CA1178965A - Polycyclic fused pyrazole compounds useful as anti- inflammatory agents and preparation thereof - Google Patents
Polycyclic fused pyrazole compounds useful as anti- inflammatory agents and preparation thereofInfo
- Publication number
- CA1178965A CA1178965A CA000411268A CA411268A CA1178965A CA 1178965 A CA1178965 A CA 1178965A CA 000411268 A CA000411268 A CA 000411268A CA 411268 A CA411268 A CA 411268A CA 1178965 A CA1178965 A CA 1178965A
- Authority
- CA
- Canada
- Prior art keywords
- methyl
- pyrazole
- fluorophenyl
- compound
- ethenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000002360 preparation method Methods 0.000 title description 4
- 229940121363 anti-inflammatory agent Drugs 0.000 title description 2
- 239000002260 anti-inflammatory agent Substances 0.000 title description 2
- 125000003367 polycyclic group Chemical group 0.000 title description 2
- 150000003217 pyrazoles Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- QYCRSSYBLMPFGL-UHFFFAOYSA-N 1-ethenyl-6-(4-fluorophenyl)-9a-methyl-3,3a,4,5,6,9-hexahydro-2h-benzo[f]indazole Chemical compound C1C(CNN2C=C)C2(C)CC(C=C2)=C1CC2C1=CC=C(F)C=C1 QYCRSSYBLMPFGL-UHFFFAOYSA-N 0.000 claims description 5
- OTSKZNVDZOOHRX-ONEGZZNKSA-N (e)-hex-3-ene-2,5-dione Chemical compound CC(=O)\C=C\C(C)=O OTSKZNVDZOOHRX-ONEGZZNKSA-N 0.000 claims description 3
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 3
- BQHDXNZNSPVVKB-UHFFFAOYSA-N diethyl 2-methylidenepropanedioate Chemical compound CCOC(=O)C(=C)C(=O)OCC BQHDXNZNSPVVKB-UHFFFAOYSA-N 0.000 claims description 3
- SNVLJLYUUXKWOJ-UHFFFAOYSA-N methylidenecarbene Chemical compound C=[C] SNVLJLYUUXKWOJ-UHFFFAOYSA-N 0.000 claims description 3
- ZXBMIRYQUFQQNX-UHFFFAOYSA-N (4-fluorophenyl)hydrazine Chemical compound NNC1=CC=C(F)C=C1 ZXBMIRYQUFQQNX-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- OIFNZXMIWPWKMW-UHFFFAOYSA-N diethyl 8-(4-fluorophenyl)-11a-methyl-2,3,4a,5,6,11-hexahydronaphtho[1,2-f]indazole-4,4-dicarboxylate Chemical compound CCOC(=O)C1(C(=O)OCC)CCC=C(C2(C3)C)C1CCC2=CC1=C3C=NN1C1=CC=C(F)C=C1 OIFNZXMIWPWKMW-UHFFFAOYSA-N 0.000 claims 2
- 239000000126 substance Substances 0.000 claims 2
- FMYJTJNSCOXCIK-UHFFFAOYSA-N 1-[4-acetyl-8-(4-fluorophenyl)-11a-methyl-3,4,4a,5,6,11-hexahydro-2h-naphtho[1,2-f]indazol-3-yl]ethanone Chemical compound CC(=O)C1C(C(=O)C)CC=C(C2(C3)C)C1CCC2=CC1=C3C=NN1C1=CC=C(F)C=C1 FMYJTJNSCOXCIK-UHFFFAOYSA-N 0.000 claims 1
- DYRCZMWPDOABLI-UHFFFAOYSA-N 5-ethenyl-3-(hydroxymethylidene)-4a-methyl-7,8-dihydro-4h-naphthalen-2-one Chemical compound C1C(=CO)C(=O)C=C2CCC=C(C=C)C21C DYRCZMWPDOABLI-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 5
- 239000003862 glucocorticoid Substances 0.000 abstract description 4
- 238000012360 testing method Methods 0.000 description 11
- 241000700159 Rattus Species 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 5
- 230000003110 anti-inflammatory effect Effects 0.000 description 5
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 5
- WQGWDDDVZFFDIG-UHFFFAOYSA-N pyrogallol Chemical compound OC1=CC=CC(O)=C1O WQGWDDDVZFFDIG-UHFFFAOYSA-N 0.000 description 5
- 150000003431 steroids Chemical class 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000001919 adrenal effect Effects 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229920002527 Glycogen Polymers 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000002124 endocrine Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 229940096919 glycogen Drugs 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 210000001541 thymus gland Anatomy 0.000 description 3
- 229960001295 tocopherol Drugs 0.000 description 3
- 239000011732 tocopherol Substances 0.000 description 3
- 235000019786 weight gain Nutrition 0.000 description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 2
- 235000012631 food intake Nutrition 0.000 description 2
- -1 for example Chemical group 0.000 description 2
- 230000002394 glycogenic effect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- FEKUXLUOKFSMRO-UHFFFAOYSA-N (4-fluorophenyl)hydrazine;hydron;chloride Chemical compound Cl.NNC1=CC=C(F)C=C1 FEKUXLUOKFSMRO-UHFFFAOYSA-N 0.000 description 1
- OLYFJHTYMIDQGR-BQYQJAHWSA-N (e)-dec-5-ene-4,7-dione Chemical compound CCCC(=O)\C=C\C(=O)CCC OLYFJHTYMIDQGR-BQYQJAHWSA-N 0.000 description 1
