ZA200206851B - 6-hydroxy-indazole derivatives for treating glaucoma. - Google Patents
6-hydroxy-indazole derivatives for treating glaucoma. Download PDFInfo
- Publication number
- ZA200206851B ZA200206851B ZA200206851A ZA200206851A ZA200206851B ZA 200206851 B ZA200206851 B ZA 200206851B ZA 200206851 A ZA200206851 A ZA 200206851A ZA 200206851 A ZA200206851 A ZA 200206851A ZA 200206851 B ZA200206851 B ZA 200206851B
- Authority
- ZA
- South Africa
- Prior art keywords
- hydrogen
- alkyl
- halogen
- independently chosen
- trifluoromethyl
- Prior art date
Links
- 208000010412 Glaucoma Diseases 0.000 title claims description 16
- NUYZVDBIVNOTSC-UHFFFAOYSA-N 1H-indazol-6-ol Chemical class OC1=CC=C2C=NNC2=C1 NUYZVDBIVNOTSC-UHFFFAOYSA-N 0.000 title description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 63
- 239000001257 hydrogen Substances 0.000 claims description 63
- 150000001875 compounds Chemical class 0.000 claims description 61
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 32
- 150000002367 halogens Chemical class 0.000 claims description 31
- 150000002431 hydrogen Chemical class 0.000 claims description 30
- 239000000203 mixture Substances 0.000 claims description 30
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
- 239000000556 agonist Substances 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- -1 CO.C Chemical group 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 230000000699 topical effect Effects 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 238000002360 preparation method Methods 0.000 claims description 5
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 claims description 4
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 claims description 2
- 229930182837 (R)-adrenaline Natural products 0.000 claims description 2
- GGUSQTSTQSHJAH-FQEVSTJZSA-N (R)-eliprodil Chemical compound C([C@H](O)C=1C=CC(Cl)=CC=1)N(CC1)CCC1CC1=CC=C(F)C=C1 GGUSQTSTQSHJAH-FQEVSTJZSA-N 0.000 claims description 2
- NWIUTZDMDHAVTP-KRWDZBQOSA-N (S)-betaxolol Chemical compound C1=CC(OC[C@@H](O)CNC(C)C)=CC=C1CCOCC1CC1 NWIUTZDMDHAVTP-KRWDZBQOSA-N 0.000 claims description 2
- TVFHFCCUCRPIGS-UHFFFAOYSA-N 1-(2-aminopropyl)-3-chloroindazol-6-ol Chemical compound C1=C(O)C=C2N(CC(N)C)N=C(Cl)C2=C1 TVFHFCCUCRPIGS-UHFFFAOYSA-N 0.000 claims description 2
- GGUSQTSTQSHJAH-UHFFFAOYSA-N 1-(4-chlorophenyl)-2-[4-(4-fluorobenzyl)piperidin-1-yl]ethanol Chemical compound C=1C=C(Cl)C=CC=1C(O)CN(CC1)CCC1CC1=CC=C(F)C=C1 GGUSQTSTQSHJAH-UHFFFAOYSA-N 0.000 claims description 2
- XYLJNLCSTIOKRM-UHFFFAOYSA-N Alphagan Chemical compound C1=CC2=NC=CN=C2C(Br)=C1NC1=NCCN1 XYLJNLCSTIOKRM-UHFFFAOYSA-N 0.000 claims description 2
- OMCPLEZZPVJJIS-UHFFFAOYSA-N Hypadil (TN) Chemical compound C1C(O[N+]([O-])=O)COC2=C1C=CC=C2OCC(O)CNC(C)C OMCPLEZZPVJJIS-UHFFFAOYSA-N 0.000 claims description 2
- 208000001953 Hypotension Diseases 0.000 claims description 2
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 claims description 2
- 239000005557 antagonist Substances 0.000 claims description 2
- 229940006133 antiglaucoma drug and miotics carbonic anhydrase inhibitors Drugs 0.000 claims description 2
- IEJXVRYNEISIKR-UHFFFAOYSA-N apraclonidine Chemical compound ClC1=CC(N)=CC(Cl)=C1NC1=NCCN1 IEJXVRYNEISIKR-UHFFFAOYSA-N 0.000 claims description 2
- AQOKCDNYWBIDND-FTOWTWDKSA-N bimatoprost Chemical compound CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-FTOWTWDKSA-N 0.000 claims description 2
- 229960003679 brimonidine Drugs 0.000 claims description 2
- 229960000722 brinzolamide Drugs 0.000 claims description 2
- HCRKCZRJWPKOAR-JTQLQIEISA-N brinzolamide Chemical compound CCN[C@H]1CN(CCCOC)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 HCRKCZRJWPKOAR-JTQLQIEISA-N 0.000 claims description 2
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 claims description 2
- 229960001222 carteolol Drugs 0.000 claims description 2
- LWAFSWPYPHEXKX-UHFFFAOYSA-N carteolol Chemical compound N1C(=O)CCC2=C1C=CC=C2OCC(O)CNC(C)(C)C LWAFSWPYPHEXKX-UHFFFAOYSA-N 0.000 claims description 2
- 229960003933 dorzolamide Drugs 0.000 claims description 2
- IAVUPMFITXYVAF-XPUUQOCRSA-N dorzolamide Chemical compound CCN[C@H]1C[C@H](C)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 IAVUPMFITXYVAF-XPUUQOCRSA-N 0.000 claims description 2
- 229950005455 eliprodil Drugs 0.000 claims description 2
- 229960005139 epinephrine Drugs 0.000 claims description 2
- 208000021822 hypotensive Diseases 0.000 claims description 2
- 230000001077 hypotensive effect Effects 0.000 claims description 2
- 229940095437 iopidine Drugs 0.000 claims description 2
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 claims description 2
- 229960001160 latanoprost Drugs 0.000 claims description 2
- 229960004771 levobetaxolol Drugs 0.000 claims description 2
- 229960000831 levobunolol Drugs 0.000 claims description 2
- IXHBTMCLRNMKHZ-LBPRGKRZSA-N levobunolol Chemical compound O=C1CCCC2=C1C=CC=C2OC[C@@H](O)CNC(C)(C)C IXHBTMCLRNMKHZ-LBPRGKRZSA-N 0.000 claims description 2
- 150000002632 lipids Chemical class 0.000 claims description 2
- 229940112534 lumigan Drugs 0.000 claims description 2
- 230000003547 miosis Effects 0.000 claims description 2
- 239000003604 miotic agent Substances 0.000 claims description 2
- 239000004090 neuroprotective agent Substances 0.000 claims description 2
- 229950000754 nipradilol Drugs 0.000 claims description 2
- 229960001416 pilocarpine Drugs 0.000 claims description 2
- 229960003712 propranolol Drugs 0.000 claims description 2
- 150000003180 prostaglandins Chemical class 0.000 claims description 2
- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 claims description 2
- 229960002368 travoprost Drugs 0.000 claims description 2
- TVHAZVBUYQMHBC-SNHXEXRGSA-N unoprostone Chemical compound CCCCCCCC(=O)CC[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(O)=O TVHAZVBUYQMHBC-SNHXEXRGSA-N 0.000 claims description 2
- 229960004317 unoprostone Drugs 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- 125000003342 alkenyl group Chemical group 0.000 claims 2
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 claims 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 229960004324 betaxolol Drugs 0.000 claims 1
- NWIUTZDMDHAVTP-UHFFFAOYSA-N betaxolol Chemical compound C1=CC(OCC(O)CNC(C)C)=CC=C1CCOCC1CC1 NWIUTZDMDHAVTP-UHFFFAOYSA-N 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 229960004605 timolol Drugs 0.000 claims 1
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- 238000000034 method Methods 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 102000005962 receptors Human genes 0.000 description 12
- 108020003175 receptors Proteins 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 230000004410 intraocular pressure Effects 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 239000000284 extract Substances 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- 210000003169 central nervous system Anatomy 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000000377 silicon dioxide Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 150000002473 indoazoles Chemical class 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 229940054534 ophthalmic solution Drugs 0.000 description 4
- 150000002989 phenols Chemical class 0.000 description 4
- 150000003906 phosphoinositides Chemical class 0.000 description 4
- 230000000862 serotonergic effect Effects 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 206010030043 Ocular hypertension Diseases 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000027455 binding Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 229940124274 edetate disodium Drugs 0.000 description 3
- 230000004406 elevated intraocular pressure Effects 0.000 description 3
- 229960000367 inositol Drugs 0.000 description 3
- LIHGLLXHHBMMCF-UHFFFAOYSA-N n-ethylindazol-1-amine Chemical group C1=CC=C2N(NCC)N=CC2=C1 LIHGLLXHHBMMCF-UHFFFAOYSA-N 0.000 description 3
