HRP980058A2 - Arylsulfonylamino hydroxamic acid derivatives - Google Patents
Arylsulfonylamino hydroxamic acid derivativesInfo
- Publication number
- HRP980058A2 HRP980058A2 HR60/036,857A HRP980058A HRP980058A2 HR P980058 A2 HRP980058 A2 HR P980058A2 HR P980058 A HRP980058 A HR P980058A HR P980058 A2 HRP980058 A2 HR P980058A2
- Authority
- HR
- Croatia
- Prior art keywords
- aryl
- heteroaryl
- alkyl
- carboxylic acid
- acid hydroxyamide
- Prior art date
Links
- -1 Arylsulfonylamino hydroxamic Chemical compound 0.000 title description 20
- 239000002253 acid Substances 0.000 title description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 55
- 150000001875 compounds Chemical class 0.000 claims description 54
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 27
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 24
- 102000003390 tumor necrosis factor Human genes 0.000 claims description 24
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 16
- 125000004104 aryloxy group Chemical group 0.000 claims description 13
- 230000005764 inhibitory process Effects 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 102000002274 Matrix Metalloproteinases Human genes 0.000 claims description 12
- 108010000684 Matrix Metalloproteinases Proteins 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 12
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 241000124008 Mammalia Species 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 201000011510 cancer Diseases 0.000 claims description 7
- 125000006719 (C6-C10) aryl (C1-C6) alkyl group Chemical group 0.000 claims description 6
- 208000033809 Suppuration Diseases 0.000 claims description 6
- ZXKINMCYCKHYFR-UHFFFAOYSA-N aminooxidanide Chemical compound [O-]N ZXKINMCYCKHYFR-UHFFFAOYSA-N 0.000 claims description 6
- 206010003246 arthritis Diseases 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 5
- SHSBTGZNXOPCNV-UHFFFAOYSA-N 1-[[4-(4-fluorophenoxy)phenyl]sulfonylamino]-n-hydroxycyclobutane-1-carboxamide Chemical compound C=1C=C(OC=2C=CC(F)=CC=2)C=CC=1S(=O)(=O)NC1(C(=O)NO)CCC1 SHSBTGZNXOPCNV-UHFFFAOYSA-N 0.000 claims description 5
- 206010040047 Sepsis Diseases 0.000 claims description 5
- 206010040070 Septic Shock Diseases 0.000 claims description 5
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 208000028169 periodontal disease Diseases 0.000 claims description 5
- 230000036303 septic shock Effects 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- 208000030507 AIDS Diseases 0.000 claims description 4
- 206010014989 Epidermolysis bullosa Diseases 0.000 claims description 4
- 208000034189 Sclerosis Diseases 0.000 claims description 4
- 229940035676 analgesics Drugs 0.000 claims description 4
- 239000000730 antalgic agent Substances 0.000 claims description 4
- XQANXZMSFKECBQ-UHFFFAOYSA-N n-hydroxy-2-methyl-2-[(5-pyridin-2-ylthiophen-2-yl)sulfonylamino]propanamide Chemical compound S1C(S(=O)(=O)NC(C)(C)C(=O)NO)=CC=C1C1=CC=CC=N1 XQANXZMSFKECBQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims description 4
- 208000037803 restenosis Diseases 0.000 claims description 4
- CMENTMLKKMZGPM-UHFFFAOYSA-N 1-[[4-(4-fluorophenoxy)phenyl]sulfonylamino]-n-hydroxycyclohexane-1-carboxamide Chemical compound C=1C=C(OC=2C=CC(F)=CC=2)C=CC=1S(=O)(=O)NC1(C(=O)NO)CCCCC1 CMENTMLKKMZGPM-UHFFFAOYSA-N 0.000 claims description 3
- SQQHSADBIVCBBM-UHFFFAOYSA-N 1-[[4-(4-fluorophenoxy)phenyl]sulfonylamino]-n-hydroxycyclopentane-1-carboxamide Chemical compound C=1C=C(OC=2C=CC(F)=CC=2)C=CC=1S(=O)(=O)NC1(C(=O)NO)CCCC1 SQQHSADBIVCBBM-UHFFFAOYSA-N 0.000 claims description 3
- OCDVFODZPZVZMF-UHFFFAOYSA-N 1-[[4-(4-fluorophenoxy)phenyl]sulfonylamino]-n-hydroxycyclopropane-1-carboxamide Chemical compound C=1C=C(OC=2C=CC(F)=CC=2)C=CC=1S(=O)(=O)NC1(C(=O)NO)CC1 OCDVFODZPZVZMF-UHFFFAOYSA-N 0.000 claims description 3
- QCOQJYRPDUMCNP-UHFFFAOYSA-N 2-[[4-(4-fluorophenoxy)phenyl]sulfonylamino]-n-hydroxy-2-methylpropanamide Chemical compound C1=CC(S(=O)(=O)NC(C)(C)C(=O)NO)=CC=C1OC1=CC=C(F)C=C1 QCOQJYRPDUMCNP-UHFFFAOYSA-N 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 208000002780 macular degeneration Diseases 0.000 claims description 3
- XPWGEUXPCQVZKF-UHFFFAOYSA-N n-hydroxy-1-[(5-pyridin-2-ylthiophen-2-yl)sulfonylamino]cyclopentane-1-carboxamide Chemical compound C=1C=C(C=2N=CC=CC=2)SC=1S(=O)(=O)NC1(C(=O)NO)CCCC1 XPWGEUXPCQVZKF-UHFFFAOYSA-N 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000006720 (C1-C6) alkyl (C6-C10) aryl group Chemical group 0.000 claims description 2
- GLDRXIBLBZWPFO-UHFFFAOYSA-N 1-[[4-(4-chlorophenoxy)phenyl]sulfonylamino]-n-hydroxycyclobutane-1-carboxamide Chemical compound C=1C=C(OC=2C=CC(Cl)=CC=2)C=CC=1S(=O)(=O)NC1(C(=O)NO)CCC1 GLDRXIBLBZWPFO-UHFFFAOYSA-N 0.000 claims description 2
- OMAOBBMMKLNINP-UHFFFAOYSA-N 1-[[4-(4-chlorophenoxy)phenyl]sulfonylamino]-n-hydroxycyclopropane-1-carboxamide Chemical compound C=1C=C(OC=2C=CC(Cl)=CC=2)C=CC=1S(=O)(=O)NC1(C(=O)NO)CC1 OMAOBBMMKLNINP-UHFFFAOYSA-N 0.000 claims description 2
- OVCCDBZTYIZFMK-UHFFFAOYSA-N 2-[[4-(4-chlorophenoxy)phenyl]sulfonylamino]-n-hydroxy-2-methylpropanamide Chemical compound C1=CC(S(=O)(=O)NC(C)(C)C(=O)NO)=CC=C1OC1=CC=C(Cl)C=C1 OVCCDBZTYIZFMK-UHFFFAOYSA-N 0.000 claims description 2
- LVYWHFWCJMTOJI-UHFFFAOYSA-N 2-[[4-(4-fluorophenoxy)phenyl]sulfonylamino]-n-hydroxy-1,3-dihydroindene-2-carboxamide Chemical compound C1C2=CC=CC=C2CC1(C(=O)NO)NS(=O)(=O)C(C=C1)=CC=C1OC1=CC=C(F)C=C1 LVYWHFWCJMTOJI-UHFFFAOYSA-N 0.000 claims description 2
- WNLSBYSBOXDYRG-UHFFFAOYSA-N 3-[[4-(4-fluorophenoxy)phenyl]sulfonylamino]-n-hydroxyazetidine-3-carboxamide Chemical compound C=1C=C(OC=2C=CC(F)=CC=2)C=CC=1S(=O)(=O)NC1(C(=O)NO)CNC1 WNLSBYSBOXDYRG-UHFFFAOYSA-N 0.000 claims description 2
- PJZCTXMYWAEUEH-UHFFFAOYSA-N 4-[[4-(4-fluorophenoxy)phenyl]sulfonylamino]-n-hydroxypiperidine-4-carboxamide Chemical compound C=1C=C(OC=2C=CC(F)=CC=2)C=CC=1S(=O)(=O)NC1(C(=O)NO)CCNCC1 PJZCTXMYWAEUEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-N 0.000 claims description 2
- 231100000433 cytotoxic Toxicity 0.000 claims description 2
- 230000001472 cytotoxic effect Effects 0.000 claims description 2
- LTVOKYUPTHZZQH-UHFFFAOYSA-N difluoromethane Chemical group F[C]F LTVOKYUPTHZZQH-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 2
- VGOLSFZTWVYSTF-UHFFFAOYSA-N n-hydroxy-2-[(4-methoxyphenyl)sulfonylamino]-1,3-dihydroindene-2-carboxamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)NC1(C(=O)NO)CC2=CC=CC=C2C1 VGOLSFZTWVYSTF-UHFFFAOYSA-N 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 239000000243 solution Substances 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000000203 mixture Substances 0.000 description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 108060005980 Collagenase Proteins 0.000 description 17
- 102000029816 Collagenase Human genes 0.000 description 17
- 229960002424 collagenase Drugs 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- 239000003112 inhibitor Substances 0.000 description 16
- 239000007787 solid Substances 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 12
- 239000000758 substrate Substances 0.000 description 12
- 239000012267 brine Substances 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 102000004142 Trypsin Human genes 0.000 description 8
- 108090000631 Trypsin Proteins 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 239000012588 trypsin Substances 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 238000007792 addition Methods 0.000 description 7
- 229940088598 enzyme Drugs 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 150000002443 hydroxylamines Chemical class 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 6
- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 239000012131 assay buffer Substances 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- NILQLFBWTXNUOE-UHFFFAOYSA-N 1-aminocyclopentanecarboxylic acid Chemical compound OC(=O)C1(N)CCCC1 NILQLFBWTXNUOE-UHFFFAOYSA-N 0.000 description 5
- PDAYRCHIAPCRRD-UHFFFAOYSA-N 4-(4-fluorophenoxy)benzenesulfonyl chloride Chemical compound C1=CC(F)=CC=C1OC1=CC=C(S(Cl)(=O)=O)C=C1 PDAYRCHIAPCRRD-UHFFFAOYSA-N 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 210000001519 tissue Anatomy 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
- 108010026132 Gelatinases Proteins 0.000 description 4
- 102000013382 Gelatinases Human genes 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- OXUUEIDXKLFLER-UHFFFAOYSA-N benzyl 2-amino-2-methylpropanoate;hydron;chloride Chemical compound Cl.CC(C)(N)C(=O)OCC1=CC=CC=C1 OXUUEIDXKLFLER-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 3
- HATLZQXBVKJRIA-UHFFFAOYSA-N 2-(4-fluorophenyl)benzenesulfonyl chloride Chemical compound C1=CC(F)=CC=C1C1=CC=CC=C1S(Cl)(=O)=O HATLZQXBVKJRIA-UHFFFAOYSA-N 0.000 description 3
- 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 3
- QZMKMIOBMCHVJC-UHFFFAOYSA-N 4-(3-methylbutoxy)benzenesulfonyl chloride Chemical compound CC(C)CCOC1=CC=C(S(Cl)(=O)=O)C=C1 QZMKMIOBMCHVJC-UHFFFAOYSA-N 0.000 description 3
- XOXRXINFTQAJBW-UHFFFAOYSA-N 4-(4-chlorophenoxy)benzenesulfonyl chloride Chemical compound C1=CC(Cl)=CC=C1OC1=CC=C(S(Cl)(=O)=O)C=C1 XOXRXINFTQAJBW-UHFFFAOYSA-N 0.000 description 3
- DAABFHOAKKNNRE-UHFFFAOYSA-N 4-[(4-fluorophenyl)methoxy]benzenesulfonyl chloride Chemical compound C1=CC(F)=CC=C1COC1=CC=C(S(Cl)(=O)=O)C=C1 DAABFHOAKKNNRE-UHFFFAOYSA-N 0.000 description 3
- DTJVECUKADWGMO-UHFFFAOYSA-N 4-methoxybenzenesulfonyl chloride Chemical compound COC1=CC=C(S(Cl)(=O)=O)C=C1 DTJVECUKADWGMO-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-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
- 239000004677 Nylon Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 229920001778 nylon Polymers 0.000 description 3
- HYDZPXNVHXJHBG-UHFFFAOYSA-N o-benzylhydroxylamine;hydron;chloride Chemical compound Cl.NOCC1=CC=CC=C1 HYDZPXNVHXJHBG-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- GASFYQFDNVFYQD-UHFFFAOYSA-M sodium;4-[(4-fluorophenyl)methoxy]benzenesulfonate Chemical compound [Na+].C1=CC(S(=O)(=O)[O-])=CC=C1OCC1=CC=C(F)C=C1 GASFYQFDNVFYQD-UHFFFAOYSA-M 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- PIYOTRAMASYZKS-UHFFFAOYSA-N 1-[(4-methoxyphenyl)sulfonylamino]cyclopentane-1-carboxylic acid Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)NC1(C(O)=O)CCCC1 PIYOTRAMASYZKS-UHFFFAOYSA-N 0.000 description 2
- WOXWUZCRWJWTRT-UHFFFAOYSA-N 1-amino-1-cyclohexanecarboxylic acid Chemical compound OC(=O)C1(N)CCCCC1 WOXWUZCRWJWTRT-UHFFFAOYSA-N 0.000 description 2
- PAJPWUMXBYXFCZ-UHFFFAOYSA-N 1-aminocyclopropanecarboxylic acid Chemical compound OC(=O)C1(N)CC1 PAJPWUMXBYXFCZ-UHFFFAOYSA-N 0.000 description 2
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 2
- KWPGOOWCMCQZCB-UHFFFAOYSA-N 2-[(4-methoxyphenyl)sulfonylamino]-2-methyl-n-phenylmethoxypropanamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)NC(C)(C)C(=O)NOCC1=CC=CC=C1 KWPGOOWCMCQZCB-UHFFFAOYSA-N 0.000 description 2
- HXLGKHCIQPGCOB-UHFFFAOYSA-N 2-[(4-methoxyphenyl)sulfonylamino]-2-methylpropanoic acid Chemical compound COC1=CC=C(S(=O)(=O)NC(C)(C)C(O)=O)C=C1 HXLGKHCIQPGCOB-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- FEPBITJSIHRMRT-UHFFFAOYSA-N 4-hydroxybenzenesulfonic acid Chemical compound OC1=CC=C(S(O)(=O)=O)C=C1 FEPBITJSIHRMRT-UHFFFAOYSA-N 0.000 description 2
- OGOMWPWAEIDEOU-UHFFFAOYSA-N 5-pyridin-2-ylthiophene-2-sulfonyl chloride Chemical compound S1C(S(=O)(=O)Cl)=CC=C1C1=CC=CC=N1 OGOMWPWAEIDEOU-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
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- CLFNWXLKMQBOMN-UHFFFAOYSA-N ethyl 4-[4-[(4-fluorophenyl)sulfamoyl]anilino]-4-oxobutanoate Chemical compound C1=CC(NC(=O)CCC(=O)OCC)=CC=C1S(=O)(=O)NC1=CC=C(F)C=C1 CLFNWXLKMQBOMN-UHFFFAOYSA-N 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 239000002038 ethyl acetate fraction Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- BRMYZIKAHFEUFJ-UHFFFAOYSA-L mercury diacetate Chemical compound CC(=O)O[Hg]OC(C)=O BRMYZIKAHFEUFJ-UHFFFAOYSA-L 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- HFRJPVNBQJAJIX-UHFFFAOYSA-N n-hydroxy-1-[(4-methoxyphenyl)sulfonylamino]cyclohexane-1-carboxamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)NC1(C(=O)NO)CCCCC1 HFRJPVNBQJAJIX-UHFFFAOYSA-N 0.000 description 1
- SJOAPUIGDHYNSF-UHFFFAOYSA-N n-hydroxy-2-methyl-2-[[4-(3-methylbutoxy)phenyl]sulfonylamino]propanamide Chemical compound CC(C)CCOC1=CC=C(S(=O)(=O)NC(C)(C)C(=O)NO)C=C1 SJOAPUIGDHYNSF-UHFFFAOYSA-N 0.000 description 1
- ZDNNDTUAVSQNGB-UHFFFAOYSA-N o-(2-trimethylsilylethyl)hydroxylamine;hydrochloride Chemical compound Cl.C[Si](C)(C)CCON ZDNNDTUAVSQNGB-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 108091007196 stromelysin Proteins 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical group CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- DRDCQJADRSJFFD-UHFFFAOYSA-N tris-hydroxymethyl-methyl-ammonium Chemical compound OC[N+](C)(CO)CO DRDCQJADRSJFFD-UHFFFAOYSA-N 0.000 description 1
- 230000006433 tumor necrosis factor production Effects 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/20—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
- C07D211/66—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having a hetero atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
Description
Ovaj izum se odnosi na derivate arilsulfonilamino hidroksaminske kiseline koji su inhibitori matričnih metaloproteinaza ili proizvodnje faktora nekroze tumora (TNF), i kao takvi su korisni u tretmanu stanja izabranog iz grupe koja sadrži artritis, rak, gnojenje tkiva, restenozu, peridontalno oboljenje, epidermolysis bullosa, sklerozu i druga oboljenja karakterizirana sa aktivnošću matrične metaloproteinaze, AIDS, sepsu, septički šok i druga oboljenja koja uključuju proizvodnju TNF. Nadalje, spojevi iz ovog izuma mogu se koristiti u kombiniranoj terapiji sa standardnim nesteroidnim anti-upalnim lijekovima (u daljnjem tekstu: "NSAID’S") i analgeticima za tretman artritisa, i u kombinaciji sa citotoksičnim lijekovima takvim kao što su adriamicin, daunomicin, cis-platina, etopoksid, taksol, taksoter i alakloidima, takvim 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 u te svrhe.
Ima više enzima koji utiču na kidanje strukturnih proteina i koji su strukturne vezane metaloproteinaze. Matrično razgradljive metalo proteinaze, takve kao što su želatinaza, stromelsin i kolagenaza, uključene su u razgradnju matričnog tkiva (tj. kolagen kolaps) i uključene su u mnoga patološka stanja, uključujući abnormalno vezivno tkivo i metabolizam matrične bazne membrane, takve kao što su artritis (npr. osteoartritis i reumatski artritis), gnojenje tkiva (npr. kornealno, epidermano i želudačno gnojenje), abnormalno liječene rane, peridontalno oboljenje, oboljenje kostiju (tj. Paget-ovo oboljenje i osteporoza), metastaza tumora ili invazija, isto kao HIV-infekicja ("J. Leuk. Biol.", 52 (2), 244-248, (1992.)).
Poznato je faktor nekroze tumora treba biti uključen u mnoga infektivna i imuna oboljenja (W. Fiers: "FEBS Letters", 285, 199, (1991.)). Dalje, pokazano je da je TNF prvi posrednik kod upalnog odziva viđenog kod sepese i septičkog šoka (C. E. Spooner i dr.: "Clinical Immnology and Immunopathology", 62 S11, (1991.)).