- GDUNUVQVVHHADI-AATRIKPKSA-N (e)-oct-4-ene-3,6-dione Chemical compound CCC(=O)\C=C\C(=O)CC GDUNUVQVVHHADI-AATRIKPKSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- PSZAEHPBBUYICS-UHFFFAOYSA-N 2-methylidenepropanedioic acid Chemical compound OC(=O)C(=C)C(O)=O PSZAEHPBBUYICS-UHFFFAOYSA-N 0.000 description 1
- RZPFVRFSYMUDJO-UHFFFAOYSA-N 2h-naphthalen-1-one Chemical compound C1=CC=C2C(=O)CC=CC2=C1 RZPFVRFSYMUDJO-UHFFFAOYSA-N 0.000 description 1
- KJTRXVXWSSPHRV-UHFFFAOYSA-N 4-benzoyl-5-methyl-2-phenyl-1h-pyrazol-3-one Chemical compound O=C1C(C(=O)C=2C=CC=CC=2)=C(C)NN1C1=CC=CC=C1 KJTRXVXWSSPHRV-UHFFFAOYSA-N 0.000 description 1
- VOLBAJZNPOEMFU-UHFFFAOYSA-N 5-ethenyl-4a-methyl-3,4,7,8-tetrahydronaphthalen-2-one Chemical compound C1CC(=O)C=C2CCC=C(C=C)C21C VOLBAJZNPOEMFU-UHFFFAOYSA-N 0.000 description 1
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 1
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- ZPFDRMZDXDVXOP-UHFFFAOYSA-N dibutyl 2-methylidenepropanedioate Chemical compound CCCCOC(=O)C(=C)C(=O)OCCCC ZPFDRMZDXDVXOP-UHFFFAOYSA-N 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- KTLZQSZGORXBED-UHFFFAOYSA-N dimethyl 2-methylidenepropanedioate Chemical compound COC(=O)C(=C)C(=O)OC KTLZQSZGORXBED-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- MRDQECHJLFDXIF-UHFFFAOYSA-N dipropyl 2-methylidenepropanedioate Chemical compound CCCOC(=O)C(=C)C(=O)OCCC MRDQECHJLFDXIF-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- IOOLVWWWFKRJGD-UHFFFAOYSA-N dodec-6-ene-5,8-dione Chemical compound CCCCC(=O)C=CC(=O)CCCC IOOLVWWWFKRJGD-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 210000000416 exudates and transudate Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940079877 pyrogallol Drugs 0.000 description 1
- 150000003254 radicals Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000002683 reaction inhibitor Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 231100001038 reduction in thymus weight Toxicity 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT
The compounds of the formulas and where R and R' are lower-alkyl possess glucocorticoid activity, and are prepared by reacting the compound of the formula
The compounds of the formulas and where R and R' are lower-alkyl possess glucocorticoid activity, and are prepared by reacting the compound of the formula
Description
~.~ 7t~ 5 The present invention relates to novel polycyclic fuaed pyrazole compounds, useful as anti-inflammatory agents, and the preparation thereof.
Typical glucocorticoid activity is rarely found 5 in structures which do not possess an intact steroid nucleus.
Such activity is found in naturally occurring steroids such as cortisone, hydrocortisone and aldosterone, as well as numerous synthetic modifications thereof, all containing the intact steroid nucleus. An example of a synthetic 10 cortical steroid having high activity is a fluorophenylpyrazole derivative reported by Fried et al., J. Am. Chem. Soc. 85, 236 (1963), having the structure f H2H
C=O
...CH3 ~, r F
t ~
The pxesent invention relates to compounds having the formulas:
o and ~(CO~2 II
wherein R and R' are lower-alkyl groups. Said compounds 5 can be used in a pharmaceutical composition for treating inflammation in mammals which comprises an anti-inflammatorily effective amount of said compound of Formula I or II and a pharmaceutically acceptable carrier. One can reduce inflammation in a mammal by administering to said mammal 10 an anti-inflammatorily effective amount of a compound of Formula I or II.
The invention also relates to an intermediate for use in the preparation of the compounds of Formulas I and II, said intermediate having the formula:
¢~
F
III
7~6~
One can prepare the compounds of Formulas I or II
by reacting the compound of Formula III with a compound of the formula RCOCE~=CHCOR or CH2=C ~COOR')2, respectîvely.
The novel intermediate of Formula III is prepared 5 from a known starting material, 5-ethenyl-4,4a,7,8-tetrahydro-4a-methyl-2(3~)-naph~halenone (cf. Bell et al~
U.S. Patent 4,157,349, June 5, 1979) in accordance with the following reactions:
CH=CH2 c~ NaOCH3 CH=CH2 NHNH
CH ¦ 1 2 ~lOC~ ~ ~
l o ~; J +
'rhe trienone starting material i8 reacted with methyl formate in the presence of sodium methoxide in an i~ert solvent such as tetrahydrofuran to afford 5-ethenyl-3-hydroxymethylene-4,4a,7,8-tetrahydro-4a-methyl-2 (3H~-15 naphthalenone, and the latter is then reacted with 4-fluorophenylhydrazine or an acid-addition salt thereof în the presence of acetic acid to give the compound of Formula III.
