 2 0 or R2° and R21 in combination form an o:~ygen atom of epoxide ring) ; or (c) cyclopentyl wherein cyclopentyl is substituted by methoxymethyl, optionally protected hydroxymethyl where desired, ,acyloxymethyl (wherein aryl moiety is optionally quaternized dirnethylamino or optionally esterified carboxy), one or more optionally protected amino and/or hydroxy, or arninooxalyloxymethyl. Preferable examiple 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" includc: linear or branched fatty WO 00/38703 PCT/.TP99/07I61 hydrocarbon residue having one double bond, such as lower alkenyl {e.g., vinyl, propenyl (e.g., allyl and the like), butenyl, methyipropenyi, pentenyl, hexenyl and the like.
Preferable examples of "aryl" include phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl and the like.
Preferable examples of the protective gi: oup for "protected hydro~ry" and "protected amino" include 1-{loweralkylthio)(lower)alkyl such as lower alkylthiomethyl (e.g., methylthiomethyl, ethyltYuomethyl, propylthiomethyl, isopropyithiomethyl, butylthiomethyl, isobutylthiomethyl, hexylthiomethyl and the like), with more preference given to C1- C4 alkylthiomethyl and most preference given to methylthiomethyl;
tri-substituted silyl such as tri(lower)alkylsilyl (e.g., trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyl dimethylsilyl, tri-test-butylsilyl and the like), and lower alky_idiarylsilyl (e.g., methyldiphenylailyl, ethyldiph~nylsilyl,_ ~
_ propyldiphenylsilyl, tert-butyldiphenylsilyl and. the like, with more preference given to tri(Cl - C~)alkylsilyl and C1 - C4 alkyldiphenylsilyl, and most prefererence given to tert-butyl-dimethylsilyl, tert-butyldiphenylsilyl;
aryl such as fatty aryl derived from cao: boxylic acid, sulfonic acid and carbamic acid, fatty aryl substituted by aromatic aryl and aromatic, and the like.
2 0 The fatty aryl is exemplified by lower aLkanoyl optionally having 1 or more suitable substituent{s) (e.g., carboxy) such as fbrmyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl, carboxyhexanoyl and the like ;
cyclo(lower)alkyloxy(lower)alkanoyl optionally having 1 or more suitable substituent(s) (e.g., lower alkyl) such as cyclopropyloxyacetyl, cyclobutyioxypropionyl, cycloheptyloxybutyryl, mentyloxyacetyl, mentyloxypropionyl, mentyloxybutyryl, mentytoxypentanoyl, mentyloxyhexanoyl and the like, camphorsulfonyl ;
lower alkylcarbamoyl having one or more suit<~ble substituent(s) such as carboxy or protected carboxy and the like, such as carlnoxy(lower)alkylcarbamoyl (e.g., carboxymethylcarbamoyl, carboxyethylcarbamoyl, carboxypropylcarbamoyl, carboxybutylcarbamoyl, carboxypentylcarbamoyl, carboxyhexylcarbamoyl) and WO 00/38703 PCT/JP99I0~161 tri(lower)alkyisilyl(lower)alkyloxycarbonyl(lower)alkylcarbamoyl (e.g., trimethylsilylmethoxycarbonylethyicarbarnoyl, trimethylsilylethoxycarbonylpropylcarbamoyl, triethylsilylethoxycarbonylpropylcarbamoyl, tert-butyl dirnethylsilylethoxycarboizyipropylcarbamoyl, trimethylsilylpropoxycarbonylbutylcarbamoyl).
Aromatic aryl is exemplified by aroyl optionally having suitable substituent(s) (e.g., vitro), such as benzoyl, toluoyl, xyloyl, naphthoyl, nitrobenzoyl, dinitrobenzoyl, nitronaphthoyl and the like ; and arenesulfonyl optionally having one or more suii;able substituent(s) (e.g., halogen), such as benzenesulfonyl, toluenesulfonyl, xylenesulfonyl, naphthalenesulfonyl, ffuorobenzenesulfonyl, chiorobenzenesulfonyl, bromobenzenesulfonyl, iodobenzenesulfonyl and the like.
