HRP980004A2 - Cyclic sulfone derivatives - Google Patents
Cyclic sulfone derivativesInfo
- Publication number
- HRP980004A2 HRP980004A2 HR60/034,535A HRP980004A HRP980004A2 HR P980004 A2 HRP980004 A2 HR P980004A2 HR P980004 A HRP980004 A HR P980004A HR P980004 A2 HRP980004 A2 HR P980004A2
- Authority
- HR
- Croatia
- Prior art keywords
- alkyl
- aryl
- alkoxy
- heteroaryl
- aryloxy
- Prior art date
Links
- -1 Cyclic sulfone Chemical class 0.000 title claims description 25
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 54
- 150000001875 compounds Chemical class 0.000 claims description 41
- 125000001072 heteroaryl group Chemical group 0.000 claims description 29
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 24
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 22
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 21
- 102000003390 tumor necrosis factor Human genes 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 230000005764 inhibitory process Effects 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 125000004104 aryloxy group Chemical group 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 241000124008 Mammalia Species 0.000 claims description 11
- 102000002274 Matrix Metalloproteinases Human genes 0.000 claims description 10
- 108010000684 Matrix Metalloproteinases Proteins 0.000 claims description 10
- 206010028980 Neoplasm Diseases 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 9
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 208000033809 Suppuration Diseases 0.000 claims description 7
- 206010003246 arthritis Diseases 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 239000011159 matrix material Substances 0.000 claims description 7
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 6
- 125000006719 (C6-C10) aryl (C1-C6) alkyl group Chemical group 0.000 claims description 6
- 206010040047 Sepsis Diseases 0.000 claims description 6
- 206010040070 Septic Shock Diseases 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 6
- 208000028169 periodontal disease Diseases 0.000 claims description 6
- 125000005936 piperidyl group Chemical group 0.000 claims description 6
- 230000036303 septic shock Effects 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 208000030507 AIDS Diseases 0.000 claims description 5
- 206010014989 Epidermolysis bullosa Diseases 0.000 claims description 5
- 102000035195 Peptidases Human genes 0.000 claims description 5
- 108091005804 Peptidases Proteins 0.000 claims description 5
- 208000034189 Sclerosis Diseases 0.000 claims description 5
- 125000004423 acyloxy group Chemical group 0.000 claims description 5
- 229940035676 analgesics Drugs 0.000 claims description 5
- 239000000730 antalgic agent Substances 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims description 5
- 235000019833 protease Nutrition 0.000 claims description 5
- 208000037803 restenosis Diseases 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 4
- 125000005110 aryl thio group Chemical group 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- LTVOKYUPTHZZQH-UHFFFAOYSA-N difluoromethane Chemical group F[C]F LTVOKYUPTHZZQH-UHFFFAOYSA-N 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 208000002780 macular degeneration Diseases 0.000 claims description 4
- 125000004442 acylamino group Chemical group 0.000 claims description 3
- 239000002254 cytotoxic agent Substances 0.000 claims description 3
- 229940127089 cytotoxic agent Drugs 0.000 claims description 3
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 125000006720 (C1-C6) alkyl (C6-C10) aryl group Chemical group 0.000 claims description 2
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 2
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims description 2
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 2
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 claims description 2
- 101100439663 Arabidopsis thaliana CHR7 gene Proteins 0.000 claims description 2
- 101100244083 Arabidopsis thaliana PKL gene Proteins 0.000 claims description 2
- 101100134929 Gallus gallus COR9 gene Proteins 0.000 claims description 2
- 125000005035 acylthio group Chemical group 0.000 claims description 2
- 150000003973 alkyl amines Chemical class 0.000 claims description 2
- 125000005332 alkyl sulfoxy group Chemical group 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000001769 aryl amino group Chemical group 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 231100000433 cytotoxic Toxicity 0.000 claims description 2
- 230000001472 cytotoxic effect Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000005241 heteroarylamino group Chemical group 0.000 claims description 2
- 125000005368 heteroarylthio group Chemical group 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 102000029816 Collagenase Human genes 0.000 description 17
- 108060005980 Collagenase Proteins 0.000 description 17
- 229960002424 collagenase Drugs 0.000 description 17
- 239000003112 inhibitor Substances 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- 238000002474 experimental method Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 239000000758 substrate Substances 0.000 description 10
- 102000004142 Trypsin Human genes 0.000 description 9
- 108090000631 Trypsin Proteins 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 239000012588 trypsin Substances 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 229940088598 enzyme Drugs 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 7
- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 7
- 239000003880 polar aprotic solvent Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000012131 assay buffer Substances 0.000 description 6
- 230000006433 tumor necrosis factor production Effects 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 229910004373 HOAc Inorganic materials 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 4
- FQVNCEFTUOXAGQ-UHFFFAOYSA-N 3-(4-methoxyphenyl)sulfonylprop-2-enoic acid Chemical compound COC1=CC=C(S(=O)(=O)C=CC(O)=O)C=C1 FQVNCEFTUOXAGQ-UHFFFAOYSA-N 0.000 description 4
- NCQJBPXXRXOIJD-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxycarbonylamino]-3-naphthalen-2-ylpropanoic acid Chemical compound C1=CC=CC2=CC(C(CC(O)=O)NC(=O)OC(C)(C)C)=CC=C21 NCQJBPXXRXOIJD-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 102000013382 Gelatinases Human genes 0.000 description 4
- 108010026132 Gelatinases Proteins 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- VKUYLANQOAKALN-UHFFFAOYSA-N 2-[benzyl-(4-methoxyphenyl)sulfonylamino]-n-hydroxy-4-methylpentanamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(C(CC(C)C)C(=O)NO)CC1=CC=CC=C1 VKUYLANQOAKALN-UHFFFAOYSA-N 0.000 description 3
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000012981 Hank's balanced salt solution Substances 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 102100030416 Stromelysin-1 Human genes 0.000 description 3
- 101710108790 Stromelysin-1 Proteins 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- JSRCVSZOQGQNOT-UHFFFAOYSA-N 2-iodo-3-(4-methoxyphenyl)sulfonylpropanoic acid Chemical compound COC1=CC=C(S(=O)(=O)CC(I)C(O)=O)C=C1 JSRCVSZOQGQNOT-UHFFFAOYSA-N 0.000 description 2
- ALRVJNLGCAMAAQ-UHFFFAOYSA-N 3-(4-phenoxyphenyl)sulfonyl-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid Chemical compound OC(=O)C1C(O2)CCC2C1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 ALRVJNLGCAMAAQ-UHFFFAOYSA-N 0.000 description 2
- OZTNSYFVIJCBNE-UHFFFAOYSA-N 3-(4-phenoxyphenyl)sulfonylprop-2-enoic acid Chemical compound C1=CC(S(=O)(=O)C=CC(=O)O)=CC=C1OC1=CC=CC=C1 OZTNSYFVIJCBNE-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 210000005087 mononuclear cell Anatomy 0.000 description 2
- XYEOALKITRFCJJ-UHFFFAOYSA-N o-benzylhydroxylamine Chemical compound NOCC1=CC=CC=C1 XYEOALKITRFCJJ-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- JZEDOEPVMYKFAB-UHFFFAOYSA-M sodium;4-methoxybenzenesulfinate Chemical compound [Na+].COC1=CC=C(S([O-])=O)C=C1 JZEDOEPVMYKFAB-UHFFFAOYSA-M 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 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 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 1
- NKBWMBRPILTCRD-UHFFFAOYSA-N 2-Methylheptanoic acid Chemical compound CCCCCC(C)C(O)=O NKBWMBRPILTCRD-UHFFFAOYSA-N 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- QLTBQPAFZUQVQM-UHFFFAOYSA-N 3-(4-methoxyphenyl)sulfonyl-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)C1C(C(O)=O)C2OC1C=C2 QLTBQPAFZUQVQM-UHFFFAOYSA-N 0.000 description 1
- YHCBOUDBLDPCOW-UHFFFAOYSA-N 3-(4-phenoxyphenyl)sulfonyl-n-phenylmethoxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide Chemical compound O1C2CCC1C(S(=O)(=O)C=1C=CC(OC=3C=CC=CC=3)=CC=1)C2C(=O)NOCC1=CC=CC=C1 YHCBOUDBLDPCOW-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
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Description
Stanje tehnike izuma
Ovaj izum se odnosi na ciklične derivate sulfona koji su inhibitori matričnih metaloproteinaza ili faktora nekroze tumora (TNF) i kao takvi su korisni u tretmanu stanja odabranog iz grupe koja sadrži artritis, rak, gnojenje tkiva, restenozu, peridontalno oboljenje, epidermolysis bullosa, sklerozu i druga oboljenja karakterizirana sa aktivnošću matrične metaloproteinaze, AIDS, sepsu, sepstički udar i druga oboljenja koja uključuju proizvodnju TNF. Nadalje, spojevi iz ovog izuma mogu se koristiti u kombiniranoj terapiji sa standardnim ne-steroidnim anti-upalnim lijekovima (u daljnjem tekstu "NSAID’S") i analegeticima za tretman artritisa sa citotoksičnim lijekovima takvim kao što su adriamicin, daunomicin, cis-platina, etopisid, taksol, taksoter i alkaloidi, takvi kao što je vincristin, u tretmanu raka.
