ITRM20130155A1 - NEW 1,2,4-OXADIAZOLIC ACTIVE COMPOUNDS AGAINST GRAM-POSITIVE PATHOGENS. - Google Patents
NEW 1,2,4-OXADIAZOLIC ACTIVE COMPOUNDS AGAINST GRAM-POSITIVE PATHOGENS.Info
- Publication number
- ITRM20130155A1 ITRM20130155A1 IT000155A ITRM20130155A ITRM20130155A1 IT RM20130155 A1 ITRM20130155 A1 IT RM20130155A1 IT 000155 A IT000155 A IT 000155A IT RM20130155 A ITRM20130155 A IT RM20130155A IT RM20130155 A1 ITRM20130155 A1 IT RM20130155A1
- Authority
- IT
- Italy
- Prior art keywords
- nhc
- alkyl
- compounds
- compounds according
- aryl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 112
- 244000000059 gram-positive pathogen Species 0.000 title description 3
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 claims description 44
- 239000000203 mixture Substances 0.000 claims description 44
- 229960003907 linezolid Drugs 0.000 claims description 42
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 40
- 229910052731 fluorine Inorganic materials 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 26
- 229910052717 sulfur Inorganic materials 0.000 claims description 25
- 229910052801 chlorine Inorganic materials 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 20
- 239000003242 anti bacterial agent Substances 0.000 claims description 19
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 208000015181 infectious disease Diseases 0.000 claims description 15
- 125000001607 1,2,3-triazol-1-yl group Chemical group [*]N1N=NC([H])=C1[H] 0.000 claims description 14
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 claims description 13
- 229940088710 antibiotic agent Drugs 0.000 claims description 13
- 229960003085 meticillin Drugs 0.000 claims description 13
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 12
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 11
- 241000191967 Staphylococcus aureus Species 0.000 claims description 10
- WBLIXGSTEMXDSM-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH2] WBLIXGSTEMXDSM-UHFFFAOYSA-N 0.000 claims description 10
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 241000192125 Firmicutes Species 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- -1 N-substituted azoles Chemical class 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 241000194031 Enterococcus faecium Species 0.000 claims description 5
- 108010059993 Vancomycin Proteins 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 239000000839 emulsion Substances 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 claims description 5
- 229960003165 vancomycin Drugs 0.000 claims description 5
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 claims description 5
- 101100516563 Caenorhabditis elegans nhr-6 gene Proteins 0.000 claims description 4
- 101100516568 Caenorhabditis elegans nhr-7 gene Proteins 0.000 claims description 4
- 241000191940 Staphylococcus Species 0.000 claims description 4
- 241000191963 Staphylococcus epidermidis Species 0.000 claims description 4
- 241000193998 Streptococcus pneumoniae Species 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 229940031000 streptococcus pneumoniae Drugs 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 claims description 3
- 241000194033 Enterococcus Species 0.000 claims description 3
- 241000194032 Enterococcus faecalis Species 0.000 claims description 3
- 241000194017 Streptococcus Species 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 3
- 229940032049 enterococcus faecalis Drugs 0.000 claims description 3
- 230000000699 topical effect Effects 0.000 claims description 3
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 2
- 241000192087 Staphylococcus hominis Species 0.000 claims description 2
- 239000006071 cream Substances 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 208000035143 Bacterial infection Diseases 0.000 claims 1
- 208000022362 bacterial infectious disease Diseases 0.000 claims 1
- 239000002775 capsule Substances 0.000 claims 1
- 208000027136 gram-positive bacterial infections Diseases 0.000 claims 1
- 239000003826 tablet Substances 0.000 claims 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 31
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 28
- 210000004027 cell Anatomy 0.000 description 28
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 19
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 16
- 230000000694 effects Effects 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- UHCBBWUQDAVSMS-UHFFFAOYSA-N fluoroethane Chemical compound CCF UHCBBWUQDAVSMS-UHFFFAOYSA-N 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 230000003833 cell viability Effects 0.000 description 11
- 230000001580 bacterial effect Effects 0.000 description 9
- 230000000844 anti-bacterial effect Effects 0.000 description 8
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 8
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 8
- 241000894006 Bacteria Species 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 6
