EP1140134A1 - Agent permettant le traitement d'un trouble fonctionnel de cellules de la vision - Google Patents

Agent permettant le traitement d'un trouble fonctionnel de cellules de la vision

Info

Publication number
EP1140134A1
EP1140134A1 EP99959930A EP99959930A EP1140134A1 EP 1140134 A1 EP1140134 A1 EP 1140134A1 EP 99959930 A EP99959930 A EP 99959930A EP 99959930 A EP99959930 A EP 99959930A EP 1140134 A1 EP1140134 A1 EP 1140134A1
Authority
EP
European Patent Office
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.)
Withdrawn
Application number
EP99959930A
Other languages
German (de)
English (en)
Inventor
Ryuji Ueno
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sucampo GmbH
Original Assignee
R Tech Ueno Ltd
Fujisawa Pharmaceutical Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by R Tech Ueno Ltd, Fujisawa Pharmaceutical Co Ltd filed Critical R Tech Ueno Ltd
Publication of EP1140134A1 publication Critical patent/EP1140134A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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

Definitions

  • the present invention relates to an agent for treating visual cell function disorder.
  • ERG electroretinograrn
  • each wave When the retinal function is damaged for some reason, it appears as changes in the peak latency and amplitude of each wave.
  • 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.
  • 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.
  • a-wave is the most important component, and if changes in peak latency and amplitude of a wave, which are caused by the damaged function of visual cell, can be suppressed or recovered, the visual cell function disorder is expected to be effectively treated.
  • interleukin 2 hereinafter sometimes referred to simply as IL-2
  • IL-2 interleukin 2
  • the present invention provides the following.
  • An agent for treating visual cell function disorder comprising an interleukin 2 inhibitor as an active ingredient.
  • 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 1 ;
  • R 8 and R 9 each independently show hydrogen atom or hydroxy ;
  • R 10 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 U R 12 or N-OR 13 ;
  • R 11 and R 12 each independently show hydrogen atom, alkyl, aryl or tosyl ;
  • R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 22 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.
  • Y, R 10 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 H 5 ), and alkyl substituted by one or more hydroxy, or a pharmaceutically acceptable salt thereof.
  • a method for treating visual cell function disorder comprising adrnudistering an effective amount of an interleukin 2 inhibitor to a subject in need of the treatment of visual cell function disorder.
  • the IL-2 inhibitor to be used in the present invention is not particularly lirnited and may be any as long as it has an IL-2 inhibitory activity.
  • One example 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 cyelosporins and the like.
  • macrolide compound examples include tricyclo compound (I) of the following formula and a pharmaceutically acceptable salt thereof.
  • 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 1 ;
  • R 8 and R 9 each independently show hydrogen atom or hydroxy ;
  • R 10 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 1 *R 12 or N-OR 13 ;
  • R 11 and R 12 each independently show hydrogen atom, alkyl, aryl or tosyl ;
  • R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 22 and R 23 each independently show hydrogen atom or alkyl ;
  • R 24 is a optionally substituted ring that may contain one or more hetero atom(s) ; and n is 1 or 2.
  • Y, R 10 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.
