JPS6232171B2 - - Google Patents
Info
- Publication number
- JPS6232171B2 JPS6232171B2 JP54171912A JP17191279A JPS6232171B2 JP S6232171 B2 JPS6232171 B2 JP S6232171B2 JP 54171912 A JP54171912 A JP 54171912A JP 17191279 A JP17191279 A JP 17191279A JP S6232171 B2 JPS6232171 B2 JP S6232171B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- hydroxy
- propoxy
- dihydrocarbostyryl
- formula
- 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.)
- Expired
Links
- 239000003814 drug Substances 0.000 claims description 27
- 208000010412 Glaucoma Diseases 0.000 claims description 23
- 229940124597 therapeutic agent Drugs 0.000 claims description 23
- 239000004480 active ingredient Substances 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 4
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- -1 2,3-epoxy-propoxy compound Chemical class 0.000 description 23
- 239000003889 eye drop Substances 0.000 description 18
- 229940012356 eye drops Drugs 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 15
- 239000012153 distilled water Substances 0.000 description 14
- 235000002639 sodium chloride Nutrition 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000012360 testing method Methods 0.000 description 13
- 230000004410 intraocular pressure Effects 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 8
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 8
- 235000019799 monosodium phosphate Nutrition 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical class OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000006196 drop Substances 0.000 description 4
- 239000003885 eye ointment Substances 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 3
- 238000011047 acute toxicity test Methods 0.000 description 3
- 229960000686 benzalkonium chloride Drugs 0.000 description 3
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical class OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 235000019800 disodium phosphate Nutrition 0.000 description 2
- 210000000744 eyelid Anatomy 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000011975 tartaric acid Chemical class 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Chemical class OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 description 1
- MUHFRORXWCGZGE-KTKRTIGZSA-N 2-hydroxyethyl (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCCO MUHFRORXWCGZGE-KTKRTIGZSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- TZOYXRMEFDYWDQ-UHFFFAOYSA-N 3,4-dihydro-1h-quinolin-2-one Chemical compound C1=CC=C2NC(=O)CCC2=C1 TZOYXRMEFDYWDQ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical class NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- HBNKDRKDIGEFQB-UHFFFAOYSA-N 3-propoxy-3,4-dihydro-1H-quinolin-2-one hydrochloride Chemical compound Cl.CCCOC1Cc2ccccc2NC1=O HBNKDRKDIGEFQB-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- CJJRJIBMJLNTIA-UHFFFAOYSA-N 5-[3-(cyclohexylamino)-2-hydroxypropoxy]-3,4-dihydro-1h-quinolin-2-one;hydrochloride Chemical compound Cl.C=1C=CC=2NC(=O)CCC=2C=1OCC(O)CNC1CCCCC1 CJJRJIBMJLNTIA-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Chemical class OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 125000005336 allyloxy group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 238000009530 blood pressure measurement Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 235000010338 boric acid Nutrition 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005606 carbostyryl group Chemical group 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- LNGNZSMIUVQZOX-UHFFFAOYSA-L disodium;dioxido(sulfanylidene)-$l^{4}-sulfane Chemical compound [Na+].[Na+].[O-]S([O-])=S LNGNZSMIUVQZOX-UHFFFAOYSA-L 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 125000005290 ethynyloxy group Chemical group C(#C)O* 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000001530 fumaric acid Chemical class 0.000 description 1
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 238000002690 local anesthesia Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical class OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000004382 visual function Effects 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
Description
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The present invention relates to a therapeutic agent for glaucoma. Glaucoma is a group of diseases that are based on persistent or repeated increases in intraocular pressure and cause functional and organic damage to the eye.The treatment is to bring the intraocular pressure back to normal levels in order to preserve visual function. There is an urgent need to reduce the reduction (Masayoshi Mikuni, Kazuo Iwata,
Glaucoma, Kanehara Publishing Co., Ltd., 1968). The active ingredient compounds of conventional glaucoma treatment agents include:
Various alkaloids and cholinesterase inhibitors are known. The present inventors discovered that a certain type of carbostyril derivative, which is completely unrelated in its chemical structure to the above-mentioned known compounds, exerts a relatively strong intraocular pressure-lowering effect and has low toxicity, so it can be used as a therapeutic agent for glaucoma. found that it was effective, and completed the invention based on the above knowledge (patent application 1983-10108).