The preparation of a compound of Formula I by 20 reacting the compound of Formula III wi~h an unsaturated diketone of *he formula RCOCH=CHCOR takes place by heating the reactants in an inert solvent at a temperature between about 50 and 150C. Similarly, a compound of Formula II
îs prepared by heating III with a di-lower-alkyl 25 methylenemalonate [CH2=C (COOR')2]. In order to suppress the tendency of the diene to polymerize, a small quantity of a free radical chain reaction inhibitor such as 1,2,3-1~7~
benzenetriol (pyrogallol), may be added.
The lower-alkyl groups R and R' preferably ha~e from one to four carbon atoms, including, for example, methyl, ethyl, propyl, isopropyl, butyl and isobutyl.
The compounds of Formulas I and II exhibit an endocrinological profile characteristic of compounds pos6es~ing glucocorticoid properties and systemic and~or topical anti-inflammatory activity; cf. R.H. Sil~er, The Biology of Anti-inflammatory Steroids, Annals of the 10 New York Academy of Sciences, Vol. 82, Art. 4. pp. 821-828.
When the compounds of Formulas I and II are administered orally to rats they cause a significant depression in thymus weight, adrenal weight and body weight gain without a change in food consumption.
The compound of Formula I where R is methyl ha~
al~o been found to posses~ oral glucocorticoid activity by the liver glycogen deposition test and anti-inflammatory a¢tivity by the a-tocopherol pouch test in rats.
The test procedures u3ed to determine the 20 biological activities of the cQmpounds of the invention were ¢arried out a~ follows:
Endocrino Profile: Mature female rats with an average body weight of 202 g and a body weight range of 15 g or le~s were medicated orally with test compound for 2 weeks. The 25 test compound was prepared as a solution or ~uspens$on in 1% gum tragacanth or 0.75% methyl cellulose. On the day following the last medication, the rats were killed and the thymus and adrenal of each rat were removed, cleaned, and weighed. Body weights and food consumptions were also 30 re¢orded.
Anti-inflammatory Activity ~a-tocop~erol pouch test):
Male rats which weighed 120 g were selected for testing.
A rapid subcutaneous injection of 25 mL of air was made b~bæen t~e s~api~e of each rat. This resulted in the 35 e~tablishment of an airfilled pouch into which 0.5 mL of dl-~-tocopherol was injected. The te~t compound was administered in daily oral doses for 7 days beginning on ";
1~78g~5 the day of pouch formation. The compound to be tested ~as suspended in 1% gum tragacanth. Twenty-four hours a~ter the last medication, the pouches were dissected free, and the fluid volume was measured. The inhibition of liquid 5 exudate is a measure of the anti-inflammatory activity.
Glycogenic Activity: Mature male rats were bilaterally adrenalectomized 5 days prior to the test. These rats were medicated orally with the test compound for 5 days. Seven hours after the last medication, the rats (which have been 10 fasted overnight) were anesthetized with sodium pentobarbital and a portion of one lobe of the liver was removed and frozen on dry ice for subsequent glycogen determination.
The compounds of the invention can be formulated for topical application by solution of dispersion in a lS conventional pharmaceutically acceptable liquid, cream or ointment base. The effective ingredient is preferably pre~ent in a concentration of 0.01% to 5.0~ by weight.
The compounds of the invention can be formulated ~or oral administration in tablet or capsule form w~th 20 conventional excipients. The active ingredient i8 pre-~erably present in an amount of 1 mg to 100 mg per unit dosage form, The followlng examples will further illustrate the invention.
Example 1 (a~ 5-Ethenyl-3-hydroxymethylene-4,4a,7,8-tetrahydro-4a-me ~ l-2~3H)-naphthalenone.
A solution of 50.0 g (0.265 mol) of 5-ethenyl-4, 4a,7,8-tetrahydro-4a-methyl-2(3H)-naphthalenone in 350 mL
30 of tetrahydrofuran was cooled to -5C. in an ice-methanol bath and stirred under nitrogen while 57.2 g (1.06 mol) of sodium methoxide was added. The resulting mixture wa~
stirred for 30 min at -5C. and then a solution of 114 mL
~1.85 mol) of methyl formate in 100 mL of tetrahydrofuran 35 was added slowly. The mixture was stirred overnight at room temperature and then poured onto a mixture of ice-water ~1500 mL) and 6N hydrochloric acid (265 mL). The ~ ~ 7~96~
product was extracted with ether and the combined extracts were washed with water. The dried extract was dried over anhydrous magnesium sulfate and concentrated ln vacuo to afford an oil. This oil was triturated with hexane 5 (4 x 250 mL) and the combined triturates were dried over magne~ium sulfate and concentrated ln vacuo to afford 55.37 g of a red oil, consisting essentially of the above-entitled compound as established by proton NMR (PMR) spectral data.
(b~ l-Ethenyl-6-(4-fluorophenyl)-3,4,9,9a-tetrahydro-9a-10 ~ (III).
