NO179245B - Arylalkylestere av 4,5-dihydroksy-9,10-dihydro-9,10-diokso-2-antracenkarboksylsyre med terapeutisk aktivitet - Google Patents
Arylalkylestere av 4,5-dihydroksy-9,10-dihydro-9,10-diokso-2-antracenkarboksylsyre med terapeutisk aktivitet Download PDFInfo
- Publication number
- NO179245B NO179245B NO925048A NO925048A NO179245B NO 179245 B NO179245 B NO 179245B NO 925048 A NO925048 A NO 925048A NO 925048 A NO925048 A NO 925048A NO 179245 B NO179245 B NO 179245B
- Authority
- NO
- Norway
- Prior art keywords
- acid
- acids
- salicylic
- dihydro
- dioxo
- Prior art date
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- FCDLCPWAQCPTKC-UHFFFAOYSA-N Rhein Chemical compound C1=CC=C2C(=O)C3=CC(C(=O)O)=CC(O)=C3C(=O)C2=C1O FCDLCPWAQCPTKC-UHFFFAOYSA-N 0.000 title description 3
- 125000003710 aryl alkyl group Chemical group 0.000 title description 2
- 230000001225 therapeutic effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 206010003246 arthritis Diseases 0.000 claims abstract 2
- 239000002253 acid Substances 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 10
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims description 8
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 8
- -1 benzadac Chemical compound 0.000 claims description 6
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 4
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims description 4
- MITFXPHMIHQXPI-UHFFFAOYSA-N Oraflex Chemical compound N=1C2=CC(C(C(O)=O)C)=CC=C2OC=1C1=CC=C(Cl)C=C1 MITFXPHMIHQXPI-UHFFFAOYSA-N 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 4
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 claims description 4
- 229960000616 diflunisal Drugs 0.000 claims description 4
- 229960001680 ibuprofen Drugs 0.000 claims description 4
- 229960000905 indomethacin Drugs 0.000 claims description 4
- 229960002009 naproxen Drugs 0.000 claims description 4
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 4
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 4
- 229960004889 salicylic acid Drugs 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 claims description 3
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 3
- MDKGKXOCJGEUJW-VIFPVBQESA-N (2s)-2-[4-(thiophene-2-carbonyl)phenyl]propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-VIFPVBQESA-N 0.000 claims description 2
- 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 claims description 2
- OIRAEJWYWSAQNG-UHFFFAOYSA-N Clidanac Chemical compound ClC=1C=C2C(C(=O)O)CCC2=CC=1C1CCCCC1 OIRAEJWYWSAQNG-UHFFFAOYSA-N 0.000 claims description 2
- ACEWLPOYLGNNHV-UHFFFAOYSA-N Ibuprofen piconol Chemical compound C1=CC(CC(C)C)=CC=C1C(C)C(=O)OCC1=CC=CC=N1 ACEWLPOYLGNNHV-UHFFFAOYSA-N 0.000 claims description 2
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 claims description 2
- JZFPYUNJRRFVQU-UHFFFAOYSA-N Niflumic acid Chemical compound OC(=O)C1=CC=CN=C1NC1=CC=CC(C(F)(F)F)=C1 JZFPYUNJRRFVQU-UHFFFAOYSA-N 0.000 claims description 2
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 claims description 2
- 229960004892 acemetacin Drugs 0.000 claims description 2
- FSQKKOOTNAMONP-UHFFFAOYSA-N acemetacin Chemical compound CC1=C(CC(=O)OCC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 FSQKKOOTNAMONP-UHFFFAOYSA-N 0.000 claims description 2
- 229960005142 alclofenac Drugs 0.000 claims description 2
- ARHWPKZXBHOEEE-UHFFFAOYSA-N alclofenac Chemical compound OC(=O)CC1=CC=C(OCC=C)C(Cl)=C1 ARHWPKZXBHOEEE-UHFFFAOYSA-N 0.000 claims description 2
- 229950008930 amfenac Drugs 0.000 claims description 2
- SOYCMDCMZDHQFP-UHFFFAOYSA-N amfenac Chemical compound NC1=C(CC(O)=O)C=CC=C1C(=O)C1=CC=CC=C1 SOYCMDCMZDHQFP-UHFFFAOYSA-N 0.000 claims description 2
- 229960005430 benoxaprofen Drugs 0.000 claims description 2