(No. 54-70361). As a result of further repeated research, the present inventors found that a carbostyril derivative, which is different from the derivative related to the above-mentioned application, exhibits an intraocular pressure-lowering effect almost similar to that of the above-mentioned compound, and is therefore effective in the treatment of glaucoma. The inventors discovered that an effective compound exists and completed the present invention. That is, the present invention is based on the general formula [In the formula, R 1 represents a hydrogen atom, a lower alkyl group, or a lower alkenyl group. R 2 is a hydrogen atom or group
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[Formula] (R 4 represents a lower alkyl group, a cycloalkyl group, or a lower alkyl group substituted with a phenyl group which may have a lower alkoxy group as a substituent on the phenyl ring).
If R 2 is a hydrogen atom, R 3 is
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[Formula] indicates a hydrogen atom, a hydroxyl group, a ureido group, a lower alkynyloxy group, a lower alkoxy group having a lower alkanoyl group as a substituent, a lower alkanoylamino group, or a lower alkenyloxy group. however
When R 1 and R 3 are both hydrogen atoms, R 2 is a group
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çµæãäžèšç¬¬ïŒè¡šã«ç€ºããIt must not be [Formula] (R 4 ' is a lower alkyl group). ] The present invention relates to a therapeutic agent for glaucoma, which contains as an active ingredient at least one selected from carbostyril derivatives represented by the following and pharmacologically acceptable acid addition salts thereof. The carbostyril derivative represented by the above general formula [] which is used as an active ingredient in the glaucoma therapeutic agent of the present invention can be used, for example, in West German Published Patent Application No. 2302027 and German Publication No. 2302027;
2711719, U.S. Patent No. 3953456, U.S. Patent No. 4081447
and No. 4147869, or can be easily produced according to the methods described in these documents. For example, it is produced by reacting a suitable hydroxycarbostyryl derivative with epichlorohydrin, and then reacting the obtained 2,3-epoxy-propoxy compound, 3-chloro-2-hydroxy-propoxy compound, or a mixture thereof with a suitable amine. can. Each of the above-mentioned documents describes that the derivatives included in the above general formula [] can be used as therapeutic agents for arrhythmia and angina pectoris or as antihypertensive agents, but it goes without saying that the derivatives have an effect of lowering intraocular pressure. There is no disclosure whatsoever regarding its use in the treatment of glaucoma. Examples of each group represented by R 1 to R 3 in the above general formula [] include the following. Lower alkyl group: a linear or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl group, etc. Lower alkenyl group: a linear or branched alkenyl group having 2 to 4 carbon atoms, such as vinyl, allyl,