Ovaj izum se odnosi na spoj formule
[image]
ili njegove farmaceutski prihvatljive soli gdje
R1 i R2 su svaki nezavisno odabrani od (C1-C6) alkila, trifluorometila, trifluorometil (C1-C6) alkila, (C1-C6) alkil (difluorometilen), (C1-C3) alkil (difluorometilen (C1-C3) alkila, (C6-C10) arila, (C2-C9) heteroarila, (C6-C10) aril (C1-C6) alkila, (C2-C9) heteroaril (C1-C6) alkila, ili R1 i R2 mogu biti uzeti zajedno da formiraju (C3-C6) cikloalkil ili benzo-stopljen (C3-C6) cikloalkil prsten ili grupu formule
[image]
gdje n i m su nezavisno 1 ili 2, i X je CF2, S, O ili NR3, gdje R3 je vodik, (C1-C6) alkil, (C6-C10) aril, (C2-C9) heteroaril, (C6-C10) aril (C1-C6) alkil, (C2-C9) heteroaril (C1-C6) alkil, (C1-C6) alkilsulfonil, (C6-C10) arilsulfonil ili acil; i
Q 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) aril, (C6-C10) aril (C2-C9) heteroaril, (C6-C10) ariloksi (C2-C9) heteroaril, (C2-C9) heteroaril, (C2-C9) heteroaril (C2-C9) heteraoaril, (C2-C9) heteroaril (C6-C10) aril, (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, (C2-C9) heteroariloksi (C6-C10) aril, (C1-C6) alkil (C2-C9) heteroaril, (C1-C6) alkoksi (C2-C9) heteroaril, (C6-C10) aril (C1-C6) alkoksi (C2-C9) heteroaril, (C2-C9) heteroariloksi (C2-C9) heteroaril, (C6-C10) ariloksi (C1-C6) alkil, (C2-C9) heteroariloksi (C1-C6) alkil, (C1-C6) alkil (C6-C10) ariloksi (C6-C10) aril, (C1-C6) alkil (C2-C9) heteroariloksi (C6-C10) aril, (C1-C6) alkil (C6-C10) ariloksi (C2-C9) heteroaril, (C1-C6) alkoksi (C6-C10) ariloksi (C6-C10) aril, (C1-C6) alkoksi (C2-C9) heteroariloksi (C6-C10) aril ili (C1-C6) alkoksi (C6-C10) ariloksi (C2-C9) heteroaril, gdje je svaka 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 radikale zasićenog monovalentnog ugljikovodika koji imaju normalne, razgranate ili ciklične dijelove ili njihove kombinacije.
Termin "alkoksi", kako je ovdje korišten, uključuje O-alkil grupe, gdje je "alkil" definiran gore.
Termin "aril", kako je ovdje korišten, ako nije drugačije naznačeno uključuje organski radikal izveden od aromatičnog ugljikovodika sa uklanjanjem 1 do 3 supstituenta iz grupe koja sadrži fluoro, kloro, 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, takvog kao što je piridil, furil, piroil, tienil, izotiazolil, imidazolil, benzimidazolil, tetrazolil, pirazinil, pirimidil, hinolil, izohinolil, benzofuril, izobenzofuril, benzotienil, pirazolil, indolil, izoindolil, purinil, karbazolil, izoksazolil, tiazolil, oksazolil, benztiazolil ili benzoksazolil, opcionalno susptituiran sa 1 do 2 supstituenta odabrana 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 O-acil grupe, gdje je "acil" definiran gore.
Spoj formule I može imati hiralne centre i zato postoji u različitim enantiomernim oblicima. Ovaj izum se odnosi na sve optičke izomere i stereoizomere spoja formule I i njihovih smjesa.
Poželjna spojevi formule I uključuju one gdje su R1 i R2 uzeti zajedno da formiraju (C3-C6) cikloalkil ili benzo-stopljen (C3-C6) cikloalkil prsten ili grupu formule
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gdje n i m su nezavisno 1 ili 2, i X je CF2, S, O ili NR3, gdje R3 je vodik, (C1-C6) alkil, (C6-C10) aril, (C2-C9) heteroaril, (C6-C10) aril (C1-C6) alkil, (C2-C9) heteroaril (C1-C6) alkil, (C1-C6) alkilsulfonil, (C6-C10) arilsulfonil ili acil.
Drugi poželjni spojevi formule I uključuju one gdje su R1 i R2 uzeti zajedno da formiraju (C3-C6) cikloalkil ili benzo-stopljen (C3-C6) cikloalkil prsten.
Drugi poželjni spojevi formule I uključuju one gdje Q je (C6-C10) aril, (C6-C10) aril (C6-C10) aril, (C6-C10) ariloksi (C6-C10) aril, (C6-C10) ariloksi (C2-C9) heteroaril, (C2-C9) heteroaril, (C2-C9) heteroaril (C2-C9) heteroaril, (C6-C10) aril (C2-C9) heteroaril, (C2-C9) heteroaril (C6-C10) aril ili (C2-C9) heteroariloksi (C6-C10) aril.
Drugi poželjni spojevi formule I uključuju one gdje Q je (C6-C10) ariloksi (C6-C10) aril.
Drugi poželjni spojevi formule I uključuju one gdje su R1 i R2 svaki nezavisno (C1-C6) alkil.
Poželjniji spojevi formule I uključuju one gdje su R1 i R2 uzeti zajedno da formiraju (C3-C6) cikloalkil ili benzostopljen (C3-C6) cikloalkil prsten ili grupu formule
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gdje n i m su nezavisno 1 ili 2, i X je CF2, S, O ili NR3, gdje R3 je vodik, (C1-C6) alkil, (C6-C10) aril, (C2-C9) heteroaril, (C6-C10) aril (C1-C9) alkil, (C2-C9) heteroaril (C1-C6) alkil, (C1-C6) alkilsulfonil, (C6-C10) arilsulfonil ili acil; i Q je (C6-C10) aril, (C6-C10) aril (C6-C10) aril, (C6-C10) ariloksi (C6-C10) aril, (C6-C10) ariloksi (C2-C9) heteroaril, (C2-C9) heteroaril, (C2-C9) heteroaril (C2-C9) heteroaril, (C6-C10) aril (C2-C9) heteroaril, (C2-C9) heteroaril (C6-C10) aril ili (C2-C9) heteroariloksi (C6-C10) aril.
Poželjniji spojevi formule I uključuju one gdje su R1 i R2 uzeti zajedno da formiraju (C3-C6) cikloalkil ili benzostupljen (C3-C6) cikloalkil prsten; i Q je (C6-C10) aril, (C6-C10) aril (C6-C10) aril, (C6-C10) ariloksi (C6-C10) aril, (C6-C10) ariloksi (C2-C9) heteroaril, (C2-C9) heteroaril, (C2-C9) heteroaril (C2-C9) heteroaril, (C6-C10) aril (C6-C10) (C2-C9) heteroaril, (C2-C9) heteroaril (C6-C10) aril ili (C2-C9) heteroariloksi (C6-C10) aril.
Poželjniji spojevi formule I uključuju one gdje su R1 i R2 svaki nezavisno (C1-C6) alkil; i Q je (C6-C10) aril, (C6-C10) aril (C6-C10) aril, (C6-C10) ariloksi (C6-C10) aril, (C6-C10) ariloksi (C2-C9) heteroaril, (C2-C9) heteroaril, (C2-C9) heteroaril (C2-C9) heteroaril, (C6-C10) aril (C2-C9) heteroaril, (C2-C9) heteroaril (C6-C10) aril ili (C2-C9) heteroariloksi (C6-C10) aril.
Poželjniji spojevi formule I uključuju one gdje su R1 i R2 svaki nezavisno (C1-C6) alkil; i Q je (C6-C10) ariloksi (C6-C10) aril.
Specifično poželjni spojevi formule I uključuju slijedeće:
3-[4-(4-fluorofenoksi)benzensulfonilamino]azetidin-3-karboksilna kiselina hidroksiamid;
4-[4-(4-fluorofenoksi)benzensulfonilamino]piperidin-4-karboksilna kiselina hidroksiamid;
1-[4-(4-fluorofenoksi)benzensulfonilamino]ciklopropan-1-karboksilna kiselina hidroksiamid;
1-[4-(4-klororofenoksi)benzensulfonilamino]ciklopropan-1-karboksilna kiselina hidroksiamid;
1-[4-(4-fluorofenoksi)benzensulfonilamino]ciklobutan-1-karboksilna kiselina hidroksiamid;
1-[4-(4-klororofenoksi)benzensulfonilamino]ciklobutan-1-karboksilna kiselina hidroksiamid;
1-[4-(4-fluorofenoksi)benzensulfonilamino]ciklopentan-1-karboksilna kiselina hidroksiamid;
1-[4-(4-fluorofenoksi)benzensulfonilamino]ciklobutan-1-karboksilna kiselina hidroksiamid;
1-[4-(4-fluorofenoksi)benzensulfonilamino]cikloheksan-1-karboksilna kiselina hidroksiamid;
2-[4-(4-fluorofenoksi)benzensulfonilamino]-N-hidroksi-2-metilpropionamid;
2-[4-(4-klorofenoksi)benzensulfonilamino]-N-hidroksi-2-metil-propionamid;
N-hidroksi-2-metil-2-(5-piridin-2-iltiofen-2-sulfonilamino)propionamid;
1-(5-piridin-2-il-tiofen-2-sulfonilamino)ciklopentan-1-karboksilna kiselina hidroksiamid;
1-(4’-fluorofenil-4-sulfonilamino)ciklopropan-1-karboksilna kiselina hidroksiamid;
1-(4’-fluorofenil-4-sulfonilamino)ciklobutan-1-karboksilna kiselina hidroksiamid;
1-(4’-fluorofenil-4-sulfonilamino)ciklopentan-1-karboksilna kiselina hidroksiamid;
2-(4-metoksibenzensulfonilamino)indan-2-karboksilna kiselina hidroksiamid; i
2-[4-(4-fluorofenoksi)benzensulfonilamino]-indan-2-karboksilna kiselina hidroksiamid.
Ovaj izum se također odnosi na farmaceutski preparat za: (a) tretman stanja odabranog 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, septički šok i druga oboljenja koja uključuju proizvodnju faktora nekroze tumora (TNF); ili (b) inhibiciju matričnih metaloproteinaza ili proizvodnje faktora nekroze tumora (TNF) kod sisavaca, uključujući i čovjeka, koji sadrži količinu spoja formule I ili njegove farmaceutski prihvatljive soli efikasne u takvim tretmanima i farmaceutski prihvatljivi nosač.