- LGDSHSYDSCRFAB-UHFFFAOYSA-N Methyl isothiocyanate Chemical compound CN=C=S LGDSHSYDSCRFAB-UHFFFAOYSA-N 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000003115 biocidal effect Effects 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 229930182555 Penicillin Natural products 0.000 description 5
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 229940049954 penicillin Drugs 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 150000005071 1,2,4-oxadiazoles Chemical class 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 4
- 229940125833 compound 23 Drugs 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 3
- 241000606768 Haemophilus influenzae Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000012346 acetyl chloride Substances 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229940047650 haemophilus influenzae Drugs 0.000 description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 229960005322 streptomycin Drugs 0.000 description 3
- 230000035899 viability Effects 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- JSWRVDNTKPAJLB-UHFFFAOYSA-N 2,4-difluorobenzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C(F)=C1 JSWRVDNTKPAJLB-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- CZKLEJHVLCMVQR-UHFFFAOYSA-N 4-fluorobenzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C=C1 CZKLEJHVLCMVQR-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- 108010081348 HRT1 protein Hairy Proteins 0.000 description 2
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- 229930182816 L-glutamine Natural products 0.000 description 2
- 102000010909 Monoamine Oxidase Human genes 0.000 description 2
- 108010062431 Monoamine oxidase Proteins 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 206010034133 Pathogen resistance Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 150000007980 azole derivatives Chemical class 0.000 description 2
- AOJDZKCUAATBGE-UHFFFAOYSA-N bromomethane Chemical compound Br[CH2] AOJDZKCUAATBGE-UHFFFAOYSA-N 0.000 description 2
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000013375 chromatographic separation Methods 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
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- HFPGRVHMFSJMOL-UHFFFAOYSA-N dibromomethane Chemical compound Br[CH]Br HFPGRVHMFSJMOL-UHFFFAOYSA-N 0.000 description 2
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- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 2
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 150000003556 thioamides Chemical class 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- ROWMQJJMCWDJDT-UHFFFAOYSA-N tribromomethane Chemical compound Br[C](Br)Br ROWMQJJMCWDJDT-UHFFFAOYSA-N 0.000 description 2
- ZBZJXHCVGLJWFG-UHFFFAOYSA-N trichloromethyl(.) Chemical compound Cl[C](Cl)Cl ZBZJXHCVGLJWFG-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
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- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
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- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- AEXITZJSLGALNH-UHFFFAOYSA-N n'-hydroxyethanimidamide Chemical compound CC(N)=NO AEXITZJSLGALNH-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
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- 235000011837 pasties Nutrition 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
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- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Nuovi composti 1,2,4-ossadiazolici attivi contro patogeni Grampositivi. New 1,2,4-oxadiazole compounds active against gram-positive pathogens.
DESCRIZIONE DESCRIPTION
STATO DELLA TECNICA ANTERIORE. STATE OF THE PRIOR ART.
L’uso e l’abuso di agenti antibatterici hanno portato allo sviluppo della resistenza batterica nei confronti di tutti gli antibiotici in uso clinico, indipendentemente dalla classe di appartenenza o bersaglio molecolare del farmaco. Infezioni causate da cocchi Gram-positivi multiresistenti, come Staphylococcus aureus resistente alla meticillina (MRSA), enterococchi resistenti alla vancomicina (VRE) e Streptococcus pneumoniae penicillino-resistenti (PNSSP), sono emersi come rilevante problematica nell'ambito della salute pubblica, sia in ospedale che a livello di comunità o di tutto il mondo. La necessità di nuovi antibiotici ha esortato la “Infectious Disease Society of America†(IDSA) a rilanciare la sfida di sviluppare dieci nuovi antibiotici entro il 2020. The use and abuse of antibacterial agents have led to the development of bacterial resistance against all antibiotics in clinical use, regardless of the class or molecular target of the drug. Infections caused by multidrug-resistant Gram-positive cocci, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and penicillin-resistant Streptococcus pneumoniae (PNSSP), have emerged as a major public health concern, both in hospital that at the community level or around the world. The need for new antibiotics has urged the Infectious Disease Society of America (IDSA) to raise the challenge of developing ten new antibiotics by 2020.
