ES2372769B1 - METIL SULFON FENIL WITH ANTI-FLAMMING ACTIVITY AND ANTITUMORAL ACTIVITY. - Google Patents
METIL SULFON FENIL WITH ANTI-FLAMMING ACTIVITY AND ANTITUMORAL ACTIVITY. Download PDFInfo
- Publication number
- ES2372769B1 ES2372769B1 ES201031044A ES201031044A ES2372769B1 ES 2372769 B1 ES2372769 B1 ES 2372769B1 ES 201031044 A ES201031044 A ES 201031044A ES 201031044 A ES201031044 A ES 201031044A ES 2372769 B1 ES2372769 B1 ES 2372769B1
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- ES
- Spain
- Prior art keywords
- pyrrol
- uorophenyl
- indole
- pyrrole
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- 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.)
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- 230000000694 effects Effects 0.000 title claims description 11
- 230000000259 anti-tumor effect Effects 0.000 title abstract description 7
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 title 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 title 1
- -1 thiophene-2-yl Chemical group 0.000 claims abstract description 113
- 150000001875 compounds Chemical class 0.000 claims abstract description 75
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims abstract description 25
- 238000011282 treatment Methods 0.000 claims abstract description 23
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 21
- 201000011510 cancer Diseases 0.000 claims abstract description 21
- 230000002265 prevention Effects 0.000 claims abstract description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 15
- 230000003110 anti-inflammatory effect Effects 0.000 claims abstract description 13
- 206010061218 Inflammation Diseases 0.000 claims abstract description 12
- 230000004054 inflammatory process Effects 0.000 claims abstract description 12
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims abstract description 11
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims abstract description 11
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 11
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 11
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 11
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 11
- 125000001424 substituent group Chemical group 0.000 claims abstract description 11
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims abstract description 9
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 9
- JCDWETOKTFWTHA-UHFFFAOYSA-N methylsulfonylbenzene Chemical class CS(=O)(=O)C1=CC=CC=C1 JCDWETOKTFWTHA-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims description 41
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 14
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- FOEUPKDQBBKJIV-UHFFFAOYSA-N (1-methylindol-3-yl)-(4-methylsulfonylphenyl)methanone Chemical compound C12=CC=CC=C2N(C)C=C1C(=O)C1=CC=C(S(C)(=O)=O)C=C1 FOEUPKDQBBKJIV-UHFFFAOYSA-N 0.000 claims description 3
- XYKMPECPWAFYIN-UHFFFAOYSA-N (4-methylsulfonylphenyl)-thiophen-2-ylmethanone Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C(=O)C1=CC=CS1 XYKMPECPWAFYIN-UHFFFAOYSA-N 0.000 claims description 3
- UINJFISXUJQXRO-UHFFFAOYSA-N (4-methylsulfonylphenyl)-thiophen-3-ylmethanone Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C(=O)C1=CSC=C1 UINJFISXUJQXRO-UHFFFAOYSA-N 0.000 claims description 3
- RKEQYMMBIKIYDW-UHFFFAOYSA-N 1h-indol-3-yl-(4-methylsulfonylphenyl)methanone Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C(=O)C1=CNC2=CC=CC=C12 RKEQYMMBIKIYDW-UHFFFAOYSA-N 0.000 claims description 3
- 230000003389 potentiating effect Effects 0.000 claims description 3
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 102000010907 Cyclooxygenase 2 Human genes 0.000 claims 5
- 108010037462 Cyclooxygenase 2 Proteins 0.000 claims 5
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 claims 4
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 claims 4
- 239000003112 inhibitor Substances 0.000 claims 4
- 229940124639 Selective inhibitor Drugs 0.000 claims 3
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 claims 3
- 229940127204 compound 29 Drugs 0.000 claims 3
- 229940054051 antipsychotic indole derivative Drugs 0.000 claims 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims 2
- 230000015572 biosynthetic process Effects 0.000 claims 2
- 229940111134 coxibs Drugs 0.000 claims 2
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- 150000002367 halogens Chemical class 0.000 claims 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims 2
- 238000003786 synthesis reaction Methods 0.000 claims 2
- RAVPPTBOIFGUCW-UHFFFAOYSA-N 3-methylsulfonyl-2-phenyl-1H-indole Chemical group CS(=O)(=O)C1=C(NC2=CC=CC=C12)C1=CC=CC=C1 RAVPPTBOIFGUCW-UHFFFAOYSA-N 0.000 claims 1
- 108010044467 Isoenzymes Proteins 0.000 claims 1
- 230000000202 analgesic effect Effects 0.000 claims 1
- 230000001754 anti-pyretic effect Effects 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 claims 1
- 229940125904 compound 1 Drugs 0.000 claims 1
- 125000001207 fluorophenyl group Chemical group 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 125000001041 indolyl group Chemical group 0.000 claims 1
- 125000000168 pyrrolyl group Chemical group 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 abstract description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 75
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 238000007429 general method Methods 0.000 description 18
- 239000000843 powder Substances 0.000 description 16
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 14
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- 230000003833 cell viability Effects 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 230000003647 oxidation Effects 0.000 description 8
- 238000007254 oxidation reaction Methods 0.000 description 8
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 7
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 7
- 229960001680 ibuprofen Drugs 0.000 description 7
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
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- 229920001525 carrageenan Polymers 0.000 description 6
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 6
- YEUYZNNBXLMFCW-UHFFFAOYSA-N 1-bromo-4-methylsulfanylbenzene Chemical compound CSC1=CC=C(Br)C=C1 YEUYZNNBXLMFCW-UHFFFAOYSA-N 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 5
- 235000010418 carrageenan Nutrition 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 206010030113 Oedema Diseases 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
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- 206010009944 Colon cancer Diseases 0.000 description 3
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
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- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- FTZIQBGFCYJWKA-UHFFFAOYSA-N 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium Chemical compound S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 FTZIQBGFCYJWKA-UHFFFAOYSA-N 0.000 description 2
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- 125000006416 CBr Chemical group BrC* 0.000 description 2
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- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
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- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
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- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
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- AHEXWNJBAFOCFO-UHFFFAOYSA-N furan-2-yl-(4-methylphenyl)methanethione Chemical compound C1=CC(C)=CC=C1C(=S)C1=CC=CO1 AHEXWNJBAFOCFO-UHFFFAOYSA-N 0.000 description 1
- CTQLYYYBVSXLSD-UHFFFAOYSA-N furan-2-yl-(4-methylsulfanylphenyl)methanol Chemical compound C1=CC(SC)=CC=C1C(O)C1=CC=CO1 CTQLYYYBVSXLSD-UHFFFAOYSA-N 0.000 description 1
- CWRZECMEZICAFW-UHFFFAOYSA-N furan-2-yl-(4-methylsulfonylphenyl)methanone Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C(=O)C1=CC=CO1 CWRZECMEZICAFW-UHFFFAOYSA-N 0.000 description 1
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- FOJXUDRAYMMHOV-UHFFFAOYSA-N furan-3-yl-(4-methylsulfanylphenyl)methanol Chemical compound C1=CC(SC)=CC=C1C(O)C1=COC=C1 FOJXUDRAYMMHOV-UHFFFAOYSA-N 0.000 description 1
- ULFFSZMVURLRPK-UHFFFAOYSA-N furan-3-yl-(4-methylsulfonylphenyl)methanone Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C(=O)C1=COC=C1 ULFFSZMVURLRPK-UHFFFAOYSA-N 0.000 description 1
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
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- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-M naproxen(1-) Chemical compound C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-M 0.000 description 1
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 1
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- 210000000056 organ Anatomy 0.000 description 1
- OTYPIDNRISCWQY-UHFFFAOYSA-L palladium(2+);tris(2-methylphenyl)phosphane;dichloride Chemical compound Cl[Pd]Cl.CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C.CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C OTYPIDNRISCWQY-UHFFFAOYSA-L 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
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- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
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- 239000002510 pyrogen Substances 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
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- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- 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 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
- A61K31/10—Sulfides; Sulfoxides; Sulfones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/14—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/24—Sulfones; Sulfoxides having sulfone or sulfoxide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
- C07C317/36—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atoms of the amino groups bound to hydrogen atoms or to carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
Fenil metil sulfonas con actividad antiinflamatoria y actividad antitumoral.#Los compuestos de fórmula (I) donde -X- es un enlace simple, -NH- o -CO-, y -Ar es un radical aromático seleccionado entre fenilo, fenilo 2-, 3- y 4-mono-sustituido, donde el sustituyente es F, Cl, Br o I, furan-2-ilo, furan-3-ilo, tiofen-2-ilo, tiofen-3-ilo, pirrol-1-ilo, pirrol-2-ilo, N-(2-fluorofenil)pirrol-2-ilo, N-(3-fluorofenil)pirrol-2-ilo, pirrol-3-ilo, N-(2-fluorofenil)pirrol-3-ilo, N-(3-fluorofenil)pirrol-3-ilo, indol-1-ilo, indol-2-ilo, N-metilindol-2-ilo, indol-3-ilo, N-metilindol-3-ilo, 2-piridilo y 3-piridilo son principios activos farmacéuticos útiles para el tratamiento y/o prevención de la inflamación y/o el cáncer.Phenyl methyl sulfones with anti-inflammatory activity and anti-tumor activity. # The compounds of formula (I) where -X- is a single bond, -NH- or -CO-, and -Ar is an aromatic radical selected from phenyl, phenyl 2-, 3- and 4-mono-substituted, where the substituent is F, Cl, Br or I, furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl, pyrrole-1-yl , pyrrol-2-yl, N- (2-fluorophenyl) pyrrol-2-yl, N- (3-fluorophenyl) pyrrol-2-yl, pyrrole-3-yl, N- (2-fluorophenyl) pyrrole-3- yl, N- (3-fluorophenyl) pyrrole-3-yl, indole-1-yl, indole-2-yl, N-methylindole-2-yl, indole-3-yl, N-methylindole-3-yl, 2 -pyridyl and 3-pyridyl are pharmaceutical active ingredients useful for the treatment and / or prevention of inflammation and / or cancer.
Description
Fenil metil sulfonas con actividad antiinflamatoria y actividad antitumoral. Phenyl methyl sulfones with anti-inflammatory activity and anti-tumor activity.
La presente invención se refiere a nuevos compuestos útiles como principios activos farmacéuticos contra la inflamación y/o el cáncer. The present invention refers to new compounds useful as pharmaceutical active ingredients against inflammation and / or cancer.