  • R 24 is, for example, cyclo(C 5 -C 7 )alkyl optionally having suitable substituent, such as the following.
  • cyclopentyl wherein cyclopentyl is substituted by methoxymethyl, optionally protected hydroxymethyl where desired, acyloxymethyl (wherein acyl moiety is optionally quaternized dimetliylamino or optionally esterified carboxy), one or more optionally protected arnino and/ or hydroxy, or aminooxalyloxyniethyl.
  • Preferable example includes 2-formyl-cyclopentyl.
  • “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 (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, hexyl and the like).
  • alkenyl include linear or branched fatty hydrocarbon residue having one double bond, such as lower alkenyl (e.g., vinyl, propenyl (e.g., allyl and the like), butenyl, methylpropenyl, pentenyl, hexenyl and the like.
  • lower alkenyl e.g., vinyl, propenyl (e.g., allyl and the like)
  • butenyl methylpropenyl
  • pentenyl hexenyl and the like.
  • aryF include phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl and the like.
  • the protective group for "protected hydroxy" and “protected arnino” include l-(loweralkylthio)flower)alkyl such as lower alkylthiomethyl (e.g., methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, isobutylthiomethyl, hexylthiomethyl and the like), with more preference given to Cj - C 4 alkylthiomethyl and most preference given to methylthiomethyl; tri-substituted silyl such as tri(lower)alkylsilyl (e.g., trirnethylsilyl, triethylsilyl, tributylsilyl, tert-butyl dimethylsilyl, tri-tert-butylsilyl and the like), and lower alkyldiarylsilyl (e.g., methyldiphenyl
  • the fatty acyl is exemplified by lower alkanoyl optionally having 1 or more suitable substituent(s) (e.g., carboxy) such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeiyl, isovaleryl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl, carboxyhexanoyl and the like ;
  • suitable substituent(s) e.g., carboxy
  • suitable substituent(s) e.g., carboxy
  • suitable substituent(s) e.g., carboxy
  • suitable substituent(s) e.g., carboxy
  • suitable substituent(s) e.g., carboxy
  • suitable substituent(s) e.g., carboxy
  • suitable substituent(s) e.g., carboxy
  • suitable substituent(s) e.g., carboxy
  • ⁇ clo(lower)alkyloxy(lower)alkanoyl optionally having 1 or more suitable substituent(s) (e.g., lower alkyl) such as cyclopropyloxyacetyl, cyclobutyloxypropionyl, cycloheptyloxybutyryl, mentyloxyacetyl, mentyloxypropionyl, mentyloxybutyryl, mentyloxypentanoyl, mentyloxyhexanoyl and the like, camphorsulfonyl ; lower alkylcarbamoyl having one or more suitable substituent(s) such as carboxy or protected carboxy and the like, such as carboxy(lower)alkylcarbamoyl (e.g., carboxymethylcarbamoyl, carboxyethylcarbamoyl, carboxypropylcarbamoyl, carboxybutylcarbamoyl, carboxypenty
  • Aromatic acyl is exemplified by aroyl optionally having suitable substituent(s) (e.g., nitro), such as benzoyl, toluoyl, xyloyl, naphthoyl, nitrobenzoyl, dinitrobenzoyl, nitronaphthoyl and the like ; and arenesulfonyl optionally having one or more suitable substituent(s) (e.g., halogen), such as benzenesulfonyl, toluenesulfonyl, xylenesulfonyl, naphthalenesulfonyl, fluorobenzenesulfonyl, chlorobenzenesulfonyl, bromobenzenesulfonyl, iodobenzenesulfonyl and the like.
  • suitable substituent(s) e.g., nitro
  • suitable substituent(s) e.
  • the aliphatic acyl substituted by aromatic group may be, for example, ar(lower)alkanoyl optionally having one or more suitable substituent(s) (e.g., lower alkyloxy or trihalo(lower)alkyl and the like), wherein specific examples are phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2- phenylacetyl, 2-ethyl-2-trifluoromethyl-2-phenylacetyl, 2-trifluoromethyl-2- propoxy-2 -phenylacetyl and the like.