The, aliphatic aryl substituted by aromatic group rxxay be, for..example, Z 5 ar(lower)alkanoyl optionally having one or more suitable substituent(s) (e.g., lower alkyloxy or trihalo(lower)alkyl and the like), wherein speck examples are phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifiuoromethyl-2-methoxy-2-phenylacetyl, 2-ethyl-2-triffuoromethyl-2-phenylacetyl, 2-trifluoromethyl-2-propoxy-2-phenylacetyi and the like.
2 0 Of the above-mentiond acyi, more prefer able acyi includes C 1- C4 alkanoyl optionally having carboxy, cyclo(C5 - C6)alkyioxy{C1 - C4)alkaxioyl having two {C1 _ C4)alkyl in the cycloalkyl moiety, camphorsulfonyl, carboxy (Cl -C4)aikylcarbamoyl, tri(C1 - C4)alkylsilyl(C~ - C4)a:lkyloxycarbonyl(C1 -C4)alkylcarbamoyl, benzoyl optionally having 1 or 2 vitro groups, and 25 benzenesulfonyl having halogen, phenyl(C1 - C4)alkanoyl having C1 -C4alkyloxy and trihalo(CF - C4)alkyl. Of these, most preferred are acetyl, carboxypropionyl, mentyloxyacetyi, camphorsulfonyl, benzoyl, nitr obenzoyl, 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, tetrahydrofuryl and the like.
The "heteroaryl optionally having a suitable substituent moiety" of the "heteroaryioxy optionally having a suitable substituent" is that exemplified for R' of WO 00/38703 PCTlJP99l07161 the compound of the formula i of EP-A-532,088, with preference given to 1-hydroxyethylindol-5 yl. The disclosure is incorporated hereinto by reference.
The tricyclo compound (1) 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 prophyla:xis 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-184 I62, EP-A-32;3042, 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, 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 FR~900506 (=FK506), FR900520 , (Ascomycin), FR900523 and FR900525 are produced by the genus S~reptomyoes, such as Streptomyaes tsukubaenszs, 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-chorne, 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 Str~ptorriyoes 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 2 5 (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 (ERA-0184162), and the compound of the following formula, FK506 (general name : Tacrolimus) is a representative compound.
In addition to the meaning noted above, 'Y, Rl° and R23 may show, together with the carbon atom they bind with, a saturated or unsaturated 5 or 6-membered heterocyclic group containing nitrogen atom, su:lfut° atom and/ or oxygen atom, wherein the heterocyclic group may be substituted by one or more groups) selected from alkyl, hydroxy, alkyloxy, benzyl, a group of the formula -CH2Se(C6H5), and alkyl substituted by one or more hydroxy.
Preferable R24 is, for example, cyclo(C5-C:~)alkyl optionally having suitable substituent, such as the following.
(a) 3,4-dioxocyclohexyl ;
(b) 3-R2°-4-R21-cyclohexyl, .____ . .._ . wherein_R?° is hydroxy, alkyloxy or -OCH.,OCH2CH20CH3, and R21 is hydroxy, -OCN, alkyloxy, heteroar~,rloxy having suitable substituent, -OCHZOCH2CH2OCH3, protected hydroxy, chloro, bromo, iodo, aminooxalyloxy; azide, p-tolyloxythiocarbonyloxy, or R25R26CHC00-(wherein R25 is hydroxy optionally protected where desired or protected amino, and R26 is hydrogen atom or methyl, 2 0 or R2° and R21 in combination form an o:~ygen atom of epoxide ring) ; or (c) cyclopentyl wherein cyclopentyl is substituted by methoxymethyl, optionally protected hydroxymethyl where desired, ,acyloxymethyl (wherein aryl moiety is optionally quaternized dirnethylamino or optionally esterified carboxy), one or more optionally protected amino and/or hydroxy, or arninooxalyloxymethyl. Preferable examiple 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" includc: linear or branched fatty WO 00/38703 PCT/.TP99/07I61 hydrocarbon residue having one double bond, such as lower alkenyl {e.g., vinyl, propenyl (e.g., allyl and the like), butenyl, methyipropenyi, pentenyl, hexenyl and the like.