Ovaj izum se također odnosi na postupak za inhibiciju: (a) matričnih metaloproteinaza; 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 odabranog iz grupe koja sadrži artritis, rak, gnojenje tkiva, pjegavu degeneraciju, restenozu, peridontalno oboljenje, epidermolysis bullosa, sklerozu, spojevi formule I mogu se koristiti 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, septički šok i druge bolesti koja uključuju 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.
Sljedeće reakcijske sheme ilustriraju dobivanje spojeva iz ovog izuma. Ako nije drugačije naznačeno R1, R2 i Q u reakcijskim shemama i u diskusiji koja slijedi definirani su kao gore.
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U reakciji 1 dobivanja A, amino kiselina formule III tretira se sa benzil alkoholom formule HX, gdje X je poželjno 4-toluensulfonat, u inertnom otapalu takvom kao što je benzen ili toluen (poželjno toluen) radi dobivanja odgovarajuće soli benzil ester kiseline formule V. Reakcija se normalno vrši tokom perioda vremena između oko 1 sat do oko 24 sata, na temperaturi ključanja korištenog otapala. Voda formirana tokom razvoja reakcije sakuplja se normalno u Dean-Stark-ovoj posudi.
U reakciji 2 dobivanja A, spoj formule V konvertira se u odgovarajući spoj formule VI sa reagiranjem V sa reaktivnim funkcionalnim derivatom sulfonske kiseline (QSO2OH), takvim kao što je sulfonil klorid (QSO2Cl), u prisustvu baze takve kao što je natrij hidroksid ili trietilamin, i otapala, takvog kao što je metilen klorid, tetrahidrofuran, dioksan, voda ili acetonitril, poželjno smjesa dioksana i vode. Reakcijska smjesa je miješana na temperaturi između oko 0 °C do oko 50 °C, poželjno na sobnoj temperaturi, tokom perioda vremena između oko 10 minuta do oko 2 dana, poželjno oko 60 minuta.
U reakciji 3 dobivanja A, spoj intermedijera formule VI se hidrogenizira radi dobivanja intermedijera formule II. Reakcija se vrši u otapalu takvom kao što je etanol, pod atmosferom vodika (poželjno na tlaku od 3 bara) korištenjem katalizatora takvog kao što je 10 % paladija na aktivnom ugljiku. Reakcija se normalno trese na sobnoj temperaturi tokom perioda vremena između oko 30 minuta do oko 24 sata, poželjno oko 1,5 sata.
U reakciji 1 sheme 1, spoj amino kiseline formule III konvertira se u odgovarajući spoj formule II sa reagiranjem III sa reaktivnim funkcionalnim derivatom sulfonske kiseline formule QSO2OH, gdje Q je definiran gore, takvim kao što je sulfonil klorid (QSO2Cl), u prisustvu baze, takve kao što je natrij hidroksid ili trietilamin, i polarnog otapala takvog kao što je tetrahidrofuran, dioksan, voda ili acetonitril, poželjno smjesa dioksana i vode. Reakcijska smjesa se miješa na temperaturi između oko 0 °C do oko 50 °C, poželjno na sobnoj temperaturi, tokom perioda vremena između 10 minuta do oko 2 dana, poželjno oko 60 minuta.
U reakciji 2 sheme 1, karboksilna kiselina formule II konvertira se u spoj hidroksaminske kiseline formule I sa tretiranejm II sa 1-(3-dimetilaminopropil)-3-etilkarbodimidom i 1-hidroksibenzotriazolom u polarnom otapalu takvom kao što je N,N-dimetilformamid, što je praćeno sa dodavanjem hidroksilamina u reakcijsku smjesu posle perioda vremena između oko 15 minuta do oko 1 sat, poželjno oko 30 minuta. Hidroksilamin se poželjno generira in situ u obliku soli, takve kao što je hidroksilamin hidroklorid, u prisustvu baze, takve kao što je trietilamin. Alternativno, zaštićeni derivat hidroksilamina ili njegovog oblika soli, gdje hidroksil grupa je zaštićena kao tert-butil, alil ili 2-trimetilsililetil eter, može se koristiti umjesto hidroksilamina ili soli hidroksilamina. Uklanjanje hidroksil zaštitne grupe vrši se sa hidrigenolizom za benzil zaštitnu grupu (poželjni katalizator je 5 % paladija na barij sulfatu) ili tretmanom sa jakom kiselinom, takvom kao što je trifluorooctena kiselina, za tert-butil zaštitnu grupu. Alil zaštitna grupa može biti uklonjena sa tretmanom sa tributilkositarhidridom i octenom kiselinom u prisustvu katalitičkog bis(trifenilfosfin) paladij(II) klorida. 2-trimetilsililetil eter može se ukloniti reakcijom sa jakom kiselinom, takvom kao što je trifluorooctena kiselina ili reakcijom sa izvorom fluorida, takvim kao što je bor trifluorid eterat. Reakcija II sa hidroksilaminom, soli hidroksilamina, zaštićenim derivatom hidroksilamina ili soli zaštićenog derivata hidroksilamina može se također vršiti u prisustvu (benztriazol-1-iloksi)tris(dimetilamino)-fosfonij heksafluorofosafata i baze, takve kao što je trietilamin, u inertnom otapalu, takvom kao metilen klorid. Reakcijska smjesa se miješa na temperaturi između oko 0 °C do oko 50 °C, poželjno na sobnoj temperaturi, tokom perioda vremena oko 1 sat do oko 3 dana, poželjno oko 1 dan. Poželjni postupak za konvertiranje spoja II u spoj I je da reagira II sa O-benzil hidroksilamin hidrokloridom u prisustvu (benzotriazol-1-iloksi)tris(dimetilamino)-fosfonij heksafluorofosfata i triaetilamina korištenjem metilen klorida kao otapala. Sljedeće uklanjanje O-benzil zaštitne grupe radi dobivanja spoja formule I vrši se sa hidrogenolizom pod 3 bara vodika na sobnoj temperaturi korištenjem 5 % paladija na barij sulfata kao katalizatora. Poželjno otapalo je metanol. Reakcijsko vrijeme može se mijenjati od oko 1 sat do oko 5 sati (3,5 sata poželjno).
U nekim slučajevima poželjno je da se dobije spoj formule I sa reakcijom hidroksilamina, soli hidroksilamina, zaštićenog derivata hidroksilamina ili soli zaštićenog derivata hidroksilamina sa aktivnim esterom formule IV, kako je pokazano u reakciji 3 sheme 1. Reakcija se vrši u inertnom otapalu, takvom kao što je N,N-dimetil-formamid na temperaturi u opsegu od oko sobne temperature do oko 80 °C, poželjno oko 50 °C tokom perioda vremena od oko 1 sata do oko 2 dana. Ako se koristi zaštićeni derivat hidroksilamina ili sol zaštićenog derivata hidroksilamina, uklanjanje zaštitne grupe se vrši kako je gore opisano. Aktivni ester derivat formule IV dobiva se tretmanom spoja formule II sa (benzotriazol-1-iloksi)tris(dimetilamino)-fosfonij heksafluorofosfatom i bazom, takvom kao što je trietilamin, u inertnom otapalu, takvom kao što je metilen klorid (reakcija 4, shema 1). Reakcijska smjesa se miješa na temperaturi između oko 0 °C do oko 50 °C, poželjno sobnoj temperaturi, tokom perioda vremena između oko 1 sat do oko 3 dana, poželjno oko 1 dan.
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 su natrij, kalij, kalcij, magnezij, isto kao i soli amonija, takve kao što su soli amonija, trimetil-amonija, dietilamonija, i tris-(hidroksimetil)-metilamonija.
Slično kod adicijskih soli kiseline, takvih kao što su neorganske kiseline, organske karboksilne i organske sulfonske kiseline, napr. klorovodična kiselina, metansulfonska kiselina, maleinska kiselina, također se lako osigurava bazna grupa, takva kao što je piridil, koja formira dio strukture.
Sposobnost spojeva formule I ili njihovih farmaceutski prihvatljivih soli (u daljnjem tekstu: "spojevi iz izuma") da inhibiraju matrične metaloproteinaze ili proizvodnju faktora nekroze tumora (TNF) i, iz čega proizlazi demonstracija njihove efikasnost za tretiranje oboljenja karakteriziranih sa matričnom metaloproteinazom ili proizvodnjom faktora nekroze tumora, pokazana je sa slijedećim in vitro pokusnim testovima.
BIOLOŠKI POKUSI
Inhibicija ljudske kolagenaze (MMP-1)
Ljudska rekombinantna kolagenaza aktivirana je sa tripsinom korištenjem slijedećeg odnosa: 10 µg tripsina na 100 µg kolagenaze. Tripsin i kolagenaza inkubirane su na sobnoj temperaturi tokom 10 minuta, a zatim je dodan peterostruki višak (50 µg/10 µg tripsina) inhibitora tripsina soje.
10 mM stok otopine inhibitora napravljene su u dimetil sulfoksidu, a zatim su razblažene korištenjem slijedeće sheme:
10 mM —> 120 µM —> 12 µM —> 1,2 µM —> 0,12 µM
Zatim je u triplikatu dodano 25 µl svake koncentracije u odgovarajuće otvore mikroflor ploče sa 96 otvora. Finalna koncentracija inhibitora biti će 1:4 razblažena posle dodavanja enzima i supstrata. Pozitivne kontrole (enzim, ne-inhibitor) postavljaju se u otvore D1-D6, a prazne kontrole (ne-enzim, ne-inhibitor) postavljaju se u otvore D7-D12.
Kolagenaza je razblažena na 400 ng/ml, a zatim je dodano 25 µl u prikladne otvore mikrofluor ploče. Finalna koncentracija kolagenaze u pokusu je 100 ng/ml.
Napravljen je supstrat (DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2) kao 5 mM stok u dimetil sulfoksidu, a zatim je razblažen na 20 µM u pokusnom puferu. Pokus je iniciran sa dodavanjem 50 µl supstrata po otvoru mikrofluor ploče radi dobivanja finalne koncentracije od 10 µM.