Gli ossazolidinoni sono una classe di agenti antibatterici attivi contro un'ampia gamma di patogeni Gram-positivi e sono molto potenti contro batteri multi antibiotico-resistenti. In particolare, gli ossazolidinoni sono usati per trattare infezioni della pelle e delle vie respiratorie causate da ceppi di Staphylococcus aureus e streptococchi, oltre che attivi contro Enterococcus faecium resistente alla vancomicina. Il linezolid (Figura 1), il primo antibiotico ossazolidinonico approvato per uso clinico, ha mostrato la capacità di inibire il processo di traduzione durante la fase iniziale della sintesi proteica nei batteri, legandosi alla subunità ribosomiale maggiore 50S. A partire dal 2001, tuttavia, la resistenza al linezolid ha cominciato a manifestarsi con il suo uso in isolati clinici di Staphylococcus aureus ed Enterococcus faecium e il tasso di resistenza si à ̈ dimostrato più elevato soprattutto tra gli enterococchi e in ceppi di Staphylococcus epidermidis. [1-4]. Inoltre, la terapia con linezolid non à ̈ scevra di effetti indesiderati quali la mielosoppressione reversibile e inibizione delle monoaminossidasi (MAO). Oxazolidinones are a class of antibacterial agents that are active against a wide range of Gram-positive pathogens and are very potent against multi-antibiotic-resistant bacteria. In particular, oxazolidinones are used to treat skin and respiratory tract infections caused by strains of Staphylococcus aureus and streptococci, as well as active against vancomycin-resistant Enterococcus faecium. Linezolid (Figure 1), the first oxazolidinone antibiotic approved for clinical use, has been shown to inhibit the translation process during the early phase of protein synthesis in bacteria by binding to the 50S major ribosomal subunit. Since 2001, however, resistance to linezolid has begun to manifest itself with its use in clinical isolates of Staphylococcus aureus and Enterococcus faecium and the rate of resistance has been shown to be higher especially among enterococci and in Staphylococcus epidermidis strains. [1-4]. Furthermore, linezolid therapy is not free from undesirable effects such as reversible myelosuppression and monoamine oxidase (MAO) inhibition.
Un certo numero di soluzioni al problema della resistenza batterica sono possibili. Strategie di successo includono le combinazioni di agenti antibatterici esistenti con altri farmaci, nonché lo sviluppo di migliori procedure diagnostiche che possono portare ad una rapida identificazione del patogeno responsabile e consentire l'uso di agenti antibatterici con uno più ristretto spettro di attività . Un'altra strategia à ̈ la scoperta di nuove classi di agenti antibatterici che agiscono attraverso nuovi meccanismi di azione. Altra strategia à ̈ poi la modificazione delle classi esistenti di agenti antibatterici fornendo così nuovi analoghi strutturali con migliorate attività , anche se attività e tossicità dei nuovi analoghi non à ̈ facilmente prevedibile. A number of solutions to the bacterial resistance problem are possible. Successful strategies include combinations of existing antibacterial agents with other drugs, as well as the development of better diagnostic procedures that can lead to rapid identification of the responsible pathogen and allow the use of antibacterial agents with a narrower spectrum of activity. Another strategy is the discovery of new classes of antibacterial agents that act through new mechanisms of action. Another strategy is the modification of the existing classes of antibacterial agents thus providing new structural analogues with improved activity, even if the activity and toxicity of the new analogues is not easily predictable.