- IJTPQQVCKPZIMV-UHFFFAOYSA-N bucloxic acid Chemical compound ClC1=CC(C(=O)CCC(=O)O)=CC=C1C1CCCCC1 IJTPQQVCKPZIMV-UHFFFAOYSA-N 0.000 claims description 2
- 229950005608 bucloxic acid Drugs 0.000 claims description 2
- 229960000962 bufexamac Drugs 0.000 claims description 2
- MXJWRABVEGLYDG-UHFFFAOYSA-N bufexamac Chemical compound CCCCOC1=CC=C(CC(=O)NO)C=C1 MXJWRABVEGLYDG-UHFFFAOYSA-N 0.000 claims description 2
- 229960003354 bumadizone Drugs 0.000 claims description 2
- FLWFHHFTIRLFPV-UHFFFAOYSA-N bumadizone Chemical compound C=1C=CC=CC=1N(C(=O)C(C(O)=O)CCCC)NC1=CC=CC=C1 FLWFHHFTIRLFPV-UHFFFAOYSA-N 0.000 claims description 2
- 229960003184 carprofen Drugs 0.000 claims description 2
- IVUMCTKHWDRRMH-UHFFFAOYSA-N carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 claims description 2
- 229950011171 cinmetacin Drugs 0.000 claims description 2
- NKPPORKKCMYYTO-DHZHZOJOSA-N cinmetacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)\C=C\C1=CC=CC=C1 NKPPORKKCMYYTO-DHZHZOJOSA-N 0.000 claims description 2
- 229950010886 clidanac Drugs 0.000 claims description 2
- 229950001647 clometacin Drugs 0.000 claims description 2
- DGMZLCLHHVYDIS-UHFFFAOYSA-N clometacin Chemical compound CC=1N(CC(O)=O)C2=CC(OC)=CC=C2C=1C(=O)C1=CC=C(Cl)C=C1 DGMZLCLHHVYDIS-UHFFFAOYSA-N 0.000 claims description 2
- 229950009185 clopirac Drugs 0.000 claims description 2
- SJCRQMUYEQHNTC-UHFFFAOYSA-N clopirac Chemical compound CC1=CC(CC(O)=O)=C(C)N1C1=CC=C(Cl)C=C1 SJCRQMUYEQHNTC-UHFFFAOYSA-N 0.000 claims description 2
- 229960001259 diclofenac Drugs 0.000 claims description 2
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 229960005293 etodolac Drugs 0.000 claims description 2
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 claims description 2
- 229950006236 fenclofenac Drugs 0.000 claims description 2
- IDKAXRLETRCXKS-UHFFFAOYSA-N fenclofenac Chemical compound OC(=O)CC1=CC=CC=C1OC1=CC=C(Cl)C=C1Cl IDKAXRLETRCXKS-UHFFFAOYSA-N 0.000 claims description 2
- HAWWPSYXSLJRBO-UHFFFAOYSA-N fendosal Chemical compound C1=C(O)C(C(=O)O)=CC(N2C(=CC=3C4=CC=CC=C4CCC=32)C=2C=CC=CC=2)=C1 HAWWPSYXSLJRBO-UHFFFAOYSA-N 0.000 claims description 2
- 229950005416 fendosal Drugs 0.000 claims description 2
- 229960004369 flufenamic acid Drugs 0.000 claims description 2
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 claims description 2
- 229960002390 flurbiprofen Drugs 0.000 claims description 2
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 claims description 2
- CYWFCPPBTWOZSF-UHFFFAOYSA-N ibufenac Chemical compound CC(C)CC1=CC=C(CC(O)=O)C=C1 CYWFCPPBTWOZSF-UHFFFAOYSA-N 0.000 claims description 2
- 229950009183 ibufenac Drugs 0.000 claims description 2
- 229960003422 indobufen Drugs 0.000 claims description 2
- AYDXAULLCROVIT-UHFFFAOYSA-N indobufen Chemical compound C1=CC(C(C(O)=O)CC)=CC=C1N1C(=O)C2=CC=CC=C2C1 AYDXAULLCROVIT-UHFFFAOYSA-N 0.000 claims description 2
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims description 2
- 229960000991 ketoprofen Drugs 0.000 claims description 2
- 229960002373 loxoprofen Drugs 0.000 claims description 2
- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical compound O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229960003803 meclofenamic acid Drugs 0.000 claims description 2
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 claims description 2
- 229960004963 mesalazine Drugs 0.000 claims description 2
- 229950005798 metiazinic acid Drugs 0.000 claims description 2
- LMINNBXUMGNKMM-UHFFFAOYSA-N metiazinic acid Chemical compound C1=C(CC(O)=O)C=C2N(C)C3=CC=CC=C3SC2=C1 LMINNBXUMGNKMM-UHFFFAOYSA-N 0.000 claims description 2
- 229960000916 niflumic acid Drugs 0.000 claims description 2
- OFPXSFXSNFPTHF-UHFFFAOYSA-N oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 claims description 2
