EP1140134A1 - Agent for treating visual cell function disorder - Google Patents
Agent for treating visual cell function disorderInfo
- 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- Withdrawn
Links
- 230000000007 visual effect Effects 0.000 title claims abstract description 29
- 230000003915 cell function Effects 0.000 title claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 24
- 239000003120 macrolide antibiotic agent Substances 0.000 claims abstract description 12
- 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 11
- 239000003112 inhibitor Substances 0.000 claims abstract description 11
- 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 41
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 37
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 25
- 208000017442 Retinal disease Diseases 0.000 claims description 16
- 206010038923 Retinopathy Diseases 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 11
- 108010045851 interleukin 2 inhibitor Proteins 0.000 claims description 10
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 125000003118 aryl group Chemical group 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
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 4
- 229930105110 Cyclosporin A Natural products 0.000 claims description 4
- 108010036949 Cyclosporine Proteins 0.000 claims description 4
- 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
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 229960001265 ciclosporin Drugs 0.000 claims description 4
- 229930182912 cyclosporin Natural products 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 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
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 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 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 102000015696 Interleukins Human genes 0.000 abstract 1
- 108010063738 Interleukins Proteins 0.000 abstract 1
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- 238000012360 testing method Methods 0.000 description 10
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- 230000006870 function Effects 0.000 description 8
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 7
- 239000003889 eye drop Substances 0.000 description 7
- 210000001525 retina Anatomy 0.000 description 7
- 241000700159 Rattus Species 0.000 description 5
- 125000001589 carboacyl group Chemical group 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
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- 230000010410 reperfusion Effects 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 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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- 230000002238 attenuated effect Effects 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000003885 eye ointment Substances 0.000 description 3
- 125000001924 fatty-acyl group Chemical group 0.000 description 3
- 230000002207 retinal effect Effects 0.000 description 3
- 108010036941 Cyclosporins Proteins 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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- 206010038926 Retinopathy hypertensive Diseases 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
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- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
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- 229910052736 halogen Inorganic materials 0.000 description 2
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- 125000005553 heteroaryloxy group Chemical group 0.000 description 2
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- 230000002401 inhibitory effect Effects 0.000 description 2
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- 230000002265 prevention Effects 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
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
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11393998P | 1998-12-24 | 1998-12-24 | |
| US113939P | 1998-12-24 | ||
| PCT/JP1999/007161 WO2000038703A1 (en) | 1998-12-24 | 1999-12-20 | Agent for treating visual cell function disorder |
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| EP1140134A1 true EP1140134A1 (en) | 2001-10-10 |
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| Application Number | Title | Priority Date | Filing Date |
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| EP99959930A Withdrawn EP1140134A1 (en) | 1998-12-24 | 1999-12-20 | Agent for treating visual cell function disorder |
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|---|---|
| EP (1) | EP1140134A1 (zh) |
| JP (1) | JP2002542150A (zh) |
| KR (1) | KR20010099928A (zh) |
| CN (1) | CN1224420C (zh) |
| AR (1) | AR022017A1 (zh) |
| AU (1) | AU781049B2 (zh) |
| BR (1) | BR9917113A (zh) |
| CA (1) | CA2356382A1 (zh) |
| MX (1) | MXPA01006449A (zh) |
| NO (1) | NO20013146L (zh) |
| NZ (1) | NZ513111A (zh) |
| TW (1) | TW546145B (zh) |
| WO (1) | WO2000038703A1 (zh) |
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| US20070032853A1 (en) | 2002-03-27 | 2007-02-08 | Hossainy Syed F | 40-O-(2-hydroxy)ethyl-rapamycin coated stent |
| WO2003061519A2 (en) | 2002-01-18 | 2003-07-31 | Massachusetts Eye And Ear Infirmary | Methods and compositions for preserving the viability of photoreceptor cells |
| AU2003272471B2 (en) | 2002-09-18 | 2010-10-07 | Trustees Of The University Of Pennsylvania | Method of inhibiting choroidal neovascularization |
| US20050118344A1 (en) | 2003-12-01 | 2005-06-02 | Pacetti Stephen D. | Temperature controlled crimping |
| US8637070B2 (en) | 2005-02-09 | 2014-01-28 | Santen Pharmaceutical Co., Ltd. | Rapamycin formulations and methods of their use |
| WO2007019427A2 (en) * | 2005-08-08 | 2007-02-15 | Massachusetts Eye & Ear Infirmary | Methods and compositions for preserving the viability of photoreceptor cells |
| EP2001438A2 (en) | 2006-02-09 | 2008-12-17 | Macusight, Inc. | Stable formulations, and methods of their preparation and use |
| ES2563288T3 (es) | 2006-03-23 | 2016-03-14 | Santen Pharmaceutical Co., Ltd | Rapamicina en dosis bajas para el tratamiento de enfermedades relacionadas con la permeabilidad vascular |
| US20210338770A1 (en) * | 2018-10-15 | 2021-11-04 | Osaka University | Medicament for improving or preventing symptoms relating to retina and/or light reception and method for screening for substance capable of improving or preventing symptoms relating to retina and/or light reception |
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| WO1992003049A1 (en) * | 1990-08-23 | 1992-03-05 | New York University | Methods and compositions for treating 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 |
| JP2002511868A (ja) * | 1997-06-30 | 2002-04-16 | アラーガン・セイルズ・インコーポレイテッド | 増殖性硝子体網膜症を治療するためのカルシウム遮断薬 |
| 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 |
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1999
- 1999-12-20 BR BR9917113-9A patent/BR9917113A/pt not_active IP Right Cessation
- 1999-12-20 CA CA002356382A patent/CA2356382A1/en not_active Abandoned
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- 1999-12-20 AU AU16906/00A patent/AU781049B2/en not_active Ceased
- 1999-12-20 MX MXPA01006449A patent/MXPA01006449A/es unknown
- 1999-12-20 JP JP2000590655A patent/JP2002542150A/ja active Pending
- 1999-12-20 NZ NZ513111A patent/NZ513111A/en unknown
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- 1999-12-20 EP EP99959930A patent/EP1140134A1/en not_active Withdrawn
- 1999-12-20 CN CNB998162760A patent/CN1224420C/zh not_active Expired - Fee Related
- 1999-12-22 TW TW088122634A patent/TW546145B/zh not_active IP Right Cessation
- 1999-12-23 AR ARP990106748A patent/AR022017A1/es not_active Application Discontinuation
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| Publication number | Publication date |
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| AU1690600A (en) | 2000-07-31 |
| NO20013146L (no) | 2001-08-20 |
| NZ513111A (en) | 2003-10-31 |
| WO2000038703A1 (en) | 2000-07-06 |
| TW546145B (en) | 2003-08-11 |
| JP2002542150A (ja) | 2002-12-10 |
| AU781049B2 (en) | 2005-05-05 |
| KR20010099928A (ko) | 2001-11-09 |
| NO20013146D0 (no) | 2001-06-22 |
| CN1224420C (zh) | 2005-10-26 |
| CA2356382A1 (en) | 2000-07-06 |
| AR022017A1 (es) | 2002-09-04 |
| BR9917113A (pt) | 2001-10-23 |
| MXPA01006449A (es) | 2002-04-24 |
| CN1352565A (zh) | 2002-06-05 |
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