  • suitable substituent(s) e.g., lower alkyloxy or trihalo(lower)alkyl and the like
  • acyl includes Ci - C 4 alkanoyl optionally having carboxy, cyclo(C 5 - C 6 )alkyloxy(C 1 - C ⁇ alkanoyl having two (C x - C 4 )alkyl in the cycloalkyl moiety, camphorsulfonyl, carboxy (C x - C 4 )alkylcarbamoyl, tri(C 1 - C 4 )alkylsilyl(C 1 - C 4 )alkyloxycarbonyl(C 1 - C 4 )alkylcarbamoyl, benzoyl optionally having 1 or 2 nitro groups, and benzenesulfonyl having halogen, phenyl(C ⁇ - C 4 )alkanoyl having Ci - C 4 alkyloxy and trihalo Ci - C 4 )alkyl.
  • acetyl carboxypropionyl, mentyloxyacetyl, camphorsulfonyl, benzoyl, nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl and the like.
  • acetyl carboxypropionyl, mentyloxyacetyl, camphorsulfonyl, benzoyl, nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl and the like.
  • heterocyclic group consisting of saturated or unsaturated 5 or 6-membered ring having nitrogen atom, sulfur atom and/ or oxygen atom
  • pyrolyl tetrahydrofuiyl and the like.
  • heteroaryl optionally having a suitable substituent moiety of the “heteroaryloxy optionally having a suitable substituent” is that exemplified for R 1 of 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 (I) and a pharmaceutically acceptable salt thereof to be used in the present invention have superior IL-2 inhibitory action and irrirnunosuppressive 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, WO89/05303, WO93/05058, WO96/31514, W091/ 13889, WO91/ 19495, WO93/5059 and the like, all of these publications are hereby incorporated by reference.
  • 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.
  • tricyclo compounds (I) More preferred is a compound wherein adjacent pairs of R 3 and R 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 ;
  • R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 22 each independently show methyl ;
  • R 24 is 3-R 20 -4-R 1 -cyclohexyl, wherein R 20 is hydroxy, alkyloxy or -OCH 2 OCH 2 CH 2 OCH 3 , and R 21 is hydroxy,-OCN, alkyloxy, heteroaiyloxy having suitable substituent, -OCH 2 OCH 2 CH 2 OCH 3 , protected hydroxy, chloro, bromo, iodo, arninooxalyloxy, azide, p-tolyloxythiocarbonyloxy or R 25 R 26 CHCOO- wherein R 25 is optionally protected hydroxy as desired, or protected arnino, and R 26 is hydrogen atom or methyl), or R 20 and R 21 in combination form an oxygen atom of epoxide ring; and n is 1 or 2.
  • tricyclo compound (I) include, besides FK506, Ascomycin derivatives such as halogenated derivative of 33-epi-chloro-33-desoxy Ascomycin described in Example 66a of EP-A-427,680 and the like.
  • IL-2 inhibitors 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 WO95/ 16691, formula A, wherein the 40* hydroxy is -OR ⁇ (wherein Ri is hydroxyalkyl, hyclroalkyloxyalkyl, acylaminoalkyl and ammoalkyl), such as 40-O-(2-hydroxy)ethyl Rapamycin, 40-O-(3-hydroxy)propyl Rapamycin, 40-O-[2- (2-hydroxy)ethoxy]ethyl Rapamycin and 40-O-(2-acetaminoethyl)-Rapamycin.
  • 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 CCl 3 C(NH)O and CF 3 SO 3 )).
  • RX organic radical bound with leaving group
  • the conditions are: when X is CCl 3 C(NH)O, acidic or neutral conditions, such as in the presence of trifluorornethanesulfonic 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, cliisopropylethylamine and pentamethylpiperidine.
  • the most preferable Rapamycin derivative is 40-O-(2- hydroxyjethyl Rapamycin as disclosed in WO94/09010, which is hereby incorporated into the specification by reference.