- 229960002739 oxaprozin Drugs 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 229960000851 pirprofen Drugs 0.000 claims description 2
- PIDSZXPFGCURGN-UHFFFAOYSA-N pirprofen Chemical compound ClC1=CC(C(C(O)=O)C)=CC=C1N1CC=CC1 PIDSZXPFGCURGN-UHFFFAOYSA-N 0.000 claims description 2
- 229960003101 pranoprofen Drugs 0.000 claims description 2
- 150000003870 salicylic acids Chemical class 0.000 claims description 2
- 229960000894 sulindac Drugs 0.000 claims description 2
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 claims description 2
- 229960004492 suprofen Drugs 0.000 claims description 2
- 229960002905 tolfenamic acid Drugs 0.000 claims description 2
- YEZNLOUZAIOMLT-UHFFFAOYSA-N tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 claims description 2
- 229960001017 tolmetin Drugs 0.000 claims description 2
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 claims description 2
- 229960003414 zomepirac Drugs 0.000 claims description 2
- ZXVNMYWKKDOREA-UHFFFAOYSA-N zomepirac Chemical compound C1=C(CC(O)=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZXVNMYWKKDOREA-UHFFFAOYSA-N 0.000 claims description 2
- PJJGZPJJTHBVMX-UHFFFAOYSA-N 5,7-Dihydroxyisoflavone Chemical compound C=1C(O)=CC(O)=C(C2=O)C=1OC=C2C1=CC=CC=C1 PJJGZPJJTHBVMX-UHFFFAOYSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical class NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 229960003464 mefenamic acid Drugs 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- CQRYARSYNCAZFO-UHFFFAOYSA-N salicyl alcohol Chemical compound OCC1=CC=CC=C1O CQRYARSYNCAZFO-UHFFFAOYSA-N 0.000 description 2
- IFCKVIVGYKVRLO-UHFFFAOYSA-N (8-acetyloxy-6-carbonochloridoyl-9,10-dioxoanthracen-1-yl) acetate Chemical compound O=C1C2=CC(C(Cl)=O)=CC(OC(C)=O)=C2C(=O)C2=C1C=CC=C2OC(=O)C IFCKVIVGYKVRLO-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- IZXWIWYERZDWOA-UHFFFAOYSA-N 2-[4-(2-methylpropyl)phenyl]propan-1-ol Chemical compound CC(C)CC1=CC=C(C(C)CO)C=C1 IZXWIWYERZDWOA-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Natural products C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 1
- 125000005577 anthracene group Chemical group 0.000 description 1
- RGHILYZRVFRRNK-UHFFFAOYSA-N anthracene-1,2-dione Chemical group C1=CC=C2C=C(C(C(=O)C=C3)=O)C3=CC2=C1 RGHILYZRVFRRNK-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Substances OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/95—Esters of quinone carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
- C07C2603/24—Anthracenes; Hydrogenated anthracenes
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Pain & Pain Management (AREA)
- Animal Behavior & Ethology (AREA)
- Rheumatology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Steroid Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører arylalkyl-estere
av 4,5-dihydroksy-9,10-dihydro-9,10-dioksø-2-antracenkar-boksylsyre med den generelle formel (I):
hvor R-CH2-0- er resten av en R-CH2OH-alkohol avledet ved reduksjon av en R-COOH-karboksylsyre som har antiflamma-torisk virkning, og som tilhører klassen: salicylsyrer: salicylsyre, acetylsalicylsyre, 5-amino-salicylsyre, diflunisal, fendosal;
aryleddiksyrer: acemetacin, alclofenac, amfenac, benzadac, bufexamac, bumadizone, cinmetacin, clidanac, clometacin, clopirac, diclofenac, etodolac, fenclofenac, indobufen, indometacin, methiazinsyre, sulindac, tolmetin, zomepirac; pro<p>ionsyrer: alminprofen, benoxaprofen, bucloxisyre, carprofen, flurbiprofen, ibuprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, protizinsyre, pineprofen, pirprofen, pranoprofen, suprofen, thiaprofensyre;
antrani1syrer: flufenaminsyre, meclofenamsyre, mefehamsyre, niflumsyre, lobenzarit, tolfenamsyre,
enantiomer, diastereomer og blandinger derav og farmasøy-tisk akseptable salter derav.