Crotyl, 1-methylallyl group, etc. Cycloalkyl group...Cycloalkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, cyclooctyl group, etc. A lower alkyl group substituted with a phenyl group that may have a lower alkoxy group as a substituent on the phenyl ring... 1 to 3 linear or branched alkoxy groups having 1 to 4 carbon atoms on the phenyl ring A group in which a phenyl group, which may have
-Phenylbutyl, 1,1-dimethyl-2-phenethyl, β-3,4-dimethoxyphenethyl, 4
-methoxybenzyl, β-3,4,5-trimethoxyphenethyl group, etc. Lower alkynyloxy group: an alkynyloxy group having 2 to 4 carbon atoms, such as ethynyloxy, propynyloxy, butynyloxy, 2-methylpropynyloxy group, etc. Lower alkoxy group having a lower alkanoyl group as a substituent: an alkoxy group having 1 to 4 carbon atoms having an alkanoyl group having 2 to 5 carbon atoms as a substituent, such as methylcarbonylmethoxy, 2-methylcarbonylethoxy, 2-ethylcarbonyl Ethoxy, 3-methylcarbonylpropoxy, 4-
Methylcarbonylbutoxy, ethylcarbonylmethoxy, butylcarbonylmethoxy, 4-butylcarbonylbutoxy groups, etc. Lower alkanoylamino group: a linear or branched alkanoylamino group having 1 to 4 carbon atoms, such as formylamino, acetylamino, propionylamino, butyrylamino group, etc. Lower alkenyloxy group: a linear or branched alkenyloxy group having 2 to 4 carbon atoms, such as vinyloxy, allyloxy, crotyloxy, 1-
Methylallyloxy group, etc. The acid addition salts of the carbostyril derivatives represented by the above general formula [] include the usual pharmaceutically acceptable acid addition salts of the derivatives, such as hydrochloric acid, sulfuric acid, nitric acid,
Included are salts of hydrobromic acid, oxalic acid, maleic acid, fumaric acid, citric acid, tartaric acid, and the like. Representative examples of the active ingredient compound of the glaucoma therapeutic agent of the present invention represented by the above general formula [] include the following. Π5-[2-hydroxy-3-(β-3,4-
dimethoxyphenethylamino)]propoxy-
3,4-dihydrocarbostyryl Î 8-methylcarbonylmethoxy-5-[2-
Hydroxy-3-(β-3,4-dimethoxyphenethylamino)]propoxy-3,4-dihydrocarbostyryl Π8-hydroxy-5-[2-hydroxy-3
-(β-3,4-dimethoxyphenethylamino)]propoxy-3,4-dihydrocarbostyryl Π5-(2-hydroxy-3-benzylamino)propoxy-3,4-dihydrocarbostyryl Π5-( 2-Hydroxy-3-cyclohexylamino)propoxy-3,4-dihydrocarbostyryl Π1-ethyl-5-(2-hydroxy-3-cyclohexylamino)propoxy-3,4-dihydrocarbostyryl Π8-[2- Hydroxy-3-isopropylamino)propoxy-3,4-dihydrocarbostyryl Π8-(2-hydroxy-3-cyclohexylamino)propoxy-3,4-dihydrocarbostyryl Π8-[2-hydroxy-3-(β -3,4-
dimethoxyphenethylamino)]propoxy-
3,4-dihydrocarbostyryl Î 8-(2-hydroxy-3-tert-butylamino)propoxy-3,4-dihydrocarbostyryl Î 8-ureido-5-[2-hydroxy-3-
(β-3,4-dimethoxyphenethylamino)]
Propoxy-3,4-dihydrocarbostyryl Î 8-ureido-5-(2-hydroxy-3-
tert-butylamino)propoxy-3,4-dihydrocarbostyryl Π8-propynyloxy-5-[2-hydroxy-3-(β-3,4-dimethoxyphenethylamino)]propoxy-3,4-dihydro Carbostyryl Π8-propynyloxy-5-(2-hydroxy-3-cyclohexylamino)propoxy-
3,4-dihydrocarbostyryl Î 8-ureido-5-(2-hydroxy-3-
cyclohexylamino)propoxy-3,4-
Dihydrocarbostyryl Î 8-propynyloxy-5-(2-hydroxy-3-tert-butylaminopropoxy-3,
4-dihydrocarbostyryl Π8-butynyloxy-5-[2-hydroxy-3-(β-3,4-dimethoxyphenethylamino)] propoxy-3,4-dihydrocarbostyryl Π8-hydroxy-5-( 2-hydroxy-3