Fluorescentna čitanja (360 nm eksitacija, 450 nm emisija) uzeta su u vremenu 0 i u intervalima od 20 minuta. Pokus je vršen na sobnoj temperaturi, sa tipičnim vremenom pokusa od 3 sata.
Zatim je nacrtana krivulja fluoroescencije prema vremenu za prazne uzorke koji su sadržavali kolagenazu (podaci u trostrukim određivanjima su usrednjeni). Točka vremena koja omogućava dobar signal (prazno) i ona gdje je linearni dio krivulje (obično oko 120 minuta) izabrane su za određivanje IC50 vrijednosti. Nulto vrijeme se koristi kao prazno za svaki spoj u svakoj koncentraciji i ove vrijednosti su oduzete od podataka 120 minuta. Podaci su nacrtani kao koncentracija inhibitora prema % kontrole (fluorescencija inhibitora podijeljena sa fluorescencijom same kolagenaze × 100). IC50 su određeni iz koncentracije inhibitora koja daje signal koji je 50 % od kontrole.
Ako je zapisano da su IC50 < 0,03 µM, tada su inhibitori ispitivani u koncentracijama od 0,3 µM, 0,03 µM, 0,03 µM i 0,003 µM.
Inhibicija želatinaze (MMP-2)
Aktivnost 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).
72 kD želatinaze aktivirano je sa 1 mM APMA (p-aminofenil živin acetat) tokom 15 sati na 4 °C i razblažena je da se dobije finalna koncentracija u pokusu od 100 mg/ml. Inhibitori su razblaženi kao inhibicija ljudske kolagenaze (MMP-1) radi dobivanja finalnih koncentracija u pokusu od 30 µM, 3 µM, 0,3 µM i 0,03 µM. Svaka koncentracija je rađena u triplikatu.
Fluorescentna čitanja (360 nm eksitacija, 450 nm emisija) uzeta su u vremenu 0 i u intervalima od 20 minuta tokom 4 sata.
IC50 određeni su kao za inhibiciju ljudske kolagenaze (MMP-1). Ako je zapisano da su IC50 < od 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 stromelsiana bazirana je na modificiranom spektro-fotokemijskom pokusu koji su opisali Weingarten, H. i Feder, J.: "Spectrophotometric Assay for Vertebrate Collagenase, Anal, Biochem." 147, 437-440, (1985.). Hidroliza supstrata tio peptida (Ac-Pro-Leu-Gly-SCH(CH2CH) cH3)2) cO-Leu-Gly-OC2H5) daje fragment merkaptana moji se može prikazati u prisustvu Ellman-ovog reagensa.
Ljudski rekombinantni prostromelsin aktiviran je sa tripsinom korištenjem odnosa 1 µl od 10 mg/ml tripsin stoka na 26 µg stromelsina. Tripsin i stromelsin inkubirani su na 37 °C tokom 15 minuta, što je 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 pokusnog pufera (200 nM natrij klorida, 50 mM MES, i 10 mM kalcij klorida, pH = 6,0) u mikroliter pločama sa 96 otvora. Aktivni stromelsin razblažen je u pokusnom puferu na 25 µg/ml. Ellman-ov reagens (3-karboksi-4-nitrofenil disulfid) napravljen je kao 1M stok u dimetil formamidu i razblažen na 5mM u pokusnom puferu sa 50 µl po otvoru, dajući 1 mM finalne koncentracije.
10 mM stok otopine inhibitora napravljene su u dimetil sulfoksidu i razblažene u pokusnom puferu, 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 stok otopine supstarata peptida razblaženo je u 15 mM u pokusnom puferu i pokus je iniciran sa dodavanjem 50 µg u svaki otvor, radi dobivanja finalne koncentracije od 3 mM supatrata. Prazni se sastoje od peptid supstrata i Ellman-ovog reagensa bez enzima. Formiranje proizvoda prikazano je na 405 nm sa Molecular Devices UVmax čitačem ploče.
IC50 vrijednosti određene su na isti način kao za kolagenazu.
Inhibicija MMP-3
Ljudski rekombinantni MMP-13 aktiviran je sa 2mM APMA (p-1minofenil živin acetat) tokom 1,5 sata, na 37 °C i razblažen je na 400 mg/ml u pokusnom puferu (50 mM Tris, pH = 7,5, 200 mM natrij klorid, 5 mM kalcij klorid, 20 µM cink klorid, 0,02 % brij). Po otvoru od mikrofluor ploče sa 96 otvora dodano je 25 µl razblaženog enzima. Tokim pokusa enzim je razblažen u odnosu 1:4 sa dodavanjem inhibitora i supstrata, radi dobivanja finalne koncentracije u pokusu od 100 mg/ml.
10 mM stok otopine su napravljene u dimetil sulfoksidu i zatim razblažene u pokusnom puferu kao za shemu razblaženja inhibitora za inhibiciju ljudske kolagenaze (MMO-1): U triplikatu je dodano 25 µl svake koncentracije u mikrofluor ploču. Finalne koncentracije u pokusu su 30 µM, 3 µM, 0,3 µM, i 0,03 µM.
Supstrat (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 u pokusu od 10 µM. Fluorescentna čitanja (360 nM eksitacija; 450 emisija) uzete su u vremenu 0 i svakih 5 minuta tokom 1 sata.
Pozitivne kontrole se sastoje od enzima i supstrata bez inhibitora, a prazne se sastoje samo od supstrata.
IC50 su određeni kao za inhibiciju 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 proizvodnje TNF
Sposobnost spojeva ili njihovih farmaceutski prihvatljivih soli da inhibiraju proizvodnju TNF i, iz čega proizlazi pokazivanje njihove efikasnost za tretiranje oboljenja koja uključuju proizvodnju TNF, pokazana je sa slijedećim in vitro pokusom:
Ljudske mononuklearne stanice su izolirane iz ljudske nezgrušane krvi korištenjem jednofazne tehnike izdvajanja Ficoll-hypaque. Nakon toga mononuklearne stanice su isprane tri puta u Hanks-ovoj balansiranoj otopini soli (HBSS) sa divalentnim kationima i ponovo su suspendirane na gustoću od 2 × 106 /ml u HBSS koji sadrži 1 % BSA. Diferencijalni brojevi određeni su korištenjem Abbot Cell Dyn 3500 analizatora, koji je pokazao da su monociti od 17 do 24 % ukupnih stanica u ovim dobivanjima.
180 µ suspenzije stanice alikvotno je sipano na ravno dno ploče sa 96 otvora (Costar). Dodavanja spoja i LPS (100 ng/ml finalne koncentracije) dala su finalni sadržaj od 200 µl. Svi uvjeti su izvršeni u triplikatu. Posle 4 sata inkubacije na 37 °C i vlaženja CO2 inkubatora, ploče su uklonjene i centrifugirane (10 minuta na približno 250 × g) i supernatanti su uklonjeni i ispitivani za TNF� korištenjem R&D ELISA kita.
Za unošenje u sisavce, uključujući i ljude, za inhibiciju matričnih metaloproteinaza ili proizvodnje faktora nekroze tumora (TNF), može se koristiti više konvencionalnih putova, uključujući oralno, parenteralno i mesno. Općenito, aktivni spoj biti će unijet oralno ili parenteralno u dozama između oko 0,1 i 25 mg/kg masene težine subjekta koji se tretira po danu, poželjno od oko 0,3 do 5 mg/kg. zavisno od stanja subjekta koji se tretira moguće su i neke varijacije u doziranju. Stručnjak odgovoran za unošenje u svakom će slučaju odrediti prikladnu dozu za pojedinačnog subjekta.
Spojevi iz ovog izuma mogu se unositi u velikom mnoštvu raznih doznih oblika. Općenito, terapeutski efikasni spojevi iz ovog izuma prisutna su u takvim doznim oblicima u nivoima koncentracije u opsegu od oko 5,0 masenih % do oko 70 masenih %.
Za oralno unošenje, tablete koje sadrže razne ekcipijente, takve kao što su mikrokristalna celuloza, natrij citrat, kalcij karbonat, dikalcij fosfat i glicin, mogu se koristiti zajedno sa raznim razgrađivačima, takvim kao što je škrob (poželjno škrob žita, krompira i tapioke), alginska kiselina i neki kompleksni silikati, zajedno sa vezivima granulacije sličnim polivinilpirolidonu, sukrozi, želatinu i akaciji. Dodatno, sredstva podmazivanja, takva kao što je magnezij stearat, natrij lauril sulfat i talk, često su vrlo korisna za potrebe tabletiranja. Čvrsti preparati sličnog tipa mogu se 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 se vodene suspenzije i/ili eliksiri žele za oralno unošenje, aktivni sastojak može se kombinirati sa raznim zaslađivačima ili mirisnim sredstvima, materijalom za bojenje ili bojama, a također, ako se želi, i sredstvima emulgiranja i/ili suspendiranja, zajedno sa razblaživačima, takvim kao voda što je , etanol, propilen glikol, glicerin i razne njihove slične kombinacije. U slučaju životinja, oni su sadržani u hrani životinja ili vodi za piće u koncentraciji od 5-5000 ppm, poželjno 25 do 500 ppm.
Za parenteralno unošenje (intramuskularna, intraperitonealmno, potkožna i intravenska primjena) obično se dobiva sterilna ubrizgavajuća otopina aktivnog sastojka. Mogu se koristiti iotopine terapeutskih spojeva iz ovog izuma u ulju sezama ili kikirikija ili u vodenom propilen glikolu. Vodene otopine trebaju biti prikladno podešene i puferirane, poželjno na pH većem od 8, a ako je potrebno tekući razblaživač se prvo vrati u izotonsko stanje. Ove vodene otopine prikladne su za potrebe intravenske injekcije. Uljne otopine su prikladne za intrartikularne, intramuskularne i potkožne potrebe. Dobivanje svih ovih otopina pod sterilnim uvjetima lako se odvija 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, najprikladnije 0,2 do 10 mg/kg/dan dato u jednoj dozi ili do 3 podijeljene doze.