- 239000002997 ophthalmic solution Substances 0.000 description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229940068968 polysorbate 80 Drugs 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000004382 visual function Effects 0.000 description 3
- WSEWULCWBQDNEH-UHFFFAOYSA-N 1-(6-methoxyindazol-1-yl)propan-2-amine Chemical compound COC1=CC=C2C=NN(CC(C)N)C2=C1 WSEWULCWBQDNEH-UHFFFAOYSA-N 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- 239000004166 Lanolin Substances 0.000 description 2
- RLJFTICUTYVZDG-UHFFFAOYSA-N Methiothepine Chemical compound C12=CC(SC)=CC=C2SC2=CC=CC=C2CC1N1CCN(C)CC1 RLJFTICUTYVZDG-UHFFFAOYSA-N 0.000 description 2
- 206010067013 Normal tension glaucoma Diseases 0.000 description 2
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 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
- 229940061607 dibasic sodium phosphate Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 238000002825 functional assay Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 229940039717 lanolin Drugs 0.000 description 2
- 235000019388 lanolin Nutrition 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 201000002978 low tension glaucoma Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 230000004493 normal intraocular pressure Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 235000019271 petrolatum Nutrition 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- 230000007306 turnover Effects 0.000 description 2
- 239000003871 white petrolatum Substances 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- FGQUUCRNAOILHX-WLHGVMLRSA-N (e)-but-2-enedioic acid;1-(6-methoxy-3-methylindazol-1-yl)propan-2-amine Chemical compound OC(=O)\C=C\C(O)=O.COC1=CC=C2C(C)=NN(CC(C)N)C2=C1 FGQUUCRNAOILHX-WLHGVMLRSA-N 0.000 description 1
- WBYHTZYHAFNBKW-UHFFFAOYSA-N 1-((s)-2-aminopropyl)-1h-indazol-6-ol Chemical compound C1=C(O)C=C2N(CC(N)C)N=CC2=C1 WBYHTZYHAFNBKW-UHFFFAOYSA-N 0.000 description 1
- ZCZIRBNZMFUCOH-UHFFFAOYSA-N 1-(2-fluoro-4-hydroxyphenyl)ethanone Chemical compound CC(=O)C1=CC=C(O)C=C1F ZCZIRBNZMFUCOH-UHFFFAOYSA-N 0.000 description 1
- PIRRWUMTIBFCCW-UHFFFAOYSA-N 1-(2-fluoro-4-methoxyphenyl)ethanone Chemical compound COC1=CC=C(C(C)=O)C(F)=C1 PIRRWUMTIBFCCW-UHFFFAOYSA-N 0.000 description 1
- HWCVHUGKSVUQAK-UHFFFAOYSA-N 1-(2-fluoro-4-phenylmethoxyphenyl)ethanone Chemical compound C1=C(F)C(C(=O)C)=CC=C1OCC1=CC=CC=C1 HWCVHUGKSVUQAK-UHFFFAOYSA-N 0.000 description 1
- PNHDUSKIMUKQDR-UHFFFAOYSA-N 1-(3-chloro-6-methoxyindazol-1-yl)propan-2-amine Chemical compound COC1=CC=C2C(Cl)=NN(CC(C)N)C2=C1 PNHDUSKIMUKQDR-UHFFFAOYSA-N 0.000 description 1
- VTQZIJAHXKYERA-UHFFFAOYSA-N 1-(3-methyl-6-phenylmethoxyindazol-1-yl)propan-2-one Chemical compound C1=C2N(CC(=O)C)N=C(C)C2=CC=C1OCC1=CC=CC=C1 VTQZIJAHXKYERA-UHFFFAOYSA-N 0.000 description 1
- RDEVDEVIDINKGP-UHFFFAOYSA-N 1-(3-methylindazol-1-yl)propan-2-amine Chemical compound C1=CC=C2N(CC(N)C)N=C(C)C2=C1 RDEVDEVIDINKGP-UHFFFAOYSA-N 0.000 description 1
- FLXBPPLSJBZWFG-UHFFFAOYSA-N 1-(6-methoxy-3-methylindazol-1-yl)propan-2-ol Chemical compound COC1=CC=C2C(C)=NN(CC(C)O)C2=C1 FLXBPPLSJBZWFG-UHFFFAOYSA-N 0.000 description 1
- ALFIEMDSTZZZLZ-UHFFFAOYSA-N 1-(6-methoxy-3-methylindazol-1-yl)propan-2-one Chemical compound COC1=CC=C2C(C)=NN(CC(C)=O)C2=C1 ALFIEMDSTZZZLZ-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- XVAUPZUXDFQBRK-UHFFFAOYSA-N 2-acetamido-4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C(NC(C)=O)=C1 XVAUPZUXDFQBRK-UHFFFAOYSA-N 0.000 description 1
- LROZHGNPZCOCGT-UHFFFAOYSA-N 2-hydrazinyl-4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C(NN)=C1 LROZHGNPZCOCGT-UHFFFAOYSA-N 0.000 description 1
- BXEFQUSYBZYTAE-UHFFFAOYSA-N 2-indol-1-ylethanamine Chemical class C1=CC=C2N(CCN)C=CC2=C1 BXEFQUSYBZYTAE-UHFFFAOYSA-N 0.000 description 1
- JZPHAJFIZZEAEK-UHFFFAOYSA-N 3-chloro-6-methoxy-2h-indazole Chemical compound COC1=CC=C2C(Cl)=NNC2=C1 JZPHAJFIZZEAEK-UHFFFAOYSA-N 0.000 description 1
- QPHSPVMKEAIENO-UHFFFAOYSA-N 3-methyl-6-phenylmethoxy-2h-indazole Chemical compound C=1C=C2C(C)=NNC2=CC=1OCC1=CC=CC=C1 QPHSPVMKEAIENO-UHFFFAOYSA-N 0.000 description 1
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- BSMAHLLCCMSTGQ-UHFFFAOYSA-N 6-methoxy-1,2-dihydroindazol-3-one Chemical compound COC1=CC=C2C(O)=NNC2=C1 BSMAHLLCCMSTGQ-UHFFFAOYSA-N 0.000 description 1
- VDRWFBGSDLRPLK-UHFFFAOYSA-N 6-methoxy-3-methyl-2h-indazole Chemical compound COC1=CC=C2C(C)=NNC2=C1 VDRWFBGSDLRPLK-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 208000030814 Eating disease Diseases 0.000 description 1
- 241000978494 Emex Species 0.000 description 1
- 235000006369 Emex spinosa Nutrition 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 208000019454 Feeding and Eating disease Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102000014630 G protein-coupled serotonin receptor activity proteins Human genes 0.000 description 1
- 229920002148 Gellan gum Polymers 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- SNIXRMIHFOIVBB-UHFFFAOYSA-N N-Hydroxyl-tryptamine Chemical class C1=CC=C2C(CCNO)=CNC2=C1 SNIXRMIHFOIVBB-UHFFFAOYSA-N 0.000 description 1
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 1
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 102000014384 Type C Phospholipases Human genes 0.000 description 1
- 108010079194 Type C Phospholipases Proteins 0.000 description 1
- OMEBHZQIIMCJGK-WLHGVMLRSA-N [1-(2-aminopropyl)indazol-6-yl] 2,2-dimethylpropanoate;(e)-but-2-enedioic acid Chemical compound OC(=O)\C=C\C(O)=O.C1=C(OC(=O)C(C)(C)C)C=C2N(CC(N)C)N=CC2=C1 OMEBHZQIIMCJGK-WLHGVMLRSA-N 0.000 description 1
- DVJJRWLADVSEIU-UHFFFAOYSA-N [1-(2-oxopropyl)indazol-6-yl] 2,2-dimethylpropanoate Chemical compound C1=C(OC(=O)C(C)(C)C)C=C2N(CC(=O)C)N=CC2=C1 DVJJRWLADVSEIU-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 230000004509 aqueous humor production Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- RVIXKYOFEMDOPL-UHFFFAOYSA-N benzyl N-[1-(6-hydroxyindazol-1-yl)propan-2-yl]carbamate Chemical compound N1=CC2=CC=C(O)C=C2N1CC(C)NC(=O)OCC1=CC=CC=C1 RVIXKYOFEMDOPL-UHFFFAOYSA-N 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 230000007073 chemical hydrolysis Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940124447 delivery agent Drugs 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000014632 disordered eating Nutrition 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000000216 gellan gum Substances 0.000 description 1
- 235000010492 gellan gum Nutrition 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000003400 hallucinatory effect Effects 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 1
- 229960004640 memantine Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 229940042472 mineral oil Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 229940100655 ophthalmic gel Drugs 0.000 description 1
- 229940069265 ophthalmic ointment Drugs 0.000 description 1
- 229940100654 ophthalmic suspension Drugs 0.000 description 1
- 210000001328 optic nerve Anatomy 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 208000022821 personality disease Diseases 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 208000007232 portal hypertension Diseases 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 238000003345 scintillation counting Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical class C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- 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
- A61P27/06—Antiglaucoma agents or miotics
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Ophthalmology & Optometry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
6-HYDROXY-INDAZOLE DERIVATIVES FOR TREATING GLAUCOMA
The present invention is directed to novel substituted 1-(a-alkyl-ethylamino)- 1H-indazol-6-ols. These novel compounds are useful for lowering and controlling normal or elevated intraocular pressure (IOP) and treating glaucoma.