-tert-butylamino)propoxy-3,4-
Dihydrocarbostyryl Î 8-hydroxy-5-(2-hydroxy-3
-cyclohexylamino)propoxy-3,4
-dihydrocarbostyryl Î 8-methylcarbonylmethoxy-5-(2-
Hydroxy-3-tert-butylamino)propoxy-3,4-dihydrocarbostyryl Î 8-methylcarbonylmethoxy-5-(2-
Hydroxy-3-cyclohexylamino)propoxy-3,4-dihydrocarbostyryl Î 8-ethylcarbonylmethoxy-5-(2-
Hydroxy-3-isopropylamino)propoxy-3,4-dihydrocarbostyryl Î 8-(4-butylcarbonylbutoxy)-5
-[2-hydroxy-3-(β-3,4-dimethoxyphenethylamino)]propoxy-3,
4-dihydrocarbostyryl Î 5-(2-hydroxy-3-cyclooctylamino)propoxy-3,4-dihydrocarbostyryl Î 8-methylcarbonylmethoxy-5-[2-
Hydroxy-3-(4-phenylbutylamino)]propoxy-3,4-dihydrocarbostyrylΠ8-propynyloxy-5-[2-hydroxy-3-(β-3,4,5-trimethoxyphene) thylamino)] propoxy-3,4-dihydrocarbostyryl Π8-ureido-5-[2-hydroxy-3-
(4-methoxybenzylamino)]-3,4-dihydrocarbostyryl Î 1-methyl-5-(2-hydroxy-3-
tert-butylamino)propoxy-3,4-dihydrocarbostyryl Î 1-butyl-5-[2-hydroxy-3-
(β-3,4-dimethoxyphenethylamino)]
Propoxy-3,4-dihydrocarbostyryl Π1-methyl-8-methylcarbonylmethoxy-5-[2-hydroxy-3-(β-3,4-
dimethoxyphenethylamino)]propoxy-
3,4-dihydrocarbostyryl Π1-methyl-8-hydroxy-5-(2-hydroxy-3-tert-butylamino)propoxy-3,4-dihydrocarbostyryl Π8-acetylamino-5-[2- Hydroxy-3-(β-3,4-dimethoxyphenethylamino)]propoxy-3,4-dihydrocarbostyryl Π8-propionylamino-5-(2-hydroxy-3-tert-butylamino)propoxy-
3,4-dihydrocarbostyryl Î 8-allyloxy-5-[2-hydroxy-
3-(β-3,4-dimethoxyphenethylamino)]propoxy-3,4-dihydrocarbostyryl Π1-allyl-5-(2-hydroxy-3-
tert-butylamino)propoxy-3,4-dihydrocarbostyryl Î 1-crotyl-5-(2-hydroxy-3-
cyclohexylamino)propoxy-3,4-
Dihydrocarbostyryl Î 1-allyl-5-[2-hydroxy-3-
(β-3,4-dimethoxyphenethylamino)]
Propoxy-3,4-dihydrocarbostyryl Π1-allyl-8-methylcarbonylmethoxy-5-[2-hydroxy-3-(β-3,4-
dimethoxyphenethylamino)]propoxy-
3,4-dihydrocarbostyryl Î 8-allyloxy-5-(2-hydroxy-
3-tert-butylamino)propoxy-3,4
-Dihydrocarbostyryl Î 8-crotyloxy-5-(2-hydroxy-3-cyclohexylamino)propoxy-
3,4-Dihydrocarbostyril The therapeutic agent for glaucoma of the present invention is usually prepared in a suitable dosage unit form by mixing the derivative represented by the general formula [ ] or its acid addition salt with a commonly used carrier for ophthalmic preparations. be done. As the dosage unit form, various usual forms can be arbitrarily adopted, but mainly forms suitable for topical administration, such as eye ointments,
Eye drops etc. are preferably used as eye drops. It may also be in a form suitable for systemic administration, such as a tablet, granule, or injection. The dosage of the therapeutic agent of the present invention is not particularly limited, but the amount of active ingredient in the therapeutic agent is usually 0.01 per adult per day.
The amount is preferably 5 mg, preferably 0.05 to 1 mg, and administration is preferably carried out in 1 to 3 divided doses a day.
Furthermore, the amount of active ingredient in the therapeutic agent is not particularly limited and can be appropriately determined depending on the dosage form. For example, when formulated into a form suitable for topical administration such as eye drops, it is usually approx.