In questo contesto, molti ricercatori hanno cercato di modificare, senza ottenere ancora risultati tali da condurre all’approvazione all’uso di nuove molecole, la struttura del linezolid per migliorare l'attività antibatterica. Al fine di razionalizzare il sito oggetto di modifiche, la struttura del linezolid può formalmente essere divisa in quattro parti secondo la nomenclatura utilizzata per gli ossazolidinoni [5]: i) l'anello A, costituito dalla centrale ossazolidinone eterociclico; ii) l'anello B, costituito da una porzione N-arile legato all'azoto ossazolidinonico; iii) l’anello C, che comprende un gruppo funzionale carbo-eterociclico, non necessariamente aromatico; iv) la catena laterale, costituito da qualsiasi gruppo funzionale legato al C ossazolidinonico (5) o in una posizione isosterica rispetto ad un A-anello di tipo generale (Figura 1). In this context, many researchers have tried to modify the structure of linezolid to improve antibacterial activity, without yet obtaining results such as to lead to approval for the use of new molecules. In order to rationalize the site subject to changes, the structure of linezolid can formally be divided into four parts according to the nomenclature used for oxazolidinones [5]: i) ring A, consisting of the central heterocyclic oxazolidinone; ii) ring B, consisting of an N-aryl portion bonded to the oxazolidinone nitrogen; iii) the C ring, which includes a carbo-heterocyclic functional group, not necessarily aromatic; iv) the side chain, consisting of any functional group linked to the C oxazolidinone (5) or in an isosteric position with respect to a general type A-ring (Figure 1).
O OR
O OR
O N N H O N N H
NONO
F F.
C-ring B-ring A-ring C5 side-chain C-ring B-ring A-ring C5 side-chain
Linezolid Linezolid
Figura 1 Figure 1
Diversi tipi di modifiche sono riportati in letteratura. La più comune riguarda l’anello C, mentre solo poche modifiche sono stati riportate per l'anello A, e in alcuni casi una buona attività à ̈ stata mantenuta [6, 7]. Several types of modifications are reported in the literature. The most common concerns the C ring, while only a few modifications have been reported for the A ring, and in some cases a good activity has been maintained [6, 7].
Il nostro gruppo ha precedentemente riportato che la sostituzione dell’ossazolidinone (A-ring) con un 1,2,4-ossadiazolo, anello eteroaromatico, ha comportato una mancanza di attività [8]. Pertanto, questi composti sono stati scelti come riferimenti per composti inattivi di tipo linezolid-simili in un approccio di screening virtuale. Our group has previously reported that replacing oxazolidinone (A-ring) with a heteroaromatic ring 1,2,4-oxadiazole resulted in a lack of activity [8]. Therefore, these compounds were chosen as references for linezolid-like inactive compounds in a virtual screening approach.
Scopo della presente invenzione à ̈ quello di trovare nuove molecole idonee come medicamenti che superassero i limiti e gli svantaggi delle molecole dell’arte anteriore, in termini di attività antibatterica, soprattutto su ceppi resistenti e di innocuità . The purpose of the present invention is to find new molecules suitable as medicaments that overcome the limits and disadvantages of the prior art molecules, in terms of antibacterial activity, especially on resistant and harmless strains.
SOMMARIO DELL’INVENZIONE SUMMARY OF THE INVENTION
La presente invenzione si fonda suIla scoperta che l'introduzione come anello C, nei derivati del Linezolid, di un gruppo eterociclico a 5 atomi, anche sostituito, contenente 2 o 3 eteroatomi à ̈ efficace per l’ottenimento di nuovi antibiotici ossazolidinonici, la cui attività à ̈ ulteriormente modulata dalla presenza di sostituzioni nell’anello B, e dalla struttura della catena laterale C(5) del nucleo ossazolidinone. The present invention is based on the discovery that the introduction as C-ring, in Linezolid derivatives, of a heterocyclic group with 5 atoms, also substituted, containing 2 or 3 heteroatoms is effective for obtaining new oxazolidinone antibiotics, the whose activity is further modulated by the presence of substitutions in the B ring, and by the structure of the C (5) side chain of the oxazolidinone nucleus.