Ovaj izum je ilustriran sa slijedećim primjerima, ali nije ograničen na njihove detalje.
Dobivanje A
4-(4-fluorofenoksi)benzensulfonil klorid
Klorosulfonska kiselina (26 ml, 0,392 mola) dodana je ukapavanjem u ledom ohlađeni 4-fluorofenoksibenzen (36,9 grama, 0,196 mola) sa mehaničkim miješanjem. Kada je završeno dodavanje, smjesa je miješana na sobnoj temperaturi tokom 4 sata. Smjesa je zatim sipana u ledeno hladnu vodu. Proizvod, 4-(4-fluorofenoksi)benzen-sulfonilklorid (18,6 grama, 33 %) sakupljen je sa filtriranje i osušen na zraku.
Dobivanje B
Natrij 4-(3-metilbutoksi)benzensulfonat
Otopina 4-hidroksibenzensulfinske kiseline (10,0 grama, 43,1 mmola) i natrij hidroksida (3,3 grama, 83 mmola) u vodi (40 ml) pomiješana je sa otopinom 1-jodo-3-metilbutana (11,3 ml, 86,4 mmola) u izopropanolu (60 ml) i rezultirajuća smjesa je grijana na refluksu tokom 2 dana. Izopropanol je uklonjen sa isparavanjem pod vakuumom. Spoj iz naslova, 10,0 grama (87 %), sakupljen je sa filtriranjem i ispiranjem sa izopropanolom.
Dobivanje C
4-(3-metilbutoksi)benzensulfonil klorid
Smjesa natrij 4-(3-metilbutoksi)benzensulfonata (2,5 grama, 9,4 mmola), tionil klorida (10 ml), i 5 kapi N,N-dimetilformamida grijana je na refluksu tokom 5 sati. Posle hlađenja, višak tionil klorida je isparen i ostatak je uzet u etil acetatu. Otopina je ohlađena u kadi s ledom i dodana je voda. Organska faza je izdvojena i isprana sa vodom i slanom vodom. Posle sušenja preko natrij sulfata, otapalo je ispareno radi dobivanja spoja iz naslova kao ulje, 2,34 grama (95 %).
Dobivanje D
Natrij 4-(2-ciklopentiletoksi)benzensulfonat
Otopina 4-hidroksibenzensulfonske kiseline (6,5 grama, 28,2 mmola) i natrij hidroksida (2,2 grama, 55 mmola) u vodi (15 ml) pomiješana je sa otopinom 2-(bromoetil) ciklopentana (15,0 grama, 84,7 mmola) u izopropanolu (40 ml) i rezultirajuća smjesa je grijana na refluksu tokom 2 dana. Izopropanol je uklonjen sa isparavanjem pod vakuumom. Spoj iz naslova, 4,7 grama (57 %), sakupljen je sa filtriranjem i ispiranjem sa izopropanolom.
Dobivanje E
4-(3-metilbutoksi)benzensulfonil klorid
Smjesa natrij 4-(2-ciklopentiletoksi)-benzensulfonata (2,5 grama, 8,6 mmola), tionil klorida (15 ml), i nekoliko kapi N,N-dimetilformamida grijana je na refluksu tokom 5 sati. Posle hlađenja, višak tionil klorida je isparen i ostatak je uzet u etil acetatu. Otopina je ohlađena u kadi s ledom i dodana je voda. Organska faza je izdvojena i isprana sa vodom i slanom vodom. Posle sušenja preko natrij sulfata, otapalo je ispareno radi dobivanja spoja iz naslova kao ulje, 2,24 grama (90 %).
Dobivanje F
4’-fluorobifenilsulfonil klorid
Klorosulfonska kiselina (8,7 ml, 0,13 mola) dodana je ukapavanjem u 4-fluorofenil (10,2 grama, 59 mmola) sa miješanjem u kadi sa ledom. Miješanje je nastavljeno sa hlađenjem ledom tokom 0,5 sati i reakcija je zatim sipana na led. Rezultirajući bijeli talog sakupljen je sa filtriranjem i otopljen u kloroformu. Kloroform otopina isprana je sa vodom i slanom vodom, osušena preko magnezij sulfata i koncentrirana radi dobivanja bijelog čvrstog materijala. Željeni proizvod, 4’-fluorobifenilsulfonil klorid (4,3 grama, 27 %), izdvojen je od 4’-fluorobifenilsulfonske kiseline (neželjeni sporedni proizvod) sa kristalizacijom iz etil acetata i kristalizacijom preostalog materijala iz heksana.
Dobivanje G
Natrij 4-(4-fluorobenziloksi)benzensulfonat
U otopinu 4-hidroksiebenzensulfonske kiseline (5,13 grama, 22,1 mmola) u 1N vodenoj otopini natrij hidroksida (23 ml) dodana je otopina 4-fluorobenzilbromida (3,3 ml, 26,5 ml). Rezultirajuća smjesa je grijana na refluksu 2 dana. Posle hlađenja i stajanja, istaložio se bijeli čvrsti materijal. Istaloženi proizvod, natrij 4-(4-fluorobenziloksi)benzensulfonat, 4,95 grama (74 %), sakupljen je sa filtriranjem i ispiranjem sa etil acetatom i dietil eterom.
Dobivanje H
4-(4-fluorobenziloksi)benzensulfonil klorid
U suspenziju natrij 4-(4-fluorobenziloksi)benzensulfonata (0,5 grama, 1,64 mmola), u metilen kloridu (5 ml) dodan je fosfor pentaklorid (275 mg, 1,31 mmola). Rezultirajuća smjesa je grijana na refluksu tokom 7 sati. Posle hlađenja u kadi s ledom i gašenja sa vodom (15 ml), smjesa je ekstrahirana sa etil acetatom. Organska faza je isprana sa slanom vodom, osušena preko natrij sulfata, i koncentrirana radi dobivanja 4-(4-fluorobenziloksi)benzensulfonil klorida kao bijeli čvrsti proizvod (130 mg, 26 %).
Dobivanje I
4-(4-klorofenoksi)benzensulfonil klorida
Klorosulfonska kiselina (9,7 ml, 0,147 mola) dodana je ukapavanjem u 4-klorofenoksibenzen (12,6 ml, 73,4 mmola) na sobnoj temperaturi uz miješanje. Kada je završeno dodavanje, smjesa je miješana na sobnoj temperaturi tokom 1 sata, a zatim je sipana u ledeno hladnu vodu. Čvrsti materijal je sakupljen filtriranjem, osušen na zraku, i ponovo kristaliziran iz petrolej etera i etil acetata, radi dobivanja 4-(4klorofenoksi)benzensulfonil klorida (7,43 grama, 33 %).
Primjer 1
1-(4-metoksibenzensulfonilamino)ciklopentan-1-karboksilna kiselinahidroksiamid
(A) U otopinu 1-aminociklopentan-1-karboksilne kiseline (6,0 grama, 46,5 mmola) i trietilamina (14 ml, 100 mmola) u dioksanu (90 ml) i vodi (90 ml) dodan je 4-metoksibenzensulfonil klorid (10,6 grama, 51,3 mmola). Rezultirajuća smjesa je miješana na sobnoj temperaturi tokom 4 sata, zakiseljena sa 1N vodenom otopinom klorovodične kiseline, i ekstrahirana dva puta sa etil acetatom. Kombinirani ekstrakti etil acetata isprani su sa slanom vodom, osušeni preko magnezij sulfata i koncentrirani radi dobivanja čvrstog žuto-smeđeg materijala koji je trituriran sa kloroformom, radi dobivanja 1-(4-metoksibenzensulfonilamino)-ciklopentan-1-karboksilne kiseline kao bijeli čvrsti proizvod, 5,42 grama (39 %).
(B) U otopinu 1-(4-metoksibenzensulfonilamino) ciklopentan-1-karboksilen kiseline (4,65 grama, 15,2 mmola) i trietilamina (2,5 ml, 17,9 mmola) u metilenkloridu (120 ml) dodan je benzotriazol-1-iloksi)tris(dimetilamino)fosfonij heksafluorofosfat (7,4 grama, 16,3 mmola). Rezultirajuća smjesa je miješana na sobnoj temperaturi tokom 2,5 dana. Otapalo je ispareno i ostatak je uzet u etil acetatu. Otopina je isprana sukcesivno sa vodenom otopinom 0,5 N klorovodičnom kiselinom, vodom i slanom vodom. Posle sušenja preko magnezij sulfata, otapalo je ispareno radi dobivanja 1-(4-metoksibenzesulfonilamino)ciklopentan-karboksilna kiselina benzotriazol-1-il estera kao žuti čvrsti materijal. Ovaj je otopljen u N,N-dimetilformamidu (120 ml), a u rezultirajuću otopinu dodan je diizopropiletilamin (5,3 ml, 30 mmola) i O-benzilhidroksilamin hidroklorid (3,2 grama, 20 mmola). Smjesa je grijana u kadi s uljem na 50 °C tokom 20 sati. Otapalo je ispareno i dodan je etil acetat. Smjesa je filtrirana radi sakupljanja bijelog čvrstog materijala. Filtrat je ispran uzastopno sa vodenom otopinom 0,5N klorovodične kiseline, vodenom zasićenom otopinom natrij bikarbonata i slanom vodom. Posle isparavanja otapala, dobiven je čvrsti materijal koji je kombiniran sa onim izoliranim sa filtriranjem i trituriran sa etil acetatom, radi dobivanja 1-(4-metoksibenzensulfonilamino) ciklopentan-1-karboksilna kiselina benzil oksiamida kao bijeli čvrsti proizvod, 2,92 grama (47 %).