4-Fluorophenylhydrazine hydrochloride (45.85 g, 0.282 mol~ and sodium acetate (23.14 g, 0.282 mol~ were added to a solution of 55.37 g (0.256 mol) of the product obtained in part (a) above in 225 mL of glacial acetic acid.
15 The mixture ~as stirred overnight at room temperature and then concentrated in vacuo to afford a semi-solid. This material was suspended in ether (1 L) and filtered to remove sodium chloride. The ether filtrate was washed with water (4 x 250 mL), saturated sodium bicarbonate (until weakly 20 ba~ic) and ~aturated sodium chloride (100 mL). The extract was dried over anhydrous magnesium sulfate, decolorized with charcoal and concentrated ln vacuo to afford an oil.
~h~s oil was triturated with 1:2 ether-hexane (3 x 750 mL) to afford 69.58 g of a dark brown oil. An analytical sample 25 was prepared by using high-performance li~uid chromatography ~ith 1:3 ether-hexane as solvent. The resulting yellow oil was triturated with pentane to afford 1-ethenyl-6-(4-fluorophenyl)-3~4~9~9a-tetrahydro-9a-methyl-6H-naphtho [2,3-c]pyrazole as a yellow solid, m.p. 70-72C., with a 30 consistent PMR spectrum.
Example~ 2 ~ [8-(4-Fluorophenyl)-2,3,4,4a,5,6,11,11a-octahydro-lla-methyl-8~ henanthro[2,3-c]pyrazole-3,4-diyl~bis[ethanone]
(~; R = CH3).
A solution of 20 g (0.065 mol) of 1-ethenyl-6-(4-fluorophenyl)-3,4,9,9a-tetrahydro-9a-methyl-6H-naphthol [2,3-c]-pyrazole in 200 mL benzene and 8.07 g (0.072 mol) li7~g6S
of 3-hexene-2,5-dione was stirred at reflux for 40 hours under nitrogen. The cooled reaction mixture was filtered through silica gel and concentrated in vacuo. The resultant oil was triturated with ether to afford 7.54 g of a gold 5 solid as a mixture of isomers, m.p. 138-142C., as determined by PUR spectroscopy. Five g of this mixture of isomers was separated using high-performance liquid chromatography with 1:4 ethyl acetate-hexane. The major isomer was recrystallîzed from CH2C12-isooctane to afford 3.0 g of 1,1'-[8-(4-10 fluorophenyl)-2,3,4,4a,5,6,11,11a-octahydro-lla-methyl-8H-phenanthro[2,3-c]pyrazole-3,4-diyl]bis~ethanone], a white ~olid, m.p. 157-159C., a single isomer as determined by PMR spectro~copy.
In the endocrine profile determination, Compound I
15 (R - CH3) at a dose level of 5 mg/kg caused a 59~ reduction in weight of the thymus, 40% reduction in adrenal weight and 80% reduction in body weight gain as compared with the control~. In the ~-tocopherol pouch test, Compound I (R = CH
was active with ED50 = 23 mg/kg. In the glycogenic activity 20 test, Compound I (R = CH3) at dose levels of 9 and 27 mg/kg/day x 5 produced liver glycogen deposition values of 9.42 + 0.65 and 25.48 + 3.39 mg/g of tissue, respectively, as compared to 1.75 + 0.04 mg/g for the vehicle ~ethanol:
cottonseed oil 1:9 v/v) alone.
By replacing the 3-hexene-2,5 dione in the procedure of Example 2 by a molar equivalent amount of 4-octene-3,6-dione, 5-decene-4,7-dione or 6-dodecene-5,8-dione, it is contemplated that there can be obtained 1,1'-18-(4-fluorophenyl)-2,3,4,4a,5,6,11,11a-octahydro-lla-30 methyl-8H- phenanthro[2,3-c]-pyrazole-3,4-diyl]bis[propanone]
(I~ R = CH2CH3), 1,1'-[8-(4-fluorophenyl)-2,3,4,4a,5,6,11, lla-octahydro-lla-methyl-8H- phenanthro[2~3-c]pyrazole-3~4 diyl]bis[butanone] (I; R = CH2CH2CH3), or 1,1'-[8-(4-fluorophenyl)-2,3,4,4a,5,6,11,11a-octahydro-lla-methyl-35 8H-ph~nthro[2,3-c]pyrazole-3,4-diyl]bis-[pentanone]
(I; R = CH2CH2CH2CH3), respectively 1~'7~9~;5 Example 3 Die~thyl 8-(4-fluorophenyl)-2,3,4,4a,5,6,11,11a-octahydro-lla-methy~-8H~ enanthro[2,3-c]pyrazole-4,4-dicarboxylate (II; R = CH2CH3).