The disease state referred to as glaucoma is characterized by a permanent loss of visual function due to irreversible damage to the optic nerve. The several morphologically or functionally distinct types of glaucoma are typically characterized by elevated IOP, which is considered to be causally related to the pathological course of the disease. Ocular hypertension is a condition wherein intraocular pressure is elevated but no apparent loss of visual function has occurred; such patients are considered to be a high risk for the eventual development of the visual loss associated with glaucoma. Some patients with glaucomatous field loss have relatively low intraocular pressure. These so called normotension or low tension glaucoma patients can also benefit from agents that lower and control IOP. If glaucoma or ocular hypertension is detected early and treated promptly with medications that effectively reduce elevated intraocular pressure, loss of visual function or its progressive deterioration can generally be ameliorated. Drug therapies that have proven to be effective for the reduction of intraocular pressure include both agents that decrease aqueous humor production and agents that increase the outflow facility. Such therapies are in general administered by one of two possible routes, topically (direct application to the eye) or orally.
There are some individuals who do not respond well when treated with certain existing glaucoma therapies. There is, therefore, a need for other topical therapeutic agents that control IOP.
It has been found that serotonergic compounds which possess agonist activity at 5-HT, receptors effectively lower and control normal and elevated IOP and are useful for treating glaucoma, see commonly owned co-pending application,
PCT/US99/19888. Compounds that act as agonists at 5-HT, receptors are well known 3s and have shown a variety of utilities, primarily for disorders or conditions associated with the central nervous system (CNS). U.S. Patent 5,494,928 discloses certain 2- (indol-1-yl)-ethylamine derivatives that are 5-HT,c agonists for the treatment of obsessive compulsive disorder and other CNS derived personality disorders. U.S.
Patent 5,571,833 discloses tryptamine derivatives that are 5-HT, agonists for the treatment of portal hypertension and migraine. U.S. Patent 5,874,477 discloses a method for treating malaria using 5-HT,a/c agonists. U.S. Patent 5,902,815 discloses the use of 5-HT,a agonists to prevent adverse effects of NMDA receptor hypo- function. Published International Patent Application No. W0O98/30548 discloses that selected 1-ethylamino-1H-indazoles substituted at ring positions 4-, 5-, 6-, or 7- have selective affinity for the 5-HT,c receptor and thereby have utility in the treatment of central nervous system diseases. International Patent Application Nos. WO00/12481 and WOO00/17170 disclose yet other 1-ethylamino-1H-indazoles that have selective —~ affinity for the 5-HT¢ receptor and thereby have utility in the treatment of disorders of the central nervous system. Published International Patent Application No.
WO098/31354A2 discloses 5-HT,p agonists for the treatment of depression and other
CNS conditions. WO000/35922 discloses certain pyrazino[1,2-ajquinoxaline derivatives as 5-HT,c agonists for the treatment of obsessive-compulsive disorder, depression, eating disorders, and other disorders involving the CNS. Agonist response at the 5-HT,s receptor is reported to be the primary activity responsible for oo hallucinogenic activity, with some lesser involvement of the 5-HT,¢ receptor possible [Psychopharmacology, Vol. 121:357, 1995].
The present invention is directed to novel substituted 1-(a-alkyl-ethylamino)- 1H-indazol-6-ols. It has been determined that these novel compounds have a high affinity for and function as agonists at the serotonergic 5S-HT); receptor, and are useful for lowering and controlling normal or elevated intraocular pressure (IOP) and treating glaucoma. When a phenolic moiety is included in this substitution, e.g. a hydroxyl group at indazole ring position six, such compounds can be particularly sensitive to oxidation reactions well known io oocw wii phenolic compounds in general, including hydroxytryptamines [J. Phys. Chem. 103, 8606 (1999), Chem. Res. Toxicol. 11, 639 (1998), J. Org. Chem. 52, 2817 (1987), J. Pharm. Sci. 77, 911 (1988)], which are of particular relevance to the present application. Protection of such phenols from oxidation can be accomplished by derivatization of the aryl hydroxyl group to provide a suitable ester, carbamate, or carbonate. Though the ester, carbamate, or carbonate derivatives do not themselves possess a high affinity for the above mentioned receptors, they do have utility in the treatment of glaucoma since suitably protected phenols can be cleaved in vivo either by chemical hydrolysis or through the action of tissue esterases, thereby delivering the desired therapeutic agent, that is, the desired novel 6-hydroxy-indazole compounds of the present invention. The concept of utilizing such derivatized phenolic compounds as chemical delivery agents is well known in the art [Drugs Pharm. Sci. 53, 221 (1992), Pharm. Res., 168 (1984)]. 22a
The present invention is directed to new and known derivatives of 1- (ethylamino)- 1 H-indazole that can be used to lower and control IOP associated with normal-tension glaucoma, ocular hypertension, and glaucoma in warm-blooded animals, including man. The compounds are formulated in phammaceutical compositions suitable for topical delivery to the eye.
Compounds that are useful according to the present invention are represented by the following Formula I.
FORMULA
- wR r' rR’ brs pe
R
RF wherein R! to R* are independently chosen from hydrogen, halogen, Ci_salkyl, trifluoromethyl, O-W, C; alkylthio, C;.salkylsulfoxyl, Cisalkylsulfonyl, or cyano;
R® can be hydrogen, C;.salkyl, or C;salkoxy, halogen, trifluoromethyl, cyano,
NR’R! 1.
R® and R’ are independently chosen from hydrogen, C;4atkyl or R®, R and the carbon atom to which they are attached can form a cyclopropyl ring, or furthermore, R’ and
R® together can be (CH,),, to form a saturated heterocycle;
R® and R® are independently chosen from hydrogen or C;4alkyl;
R'® and R!' are independently chosen from hydrogen or C; alkyl, or R'%,R'! and the nitrogen atom to which they are attached can form a saturated heterocyclic ring . selected from pyrrolidine, piperidine, piperazine, or morpholine;
R! to R? cannot simultaneously be hydrogen;
R® and R’ cannot both be hydrogen;
W is hydrogen, C;alkyl, C(=0)X, or P(=0)(OY )(OZ);
X is Crealkyl, NR®R®, N(R®)CH2(CH2).C(=0)NR¥(R?), OC;.salkyl, C;salkyl (which can be substituted with halogen, hydroxyl, CO,C,4alkyl, CON(C;alkyl),,
C(=NH)NH,, NHC(=NH)NH,, NH>), C;4alkenyl (substituted by phenyl, unsubstituted or substituted with one or more of C,4alkyl, Cj4alkoxy or halogen);
Y and Z are independently chosen from hydrogen, Cy.10 alkyl or Y and Z can together form a lower alkyl chain of (CH); mis2-4; nis 1 or2; and pharmaceutically acceptable salts and solvates of the compounds of Formula I.
Compounds that are novel and which are useful according to the present invention can be defined as follows: wherein R' to R* are independently chosen from hydrogen, halogen, C,.¢alkyl, trifluoromethyl, O-W, C;_salkylthio, C;.salkylsulfoxyl, C,.salkylsulfonyl, or cyano;
R® can be halogen, trifluoromethyl, cyano, NR'’R'’;
R® and R’ are independently chosen from hydrogen, Cyalkyl or R®, R’ and the carbon atom to which they are attached can form a cyclopropyl ring, or furthermore, R’ and
Co R® together can be (CH) to form a saturated heterocycle;
R® and R® are independently chosen from hydrogen or C;.alkyl;
R'% and R!! are independently chosen from hydrogen or C;4alkyl, or R'%, R! and the nitrogen atom to which they are attached can form a saturated heterocyclic ring selected from pyrrolidine, piperidine, piperazine, or morpholine;
R! to R* cannot simultaneously be hydrogen;
R® and R’ cannot both be hydrogen;
W is hydrogen, C,4alkyl, C(=0)X, or P(=0)(OY)(0Z);
X is C1.¢alkyl, NR®R®, N(R*)CH,(CH,).C(=O)N(R®*)(R’), OC; .salkyl, Ci.salkyl (which can be substituted wiih halogen, hydroxyl, CO,Cjaalkyl, CON(C,4alkyl),,
C(=NH)NH,, NHC(=NH)NH,, NH), C;.4alkenyl (substituted by phenyl, unsubstituted or substituted with one or more of C;4alkyl, C;4alkoxy or halogen);
Y and Z are independently chosen from hydrogen, Ci.10 alkyl or Y and Z can together form a lower alkyl chain of (CH2)m; mis3or4; nis1or2; . and pharmaceutically acceptable salts and solvates of the compounds of Formula I. . 35 Preferred compounds are:
R! and R? are independently chosen from hydrogen, halogen, Ci.salkyl, trifluoromethyl, O-W, C, alkylthio, C..salkylsulfoxyl, C;.galkylsulfonyl, or cyano;
R® and R? are independently chosen from hydrogen, halogen, C,_salkyl, trifluoromethyl, or cyano;
R® can be hydrogen, C;.alkyl, halogen, trifluoromethyl, or Cy.alkoxy; , R%and R are independently chosen from hydrogen or C; alkyl, or R®, R’ and the carbon atom to which they are attached can form a cyclopropyl ring, or furthermore, } R’ and R® together can be (CH;)m to form a saturated heterocycle;
R® and R® are independently chosen from hydrogen or C; alkyl;
R! to R* cannot simultaneously be hydrogen;
R® and R’ cannot both be hydrogen;
W is hydrogen, C,salkyl, C(=0)X, or P(=0)(OY)(02Z),
X is Ciealkyl, NR®R®, N(R¥)CH,(CH2).C(=O)NR?R®, OC; _salkyl, C; alkyl (which can be substituted with halogen, hydroxyl, CO,C;4alkyl, CON(C, alkyl),
C(=NH)NH,, NHC(=NH)NH,, NH;), C;.4alkenyl (substituted by phenyl, unsubstituted or substituted with one or more of C, 4alkyl, C;.salkoxy or halogen);
Y and Z are independently chosen from hydrogen, C;.jpalkyl or Y and Z can together form a lower alkyl chain of (CH); mis 3; nis 1or?2;
The more preferred compounds are: where R}, R?, and R* are independently chosen from hydrogen, halogen, C;.ealkyl, trifluoromethyl, or cyano;
R? is chosen from O-W;
R’ canbe hydrogen, C;.salkyl, halogen, trifluoromethyl, or C,.4alkoxy;
RS is hydrogen and R’ is methyl;
R? and R? are independently chiusen from hydrogen or Cjualkyl;
W is hydrogen, C; alkyl, or C(=0)X;
X is Ciealkyl, NR®R®, or N(R®)CH,(CH,),C(=O0)N(R*)(R®); nis 1or2;
The most preferred compounds are: where R, R?, and R* are independently chosen from hydrogen or halogen;
R’is O-W;
R’ is hydrogen or C;_alky}; ) 35 R® is hydrogen and R’ is methyl;
R® and R® are hydrogen;
W is hydrogen, C,_salkyl; _5-
It is recognized that compounds of Formula I can contain one or more chiral centers. This invention contemplates all enantiomers, diastereomers and, mixtures thereof.