It is preferably in the range of 0.1 to 2% by weight. The therapeutic agent of the present invention can be manufactured by conventional methods. Specifically, it is produced by using a carbostyril derivative represented by the general formula [ ] or an acid addition salt thereof as an active ingredient, mixing this with an appropriate base, and then shaping as necessary. When the therapeutic agent is an eye ointment, eye drops, injection, etc., it is manufactured by further sterilization. In the above, the base may be appropriately determined depending on the form of the therapeutic agent. For example, when producing an eye ointment, a conventional emulsion base,
Water-soluble bases, suspendable bases, etc. can be used. Representative examples of such bases include white petrolatum, purified lanolin, liquid paraffin, and the like. Furthermore, in producing eye drops, for example, sterile distilled water can typically be used as a base. The therapeutic agent of the present invention may further contain, for example, solubilizing agents, stabilizers, buffers, antioxidants, preservatives, and the like. Examples of solubilizing agents include sodium carboxymethyl cellulose, polyoxyethylene glycol ethers such as polyoxyethylene lauryl ether and polyoxyethylene oleyl ether, and higher grade polyethylene glycols such as polyethylene glycol monolaurate and polyethylene glycol monooleate. Examples include fatty acid esters, polyoxyethylene fatty acid esters such as polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan monooleate. Specific examples of the stabilizer include hydroxypropyl methyl cellulose, polypynyl alcohol, carboxymethyl cellulose, hydroxyethyl cellulose, glycerin, and EDTA. Examples of the buffer include sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, boric acid, sodium borate, citric acid, sodium citrate, tartaric acid, and sodium tartrate. Examples of the antioxidant include sodium bisulfite, sodium thiosulfite, and ascorbic acid. Chlorobutanol as a preservative
Examples include benzathonium chloride, benzalkonium chloride, cetylpyridium chloride, thimerosal, phenethyl alcohol, methylparaben, and propylparaben. Furthermore, when the therapeutic agent of the present invention is in the form of eye drops, the eye drops are preferably isotonic with lachrymal fluid;
Therefore, an isotonizing agent such as common salt can be added if necessary. Furthermore, the eye drops have a pH of 5.5 to 8.5, preferably 6.5 to 8.5.
Preferably adjusted to 7.5. The therapeutic agent for glaucoma of the present invention thus obtained is administered by various administration methods depending on its dosage unit form. For example, in the case of eye drops, they are dropped into the eye from a suitable drop container or sprayed into the eye from a spray device. In the case of eye ointment, it is applied to the eye. In the case of tablets, granules, etc., they are administered orally, and in the case of injections, they are administered subcutaneously, intramuscularly, or intravenously; in either case, the desired therapeutic effect can be achieved. Formulation examples and drug efficacy tests are listed below to explain the present invention in more detail, but the present invention is not limited thereto. Formulation example 1 8-Methylcarbonylmethoxy-5-[2-hydroxy-3-(β-3,4-dimethoxyphenethylamino)]propoxy-3,4-dihydrocarbostyryl oxalate 20mg Benzathonium chloride 0.1mg Sodium chloride 3 mg Sodium dihydrogen phosphate 5 mg Sodium hydrogen phosphate, 12H 2 O 11.8 mg Distilled water Appropriate amount 1 ml Dissolve each of the above ingredients in distilled water, sterilize it using appropriate filter paper, and make eye drops. The glaucoma therapeutic agent of the present invention having the following form is manufactured. Production example 2 8-hydroxy-5-[2-hydroxy-3-
(β-3,4-dimethoxyphenethylamino)]
Propoxy-3,4-dihydrocarbostyril hydrochloride 10mg Benzathonium chloride 0.1mg Sodium chloride 3mg Sodium dihydrogen phosphate 5mg Sodium monohydrogen phosphate 12H2O 11.8mg Distilled water Appropriate amount 1 ml Add each of the above ingredients to distilled water The glaucoma therapeutic agent of the present invention in the form of eye drops is produced in the same manner as in Formulation Example 1. Formulation example 3 5-(2-hydroxy-3-cyclohexylamino)propoxy-3,4-dihydrocarbostyryl oxalate 10mg Benzathonium chloride 0.1mg Sodium chloride 3mg Sodium dihydrogen phosphate 5mg Sodium monohydrogen phosphate 12H 2 O 11.8 mg Distilled water Appropriate amount Total 1 ml Each of the above components is dissolved in distilled water, and the glaucoma therapeutic agent of the present invention in the form of eye drops is prepared in the same manner as in Formulation Example 1. Formulation example 4 8-Methylcarbonylmethoxy-5-[2-hydroxy-3-(β-3,4-dimethoxyphenethylamino)]propoxy-3,4-dihydrocarbostyryl oxalate 10mg 10% benzalkonium chloride Solution 1 Ό Sodium chloride 6.9 mg Sodium dihydrogen phosphate 0.4 mg Sodium monohydrogen phosphate 12H 2 O 1.0 mg Distilled water Measurement 1 ml Dissolve each of the above ingredients in distilled water and prepare eye drops in the same manner as in Formulation Example 1. The glaucoma therapeutic agent of the present invention is prepared in the following form. Production example 5 5-(2-hydroxy-3-benzylamino)
Propoxy-3,4-dihydrocarbostyryl hydrochloride 20mg 10% benzalkonium chloride solution 1Ό Sodium chloride 5.0mg Sodium monohydrogen phosphate 0.4mg Sodium dihydrogen phosphate 12H2O 1.0mg Distilled water Measurement 1 ml Above Each component is dissolved in distilled water, and the glaucoma therapeutic agent of the present invention in the form of eye drops is produced in the same manner as in Formulation Example 1. Drug efficacy test (method) Male New Zealand Albino Rabbit (body weight) was used as an experimental animal.