Preferable examples of "aryl" include phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl and the like.
Preferable examples of the protective gi: oup for "protected hydro~ry" and "protected amino" include 1-{loweralkylthio)(lower)alkyl such as lower alkylthiomethyl (e.g., methylthiomethyl, ethyltYuomethyl, propylthiomethyl, isopropyithiomethyl, butylthiomethyl, isobutylthiomethyl, hexylthiomethyl and the like), with more preference given to C1- C4 alkylthiomethyl and most preference given to methylthiomethyl;
tri-substituted silyl such as tri(lower)alkylsilyl (e.g., trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyl dimethylsilyl, tri-test-butylsilyl and the like), and lower alky_idiarylsilyl (e.g., methyldiphenylailyl, ethyldiph~nylsilyl,_ ~
_ propyldiphenylsilyl, tert-butyldiphenylsilyl and. the like, with more preference given to tri(Cl - C~)alkylsilyl and C1 - C4 alkyldiphenylsilyl, and most prefererence given to tert-butyl-dimethylsilyl, tert-butyldiphenylsilyl;
aryl such as fatty aryl derived from cao: boxylic acid, sulfonic acid and carbamic acid, fatty aryl substituted by aromatic aryl and aromatic, and the like.
2 0 The fatty aryl is exemplified by lower aLkanoyl optionally having 1 or more suitable substituent{s) (e.g., carboxy) such as fbrmyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl, carboxyhexanoyl and the like ;
cyclo(lower)alkyloxy(lower)alkanoyl optionally having 1 or more suitable substituent(s) (e.g., lower alkyl) such as cyclopropyloxyacetyl, cyclobutyioxypropionyl, cycloheptyloxybutyryl, mentyloxyacetyl, mentyloxypropionyl, mentyloxybutyryl, mentytoxypentanoyl, mentyloxyhexanoyl and the like, camphorsulfonyl ;
lower alkylcarbamoyl having one or more suit<~ble substituent(s) such as carboxy or protected carboxy and the like, such as carlnoxy(lower)alkylcarbamoyl (e.g., carboxymethylcarbamoyl, carboxyethylcarbamoyl, carboxypropylcarbamoyl, carboxybutylcarbamoyl, carboxypentylcarbamoyl, carboxyhexylcarbamoyl) and WO 00/38703 PCT/JP99I0~161 tri(lower)alkyisilyl(lower)alkyloxycarbonyl(lower)alkylcarbamoyl (e.g., trimethylsilylmethoxycarbonylethyicarbarnoyl, trimethylsilylethoxycarbonylpropylcarbamoyl, triethylsilylethoxycarbonylpropylcarbamoyl, tert-butyl dirnethylsilylethoxycarboizyipropylcarbamoyl, trimethylsilylpropoxycarbonylbutylcarbamoyl).
Aromatic aryl is exemplified by aroyl optionally having suitable substituent(s) (e.g., vitro), such as benzoyl, toluoyl, xyloyl, naphthoyl, nitrobenzoyl, dinitrobenzoyl, nitronaphthoyl and the like ; and arenesulfonyl optionally having one or more suii;able substituent(s) (e.g., halogen), such as benzenesulfonyl, toluenesulfonyl, xylenesulfonyl, naphthalenesulfonyl, ffuorobenzenesulfonyl, chiorobenzenesulfonyl, bromobenzenesulfonyl, iodobenzenesulfonyl and the like.
The, aliphatic aryl substituted by aromatic group rxxay be, for..example, Z 5 ar(lower)alkanoyl optionally having one or more suitable substituent(s) (e.g., lower alkyloxy or trihalo(lower)alkyl and the like), wherein speck examples are phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifiuoromethyl-2-methoxy-2-phenylacetyl, 2-ethyl-2-triffuoromethyl-2-phenylacetyl, 2-trifluoromethyl-2-propoxy-2-phenylacetyi and the like.