A solution of 25.81 g (0.084 mol~ of 1-ethenyl-6-(4-fluorophenyl)-3,4,9,9a-tetrahydro-9a-methyl-6H-naphtho [2,3-c]-pyrazole, 18.1 g (O.lOS mol) of diethyl methylenemalonate and S00 mg of 1,2,3-benzenetriol in 200 mL
of xylene was refluxed for 20 hours. The cooled reaction 10 mixture was filtered through silica gel and concentrated in vacuo to afford 41.93 g of a brown oil. The oil was purified by uQing high-performance liquid chromatography ~ith 3.97 ethyl acetate-CH2C12 followed by recrystallization ~rom methanol to afford 10.98 g of diethyl 8-(4-fluoro-15 phenyl)-2~3~4~4a~5~6~ lla-octahydro-lla-methyl-8H-phenanthro-[2,3-c]pyrazole-4,4-dicarboxylate as a colorles6 solid, m.p. 133-135C. m e PMR spectrum was consistent with the a3signed ~tructure.
In the endocrine profile determination, Compound II
20 (R ~ CH2CH3) at a dose level of 100 mg/kg caused an 80%
reduction in thymus weight, 47% reduction in adrenal weight and 186~ reduction in body weight gain as compared with ; the controls. Compound II (R = CH2CH3) was inactive in the ~-tocopherol pouch test at 100 mg/kg.
By replacing the diethyl methylenemalonate in the procedure of Example 3 by a molar equivalent amount of dimethyl methylenemalonate, dipropyl methylenemalonate or dibutyl methylenemalonate, it i8 contemplated that there can be obtained dimethyl 8-~4-fluorophenyl)-2,3,4,4a,5,6, 30 ll,lla-octahydro-lla-methyl-8H- phenanthro[2,3-c]pyrazole-4,4-dicarboxylate (II; R = CH3), dipropyl 8-(4-fluorophenyl~-
Typical glucocorticoid activity is rarely found 5 in structures which do not possess an intact steroid nucleus.
Such activity is found in naturally occurring steroids such as cortisone, hydrocortisone and aldosterone, as well as numerous synthetic modifications thereof, all containing the intact steroid nucleus. An example of a synthetic 10 cortical steroid having high activity is a fluorophenylpyrazole derivative reported by Fried et al., J. Am. Chem. Soc. 85, 236 (1963), having the structure f H2H
C=O
...CH3 ~, r F
t ~
The pxesent invention relates to compounds having the formulas:
o and ~(CO~2 II
wherein R and R' are lower-alkyl groups. Said compounds 5 can be used in a pharmaceutical composition for treating inflammation in mammals which comprises an anti-inflammatorily effective amount of said compound of Formula I or II and a pharmaceutically acceptable carrier. One can reduce inflammation in a mammal by administering to said mammal 10 an anti-inflammatorily effective amount of a compound of Formula I or II.
The invention also relates to an intermediate for use in the preparation of the compounds of Formulas I and II, said intermediate having the formula:
¢~
F
III
7~6~
One can prepare the compounds of Formulas I or II
by reacting the compound of Formula III with a compound of the formula RCOCE~=CHCOR or CH2=C ~COOR')2, respectîvely.
The novel intermediate of Formula III is prepared 5 from a known starting material, 5-ethenyl-4,4a,7,8-tetrahydro-4a-methyl-2(3~)-naph~halenone (cf. Bell et al~
U.S. Patent 4,157,349, June 5, 1979) in accordance with the following reactions:
CH=CH2 c~ NaOCH3 CH=CH2 NHNH
CH ¦ 1 2 ~lOC~ ~ ~
l o ~; J +
'rhe trienone starting material i8 reacted with methyl formate in the presence of sodium methoxide in an i~ert solvent such as tetrahydrofuran to afford 5-ethenyl-3-hydroxymethylene-4,4a,7,8-tetrahydro-4a-methyl-2 (3H~-15 naphthalenone, and the latter is then reacted with 4-fluorophenylhydrazine or an acid-addition salt thereof în the presence of acetic acid to give the compound of Formula III.
The preparation of a compound of Formula I by 20 reacting the compound of Formula III wi~h an unsaturated diketone of *he formula RCOCH=CHCOR takes place by heating the reactants in an inert solvent at a temperature between about 50 and 150C. Similarly, a compound of Formula II
îs prepared by heating III with a di-lower-alkyl 25 methylenemalonate [CH2=C (COOR')2]. In order to suppress the tendency of the diene to polymerize, a small quantity of a free radical chain reaction inhibitor such as 1,2,3-1~7~
benzenetriol (pyrogallol), may be added.
The lower-alkyl groups R and R' preferably ha~e from one to four carbon atoms, including, for example, methyl, ethyl, propyl, isopropyl, butyl and isobutyl.
The compounds of Formulas I and II exhibit an endocrinological profile characteristic of compounds pos6es~ing glucocorticoid properties and systemic and~or topical anti-inflammatory activity; cf. R.H. Sil~er, The Biology of Anti-inflammatory Steroids, Annals of the 10 New York Academy of Sciences, Vol. 82, Art. 4. pp. 821-828.
When the compounds of Formulas I and II are administered orally to rats they cause a significant depression in thymus weight, adrenal weight and body weight gain without a change in food consumption.
The compound of Formula I where R is methyl ha~
al~o been found to posses~ oral glucocorticoid activity by the liver glycogen deposition test and anti-inflammatory a¢tivity by the a-tocopherol pouch test in rats.