Estado de la técnica State of the art
La combinación de medicamentos antiinflamatorios no esteroideos (“non-steroidal anti-inflammatory drugs”, NSAIDs) (p.ej. ibuprofeno, tolmetin, indometacina, sulindaco, suprofeno, fenilbutazona y naproxeno) y agentes antitumorales para tratar carcinoma en la cavidad peritoneal ya es conocida (cf. p.ej. EP 334.576 A, publicada en 1989). The combination of non-steroidal anti-inflammatory drugs (“non-steroidal anti-inflammatory drugs”, NSAIDs) (eg ibuprofen, tolmetin, indomethacin, sulindac, supphene, phenylbutazone and naproxen) and anti-tumor agents to treat carcinoma in the peritoneal cavity It is known (cf. eg EP 334,576 A, published in 1989).
También es conocido que los NSAIDs son potentes antioxidantes que poseen ambas actividades antiinflamatoria y antitumoral, como se ilustra p.ej. en el artículo de revisión: R.E. Harris y al., “Aspirin, ibuprofen, and other nonsteroidal anti-inflammatory drugs in the cancer prevention: a critical review de non-selective COX-2 blockade (Review)”, Oncology Reports 2004, vol. 13, pp. 559-583). Este artículo de revisión muestra que, entre veinte estudios epidemiológicos enfocados a la asociación entre la toma de NSAIDs y el riesgo de cáncer humano, 13 mencionan una reducción estadísticamente significativa del cáncer. También se menciona, a partir de 91 estudios publicados, que los NSAIDs no selectivos (principalmente aspirina e ibuprofeno), tomados a pequeñas dosis más de cinco años, tienen significantes efectos quimiopreventivos contra una variedad de neoplasmas malignos incluyendo los cuatro tipos mayoritarios: pulmón, mama, colon y próstata. It is also known that NSAIDs are potent antioxidants that possess both anti-inflammatory and anti-tumor activities, as illustrated, for example, in the review article: R.E. Harris et al., "Aspirin, ibuprofen, and other nonsteroidal anti-inflammatory drugs in the cancer prevention: a critical review of non-selective COX-2 blockade (Review)", Oncology Reports 2004, vol. 13, pp. 559-583). This review article shows that, among twenty epidemiological studies focused on the association between taking NSAIDs and the risk of human cancer, 13 mention a statistically significant reduction in cancer. It is also mentioned, from 91 published studies, that non-selective NSAIDs (mainly aspirin and ibuprofen), taken at small doses over five years, have significant chemopreventive effects against a variety of malignant neoplasms including the four major types: lung, breast, colon and prostate.
A pesar del interés de disponer de principios activos farmacéuticos que simultáneamente muestren actividad antiinflamatoria y actividad antitumoral, no hay ninguno en el mercado que explícitamente mencione las dos indicaciones médicas. Despite the interest of having pharmaceutical active ingredients that simultaneously show anti-inflammatory activity and anti-tumor activity, there is none in the market that explicitly mentions the two medical indications.
Explicación de la invención Explanation of the invention.
La presente invención proporciona compuestos con la ventaja de que pueden usarse, por una parte, para los cuatro propósitos médicos que simultáneamente involucran ambos tipos de patologías, a saber: tratamiento de la inflamación y prevención del cáncer, prevención de la inflamación y tratamiento del cáncer, tratamiento de ambos, inflamación y cáncer, o prevención de ambos; y, por otra parte, para los cuatro propósitos que involucran sólo uno de los dos tipos de patologías, a saber: tratamiento de la inflamación, tratamiento del cáncer, prevención de la inflamación o prevención del cáncer. Conjuntamente estas ocho posibilidades se refieren aquí mediante la expresión “tratamiento y/o prevención de la inflamación y/o el cáncer”. The present invention provides compounds with the advantage that they can be used, on the one hand, for the four medical purposes that simultaneously involve both types of pathologies, namely: in fl ammation treatment and cancer prevention, in fl ammation prevention and cancer treatment. , treatment of both, inflammation and cancer, or prevention of both; and, on the other hand, for the four purposes that involve only one of the two types of pathologies, namely: in fl ammation treatment, cancer treatment, in fl ammation prevention or cancer prevention. Together these eight possibilities are referred to here by the expression "treatment and / or prevention of inflammation and / or cancer".
Un aspecto de la presente invención se refiere al compuesto de fórmula (I) One aspect of the present invention refers to the compound of formula (I)
donde: -X-es seleccionado del grupo que consiste en un enlace sencillo, un birradical -NH-y un birradical -CO-; y -Ar es un radical aromático seleccionado del grupo que consiste en: fenilo y fenilo 2-, 3-y 4-mono-sustituido, donde el sustituyente es F, Cl, Br o I; furan-2-ilo, furan-3-ilo, tiofen-2-ilo y tiofen-3-ilo; pirrol-1-ilo, pirrol-2-ilo, N(2-fluorofenil)pirrol-2-ilo, N-(3-fluorofenil)pirrol-2-ilo, pirrol-3-ilo, N-(2-fluorofenil)pirrol-3-ilo y N-(3-fluorofenil) pirrol-3-ilo; indol-1-ilo, indol-2-ilo, N-metilindol-2-ilo, indol-3-ilo y N-metilindol-3-ilo; y 2-piridilo y 3-piridilo; o una sal farmacéuticamente aceptable del mismo, o un solvato farmacéuticamente aceptable del mismo, para uso como principio activo farmacéutico. En una realización particular, el compuesto es para uso en el tratamiento y/o prevención de la inflamación y/o el cáncer en humanos. En una realización preferida es para uso en el tratamiento y/o prevención de la inflamación. En otra realización preferida es para uso en el tratamiento y/o prevención del cáncer. where: -X- is selected from the group consisting of a single bond, a birradical -NH- and a birradical -CO-; and -Ar is an aromatic radical selected from the group consisting of: 2-, 3- and 4-mono-substituted phenyl and phenyl, where the substituent is F, Cl, Br or I; furan-2-yl, furan-3-yl, thiophene-2-yl and thiophene-3-yl; pyrrol-1-yl, pyrrol-2-yl, N (2- fl uorophenyl) pyrrol-2-yl, N- (3- fl uorophenyl) pyrrol-2-yl, pyrrole-3-yl, N- (2- fl uorophenyl) pyrrol-3-yl and N- (3- fl uorophenyl) pyrrol-3-yl; indole-1-yl, indole-2-yl, N-methylindole-2-yl, indole-3-yl and N-methylindole-3-yl; and 2-pyridyl and 3-pyridyl; or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use as a pharmaceutical active ingredient. In a particular embodiment, the compound is for use in the treatment and / or prevention of inflammation and / or cancer in humans. In a preferred embodiment it is for use in the treatment and / or prevention of inflammation. In another preferred embodiment it is for use in the treatment and / or prevention of cancer.
Así, la presente invención se refiere al uso de un compuesto, tal como se define en el párrafo anterior, para la preparación de un medicamento para el tratamiento y/o la prevención de la inflamación y/o el cáncer en humanos. En otras palabras, la presente invención se refiere a un método de tratamiento de un humano que sufre de inflamación y/o cáncer que comprende la administración de una cantidad terapéuticamente efectiva de un compuesto tal como se define en el párrafo anterior, conjuntamente con cantidades suficientes de excipientes o portadores farmacéuticamente aceptables. La expresión “cantidad terapéuticamente efectiva” como se usa aquí, se refiere a la cantidad de un compuesto que, cuando se administra, es suficiente para prevenir el desarrollo, o aliviar en cierto grado, uno o más de los síntomas de la enfermedad a la que se dirige. La dosis particular de compuesto administrado según esta invención será por supuesto determinada por las condiciones particulares que rodean el caso, incluyendo el compuesto administrado, la ruta de administración, la condición particular que se está tratando, y las consideraciones similares. La expresión “excipientes o portadores farmacéuticamente aceptables” se refiere a materiales farmacéuticamente aceptables, composiciones o vehículos. Cada componente debe ser farmacéuticamente aceptable en el sentido de ser compatible con los otros ingredientes de la composición farmacéutica. Debe ser también apto para el uso en contacto con tejidos u órganos de humanos y animales sin demasiada toxicidad, irritación, respuesta alérgica, immunogenicidad u otros problemas o complicaciones acorde con una relación beneficio/riesgo razonable. Thus, the present invention relates to the use of a compound, as defined in the preceding paragraph, for the preparation of a medicament for the treatment and / or prevention of inflammation and / or cancer in humans. In other words, the present invention relates to a method of treating a human suffering from inflammation and / or cancer comprising the administration of a therapeutically effective amount of a compound as defined in the preceding paragraph, together with sufficient amounts. of pharmaceutically acceptable carriers or excipients. The term "therapeutically effective amount" as used herein refers to the amount of a compound that, when administered, is sufficient to prevent the development, or to alleviate to some degree, one or more of the symptoms of the disease at That is headed. The particular dose of compound administered according to this invention will of course be determined by the particular conditions surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar considerations. The term "pharmaceutically acceptable excipients or carriers" refers to pharmaceutically acceptable materials, compositions or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with human or animal tissues or organs without too much toxicity, irritation, allergic response, immunogenicity or other problems or complications in accordance with a reasonable benefit / risk relationship.
En una realización particular del compuesto (I), -X-es -CO-. En una realización preferida -Ar es seleccionado del grupo que consiste en: fenilo y fenilo 2-y 3-mono-sustituido, donde el sustituyente es F, Cl, Br o I; furan-3ilo y tiofen-3-ilo; pirrol-1-ilo, pirrol-2-ilo, N-(2-fluorofenil)pirrol-2-ilo, N-(3-fluorofenilo)pirrol-2-ilo, pirrol-3-ilo, N(2-fluorofenil)pirrol-3-ilo y N-(3-fluorofenil)pirrol-3-ilo; indol-1-ilo, indol-2-ilo, N-metilindol-2-ilo, indol-3-ilo y Nmetilindol-3-ilo; y 2-piridilo y 3-piridilo. In a particular embodiment of the compound (I), -X-is -CO-. In a preferred embodiment -Ar is selected from the group consisting of: 2-and 3-mono-substituted phenyl and phenyl, where the substituent is F, Cl, Br or I; furan-3yl and thiophene-3-yl; pyrrol-1-yl, pyrrole-2-yl, N- (2- fl uorophenyl) pyrrol-2-yl, N- (3- fl uorophenyl) pyrrol-2-yl, pyrrole-3-yl, N (2- fl uorophenyl) pyrrol-3-yl and N- (3- fl uorophenyl) pyrrol-3-yl; indole-1-yl, indole-2-yl, N-methylindole-2-yl, indole-3-yl and N-methylindole-3-yl; and 2-pyridyl and 3-pyridyl.