2 0 Of the above-mentiond acyi, more prefer able acyi includes C 1- C4 alkanoyl optionally having carboxy, cyclo(C5 - C6)alkyioxy{C1 - C4)alkaxioyl having two {C1 _ C4)alkyl in the cycloalkyl moiety, camphorsulfonyl, carboxy (Cl -C4)aikylcarbamoyl, tri(C1 - C4)alkylsilyl(C~ - C4)a:lkyloxycarbonyl(C1 -C4)alkylcarbamoyl, benzoyl optionally having 1 or 2 vitro groups, and 25 benzenesulfonyl having halogen, phenyl(C1 - C4)alkanoyl having C1 -C4alkyloxy and trihalo(CF - C4)alkyl. Of these, most preferred are acetyl, carboxypropionyl, mentyloxyacetyi, camphorsulfonyl, benzoyl, nitr obenzoyl, 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, tetrahydrofuryl and the like.
The "heteroaryl optionally having a suitable substituent moiety" of the "heteroaryioxy optionally having a suitable substituent" is that exemplified for R' of WO 00/38703 PCTlJP99l07161 the compound of the formula i of EP-A-532,088, with preference given to 1-hydroxyethylindol-5 yl. The disclosure is incorporated hereinto by reference.
The tricyclo compound (1) 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 prophyla:xis 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-184 I62, EP-A-32;3042, 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, 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 FR~900506 (=FK506), FR900520 , (Ascomycin), FR900523 and FR900525 are produced by the genus S~reptomyoes, such as Streptomyaes tsukubaenszs, 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-chorne, 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 Str~ptorriyoes 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 2 5 (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 (ERA-0184162), and the compound of the following formula, FK506 (general name : Tacrolimus) is a representative compound.
CH
-CH=CHI
Chemical name : 17-allyl-1,14-dihydroxy- I2-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13, I9,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04°9Jactacos-18-ene-2,3,10, I5-tetraone Of the tricyclo compounds (I), more preferred is a compound wherein adjacent pairs of R3 and R4, and R5 and R6 each independently form another band optionally between carbon atoms binding with the members of said pairs ;
R8 and R23 each independently show hydrog~:n atom ;
R9 is hydroxy ;
Rl° is methyl, ethyl, propyl or allyl ;
X is (hydrogen atom, hydrogen atom) or oxo ;
Y is oxo ;
R14, R15, R16, Rl~, R18, Ri9 and R22 each independently show methyl ;
R24 is 3-R2°-4-R2I-cyclohexyl, wherein R2° is hydroxy, alkyloxy or -OCIH2OCHZCH2OCH3, and R21 is hydroxy,-OCN, aJkyloxy, heteroaryloxy having suitable substituent, -OCH20CH2CH20CH3, protected hydro~y, chloro, bromo, iodo, 2 0 aminooxalyloxy, azide, p-tolyloxythiocai bonyloxy or R25R~CHC00- wherein R25 is optionally protected hydroxy as desired, or protected amino, and R26 fs hydrogen atom or methyl), or R2° and R21 in combination form an oxygen atom of epoxide ring; and n is 1 or 2.
-CH=CHI
Chemical name : 17-allyl-1,14-dihydroxy- I2-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13, I9,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04°9Jactacos-18-ene-2,3,10, I5-tetraone Of the tricyclo compounds (I), more preferred is a compound wherein adjacent pairs of R3 and R4, and R5 and R6 each independently form another band optionally between carbon atoms binding with the members of said pairs ;
R8 and R23 each independently show hydrog~:n atom ;
R9 is hydroxy ;
Rl° is methyl, ethyl, propyl or allyl ;
X is (hydrogen atom, hydrogen atom) or oxo ;
Y is oxo ;
R14, R15, R16, Rl~, R18, Ri9 and R22 each independently show methyl ;
R24 is 3-R2°-4-R2I-cyclohexyl, wherein R2° is hydroxy, alkyloxy or -OCIH2OCHZCH2OCH3, and R21 is hydroxy,-OCN, aJkyloxy, heteroaryloxy having suitable substituent, -OCH20CH2CH20CH3, protected hydro~y, chloro, bromo, iodo, 2 0 aminooxalyloxy, azide, p-tolyloxythiocai bonyloxy or R25R~CHC00- wherein R25 is optionally protected hydroxy as desired, or protected amino, and R26 fs hydrogen atom or methyl), or R2° and R21 in combination form an oxygen atom of epoxide ring; and n is 1 or 2.