1.8-2.5Kg). For intraocular pressure measurement, the experimental animal is fixed in a cylindrical rabbit fixator, and intraocular pressure is measured without local anesthesia using an Alcon pneumatic applanation tonometer. Each test compound was dissolved in physiological saline at 1% (w/
v) Make a solution, add 0.01N-NaOH aqueous solution, and adjust the pH.
Adjust to 6.5-7.0. Each drug solution is administered using a microsyringe after measuring the intraocular pressure twice before administration.
Administer exactly 100Ό by instillation into either the left or right eye. After applying the eyelids, hold the eyelids for 1 minute to prevent the medicine from flowing out. The effect of each test compound was examined by measuring intraocular pressure 30 minutes and 1 hour after instillation and comparing it with the previous value (pre-administration intraocular pressure). As a control test, 100Ό of physiological saline containing no test compound was similarly instilled into the eyes, and the intraocular pressure was measured in the same manner. For reference, 5-(2-hydroxy-3-
tert-butylamino)propoxy-3,4-dihydrocarbostyryl hydrochloride (Reference Example 1) and 5-
The same test was conducted using (2-hydroxy-3-tert-butylamino)propoxycarbostyryl hydrochloride (Reference Example 2). (Test compound) Compound A 8-methylcarbonylmethoxy-5-
[2-hydroxy-3-(β-3,4
-dimethoxyphenethylamino)]propoxy-3,4-dihydrocarbostyryl oxalate compound B 8-hydroxy-5-[2-hydroxy-3-(β-3,4-dimethoxyphenethylamino)]propoxy- 3,
4-dihydrocarbostyryl hydrochloride compound C 5-(2-hydroxy-3-benzylamino)propoxy-3,4-dihydrocarbostyryl hydrochloride compound D 5-(2-hydroxy-3-cyclohexylamino)propoxy-3, 4-
Dihydrocarbostyril hydrochloride compound E 1-ethyl-5-(2-hydroxy-
3-Cyclohexylamino)propoxy-3,4-dihydrocarbostyryl hydrochloride Compound F 8-(2-hydroxy-3-isopropylamino)propoxy-3,4-dihydrocarbostyryl hydrochloride Compound G 8-Ureido-5-[ 2-Hydroxy-3-(β-3,4-dimethoxyphenethylamino)]propoxy-3,4
-Dihydrocarbostyryl hydrochloride compound H 8-Propynyloxy-5-[2-hydroxy-3-(β-3,4-dimethoxyphenethylamino)]propoxy-3,4-dihydrocarbostyryl oxalate compound I 8 -Acetylamino-5-[2-hydroxy-3-(β-3,4-dimethoxyphenethylamino)]propoxy-
3,4-dihydrocarbostyryl hydrochloride compound J 8-allyloxy-5-(2-hydroxy-3-tert-butylamino)propoxy-3,4-dihydrocarbostyryl hydrochloride compound K 1-allyl-5-(2 -Hydroxy-
3-tert-butylamino)propoxy-3,4-dihydrocarbostyryl hydrochloride The results are shown in Table 1 below.