En otra realización particular del compuesto (I), -X-es un enlace sencillo. En una realización preferida -Ar es seleccionado del grupo que consiste en: fenilo y fenilo 2-, 3-y 4-mono-sustituido, donde el sustituyente es F, Cl, Br o I; furan-2-ilo, furan-3-ilo, tiofen-2-ilo y tiofen-3-ilo; pirrol-1-ilo, pirrol-2-ilo, N-(2-fluorofenil)pirrol-2-ilo, N-(3-fluorofenil)pirrol-2-ilo, pirrol-3-ilo, N-(2-fluorofenilo)pirrol-3-ilo y N-(3-fluorofenil)pirrol-3-ilo; indol-2-il, N-metilindol2-ilo, indol-3-ilo y N-metilindol-3-ilo; y 3-piridilo. In another particular embodiment of compound (I), -X- is a single bond. In a preferred embodiment -Ar is selected from the group consisting of: 2-, 3- and 4-mono-substituted phenyl and phenyl, where the substituent is F, Cl, Br or I; furan-2-yl, furan-3-yl, thiophene-2-yl and thiophene-3-yl; pyrrol-1-yl, pyrrol-2-yl, N- (2- fl uorophenyl) pyrrol-2-yl, N- (3- fl uorophenyl) pyrrol-2-yl, pyrrole-3-yl, N- (2- fl uorophenyl ) pyrrol-3-yl and N- (3- fl uorophenyl) pyrrol-3-yl; indole-2-yl, N-methylindole-2-yl, indole-3-yl and N-methylindole-3-yl; and 3-pyridyl.
Los compuestos de fórmula (I) de la presente invención son fenil metil sulfonas que pueden prepararse por métodos conocidos en la técnica. Rutas sintéticas generales se muestran en Figuras 1-4, y se ilustran en los ejemplos de preparación que se acompañan. The compounds of formula (I) of the present invention are phenyl methyl sulfones that can be prepared by methods known in the art. General synthetic routes are shown in Figures 1-4, and are illustrated in the accompanying preparation examples.
Otro aspecto de la invención se refiere a nuevos compuestos de fórmula (I) Another aspect of the invention relates to new compounds of formula (I)
donde: -X-es seleccionado del grupo que consiste en un enlace sencillo, un birradical -NH-y un birradical -CO-; y -Ar es un radical aromático seleccionado del grupo que consiste en: fenilo y fenilo 2-, 3-y 4-mono-sustituido, donde el sustituyente es F, Cl, Br o I; furan-2-ilo, furan-3-ilo, tiofen-2-ilo y tiofen-3-ilo; pirrol-1-ilo, pirrol-2-ilo, N(2-fluorofenilo)pirrol-2-ilo, N-(3-fluorofenilo)pirrol-2-ilo, pirrol-3-ilo, N-(2-fluorofenil)pirrol-3-ilo y N-(3-fluorofenil) pirrol-3-ilo; indol-1-ilo, indol-2-ilo, N-metilindol-2-ilo, indol-3-ilo y N-metilindol-3-ilo; 2-piridilo y 3-piridilo; o una sal farmacéuticamente aceptable de los mismos, o un solvato farmacéuticamente aceptable de los mismos, con la salvedad de que: cuando -X-es -CO-, -Ar no es 4-fluorofenilo, ni 4-bromofenilo, ni furan-2-ilo, ni tiofen-2-ilo; y cuando -X-es un enlace sencillo, -Ar no es indol-1-ilo ni 2-piridilo. where: -X- is selected from the group consisting of a single bond, a birradical -NH- and a birradical -CO-; and -Ar is an aromatic radical selected from the group consisting of: 2-, 3- and 4-mono-substituted phenyl and phenyl, where the substituent is F, Cl, Br or I; furan-2-yl, furan-3-yl, thiophene-2-yl and thiophene-3-yl; pyrrol-1-yl, pyrrol-2-yl, N (2- fl uorophenyl) pyrrol-2-yl, N- (3- fl uorophenyl) pyrrol-2-yl, pyrrole-3-yl, N- (2- fl uorophenyl) pyrrol-3-yl and N- (3- fl uorophenyl) pyrrol-3-yl; indole-1-yl, indole-2-yl, N-methylindole-2-yl, indole-3-yl and N-methylindole-3-yl; 2-pyridyl and 3-pyridyl; or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, with the proviso that: when -X-is -CO-, -Ar is not 4-fl uorophenyl, nor 4-bromophenyl, nor furan-2 -yl or thiophene-2-yl; and when -X- is a single bond, -Ar is not indole-1-yl or 2-pyridyl.
En una realización particular en el compuesto (I) -X-es -CO-. En otra realización particular -X-es un enlace sencillo. En otra realización particular -Ar es seleccionado del grupo que consiste en: fenilo y fenilo 2-y 3-monosustituido, donde el sustituyente es F, Cl, Br o I; furan-3-ilo y tiofen-3-ilo; pirrol-2-ilo, N-(2-fluorofenil)pirrol-2ilo, N-(3-fluorofenil)pirrol-2-ilo, pirrol-3-ilo, N-(2-fluorofenil)pirrol-3-ilo y N-(3-fluorofenilo)pirrol-3-ilo; indol-2-ilo, N-metilindol-2-ilo, indol-3-ilo y N-metilindol-3-ilo; y 3-piridilo. In a particular embodiment in the compound (I) -X-is -CO-. In another particular embodiment -X- is a simple link. In another particular embodiment -Ar is selected from the group consisting of: phenyl and 2-and 3-mono-substituted phenyl, where the substituent is F, Cl, Br or I; furan-3-yl and thiophene-3-yl; pyrrol-2-yl, N- (2- fl uorophenyl) pyrrol-2yl, N- (3- fl uorophenyl) pyrrol-2-yl, pyrrol-3-yl, N- (2- fl uorophenyl) pyrrol-3-yl and N - (3-fl uorophenyl) pyrrol-3-yl; indole-2-yl, N-methylindole-2-yl, indole-3-yl and N-methylindole-3-yl; and 3-pyridyl.
Un compuesto preferido (I) se selecciona de la lista que consistente en: N-metil-3-(p-metilsulfonilbenzoil)indol; N(2-fluorofenil)-2-(p-metilsulfonilbenzoil)pirrol; N-(2-fluorofenil)-3-(p-metilsulfonilbenzoil)pirrol; 3-(p-metilsulfonilbenzoil)indol; 2-(p-metilsulfonilbenzoil)tiofeno; y 3-(p-metilsulfonilbenzoil)tiofeno. A preferred compound (I) is selected from the list consisting of: N-methyl-3- (p-methylsulfonylbenzoyl) indole; N (2- fl uorophenyl) -2- (p-methylsulfonylbenzoyl) pyrrole; N- (2- fl uorophenyl) -3- (p-methylsulfonylbenzoyl) pyrrole; 3- (p-methylsulfonylbenzoyl) indole; 2- (p-methylsulfonylbenzoyl) thiophene; and 3- (p-methylsulfonylbenzoyl) thiophene.
Los resultados de los ensayos de actividad antiinflamatoria in vivo (ensayo de reducción de edema en pata de rata inducido por carragenina, Tabla 1) de los ejemplos ilustran la actividad antiinflamatoria de los compuestos de la presente invención. Los resultados de viabilidad celular de líneas celulares de cáncer de NCI-H460 (Tabla 2) y de HT-29 (Tabla 3) ilustran la actividad antitumoral de los compuestos de la presente invención. La presencia de ambos tipos de actividad representa una ventaja, que hace los compuestos útiles para el tratamiento y/o prevención de la inflamación y/o el cáncer. The results of the in vivo anti-inflammatory activity assays (carragenin-induced rat leg edema reduction test, Table 1) of the examples illustrate the anti-inflammatory activity of the compounds of the present invention. The cell viability results of NCI-H460 (Table 2) and HT-29 (Table 3) cancer cell lines illustrate the antitumor activity of the compounds of the present invention. The presence of both types of activity represents an advantage, which makes the compounds useful for the treatment and / or prevention of inflammation and / or cancer.
A lo largo de la descripción y las reivindicaciones la palabra “comprende” y sus variantes no pretenden excluir otras características técnicas, aditivos, componentes o pasos. Para los expertos en la materia, otros objetos, ventajas y características de la invención se desprenderán en parte de la descripción y en parte de la práctica de la invención. Los siguientes ejemplos y dibujos se proporcionan a modo de ilustración, y no se pretende que sean limitativos de la presente invención. Además, la presente invención cubre todas las posibles combinaciones de realizaciones particulares y preferidas aquí indicadas. Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and characteristics of the invention will be derived partly from the description and partly from the practice of the invention. The following examples and drawings are provided by way of illustration, and are not intended to be limiting of the present invention. In addition, the present invention covers all possible combinations of particular and preferred embodiments indicated herein.
Breve descripción de los dibujos Brief description of the drawings
La Fig. 1. muestra las condiciones de reacción para la preparación de fenil metil sulfonas por oxidación de2o3-(p(metiltio)benzoil)heterociclo usando m-CPBA, donde la diarilcetona intermedia (3-8 y 16-19) se obtiene en dos etapas a partir del correspondiente arilaldehído y p-bromotioanisol usando butil-litio para el intercambio Br/Li, seguidas de oxidación del carbinol obtenido (2a-f): i) BuLi/ArCHO. ii) MnO2/CH2Cl2. iii) m-CPBA/0ºC. Fig. 1. shows the reaction conditions for the preparation of phenyl methyl sulfones by oxidation of 2o3- (p (methylthio) benzoyl) heterocycle using m-CPBA, where the intermediate diaryl ketone (3-8 and 16-19) is obtained in Two steps from the corresponding arylaldehyde and p-bromothioanisole using butyl lithium for the Br / Li exchange, followed by oxidation of the carbinol obtained (2a-f): i) BuLi / ArCHO. ii) MnO2 / CH2Cl2. iii) m-CPBA / 0 ° C.
La Fig. 2. muestra las condiciones de reacción para la preparación de fenil metil sulfonas directamente por acilación del tioanisol 15 con el correspondiente cloruro de arilacilo bajo condiciones clásicas: i) ArCOCl/CH2Cl2. ii) m-CPBA/0ºC. Fig. 2. shows the reaction conditions for the preparation of phenyl methyl sulfones directly by acylation of thioanisole 15 with the corresponding arylacil chloride under classical conditions: i) ArCOCl / CH2Cl2. ii) m-CPBA / 0 ° C.
La Fig. 3. muestra las condiciones de reacción para la preparación de la 2-arilpiridina 26 por reacción y acoplamiento de la 2-bromopiridina (24) y el p-metiltiobromobenceno (1) bajo condiciones clásicas de Ullmann, seguida de oxidación del grupo metiltio usando m-CPBA: i) Cu/K2CO3. ii) m-CPBA/0ºC. Fig. 3. shows the reaction conditions for the preparation of 2-arylpyridine 26 by reaction and coupling of 2-bromopyridine (24) and p-methylthiobromobenzene (1) under classical Ullmann conditions, followed by oxidation of the group methylthio using m-CPBA: i) Cu / K2CO3. ii) m-CPBA / 0 ° C.