The test procedures u3ed to determine the 20 biological activities of the cQmpounds of the invention were ¢arried out a~ follows:
Endocrino Profile: Mature female rats with an average body weight of 202 g and a body weight range of 15 g or le~s were medicated orally with test compound for 2 weeks. The 25 test compound was prepared as a solution or ~uspens$on in 1% gum tragacanth or 0.75% methyl cellulose. On the day following the last medication, the rats were killed and the thymus and adrenal of each rat were removed, cleaned, and weighed. Body weights and food consumptions were also 30 re¢orded.
Anti-inflammatory Activity ~a-tocop~erol pouch test):
Male rats which weighed 120 g were selected for testing.
A rapid subcutaneous injection of 25 mL of air was made b~bæen t~e s~api~e of each rat. This resulted in the 35 e~tablishment of an airfilled pouch into which 0.5 mL of dl-~-tocopherol was injected. The te~t compound was administered in daily oral doses for 7 days beginning on ";
1~78g~5 the day of pouch formation. The compound to be tested ~as suspended in 1% gum tragacanth. Twenty-four hours a~ter the last medication, the pouches were dissected free, and the fluid volume was measured. The inhibition of liquid 5 exudate is a measure of the anti-inflammatory activity.
Glycogenic Activity: Mature male rats were bilaterally adrenalectomized 5 days prior to the test. These rats were medicated orally with the test compound for 5 days. Seven hours after the last medication, the rats (which have been 10 fasted overnight) were anesthetized with sodium pentobarbital and a portion of one lobe of the liver was removed and frozen on dry ice for subsequent glycogen determination.
The compounds of the invention can be formulated for topical application by solution of dispersion in a lS conventional pharmaceutically acceptable liquid, cream or ointment base. The effective ingredient is preferably pre~ent in a concentration of 0.01% to 5.0~ by weight.
The compounds of the invention can be formulated ~or oral administration in tablet or capsule form w~th 20 conventional excipients. The active ingredient i8 pre-~erably present in an amount of 1 mg to 100 mg per unit dosage form, The followlng examples will further illustrate the invention.
Example 1 (a~ 5-Ethenyl-3-hydroxymethylene-4,4a,7,8-tetrahydro-4a-me ~ l-2~3H)-naphthalenone.
A solution of 50.0 g (0.265 mol) of 5-ethenyl-4, 4a,7,8-tetrahydro-4a-methyl-2(3H)-naphthalenone in 350 mL
30 of tetrahydrofuran was cooled to -5C. in an ice-methanol bath and stirred under nitrogen while 57.2 g (1.06 mol) of sodium methoxide was added. The resulting mixture wa~
stirred for 30 min at -5C. and then a solution of 114 mL
~1.85 mol) of methyl formate in 100 mL of tetrahydrofuran 35 was added slowly. The mixture was stirred overnight at room temperature and then poured onto a mixture of ice-water ~1500 mL) and 6N hydrochloric acid (265 mL). The ~ ~ 7~96~
product was extracted with ether and the combined extracts were washed with water. The dried extract was dried over anhydrous magnesium sulfate and concentrated ln vacuo to afford an oil. This oil was triturated with hexane 5 (4 x 250 mL) and the combined triturates were dried over magne~ium sulfate and concentrated ln vacuo to afford 55.37 g of a red oil, consisting essentially of the above-entitled compound as established by proton NMR (PMR) spectral data.
(b~ l-Ethenyl-6-(4-fluorophenyl)-3,4,9,9a-tetrahydro-9a-10 ~ (III).
4-Fluorophenylhydrazine hydrochloride (45.85 g, 0.282 mol~ and sodium acetate (23.14 g, 0.282 mol~ were added to a solution of 55.37 g (0.256 mol) of the product obtained in part (a) above in 225 mL of glacial acetic acid.
15 The mixture ~as stirred overnight at room temperature and then concentrated in vacuo to afford a semi-solid. This material was suspended in ether (1 L) and filtered to remove sodium chloride. The ether filtrate was washed with water (4 x 250 mL), saturated sodium bicarbonate (until weakly 20 ba~ic) and ~aturated sodium chloride (100 mL). The extract was dried over anhydrous magnesium sulfate, decolorized with charcoal and concentrated ln vacuo to afford an oil.
~h~s oil was triturated with 1:2 ether-hexane (3 x 750 mL) to afford 69.58 g of a dark brown oil. An analytical sample 25 was prepared by using high-performance li~uid chromatography ~ith 1:3 ether-hexane as solvent. The resulting yellow oil was triturated with pentane to afford 1-ethenyl-6-(4-fluorophenyl)-3~4~9~9a-tetrahydro-9a-methyl-6H-naphtho [2,3-c]pyrazole as a yellow solid, m.p. 70-72C., with a 30 consistent PMR spectrum.
Example~ 2 ~ [8-(4-Fluorophenyl)-2,3,4,4a,5,6,11,11a-octahydro-lla-methyl-8~ henanthro[2,3-c]pyrazole-3,4-diyl~bis[ethanone]
(~; R = CH3).