L In the above definitions, the total number of carbon atoms in a substituent group is indicated by the C;; prefix where the numbers i and j define the number of carbon atoms; this definition includes straight chain, branched chain, and cyclic alkyl or (cyclic alkyl)alkyl groups.
It is important to recognize that a substituent may be present either singly or multiply when incorporated into the indicated structural unit. For example, the substituent halogen, which means fluorine, chlorine, bromine, or iodine, would indicate that the unit to which it is attached may be substituted with one or more halogen atoms, which may be the same or different.
SYNTHESIS
The compounds of Formula I can be prepared by processes analogous to those known in the art. The preparation of compounds of Formula I wherein R? is OH and
R' and R*-R® are as defined above can be prepared from the appropriate O-protected substituted-indazol-6-ol (1), suitable O-protective groups are e.g. methyl or benzyl, and can be prepared by methods well known in the art and described in Scheme 1 [U.S. Patent 5,494,928 (1997), WO98/30548 (1998)]. Alkylation of indazole 1 with the desired epoxide, e.g. propylene oxide, provides the intermediate alcohol 2.
Alternately, it can be advantageous for certain compounds to alkylate 1 using chloroaccione iviluwed py reduction, e.g. with NaBH,, of the intermediate ketone to obtain the intermediate 2.
SCHEME 1
Rr
Rr! Rr’ ~ 0, _ OH
Pg—0 N a, Pg—0 Ny
Vj NaOH, MeOH N 4
R® R pO Bo, RF 1. MsCl 2. NaN,/DMF
R® | R®
R' ~~ R! ~~
Ho NM Ma Pg—0 N Ny mW H, /Pd-C pe rR deprotect & rR * g ® 4 Ry
The indazoles 1 can be prepared by conducting suitable functional group transformations on indazoles that are commercially available or that can be prepared according to literature procedures, generally starting from either the desired alkoxy-2- aminophenyl ketone (5), or the suitably substituted alkoxy-2-fluorophenyl ketone (6), depending on availability of suitable precursors (Scheme 2) [J. Heterocycl. Chem. 33, 895 (1998); J. Med. Chem. 40, 2706 (1997); Comp. Heterocycl. Chem. 11, Vol. 3, 1 (1996)]. Also, certain indazoles 1 can be prepared from other indazoles 1 by direct substitution or by selective functional group transformations well known to the art.
SCHEME 2
K 2°
Rr ° NaNO,
Pg—0 NH, snc
R 5 ~~ R RS
Rr pps /
R* R® Pg—0 N a [o) Pad : 1
Pg—O F
R! 6
Intermediates 2 of Scheme 1 can also be prepared from the suitably substituted alkoxy-2-fluorophenyl ketones, for example by reaction of 6 with 1-hydrazino-2-
propanol [J. Amer. Chem. Soc. 76, 1283 (1954)] using procedures analogous to those known in the art [J. Med. Chem. 41, 5429 (1998)]. 3 The compounds of Formula I wherein R? is OC(=0)X can be prepared by procedures analogous to those known in the art. For example, when the substituent . OC(C=0)X is compatible with the subsequent reaction conditions as described above, such compounds can be prepared as described in Schemes 1 and 2. Alternately, and preferably, compounds of Formula I wherein R? is OC(=0)X can be prepared by reacting the appropriate indazole 7, or preferably a suitable amino-protected intermediate, e.g. 8 (Scheme 3) with the desired activated acid derivative, such as an acid halide or active ester, or the like, to provide, for example, the esters 9. Removal of the N-protective group from the intermediate 9 provides the desired compounds 10 of Formula I.
SCHEME 3 om, CH, rR !
HO oo NH, HO 1 ~~ Na ; — J
R Rr
R* R* rR R® 7 8
CH, | CH, rR’ t x " ; ~~ NH, x. 0 1 A
Y \ No H . lo] Va a e— hg ry ] [s} - 4
R* R® i rR” 10 J
The indazole derivatives of interest for use as starting materials for the preparation of compounds 10 can be prepared by methods described above and in
Scheme 1.
The compounds of this invention, Formula I, can be incorporated into various types of ophthalmic formulations for delivery to the eye (e.g, topically, intracamerally, or via an implant). The compounds are preferably incorporated into topical ophthalmic formulations for delivery to the eye. The compounds may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution. Ophthalmic solution formulations may be prepared by dissolving a compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound. Furthermore, the ophthalmic solution may contain an agent to increase viscosity, such as, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethyicellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac. Gelling agents can also be used, including, but not limited to, gellan and xanthan gum. In order to prepare sterile ophthalmic ointment formulations, the active ingredient is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations may be prepared by suspending the active ingredient in a hydrophilic base prepared from the combination of, for example, carbopol-974, or the like, according to the published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can be incorporated.
The compounds are preferably formulated as topical ophthalmic suspensions or solutions, with a pH of about 5 to 8. The compounds will normally be contained in these formulations in an amount 0.01% to 5% by weight, but preferably in an amount of 0.25% to 2% by weight. Thus, for topical presentation 1 to 2 drops of these formulations would be delivered to the surface of the eye 1 to 4 times per day according to the discretion of a skilled clinician.
The compounds can also be used in combination with other agents for treating glaucoma, such as. but not limited to R-blockers (eg, timelel, betaxclcl, levobetaxolol, carteolol, levobunolol, propranolol), carbonic anhydrase inhibitors (e.g., brinzolamide and dorzolamide), a, antagonists (e.g. nipradolol), a, agonists (e.g., iopidine and brimonidine), miotics (e.g., pilocarpine and epinephrine), prostaglandin analogs (e.g., latanoprost, travaprost, unoprostone, and compounds set forth in U.S. Patent Nos. 5,889,052; 5,296,504; 5,422,368, and 5,151,444, “hypotensive lipids” (e.g., lumigan and compounds set forth in 5,352,708), and . neuroprotectants (e.g., compounds from U.S. Patent No. 4,690,931, particularly eliprodil and R-eliprodil, as set forth in a pending application U.S.S.N. 06/203350, i 35 and appropriate compounds from W(094/13275, including memantine.
The following examples are given to illustrate the preparation of compounds that are the subject of this invention but should not be construed as implying any limitations to the claims. The preferred compounds of Formula I are described in
Examples 2, 5 and 7. The most preferred is the compound of Example 2. The proton magnetic resonance spectrum of each compound of the Examples was consistent with . the assigned structure
X METHOD 1 5-HT; Receptor Binding Assay
In order to determine the relative affinities of serotonergic compounds at the 5-HT, receptors, their ability to compete for the binding of the agonist radioligand ['**I]DOI to brain 5-HT, receptors is determined as described below with minor modification of the literature procedure [Neuropharmacology, 26, 1803 (1987).