La Fig. 4 muestra las condiciones de reacción para la preparación de las arilaminas 30, 32-33 usando Pd-catálisis para la aminación de halogenuros de arilo: i) m-CPBA 0ºC. ii) Pd[P(o-tolil)3]2Cl2/BINAP/Cs2CO3/NHR1R2. Fig. 4 shows the reaction conditions for the preparation of arylamines 30, 32-33 using Pd-catalysis for the amination of aryl halides: i) m-CPBA 0 ° C. ii) Pd [P (o-tolyl) 3] 2Cl2 / BINAP / Cs2CO3 / NHR1R2.
Descripción detallada de realizaciones particulares Detailed description of particular embodiments
Método general para la preparación de diarilalcoholes y oxidación a cetonas General method for the preparation of diarylalcohols and oxidation to ketones
- (A) (TO)
- A una solución de bromotioanisol (450 mg, 2.22 mmol) en THF (4 mL), se añadió una solución de n-BuLi en hexano (1.4 mL, 2.22 mmol) a -78ºC bajo atmósfera de argón. La mezcla se agitó a la misma temperatura durante 1 h. Después, se añadió una solución del correspondiente aldehído o cetona (2.50 mmol) en THF recién destilado (2 mL) y la mezcla recuperó despacio los 20ºC, en este momento se añadió una solución de NH4Cl saturado (3 mL) y la mezcla se agitó 20 min. más. Finalmente se extrajo con éter (3x20 mL) y la fase acuosa se acidificó con HCl 2N y se extrajo con CH2Cl2 (3x20 mL). Las fases orgánicas se secaron (Na2SO4), filtraron, y concentraron bajo el vacío y el producto crudo se purificó por cromatografía de columna de gel de sílice. Usando una mezcla de hexano/acetato de etilo (5:95) como eluyente, se obtuvo el alcohol deseado. To a solution of bromothioanisole (450 mg, 2.22 mmol) in THF (4 mL), a solution of n-BuLi in hexane (1.4 mL, 2.22 mmol) was added at -78 ° C under an argon atmosphere. The mixture was stirred at the same temperature for 1 h. Then, a solution of the corresponding aldehyde or ketone (2.50 mmol) in freshly distilled THF (2 mL) was added and the mixture slowly recovered at 20 ° C, at this time a saturated NH4Cl solution (3 mL) was added and the mixture was stirred 20 min. plus. Finally, it was extracted with ether (3x20 mL) and the aqueous phase was acidified with 2N HCl and extracted with CH2Cl2 (3x20 mL). The organic phases were dried (Na2SO4), filtered, and concentrated under vacuum and the crude product was purified by silica gel column chromatography. Using a hexane / ethyl acetate mixture (5:95) as eluent, the desired alcohol was obtained.
- (B) (B)
- Alcohol intermedio (1 mmol) se trató rápidamente con MnO2 (3 mmol) en diclorometano (15 mL). La mezcla de reacción se agitó 12 h a temperatura ambiente. El crudo de reacción se filtró, se lavó con diclorometano y el disolvente se eliminó en el evaporador rotatorio. El residuo obtenido se purificó por cromatografía de columna de gel de sílice usando 8:2 hexano/acetato de etilo como eluyente. Intermediate alcohol (1 mmol) was quickly treated with MnO2 (3 mmol) in dichloromethane (15 mL). The reaction mixture was stirred 12 h at room temperature. The reaction crude was filtered, washed with dichloromethane and the solvent was removed on the rotary evaporator. The obtained residue was purified by silica gel column chromatography using 8: 2 hexane / ethyl acetate as eluent.
Preparación de 2-(p-metiltiofenilhidroximetil)furano (2a). Usando el método descrito arriba, el furan-2-carbaldehído se convirtió en el alcohol del título como un aceite en 92% de rendimiento. El crudo de reacción obtenido se oxidó rápidamente con MnO2 debido a su alta inestabilidad. Preparation of 2- (p-methylthiophenylhydroxymethyl) furan (2a). Using the method described above, furan-2-carbaldehyde was converted to the title alcohol as an oil in 92% yield. The reaction crude obtained was rapidly oxidized with MnO2 due to its high instability.
Preparación de 3-(p-metilltiofenilhidroximetil)furano (2b). Usando el método descrito arriba, el furan-3-carbaldehído (400 mg, 4.16 mmol) se convirtió en el alcohol del título como un aceite (798 mg, 3.62 mmol) en 87% de rendimiento. El crudo de reacción se oxidó rápidamente con MnO2 debido a su alta inestabilidad. IR (KBr), ν (cm−1): 3300 (OH); 1212 (Ar-O); 1086 (C-S). Preparation of 3- (p-Methylthiophenylhydroxymethyl) furan (2b). Using the method described above, furan-3-carbaldehyde (400 mg, 4.16 mmol) was converted to the title alcohol as an oil (798 mg, 3.62 mmol) in 87% yield. The reaction crude was rapidly oxidized with MnO2 due to its high instability. IR (KBr), ν (cm − 1): 3300 (OH); 1212 (Ar-O); 1086 (C-S).
Preparación de N-(metil)-2-(p-metiltiofenilhidroximetil)indol (2c). Usando el método descrito arriba, el indol-2carbaldehído se convirtió en el alcohol del título como un aceite (674 mg, 2.3 mmol) en 93% de rendimiento. IR (KBr), ν (cm−1): 3260 (OH); 1234 (Ar-O); 1088 (C-S). Preparation of N- (methyl) -2- (p-methylthiophenylhydroxymethyl) indole (2c). Using the method described above, indole-2carbaldehyde was converted to the title alcohol as an oil (674 mg, 2.3 mmol) in 93% yield. IR (KBr), ν (cm − 1): 3260 (OH); 1234 (Ar-O); 1088 (C-S).
Preparación de N-(2-fluorofenil)-3-(p-metiltiofenilhidroximetil)pirrol (2e). Usando el procedimiento descrito arriba, el pirrol-3-carbaldehído se convirtió en el alcohol del título como un aceite en 86% de rendimiento. 1H-NMR (CDCl3, 200 MHz) δ (ppm): 2.47 (s, 3H, CH3-S); 5.72 (d, J = 4 Hz, 1H, CH-O); 6.56 (m, 1H, C-4H); 6.68 (s, 1H, C2H); 6.72 (m, 1H, C-5H); 7.08 (m, 1H, C-3’H); 7.09 (m, 1H, C-5’H); 7.10 (m, 2H, C-2”H, C-6”H); 7.14 (m, 4H, C-3”H, C-5”H, C-4’H, C-6’H). El crudo de reacción se oxidó rápidamente con MnO2 debido a su alta inestabilidad. Preparation of N- (2- fl uorophenyl) -3- (p-methylthiophenylhydroxymethyl) pyrrole (2e). Using the procedure described above, pyrrol-3-carbaldehyde was converted to the title alcohol as an oil in 86% yield. 1H-NMR (CDCl3, 200 MHz) δ (ppm): 2.47 (s, 3H, CH3-S); 5.72 (d, J = 4 Hz, 1H, CH-O); 6.56 (m, 1H, C-4H); 6.68 (s, 1H, C2H); 6.72 (m, 1H, C-5H); 7.08 (m, 1H, C-3’H); 7.09 (m, 1H, C-5’H); 7.10 (m, 2H, C-2 "H, C-6" H); 7.14 (m, 4H, C-3 ”H, C-5” H, C-4’H, C-6’H). The reaction crude was rapidly oxidized with MnO2 due to its high instability.
Preparación de 2-(p-metiltiobenzoil)furano (3). A partir de p-bromotioanisol (500 mg, 2.46 mmol) y de furfural Preparation of 2- (p-methylthiobenzoyl) furan (3). From p-bromothioanisole (500 mg, 2.46 mmol) and furfural
(196.8 mg, 2.05 mmol) siguiendo el método descrito anteriormente, usando BuLi en THF a -78ºC se obtuvo el correspondiente diarilmetanol, que se obtuvo con suficiente pureza para pasar a la nueva etapa de oxidación a cetona usando MnO2. El compuesto del título se obtuvo como un sólido blanco (406 mg, 1.87 mmol) en 91% de rendimiento. Pf.: 81-83ºC (hexano/acetato de etilo). IR (KBr), ν (cm−1): 1633 (CO); 1296 (Ar-O); 1091 (C-S). (196.8 mg, 2.05 mmol) following the method described above, using BuLi in THF at -78 ° C, the corresponding diaryl methanol was obtained, which was obtained with sufficient purity to pass to the new stage of ketone oxidation using MnO 2. The title compound was obtained as a white solid (406 mg, 1.87 mmol) in 91% yield. Mp .: 81-83 ° C (hexane / ethyl acetate). IR (KBr), ν (cm − 1): 1633 (CO); 1296 (Ar-O); 1091 (C-S).
Preparación de 3-(p-metiltiobenzoil)furano (4). La oxidación del carbinol (970 mg, 4.41 mmol) a la correspondiente cetona se obtuvo según el método general descrito anteriormente. El compuesto del título se obtuvo como un sólido blanco (970 mg, 4.37 mmol) en 92% de rendimiento. Pf.: 132-136ºC (hexano/acetato de etilo). IR (KBr), ν (cm−1): 1654 (CO); 1224 (Ar-O); 1102 (C-S). Preparation of 3- (p-methylthiobenzoyl) furan (4). The oxidation of carbinol (970 mg, 4.41 mmol) to the corresponding ketone was obtained according to the general method described above. The title compound was obtained as a white solid (970 mg, 4.37 mmol) in 92% yield. Mp .: 132-136 ° C (hexane / ethyl acetate). IR (KBr), ν (cm − 1): 1654 (CO); 1224 (Ar-O); 1102 (C-S).
Preparación de N-(metil)-2-((p-metiltiobenzoil)indol (5). La oxidación del carbinol (674 mg, 2,3 mmol) a la correspondiente cetona se obtuvo según el método general descrito anteriormente usando MnO2. El compuesto del título se obtuvo como polvo blanco (575 mg, 2.05 mmol) en 89% de rendimiento. Pf.: 142-144ºC (hexano/acetato de etilo). IR (KBr), ν (cm−1): 1665 (CO); 1234 (Ar-O); 1087 (C-S). Preparation of N- (methyl) -2 - ((p-methylthiobenzoyl) indole (5) Oxidation of carbinol (674 mg, 2.3 mmol) to the corresponding ketone was obtained according to the general method described above using MnO2. The title compound was obtained as a white powder (575 mg, 2.05 mmol) in 89% yield, mp .: 142-144 ° C (hexane / ethyl acetate) IR (KBr), ν (cm -1): 1665 (CO ); 1234 (Ar-O); 1087 (CS).