Spesielt foretrukket er forbindelsene med formelen (I) hvor R er, i henhold til ovenstående definisjon, en rest fra følgende forbindelser: salicylsyre, acetylsalicylsyre, diflunisal, ibufenac, ibuprofen, naproxen, indometacin.
Foreliggende oppfinnelse vedrører også forbindelser med formel (I) hvor hydroksygruppene i 4,5-stiIlingene på antracendionringen og enhver hydroksygruppe som er tilstede i aryIdelen av R-resten, er esterifisert med lavere alifatiske syrer. Foreliggende oppfinnelse vedrører videre forbindelser med formel (I) hvor en hver tilstedeværende aminogruppe i R-restene er acetylert eller, hvis mulig,
i saltform.
Forbindelsene med formel (I) fremstilles ved å omsette 4,5-di(acetyloksy)-9,10 dihydro-9,10-diokso-2-antra-cenkarboksylsyreklorid med formel (II)
med en primær alkohol R-CH20H, hvor R er som definert ovenfor.
Syrekloridet (II) kan erstattes med et hvert reaktivt derivat av nevnte syre (såsom esteren, det blandede anhydrid og lignende); eller syren kan omsettes direkte med en alkohol R-CH20H i nærvær av dicykloheksylkarbodiimid og lignende.
Esterifiseringsreaksjonen utføres i et inert løsnings-middel, såsom kloroform, i nærvær av et syrebindende middel, f.eks. trietylamin.
Den resulterende ester behandles med vandig ammoniakk, fortrinnsvis 10% ammoniakk, for å deacetylere hydroksygruppene i 4- og 5-stillingene på antracenringen, for å gi en forbindelse med formel (I) hvor nevnte hydro-oksygrupper er frie.
Forbindelsene ifølge oppfinnelsen har interesante farmakologiske egenskaper, og disse er høyere enn hva som kunne forutsies ved ren addisjon av forbindelser med anti-flammatorisk aktivitet med rheinmolekylet 4,5-dihydroksy-9,10-dihydro-9,10-diokso-2-antracenkarboksylsyre, som allerede anvendes i osteoartritt-terapien.
De fordelaktive farmakologiske egenskaper hos forbindelsene ifølge oppfinnelsen gjør dem nyttige som sådanne eller i form av farmasøytiske akseptable salter (eller estere) derav for fremstilling av medikamenter, i blanding med egnede konvensjonelle bærestoffer. Eksempler på farma-søytiske sammensetninger er tabletter, kapsler, piller, injiserbare løsninger eller suspensjoner, salver, kremer og lignende. Dosene vil variere fra 5 til 500 mg for enkelt-doser, og den daglige dose vil avhenge av alvoret i tilstanden som skal behandles, samt av pasientens generelle tilstand.
Følgende eksempler illustrerer ytterligere oppfinnelsen.
EKSEMPEL
2- Hvdroksybenzyl- 4. 5- dihYdroksy- 9. lO- dih. Ydro- 9. 10- diokso- 2-antracenkarboksylat
Til en løsning av 1,55 g (12,5 mmol) 2-hydroksybenzyl-alkohol i 20 ml vannfri kloroform, avkjølt i isbad tilset-tes 1,66 ml (12 mmol) vannfritt trietylamin. En løsning av 4,7 g (12 mmol) 4,5-acetoksy-9,10-dihydro-9,10-dioksy-2-antracenkarboksysyreklorid i 80 ml vannfri kloroform til-settes til den omrørte løsning under avkjøling. Reaksjons-blandingen for stå å reagere ved værelsestemperatur i 4 timer. Etter det dampes kloroformen vekk under redusert trykk, og residuet holdes under magnetisk omrøring over natten i en natriumbikarbonatmettet løsning. Deretter ekstraheres blandingen med kloroform, løsningsmiddelet dampes vekk under redusert trykk, og det ubehandlede residuet omrøres over natten i 60 ml 10% vandig ammoniakkløs-ning. Blandingen surgjøres med konsentrert HCl til pH 5 og ekstraheres med kloroform som deretter dampes vekk under redusert trykk, og det ubehandlede residuum som inneholder tittelforbindelsen, renses ved hjelp av kiselgelkromatografi med en 3:7 etylacetat/cykloheksanblanding.