Ovaj izum se također odnosi na postupak korištenja takvih spojeva u tretmanu gornjih oboljenja kod sisavaca, specijalno čovjeka, i na farmaceutske preparate korisne za to.
Ima više enzima koji izazivaju slom strukturnih proteina i koji su strukturno vezane metaloproteinaze. Metaloproteinaze razgrađivanja matrice, takve kao što su želatinaza, stromelsin i kolagenaza, uključene su u matricu razgrađivanja tkiva (npr. kolagen kolaps) i imaju za posljedicu mnoga patološka stanja koja uključuju abnormalno spojno tkivo i metabolizam matrice bazne membrane, takva kao što je artritis (npr. osteoartritis i reumatski artritis), gnojenje tkiva (npr. kornealno, epidermalno i želučano gnojenje), abnormalno liječenje rane, peridontalno oboljenje, oboljenje kosti (npr. Paget-ovo oboljenje i osteoporoza), metastaza tumora ili najezda, isto kao HIV-infekcija ("J. Leuk. Biol.", 52 (2), str. 244-248, (1992.)).
Za faktor nekroze tumora poznato je da je uključen kod mnogih infektivnih i autoimunih oboljenja (W. Fiers: "FEBS Letters", 285, 199, (1991.)). Dalje, pokazano je da je TNF glavni posrednik upalnog odziva viđenog kod sepse i sepstičkog šoka (C.E. Spooner i dr.: "Clinical Immunology and Immunopathology", 62, S11, (1992.)).
Kratki pregled izuma
Ovaj izum se odnosi na spoj formule
[image]
ili njegovu farmaceutski prihvatljivu sol, gdje isprekidana linija predstavlja opcionalnu dvostruku vezu;
n je 0, 1 ili 2;
X i Y su svaki nezavisno CR1, gdje je R1 vodik, (C1-C6) alkil opcionalno supstituiran sa (C1-C6) alkilamino,
(C1-C6) alkiltio, (C1-C6) alkoksi, trifluorometilom, (C6-C10) arilom, (C5-C9) heteroarilom, (C6-C10) arilaminom, (C6-C10) ariltio, (C6-C10) ariloksi, (C5-C9) heteroarilaminom, (C5-C9) heteroariltio, (C5-C9) heteroariloksi,
(C6-C10) aril (C6-C10) arilom, (C3-C6) cikloalkilom, hidroksi (C1-C6) alkilom, (C1-C6) alkil (hidroksimetilenom), piperazinilom, (C6-C10) aril (C1-C6) alkoksi, (C5-C9) heteroaril (C1-C6) alkoksi, (C1-C6) acilaminom,
(C1-C6) aciltio, (C1-C6) aciloksi, (C1-C6) alkilsulfinilom, (C6-C10) arilsulfinilom, (C1-C6) alkilsulfonilom,
(C6-C10) arilsulfonilom, aminom, (C1-C6) alkilaminom ili ((C1-C6) alkil)2 aminom; trifluorometil,
(C1-C6) alkil (difluorometilen), (C1C3) alkil (difluorometilen) (C1-C3) alkil, (C6-C10) aril, (C5-C9) heteroaril,
(C3-C6) cikloalkil, (C1-C6) alkil-(hidroksimetilen), R3 (C1-C6) alkil, gdje R3 je (C1-C6) acilpiperazino,
(C6-C10) arilpiperazino, (C5-C9) heteroarilpiperazino, (C1-C6) alkilpiperazino,
(C6-C10) aril (C1-C6) alkilpiperazino, (C5-C9) heteroaril (C1-C6) alkilpiperazino, morfolino, trimorfolino, piperidino, pilodino, piperidil, (C1-C6) alkilpiperidil, (C6-C10) arilpiperidil, (C5-C9) heteroarilpiperidil,
(C1-C6) alkilpiperidil (C1-C6) alkil, (C5-C9) heteroarilpiperidil (C1-C6) alkil ili (C1-C6) acilpiperidil;
ili grupu formule
[image]
gdje r je 0 ili 6;
D je hidroksi, (C1-C6) alkoksi, piperidil, (C1-C6) alkilpiperidil, (C6-C10) arilpiperidil, (C5-C9) heteroarilpiperidil, (C1-C6) acilpiperidil ili NR4R5, gdje su R4 i R5 svaki nezavisno odabrani iz grupe koja sadrži vodik, (C1-C6) alkil opcionalno supstituiran sa (C1-C6) alkilpiperidilom, (C6-C10) arilpiperidilom, (C5-C9) heteroarilpiperidilom,
(C6-C10) arilom, (C5-C9) heteroarilom, (C6-C10) aril (C6-C10) arilom ili (C3-C6) cikloalkilom; (C6-C10) aril,
(C5-C9) heteroaril, (C6-C10) aril (C6-C10) aril, (C3-C6) cikloalkil, R6 (C2-C6) alkil,
(C1-C5) alkil (CHR6) (C1-C6) alkil, gdje R6 je hidroksi, (C1-C6) aciloksi, (C1-C6) alkoksi, piperazino,
(C1-C6) acilamino, (C1-C6) alkiltio, (C6-C10) ariltio, (C1-C6) alkilsulfinil, (C6-C10) arilsulfinil,
(C1-C6) alkilsulfoksi, (C6-C10) arilsulfoksil, amino, (C1-C6) alkilamino, ((C1-C6) alkil)2 amino,
(C1-C6) acilpiperazino, (C1-C6) alkilpiperazino, (C6-C10) aril (C1-C6) alkilpiperazino,
(C5-C9) heteroaril (C1-C6) alkilpiperazino, morfolino, tiomorfolino, piperidino ili pirolidino; R7 (C1-C6) alkil, (C1-C5) alkil (CHR7) (C1-C6) alkil, gdje R7 je piperidil ili (C1-C6) alkilpiperidil; i CH (R8)COR9, gdje R8 je vodik, (C1-C6) alkil, (C6-C10) aril (C1-C6) alkil, (C5-C9) heteroaril (C1-C6) alkil, (C1-C6) alkiltio (C1-C6) alkil,
(C6-C10) ariltio (C1-C6) alkil, (C1-C6) alkilsulfinil (C1-C6) alkil, (C6-C10) arilsulfinil (C1-C6) alkil,
(C1-C6) alkilsulfonil (C1-C6) alkil, (C6-C10) arilsulfonil (C1-C6) alkil, hidroksi (C1-C6) alkil, amino (C1-C6) alkil, (C1-C6) alkilamino (C1-C6) alkil, ((C1-C6)alkilamino)2 (C1-C6) alkil, R10R11NCO (C1-C6) alkil ili
R10OCO (C1-C6) alkil, gdje su R10 i R11 svaki nezavisno odabrani iz grupe koja sadrži vodik, (C1-C6) alkil,
(C6-C10) aril (C1-C6) alkil i (C5-C9) heteroaril (C1-C6) alkil; i R9 je R12O ili R12R13N, gdje su R12i R13 svaki nezavisno odabrani iz grupe koja sadrži vodik, (C1-C6) alkil, (C6-C10) aril (C1-C6) alkil i
(C5-C9) heteroaril (C1-C6) alkil; i
Ar je (C1-C6) alkil, (C6-C10) aril, (C6-C10) ariloksi (C6-C10) aril, (C6-C10) aril (C6-C10) aril,
(C6-C10) aril (C6-C10) aril (C1-C6) alkil, (C6-C10) ariloksi (C5-C9) heteroaril, (C5-C9) heteroaril,
(C1-C6) alkil (C6-C10) aril, (C1-C6) alkoksi (C6-C10) aril, (C6-C10) aril (C1-C6) alkoksi (C6-C10) aril,
(C6-C10) aril (C1-C6) alkoksi (C1-C6) alkil, (C5-C9) heteroariloksi (C6-C10) aril, (C1-C6) alkil (C5-C9) heteroaril, (C1-C6) alkoksi (C5-C9) heteroaril, (C6-C10) aril (C1-C6) alkoksi (C5-C9) heteroaril,
(C5-C9) heteroariloksi (C5-C9) heteroaril, (C6-C10) ariloksi (C1-C6) alkil, (C5-C9) heteroariloksi (C1-C6) alkil,
(C1-C6) alkil (C6-C10) ariloksi (C6-C10) aril, (C1-C6) alkil (C5-C9) heteroariloksi (C6-C10) aril,
(C1-C6) alkil (C6-C10) ariloksi (C5-C9) heteroaril, (C1-C6) alkoksi (C6-C10) ariloksi (C6-C10) aril,
(C1-C6) alkoksi (C5-C9) heteroariloksi (C6-C10) aril ili (C1-C6) alkoksi (C6-C10) ariloksi (C5-C9) heteroaril, gdje je spomenuta aril grupa opcionalno supstituirana sa fluoro, kloro, bromo, (C1-C6) alkilom, (C1-C6) alkoksi ili perfluoro (C1-C3) alkilom.