Preparación de N-(2-fluorofenil)-2-(p-metiltiobenzoil)pirrol (6). Se preparó a partir de metiltio derivado (320 mg, 1 mmol) siguiendo el método descrito anteriormente. El compuesto del título se obtuvo como un polvo blanco (210 mg, 0.67 mmol) en 52% de rendimiento. 1H-NMR (CDCl3, 200 MHz) δ (ppm): 2.53 (s, 3H, CH3-S); 6,38 (m, 1H, H4); 6.88 (m, 1H, H-3); 7.06 (m, 1H, H-5); 7.18 (m, 2H, C-3’H y C-5’H); 7.22 (m, 2H, Ar); 7.31 (m, 2H, Ar); 7.80 (m, 2H, C-2’H y C-6’H). Preparation of N- (2- fl uorophenyl) -2- (p-methylthiobenzoyl) pyrrole (6). It was prepared from methylthio derivative (320 mg, 1 mmol) following the method described above. The title compound was obtained as a white powder (210 mg, 0.67 mmol) in 52% yield. 1H-NMR (CDCl3, 200 MHz) δ (ppm): 2.53 (s, 3H, CH3-S); 6.38 (m, 1H, H4); 6.88 (m, 1H, H-3); 7.06 (m, 1H, H-5); 7.18 (m, 2H, C-3’H and C-5’H); 7.22 (m, 2H, Ar); 7.31 (m, 2H, Ar); 7.80 (m, 2H, C-2’H and C-6’H).
Preparación de N-(2-fluorofenil)-3-(p-metilltiobenzoil)pirrol (7). El compuesto del título se preparó a partir de metiltio derivado (636.9 mg, 2.04 mmol) siguiendo el método descrito anteriormente. El compuesto esperado 7 se obtuvo como un polvo blanco (529 mg, 1.70 mmol) en 83% de rendimiento. Pf.: 104-106ºC (hexano/acetato de etilo). IR (KBr), ν (cm−1): 1625 (CO); 1507 (C=C); 1468 (SO2); 1230 ((Ar-O); 1200 (C-O); 1091 (S=O). Preparation of N- (2- fl uorophenyl) -3- (p-methylthiobenzoyl) pyrrole (7). The title compound was prepared from methylthio derivative (636.9 mg, 2.04 mmol) following the method described above. The expected compound 7 was obtained as a white powder (529 mg, 1.70 mmol) in 83% yield. Mp .: 104-106 ° C (hexane / ethyl acetate). IR (KBr), ν (cm − 1): 1625 (CO); 1507 (C = C); 1468 (SO2); 1230 ((Ar-O); 1200 (C-O); 1091 (S = O).
Preparación de 3-(p-metilltiobenzoil)indol (8). El compuesto del título se preparó a partir de metiltio derivado (100 mg, 0.34 mmol) siguiendo el método descrito anteriormente. El compuesto esperado 8 se obtuvo como un polvo blanco (53 mg, 0.2 mmol) en 4% de rendimiento. IR (KBr), ν (cm−1): 1632 (CO); 1502 (C=C); 1215 ((Ar-S). HMS (ESIpos.m) 268.0788 (M•)+ . Preparation of 3- (p-methylthiobenzoyl) indole (8). The title compound was prepared from methylthio derivative (100 mg, 0.34 mmol) following the method described above. The expected compound 8 was obtained as a white powder (53 mg, 0.2 mmol) in 4% yield. IR (KBr), ν (cm − 1): 1632 (CO); 1502 (C = C); 1215 ((Ar-S). HMS (ESIpos.m) 268.0788 (M •) +.
Método general para la preparación de diarilcetonas. Una solución en agitación de tioanisol (127 mg, 1.02 mmol) en diclorometano seco (15 mL) se enfrió a 0ºC bajo atmósfera de argón. La solución se agitó vigorosamente y se añadió despacio una solución de tetracloruro de titanio (0.15 mL, 1.36 mmol). Una solución del correspondiente cloruro de ácido (0.80 mmol) en diclorometano (2 mL) se añadió a la mezcla. La mezcla de reacción se agitó 10 h a temperatura ambiente. El crudo de la reacción se introdujo dentro de 40 mL de hielo agua y la fase acuosa se separó. La fase orgánica se lavó con NaHCO3 saturado, se secó sobre Na2SO4 y se evaporó para dar un residuo que se purificó por cromatografía de columna usando 8:2 hexano/acetato de etilo. General method for the preparation of diaryl ketones. A stirring solution of thioanisole (127 mg, 1.02 mmol) in dry dichloromethane (15 mL) was cooled to 0 ° C under an argon atmosphere. The solution was vigorously stirred and a solution of titanium tetrachloride (0.15 mL, 1.36 mmol) was added slowly. A solution of the corresponding acid chloride (0.80 mmol) in dichloromethane (2 mL) was added to the mixture. The reaction mixture was stirred 10 h at room temperature. The reaction crude was introduced into 40 mL of ice water and the aqueous phase separated. The organic phase was washed with saturated NaHCO3, dried over Na2SO4 and evaporated to give a residue that was purified by column chromatography using 8: 2 hexane / ethyl acetate.
Preparación de 2-(p-metiltiobenzoil)tiofeno (16). El compuesto del título se preparó a partir de cloruro del ácido 2-tiofeno carboxílico en 50% de rendimiento después de purificación por cromatografía en columna. Pf.: 64-66ºC (hexano/acetato de etilo). IR (KBr): ν (cm−1): 1622 (C=O); 1088 (S-CH3). Preparation of 2- (p-methylthiobenzoyl) thiophene (16). The title compound was prepared from 2-thiophene carboxylic acid chloride in 50% yield after purification by column chromatography. Mp .: 64-66 ° C (hexane / ethyl acetate). IR (KBr): ν (cm − 1): 1622 (C = O); 1088 (S-CH3).
Preparación de 3-(p-metiltiobenzoil)tiofeno (17). El compuesto del título se preparó a partir de cloruro del ácido 2-tiofeno carboxílico en 65% de rendimiento después de purificación por cromatografía en columna. Pf.: 65-68ºC (hexano/acetato de etilo). IR (KBr): ν (cm−1): 1645 (C=O); 1100 (S-CH3). Preparation of 3- (p-methylthiobenzoyl) thiophene (17). The title compound was prepared from 2-thiophene carboxylic acid chloride in 65% yield after purification by column chromatography. Mp .: 65-68 ° C (hexane / ethyl acetate). IR (KBr): ν (cm − 1): 1645 (C = O); 1100 (S-CH3).
Preparación de 4-bromo-4’-(metiltio)benzofenona (18). El compuesto del título se obtuvo a partir de cloruro de 4bromobenzoilo y metiltiobenzeno como se describe anteriormente como un polvo blanco en 85% de rendimiento. Pf.: 143-145ºC (hexano/acetato de etilo). IR (KBr), ν (cm−1): 1634 (C=O); 767 (C-Br). Preparation of 4-bromo-4 ’- (methylthio) benzophenone (18). The title compound was obtained from 4-bromobenzoyl chloride and methylthiobenzene as described above as a white powder in 85% yield. Mp .: 143-145 ° C (hexane / ethyl acetate). IR (KBr), ν (cm − 1): 1634 (C = O); 767 (C-Br).
Preparación de 4-fluoro-4’-(metiltio)benzofenona (19). El compuesto del título se obtuvo a partir de cloruro de 4-fluorobenzoilo (500 mg, 3.15 mmol) y de metiltiobenzeno (3.78 mmol) como se describe previamente, como un polvo blanco en 34% de rendimiento (260 mg, 1.05). Pf.: 94-97ºC (hexano/acetato de etilo). IR (KBr), ν (cm−1): 1717 (C=O); 1595 (C=); 1221 (Ar-S); 1089 (C-S); 754 (C-F). Preparation of 4-fl uoro-4 ’- (methylthio) benzophenone (19). The title compound was obtained from 4-fluorobenzoyl chloride (500 mg, 3.15 mmol) and methylthiobenzene (3.78 mmol) as previously described, as a white powder in 34% yield (260 mg, 1.05). Mp .: 94-97 ° C (hexane / ethyl acetate). IR (KBr), ν (cm − 1): 1717 (C = O); 1595 (C =); 1221 (Ar-S); 1089 (C-S); 754 (C-F).
Método general para la oxidación de metiltioderivados a sulfonas. A una solución de metiltio derivado (100 mg, General method for the oxidation of methylthioderivatives to sulfones. To a solution of methylthio derivative (100 mg,
0.34 mmol) en 25 mL de diclorometano seco enfriado a 0ºC se añadió lentamente m-CPBA (129 mg, 0.75 mmol). La mezcla de reacción se agitó a temperatura ambiente 4 h. Después la mezcla se trató con una solución de NaOH 2N (3x25 mL), la fase orgánica se separó y se secó sobre sulfato sódico anhidro, se filtró, y el disolvente se eliminó por evaporación. El residuo se purificó entonces por cromatografía de columna de gel de sílice, eluyendo con mezcla 7: 3 hexano/acetato de etilo. 0.34 mmol) in 25 mL of dry dichloromethane cooled to 0 ° C m-CPBA (129 mg, 0.75 mmol) was added slowly. The reaction mixture was stirred at room temperature 4 h. After the mixture was treated with a solution of 2N NaOH (3x25 mL), the organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the solvent was removed by evaporation. The residue was then purified by silica gel column chromatography, eluting with 7: 3 hexane / ethyl acetate mixture.
Preparación de 2-(p-metilsulfonilbenzoil)furano (9). A partir del metiltio derivado correspondiente (218.27 mg, 1 mmol) y siguiendo el método general descrito arriba, el compuesto del título se obtuvo (207.1 mg, 0.95 mmol) como un polvo blanco en 95% de rendimiento. Pf.: 96-98ºC (hexano/acetato de etilo). IR (KBr), ν (cm−1): 1642 (CO); 1434 (SO2); 1278 (Ar-S); 1099 (C-O). Preparation of 2- (p-methylsulfonylbenzoyl) furan (9). From the corresponding methylthio derivative (218.27 mg, 1 mmol) and following the general method described above, the title compound was obtained (207.1 mg, 0.95 mmol) as a white powder in 95% yield. Mp .: 96-98 ° C (hexane / ethyl acetate). IR (KBr), ν (cm − 1): 1642 (CO); 1434 (SO2); 1278 (Ar-S); 1099 (C-O).