  • the pharmaceutically acceptable salt of tricyclo compound (I), Rapamycin and derivatives thereof are nontoxic and pharmaceutically acceptable conventional salts, which are exemplified by salts with inorganic or organic base such as alkali metal salt (e.g., sodium salt, potassium salt and the like), alkaline earth metal salt (e.g., calcium salt, magnesium salt and the like), ammonium salt, and amine salt (e.g., triethylamine salt, N-benzyl-N-methylamine salt and the like).
  • alkali metal salt e.g., sodium salt, potassium salt and the like
  • alkaline earth metal salt e.g., calcium salt, magnesium salt and the like
  • ammonium salt e.g., triethylamine salt, N-benzyl-N-methylamine salt and the like
  • amine salt e.g., triethylamine salt, N-benzyl-N-methylamine salt and the like.
  • one or more pairs of stereoisomers such as optical
  • 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. Acta, 60, 1568 (1977) and 65,1655 (1982) and Transplant. Proc. 17, 1362 (1985) and the like.
  • they are cyclosporins such as cyclosporin A, B, C, D, E, F and G and derivatives thereof.
  • Particularly preferred is cyclosporin A.
  • the tricyclo compound (I), 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.
  • 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.
  • the agent of the present invention for the treatment of visual cell function disorder can be used for treating retinopathy.
  • 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.
  • 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.
  • the mterleukin 2 inhibitor to be used in the present invention can be used as a pharmaceutical agent for human and animals, and can be a ⁇ inistered systemically or locally by oral adrninistration, intravenous adrriinistration (inclusive of transfusion), subcutaneous administration, rectal or virginal adrriir ⁇ stration, 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 mterleukin 2 inhibitor varies depending on the kind, age, body weight of the adrriinistration object such as human and animal, condition to be treated, desired therapeutic effect, adrriinistration 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.
  • an interleukin 2 inhibitor which is an active ingredient, can be adrninistered alone or in combination with other pharmacologically active components.
  • 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.
  • an oral preparation is preferably a solid solution preparation produced in the same manner as in the preparation of EP-A-0240773.
  • an eye drop as described in EP-A-0406791 is preferable.
  • additives generally used for eye drop such as isotonizing agent (e.g., sodium chloride), buffer (e.g., boric acid, phosphoric acid-sodium hydrogen, sodium dihydrogenphosphate and the like), preservative (e.g., benzalkonium chloride, benz ⁇ tonium 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.
  • isotonizing agent e.g., sodium chloride
  • buffer e.g., boric acid
  • Test substance and acuriinistration 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
  • the base agent of an eye drop without the active ingredient was used as the control.
  • the test drug was instilled to the eye by 10 ⁇ l/ eye using a micropipette 3 times a day (8 : 00, 13 : 00, 18 : 00) from day 1 to day 7 of the test.
  • the control agent was also adrriinistered by instillation in the same manner.
  • the rats were anesthetized by intraperitoneal a ⁇ nistration 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 rninutes and reperfused by releasing the ligation.
  • the apparatus and parameter were standarized by the following.
  • ERG determination parameter amplifier high pass filter : 500 Hz low pass filter : 0.3 Hz notch filter : off amplitude : 50 ⁇ V/ division (maximum 1500 ⁇ V) time : 20 ms/ division (maximum 2500 ms) cornea electrode impedance : 10 to 20 K ⁇ optical stimulation single flash : 15 ms intensity : 2.289 cd. s.m "2 ganzfeld filter : none