Termin "alkil", kako je ovdje korišten, ako nije drugačije naznačeno, uključuje zasićene radikale monovalentnog ugljikovodika koji imaju normalne, račvaste ili ciklične dijelove ili njihove kombinacije.
Termin "alkoksi", kako je ovdje korišten, uključuje alkil-O grupe, gdje je termin "alkil" definiran gore.
Termin "aril", kako je ovdje korišten, ako nije drugačije naznačeno, uključuje organski radikal izveden od aromatičnog ugljikovodika sa uklanjanjem jednog vodika, takav kao što je fenil ili naftil, opcionalno supstituiran sa 1 do 3 supstituenta nezavisno odabranih iz grupe koja sadrži fluoro, kloro, ciano, nitro, trifluorometil, (C1-C6) alkoksi, (C6-C10) ariloksi, trifluorometoksi, difluorometoksi i (C1-C6) alkil.
Termin "heteroaril", kako je ovdje korišten, ako nije drugačije naznačeno, uključuje organski radikal izveden od aromatičnog heterocikličnog spoja sa uklanjanjem jednog vodika, takav kao što je piridil, furil, pirolil, tienil, izotiazolil, imidazolil, benzimidazolil, tetrazolil, pirazinil, pirimidil, hinolil, izohinolil, benzofuril, izobenzofuril, benzotienil, pirazolil, indolil, izoindolil, purinil, karbazolil, izoksazolil, tiazolil, oksazolil, benzitiazolil ili benzoksazolil, opcionalno supstituiran sa 1 do 2 supstituenta nezavisno odabranih iz grupe koja sadrži fluoro, kloro, trifluorometil, (C1-C6) alkoksi, (C6-C10) ariloksi, trifluorometoksi, difluorometoksi i (C1-C6) alkil.
Termin "acil", kako je ovdje korišten, ako nije drugačije naznačeno, uključuje radikal opće formule RCO, gdje R je alkil, alkoksi, aril, arilalkil ili arilalkiloksi, a termini "alkil" ili "aril" su definirani gore.
Termin "aciloksi", kako je ovdje korišten, uključuje acil-O grupe, gdje je termin "acil" definiran gore.
Poželjni spojevi formule I uključuju one gdje n je 2.
Drugi poželjni spojevi formule I uključuju one gdje su X i Y oba CR1, gdje je R1 vodik.
Drugi poželjni spojevi formule I uključuju one gdje Ar je (C1-C6) alkoksi (C6-C10) aril,
(C6-C10) aril (C1-C6) alkoksi (C6-C10) aril, 4-fluorofenoksi (C6-C10) aril, 4-fluorobenziloksi (C6-C10) aril ili
(C1-C6) alkil (C6-C10) ariloksi (C6-C10) aril.
Još poželjniji spojevi formule I uključuju one, gdje n je 2, X i Y su oba CR1, gdje je R1 vodik, a Ar je
(C1-C6) alkoksi (C6-C10) aril, (C6-C10) aril (C1-C6) alkoksi (C6-C10) aril, 4-fluorofenoksi (C6-C10) aril,
4-fluorobenziloksi (C6-C10) aril ili (C1-C6) alkil (C6-C10) ariloksi (C6-C10) aril.
Ovaj izum se odnosi također na farmaceutski preparat za: (a) tretman stanja izabranog iz grupe koja sadrži artritis, rak, sinergiju sa citotoksičnim agensima protiv raka, gnojenje tkiva, pjegavu degeneraciju, restenozu, peridontalno oboljenje, epidermolysis bullosa, sklerozu, u kombinaciji sa standardnim NSAID’S i analgeticima i drugim oboljenjima karakteriziranim sa aktivnošću matrične metaloproteinaze, AIDS, sepsu, sepstički udar i druga oboljenja koja uključuju proizvodnju TNF; ili (b) inhibiciju matričnih proteinaza ili proizvodnju faktora nekroze tumora (TNF) kod sisavaca, uključujući i čovjeka, koji sadrži količinu spoja formule (I) ili njegove farmaceutski prihvatljive soli efikasnu u takvom tretmanu i farmaceutski prihvatljivi nosač.
Ovaj izum se također odnosi na postupak inhibicije: (a) matričnih proteinaza; ili (b) proizvodnje faktora nekroze tumora (TNF) kod sisavaca, uključujući i čovjeka, koji obuhvaća unošenje u spomenute sisavce efikasne količine spoja formule I ili njegove farmaceutski prihvatljive soli.
Ovaj izum se također odnosi na postupak za tretiranje stanja izabranog iz grupe koja sadrži artritis, rak, gnojenje tkiva, pjegavu degeneraciju, restenozu, peridontalno oboljenje, epidermolysis bullosa, sklerozu, gdje se spojevi formule I mogu koristiti u kombinaciji sa standardnim NSAID’S i analgeticima i u kombinaciji sa citotoksičnim agensima protiv raka, i druga oboljenja karakterizirana sa aktivnošću matrične metaloproteinaze, AIDS, sepsu, sepstički udar i druga oboljenja koja uključuju proizvodnju TNF ili inhibiciju matričnih proteinaza ili proizvodnju faktora nekroze tumora (TNF) kod sisavaca, uključujući i čovjeka, koji obuhvaća unošenje u spomenute sisavce količine spoja formule (I) ili njegove farmaceutski prihvatljive soli efikasne u tretiranju takvog stanja.
Detaljni opis izuma
Sljedeće reakcijske sheme ilustriraju dobivanje spojeva iz ovog izuma. Ako nije drugačije naznačeno X, Y i Ar u reakcijskim shemama i diskusija koja slijedi definirani su kao gore.
[image]
U reakciji 1 sheme 1, spoj aril sulfonil klorida formule VII konvertira se u odgovarajući spoj natrij aril sulfonata formule VI, reagiranjem spoja VII sa natrij jodom u prisustvu polarnog aprotičnog otapala, takvog kao što je aceton, pod inertnom atmosferom. Reakcijska smjesa je miješana, na sobnoj temperaturi, tokom vremenskog perioda između oko 12 sati do oko 18 sati, poželjno oko 15 sati.
U reakciji 2 sheme 1, spoj formule VI konvertira se u odgovarajući 2-jodo-3-(aril) spoj sulfonil propionske kiseline formule V, reagiranjem spoja VI sa akrilnom kiselinom i jodom u prisustvu polarnog aprotičnog otapala, takvog kao što je metilen klorid. Reakcijska smjesa je miješana pod inertnim otapalom, na sobnoj temperaturi, tokom vremenskog perioda između oko 12 sati do oko 3,5 dana, poželjno oko 3 dana.
U reakciji 3 sheme 1, spoj formule V konvertira se u odgovarajući spoj (E)-3-(aril)sulfonil-prop-enoinske kiseline formule IV, tretiranjem spoja V sa bazom, takvom kao što je trietilamin, u polarnom otapalu, takvom kao što je metilen klorid, pod inertnom atmosferom. Reakcija je miješana na sobnoj temperaturi, tokom vremenskog perioda između oko 10 sati do oko 24 sata, poželjno oko 12 sati.
U reakciji 4 sheme 1, spoj formule IV konvertira se u odgovarajući spoj karboksilne kiseline formule III, grijanjem spoja IV sa viškom količine spoja formule
[image]
na refluksu u prisustvu polarnog aprotičnog otapala, takvog kao što je toluen, tokom vremenskog perioda između oko 24 sata do oko 56 sati, poželjno oko 48 sati.