Preparación de 3-(p-metilsulfonilbenzoil)furano (10). A partir del metiltio derivado correspondiente (220 mg, 0.87 mmol) y siguiendo el método general descrito arriba, el compuesto del título se obtuvo (148 mg, 0.59 mmol) como un polvo blanco en 95% de rendimiento. Pf.: 125-127ºC (hexano/acetato de etilo). IR (KBr), ν (cm−1): 1643 (CO); 1562 (C=C); 1443 (SO2); 1234 (Ar-S); 1108 (C-O). Preparation of 3- (p-methylsulfonylbenzoyl) furan (10). From the corresponding derivative methylthio (220 mg, 0.87 mmol) and following the general method described above, the title compound was obtained (148 mg, 0.59 mmol) as a white powder in 95% yield. Mp .: 125-127 ° C (hexane / ethyl acetate). IR (KBr), ν (cm − 1): 1643 (CO); 1562 (C = C); 1443 (SO2); 1234 (Ar-S); 1108 (C-O).
Preparación de N-metil-3-(p-metilsulfonilbenzoil)indol (11). Preparado a partir del correspondiente metiltio derivado (281 mg, 1 mmol) y siguiendo el método general descrito arriba. El compuesto del título se obtuvo como un polvo blanco (261.33 mg, 0.93 mmol) en 93% de rendimiento. Pf.: 203-205ºC (hexano/acetato de etilo). IR (KBr), ν (cm−1): 1562 (C=C); 1425 (SO2); 1212 (Ar-O); 1108 (C-O); 1047 (S=O). Preparation of N-methyl-3- (p-methylsulfonylbenzoyl) indole (11). Prepared from the corresponding methylthio derivative (281 mg, 1 mmol) and following the general method described above. The title compound was obtained as a white powder (261.33 mg, 0.93 mmol) in 93% yield. Mp .: 203-205 ° C (hexane / ethyl acetate). IR (KBr), ν (cm − 1): 1562 (C = C); 1425 (SO2); 1212 (Ar-O); 1108 (C-O); 1047 (S = O).
Preparación de N-(2-fluorofenil)-2-(p-metilsulfonilbenzoil)pirrol (12). A partir del correspondiente metiltio derivado (138 mg, 0.588 mmol) y siguiendo el método general descrito anteriormente, el compuesto del título se obtuvo (84 mg, 0.25 mmol) como un polvo blanco en 41% de rendimiento. IR (KBr), ν (cm−1): 1658 (CO); 1465 (SO2); 1243 (Ar-S); 1102 (SO2). Preparation of N- (2- fl uorophenyl) -2- (p-methylsulfonylbenzoyl) pyrrole (12). From the corresponding methylthio derivative (138 mg, 0.588 mmol) and following the general method described above, the title compound was obtained (84 mg, 0.25 mmol) as a white powder in 41% yield. IR (KBr), ν (cm − 1): 1658 (CO); 1465 (SO2); 1243 (Ar-S); 1102 (SO2).
Preparación de N-(2-fluorofenil)-3-(p-metilsulfonilbenzoil)pirrol (13). A partir del correspondiente metiltio derivado (311 mg, 1 mmol) y siguiendo el método general descrito arriba, el compuesto del título se obtuvo (286 mg, 0.92 mmol) como un polvo blanco en 92% de rendimiento. Pf.: 134-136ºC (hexano/acetato de etilo). IR (KBr), ν (cm−1): 1632 (CO); 1402 (SO2); 1283 (Ar-S); 1153 (SO2). Preparation of N- (2- fl uorophenyl) -3- (p-methylsulfonylbenzoyl) pyrrole (13). From the corresponding methylthio derivative (311 mg, 1 mmol) and following the general method described above, the title compound was obtained (286 mg, 0.92 mmol) as a white powder in 92% yield. Mp .: 134-136 ° C (hexane / ethyl acetate). IR (KBr), ν (cm − 1): 1632 (CO); 1402 (SO2); 1283 (Ar-S); 1153 (SO2).
Preparación de 3-(p-metilsulfonilbenzoil)indol (14). A partir del correspondiente metiltio derivado (100 mg, 0.34 mmol) y siguiendo el método general descrito arriba, el compuesto del título se obtuvo (16 mg, 0.05 mmol) como un polvo blanco en 14% de rendimiento. Pf.: 217-219ºC (hexano/acetato de etilo). IR (KBr), ν (cm−1): 3300 (NH); 1681 (CO); 1445 (SO2); 1271 (Ar-S); 1147 (C-S). Preparation of 3- (p-methylsulfonylbenzoyl) indole (14). From the corresponding methylthio derivative (100 mg, 0.34 mmol) and following the general method described above, the title compound was obtained (16 mg, 0.05 mmol) as a white powder in 14% yield. Mp .: 217-219 ° C (hexane / ethyl acetate). IR (KBr), ν (cm − 1): 3300 (NH); 1681 (CO); 1445 (SO2); 1271 (Ar-S); 1147 (C-S).
Preparación de 2-(p-metillsulfonilbenzoil)tiofeno (20). A partir del metiltio derivado correspondiente (120 mg, Preparation of 2- (p-methylsulfonylbenzoyl) thiophene (20). From the corresponding derivative methylthio (120 mg,
0.51 mmol) y siguiendo el método general descrito arriba, el compuesto del título se obtuvo (100 mg, 0.37 mmol) como un polvo blanco en 73% de rendimiento. Pf.: 136-138ºC (hexano/acetato de etilo). IR (KBr), ν (cm−1): 1636 (CO); 1413 (SO2); 1286 (Ar-S); 1154 (SO2). 0.51 mmol) and following the general method described above, the title compound was obtained (100 mg, 0.37 mmol) as a white powder in 73% yield. Mp .: 136-138 ° C (hexane / ethyl acetate). IR (KBr), ν (cm − 1): 1636 (CO); 1413 (SO2); 1286 (Ar-S); 1154 (SO2).
Preparación de 3-(p-metilsulfonilbenzoil)tiofeno (21). A partir del correspondiente metiltio derivado (240 mg, 1.02 mmol) y siguiendo el método general descrito arriba, el compuesto del título se obtuvo (208 mg, 075 mmol) como un polvo blanco en 74% de rendimiento. Pf.: 122-124ºC (hexano/acetato de etilo). IR (KBr), ν (cm−1): 1665 (CO); 1424 (SO2); 1212 (Ar-S); 1134 (SO2). Preparation of 3- (p-methylsulfonylbenzoyl) thiophene (21). From the corresponding methylthio derivative (240 mg, 1.02 mmol) and following the general method described above, the title compound was obtained (208 mg, 075 mmol) as a white powder in 74% yield. Mp .: 122-124 ° C (hexane / ethyl acetate). IR (KBr), ν (cm − 1): 1665 (CO); 1424 (SO2); 1212 (Ar-S); 1134 (SO2).
Preparación de 4-bromo-4’-(metilsulfonil)benzofenona (22). A partir del metilito correspondiente (300 mg, 0.97 mmol) y siguiendo el método general descrito arriba, el compuesto del título (296 mg, 0.87 mmol) se obtuvo como un polvo en 90% de rendimiento. Pf.: 186-188ºC (hexano/acetato de etilo). IR (KBr), ν (cm−1): 1649 (C=O); 1316 (SO2); 756 (C-Br). Preparation of 4-bromo-4 ’- (methylsulfonyl) benzophenone (22). From the corresponding methylite (300 mg, 0.97 mmol) and following the general method described above, the title compound (296 mg, 0.87 mmol) was obtained as a powder in 90% yield. Mp .: 186-188 ° C (hexane / ethyl acetate). IR (KBr), ν (cm − 1): 1649 (C = O); 1316 (SO2); 756 (C-Br).
Preparación de 4-fluoro-4’-(metilsulfonil)benzofenona (23). A partir del correspondiente metiltio (216 mg, 0.87 mmol) y siguiendo el método general descrito arriba, el compuesto del título (242 mg, 0.87 mmol) se obtuvo como un polvo blanco en 100% de rendimiento. Pf.: 120-123ºC (hexano/acetato de etilo). IR (KBr), ν (cm−1): 1716 (C=O); 1271 (SO2); 1270 (Ar-S); 1152 (C-S); 754 (Ar-F). Preparation of 4-fl uoro-4 ’- (methylsulfonyl) benzophenone (23). From the corresponding methylthio (216 mg, 0.87 mmol) and following the general method described above, the title compound (242 mg, 0.87 mmol) was obtained as a white powder in 100% yield. Mp .: 120-123 ° C (hexane / ethyl acetate). IR (KBr), ν (cm − 1): 1716 (C = O); 1271 (SO2); 1270 (Ar-S); 1152 (C-S); 754 (Ar-F).
Método general para obtener diarilcompuestos. Una suspensión de bromoarilo (2.46 mmol), bromopiridina (387 mg, 2.46 mmol), Cu (134 mg, 3.69 mmol), y K2CO3 anhidro (509 mg, 3.69 mmol) sin disolvente en un tubo de Schlenk se calentó a 300ºC 8 h. En este momento, la mezcla de reacción se puso en 25 mL de agua y se extrajo con éter (3x30 mL). La fase orgánica se secó y se evaporó al vacío para dar aceite incoloro. El residuo se purificó por cromatografía de columna de gel de sílice, eluyendo con 8:2 hexano/acetato de etilo. General method to obtain diaryl compounds. A suspension of bromoaryl (2.46 mmol), bromopyridine (387 mg, 2.46 mmol), Cu (134 mg, 3.69 mmol), and anhydrous K2CO3 (509 mg, 3.69 mmol) without solvent in a Schlenk tube was heated at 300 ° C for 8 h . At this time, the reaction mixture was placed in 25 mL of water and extracted with ether (3x30 mL). The organic phase was dried and evaporated in vacuo to give colorless oil. The residue was purified by silica gel column chromatography, eluting with 8: 2 hexane / ethyl acetate.
Preparación de 2-(p-metiltiofenil)piridina (25). A partir de (500 mg, 2.46 mmol) de 4-bromotioanisol y siguiendo el método general descrito anteriormente, el compuesto del título se obtuvo como un sólido blanco (50 mg, 0.25 mmol) en 10% de rendimiento. Pf.: 55-57ºC (hexano/acetato de etilo). IR (KBr), ν (cm−1): 1584 (C=C); 1463 (C=C), 843 C-S). Preparation of 2- (p-methylthiophenyl) pyridine (25). From (500 mg, 2.46 mmol) of 4-bromothioanisole and following the general method described above, the title compound was obtained as a white solid (50 mg, 0.25 mmol) in 10% yield. Mp .: 55-57 ° C (hexane / ethyl acetate). IR (KBr), ν (cm − 1): 1584 (C = C); 1463 (C = C), 843 C-S).