Aliquots of post mortem rat or human cerebral cortex homogenates (400 pl) dispersed in 50 mM TrisHCI buffer (pH 7.4) are incubated with ['’I)DOI (80 pM final) in the absence or presence of methiothepin (10 pM final) to define total and non-specific binding, respectively, in a total volume of 0.5 ml. The assay mixture is incubated for . 1 hour at 23°C in polypropylene tubes and the assays terminated by rapid vacuum filtration over Whatman GF/B glass fiber filters previously soaked in 0.3% polyethyleneimine using ice-cold buffer. Test compounds (at different concentrations) are substituted for methiothepin. Filter-bound radioactivity is determined by scintillation spectrometry on a beta counter. The data are analyzed using a non-linear, iterative curve-fitting computer program [Trends Pharmacol. Sci., 16, 413 (1995)] to determine the compound affinity parameter. The concentration of the compound needed to inhibit the ['*IJDOI binding by 50% of the maximum is termed the ICs value. A compound is considered to possess high affinity for the 5-HT receptor if the
IC:n value is less than SQ nM,
METHOD 2 5-HT; Functional Assay: Phosphoinositide (PI) turnover assay
The relative agonist activity of serotonergic compounds at the 5-HT> receptor can be determined in vitro using the ability of the compounds to stimulate the . production of [*HJinositol phosphates in [*H]myo-inositol-labeled A7r5 rat vascular smooth muscle cells by their ability to activate the enzyme phospholipase C. These 3s cells are grown in culture plates, maintained in a humidified atmosphere of 5% CO, and 95% air and fed semi-weekly with Dulbecco's modified Eagle medium (DMEM) containing 4.5 g/1 glucose and supplemented with 2mM glutamine, 10 pg/ml gentamicin, and 10% fetal bovine serum. For the purpose of conducting the phosphoinositide (PI) turnover experiments, the A7r5 cells are cultured in 24-well plates as previously [J. Pharmacol. Expt. Ther., 286, 411 (1998)]. Confluent cells are exposed for 24-30 hrs to 1.5 pCi [’H]-myo-inositol (18.3 Ci/mmol) in 0.5 ml of . serum-free medium. Cells are then rinsed once with DMEM/F-12 containing 10 mM
LiCl prior to incubation with the test agent (or solvent as the control) in 1.0 ml of the . same medium for 1 hr at 37°C, after which the medium is aspirated and 1 ml of cold 0.1 M formic acid added to stop the reaction. The chromatographic separation of [PH] inositol phosphates ([’H]-IPs) on an AG-1-X8 column is performed as previously described [J. Pharmacol. Expt. Ther. 286, 411 (1998)] with sequential washes with
H20 and 50 mM ammonium formate, followed by elution of the total [*H]-IPs fraction with 1.2 M ammonium formate containing 0.1 M formic acid. The eluate (4 ml) is collected, mixed with 15 ml scintillation fluid, and the total [*H)-IPs determined by scintillation counting on a beta-counter. Concentration-response data are analyzed by the sigmoidal fit function of the Origin Scientific Graphics software (Microcal
Software, Northampton, MA) to determine agonist potency (ECsp value) and efficacy (Emex). Serotonin (5-HT) is used as a positive control (standard) agonist compound - and the efficacy of test compounds is compared to that of 5-HT (set at 100%). The concentration of the compound needed to stimulate the production of ? H]-IPs by 50% of the maximum response is termed the ECsp value. Compounds are considered potent agonists if their ECs values in this functional assay are < 1 uM and are considered full agonists if their efficacy is > 80% of that of 5-HT.
The above procedures were used to generate the data shown in Table 1.
Table 1. 5-HT; Receptor Binding and Functional Data. [————————————————————————————————
Compound 1Csp, nM ECsp, nM Efficacy (Emaxs %0) a-Methylserotonin 35 189 104
Example 1 3.1 578 71
Example 2 3.0 483 87
Example 4 - 243 73
Example 5 2.0 541 64 ’ Example 6 22 1050 84
EXAMPLE 1 2-(6-Methoxy-3-methyl-indazol-1-yl)-1-methylethylamine fumarate . Step A: 6-Methoxy-3-methyl-1H-indazole
To a solution of 2-fluoro-4-methoxyacetophenone (1.90 g, 11.3 mmol) in , ethanol (20 ml) was added hydrazine hydrate (1.4 ml, 45.0 mmol) and heated at reflux temperature for 6 h. This mixture was evaporated to a residue and ethylene glycol (10 ml) was added. The mixture was heated at 150 °C for 18 h, cooled to room temperature, diluted with water (50 ml), and extracted with dichloromethane (3 x 60 ml). The combined extracts were washed with brine (10 ml), dried (MgSO,) and evaporated to a residue, which was crystallized from ethyl acetate to give a solid (1.1 g, 59%): MS(ES) m/z 163 (M").
Step B: 1-(6-Methoxy-3-methyl-indazol-1-yl)-propan-2-one
To a solution of the product from Step A (1.1 g, 6.7 mmol) in DMF (10 ml) was added sodium hydride (60% in oil, 0.41 g, 10.2 mmol) at room temperature. = After stirring for 30 min, chloroacetone (0.79 ml, 10.2 mmol) was added, and the solution heated at 60 °C for 6 h. The reaction mixture was diluted with a saturated aqueous solution of ammonium chloride (10 ml) and extracted with ethyl acetate (3 x 65 ml). The combined extracts were washed with brine (10m), dried (MgSO), and evaporated to give a residue which was purified by chromatography (silica, 20% to 30% ethyl acetate in hexane) to give an oil (1.3 g, 88%): MS (ES) m/z 219 (M").
Step C: 1-(6-Methoxy-3-methyl-indazol-1-yl)-propan-2-ol
Sodium borohydride (0.21 g, 5.5 mmol) was added to a solution of the product fom Step B (1.2 g, 5.5 mmol) in MeOH (10 ml) at room temperature. After stirring for 2 h at room temperature the solvent was evaporated and a saturated aqueous solution of ammonium chloride (10 mL) was added to the residue; this mixture was extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with brine (10 ml), dried (MgSO,) and evaporated to a residue which was purified by chromatography (silica, 20% to 30% ethyl acetate in hexane) to give an oil (0.68 g, 56%): MS (ES) m/z 221 (M").
Step D: 1-(2-Azido-propyl)-6-methoxy-3-methyl-1H-indazole . 35 To a solution of the product from Step C (0.66 g, 3.0 mmol) mn dichloromethane (10 ml) at 0 °C was added triethylamine (0.55 ml, 3.9 mmol) and methanesulfonyl chloride (0.31 ml, 3.9 mmol). After stirring for 30 min, ether (50 ml) and water (50 ml) were added. The organic layer was separated and the aqueous extracted with ether (2 x 50 ml). The combined ether extracts were washed with brine (30 mi), dried (MgSQy), and evaporated. The residue was taken up in DMF (6 ml) and sodium azide (0.26 g, 3.9 mmol) added. This mixture was heated at 70 °C for 12 . h, poured into water, and extracted with ether (3 x 50 ml). The combined extracts were washed with brine, dried (MgSQ,), and evaporated to a residue, which was . purified by chromatography (silica, hexane to 10% ethyl acetate in hexane) to give an oil (0.51 g, 69%): MS (ES) m/z 246 (M").
Step E: 2-(6-Methoxy-3-methyl-indazol-1-yl)-1-methylethylamine fumarate
To a solution of the product from Step D (0.50 g, 2.0 mmol) in methanol at room temperature was added palladium-on-carbon (10%, 0.10 g). This suspension was stirred for 18 h under an atmosphere of hydrogen. The reaction mixture was filtered through a filter aid and the filtrate evaporated to a residue (0.43 g, 96%) which was converted to the fumaric acid salt and crystallized from methanol/ether to give a colorless solid (0.27 g): mp 150-152 °C; MS (ES) m/z 191 (MY). Analysis.
Calculated for C;H7N;0 - 1.0 C;H404 - 1.0 CH30H: C, 55.58; H, 6.86; N, 11.44. - Found: C, 55.41; H, 6.85; N, 11.37.
EXAMPLE 2 1-(2-Aminopropyl)-3-methyl-1 H-indazol-6-0l fumarate
Step A: 1-(4-Benzyloxy-2-fluoro-phenyl)-ethanone
Potassium carbonate (5.5 g, 40.0 mmol) and benzyl bromide (4.6 ml, 38.9 mmol) were added to a solution of 2-fluoro-4-hydroxyacetophenone (5.0 g, 32.4 mmol) in ethanol (50 ml), and the mixture was heated at reflux temperature for 16 h.
The reaction nuaiure was evaporated to a residue to which 2 N HCl (100 ml) was added. This mixture was extracted with ethyl ether (3 x 60 ml) and the combined extracts were washed with brine (10 ml), dried (MgSO.,), and evaporated to a residue, which was crystallized from ethyl acetate (7.4 g, 93%): MS(ES) m/z 245 (M).
Step B: 6-Benzyloxy-3-methyl-1H-indazole
A solution of the product from Step A (7.4 g, 30.3 mmol) in ethanol (20 mL) : was treated as described for Example 1, Step A to give a colorless solid (6.1 g, 69%):
MS(ES) m/z 239 (M"). . 35
Step C: 1-(6-Benzyloxy-3-methyl-indazol-1-yl)-propan-2-one
A solution of the product from Step B (2.3 g, 9.7 mmol) in DMF (10 ml) was treated by the sequence described for Example 1, Step B to give a residue, which was oo used in the next step without further purification: MS (ES) m/z 295 (M"). ;
N Step D: 1-(6-Benzyloxy-3-methyl-indazol-1-yl)-propan-2-ol
A solution of the product from Step C (3.3 g, 5.5 mmol) in MeOH (10 ml) was treated as described for Example 1, Step C to give an oil (0.30 g, 10%): MS (ES) m/z 297 (MY).
Step E: 1-(2-Azido-propyl)-6-benzyloxy-3-methyl-1H-indazole
A solution of the product from Step D (0.28 g, 0.95 mmol) in dichloromethane (10 ml) was treated by the sequence described for Example 1, Step D to give an oil (0.16 g, 52%): MS (ES) m/z 322 (M").