Pertanto oggetto della presente domanda sono nuovi composti aventi formula generale (I), per uso nel trattamento di infezioni da batteri Grampositivi, Therefore, the subject of the present application are new compounds having general formula (I), for use in the treatment of infections by gram-positive bacteria,
R R.
Z R2Z R2
R3O R3O
Y X N O Y X N O
R1R1
R4R5R4R5
Formula (I) Formula (I)
in forma di miscela racemica o di enantiomero puro o di miscela arricchita in uno degli enantiomeri S o R in the form of a racemic mixture or pure enantiomer or a mixture enriched in one of the S or R enantiomers
dove: where is it:
X, Y, Z sono indipendentemente l’un dall’altro: CH, O, N, S, a condizione che vi siano almeno due eteroatomi; X, Y, Z are independent of each other: CH, O, N, S, provided that there are at least two heteroatoms;
R= H, F, Cl, Br, I, C1-C3 alchile (metil, etil, n-propil, iso-propil), C3-C6 cicloalchile, arile, etero-arile (tiofenil, furanil, piridil, pirimidil, piridazinil, pirrolidinil, piperidil), NH2, OH, SH, NHR6, N(R6)2, OR6con R6= C1-C3 alchile, C3-C6 ciclo-alchile, arile, eteroarile, C1-C4 acile; R = H, F, Cl, Br, I, C1-C3 alkyl (methyl, ethyl, n-propyl, iso-propyl), C3-C6 cycloalkyl, aryl, hetero-aryl (thiophenyl, furanyl, pyridyl, pyrimidyl, pyridazinyl , pyrrolidinyl, piperidyl), NH2, OH, SH, NHR6, N (R6) 2, OR6 with R6 = C1-C3 alkyl, C3-C6 cyclo-alkyl, aryl, heteroaryl, C1-C4 acyl;
R1-4= indipendentemente H o F; R1-4 = independently H or F;
R5= -NH2, -OH; N3; -NHC(X)CH3con X= O o S; -NHC(X)CH2Z con X= O, S, Z= F, Cl; -NHC(X)CHZ2con X= O, S, Z= F, Cl; -NHC(X)CZ3con X= O, S, Z= F, Cl; -NHC(X)NHR7con X= O, S, R7= H, C1-C3 alchile, C3-C6-cicloalchile, arile, (etero)arile, C1-C3-acile oppure azoli N-sostituiti scelti tra pirrolo, pirazolo, imidazolo, 1,2,3-triazolo, 1,2,4-triazolo. R5 = -NH2, -OH; N3; -NHC (X) CH3 with X = O or S; -NHC (X) CH2Z with X = O, S, Z = F, Cl; -NHC (X) CHZ2 with X = O, S, Z = F, Cl; -NHC (X) CZ3 with X = O, S, Z = F, Cl; -NHC (X) NHR7 with X = O, S, R7 = H, C1-C3 alkyl, C3-C6-cycloalkyl, aryl, (hetero) aryl, C1-C3-acyl or N-substituted azoles selected from pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole.