WO 00/38703 PCT/JP991071b1 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-q~27,680 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~ hydroxy is -ORi (wherein Rl is hydroxyalkyl, hydroalkyloxyalkyl, acylaminoalkyl and aminoalkyl), such as 40-O-(2-hydroxy)ethyl Rapamycin, 40-O-(3-hydroxy)propyl Rapamycin, 40-O-j2-(2-hydroxy)ethoxy]ethyl Rapamycin~and 40-O-(2-acetanvnoethyl)-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 as CC13C(NH)O and CF3S03)). The conditions are: when X is CC13C(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 CF3S0~, in the presence of a base such as pyridine, substituted pyridine, diisopropyletl:~ylamine and pentamethylpiperidine. The most preferable Rapamycin derivative is 40-O-{2 hydroxy)ethyl Rapamycin as disclosed in W094/09010, which is hereby incorporated into the specification by reference.
The pharmaceutically acceptable salt of tricyclo compound (I), Rapamycin and derivatives thereof are nontoxic and pharniaceutically acceptable 2 5 conventional salts, which are exemplified by salts with inorganic or organic base such as alkali metal salt (e.g., sodium salt, pot<~ssium salt and the like), alkaline earth metal salt (e.g., calcium salt, magnesium salt and the like), ammonium salt, and amine salt {e.g., triethylamine salt, N-benzyl-N-methylamine salt and the like).
In the IL-2 inhibitor of the present invention, particularly macrolide 3 0 compound, one or more pairs of stereoisomers, such as optical isomers and geometric isomers, may be included due to conformer or asymW etric carbon atom and double bond. Such conformers and isomers are also encompassed in the present invention. In addition, macrolide compounds can form solvates, which 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~ ed., No. 2821, US Patent Nos. 4,117,118, 4,215,199, 4,288,431, 4,388,307, Helv. Chim. Actor, 50, 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, cyclosporins and derivatives thereof can be class>ified as "IIf-2 production inhibitor"
that inhibit production of IIr-2. Rapamycin and derivative thereof can be classified as "IL-2 signal transduction inhibitor" that inhibit transmission of IIr2 signal.
In the present invention, visual cell func;tion disorder means the state where visual cell of retina is suffering from disor der 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 thoae 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 cel;L 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 2 5 ischemic retinopathy. The ischemic retinopaW y 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 lill~e.
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 tree eye (inclusive of eye ointment).
In consideration of systemic influence, sign~cant expression of the effect and the like, it is particularly preferably used in the forms 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 . _ . _adn~i.><'~istered locally tQ the: eye, a preparation containing the active ingredient in a 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 <~dministered 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, 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, phasphoric 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), 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.
~ F~npies F~peximental Example Z 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.
I 0 ( 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 .
I S 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 disodium hydrogenphosphate 12 hydrate 0.05 mg sodium dihydrogenphosphate 2 hydrate 0.76 mg phosphoric acid appropriate amount 2 5 sodium hydroxide appropriate amount sodium chloride 8.56 mg benzalkonium chloride 0:1 rng injectable water appropriate amount 30 Total amount 1 ~
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 3 tames a day (8 : 00, 13 : 00, 18 : 00} from day 1 to day ? 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 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.
(2) ERG determination The apparatus and parameter were standarized by the following.
"Standard for Clinical Electroretinography" (International Standardization Committee) APP~~
The Electrophysiologic Personal Interfaced Computer-2000 (LKC Technologies Incorporated) ERG determination parameter amplifier high pass filter : 500 Hz 2 0 low pass filter : 0.3 Hz notch filter : off amplitude : 50 ~V/division (maximum 15l)0 ~V) time : 20 ms/ division (maximum 2500 ms ) cornea elech ode 2 5 impedance : 10 to 20 K S~
optical stimulation single flash : 15 ms intensity : 2.289 cd. s.rri 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 35 latency of the a-wave after reperfusion was determined. It disappeared immediately after reperfusion. The results aria shown in Table 1.