U reakciji 5 sheme 1, spoj formule III konvertira se u odgovarajući spoj N-(R14)-karboksamida formule II, gdje R14 je O-supstituiran oksi, takav kao što je O-benzilhidroksi ili trimtilsilil etilhidroksi, reagiranjem spoja III sa agensom aktiviranja, takvim kao što je dimetilaminopiridin/ dicikloheksilkarbodiimid, i O-supstituiranog hidroksilamina, takvog kao što je benzilhidroksilamin hidroklorid ili O-trimetil-sililetilhidroksilamin, u prisustvu polarnog aprotičnog otapala, takvog kao što je metilen klorid, pod inertnom atmosferom. Reakcijska smjesa je miješana na sobnoj temperaturi tokom vremenskog perioda između oko 15 sati do oko 25 sati, poželjno oko 20 sati.
U reakciji 6 sheme 1, spoj formule II konvertira se u odgovarajući spoj hidroksaminske kiseline formule I sa: (1) reagiranjem spoja II sa vodikom u prisustvu katalizatora, takvog kao što je 5 % paladij na barij sulfatu, i polarnog aprotičnog otapala, takvog kao metanol; (2) tretiranjem spoja II sa trifluorooctenom kiselinom ili bor trifluorid dietil eteratom u polarnom aprotičnom otapalu, takvom kao što je metilen klorid; ili (3) tretiranjem spoja II sa tetrabutil amonij fluoridom u polarnom aprotičnom otapalu, takvom kao što je tetrahidrofuran. Reakcijska smjesa je miješana tokom vremenskog perioda između oko 2 sata do oko 4 sati, poželjno oko 3 sata.
Farmaceutski prihvatljive soli kiselih spojeva iz izuma su soli formirane sa bazama, naime kationske soli takve kao što su soli alkalnih i zemnoalkalnih metala, takvih kao što je natrij, litij, kalij, kalcij, magnezij, isto kao i soli amonija, takve kao što su soli amonija, trimetil-amonija, dietilamonija, i tris-(hidroksimetil)-metilamonija.
Slično, adicijske soli kiseline, takve kao što su neorganske kiseline, organske karboksilne i organske sulfonske kiseline, npr. klorovodična kiselina, metansulfonska kiselina, maleinska kiselina, također su moguće pod uvjetom da bazna grupa, takva kao što je piridil, formira dio strukture.
Sposobnost spojeva formule I ili njihovih farmaceutski prihvatljivih soli (u daljnjem tekstu također označenih kao "spojevi iz ovog izuma") da inhibiraju matrične metaloproteinaze ili proizvodnju faktora nekroze tumora (TNF) i, prema tome da se demonstrira njihova efikasnost za tretiranje oboljenja tretiranih sa matričnom metaloproteinazom ili proizvodnjom faktora nekroze tumora pokazana je sa sljedećim in vitro test pokusima.
BIOLOŠKI POKUSI
Inhibicija ljudske kolagenaze (MMP-1)
Ljudska rekombinantna kolagenaza aktivira se sa tripsinom korištenjem sljedećeg odnosa: 10 µg tripsina na 100 µg kolagenaze. Tripsin i kolagenaza inkubirane su na sobnoj temperaturi tokom 10 minuta, a zatim se dodaje pet puta više (50 µg/ 10 µg tripsina) tripsina soje.
10 mM sirovinske podloge otopine inhibitora napravljeni su u dimetil sulfoksidu i zatim su razblaženi korištenjem sljedeće sheme:
10 mM –—> 120 µM –—> 12 µM –—> 1,2 µM –—> 0,12 µM
Dvadesetpet mikrolitara svake koncentracije zatim je dodano u triplikatu u prikladne otvore ploče sa otvora 96 mikrofluora. Finalna koncentracija inhibitora biti će 1:4 razblažena poslije dodavanja enzima i supstrata. Pozitivne kontrole (enzim, ne inhibitor) postavljaju se u otvore, a prazne (ne enzim, ne inhibitori) postavljaju se u otvore D7-D12.
Kolagenaza je razblažena u 400 ng/ml i 25 µl zatim se doda u prikladne otvore ploče mirofluora. Finalna koncentracija kolagenaze u pokusu je 100 ng/ml.
Susptat (DNP-Pro-Cha-Cys(Me)-His-Ala-Lys(NMA)-NH2) napravljen je kao 5 mM sirovinska podloga u dimetil sulfoksidu i zatim je razblažen na 20 µM u pokusnom puferu. Pokus je iniciran sa dodavanjem 50 µl supstrata po otvoru ploče mikrofluora radi dobivanja finalne koncentracije od 10 µM.
Fluorescentna čitanja (360 nM eksitacija, 460 nm emisija) uzimana su u vremenu 0 i u intervalima od 20 minuta. Pokus je izvršen na sobnoj temperaturi sa tipičnim vremenom pokusa od 3 sata.
Fluorescencija prema vremenu zatim je nacrtana za oba prazna i kolagenazu koja sadrži uzorke (uzeta je srednja vrijednost podataka iz triplikatnih određivanja). Točka vremena koja osigurava dobar signal (prazno) i koja je na linearnom dijelu krivulje (obično oko 120 minuta) izabrana je za određivanje IC50 vrijednosti. Vrijeme 0 je korišteno kao prazno za svaki spoj na svakoj koncentraciji, a ove vrijednosti su oduzimane od podataka za 120 minuta. Podaci su nacrtani kao koncentracija inhibitora prema % kontrole (fluoescencija inhibitora podijeljena sa fluorescencijom samo kolagenaze × 100). IC50 određeni su iz koncentracije inhibitora koja daje signal koji je 50 % kontrole.
Ako se zapiše da su IC50 < 0,03 µM tada su inhibitori ispitani u koncentracijama od 0,3 µM, 0,03 µM i 0,003 µM.
Inhibicija želatinaze (MMP-2)
Inhibicija aktivnosti želatinaze ispitivana je korištenjem Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2 supstrata (10 µM) pod istim uvjetima kao inhibicija ljudske kolagenaze (MMP-1).
72kD želatinaza aktivirana je sa 1 mM APMA (p-aminofenil živin acetat) tokom 15 sati na 4 °C i razblažena je radi dobivanja finalne koncentracije u pokusu od 100 mg/ml. Inhibitori su razblaženi kao za inhibiciju ljudske kolagenaze (MMP-1) radi dobivanja finalne koncentracije u pokusu od 30 µM, 3 µM, 0,3 µM i 0,03 µM. Svaka koncentracija je dana u triplikatu.
Čitanje fluorescencije (360 nm eksitacija, 460 emisija) se uzima u vremenu 0 i zatim u intervalima od 20 minuta tokom 4 sata.
IC50 su određeni kao za inhibiciju ljudske kolagenaze (MMP-1). Ako je zapisano da su IC50 < 0,03 µM, tada su inhibitori ispitivani u finalnim koncentracijama od 0,3 µM, 0,03 µM, 0,003 µM i 0,003 µM.
Inhibicija aktivnosti stromelsina (MMP-3)
Inhibicija aktivnosti stromelsina bazirana je na modificiranom spektrofotometrijskom pokusu koga su opisali Weingarten H. i Feder J.: "Spectrofotometric Assay for Vertebrate Collagenase, Anal. Biochem.", 147, str. 437-440, (1985.). Hidroliza tio peptolid supstrata (Ac-Pro-Leu-Gly-SCH(CH2CH(CH3)2)CO-Leu-Gly-OC2H5) daje merkaptan fragment koji može biti prikazan u prisustvu Ellman reagensa.
Ljudski rekombinantni prostomelsin aktivira se sa tripsinom korištenjem odnosa od 1 µl od 10 mg/ml sirovinske podloge tripsina na 26 µg stromelsina. Tripsin i stromelsin inkubirani su na 37 °C tokom 15 minuta praćeno sa 10 µl od 10 mg/ml inhibitora tripsina soje tokom 10 minuta na 37 °C radi gašenja aktivnosti tripsina.
Pokusi su vršeni u ukupnom volumenu od 250 µl pufera iz pokusa (200 mM natrij klorid, 50 mM MES, i 10 mM kalcij klorid, pH 6,0) na mikrolitarskim pločama sa 96 otvora. Ellman reagens (3-karboksi-4-nitrofenil disulfid) napravljen je kao 1M sirovinska podloga u dimetil formamidu i razblažen je u 5 mM u puferu iz pokusa sa 50 μl po otvoru dajući 1mM finalnu koncentraciju.