A solution of 20 g (0.065 mol) of 1-ethenyl-6-(4-fluorophenyl)-3,4,9,9a-tetrahydro-9a-methyl-6H-naphthol [2,3-c]-pyrazole in 200 mL benzene and 8.07 g (0.072 mol) li7~g6S
of 3-hexene-2,5-dione was stirred at reflux for 40 hours under nitrogen. The cooled reaction mixture was filtered through silica gel and concentrated in vacuo. The resultant oil was triturated with ether to afford 7.54 g of a gold 5 solid as a mixture of isomers, m.p. 138-142C., as determined by PUR spectroscopy. Five g of this mixture of isomers was separated using high-performance liquid chromatography with 1:4 ethyl acetate-hexane. The major isomer was recrystallîzed from CH2C12-isooctane to afford 3.0 g of 1,1'-[8-(4-10 fluorophenyl)-2,3,4,4a,5,6,11,11a-octahydro-lla-methyl-8H-phenanthro[2,3-c]pyrazole-3,4-diyl]bis~ethanone], a white ~olid, m.p. 157-159C., a single isomer as determined by PMR spectro~copy.
In the endocrine profile determination, Compound I
15 (R - CH3) at a dose level of 5 mg/kg caused a 59~ reduction in weight of the thymus, 40% reduction in adrenal weight and 80% reduction in body weight gain as compared with the control~. In the ~-tocopherol pouch test, Compound I (R = CH
was active with ED50 = 23 mg/kg. In the glycogenic activity 20 test, Compound I (R = CH3) at dose levels of 9 and 27 mg/kg/day x 5 produced liver glycogen deposition values of 9.42 + 0.65 and 25.48 + 3.39 mg/g of tissue, respectively, as compared to 1.75 + 0.04 mg/g for the vehicle ~ethanol:
cottonseed oil 1:9 v/v) alone.
By replacing the 3-hexene-2,5 dione in the procedure of Example 2 by a molar equivalent amount of 4-octene-3,6-dione, 5-decene-4,7-dione or 6-dodecene-5,8-dione, it is contemplated that there can be obtained 1,1'-18-(4-fluorophenyl)-2,3,4,4a,5,6,11,11a-octahydro-lla-30 methyl-8H- phenanthro[2,3-c]-pyrazole-3,4-diyl]bis[propanone]
(I~ R = CH2CH3), 1,1'-[8-(4-fluorophenyl)-2,3,4,4a,5,6,11, lla-octahydro-lla-methyl-8H- phenanthro[2~3-c]pyrazole-3~4 diyl]bis[butanone] (I; R = CH2CH2CH3), or 1,1'-[8-(4-fluorophenyl)-2,3,4,4a,5,6,11,11a-octahydro-lla-methyl-35 8H-ph~nthro[2,3-c]pyrazole-3,4-diyl]bis-[pentanone]
(I; R = CH2CH2CH2CH3), respectively 1~'7~9~;5 Example 3 Die~thyl 8-(4-fluorophenyl)-2,3,4,4a,5,6,11,11a-octahydro-lla-methy~-8H~ enanthro[2,3-c]pyrazole-4,4-dicarboxylate (II; R = CH2CH3).
A solution of 25.81 g (0.084 mol~ of 1-ethenyl-6-(4-fluorophenyl)-3,4,9,9a-tetrahydro-9a-methyl-6H-naphtho [2,3-c]-pyrazole, 18.1 g (O.lOS mol) of diethyl methylenemalonate and S00 mg of 1,2,3-benzenetriol in 200 mL
of xylene was refluxed for 20 hours. The cooled reaction 10 mixture was filtered through silica gel and concentrated in vacuo to afford 41.93 g of a brown oil. The oil was purified by uQing high-performance liquid chromatography ~ith 3.97 ethyl acetate-CH2C12 followed by recrystallization ~rom methanol to afford 10.98 g of diethyl 8-(4-fluoro-15 phenyl)-2~3~4~4a~5~6~ lla-octahydro-lla-methyl-8H-phenanthro-[2,3-c]pyrazole-4,4-dicarboxylate as a colorles6 solid, m.p. 133-135C. m e PMR spectrum was consistent with the a3signed ~tructure.
In the endocrine profile determination, Compound II
20 (R ~ CH2CH3) at a dose level of 100 mg/kg caused an 80%
reduction in thymus weight, 47% reduction in adrenal weight and 186~ reduction in body weight gain as compared with ; the controls. Compound II (R = CH2CH3) was inactive in the ~-tocopherol pouch test at 100 mg/kg.
By replacing the diethyl methylenemalonate in the procedure of Example 3 by a molar equivalent amount of dimethyl methylenemalonate, dipropyl methylenemalonate or dibutyl methylenemalonate, it i8 contemplated that there can be obtained dimethyl 8-~4-fluorophenyl)-2,3,4,4a,5,6, 30 ll,lla-octahydro-lla-methyl-8H- phenanthro[2,3-c]pyrazole-4,4-dicarboxylate (II; R = CH3), dipropyl 8-(4-fluorophenyl~-
2,3,4,4a,5,6,11,11a-octahydro-lla-methyl-8H-phenanthro[2,3-c]
pyrazole-4,4-dicarboxylate (II; R = CH2CH2CH3), or dibutyl 8-(4-fluorophenyl)-2,3,4,4a,5,6,11,11a-octahydro-lla-methyl-35 8H-phenanthrol[2,3-c]pyrazole-4,4-dicarboxylate (II; R =
CH2CH2CH2CH3 ), re8pectively .