Table 1 Administration group(n) .~i- a-wave peak latency (% average SD) 60 min after 90 min after 120 min after re rfusion re rfusion re rfusion Control drug (8) 195.653.5 190.855.3 191.9-60.4 Test drug (8) 137.1 ~-47.1* 141.6-~-44.8*134.4-31.6*
~k P<0.05 (comparison to control drug by ANO~A detection) The a-wave peak latency disappeared i~.~nrnediately 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 America, the content of which is incorporated hereinto by reference.
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~ hydroxy is -ORi (wherein Rl is hydroxyalkyl, hydroalkyloxyalkyl, acylaminoalkyl and aminoalkyl), such as 40-O-(2-hydroxy)ethyl Rapamycin, 40-O-(3-hydroxy)propyl Rapamycin, 40-O-j2-(2-hydroxy)ethoxy]ethyl Rapamycin~and 40-O-(2-acetanvnoethyl)-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 as CC13C(NH)O and CF3S03)). The conditions are: when X is CC13C(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 CF3S0~, in the presence of a base such as pyridine, substituted pyridine, diisopropyletl:~ylamine and pentamethylpiperidine. The most preferable Rapamycin derivative is 40-O-{2 hydroxy)ethyl Rapamycin as disclosed in W094/09010, which is hereby incorporated into the specification by reference.
The pharmaceutically acceptable salt of tricyclo compound (I), Rapamycin and derivatives thereof are nontoxic and pharniaceutically acceptable 2 5 conventional salts, which are exemplified by salts with inorganic or organic base such as alkali metal salt (e.g., sodium salt, pot<~ssium salt and the like), alkaline earth metal salt (e.g., calcium salt, magnesium salt and the like), ammonium salt, and amine salt {e.g., triethylamine salt, N-benzyl-N-methylamine salt and the like).
In the IL-2 inhibitor of the present invention, particularly macrolide 3 0 compound, one or more pairs of stereoisomers, such as optical isomers and geometric isomers, may be included due to conformer or asymW etric carbon atom and double bond. Such conformers and isomers are also encompassed in the present invention. In addition, macrolide compounds can form solvates, which 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~ ed., No. 2821, US Patent Nos. 4,117,118, 4,215,199, 4,288,431, 4,388,307, Helv. Chim. Actor, 50, 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, cyclosporins and derivatives thereof can be class>ified as "IIf-2 production inhibitor"
that inhibit production of IIr-2. Rapamycin and derivative thereof can be classified as "IL-2 signal transduction inhibitor" that inhibit transmission of IIr2 signal.
In the present invention, visual cell func;tion disorder means the state where visual cell of retina is suffering from disor der 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 thoae 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 cel;L 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 2 5 ischemic retinopathy. The ischemic retinopaW y 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 lill~e.
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 tree eye (inclusive of eye ointment).
In consideration of systemic influence, sign~cant expression of the effect and the like, it is particularly preferably used in the forms 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 . _ . _adn~i.><'~istered locally tQ the: eye, a preparation containing the active ingredient in a 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 <~dministered 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, 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, phasphoric 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), 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.
~ F~npies F~peximental Example Z 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.
I 0 ( 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 .
I S 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 disodium hydrogenphosphate 12 hydrate 0.05 mg sodium dihydrogenphosphate 2 hydrate 0.76 mg phosphoric acid appropriate amount 2 5 sodium hydroxide appropriate amount sodium chloride 8.56 mg benzalkonium chloride 0:1 rng injectable water appropriate amount 30 Total amount 1 ~
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 3 tames a day (8 : 00, 13 : 00, 18 : 00} from day 1 to day ? 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 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.
(2) ERG determination The apparatus and parameter were standarized by the following.