Step F: 1-(2-Aminopropyl)-3-methyl-1H-indazol-6-ol fumarate i. A solution of the product from Step E (0.16 g, 0.50 mmol) in methanol was treated as described for Example 1, Step E to give a residue (0.10 g, 97%) which was converted to fumaric acid salt and crystallized from a mixture of methanol and ether to give a colorless solid (0.11 g): mp:166-168 °C; MS(ES) m/z 206 (M"). Analysis.
Calculated for Cy; H;sNs3o - 1.8 C4H404: C, 52.78; H, 5.40; N, 10.15. Found: C, 52.45;
H, 5.53; N, 10.29.
EXAMPLE 3 2,2-Dimethyl-propionic acid 1-(2-aminopropyl)-1H-indazol-6-yl ester fumarate
Step A: 2,2-Dimethyl-propionic acid 1 H-indazol-6-yl ester
To a solution of 1H-indazol-6-0l (0.88 g, 6.6 mmol) in dichloromethane (10 ml) at room temperature was added triethylamine (0.98 ml, 7.0 mmol) and DMAP (0.05 g) followed by trimethylacetyl chloride (0.82 ml, 6.6 mmol). After stirring for 1 h, the mixture was diluted with saturated aqueous solution of ammonium chlonde (20 ml) and extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed . with brine (10 ml), dried (MgSO), and evaporated to a residue which was purified by chromatography (silica, 10% to 20% ethyl acetate in hexane) to give an oil (1.1 g, . 35 76%): 'H NMR (CDCl) 6 8.15 (d, J = 0.8 Hz, 1H), 8.01 (s, 1H), 7.75 (s, 1H), 7.58 (d,
J =8.6 Hz, 1H), 7.01 and 6.96 (dd, J = 2.0 and 8.6 Hz, 1H), 1.59 (s, 9H); MS(ES) m/z 219 (M").
Step B: 2,2-Dimethyl-propionic acid 1-(2-oxo-propyl)-1H-indazol-6-yl ester
A solution of the product of Step A (1.5g, 6.9 mmol) in DMF (10 ml) was treated by the procedure described for Example 1, Step B to give an oil (1.3 g, 62%): . 'H NMR (CDCl) & 8.09 (d, J = 0.8 Hz, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.01 and 6.96 (dd, J = 2.0 and 8.6 Hz, 1H), 4.64 (s, 2H), 2.15 (s, 3H), . 1.56 (s, 3H) 1.27 (s, 6H); MS(ES) m/z 275 (M").
Step C: 2,2-Dimethyl-propionic acid 1-(2-hydroxy-propyl)-1H-indazol-6-y} ester
A solution of the product of Step B (0.91g, 3.6 mmol) in methanol (10 ml) was treated by the procedure described for Example 1, Step C to give an oil (0.79 g, 86%) that was used in the next reaction with further purification: '"H NMR § (CDCl) 7.99 (s, 1H), 7.98 (s, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.01 and 6.96 (dd, J] = 2.0 and 8.6 Hz, 1H,), 4.14-3.89 (m, 3H), 1.56 (s, 3H) 1.32 (s, 9H).
Step D: 2,2-Dimethyl-propionic acid 1-(2-azido-propyl)-1H-indazol-6-yl ester
A solution of the product from Step C (1.70 g, 6.2 mmol) in dichloromethane _. (10 ml) was treated by the procedure described for Example 1, Step D to give an oil (1.30 g, 69%): MS(ES) m/z 274 (M"-28).
Step E: 2,2-Dimethyl-propionic acid 1-(2-aminopropyl)-1H-indazol-6-yl ester fumarate
A solution of the Product from Step D (1.25 g, 4.1 mmol) in methanol was treated by the procedure described for Example 1, Step E to give an oil (0.13 g, 88%) which was treated with fumaric acid; the salt which formed was crystallized from a mixture of methanol and ether to give a colorless solid: mp180-182 °C; 1H NMR (DMSO-ds) 8 8.37 (s, 1H), 7.89 (s. 1H). 7.82 (d, T= R 6H, 1H) 7.12 (4, J ~ 8.6 Hz, 1H), 6.45 (s, 2H), 4.18-4.01 (m, 2H), 3.5 (m, 1H), 1.50 (s, 9H) 1.30 (d, J = 6.6Hz, 3H); MS(ES) m/z 276 (M"). Analysis. Calculated for C;5H2N;O; - 1.2 C4H4O4: C, 57.36; H, 6.27; N, 10.13. Found: C, 56.98; H, 6.57; N, 10.22.
EXAMPLE 4 2-(6-Methoxy-indazol-1-yl)-1-methyl-ethylamine
Step A: [2-(6-Hydroxy-indazol-1-yl)-1-methyl-ethyl}-carbamic acid benzyl ester 3s To a solution of 1-(2-aminopropyl)-indazol-6-ol (0.46 g, 2.4 mmol) in THF ’ (10.0 mL) was added a saturated aqueous solution of sodium bicarbonate (2.0 mL) followed by benzyl chloroformate (0.40 mL) at room temperature. After stirring for 1 h, the solution was diluted with 1 N HC1 (10 mL) and ammonium chioride (20 mL)
followed by extraction with ethyl acetate (3 x 50 mL). The combined extracts were washed with brine (10 mL), dried (MgSO) and evaporated to give a residue which was used in the next step without further purification (0.75 g, 98%); MS (ES) m/z 326
MH).
Step B: [2-(6-Methoxy-indazel-1-yl)-1-methyl-ethyl]-carbamic acid benzyl ester
To a solution of the product from Step A (0.95 g, 3.19 mmol) in DMF (10 mL) was added cesium carbonate (1.26 g, 3.70 mmol) followed by iodomethane (0.23 mL, 3.70 mmol) at room temperature. After stirring for 3 h, saturated aqueous ammonium chloride (30 mL) was added and the mixture extracted with ethyl acetate (3 x 65 mL).
The combined extracts were washed with brine (10 mL), dried (MgSO) and evaporated to a residue which was purified by chromatography (silica, 20% ethyl acetate in hexane to 30% ethyl acetate in hexane) to give a syrup (0.63 g, 92%): MS (ES) m/z 340(M").
Step C: 2-(6-Methoxy-indazol-1-yl)-1-methyl-ethylamine
To a solution of the product from Step B (0.68 g, 2.0 mmol) in methanol was added Pd/C (10%, 0.10 g) under a nitrogen atmosphere at room temperature. The mixture was stirred for 20 h under a hydrogen atmosphere and filtered through a filter aid. The filtrate was evaporated to a residue which was purified by chromatography (silica, 5% methanol in dichloromethane to 10% methanol in dichloromethane) to give a syrup (0.40 g, 97%). Treatment of the syrup with fumaric acid gave a residue that was recrystallized from methanol/ether to provide a colorless solid: mp 151- 152°C; MS (ES) m/z 206 (M"). Analysis. Calculated for C;1H;sN3O - 1.0 C4H4Oy4 - 1.0 H,O: C, 53.09; H, 6.24; N, 12.38. Found: C, 52.88; H, 6.31; N, 12.14.
EXAMPLE 5 2-(3-Chloro-6-methoxy-indazol-1-yl)-1-methyl-ethylamine
Step A: 2-Hydrazino-4-methoxy-benzoic acid
A suspension of 2-acetylamino-4-methoxy-benzoic acid (15 g, 73.7 mmol) in water (75 mL) was cooled to —5°C and conc HCI (150 mL) was added followed by cooling to —5°. To this mixture was added a solution of NaNO; (5.43 g, 77.4 mmol) ' in water (50 mL) that had been cooled to —5°; this solution was added at such a rate so as to maintain the temperature of the reaction mixture between —5° and 0°C. The ) reaction mixture was stirred for 10 min and the clear solution was added to a solution of stannous chloride (41.9 g, 221 mmol) in conc HCI (150 mL) that had been cooled to -20°C. This addition was conducted so as to maintain a temperature of ~20° to —
10°C for the reaction mixture, followed by stirring the mixture for 1.5 h at -20°C.
The solid that formed was collected by filtration, washed with chilled EtOH, and dried to give an off-white solid (10.8 g): APC/LCMS m/z 183 (M+H)".
Step B: 6-Methoxy-1H-indazol-3-ol
N A mixture of the product from Step A (10.5 g, 48 mmol), water (250 mL), and conc HCI (2.5 mL) was refluxed for 30 min. The volume of the reaction mixture was reduced by evaporation (ca 100 mL) and the pH adjusted to 7 by the slow addition of a saturated aqueous solution of sodium carbonate at room temperature. The solid that formed upon standing was collected and dried to give a gray solid (6.8 g):
APCVLCMS m/z 165 (M+H)".
Step C: 3-Chloro-6-methoxy-1H-indazole
To a solution of the product from Step B (1 g, 6.1 mmol) in pyridine (0.5 mL, 6.1 mmol) was added phosphorous oxychloride (0.9 mL, 9.2 mmol) and the mixture heated at 130-140°C for 5 h. The reaction mixture was cooled to 70°C and poured . onto ice (100 g). After standing for 24 h, the solid was collected and dried to give a cream-colored solid (0.42 g): ES/LCMS m/z 181 (M-H)".