Preparación de 2-(p-metilsulfonilfenil)piridina (26). A partir de (50 mg, 0.25 mmol) del correspondiente metilito y siguiendo el método general descrito anteriormente, el compuesto del título se obtuvo como un sólido blanco (35 mg, 0.15 mmol) en 60% de rendimiento. Pf.: 86-88ºC (hexano/acetato de etilo). IR (KBr), ν (cm−1): 1300 (SO2); 1152 (S-O). Preparation of 2- (p-methylsulfonylphenyl) pyridine (26). From (50 mg, 0.25 mmol) of the corresponding methylite and following the general method described above, the title compound was obtained as a white solid (35 mg, 0.15 mmol) in 60% yield. Mp .: 86-88 ° C (hexane / ethyl acetate). IR (KBr), ν (cm − 1): 1300 (SO2); 1152 (S-O).
Preparación de N-arlanilinas 30, 32-33. La preparación de las arilanilinas 30, 32-33 se ha descrito previamente por los inventores (ver M. Romero y al., “Preparation of N-arylpiperazines and other N-aryl compounds from aryl bromides as scaffolds of bioactive compounds”, Tetrahedron 2006, vol. 62, pp. 9010-9016). Preparation of N-arlanilines 30, 32-33. The preparation of arylanilines 30, 32-33 has been previously described by the inventors (see M. Romero et al., "Preparation of N-arylpiperazines and other N-aryl compounds from aryl bromides as scaffolds of bioactive compounds", Tetrahedron 2006 , vol. 62, pp. 9010-9016).
Ensayo de actividad antiinflamatoria In vivo. El ensayo de edema inducido en la pata de rata por la carragenina se llevó a cabo usando el método de Winter modificado, como ensayo preliminar de selección (“screening”). Las ratas (en grupos de seis animales de peso 160-200 g, adulto joven macho Sprague-Dawley) en ayuno de 24 h antes de que el compuesto (70 mg/Kg po) se administre. Los compuestos se administraron oralmente 1 hora antes de la carragenina. El edema en pata de rata se indujo por inyección suplantar de 0.1 mL de una solución 1% de carragenina en una solución de NaCl 0.9% estéril y libre de pirógenos y el volumen de la pata se midió por desplazamiento de agua en un pletismómetro S-5128, Ugo Basile. Tres y cuatro horas después de la inyección de carragenina, el volumen de la pata se volvió a medir. Todos los análisis estadísticos se procesaron por ordenador. La media de algunos tratamientos significativamente menor que la media del control fue indicativa de actividad antiinflamatoria significativa. El volumen del edema de pata de rata de animales tratados se comparó con animales que recibieron ibuprofeno para comparar la potencia relativa. No se observaron síntomas tóxicos después de la administración oral de 70 mg/Kg en los animales del ensayo. In vivo anti-inflammatory activity test. The carragenin-induced rat edema test was carried out using the modified Winter method, as a preliminary screening test. Rats (in groups of six animals weighing 160-200 g, young adult male Sprague-Dawley) fasting 24 h before the compound (70 mg / kg po) is administered. The compounds were administered orally 1 hour before carrageenan. Rat leg edema was induced by supplant injection of 0.1 mL of a 1% carrageenan solution in a sterile 0.9% NaCl solution free of pyrogens and the leg volume was measured by displacement of water on an S-plethysmometer 5128, Ugo Basile. Three and four hours after the carrageenan injection, the leg volume was measured again. All statistical analyzes were processed by computer. The mean of some treatments significantly less than the mean of the control was indicative of significant anti-inflammatory activity. The volume of rat leg edema of treated animals was compared with animals that received ibuprofen to compare the relative potency. No toxic symptoms were observed after oral administration of 70 mg / kg in the test animals.
La actividad terapéutica de estos compuestos se evaluó como actividad antiinflamatoria usando el ensayo de edema inducido de pata de rata descrito arriba. Los compuestos fueron ensayados por dos veces a 70 mg/Kg po y comparados con compuestos estándar como el ibuprofeno. La comparación de resultados está recogida en la Tabla 1. La comparación de los resultados de la tabla revela que los compuestos 20, 26, 33, 9 y 30 mostraron actividad antiinflamatoria significativa durante más tiempo que el ibuprofeno. Mientras que el ibuprofeno redujo considerablemente la actividad antiinflamatoria después de cuatro horas post-carragenina, los compuestos 20, 26 y 33 prácticamente no mostraron cambios de actividad entre cuatro y cinco horas después de la administración del producto. The therapeutic activity of these compounds was evaluated as an anti-inflammatory activity using the rat leg induced edema test described above. The compounds were tested twice at 70 mg / kg po and compared with standard compounds such as ibuprofen. The comparison of results is shown in Table 1. The comparison of the results in the table reveals that compounds 20, 26, 33, 9 and 30 showed significant anti-inflammatory activity for longer than ibuprofen. While ibuprofen significantly reduced anti-inflammatory activity after four hours post-carrageenan, compounds 20, 26 and 33 showed virtually no activity changes between four and five hours after product administration.
TABLA 1 TABLE 1
Resultados de actividad antiinflamatoria in vivo (edema inducido por carragenina) Results of anti-inflammatory activity in vivo (carrageenan-induced edema)
a) Hinchazón a la dosis de 70 mg/kg. b) Hinchazón control. NA = no actividad, atribuible a la baja solubilidad en agua. Valores que difieren significativamente del control como se indica: *P<0,05; **P<0,01; ***P<0,001; # no varían significativamente según la t de Student. a) Swelling at the dose of 70 mg / kg. b) Control swelling. NA = no activity, attributable to low water solubility. Values that differ significantly from the control as indicated: * P <0.05; ** P <0.01; *** P <0.001; # do not vary significantly according to Student's t.
Los resultados se presentan como media ± S.E.M. de 6 animales (p<0.05). El edema de la pata se produce a las 3 y 4 h después de la administración de carragenina. The results are presented as mean ± S.E.M. of 6 animals (p <0.05). The edema of the leg occurs at 3 and 4 h after the administration of carrageenan.
Actividad antitumoral. Líneas celulares y cultivos celulares. Una línea celular de cáncer de pulmón de células no pequeñas, NCI-H460, y una línea celular de cáncer de colon humano, HT-29, que constitutivamente expresa COX-2, se cultivaron en medio MEM (SIGMA-Aldrich, cat.#M4655) completado con 10% FBS, 100 U/mL de penicilina, 100 μg/mL de estreptomicina y 0.25 μg/mL de amfotericinaBa37ºC en 5% CO2. Antitumor activity. Cell lines and cell cultures. A non-small cell lung cancer cell line, NCI-H460, and a human colon cancer cell line, HT-29, constitutively expressing COX-2, were grown in MEM medium (SIGMA-Aldrich, cat. # M4655) completed with 10% FBS, 100 U / mL penicillin, 100 µg / mL streptomycin and 0.25 µg / mL amphotericin Ba37 ° C in 5% CO2.
Ensayo de proliferación. El ensayo de bromuro de 3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazolio (MTT) se usó para determinar la viabilidad celular de líneas celulares de NCI-H460 y de HT-29. MTT es una sal de tetrazolio amarilla que se acepta e hidrolizada sólo por células metabolitamente activas, que lo reducen a una coloreada sal de formazan insoluble en agua. El producto formazan disuelto se cuantificó por absorbancia a 570 nm (690 nm para blanco), que se valoró usando un formato de 96 pocillos en espectro-fotómetro (ELx-800-BioTek instruments). La absorbancia correlaciona directamente con el número de células. Las células se sembraron a 2.0 x 104 células/pocillo en 100 μL de volumen en 96-pocillos y crecieron en 72 h en medio completo MEM. Diferentes concentraciones de los compuestos o DMSO 0.1% se añadieron a los pocillos. Entonces, las células se incubaron con 10 μL de MTT (5 mg/mL) a 37ºC 3 h. Los cristales de tetrazolio se solubilizaron por la adición de 4.5 mL de isopropilo alcohol-0.5 mL tritón X-100 en 150 μL de HCl 37%. Proliferation test The 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium (MTT) bromide assay was used to determine the cell viability of NCI-H460 and HT-29 cell lines. MTT is a yellow tetrazolium salt that is accepted and hydrolyzed only by metabolically active cells, which reduce it to a colored salt of water-insoluble formazan. The dissolved formazan product was quantified by absorbance at 570 nm (690 nm for white), which was titrated using a 96-well spectrum-photometer format (ELx-800-BioTek instruments). The absorbance correlates directly with the number of cells. Cells were seeded at 2.0 x 104 cells / well in 100 µL volume in 96-wells and grown in 72 h in complete MEM medium. Different concentrations of the compounds or 0.1% DMSO were added to the wells. Then, the cells were incubated with 10 μL of MTT (5 mg / mL) at 37 ° C 3 h. Tetrazolium crystals were solubilized by the addition of 4.5 mL of isopropyl alcohol-0.5 mL triton X-100 in 150 µL of 37% HCl.
Efecto de los compuestos ensayados en la viabilidad celular. Los compuestos 9-13, 20-22, 30, 32-33 se evaluaron por sus actividades antiproliferativas contra NCI-H460 (carcinoma humano de pulmón de células no pequeñas) y HT29 (línea celular de cáncer humano de colon). El tratamiento de NCI-H460 células con el pirrol derivado 13 a la concentración de 10 μM produjo una buena disminución en la viabilidad celular de 54.8±0.70%. También se detectó que el tratamiento con 10 μM de otros compuestos no tuvo efecto citotóxico, mientras que el tratamiento con 100 μM de 12, 22, 30 y 33 mostró citotoxicidad con una media de inhibición de crecimiento de 22.0, 20.3, 43.2, y 27.3% respectivamente (Tabla 2). Effect of the compounds tested on cell viability. Compounds 9-13, 20-22, 30, 32-33 were evaluated for their antiproliferative activities against NCI-H460 (human non-small cell lung carcinoma) and HT29 (human colon cancer cell line). Treatment of NCI-H460 cells with the pyrrole derivative 13 at the concentration of 10 μM produced a good decrease in cell viability of 54.8 ± 0.70%. It was also found that treatment with 10 μM of other compounds had no cytotoxic effect, while treatment with 100 μM of 12, 22, 30 and 33 showed cytotoxicity with a mean growth inhibition of 22.0, 20.3, 43.2, and 27.3 % respectively (Table 2).