In una forma di realizzazione dell’invenzione, i nuovi composti hanno formula generale (II), In one embodiment of the invention, the new compounds have general formula (II),
R R2R R2
N R3O N R3O
N O N O NINTH
R1R1
R4R5R4R5
Formula (II) Formula (II)
in forma di miscela racemica o di enantiomero puro o di miscela arricchita in uno degli enantiomeri S o R, in the form of a racemic mixture or pure enantiomer or a mixture enriched in one of the S or R enantiomers,
dove: where is it:
R= H, F, Cl, Br, I, (C1-C3) alchile (metil, etil, n-propil, iso-propil), (C3-C6) ciclo-alchile, arile, etero-arile, NH2, OH, SH, NHR6, N(R6)2, OR6con R6= (C1-C3) alchile, (C3-C6) ciclo-alchile, arile, eteroarile, (C1-C4) acile; R = H, F, Cl, Br, I, (C1-C3) alkyl (methyl, ethyl, n-propyl, iso-propyl), (C3-C6) cyclo-alkyl, aryl, hetero-aryl, NH2, OH , SH, NHR6, N (R6) 2, OR6 with R6 = (C1-C3) alkyl, (C3-C6) cyclo-alkyl, aryl, heteroaryl, (C1-C4) acyl;
R1-4= indipendentemente H o F; R1-4 = independently H or F;
R5= -NH2, -OH; -NCS, -NHC(X)CH3con X= O o S; -NHC(X)CH2Z con X= O, S, Z= F, Cl; -NHC(X)CHZ2con X= O, S, Z= F, Cl; -NHC(X)CZ3con X= O, S, Z= F, Cl; -NHC(X)NHR7con X= O, S, R7= H, (C1-C3) alchile, (C3-C6) ciclo-alchile, arile, (etero)arile, (C1-C3) acile. R5 = -NH2, -OH; -NCS, -NHC (X) CH3 with X = O or S; -NHC (X) CH2Z with X = O, S, Z = F, Cl; -NHC (X) CHZ2 with X = O, S, Z = F, Cl; -NHC (X) CZ3 with X = O, S, Z = F, Cl; -NHC (X) NHR7 with X = O, S, R7 = H, (C1-C3) alkyl, (C3-C6) cyclo-alkyl, aryl, (hetero) aryl, (C1-C3) acyl.
Forme di realizzazione specifiche dell’invenzione consistono in composti di formula (II) in cui R à ̈ un resto metilico, etilico, n-propilico, iso-propilico; oppure composti di formula (II) in cui almeno uno dei sostituenti R1, R2, R3o R4à ̈ un atomo di fluoro, mentre gli altri sono H; Specific embodiments of the invention consist of compounds of formula (II) in which R is a methyl, ethyl, n-propyl, iso-propyl remainder; or compounds of formula (II) in which at least one of the substituents R1, R2, R3 or R4 is a fluorine atom, while the others are H;
oppure composti di formula (II) in cui R5Ã ̈ scelto tra: NHC(=O)CH3, NHC(=S)CH3, -NHC(=O)CH2F, -NHC(=S)CH2F, -NHC(=O)CH2Cl, -NHC(=S)CH2Cl, -NHC(=S)NH2, NHC(=O)NH2, -NHC(=O)NHCH3, -NHC(=S)NHCH3, -NHC(=O)NHC2H5,-NHC(=S)NHC2H5, -NCS; 1,2,3 triazol-1-il; or compounds of formula (II) in which R5 is chosen from: NHC (= O) CH3, NHC (= S) CH3, -NHC (= O) CH2F, -NHC (= S) CH2F, -NHC (= O) CH2Cl, -NHC (= S) CH2Cl, -NHC (= S) NH2, NHC (= O) NH2, -NHC (= O) NHCH3, -NHC (= S) NHCH3, -NHC (= O) NHC2H5, - NHC (= S) NHC2H5, -NCS; 1,2,3 triazol-1-yl;
oppure composti di formula (II) in cui R3 Ã ̈ un residuo metilico e R5 Ã ̈ scelto tra NHC(=O)CH3, NHC(=S)CH3, -NHC(=O)CH2F, -NHC(=S)CH2F, -NHC(=O)CH2Cl, -NHC(=S)CH2Cl, -NHC(=S)NH2, NHC(=O)NH2, NHC(=O)NHCH3, -NHC(=S)NHCH3, -NHC(=O)NHC2H5,-NHC(=S)NHC2H5, -NCS; 1,2,3 triazol-1-il; or compounds of formula (II) in which R3 is a methyl residue and R5 is selected from NHC (= O) CH3, NHC (= S) CH3, -NHC (= O) CH2F, -NHC (= S) CH2F , -NHC (= O) CH2Cl, -NHC (= S) CH2Cl, -NHC (= S) NH2, NHC (= O) NH2, NHC (= O) NHCH3, -NHC (= S) NHCH3, -NHC ( = O) NHC2H5, -NHC (= S) NHC2H5, -NCS; 1,2,3 triazol-1-yl;