Step D: [2-(3-Chloro-6-methoxy-indazol-1-yl)-1-methyl-ethyl]-carbamic acid benzyl ester
To a solution of the product from Step C (0.18 g, 1 mmol) and (2-bromo-1- methyl-ethyl)-carbamic acid benzyl ester (0.27 g, 1 mmol) in DMF (2 mL) was added potassium carbonate (0.17 g, 1.2 mmol) and the mixture stirred at 75° for 18 h. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture and the aqueous layer was separated and extracted with ethvl acetate (3 x 20 ml). The combined extracts were washed with brine (30 mL), dried (MgSOs), and evaporated to a residue that was purified by chromatography (silica, hexane to 15% ethyl acetate in hexane) to give a syrup (0.27 g): APCVLCMS m/z 374 (M+H)".
Step E: 2-(3-Chloro-6-methoxy-indazol-1-yl)-1-methyl-ethylamine
To a solution of the product from Step D (0.15 g, 0.4 mmol) in 1,2- dichloroethane (4 mL) under nitrogen was added boron tribromide-dimethylsulfide complex (2.4 mmol, 2.4 mL of a 1 N solution in 1,2-dichloroethane) and the mixture was heated at 84°C for 3 h. After cooling, saturated aqueous sodium bicarbonate (5 ’ mL) was added and the mixture was extracted with chloroform (3 x 10 mL). The combined extracts were washed with brine (10 mL), dried (MgSOa), and purified by chromatography (C-18 RP-HPLC, 5% acetonitrile/water to 70% acetonitrile/water containing 0.1% trifluoroacetic acid) to give a residue (0.03 g) that was converted to the dihydrochloride salt: ESULCMS m/z 240 (M+H)". . EXAMPLE 6 1-(2-Aminopropyl)-3-chloro-1H-indazol-6-ol
A solution of the product from Example 5, Step D (0.1 g, 0.27 mmol) was treated as described in Step E of Example 5 but the reaction mixture was heated for 8 h to give a syrup (0.015 g), which was converted to the dihydrochloride salt:
ESVLCMS m/z 226 (M+H)".
EXAMPLE 7
Amount (wt %) 1-(2-Aminopropyl)-3-methyl-1H-indazol- ° 6-ol fumarate 0.01 -2% -
Dibasic sodium phosphate (anhydrous)
Disodium EDTA (Edetate disodium) 0.01%
Polysorbate 80 0.05%
Benzalkonium chloride 0.01%
Sodium hydroxide / Hydrochloric acid For adjusting pH to 7.4
Purified water a. to 100%
EXAMPLE 8
Ton na | on indazol-6-o0} fumarate
EXAMPLE 9
Disodium EDTA (Edetate disodium) 0.01%
Polysorbate 80
EXAMPLE 10
Amount (vt %) 1-(2-Aminopropyl)-3-methyl-1H-indazol-6-ol 0.01 — 2% fumarate
White petrolatum and mineral oil and lanolin
Dibasic sodium phosphate (anhydrous)
Disodium EDTA (Edetate disodium) 0.01%
Polysorbate 80 0.05%
Benzalkonium chloride 0.01%
Sodium hydroxide / Hydrochloric acid For adjusting pH
Claims (1)
- Co. uUS0031247 . Claims ’ - A compound of the formula: \ Ps ® po R Ki & R o R* . wherein R' to R? are independently chosen from hydrogen, halogen, C, alkyl, trifluoromethyl, 0-W, C, calkylthio, C, salkylsulfoxyl, C,salkylsulfonyl, or cyano; : R? can be halogen, trifluoromethyl, cyano, or NR'R",; R® and R’ are independently chosen from hydrogen, C, alkyl or R% R’ and the carbon atom to which they are attached can form a cyclopropyl ring, or furthermore, R” and R® together can be(CH.,),, to form a saturated heterocycle; : R® and R® are independently chosen from hydrogen or C,_ alkyl; R' and R" are independently chosen from hydrogen or C, alkyl, or RY, R'" and the nitrogen oe atom to which they are attached can form a saturated heterocyclic ring selected from pyrrolidine, piperidine. piperazine, or morpholine; R!' to R* cannot simultaneously be hydrogen; : RS and R’ cannot both be hydrogen; : W is hydrogen, C, alkyl, C(=0)X, or P(=0)(OY)(OZ): X is C, alkyl, NR*R®, N(R%CH,(CH,),C(=0) NERH(R?), OC, alkyl, C, alkyl (substituted with halogen, hydroxyl, CO.C, alkyl, CON(C, alkyl), C(=NH)NH,, NHC(=NH)NH,, NH,), C, alkenyl! (substituted by phenyl, unsubstituted or substituted with one or more of C, alkyl, C,., alkoxy or halogen); Y aud Z are independently chosen from hydrogen, C,., alkyl or Y and Z can together form a lower alkyl chain of (CH,)p» mis 3 ord; nis lor; and pharmaceutically acceptable salts and solvates of the compounds.2. The compound of Claim 1 wherein: R' and R® are independently chosen from hydrogen, halogen. C, calkyl, trifluoromethyl, O-W, Cy alkylthio. C, alkylsulfoxyl. C, alkylsulfonyl. or cyano: R} and R* are independently chosen from hydrogen. halogen. C, alkyl. trifluoromethyl. or cyano; AMENDED SHEET :"01-03-2002 ° US0031247 , R?® can be halogen, trifluoromethyl, cyano or NR'RY; . R® and R’ are independently chosen from hydrogen or C,.alkyl, or R%, R and the carbon atom to which they are attached can form a cyclopropyl ring, or furthermore, R’ and R® together can be (CH,),, to form a saturated heterocycle; R® and R° are independently chosen from hydrogen or C, alkyl; R! to R® cannot simultaneously be hydrogen; R¢ and R cannot both be hydrogen; . W is hydrogen, C, alkyl, C(=0)X, or P(=0)(0Y)(OZ), X is C, alkyl, NR'R’, N(R®)CH,(CH,),C(=O)NR’R’, OC, qalkyl, C, salkyl (substituted with halogen, hydroxyl, CO,C,_alkyl, CON(C, alkyl), C(=NH)NH,, NHC(=NH)NH,, NH,), C, alkenyl (substituted by phenyl, unsubstituted or substituted with one or more of C, alkyl, C, alkoxy or halogen); Y and Z are independently chosen from hydrogen, C,...alkyl or Y and Z can together form a lower alkyl chain of (CH,)p,; ~ : m is 3; nislor2. .3. The compound of Claim 1 wherein: R', R%. and R* are independently chosen from hydrogen, halogen, C, calkyl, trifluoromethyl, or cyano; R? is chosen from O-W; R® can be halogen, trifluoromethyl, cyano or NR"R'; RS is hydrogen and R’ is methyl; RS and R? are independently chosen from hydrogen or C..alkvh W is hydrogen, C, alkyl, or C(=0)X; X is C, qalkyl, NR*R’, or N(R¥)CH,(CH,),C(=O)NR*)(R’); nislor2. .4. The compound of Claim 1 wherein: R', R}, and R* are independently chosen from hydrogen or halogen; Ris O-W; R'is halogen or trifluoromethyl; R® is hydrogen and R’ is methyl; : RS and R” are hydrogen; Wis hydrogen, C, Lalkyl. ~ AMENDED SHEET5. The compound of Claim | selected from the group consisting of: : 1-(2-aminopropyl)-3-chloro- 1 H-indazol-6-ol 2-(3-chloro-6-methoxy-indazol-1-y})-1-methyl-ethylamine.6. A topical ophthalmic composition for'lowering and controlling normal or : elevated IOP and treating glaucoma, comprising a pharmaceutically effective amount of a compound of Claim 1, 2, 3, 4, or 5 and a pharmaceutically acceptable carrier or diluent.7. ‘Composition according to claim 6 containing additionally one or more other agents for treating glaucoma.8. Composition according to claim 7 in which the other agent is selected from the group consisting of PB-blockers, carbonic anhydrase inhibitors, c antagonists, a, agonists, miotics, prostaglandin analogs, hypotensive lipids. and neuroprotectants. 9 Composition according to claim 7 in which the other agent is one or more ‘of the ) following: timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol, brinzolamide, dorzolamide, nipradolol, iopidine, brimonidine, pilocarpine, epinephrine, latanoprost. travaprost, unoprostone, lumigan, eliprodil and R-eliprodil.10. Use of a compound of claim 1. 2, 3, 4, or 5 for the preparation of 2 medicament for lowering and controlling normal or elevated IOP and treating glaucoma. [1 Use of a compound of the formula: N\A R' rR’ hy oy R* R? wherein R' to R* are independently chosen from hydrogen, halogen, Crgalkyl, trifluoromethyl, O-W, Ci.ealkylthio, Cisalkylsulfoxyl, C.salkylsulfonyl, or cyano; R’ can be hydrogen, C, alkyl, or Ci4alkoxy, halogen, trifluoromethyl, cyano, . NR'OR I! . AMENDED SHEET Amended Sheet — 2004-01-2601-03-2002 US003124715. A compound according to claim 1, other than the compounds of claim 5, as specifically described herein.16. A composition according to claim 6, substantially as herein described with reference to any one of the illustrative Examples. AMENDED SHEET Amended Sheet — 2004-01-2¢