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Ophthalmology & Optometry (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Endocrinology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

La présente invention concerne un agent permettant le traitement d'un trouble fonctionnel de cellules de la vision contenant un inhibiteur d'interleukine tel qu'un composé de macrolide, en particulier le FK506.
EP99959930A 1998-12-24 1999-12-20 Agent permettant le traitement d'un trouble fonctionnel de cellules de la vision Withdrawn EP1140134A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US11393998P 1998-12-24 1998-12-24
US113939P 1998-12-24
PCT/JP1999/007161 WO2000038703A1 (fr) 1998-12-24 1999-12-20 Agent permettant le traitement d'un trouble fonctionnel de cellules de la vision

Publications (1)

Publication Number Publication Date
EP1140134A1 true EP1140134A1 (fr) 2001-10-10

Family

ID=22352417

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99959930A Withdrawn EP1140134A1 (fr) 1998-12-24 1999-12-20 Agent permettant le traitement d'un trouble fonctionnel de cellules de la vision

Country Status (13)

Country Link
EP (1) EP1140134A1 (fr)
JP (1) JP2002542150A (fr)
KR (1) KR20010099928A (fr)
CN (1) CN1224420C (fr)
AR (1) AR022017A1 (fr)
AU (1) AU781049B2 (fr)
BR (1) BR9917113A (fr)
CA (1) CA2356382A1 (fr)
MX (1) MXPA01006449A (fr)
NO (1) NO20013146L (fr)
NZ (1) NZ513111A (fr)
TW (1) TW546145B (fr)
WO (1) WO2000038703A1 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
ES2428354T3 (es) 2002-09-18 2013-11-07 Trustees Of The University Of Pennsylvania Rapamicina para usar en la inhibición o prevención de la neovascularización coroidea
US20050118344A1 (en) 2003-12-01 2005-06-02 Pacetti Stephen D. Temperature controlled crimping
KR20070104931A (ko) 2005-02-09 2007-10-29 마커사이트, 인코포레이티드 안구 치료용 제제
US7592330B2 (en) 2005-08-08 2009-09-22 Massachusetts Eye And Ear Infirmary Methods and compositions for preserving the viability of photoreceptor cells
CA2635797C (fr) 2006-02-09 2015-03-31 Macusight, Inc. Formulations stables et leurs procedes de preparation et d'utilisation
DK2001466T3 (en) 2006-03-23 2016-02-29 Santen Pharmaceutical Co Ltd LOW-DOSAGE RAPAMYCINE FOR TREATMENT OF VASCULAR PERMEABILITY-RELATED DISEASES
EP3868407A4 (fr) * 2018-10-15 2022-02-23 Osaka University Médicament pour améliorer ou prévenir des symptômes liés à la rétine et/ou à la photoréception et procédé de criblage de substance améliorant ou prévenant les symptômes liés à la rétine et/ou à la photoréception

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0544802B1 (fr) * 1990-08-23 1997-01-22 New York University Procedes et compositions de traitement de maladies induites par les lymphocytes t
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
WO1999000129A1 (fr) * 1997-06-30 1999-01-07 Dreyer Evan B Antagonistes du calcium servant a traiter la vitreoretinopathie proliferative
CZ287497B6 (cs) * 1997-12-30 2000-12-13 Galena, A. S. Topické oční přípravky s imunosupresivními látkami
US6376517B1 (en) * 1998-08-14 2002-04-23 Gpi Nil Holdings, Inc. Pipecolic acid derivatives for vision and memory disorders

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0038703A1 *

Also Published As

Publication number Publication date
BR9917113A (pt) 2001-10-23
KR20010099928A (ko) 2001-11-09
CA2356382A1 (fr) 2000-07-06
CN1352565A (zh) 2002-06-05
WO2000038703A1 (fr) 2000-07-06
TW546145B (en) 2003-08-11
CN1224420C (zh) 2005-10-26
AU1690600A (en) 2000-07-31
AR022017A1 (es) 2002-09-04
NO20013146D0 (no) 2001-06-22
NZ513111A (en) 2003-10-31
AU781049B2 (en) 2005-05-05
MXPA01006449A (es) 2002-04-24
NO20013146L (no) 2001-08-20
JP2002542150A (ja) 2002-12-10

Similar Documents

Publication Publication Date Title
US6864232B1 (en) Agent for treating visual cell function disorder
US6872383B2 (en) Use of macrolide compounds for the treatment of dry eye
EP1056454B1 (fr) Utilisation de macrolides pour le traitement du glaucome
JP2012116857A (ja) ドライアイ処置の為のマクロライド化合物の使用
JP2011012071A (ja) アレルギー性疾患を処置する為のｆｋ５０６誘導体を含む医薬組成物及びその使用
US20020187998A1 (en) Local ophthalmic agent for treatment of ocular inflammation
AU781049B2 (en) Agent for treating visual cell function disorder
US20050070468A1 (en) Use of fk506 and analogues for treating allergic diseases
JP3367105B2 (ja) 新規用途
EP1223969A2 (fr) Utilisation combinee d'activateurs de plasminogene et d'il-2 pour la neuroprotection
AU2002248014A1 (en) Agent for topical ophthalmic treatment of ocular inflammatory diseases

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20010723

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

17Q First examination report despatched

Effective date: 20020827

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: SUCAMPO AG

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Effective date: 20061230