10 mM sirovinska podloga otopine inhibitora napravljeni su u dimetil sulfoksidu i razblaženi serijski u puferu iz pokusa tako da dodavanje 50 µl u prikladne otvore daje finalne koncentracije od 3 µM, 0,3 µM, 0,003 µM, i 0,0003 µM. Svi uvjeti su kompletirani u triplikatu.
300 mM dimetil sulfoksid sirovinske podloge otopine iz peptid supstrata razblaženo je u 15 mM u puferu iz pokusa i pokus je iniciran sa dodavanjem 50 µl u svaki otvor radi dobivanja finalne koncentracije od 3mM supstrata. Prazni se sastoje od peptid supstrata i Ellman reagensa bez enzima. Formiranje proizvoda prikazano je na 405 nm sa čitačem ploče Molecular Devices UVmax.
IC50 vrijednosti određene su na isti način kao za kolagenazu.
Inhibicija MMP-3
Ljudski rekobinantni MMP-3 aktiviran je sa 2 mM APMA (p-aminofenil živin acetat) tokom 1,5 sata, na 37 °C i razblažen je sa 400 mg/ml pufera iz pokusa (50 mM tris, pH 7,5, 200 mM natrij klorid, 5 mM kalcij klorid, 20 µM cink klorid, 0,02 % brij). 25 mikrolitara razblaženog enzima dodano je po otvoru mikrofluor ploče sa 96 otvora. Enzim je zatim razblažen u 1:4 odnosu u pokusu sa dodavanjem inhibitora i supstrata radi dobivanja finalne koncentracije u pokusu od 100 mg/ml.
10 mM sirovinske podloge otopine inhibitora napravljeni su u dimetil sulfoksidu i zatim razblaženi u puferu iz pokusa kao za shemu inhibitora razblaženja za inhibiciju ljudske kolagenaze (MMP-1): 25 mikrolitara svake koncentracije dodano je u triplikatu na ploču mikrofluora. Finalne koncentracije u pokusu su 30 µM, 3 µM, 0,3 µM, i 0,03 µM.
Suspstrat (Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2) dobiven je kao za inhibiciju ljudske kolagenaze (MMP-1) i 50 µl je dodano u svaki otvor radi dobivanja finalne koncentracije pokusa od 10 µM. Čitanja fluorescencije (360 nM eksitacija; 450 emisija) uzeta su u vremenu 0 i svakih 5 minuta tokom 1 sata.
Kozitivne kontrole sastoje se od enzima i supstrata sa ne inhibitorom, a prazne se sastoje samo od kontrola.
IC50 su određeni po inhibiciji ljudske kolagenaze (MMP-1). Ako je zapisano da su IC50 < 0,03 µM, inhibitori su tada ispitivani u finalnim koncentracijama od 0,3 µM, 0,03 µM, 0,003 µM i 0,0003 µM.
Inhibicija TNF proizvodnje
Sposobnost spojeva ili njihovih farmaceutski prihvatljivih soli da spriječi proizvodnju TNF i, prema tome da demonstrira njihovu efikasnost za tretiranje oboljenja uključujući proizvodnju TNF pokazana je sa sljedećim in vitro pokusom:
Ljudske mononuklearne stanice izolirane su iz nezgrušane stanice krvi korištenjem jednofazne tehnike izdvajanja Ficoll-hypaque. Mononuklearne stanice isprane su 3 puta u Hanks balansiranoj otopini soli (HBSS) sa divalentnim kationima i ponovo su suspendirane u gustoći od 2 × 106 /ml uHBSS koji sadrži 1 % BSA. Diferencijalna brojanja određena korištenjem Abbott Cell Dyn 3500 analizatora označila su da su monociti u opsegu od 17 do 24 % ukupnih stanica u ovim dobivanjima.
180 µ suspenzije stanice uzeto je kao uzorak u ravnom dnu ploče sa 96 otvora (Costar). Dodavanja spojeva i LPS (100 ng/ml finalne koncentracije) dala su finalni volumen od 200 µl. Svi uvjeti su izvršeni u triplikatu. Poslije inkubacije od 4 sata na 37 °C u ovlaženom CO2 inkubatoru, ploče su uklonjene i centrifugirane (10 minuta na približno 250 × g) i supernatanti su uklonjeni i ispitani za TNFα korištenjem R&D ELISA Kit.
Za unošenje u ljude za inhibiciju matričnih metaloproteinaza ili proizvodnju faktora nekroze tumora, može se koristiti mnoštvo konvencionalnih putova uključujući oralni, parenteralni i mesni. Općenito, aktivni spoj biti će unesen oralno ili parenteralno u doziranjima između oko 0,1 i 25 mg/kg težine tijela subjekta koji se tretira dnevno, poželjno od oko 0,3 do 5 mg/kg. Međutim, zavisno od stanja subjekta koji se tretira, moguće su i neke varijacija u doziranju. Osoba odgovorna za unošenje odrediti će, u svakom slučaju, prikladnu dozu za pojedinačni subjekt.
Spojevi iz ovog izuma mogu se unositi u velikom mnoštvu raznih doznih oblika. Općenito spojevi iz ovog izuma prisutna su u raznim doznim oblicima i koncentracijama u psegu od oko 5,0 masenih % do oko 70 masenih %.
Za oralno unošenje, tablete koje sadrže razne ekscipijente takve kao što je mikrokristalna celuloza, natrij citrat, kalcij karbonat, dikalcij fosfat i glicin mogu se koristiti zajedno sa raznim razgrađivačima takvim kao što je škrob (i poželjno škrob žitarica, krompira ili tapioke), alginska kiselina i neki kompleksni silikati, zajedno sa granulacijskim vezivima sličnim polivinilpirolidonu, sukrozi, želatini i akaciji. Dodatno, agensi podmazivanja takvi kao što je magnezij stearat, natrij lauril sulfat i talk često su vrlo korisni sa potrebe tabletiranja. Čvrsti preparati sličnog tipa mogu se također koristiti kao punila u želatinskim kapsulama; poželjni materijali u vezi ovog također uključuju laktozu ili mliječni šećer kao i polietilen glikole velike molekulske težine. Kada su vodene suspenzije i/ili eliksiri potrebni za oralno unošenje, aktivni sastojak može se kombinirati sa raznim agensima zaslađivanja ili mirisa, materijom za bojenje ili bojama, i agensima emulziranja i/ili suspendiranja isto tako, zajedno sa takvim razblaživačima kao što je voda, etanol, propilen glikol, glicerin i razne slične njihove kombinacije. U slučaju životinja, oni su prikladno sadržani u životinjskoj hrani ili vodi za piće u koncentraciji od 5-5000 ppm, poželjno 25 do 500 ppm.
Za parenteralno unošenje (intramuskularna, intraperitonealna, potkožna i intravenska primjena) obično se dobiva sterilni ubrizgavajući otopina aktivnog sastojka. Mogu se koristiti otopine terapeutskog spoja iz ovog izuma u ulju sezama ili kikirikija ili u vodenom propilen glikolu. Vodene otopine trebaju se prikladno podesiti ili puferirati, poželjno na pH većem od 8, ako je potrebno tekući razblaživač se prvo vraća izotonski. Ove vodene otopine su prikladne za potrebe intravenske injekcije. Uljne otopine su prikladne za potrebe intrartikularne, intramuskularne i potkožne injekcije. Dobivanje svih ovih otopina pod sterilnim uvjetima lako se obavlja sa standardnim farmaceutskim tehnikama dobro poznatim stručnjacima. U slučaju životinja, spojevi se mogu unositi intramuskularno ili potkožno u doznim nivoima od oko 0,1 do 50 mg/kg/dan, poželjno 0,2 do 10 mg/kg/dan danim u pojedinačnoj dozi ili do 3 podijeljene doze.
Nadalje, moguće je unositi spojeve iz ovog izuma mesno, tj. kada se tretiraju upalna stanja kože, a ovo se može vršiti pomoću krema, želea, gelova, pasti, i pomada u skladu sa standardnom farmaceutskom praksom.
Ovaj izum je ilustriran sa sljedećim primjerima, ali nije ograničen na njihove detalje.
Primjer 1
3-(4-metoksifenilsulfonil-7-oksabiciklo[2,2,1]heptan-2-karboksilna kiselina hidroksiamid
(a) Natrij jodid (21,76 grama, 145,2 mmol) i 4-metoksibenzensulfonil klorid (10,0 grama, 48,39 mmol) kombinirani su u suhom acetonu (osušen preko MgSO4 i filtriran) (200 ml) i miješani su na sobnoj temperaturi preko noći. Sakupljen je fini bijeli čvrsti proizvod preko usisnog filtriranja. Sušenjem na visokom vakuumu dobiveno je 9,11 grama natrij 4-metoksibenzensulfinata kao blijedo žuti fini prah (97 % prinos).