..,i
pyrazole-4,4-dicarboxylate (II; R = CH2CH2CH3), or dibutyl 8-(4-fluorophenyl)-2,3,4,4a,5,6,11,11a-octahydro-lla-methyl-35 8H-phenanthrol[2,3-c]pyrazole-4,4-dicarboxylate (II; R =
CH2CH2CH2CH3 ), re8pectively .
..,i
Claims (6)
1. A process for preparing a compound having the Formula I or II:
or I II
wherein R and R' are each lower-alkyl which comprises reacting 1-ethenyl-6-(4-fluorophenyl)-3,4,9,9a-tetrahydro-9a-methyl-6H-naphtho[2,3-c]pyrazole with a compound of the formula RCOCH=CHCOR or CH2=C(COOR')2, respectively.
or I II
wherein R and R' are each lower-alkyl which comprises reacting 1-ethenyl-6-(4-fluorophenyl)-3,4,9,9a-tetrahydro-9a-methyl-6H-naphtho[2,3-c]pyrazole with a compound of the formula RCOCH=CHCOR or CH2=C(COOR')2, respectively.
2. A process according to claim 1, for preparing 1,1'-[8-(4-fluorophenyl)-2,3,4,4a,5,6,11,11a-octahydro-11a-methyl-8H-phenanthro[2,3-c]pyrazole-3,4-diyl]bis-[ethanone], which comprises reacting 1-ethenyl-6-(4-fluorophenyl)-3,4,9,9a-tetrahydro-9a-methyl-6H-naphtho[2,3-c]pyrazole with 3-hexene-2,5-dione.
3. A process according to claim 1, for preparing diethyl 8-(4-fluorophenyl)-2,3,4,4a,5,6,11,11a-octahydro-11a-methyl-8H-phenanthro[2,3-c]pyrazole-4,4-dicarboxylate, which comprises reacting 1-ethenyl-6-(4-fluorophenyl)-3,4,9, 9a-tetrahydro-9a-methyl-6H-naphtho[2,3-c]pyrazole with diethyl methylenemalonate.
4. A process according to claim 1, wherein the 1-ethenyl-6-(4-fluorophenyl)-3,4,9,9a-tetrahydro-9a-methyl-6H-naphtho[2,3-c]pyrazole is prepared by reacting 5-ethenyl-3-hydroxymethylene-4,4a,7,8-tetrahydro-4a-methyl-2(3H)-naphthalenone with 4-fluorophenylhydrazine or an acid-addition salt thereof in the presence of acetic acid.
5. A compound of the Formula I or II as defined in claim 1, when prepared by the process according to claim 1 or 4 or by an obvious chemical equivalent thereof.
6. 1,1'-18-(4-Fluorophenyl)-2,3,4,4a,5,6,11,11a-octahydro-11a-methyl-8H-phenanthro[2,3-c]pyrazole-3,4-diyl]
bis-[ethanone] or diethyl 8-(4-fluorophenyl)-2,3,4,4a,5,6,11,11a-octahydro-11a-methyl-8H-phenanthro[2,3-c]pyrazole-4,4-dicarboxylate, when prepared by the process according to claim 2 or 3, respect-ively, or by an obvious chemical equivalent thereof.
bis-[ethanone] or diethyl 8-(4-fluorophenyl)-2,3,4,4a,5,6,11,11a-octahydro-11a-methyl-8H-phenanthro[2,3-c]pyrazole-4,4-dicarboxylate, when prepared by the process according to claim 2 or 3, respect-ively, or by an obvious chemical equivalent thereof.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004026248A3 (en) * | 2002-09-20 | 2004-07-15 | Merck & Co Inc | Octahydro-2-h-naphtho[1,2-f] indole-4-carboxamide derivatives as selective glucocorticoid receptor modulators |
| US7947726B2 (en) | 2002-01-22 | 2011-05-24 | The Regents Of The University Of California | Non-steroidal ligands for the glucocorticoid receptor, and compositions thereof |
-
1982
- 1982-09-13 CA CA000411268A patent/CA1178965A/en not_active Expired
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7947726B2 (en) | 2002-01-22 | 2011-05-24 | The Regents Of The University Of California | Non-steroidal ligands for the glucocorticoid receptor, and compositions thereof |
| WO2004026248A3 (en) * | 2002-09-20 | 2004-07-15 | Merck & Co Inc | Octahydro-2-h-naphtho[1,2-f] indole-4-carboxamide derivatives as selective glucocorticoid receptor modulators |
| JP2006503107A (en) * | 2002-09-20 | 2006-01-26 | メルク エンド カムパニー インコーポレーテッド | Octahydro-2-H-naphtho [1,2-f] indole-4-carboxamide derivatives as selective glucocorticoid receptor modulators |
| AU2003270783B2 (en) * | 2002-09-20 | 2009-12-24 | Merck Sharp & Dohme Corp. | Octahydro-2-H-naphtho[1,2-F] indole-4-carboxamide derivatives as selective glucocorticoid receptor modulators |
| AU2003270783C1 (en) * | 2002-09-20 | 2010-05-20 | Merck Sharp & Dohme Corp. | Octahydro-2-H-naphtho[1,2-F] indole-4-carboxamide derivatives as selective glucocorticoid receptor modulators |
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