ãè¡šããtableã
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äžèšç¬¬ïŒè¡šããæ¬çºæã®æå¹æåååç©ïŒäŸè©Š
ååç©No.ãïŒã¯ãããããæ£åžžãããã«å¯Ÿã
åèäŸïŒåïŒã®ååç©ãšç¥ã
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ïŒåã«ã€ããŠãäžèšåŠæ¹ã®ç¹çŒå€ã
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å§ã枬å®
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ããåå10ã11æã®éã«è¡ãªãã
ïŒåŠæ¹ïŒ
ïŒâïŒïŒâããããã·âïŒâtertâããã«ã¢ã
ãïŒããããã·âïŒïŒïŒâãžãããã«ã«ãã¹ã
ãªã«å¡©é
žå¡© 10mg
å¡©åãã³ã¶ãããŠã 0.1mg
å¡©åãããªãŠã ïŒmg
ãªã³é
žäºæ°ŽçŽ ãããªãŠã ïŒmg
ãªã³é
žäžæ°ŽçŽ ãããªãŠã ã»12H2O 11.8mgèžçæ°Ž é© é
èš ïŒ ml
äžèšåæåãèžçæ°Žã«æº¶è§£ãã補å€äŸïŒãšåæ§
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åŸãããçµæãäžèšç¬¬ïŒè¡šã«ç€ºãã[Table] From Table 1 above, all of the active ingredient compounds of the present invention (test compounds No. A to K) exhibit approximately the same intraocular pressure-lowering effect as the compounds of Reference Examples 1 and 2 in normal rabbits. It turns out that it does. Reference Test 1 For 3 glaucoma patients, 2 drops of the following prescription eye drops were instilled into the eyes, and the intraocular pressure was measured 1 and 2 days later. This measurement is performed between 10 and 11 a.m. using a Goldmann applanation tonometry device. (Prescription) 5-(2-hydroxy-3-tert-butylamino)propoxy-3,4-dihydrocarbostyryl hydrochloride 10mg Benzathonium chloride 0.1mg Sodium chloride 3mg Sodium dihydrogen phosphate 5mg Sodium monohydrogen phosphate 12H 2 O 11.8 mg Distilled water Approx. 1 ml Dissolve each of the above ingredients in distilled water and produce eye drops in the same manner as in Formulation Example 1. The results obtained are shown in Table 2 below.
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åèè©Šéš ïŒ
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ïŒåã«ã€ããŠãäžèšåŠæ¹ã®ç¹çŒå€ã
çŒã«ïŒæ»Žæ»Žäžãã滎äžååã³æ»ŽäžïŒïŒïŒåã³24æ
éåŸã«åèè©ŠéšïŒãšåæ§ã«ããŠçŒå
å§ã枬å®ã
ãã
ïŒåŠæ¹ïŒ
ïŒâïŒïŒâããããã·âïŒâtertâããã«ã¢ã
ãïŒããããã·ã«ã«ãã¹ããªã«å¡©é
žå¡© 10mg
å¡©åãã³ã¶ãããŠã 0.1mg
å¡©åãããªãŠã ïŒmg
ãªã³é
žäºæ°ŽçŽ ãããªãŠã ïŒmg
ãªã³é
žäžæ°ŽçŽ ãããªãŠã ã»12H2O 11.8mgèžçæ°Ž é© é
èš ïŒ ml
ç¹çŒå€ã®è£œé ã¯ãåèšè£œé äŸïŒã«åŸãã
çµæãäžèšç¬¬ïŒè¡šã«ç€ºãã[Table] Reference Test 2 For 3 glaucoma patients, inject 2 drops of the following prescription eye drops into the eyes, and measure the intraocular pressure in the same manner as Reference Test 1 before and 1, 4, and 24 hours after the drop. (Prescription) 5-(2-hydroxy-3-tert-butylamino)propoxycarbostyryl hydrochloride 10mg Benzathonium chloride 0.1mg Sodium chloride 3mg Sodium dihydrogen phosphate 5mg Sodium monohydrogen phosphate 12H 2 O 11.8mg Distilled water Suitable Quantity : 1 ml The eye drops were produced according to Production Example 1 above. The results are shown in Table 3 below.
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ååç©ã¯ãåªããç·å
éæ²»çå¹æãçºæ®ãåŸãã
ãšãå€ãããã®ããšãã第ïŒè¡šèšèŒã®æ¬çºæåå
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ãã§ããã
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ãªã€ãæãäžèšç¬¬ïŒè¡šèšèŒã®åLD50å€ãåŸãã[Table] From Tables 2 and 3 above, it is found that the compounds of Reference Examples 1 and 2 can exhibit excellent glaucoma treatment effects. It is clear that it is effective in treating glaucoma. Acute toxicity test Regarding the active ingredient compound of the glaucoma therapeutic agent of the present invention,
An acute toxicity test was conducted on the mice by intravenous administration, and the LD 50 values listed in Table 4 below were obtained.