Smp. 125-130°C.
IR og 'H NMR i overensstemmelse. Elementæranalyse for C22Hi407:
EKSEMPEL 2
5-( 2 , 4- Difluorfenyl)- 2- hydroksybenzyl 4. 5- dihvdroksy-9, 10- dihydro- 9, 10- dioksy- 2- antracenkarboksylat
Fremgangsmåten fra eksempel 1 gjentas, men man anvender 2,95 g (12,5 mmol) 5-(2,4-difluorfenyl)-2-hydroksy-benzyl-alkohol. Tittelforbindelsen erholdes og renses ved kiselgelkromatografi med en 2:8 etylacetat/cykloheksanblanding. Smp. 128-132°C. IR og 'H NMR i overensstemmelse. Elementæranalyse for C28H16F207:
EKSEMPEL 3
2- ( 4- Isobutylf enyl) - etyl- 4 . 5- dihydroksy- 9.10-dihvdro-9. 10-diokso- 2- antracenkarboksylat
Fremgangsmåten fra eksempel 1 gjentas, men man anvender 2,14 g (12 mmol) 2-(4-isobutifenyl)-etylalkohol. Tittelproduktet erholdes, og det renses ved kiselgelkromatografi med en 1:9 etylacetat/cykloheksan-blanding.
Smp. 117-121°C. IR og <*>H NMR i overensstemmelse. Elementæranalyse for C27H2406:
EKSEMPEL 4
2-( 4- Isobutvlfenyl)- propyl- 4. 5- dihydroksv- 9. 10- dihydro-9. lO- diokso- 2- antracenkarboksylat
Fremgangsmåten fra eksempel 1 gjentas, men man anvender 2,3 g (12 mmol) 2-(4-isobutylfenyl)-propyl-alkohol. Tittelproduktet erholdes og renses ved kiselgelkromatografi med en 1:9 etylacetat/cykloheksan-blanding. Smp. 115°C.
IR og jH NMR i overensstemmelse. Elementæranalyse for C28H2606:
EKSEMPEL 5
2-( 6- Metoksy- 2- naptyl)- propyl- 4. 5- dihydrocy- 9.10-dihydro- 9. lO- diokso- 2- antracenkarbxylat
Fremgangsmåten fra eksempel 1 gjentas, men man anvender 2,6 g (12 mmol) av 2-(6-mryoksy-2-naptyl)-propyl alkohol. Tittelproduktet erholdes og renses med kiselgelkromatografi med en 4:6 etylacetat/cykloheksan-blanding. Smp. 147-151°C. IR og ,H NMR i overensstemmelse. Elementæranalyse for
C29H2207:
EKSEMPEL 6
2- f1-( 4- Klorobenzozvl)- 2- metyl- 5- metoksy- lH- indol- 3-yl]- etyl- 4.5-dihydroksy-9. 10- dihydro- 9, 10- diokso- 2-antracenkarboksylat
Fremgangsmåten fra eksempel 1 gjentas, men man anvender 3,95 g (12 mmol) 2-[1-(4-klorobenzoyl)-2-metyl-5-metoksy-lH-indol-3-yl]-etylalkohol. Tittelproduktet erholdes og renses med kiselgelkromatografi med en 3:7 etylacetat/ cykloheksanblanding. Smp. 139-146 °C.
IR og 'H NMR i overensstemmelse. Elementæranalyse for C34H24C108<:>
Claims (4)
1. Forbindelser
karakterisert ved den generelle formel
hvor R-CH2-0- er resten av en R-CH2OH-alkohol avledet ved reduksjon av en R-COOH-karboksylsyre som har antiflamma-torisk virkning, og som tilhører klassen: salicylsyrer: salicylsyre, acetylsalicylsyre, 5-amino-salicylsyre, diflunisal, fendosal; aryleddiksyrer: acemetacin, alclofenac, amfenac, benzadac, bufexamac, bumadizone, cinmetacin, clidanac, clometacin, clopirac, diclofenac, etodolac, fenclofenac, indobufen, indometacin, methiazinsyre, sulindac, tolmetin, zomepirac;<p>ropionsyrer: alminprofen, benoxaprofen, bucloxisyre, carprofen, flurbiprofen, ibuprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, protizinsyre, pineprofen, pirprofen, pranoprofen, suprofen, thiaprofensyre; antranilsyrer: flufenaminsyre, meclofenamsyre, mefenamsyre, niflumsyre, lobenzarit, tolfenamsyre, enantiomer, diastereomer og blandinger derav og farmasøy-tisk akseptable salter derav.