TABLA 2 TABLE 2
Resultados de viabilidad celular de NCI-H460 NCI-H460 cell viability results
Se muestra la viabilidad celular de NCI-H460 después del tratamiento con 10 ó 100 μM de 9-13, 20-22, 29-33. Los valores se presentan como [control (DMSO)-tratado]/control (DMSO) y se expresan como valores medios de 2 experimentos separados repetidos cuatro veces, n.t. (no ensayado). The cell viability of NCI-H460 is shown after treatment with 10 or 100 μM of 9-13, 20-22, 29-33. The values are presented as [control (DMSO) -treated] / control (DMSO) and are expressed as mean values of 2 separate experiments repeated four times, n.t. (not tested).
El tratamiento de HT-29 a la concentración 10 μM de compuestos 9-13, 20-22, 29-33 no mostró efecto significantivo en la viabilidad celular. Mientras que el tratamiento a 50 μM produjo una disminución de la viabilidad celular (Tabla 3). El compuesto 12 inhibió significativamente in vitro la proliferación celular en líneas celulares de cáncer de colon (HT-29). También 31, 11, 21 y 33 mostraron efectos inhibitorios del crecimiento tumoral. Treatment of HT-29 at the 10 μM concentration of compounds 9-13, 20-22, 29-33 showed no significant effect on cell viability. While the treatment at 50 μM produced a decrease in cell viability (Table 3). Compound 12 significantly inhibited in vitro cell proliferation in colon cancer cell lines (HT-29). Also 31, 11, 21 and 33 showed inhibitory effects of tumor growth.
TABLA 3 TABLE 3
Resultados de viabilidad celular de HT-29 HT-29 cell viability results
Los valores IC50 se expresan como promedio de 2 experimentos separados repetidos cuatro veces. IC50 values are expressed as the average of 2 separate experiments repeated four times.
Claims (13)
- 2. 2.
- Uso según la reivindicación 1, donde -X-es -CO-. Use according to claim 1, wherein -X-is -CO-.
- 3. 3.
- Uso según la reivindicación 2, donde -Ar se selecciona del grupo que consiste en: fenilo y fenilo 2-y 3-mono-sustituido, donde el sustituyente es F, Cl, Br o I; furan-3-ilo y tiofen-3-ilo; pirrol-1-ilo, pirrol-2-ilo, N-(2-fluorofenil)pirrol-2-ilo, N-(3-fluorofenilo)pirrol-2-ilo, pirrol-3-ilo, N-(2-fluorofenil) Use according to claim 2, wherein -Ar is selected from the group consisting of: 2-and 3-mono-substituted phenyl and phenyl, where the substituent is F, Cl, Br or I; furan-3-yl and thiophene-3-yl; pyrrol-1-yl, pyrrole-2-yl, N- (2- fl uorophenyl) pyrrol-2-yl, N- (3- fl uorophenyl) pyrrol-2-yl, pyrrole-3-yl, N- (2- fl uorophenyl )
- 4. Four.
- Uso según la reivindicación 1, donde -X-es un enlace sencillo. Use according to claim 1, wherein -X- is a single link.
- 5. 5.
- Uso según la reivindicación 4, donde -Ar se selecciona del grupo que consiste en: fenilo y fenilo 2-, 3-y 4-mono-sustituido, donde el sustituyente es F, Cl, Br o I; furan-2-ilo, furan-3-ilo, tiofen-2-ilo y tiofen-3-ilo; pirrol-1-ilo, pirrol-2-ilo, N-(2-fluorofenil)pirrol-2-ilo, N-(3-fluorofenil)pirrol-2-ilo, pirrol-3-ilo, N-(2-fluorofenilo) Use according to claim 4, wherein -Ar is selected from the group consisting of: 2-, 3- and 4-mono-substituted phenyl and phenyl, where the substituent is F, Cl, Br or I; furan-2-yl, furan-3-yl, thiophene-2-yl and thiophene-3-yl; pyrrol-1-yl, pyrrol-2-yl, N- (2- fl uorophenyl) pyrrol-2-yl, N- (3- fl uorophenyl) pyrrol-2-yl, pyrrole-3-yl, N- (2- fl uorophenyl )
- 6. 6.
- Uso según cualquiera de las reivindicaciones 1-5, para la preparación de un medicamento para el tratamiento y/o la prevención de la inflamación. Use according to any of claims 1-5, for the preparation of a medicament for the treatment and / or prevention of inflammation.
- 7. 7.
- Uso según cualquiera de las reivindicaciones 1-5, para la preparación de un medicamento para el tratamiento y/o la prevención del cáncer. Use according to any of claims 1-5, for the preparation of a medicament for the treatment and / or prevention of cancer.
- 9. 9.
- Compuesto según la reivindicación 8, donde -X-es -CO-. Compound according to claim 8, wherein -X-is -CO-.
- 10. 10.
- Compuesto según reivindicación 8, donde -X-es un enlace sencillo. Compound according to claim 8, wherein -X- is a single bond.
- 11. eleven.
- Compuesto según la reivindicación 8, donde -Ar se selecciona del grupo que consiste en: fenilo y fenilo 2-y 3-mono-sustituido, donde el sustituyente es F, Cl, Br o I; furan-3-ilo y tiofen-3-ilo; pirrol-2-ilo, N-(2-fluorofenil)pirrol-2-ilo, N-(3-fluorofenil)pirrol-2-ilo, pirrol-3-ilo, N-(2-fluorofenil)pirrol-3-ilo y Compound according to claim 8, wherein -Ar is selected from the group consisting of: 2-and 3-mono-substituted phenyl and phenyl, where the substituent is F, Cl, Br or I; furan-3-yl and thiophene-3-yl; pyrrol-2-yl, N- (2- fl uorophenyl) pyrrol-2-yl, N- (3- fl uorophenyl) pyrrol-2-yl, pyrrole-3-yl, N- (2- fl uorophenyl) pyrrole-3-yl Y
- Categoría Category
- Documentos citados Reivindicaciones afectadas Documents cited Claims Affected
- X X
- ZARGHI et al.: "Design and synthesis of some 5-substituted-2-(4-azido or methylsulfonyl) phenyl)1 H-indole derivatives as selective cyclooxygenase (COX-2)inhibitors". Sci. Pharm.2008, vol. 76, páginas 361-376, página 364, fórmula 4a, tabla1. 1-12 ZARGHI et al .: "Design and synthesis of some 5-substituted-2- (4-azido or methylsulfonyl) phenyl) 1 H-indole derivatives as selective cyclooxygenase (COX-2) inhibitors". Sci. Pharm. 2008, vol. 76, pages 361-376, page 364, formula 4a, table 1. 1-12
- X X
- KHANNA, I.K. et al.: "1,2 diarylpirroles as potent and selective inhibitors of cyclooxygenase-2". J. Med. Chem. 1997, vol. 40, páginas 1619-1633, página 1620, fórmula 4. tabla 1. 1-12 KHANNA, I.K. et al .: "1,2 diarylpirroles as potent and selective inhibitors of cyclooxygenase-2". J. Med. Chem. 1997, vol. 40, pages 1619-1633, page 1620, formula 4. table 1. 1-12
- X X
- EP 0799823 A1 (SANKYO COMPANY LIMITED) 08.10.1997, tabla 1, página 12, compuesto 1-3. 1-12 EP 0799823 A1 (SANKYO COMPANY LIMITED) 08.10.1997, table 1, page 12, compound 1-3. 1-12
- X X
- PRASANNA, A.D. et al.: "A CoMFA study of COX-2 inhibitors with receptor based alignement.". Journal of Molecular Graphics and Modeling, 2004, vol. 23, páginas 239-251, página 241, compuesto 29, página 240. 1-12 PRASANNA, A.D. et al .: "A CoMFA study of COX-2 inhibitors with receptor based alignement.". Journal of Molecular Graphics and Modeling, 2004, vol. 23, pages 239-251, page 241, compound 29, page 240. 1-12
- Categoría de los documentos citados X: de particular relevancia Y: de particular relevancia combinado con otro/s de la misma categoría A: refleja el estado de la técnica O: referido a divulgación no escrita P: publicado entre la fecha de prioridad y la de presentación de la solicitud E: documento anterior, pero publicado después de la fecha de presentación de la solicitud Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application
- El presente informe ha sido realizado • para todas las reivindicaciones • para las reivindicaciones nº: This report has been prepared • for all claims • for claims no:
- Fecha de realización del informe 08.11.2011 Date of realization of the report 08.11.2011
- Examinador H. Aylagas Cancio Página 1/4 Examiner H. Aylagas Cancio Page 1/4
- Novedad (Art. 6.1 LP 11/1986) Novelty (Art. 6.1 LP 11/1986)
- Reivindicaciones Reivindicaciones 1-12 SI NO Claims Claims 1-12 IF NOT
- Actividad inventiva (Art. 8.1 LP11/1986) Inventive activity (Art. 8.1 LP11 / 1986)
- Reivindicaciones Reivindicaciones 1-12 SI NO Claims Claims 1-12 IF NOT
- Documento Document
- Número Publicación o Identificación Fecha Publicación Publication or Identification Number publication date
- D01 D01
- ZARGHI et al.: "Design and synthesis of some 5-substituted-2-(4azido or methylsulfonyl) phenyl)-1 H-indole derivatives as selective cyclooxygenase (COX-2)inhibitors". Sci. Pharm.2008, vol. 76, páginas 361-376, página 364, fórmula 4a, tabla1. ZARGHI et al .: "Design and synthesis of some 5-substituted-2- (4azido or methylsulfonyl) phenyl) -1 H-indole derivatives as selective cyclooxygenase (COX-2) inhibitors". Sci. Pharm. 2008, vol. 76, pages 361-376, page 364, formula 4a, table 1.
- D02 D02
- KHANNA, I.K. et al.: "1,2 diarylpirroles as potent and selective inhibitors of cyclooxygenase-2". J. Med. Chem. 1997, vol. 40, páginas 1619-1633, página 1620, fórmula 4. tabla 1. KHANNA, I.K. et al .: "1,2 diarylpirroles as potent and selective inhibitors of cyclooxygenase-2". J. Med. Chem. 1997, vol. 40, pages 1619-1633, page 1620, formula 4. table 1.
- D03 D03
- EP 0799823 A1 (SANKYO COMPANY LIMITED) 08.10.1997 EP 0799823 A1 (SANKYO COMPANY LIMITED) 08.10.1997
- D04 D04
- PRASANNA, A.D. et al.: "A CoMFA study of COX-2 inhibitors with receptor based alignement.". Journal of Molecular Graphics and Modeling, 2004, vol. 23, páginas 239-251, página 241, compuesto 29, página 240. PRASANNA, A.D. et al .: "A CoMFA study of COX-2 inhibitors with receptor based alignement.". Journal of Molecular Graphics and Modeling, 2004, vol. 23, pages 239-251, page 241, compound 29, page 240.
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