(b) Dodana je voda (0,85 grama, 0,85 ml) praćeno sa akrilnom kiselinom (3,42 grama, 3,25 ml), zatim I2 (12,04 grama, 47,41 mmol) u suspenziju natrij 4-metoksibenzensulfinata (9,11 grama, 46,94 mmol) u metilen kloridu (150 ml). Dodano je još metilen klorida (100 ml) tako da se suspenzija može miješati. Miješana je na sobnoj temperaturi tokom vikenda. Isprana je reakcijska otopina sa 1N Na2S2O3 (vodena) (3 × 150 ml) dok organski sloj nije postao bezbojan. Ispran je organski sloj sa slanom vodom. Osušen je (MgSO4), filtriran i koncentriran u vakuumu, radi dobivanja 4,23 grama (25 %) sirove 2-jodo-3-(4-metoksifenilsulfonil)propionske kiseline.
(c) 2-jodo-3-(4-metoksifenilsulfonil)propionska kiselina (4,23 grama, 11,43 mmol) i Et3N (3,22 ml, 2,34 grama, 23,09 mmol) kombinirani su u metilen kloridu (150 ml) i miješani preko noći na sobnoj temperaturi. Reakcijska smjesa je razblažena sa 1N klorovodičnom kiselinom (vodena) (100 ml). Izdvojeni vodeni sloj je ekstrahiran sa Et2O (2 ×). Osušeni (MgSO4) organski dijelovi su zatim filtrirani i koncentrirani u vakuumu radi dobivanja 2,58 grama sirovog proizvoda. Ovaj je filtriran, filtrat je koncentriran i ostatak je uzet u metanolu, filtriran i filtrat je koncentriran radi dobivanja 1,87 grama sirovog proizvoda. Ovaj je uzet u vrućem metilen kloridu. Fini kristali su razbijeni. Dekantiran je filtrat. Isprani su kristali metilen klorida (2 × 1 ml) (dekantirani ispirci). Osušeni su kristali u visokom vakuumu radi dobivanja 0,396 grama 3-(4-metoksifenilsulfonil)propenska kiselina kao blijedo žuti čvrsti proizvod (t.t.: 123-128,5 °C). Filtrat je koncentriran radi dobivanja 1,42 grama žutog čvrstog proizvoda koji je impulsno kromatografiran (60 % EtOAc/ heksan/ 2 %/ HOAc/ 0,5 % metanol) radi dobivanja 1,42 grama 3-(4-metoksifenilsulfonil)propenske kiseline. Druga kromatografija (40 % EtOAc/ heksan/ 2 %/ HOAc/ 0,5 % metanol) dala je 0,568 grama čiste 3-(4-metoksifenilsulfonil)propenske kiseline.
(d) 3-(4-metoksifenilsulfonil)propenska kiselina (20 mg), višak furana (5,0 ml), i suhi toluen (5,0 ml) kombinirani su i zagrijani na 55 °C (kada je polazni materijal prešao u otopinu) preko noći. Ohlađena reakcija je koncentrirana u vakuumu u žućkasto-smeđi materijal koji je smjesa polaznog materijala i proizvoda. Materijal je uzet u toluenu (5 ml) i furanu (10 ml) i grijan je na 69 °C preko noći. Ohlađena reakcijska smjesa je koncentrirana u vakuumu radi dobivanja 251 mg sirove 3-(4-metoksifenilsulfonil)-7-oksabiciklo[2,2,1]hept-5-en-2-karboksilne kiseline kao tamno žućkasto-smeđi proizvod.
(e) Dodana je O-benzilhidroksiaamin•klorovodična kiselina (0,387 grama, 2,43 mmol) u izmiješanu otopinu 3-(4-metoksi-fenilsulfonil-7-oksabiciklo[2,2,1]hept-5-en-karboksilne kiseline u metilen kloridu (5 ml). Dodan je 4-dimetilaminopiridin (0,306 grama, 2,51 mmol) i miješan je približno 30 minuta (dok se ne otopi čvrsti materijal), zatim je dodan 1,3-dicikloheksilkarbodiimid (0,250 grama, 1,21 mmol) i miješan je na sobnoj temperaturi preko noći. Reakcija je filtrirana preko umetka Celite i filtrat je koncentriran u vakuumu radi dobivanja 1,06 grama 3-(4-metoksifenilsulfonil-7-oksabiciklo[2,2,1]heptan-2-karboksilna kiselina benziloksiamida. Ovaj je uzet u metanolu i dekantiran je filtrat iz finih igličastih kristala. Koncentriranje filtrata dalo je 0,82 grama 3-(4-metoksifenilsulfonil-7-oksabiciklo[2,2,1]heptan-2-karboksilna kiselina benziloksiamida.
(f) Dodan je 5 % paladij/ barij sulfat (0,80 grama) u sirovi 3-(4-metoksifenilsulfonil-7-oksa-biciklo[2,2,1]hept-5-en-karboksilna kiselina benziloksi amid (0,82 grama) u 30 ml metanola i hidrogeniran je na 3,10275 bara (45 psi) na sobnoj temperaturi na Parr Shaker tokom 4 sata. Filtrirana je reakcija preko umetka Celite i koncentriran je filtrat u vakuumu. 1H-NMR ostatka pokazuje da je samo dvostruka veza uklonjena. Ostatak je impulsno kromatografiran (50 % EtOAc/ heksan) radi dobivanja 0,126 grama intermedijera. U ovaj je dodan 5 % paladij/ barij sulfat (0,126 grama) u metanolu (30 ml) i hidrogenacija je nastavljena na Parr Shaker na 3,10275 bara (45 psi) na sobnoj temperaturi tokom 105 minuta. Filtrirana je reakcija preko umetka Celite i koncentriran je filtrat radi dobivanja 0,101 grama sirovog 3-(4-metoksifenilsulfonil-7-oksabiciklo[2,2,1]heptan-2-karboksilna kiselina hidroksiamida. Impulsna kromatografija (70/ 30/ 8/ 1) (EtOAc/ heksan/ metanol/ HOAc) dala je 77,1 mg 3-(4-metoksifenilsulfonil-7-oksabiciklo[2,2,1]heptan-2-karboksil kiselina hidroksiamida.
1H-NMR (CD3OD) δ 1,6 (2H, m); 1,8 (2H, m); 3,11 (1H, t); 3,82 (1H, d); 3,88 (3H, s); 4,63 (1H, t); 4,91 (1H, d); 7,12 (2H, d); 7,80 (2H, d).
HRMS M++H+ izračunato: 328,0855;
nađeno: 328,0872.
Primjer 2
3-(4-fenoksifenilsulfonil-7-oksabiciklo[2,2,1]heptan-2-karboksilna kiselina hidroksiamid
(a) 3-(4-fenoksifenilsulfonil)propenska kiselina dobivena od 4-fenoksifenilsulfonil klorida i akrilne kiseline kako je opisano u primjeru 1 faze A i B impulsno je kromatografirana (60/ 40/ 1,5/ 0,5) (EtOAc/ heksan/ HOAc/ metanol) radi dobivanja 1,12 grama sasvim bijelog čvrstog proizvoda. Ovaj je kristaliziran od EtOAc/ heksana (3:1) radi dobivanja 0,61 grama čistog proizvoda kao bijeli fini kristali.
(b) U 3-(4-fenoksifenilsulfonil)propensku kiselinu (250 mg, 0,82 mmol) u toluenu (5,0 ml) (polazni materijal je netopljiv u toluenu na sobnoj temperaturi) dodan je furan (10 ml) i smjesa je grijana na blagom refluksu približno na 70 °C. Poslije približno 30 minuta reakcijska smjesa je bila otopina. Poslije 18 sati refluksa TLC mliječno bijele otopine pokazuje da je polazni materijal potrošen. Reakcijska smjesa je ohlađena i bijeli talog je sakupljen preko usisnog filtriranja i ispran sa toluenom (2 × 1 ml). Otopljen je čvrsti materijal u vrućem metanolu i koncentriran u vakuumu radi dobivanja 0,267 grama 2-(4-fenoksifenilsulfonil-7-oksabiciklo[2,2,1]hept-5-en-2-karboksilne kiseline kao bijeli kristalni čvrsti proizvod.