"Standard for Clinical Electroretinography" (International Standardization Committee) APP~~
The Electrophysiologic Personal Interfaced Computer-2000 (LKC Technologies Incorporated) ERG determination parameter amplifier high pass filter : 500 Hz 2 0 low pass filter : 0.3 Hz notch filter : off amplitude : 50 ~V/division (maximum 15l)0 ~V) time : 20 ms/ division (maximum 2500 ms ) cornea elech ode 2 5 impedance : 10 to 20 K S~
optical stimulation single flash : 15 ms intensity : 2.289 cd. s.rri 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 35 latency of the a-wave after reperfusion was determined. It disappeared immediately after reperfusion. The results aria shown in Table 1.
Table 1 Administration group(n) .~i- a-wave peak latency (% average SD) 60 min after 90 min after 120 min after re rfusion re rfusion re rfusion Control drug (8) 195.653.5 190.855.3 191.9-60.4 Test drug (8) 137.1 ~-47.1* 141.6-~-44.8*134.4-31.6*
~k P<0.05 (comparison to control drug by ANO~A detection) The a-wave peak latency disappeared i~.~nrnediately 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 America, the content of which is incorporated hereinto by reference.
Claims (10)
1. An agent for treating visual cell function disorder comprising an interleukin 2 inhibitor as an active ingredient.
2. The agent of claim 1, wherein the interleukin 2 inhibitor is a macrolide compound or a cyclosporin.
3. The agent of claim 2, wherein the macrolide compound is 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 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-NR11R12 or N-OR13;
R11 and R12 each independently show hydrogen atom, alkyl, aryl 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.
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-NR11R12 or N-OR13;
R11 and R12 each independently show hydrogen atom, alkyl, aryl 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.
4. The agent of claim 2 or claim 3, wherein the macrolide compound is FK506.
5. The agent of any of claim 1 to claim 4, which is used for the treatment of retinopathy.
6. The agent of claim 5, wherein the retinopathy is ischemic retinopathy.
7. The agent of claim 6, wherein the ischemic retinopathy is diabetic retinopathy.
8. The agent of any of claim 1 to claim 7, which is in the form of a preparation for local administration to the eye.
9. A method for treating visual cell function disorder, comprising administering an effective amount of interleukin 2 inhibitor to a subject in need of the treatment of visual cell function disorder.
10. Use of interleukin 2 inhibitor for the production of a pharmaceutical composition for the treatment of visual cell function disorder.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11393998P | 1998-12-24 | 1998-12-24 | |
| US60/113,939 | 1998-12-24 | ||
| PCT/JP1999/007161 WO2000038703A1 (en) | 1998-12-24 | 1999-12-20 | Agent for treating visual cell function disorder |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2356382A1 true CA2356382A1 (en) | 2000-07-06 |
Family
ID=22352417
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002356382A Abandoned CA2356382A1 (en) | 1998-12-24 | 1999-12-20 | Agent for treating visual cell function disorder |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP1140134A1 (en) |
| JP (1) | JP2002542150A (en) |
| KR (1) | KR20010099928A (en) |
| CN (1) | CN1224420C (en) |
| AR (1) | AR022017A1 (en) |
| AU (1) | AU781049B2 (en) |
| BR (1) | BR9917113A (en) |
| CA (1) | CA2356382A1 (en) |
| MX (1) | MXPA01006449A (en) |
| NO (1) | NO20013146L (en) |
| NZ (1) | NZ513111A (en) |
| TW (1) | TW546145B (en) |
| WO (1) | WO2000038703A1 (en) |
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| US20070032853A1 (en) | 2002-03-27 | 2007-02-08 | Hossainy Syed F | 40-O-(2-hydroxy)ethyl-rapamycin coated stent |