(C) Otopina 1-(4-metoksibenzensulfonilamino)ciklopentan-1-karboksilna kiselina benziloksiamida (1,50 grama, 3,71 mmola) u metanolu (200 ml) tretiran je sa 5 % paladija na barij sulfata (0,75 grama) i hidrogeniran je na tlaku od 3 bara tokom 3,5 sata u Parr-ovom tresaču. Katalizator je uklonjen sa prolazom preko 0,45 µm najlon filtera, a filtrat je koncentriran radi dobivanja 1-(4-metoksibenzensulfonilamino)-ciklopentan-1-karboksilna kiselina hidroksiamida kao bijeli čvrsti proizvod, 1,13 grama (97 %).
MS: 313 (M-1).
Spojevi iz naslova iz primjera 2-8 dobiveni su postupkom analognim sa onim opisanim u primjeru 1, korištenjem naznačenih reagenasa.
Primjer 2
1-(4-metoksibenzensulfonilamino)cikloheksan-1-karboksilna kiselina hidroksiamid
1-aminocikloheksan-1-karboksilna kiselina; 4-metoksibenzensulfonil klorid.
MS: 327 (M-1).
Primjer 3
1-[4-(4-fluorofenoksi)benzensulfonilamino]ciklopentan-1-karboksilna kiselina hidroksiamid
1-aminociklopentan-1-karboksilna kiselina; 4-(4-fluorofenoksi)benzensulfonil klorid.
MS: 393 (M-1).
Analiza izračunata za C18H19FN2O5S•0,25 H2O: C 54,19; H 4,93; N 7,02.
Nađeno: C 54,20; H 5,13; N 7,08.
Primjer 4
1-[4-(4-fluorofenoksi)benzensulfonilamino]cikloheksan-1-karboksilna kiselina hidroksiamid
1-aminocikloheksan-1-karboksilna kiselina; 4-(4-fluorofenoksi)benzensulfonil klorid. Ponovo kristaliziran iz kloroforma.
MP: 174 °C; MS: 407 (M-1).
Primjer 5
1-[4-(4-fluorofenoksi)benzensulfonilamino]ciklopropan-1-karboksilna kiselina hidroksiamid
1-aminociklopentan-1-karboksilna kiselina; 4-(4-fluorofenoksi)benzensulfonil klorid.
MP: 184 °C; MS: 365 (M-1).
Analiza izračunata za C16H15FN2O5S: C 52,45; H 4,13; N 7,65.
Nađeno: C 52,20; H 4,34; N 7,44.
Primjer 6
1-(4’-fluorobifenil-4-sulfonilamino) ciklopentan-1-karboksilna kiselina hidroksiamid
1-aminociklopentan-1-karboksilna kiselina; 4’-fluorobifenilsulfonil klorid. Ponovo kristaliziran iz kloroforma.
MP 159 °C; MS: 377 (M-1).
Primjer 7
1-[4-(4-fluorofenoksi)benzensulfonilamino]ciklobutan-1-karboksilna kiselina hidroksiamid
1-aminociklobutan-1-karboksilna kiselina; 4-(fluorofenoksi)benzensulfonil klorid.
MS: 379 (M-1).
Primjer 8
1-[4-(4-fluorobenziloksi)benzensulfonilamino]ciklopropan-1-karboksilna kiselina hidroksiamid
1-aminociklopropan-1-karboksilna kiselina; 4-(4-fluorobenziloksi)benzensulfonil klorid.
MS: 379 (M-1).
Primjer 9
N-hidroksi-2-(4-metoksibenzensulfonilamino)-2-metilpropionamid
(A) Otopina 2-amino-2metilpropionska kiselina benzil ester hidroklorida (12,0 grama, 52,2 mmola) i 4-metoksibenzensulfonilklorida (11,9 grama, 57,6 mmola) u dioksanu (100 ml) i vodi (100 ml) ohlađena je u kadi s ledom. Zatim je dodan trietilamin (18,2 ml, 0,13 mola). Kada s ledom je uklonjena i reakcijska smjesa je ostavljena da se miješa na sobnoj temperaturi tokom 2 dana. Otapala su uklonjena pod vakuumom i ostatak je uzet u etil acetatu i vodi. Vodeni sloj je izdvojen i ekstrahiran dva puta sa etil acetatom. Kombinirani organski slojevi su isprani sa vodenom zasićenom otopinom natrij bikarbonata, vodenom otopinom 1N klorovodične kiseline, i slanom vodom. Posle sušenja preko natrij sulfata, otapalo je ispareno radi dobivanja žutog ulja (19,3 grama) od koga je dio (10 grama) kromatografiran na silikagelu elucijom sa 3:7 etil acetat/heksanom radi dobivanja, posle ponovne kristalizacije iz etil acetat/heksana, 2-(4-metoksibenzensulfonilamino)-2-metil propionska kiselina benzil estera, kao bijeli čvrsti proizvod, 6,59 grama (67 %).
(B) Otopina 2-(4-metoksibenzensulfonilamino)-2-metilpropionska kiselina benzil estera (1,5 grama, 4,13 mmola) u etanolu (80 ml) tretirana je sa 10 % paladija na ugljiku (0,17 grama) i hidrogenirana je na tlaku od 3 bara tokom 1,5 sata u Parr-ovom tresaču. Katalizator je uklonjen sa prolazom preko 0,45 najlon filtra i filtrat je koncentriran radi dobivanja 2-(4-metoksibenzensulfonilamino)-2-metilpropionske kiseline kao bijeli čvrsti proizvod, 1,09 grama (96 %).
(C) Otopina 2-(4-metoksibenzensulfonilamino)-2-metilpropionske kiseline (1,08 grama, 3,95 mmola) u metilen kloridu (120 ml) sakupljen je u kadi s ledom. Sekvencijalno su dodani trietilamin (2,2 ml, 15,8 mmola), (benzotriazol-1-iloksi)tris(diemtilamino)-fosfonij heksafluorofosfat (2,6 grama, 5,88 mmola) i O-benzil hidroksilamin hidroklorid (0,95 grama, 5,95 mmola). Rezultirajuća smjesa je miješana na sobnoj temperaturi tokom 16 sati. Otapalo je ispareno i ostatak je uzet u etil acetatu. Otopina je isprana sukcesivno sa vodenom otopinom 1N klorovodične kiseline, vodenom zasićenom otopinom natrij bikarbonat, vodom i slanom vodom. Posle sušenja preko natrij sulfata, otapalo je ispareno radi dobivanja ulja, a bijeli čvrsti željeni proizvod, N-benziloksi-2-(4-metoksibenzensulfonilamino)-2-metil-propionamid (1,41 grama, 95 %), dobiven je sa kromatografijom na silikagelu elucijom sa 1:2 etil acetat/heksanima.
(D) Otopina N-benziloksi-2-(4-metoksibenzensulfonilamino)-2-metil-propionamida (1,40 grama, 3,70 mmola) u metanolu (80 ml) tretirana je sa 5 % paladija na barij sulfatu (0,75 grama) i hidrogenirana na tlaku od 3 bara tokom 1,5 sata u Parr-ovom tresaču. Katalizator je uklonjen sa prolazom preko 0,45 µm najlon filtra i filtrat je koncentriran radi dobivanja N-hidroksi-2-(4-metoksi-benzensulfonilamino)-2-metilpropionamida kao bijeli čvrsti proizvod, 1,06 grama (100 %).
MP: 122-125 °C. MS: 289 (M+1):
Analiza izračunata za C11H16N2O5S: C 45,82; H 5,59; N 9,72.
Nađeno: C 45,88; H 5,60; N,9,69.
Spojevi iz naslova iz primjera 10-12 dobiveni su postupkom analognim sa onim opisanim u primjeru 9, korištenjem naznačenih reagenasa.
Primjer 10
2-[4-(4-fluorofenoksi)benzensulfonilamino]-N-hidroksi-2-metil-propionamid
2-amino-2-metilpropionska kiselina benzil ester hidroklorid; 4-(4-fluoroefnoksi)-benzensulfonil klorid.
MP: 133-134 °C. MS: 369 (M+1).
Analiza izračunata za C16H17FN2O5S: C 52,17; H 4,65; N 7,60.
Nađeno: C 52,21; H 4,83; N 7,80.
Primjer 11
N-hidroksi-2-metil-[4-(3-metilbutoksi)benzensulfonilamino]-propionamid
Amino-2-metilpropionska kiselina benzil ester hidroklorid; 4-(3-metilbutoksi)-benzensulfonil klorid. Ponovo kristaliziran iz etil acetat/heksana.
MP 126,5-128 °C. MS: 343 (M-1).
Analiza izračunata za C15H24N2O5S: C 52,31; H 7,02; N 8,13.
Nađeno: C 52,30; H 7,07; N 8,16.
Primjer 12
2-[4-(2-ciklopentiletoksi)benzensulfonilamino]-N-hidroksi-2-metil-propionamid
2-amino-2-metilpropionska kiselina benzil ester hidroklorid; 4-(2-ciklopentiloksi)benzensulfonil klorid. Ponovo je kristaliziran iz etil acetat/heksana.
MP 126-127 °C. MS: 369 (M-1).
Analiza izračunata za C17H26N2O5S: C 55,12; H 7,07; N 7,56.
Nađeno: C 55,46; H 7,09; N 7,38.
Primjer 13
N-hidroksi-2-metil-2-(5-piridin-2-iltiofen-2-sulfonilamino)propionamid
(A) U otopinu 2 –amino-2-metilpropionske kiseline (2,0 grama, 19,4 mmola) u 1N vodenoj otopini natrij hidroksida (45 ml) i dioksana (45 ml) dodan je 5-piridin-2iltiofen-2-sulfonil klorid (8,41 grama, 32,4 mmola). Rezultirajuća smjesa je miješana na sobnoj temperaturi tokom 16 sati. Dodatna vodena otopina 1N natrij hidroksida (45 ml) dodana je u reakcijsku smjesu koja je zatim ekstrahirana sa dietil eterom. Organski ekstrakti su odbačeni. Vodeni sloj je zakiseljen sa otopinom 1N klorovodične kiseline i ekstrahiran sa etil acetatom. Frakcije etil acetata su isprane sa slanom vodom, osušene preko magnezij sulfata i koncentrirane u vakuumu radi dobivanja 2-metil-2-(5-piridin-2-iltiofen-2-sulfonilamino)propionske kiseline kao bijeli čvrsti proizvod (2,18 grama, 34 %).