2. Forbindelser ifølge krav 1, karakterisert ved at R-CH2-0-resten er avledet fra forbindelsene salicylsyre, diflunisal, ibufenac, ibuprofen, naproxen, indometacin.
3. Farmasøytiske sammensetninger, karakterisert ved at de inneholder forbindelsene ifølge kravene 1-2 som virkestoff i blanding med farmasøytiske akseptable bærerstoffer og eksipienser.
4. Anvendelse av forbindelsene ifølge krav 1-2 for fremstilling av et medikament for behandling av artritt.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI911215A IT1247884B (it) | 1991-05-03 | 1991-05-03 | Esteri arilalchilici dell'acido 4,5 diidrossi-9,10-diidro-9,10-diosso 2-antracencarbossilico ad azione terapeutica |
| PCT/EP1992/000881 WO1992019584A1 (en) | 1991-05-03 | 1992-04-21 | Arylalkyl esters of 4,5-dihydroxy-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid having therapeutical activity |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO925048L NO925048L (no) | 1992-12-30 |
| NO925048D0 NO925048D0 (no) | 1992-12-30 |
| NO179245B true NO179245B (no) | 1996-05-28 |
| NO179245C NO179245C (no) | 1996-09-04 |
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| NO925048A NO179245C (no) | 1991-05-03 | 1992-12-30 | Arylalkylestere av 4,5-dihydroksy-9,10-dihydro-9,10-diokso-2-antracenkarboksylsyre med terapeutisk aktivitet |
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| US (1) | US5330981A (no) |
| EP (1) | EP0537313B1 (no) |
| JP (1) | JPH0692348B2 (no) |
| KR (1) | KR100226082B1 (no) |
| AT (1) | ATE133157T1 (no) |
| AU (1) | AU648894B2 (no) |
| BR (1) | BR9205255A (no) |
| CZ (1) | CZ280027B6 (no) |
| DE (1) | DE69207698T2 (no) |
| DK (1) | DK0537313T3 (no) |
| ES (1) | ES2082468T3 (no) |
| FI (1) | FI104166B (no) |
| GR (1) | GR3019417T3 (no) |
| HU (1) | HUT63605A (no) |
| IT (1) | IT1247884B (no) |
| MX (1) | MX9202015A (no) |
| NO (1) | NO179245C (no) |
| PT (1) | PT100439B (no) |
| RU (1) | RU2087462C1 (no) |
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| ATE448194T1 (de) | 2000-08-29 | 2009-11-15 | Biocon Ltd | Verwendung einer pharmazeutischen zusammensetzung mit einem para-aminophenylessigsäurederivat für die behandlung von entzündlichen erkrankungen des magen-darmtrakts |
| US8048924B2 (en) | 2001-08-29 | 2011-11-01 | Biocon Limited | Methods and compositions employing 4-aminophenylacetic acid compounds |
| WO2006014549A2 (en) | 2004-07-07 | 2006-02-09 | Nobex Corporation | Synthesis of azo bonded immunoregulatory compounds |
| CN101475484B (zh) * | 2009-01-05 | 2012-07-18 | 东南大学 | 骨靶向抗炎药物合成方法及其应用 |
| CN103709052B (zh) * | 2014-01-12 | 2016-01-27 | 何黎琴 | 一种大黄酸胺基醇酯类化合物、其制备方法及医药用途 |
| CN104945269A (zh) * | 2015-06-23 | 2015-09-30 | 常州善美药物研究开发中心有限公司 | 一种大黄酸羧酸酯类衍生物及其应用 |
| CN109053798B (zh) * | 2018-07-23 | 2020-11-17 | 遵义医科大学 | 一种大黄酸酯衍生物及其制备方法与应用 |
| CN115521320B (zh) * | 2021-06-25 | 2023-09-05 | 沈阳兴齐眼药股份有限公司 | 一种制备普拉洛芬的方法 |
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- 1991-05-03 IT ITMI911215A patent/IT1247884B/it active IP Right Grant
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- 1992-04-21 JP JP4508484A patent/JPH0692348B2/ja not_active Expired - Lifetime
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- 1992-04-21 AT AT92909059T patent/ATE133157T1/de not_active IP Right Cessation
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- 1992-04-21 US US07/966,038 patent/US5330981A/en not_active Expired - Fee Related
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