ãè¡šã
å°äŸè©Šååç©ïŒ¡ã«ãããLD50ã¯ãã©ãã
ïŒéïŒã«å¯Ÿããçµå£æäžã«ããå€ã§ããã
ãŸãäžèšãšåäžã®æ¥æ§æ¯æ§è©Šéšãä»ã®æå¹æå
ååç©ã«ã€ãæ±ããæãããããããŠã¹éèå
æ
äžã§çŽ40mgïŒKg以äžã瀺ããã[Table] The LD 50 of Test Compound A is the value obtained by oral administration to rats (male). In addition, when the same acute toxicity test as above was conducted for other active ingredient compounds, all of them showed approximately 40 mg/Kg or more when administered intravenously to mice.
Claims (1)
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ãã«åºã§çœ®æãããäœçŽã¢ã«ãã«åºïŒã瀺ãã
R3ã¯R2ãæ°ŽçŽ ååã®å Žåã¯ã
ãåŒãïŒR4ã¯äžèšã«åãïŒ ã瀺ããR2ãåºãåŒãã®å Žå ã¯æ°ŽçŽ ååãæ°Žé žåºããŠã¬ã€ãåºãäœçŽã¢ã«ãã
ã«ãªãã·åºã眮æåºãšããŠäœçŽã¢ã«ã«ãã€ã«åºã
æããäœçŽã¢ã«ã³ãã·åºãäœçŽã¢ã«ã«ãã€ã«ã¢ã
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R1åã³R3ãå ±ã«æ°ŽçŽ ååã§ããå ŽåãR2ã¯åº
ãåŒãïŒR4â²ã¯äœçŽã¢ã«ãã« åºïŒã§ãã€ãŠã¯ãªããªããã ã§è¡šããããã«ã«ãã¹ããªã«èªå°äœåã³ãã®è¬ç
çã«èš±å®¹ãããé žä»å å¡©ããéžã°ããå°ãªããšã
ïŒçš®ãæå¹æåãšããŠå«æããããšãç¹åŸŽãšãã
ç·å éæ²»çå€ã[Claims] 1. General formula [In the formula, R 1 represents a hydrogen atom, a lower alkyl group, or a lower alkenyl group. R 2 represents a hydrogen atom or [Formula] (R 4 is a lower alkyl group, a cycloalkyl group, or a lower alkyl group substituted with a phenyl group that may have a lower alkoxy group as a substituent on the phenyl ring).
If R 2 is a hydrogen atom, R 3 is
[Formula] (R 4 is the same as above), and when R 2 is a group [Formula], hydrogen atom, hydroxyl group, ureido group, lower alkynyloxy group, lower alkoxy group having a lower alkanoyl group as a substituent, lower Indicates an alkanoylamino group or a lower alkenyloxy group. however
When R 1 and R 3 are both hydrogen atoms, R 2 must not be a group [formula] (R 4 ' is a lower alkyl group). ] A therapeutic agent for glaucoma, comprising as an active ingredient at least one selected from carbostyril derivatives represented by the following and pharmacologically acceptable acid addition salts thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP17191279A JPS5695115A (en) | 1979-12-28 | 1979-12-28 | Remedy for glaucoma |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP17191279A JPS5695115A (en) | 1979-12-28 | 1979-12-28 | Remedy for glaucoma |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5695115A JPS5695115A (en) | 1981-08-01 |
JPS6232171B2 true JPS6232171B2 (en) | 1987-07-13 |
Family
ID=15932128
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP17191279A Granted JPS5695115A (en) | 1979-12-28 | 1979-12-28 | Remedy for glaucoma |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5695115A (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2070151T3 (en) * | 1988-08-10 | 1995-06-01 | Otsuka Pharma Co Ltd | CARDIOTONIC AGENTS. |
JP2719740B2 (en) * | 1992-01-23 | 1998-02-25 | 倧å¡è£œè¬ æ ªåŒäŒç€Ÿ | Cardiotonic |
-
1979
- 1979-12-28 JP JP17191279A patent/JPS5695115A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS5695115A (en) | 1981-08-01 |
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