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US19038000P | 2000-03-17 | 2000-03-17 |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200206851B true ZA200206851B (en) | 2003-10-21 |
Family
ID=22701093
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200206851A ZA200206851B (en) | 2000-03-17 | 2002-08-27 | 6-hydroxy-indazole derivatives for treating glaucoma. |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP1268438A1 (en) |
JP (1) | JP2003528085A (en) |
KR (1) | KR20030065304A (en) |
CN (1) | CN1450994A (en) |
AR (1) | AR032138A1 (en) |
AU (1) | AU2001216072A1 (en) |
BR (1) | BR0017157A (en) |
CA (1) | CA2402403A1 (en) |
GC (1) | GC0000155A (en) |
MX (1) | MXPA02008547A (en) |
PL (1) | PL358481A1 (en) |
TW (1) | TWI221839B (en) |
WO (1) | WO2001070702A1 (en) |
ZA (1) | ZA200206851B (en) |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6960579B1 (en) | 1998-05-19 | 2005-11-01 | Alcon Manufacturing, Ltd. | Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders |
TW593302B (en) | 2001-12-20 | 2004-06-21 | Alcon Inc | Novel benzodifuranimidazoline and benzofuranimidazoline derivatives and their use for the treatment of glaucoma |
AU2002360819A1 (en) * | 2001-12-28 | 2003-07-24 | Bayer Corporation | Cyclohexano- and cycloheptapyrazole derivative compounds, for use in diseases associated with the 5-ht2c receptor |
CN100384827C (en) * | 2002-11-08 | 2008-04-30 | 默克公司 | Ophthalmic compositions for treating ocular hypertension |
WO2004043354A2 (en) | 2002-11-08 | 2004-05-27 | Merck & Co., Inc. | Ophthalmic compositions for treating ocular hypertension |
US7196082B2 (en) * | 2002-11-08 | 2007-03-27 | Merck & Co. Inc. | Ophthalmic compositions for treating ocular hypertension |
US7053085B2 (en) | 2003-03-26 | 2006-05-30 | Merck & Co. Inc. | EP4 receptor agonist, compositions and methods thereof |
AU2003300915B2 (en) | 2002-12-13 | 2008-08-28 | Alcon, Inc. | Novel benzopyran analogs and their use for the treatment of glaucoma |
JP2004262812A (en) * | 2003-02-28 | 2004-09-24 | Rohto Pharmaceut Co Ltd | Hypotonia bulbi medicine |
CA2537119A1 (en) | 2003-09-02 | 2005-03-10 | Merck & Co., Inc. | Ophthalmic compositions for treating ocular hypertension |
CN1842335A (en) | 2003-09-04 | 2006-10-04 | 默克公司 | Ophthalmic compositions for treating ocular hypertension |
ATE425971T1 (en) | 2003-09-04 | 2009-04-15 | Merck & Co Inc | OPHTHALMIC COMPOSITIONS FOR TREATING OCCULAR HYPERTONIA |
US7338972B1 (en) | 2003-12-15 | 2008-03-04 | Alcon, Inc. | Substituted 1-alkylamino-1H-indazoles for the treatment of glaucoma |
US7129257B1 (en) | 2003-12-15 | 2006-10-31 | Alcon, Inc. | Pyrazolo[3,4- e]benzoxazoles for the treatment of glaucoma |
US6989445B2 (en) | 2003-12-15 | 2006-01-24 | Alcon, Inc. | Substituted [1,4]oxazino[2,3-g]indazoles for the treatment of glaucoma |
CN1988903A (en) | 2004-07-20 | 2007-06-27 | 默克公司 | Ophthalmic compositions for treating ocular hypertension |
AP2007004024A0 (en) | 2004-11-29 | 2007-06-30 | Warner Lambert Co | Therapeutic pyrazoloÄ3,4-BÜpyridines and indazoles |
WO2006062839A1 (en) | 2004-12-08 | 2006-06-15 | Alcon, Inc. | Use of dioxindoindazoles and dioxoloindazoles for treating glaucoma |
CN101704785B (en) * | 2009-11-16 | 2012-02-29 | 东南大学 | Organic dicarboxylic acid and salts thereof and preparation method thereof |
CN105884687B (en) * | 2016-04-14 | 2018-06-22 | 梯尔希(南京)药物研发有限公司 | A kind of preparation method of 5- benzyls benzydamine |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BR9910590A (en) * | 1998-05-19 | 2001-01-23 | Alcon Lab Inc | Compound, process to decrease iop, to improve blood flow to the end of the optic nerve and the retina, and to treat retinal diseases, compositions to decrease iop, to improve blood flow to the end of the optic nerve and the retina, and to treating retinal diseases, process and composition to provide neuroprotection to the end of the optic nerve or the retina, and, process to treat people suffering from sleep disorders, depression, schizophrenia, anxiety, circadian rhythmic disorders and centrally and peripherally mediated hypertension |
DK0985414T3 (en) * | 1998-05-26 | 2003-12-29 | Pfizer Prod Inc | Drug for the treatment of glaucoma and ischemic retinopathy |
GB9819032D0 (en) * | 1998-09-01 | 1998-10-28 | Cerebrus Ltd | Chemical compounds IV |
JP2002526443A (en) * | 1998-09-18 | 2002-08-20 | アルコン ラボラトリーズ, インコーポレーテッド | Serotoninergic 5HT2 agonist for treating glaucoma |
GB9820767D0 (en) * | 1998-09-23 | 1998-11-18 | Cerebrus Ltd | Chemical compounds VIII |
-
2000
- 2000-11-14 CN CN00819346A patent/CN1450994A/en active Pending
- 2000-11-14 AU AU2001216072A patent/AU2001216072A1/en not_active Abandoned
- 2000-11-14 CA CA002402403A patent/CA2402403A1/en not_active Abandoned
- 2000-11-14 KR KR1020027011867A patent/KR20030065304A/en not_active Application Discontinuation
- 2000-11-14 JP JP2001568912A patent/JP2003528085A/en not_active Withdrawn
- 2000-11-14 BR BR0017157-3A patent/BR0017157A/en not_active IP Right Cessation
- 2000-11-14 PL PL00358481A patent/PL358481A1/en not_active Application Discontinuation
- 2000-11-14 MX MXPA02008547A patent/MXPA02008547A/en unknown
- 2000-11-14 EP EP00978628A patent/EP1268438A1/en not_active Withdrawn
- 2000-11-14 WO PCT/US2000/031247 patent/WO2001070702A1/en not_active Application Discontinuation
- 2000-11-27 TW TW089125127A patent/TWI221839B/en not_active IP Right Cessation
- 2000-12-01 AR ARP000106394A patent/AR032138A1/en not_active Application Discontinuation
- 2000-12-03 GC GCP20001082 patent/GC0000155A/en active
-
2002
- 2002-08-27 ZA ZA200206851A patent/ZA200206851B/en unknown
Also Published As
Publication number | Publication date |
---|---|
KR20030065304A (en) | 2003-08-06 |
WO2001070702A1 (en) | 2001-09-27 |
JP2003528085A (en) | 2003-09-24 |
CN1450994A (en) | 2003-10-22 |
CA2402403A1 (en) | 2001-09-27 |
GC0000155A (en) | 2005-06-29 |
TWI221839B (en) | 2004-10-11 |
AU2001216072A1 (en) | 2001-10-03 |
PL358481A1 (en) | 2004-08-09 |
AR032138A1 (en) | 2003-10-29 |
MXPA02008547A (en) | 2003-03-12 |
EP1268438A1 (en) | 2003-01-02 |
BR0017157A (en) | 2002-11-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6956036B1 (en) | 6-hydroxy-indazole derivatives for treating glaucoma | |
ZA200206851B (en) | 6-hydroxy-indazole derivatives for treating glaucoma. | |
US6660870B1 (en) | 2-acylaminobenzimidazole derivatives for treating glaucoma | |
AU2001219180B2 (en) | 5-hydroxy indazole derivatives for treating glaucoma | |
US6960608B2 (en) | Fused indazoles and indoles and their use for the treatment of glaucoma | |
WO2001040183A1 (en) | 1-aminoalkyl-1h-indoles for treating glaucoma | |
AU2001219180A1 (en) | 5-hydroxy indazole derivatives for treating glaucoma | |
WO2002098400A1 (en) | Novel arylaminopropane analogues and their use for the treatment of glaucoma | |
AU2002259312A1 (en) | Novel arylaminopropane analogues and their use for the treatment of glaucoma | |
US6806285B1 (en) | 5-Hydroxyl indole derivatives for treating glaucoma | |
EP1268482B1 (en) | Pyranoindoles for treating glaucoma | |
AU2003300915B2 (en) | Novel benzopyran analogs and their use for the treatment of glaucoma | |
AU2001216034A1 (en) | Pyranoindoles for treating glaucoma | |
US20060052431A1 (en) | 5-Hydroxy indazole derivatives for treating glaucoma | |
ZA200404473B (en) | Novel benzodifuranimidazoline and benzofuranimidazoline derivatives and their use for the treatment of glaucoma. | |
US7012090B1 (en) | Pyranoindoles for treating glaucoma | |
US7425572B2 (en) | Use of dioxindoindazoles and dioxoloindazoles for treating glaucoma | |
WO2001070686A1 (en) | 5-hydroxy indole derivatives for treating glaucoma |