(B) U otopinu 2-metil-2-(5-piridin-2-iltiofen-2-sulfonilamino)propionske kiseline (1,60 grama, 4,91 mmola) u metilen kloridu (160 ml) dodan je trietilamin (2,3 ml, 16,5 mmola), (benzotriazol-1-iloksi)tris(dimetilamino)-fosfonij heksafluorofosfat (2,4 grama, 5,41 mmola) i O-(2-trimetilsililetil)hidroksiamin hidroklorid (0,92 grama, 5,41 mmola). Rezulutujuća smjesa je miješana na sobnoj temperaturi tokom 16 sati. Otapalo je ispareno i ostatak je uzet u etil acetatu. Otopina je isprana sa vodom, zasićenom vodenom otopinom natrij bikarbonata, i slanom vodom. Posle sušenja preko magnezij sulfata, otapalo je ispareno radi dobivanja bijele pjene iz koje je željeni proizvod, 2-metil-2-(5-piridin-2-iltiofen-2-sulfonilamino)-N-(2-trimetilsililetoksi)-propionamid (220 mg, 10 %), bijeli u čvrstom stanju, izoliran sa kromatografijom na silikagelu elucijom sa 3:2 etil acetat/heksanima.
(C) 2-metil-2-(5-piridin-2-tiofen-2-sulfonilamino)-N-(2-trimetilsilanil-etoksi) propionamid (80 mg, 0,18 mmola) otopljen je u trifluorooctenoj kiselini i rezultirajuća otopina je miješana na sobnoj temperaturi tokom 16 sati. Trifluorooctena kiselina je isparena pod vakuumom, hvatanjem sa metanolom, radi dobivanja N-hidroksi-2-metil-2-(5-piridin-2-iltiofen-2-sulfonilamino)propionamida, žutog ulja (60 mg, 97 %), koje je kristalizirano iz etanola.
MP 165-1660C. MS: 342 (M+1).
Spojevi iz naslova iz primjera 14-15 dobiveni su postupkom analognim sa onim opisanim u primjeru 13, korištenjem naznačenog reagensa.
Primjer 14
1-(5-piridin-2-il-tiofen-2-sulfonilamino)ciklopentan-1-karboksilna kiselina hidroksiamid
1-aminociklopentan-1-karboksilna kiselina; 5-piridin-2-iltiofen-2-sulfonil klorid.
MS: 368 (M+1).
Primjer 15
1-[4-(4-klorofenoksi)benzensulfonilamino]ciklopentan-1-karboksilna kiselina hidroksiamid
1-aminociklopropan-1-karboksilna kiselina; 4-(4-klorofenoksi)benzensulfonil klorid.
MS: 381 (M+1).
Claims (8)
1. Spoj formule
[image]
ili njegove farmaceutski prihvatljive soli, naznačen time što
R1 i R2 su svaki nezavisno odabrani od (C1-C6) alkila, trifluorometila, trifluorometil (C1-C6) alkila, (C1-C6) alkil (difluorometilen), (C1-C3) alkil (difluorometilen (C1-C3) alkila, (C6-C10) arila, (C2-C9) heteroarila, (C6-C10) aril (C1-C6) alkila, (C2-C9) heteroaril (C1-C6) alkila, ili R1 i R2 mogu biti uzeti zajedno da formiraju (C3-C6) cikloalkil ili benzo-stopljen (C3-C6) cikloalkil prsten ili grupu formule
[image]
gdje n i m su nezavisno 1 ili 2, i X je CF2, S, O ili NR3, gdje R3 je vodik, (C1-C6) alkil, (C6-C10) aril, (C2-C9) heteroaril, (C6-C10) aril (C1-C6) alkil, (C2-C9) heteroaril (C1-C6) alkil, (C1-C6) alkilsulfonil, (C6-C10) arilsulfonil ili acil; i
Q 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) aril, (C6-C10) aril (C2-C9) heteroaril, (C6-C10) ariloksi (C2-C9) heteroaril, (C2-C9) heteroaril, (C2-C9) heteroaril (C2-C9) heteraoaril, (C2-C9) heteroaril (C6-C10) aril, (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, (C2-C9) heteroariloksi (C6-C10) aril, (C1-C6) alkil (C2-C9) heteroaril, (C1-C6) alkoksi (C2-C9) heteroaril, (C6-C10) aril (C1-C6) alkoksi (C2-C9) heteroaril, (C2-C9) heteroariloksi (C2-C9) heteroaril, (C6-C10) ariloksi (C1-C6) alkil, (C2-C9) heteroariloksi (C1-C6) alkil, (C1-C6) alkil (C6-C10) ariloksi (C6-C10) aril, (C1-C6) alkil (C2-C9) heteroariloksi (C6-C10) aril, (C1-C6) alkil (C6-C10) ariloksi (C2-C9) heteroaril, (C1-C6) alkoksi (C6-C10) ariloksi (C6-C10) aril, (C1-C6) alkoksi (C2-C9) heteroariloksi (C6-C10) aril ili (C1-C6) alkoksi (C6-C10) ariloksi (C2-C9) heteroaril, gdje je svaka 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 su R1 i R2 uzeti zajedno da formiraju (C3-C6) cikloalkil ili benzo- stopljen (C3-C6) cikloalkil prsten ili grupu formule
[image]
gdje n i m su nezavisno 1 ili 2, i X je CF2, S, O ili NR3, gdje R3 je vodik, (C1- C6) alkil, (C6-C10) aril, (C2-C9) heteroaril, (C6-C10) aril (C1-C6) alkil, (C2-C9) heteroaril (C1-C6) alkil, (C1-C6) alkilsulfonil, (C6-C10) arilsulfonil ili acil.
3. Spoj prema zahtjevu 2, naznačen time što su R1 i R2 uzeti zajedno da formiraju (C3-C6) cikloalkil ili benzo-stopljen (C3-C6) cikloalkil prsten.
4. Spoj prema zahtjevu 1, naznačen time što su R1 i R2 svaki nezavisno (C1-C6) alkil.
5. Spoj prema bilo kojem od zahtjeva 1 do 4, naznačen time što Q je (C6-C10) aril, (C6-C10) aril (C6-C10) aril, (C6-C10) ariloksi (C6-C10) aril, (C6-C10) ariloksi (C2-C9) heteroaril, (C2-C9) heteroaril, (C2-C9) heteroaril (C2-C9) heteroaril, (C6-C10) aril (C2-C9) heteroaril, (C2-C9) heteroaril (C6-C10) aril ili (C2-C9) heteroariloksi (C6-C10) aril.
6. Spoj prema zahtjevu 5, naznačen time što Q je (C6-C10) ariloksi (C6-C10) aril.
7. Spoj prema zahtjevu 1, naznačen time što je spomenuti spoj odabran iz grupe koja sadrži:
3-[4-(4-fluorofenoksi)benzensulfonilamino]azetidin-3-karboksilna kiselina hidroksiamid;
4-[4-(4-fluorofenoksi)benzensulfonilamino]piperidin-4-karboksilna kiselina hidroksiamid;
1-[4-(4-fluorofenoksi)benzensulfonilamino]ciklopropan-1-karboksilna kiselina hidroksiamid;
1-[4-(4-klororofenoksi)benzensulfonilamino]ciklopropan-1-karboksilna kiselina hidroksiamid;
1-[4-(4-fluorofenoksi)benzensulfonilamino]ciklobutan-1-karboksilna kiselina hidroksiamid;
1-[4-(4-klororofenoksi)benzensulfonilamino]ciklobutan-1-karboksilna kiselina hidroksiamid;
1-[4-(4-fluorofenoksi)benzensulfonilamino]ciklopentan-1-karboksilna kiselina hidroksiamid;
1-[4-(4-fluorofenoksi)benzensulfonilamino]ciklobutan-1-karboksilna kiselina hidroksiamid;
1-[4-(4-fluorofenoksi)benzensulfonilamino]cikloheksan-1-karboksilna kiselina hidroksiamid;
2-[4-(4-fluorofenoksi)benzensulfonilamino]-N-hidroksi-2-metilpropionamid;
2-[4-(4-klorofenoksi)benzensulfonilamino]-N-hidroksi-2-metil-propionamid;
N-hidroksi-2-metil-2-(5-piridin-2-iltiofen-2-sulfonilamino)propionamid;
1-(5-piridin-2-il-tiofen-2-sulfonilamino)ciklopentan-1-karboksilna kiselina hidroksiamid;
1-(4’-fluorofenil-4-sulfonilamino)ciklopropan-1-karboksilna kiselina hidroksiamid;
1-(4’-fluorofenil-4-sulfonilamino)ciklobutan-1-karboksilna kiselina hidroksiamid;
1-(4’-fluorofenil-4-sulfonilamino)ciklopentan-1-karboksilna kiselina hidroksiamid;
2-(4-metoksibenzensulfonilamino)indan-2-karboksilna kiselina hidroksiamid; i
2-[4-(4-fluorofenoksi)benzensulfonilamino]-indan-2-karboksilna kiselina hidroksiamid.
8. Farmaceutski preparat za: (a) tretman stanja odabranog 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, septički šok i druge bolesti koja uključuju proizvodnju faktora nekroze tumora (TNF); ili (b) inhibiciju matričnih metaloproteinaza ili proizvodnje faktora nekroze tumora (TNF) kod sisavaca, uključujući i čovjeka, naznačen time što sadrži količinu spoja iz zahtjeva 1 efikasnu u takvim tretmanima i farmaceutski prihvatljivi nosač.
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| US3685797P | 1997-02-03 | 1997-02-03 |
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| US5506242A (en) | 1993-01-06 | 1996-04-09 | Ciba-Geigy Corporation | Arylsufonamido-substituted hydroxamic acids |
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