| AU2003209297A1 (en) | 2002-01-18 | 2003-09-02 | Massachusetts Eye And Ear Infirmary | Methods and compositions for preserving the viability of photoreceptor cells |
| JP2006511475A (en) | 2002-09-18 | 2006-04-06 | トラスティーズ オブ ザ ユニバーシティ オブ ペンシルベニア | Method for suppressing choroidal neovascular disease |
| US20050118344A1 (en) | 2003-12-01 | 2005-06-02 | Pacetti Stephen D. | Temperature controlled crimping |
| SI1848431T1 (en) | 2005-02-09 | 2016-05-31 | Santen Pharmaceutical Co., Ltd. | Liquid formulations for treatment of diseases or conditions |
| US7592330B2 (en) | 2005-08-08 | 2009-09-22 | Massachusetts Eye And Ear Infirmary | Methods and compositions for preserving the viability of photoreceptor cells |
| JP5528708B2 (en) | 2006-02-09 | 2014-06-25 | 参天製薬株式会社 | Stable formulations and methods for preparing and using them |
| US8222271B2 (en) | 2006-03-23 | 2012-07-17 | Santen Pharmaceutical Co., Ltd. | Formulations and methods for vascular permeability-related diseases or conditions |
| JP7431451B2 (en) | 2018-10-15 | 2024-02-15 | 国立大学法人大阪大学 | Pharmaceuticals for improving or preventing symptoms related to the retina and/or photoreception, and methods for screening for substances that improve or preventing symptoms related to the retina and/or photoreception |
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| DE69124380T2 (en) * | 1990-08-23 | 1997-08-14 | Univ New York | METHOD AND COMPOSITIONS FOR THE TREATMENT BY T-CELL-MEDIATED DISEASES |
| ZA924953B (en) * | 1991-07-25 | 1993-04-28 | Univ Louisville Res Found | Method of treating ocular inflammation |
| US5922773A (en) * | 1992-12-04 | 1999-07-13 | The Children's Medical Center Corp. | Glaucoma treatment |
| US5597809A (en) * | 1994-06-23 | 1997-01-28 | Massachusetts Eye & Ear Infirmary | Treatment of optic neuritis |
| AU727080B2 (en) * | 1997-06-30 | 2000-11-30 | Allergan, Inc. | Calcium blockers to treat proliferative vitreoretinopathy |
| CZ287497B6 (en) * | 1997-12-30 | 2000-12-13 | Galena, A. S. | Topic eye preparations containing immunosuppressive substances |
| US6376517B1 (en) * | 1998-08-14 | 2002-04-23 | Gpi Nil Holdings, Inc. | Pipecolic acid derivatives for vision and memory disorders |
-
1999
- 1999-12-20 NZ NZ513111A patent/NZ513111A/en unknown
- 1999-12-20 BR BR9917113-9A patent/BR9917113A/en not_active IP Right Cessation
- 1999-12-20 AU AU16906/00A patent/AU781049B2/en not_active Ceased
- 1999-12-20 JP JP2000590655A patent/JP2002542150A/en active Pending
- 1999-12-20 KR KR1020017008060A patent/KR20010099928A/en not_active Application Discontinuation
- 1999-12-20 CA CA002356382A patent/CA2356382A1/en not_active Abandoned
- 1999-12-20 WO PCT/JP1999/007161 patent/WO2000038703A1/en not_active Application Discontinuation
- 1999-12-20 CN CNB998162760A patent/CN1224420C/en not_active Expired - Fee Related
- 1999-12-20 EP EP99959930A patent/EP1140134A1/en not_active Withdrawn
- 1999-12-20 MX MXPA01006449A patent/MXPA01006449A/en unknown
- 1999-12-22 TW TW088122634A patent/TW546145B/en not_active IP Right Cessation
- 1999-12-23 AR ARP990106748A patent/AR022017A1/en not_active Application Discontinuation
-
2001
- 2001-06-22 NO NO20013146A patent/NO20013146L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| MXPA01006449A (en) | 2002-04-24 |
| JP2002542150A (en) | 2002-12-10 |
| CN1224420C (en) | 2005-10-26 |
| AU1690600A (en) | 2000-07-31 |
| CN1352565A (en) | 2002-06-05 |
| BR9917113A (en) | 2001-10-23 |
| EP1140134A1 (en) | 2001-10-10 |
| KR20010099928A (en) | 2001-11-09 |
| NO20013146L (en) | 2001-08-20 |
| AU781049B2 (en) | 2005-05-05 |
| AR022017A1 (en) | 2002-09-04 |
| WO2000038703A1 (en) | 2000-07-06 |
| TW546145B (en) | 2003-08-11 |
| NO20013146D0 (en) | 2001-06-22 |
| NZ513111A (en) | 2003-10-31 |
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Legal Events
| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Dead |