(c) 3-(4-fenoksifenilsulfonil-7-oksabiciklo[2,2,1]hept-5-en-2-karboksilna kiselina (0,243 grama, 0,65 mmol) je hidrogenirana na Parr Shaker preko 5 % paladij/ barij sulfata (0,125 grama) u metanolu (30 ml) na sobnoj temperaturi na 3,10275 bara (45 psi) tokom 3 sata. Reakcija je filtrirana preko umetka Celite i filtrat je koncentriran u vakuumu radi dobivanja 0,216 grama 3-(4-fenoksifenilsulfonil)-7-oksabiciklo[2,2,1]heptan-2-karboksilne kiseline.
(d) Dodana je o-benzilhidroksilamin•klorovodična kiselina (0,28 grama, 1,73 mmol) u 3-(4-fenoksifenilsulfonil)-7-oksabiciklo[2,2,1]heptan-2-karboksilnu kiselinu (0,216 grama, 0,58 mmol) otopljenu u CHCl3 sa grijanjem radi njenog otapanja. Zatim je dodan 4-dimetilaminopiridin (0,22 grama, 1,79 mmol) i smjesa je miješana dok se ne obavi kompletno otapanje tokom približno 5 minuta. Zatim je dodan 1,3-dicikloheksilkarbodiimid (0,18 grama, 0,87 mmol).Poslije 18 sati miješanja na sobnoj temperaturi reakcija je koncentrirana u vakuumu radi dobivanja 1,05 grama sirovog proizvoda. Impulsna kromatografija (40 % EtOAc/ heksan/ 2 %/ HOAc/ 0,5 % metanol) dala je 0,32 grama nečistog proizvoda. Impulsna kromatografija (40 % EtOAc/ heksan) dala je 0,212 grama (75 %) čistog 3-(4-fenoksifenilsulfonil)-7-oksabiciklo[2,2,1]heptan-2-karboksilna kiselina benziloksi amida kao snježno bijeli pjenasti čvrsti proizvod.
(e) Kombinirana je 3-(4-fenoksifenilsulfonil)-7-oksabiciklo[2,2,1]heptan-2-karboksilna kiselina (0,21 grama, 0,438 mmol) 5 % paladij/ barij sulfat (0,11 grama) u metanolu (20 ml) i hidrogenirana je na Parr Shaker na sobnoj temperaturi na 3,10275 bara (45 psi) tokom 105 minuta. Reakcijska smjesa je filtrirana i koncentrirana u vakuumu radi dobivanja 0,175 grama 3-(4-fenoksifenilsulfonil-7-oksabiciklo[2,2,1]heptan-2-karboksilna kiselina hidroksiamida kao snježno bijeli pjenasti čvrsti proizvod, t.t. 88,9-92,9 °C.
1H-NMR (CD3OD) δ 2,5-2,7 (2H, m); 2,7-2,9 (2H, m); 3,11 (1H, t); 3,84 (1H, d); 4,64 (1H, t); 4,94 (1H, d); 7,10 (4H, d); 7,23 (1H, t); 7,44 (2, t); 7,82 (2H, d);
Mas. spec. M++NH4 407.
HRMS M++H+ izračunato: 390,1011;
nađeno: 390,1022.
Claims (8)
1. Spoj formule
[image]
ili njegova farmaceutski prihvatljiva sol, naznačen time što isprekidana linija predstavlja opcionalnu dvostruku vezu;
n je 0, 1 ili 2;
X i Y su svaki nezavisno CR1, gdje R1 je vodik, (C1-C6) alkil opcionalno supstituiran sa (C1-C6) alkilamino, (C1-C6) alkiltio, (C1-C6) alkoksi, trifluorometilom, (C6-C10) arilom, (C5-C9) heteroarilom,
(C6-C10) arilaminom, (C6-C10) ariltio, (C6-C10) ariloksi, (C5-C9) heteroarilaminom, (C5-C9) heteroariltio,
(C5-C9) heteroariloksi, (C6-C10) aril (C6-C10) arilom, (C3-C6) cikloalkilom, hidroksi (C1-C6) alkilom,
(C1-C6) alkil (hidroksimetilenom), piperazinilom, (C6-C10) aril (C1-C6) alkoksi,
(C5-C9) heteroaril (C1-C6) alkoksi, (C1-C6) acilaminom, (C1-C6) aciltio, (C1-C6) aciloksi,
(C1-C6) alkilsulfinilom, (C6-C10) arilsulfinilom, (C1-C6) alkilsulfonilom, (C6-C10) arilsulfonilom,
aminom, (C1-C6) alkilaminom ili ((C1-C6) alkil)2 aminom; trifluorometil, (C1-C6) alkil (difluorometilen), (C1C3) alkil (difluorometilen) (C1-C3) alkil, (C6-C10) aril, (C5-C9) heteroaril, (C3-C6) cikloalkil,
(C1-C6) alkil-(hidroksimetilen), R3 (C1-C6) alkil, gdje R3 je (C1-C6) acilpiperazino, (C6-C10) arilpiperazino, (C5-C9) heteroarilpiperazino, (C1-C6) alkilpiperazino, (C6-C10) aril (C1-C6) alkilpiperazino,
(C5-C9) heteroaril (C1-C6) alkilpiperazino, morfolino, trimorfolino, piperidino, pilodino, piperidil,
(C1-C6) alkilpiperidil, (C6-C10) arilpiperidil, (C5-C9) heteroarilpiperidil, (C1-C6) alkilpiperidil (C1-C6) alkil, (C5-C9) heteroarilpiperidil (C1-C6) alkil ili (C1-C6) acilpiperidil;
ili grupa formule
[image]
gdje r je 0 ili 6;
D je hidroksi, (C1-C6) alkoksi, piperidil, (C1-C6) alkilpiperidil, (C6-C10) arilpiperidil,
(C5-C9) heteroarilpiperidil, (C1-C6) acilpiperidil ili NR4R5, gdje su R4 i R5 svaki nezavisno odabrani iz grupe koja sadrži vodik, (C1-C6) alkil opcionalno supstituiran sa (C1-C6) alkilpiperidilom, (C6-C10) arilpiperidilom, (C5-C9) heteroarilpiperidilom, (C6-C10) arilom, (C5-C9) heteroarilom, (C6-C10) aril (C6-C10) arilom ili
(C3-C6) cikloalkilom; (C6-C10) aril, (C5-C9) heteroaril, (C6-C10) aril (C6-C10) aril, (C3-C6) cikloalkil,
R6 (C2-C6) alkil, (C1-C5) alkil (CHR6) (C1-C6) alkil gdje R6 je hidroksi, (C1-C6) aciloksi, (C1-C6) alkoksi, piperazino, (C1-C6) acilamino, (C1-C6) alkiltio, (C6-C10) ariltio, (C1-C6) alkilsulfinil, (C6-C10) arilsulfinil,
(C1-C6) alkilsulfoksi, (C6-C10) arilsulfoksil, amino, (C1-C6) alkilamino, ((C1-C6) alkil)2 amino,
(C1-C6) acilpiperazino, (C1-C6) alkilpiperazino, (C6-C10) aril (C1-C6) alkilpiperazino,
(C5-C9) heteroaril (C1-C6) alkilpiperazino, morfolino, tiomorfolino, piperidino ili pirolidino;
R7 (C1-C6) alkil, (C1-C5) alkil (CHR7) (C1-C6) alkil, gdje R7 je piperidil ili (C1-C6) alkilpiperidil; i
CH (R8)COR9, gdje R8 je vodik, (C1-C6) alkil, (C6-C10) aril (C1-C6) alkil, (C5-C9) heteroaril (C1-C6) alkil,
(C1-C6) alkiltio (C1-C6) alkil, (C6-C10) ariltio (C1-C6) alkil, (C1-C6) alkilsulfinil (C1-C6) alkil,
(C6-C10) arilsulfinil (C1-C6) alkil, (C1-C6) alkilsulfonil (C1-C6) alkil, (C6-C10) arilsulfonil (C1-C6) alkil, hidroksi (C1-C6) alkil, amino (C1-C6) alkil, (C1-C6) alkilamino (C1-C6) alkil,
((C1-C6)alkilamino)2 (C1-C6) alkil, R10R11NCO (C1-C6) alkil ili R10OCO (C1-C6) alkil, gdje su R10 i R11 svaki nezavisno odabrani iz grupe koja sadrži vodik, (C1-C6) alkil, (C6-C10) aril (C1-C6) alkil i
(C5-C9) heteroaril (C1-C6) alkil; i R9 je R12O ili R12R13N, gdje su R12i R13 svaki nezavisno odabrani iz grupe koja sadrži vodik, (C1-C6) alkil, (C6-C10) aril (C1-C6) alkil i (C5-C9) heteroaril (C1-C6) alkil; i
Ar je (C1-C6) alkil, (C6-C10) aril, (C6-C10) ariloksi (C6-C10) aril, (C6-C10) aril (C6-C10) aril,
(C6-C10) aril (C6-C10) aril (C1-C6) alkil, (C6-C10) ariloksi (C5-C9) heteroaril, (C5-C9) heteroaril,
(C1-C6) alkil (C6-C10) aril, (C1-C6) alkoksi (C6-C10) aril, (C6-C10) aril (C1-C6) alkoksi (C6-C10) aril,
(C6-C10) aril (C1-C6) alkoksi (C1-C6) alkil, (C5-C9) heteroariloksi (C6-C10) aril, (C1-C6) alkil (C5-C9) heteroaril, (C1-C6) alkoksi (C5-C9) heteroaril, (C6-C10) aril (C1-C6) alkoksi (C5-C9) heteroaril,
(C5-C9) heteroariloksi (C5-C9) heteroaril, (C6-C10) ariloksi (C1-C6) alkil, (C5-C9) heteroariloksi (C1-C6) alkil, (C1-C6) alkil (C6-C10) ariloksi (C6-C10) aril, (C1-C6) alkil (C5-C9) heteroariloksi (C6-C10) aril,
(C1-C6) alkil (C6-C10) ariloksi (C5-C9) heteroaril, (C1-C6) alkoksi (C6-C10) ariloksi (C6-C10) aril,
(C1-C6) alkoksi (C5-C9) heteroariloksi (C6-C10) aril ili (C1-C6) alkoksi (C6-C10) ariloksi (C5-C9) heteroaril, gdje je spomenuta aril grupa opcionalno supstituirana sa fluoro, kloro, bromo, (C1-C6) alkilom, (C1-C6) alkoksi ili perfluoro (C1-C3) alkilom.
2. Spoj prema zahtjevu 1, naznačen time što n je 2.
3. Spoj prema zahtjevu 1, naznačen time što X i Y su oba CR1, gdje je R1 vodik.
4. Spoj prema zahtjevu 1, naznačen time što Ar je (C1-C6)alkoksi(C6-C10)aril,
(C6-C10)aril(C1-C6)alkoksi(C6-C10)aril, 4-fluorofenoksi(C6-C10)aril, 4-fluorobenziloksi(C6-C10)aril ili
(C1-C6)alkil(C6-C10)ariloksi(C6-C10)aril.
5. Spoj prema zahtjevu 1, naznačen time što n je 2, X i Y su oba CR1 gdje R1 je vodik i Ar je
(C1-C6)alkoksi(C6-C10)aril, (C6-C10)aril(C1-C6)alkoksi(C6-C10)aril, 4-fluorofenoksi(C6-C10)aril,
4-fluorobenziloksi(C6-C10)aril ili (C1-C6)alkil(C6-C10)ariloksi(C6-C10)aril.
6. Farmaceutski preparat za (a) tretman stanja izabranog iz grupe koja sadrži artritis, rak, gnojenje tkiva, pjegavu degeneraciju, restenozu, peridontalno oboljenje, epidermolysis bullosa, sklerozu, u kombinaciji sa standardnim NSAID’S i analgeticima i u kombinaciji sa citotoksičnim agensima protiv raka i drugim oboljenjima karakteriziranim sa aktivnošću matrične metaloproteinaze, AIDS, sepsu, sepstički udar i druga oboljenja koja uključuju proizvodnju faktora nekroze tumora (TNF) ili (b) inhibiciju matričnih proteinaza ili proizvodnju faktora nekroze tumora (TNF) kod sisavaca, uključujući i čovjeka, naznačen time što sadrži količinu spoja iz zahtjeva 1 efikasnu u takvom tretmanu i farmaceutski prihvatljivi nosač.
7. Postupak inhibicije (a) matričnih proteinaza ili (b) proizvodnje faktora nekroze tumora (TNF) kod sisavaca, uključujući i čovjeka, naznačen time što obuhvaća unošenje u spomenute sisavce efikasne količine spoja iz zahtjeva 1.
8. Postupak za tretiranje stanja izabranog iz grupe koja sadrži artritis, rak, gnojenje tkiva, pjegavu degeneraciju, restenozu, peridontalno oboljenje, epidermolysis bullosa, sklerozu, gdje se spojevi formule I mogu koristiti u kombinaciji sa standardnim NSAID’S i analgeticima i u kombinaciji sa citotoksičnim agensima protiv raka, i druga oboljenja karakterizirana sa aktivnošću matrične metaloproteinaze, AIDS, sepsu, sepstički udar i druga oboljenja koja uključuju proizvodnju (TNF) kod sisavaca, uključujući i čovjeka, naznačen time što obuhvaća unošenje u spomenute sisavce količine spoja iz zahtjeva 1, efikasne u tretiranju takvog stanja.
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US3268539A (en) * | 1963-05-20 | 1966-08-23 | Universal Oil Prod Co | Tertiary-aminoalkyl derivatives of diaryl substituted acetohydroxamic acid esters |
JP2984077B2 (ja) * | 1990-04-19 | 1999-11-29 | 塩野義製薬株式会社 | スルホニルアミノ置換ビシクロ環系ヒドロキサム酸誘導体 |
US5455258A (en) * | 1993-01-06 | 1995-10-03 | Ciba-Geigy Corporation | Arylsulfonamido-substituted hydroxamic acids |
ATE225343T1 (de) * | 1995-12-20 | 2002-10-15 | Hoffmann La Roche | Matrix-metalloprotease inhibitoren |
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1997
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- 1997-12-18 EP EP97946016A patent/EP0950059B1/en not_active Expired - Lifetime
- 1997-12-18 DE DE69730151T patent/DE69730151T2/de not_active Expired - Fee Related
- 1997-12-18 CA CA002277100A patent/CA2277100C/en not_active Expired - Fee Related
- 1997-12-18 WO PCT/IB1997/001582 patent/WO1998030566A1/en active IP Right Grant
- 1997-12-18 DK DK97946016T patent/DK0950059T3/da active
- 1997-12-18 US US09/331,275 patent/US6077864A/en not_active Expired - Fee Related
- 1997-12-18 ES ES97946016T patent/ES2224277T3/es not_active Expired - Lifetime
- 1997-12-18 AU AU51319/98A patent/AU5131998A/en not_active Abandoned
- 1997-12-18 BR BR9714266-2A patent/BR9714266A/pt not_active Application Discontinuation
- 1997-12-18 JP JP53068598A patent/JP3338064B2/ja not_active Expired - Fee Related
- 1997-12-18 PT PT97946016T patent/PT950059E/pt unknown
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1998
- 1998-01-02 PA PA19988444201A patent/PA8444201A1/es unknown
- 1998-01-05 MA MA24918A patent/MA26463A1/fr unknown
- 1998-01-05 AR ARP980100029A patent/AR011056A1/es unknown
- 1998-01-05 TN TNTNSN98003A patent/TNSN98003A1/fr unknown
- 1998-01-05 ZA ZA9830A patent/ZA9830B/xx unknown
- 1998-01-05 HR HR60/034,535A patent/HRP980004A2/hr not_active Application Discontinuation
- 1998-01-06 AP APAP/P/1998/001174A patent/AP9801174A0/en unknown
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BR9714266A (pt) | 2000-04-18 |
AR011056A1 (es) | 2000-08-02 |
ES2224277T3 (es) | 2005-03-01 |
CA2277100C (en) | 2005-11-22 |
EP0950059B1 (en) | 2004-08-04 |
TNSN98003A1 (fr) | 2005-03-15 |
JP2000507967A (ja) | 2000-06-27 |
AU5131998A (en) | 1998-08-03 |
DE69730151D1 (de) | 2004-09-09 |
AP9801174A0 (en) | 1998-01-31 |
WO1998030566A1 (en) | 1998-07-16 |
EP0950059A1 (en) | 1999-10-20 |
JP3338064B2 (ja) | 2002-10-28 |
PT950059E (pt) | 2004-10-29 |
DE69730151T2 (de) | 2005-08-04 |
MA26463A1 (fr) | 2004-12-20 |
PA8444201A1 (es) | 2000-05-24 |
ZA9830B (en) | 1999-07-05 |
US6077864A (en) | 2000-06-20 |
DK0950059T3 (da) | 2004-11-01 |
CA2277100A1 (en) | 1998-07-16 |
ATE272640T1 (de) | 2004-08-15 |
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