oppure composti in cui R1 Ã ̈ F, R2, R3 e R4 sono H e R3 Ã ̈ un residuo metilico e R5 Ã ̈ scelto NHC(=O)CH3, NHC(=S)CH3, -NHC(=O)CH2F, -NHC(=S)CH2F, -NHC(=O)CH2Cl, -NHC(=S)CH2Cl, -NHC(=S)NH2, NHC(=O)NH2, -NHC(=O)NHCH3, -NHC(=S)NHCH3, -NHC(=O)NHC2H5,-NHC(=S)NHC2H5, -NCS; 1,2,3 triazol-1-il. or compounds in which R1 is F, R2, R3 and R4 are H and R3 is a methyl residue and R5 is chosen NHC (= O) CH3, NHC (= S) CH3, -NHC (= O) CH2F, -NHC (= S) CH2F, -NHC (= O) CH2Cl, -NHC (= S) CH2Cl, -NHC (= S) NH2, NHC (= O) NH2, -NHC (= O) NHCH3, -NHC ( = S) NHCH3, -NHC (= O) NHC2H5, -NHC (= S) NHC2H5, -NCS; 1,2,3 triazol-1-yl.
In una forma di realizzazione preferita dell’invenzione tutti i composti sopra indicati sono in forma di enantiomero S puro oppure in forma di miscela enantiomera arricchita in enantiomero S. In a preferred embodiment of the invention, all the compounds indicated above are in the form of pure S-enantiomer or in the form of an S-enantiomer enriched enantiomer mixture.
In un’ulteriore forma di realizzazione dell’invenzione i composti rivendicati sono intesi per l’uso nel trattamento di infezioni da batteri Gram-positivi, preferibilmente multi antibiotico-resistenti (anche detti multi-resistenti), per esempio nel trattamento di infezioni da Staphylococcus, Enterococcus, Streptococcus, in particolare di infezioni da Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus hominis, Enterococcus faecium, Enterococcus faecalis, Streptococcus pneumoniae. Soprattutto se resistenti ad uno o più degli antibiotici meticillina, vancomicina, penicillina, macrolidi, fluorochinoloni e linezolid. In a further embodiment of the invention the claimed compounds are intended for use in the treatment of infections by Gram-positive bacteria, preferably multi-antibiotic-resistant (also called multi-resistant), for example in the treatment of Staphylococcus, Enterococcus, Streptococcus infections, in particular Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus hominis, Enterococcus faecium, Enterococcus faecalis, Streptococcus pneumoniae infections. Especially if resistant to one or more of the antibiotics methicillin, vancomycin, penicillin, macrolides, fluoroquinolones and linezolid.
Un secondo oggetto dell’invenzione sono composizioni farmaceutiche comprendenti i composti dell’invenzione in quanto principi attivi ed un eccipiente farmaceuticamente accettabile. A second object of the invention are pharmaceutical compositions comprising the compounds of the invention as active principles and a pharmaceutically acceptable excipient.
Tali composizioni sono intese per uso nel trattamento di infezioni da batteri Gram-negativi anche multi-resistenti. Such compositions are intended for use in the treatment of infections with even multi-resistant Gram-negative bacteria.
Un terzo oggetto dell’invenzione sono procedimenti di preparazione dei composti dell’invenzione che comprende i passaggi indicati negli schemi 1, 2 e 3. A third object of the invention are procedures for the preparation of the compounds of the invention which include the steps indicated in schemes 1, 2 and 3.
In una forma di realizzazione dell’invenzione i procedimenti comprendono uno o più passaggi di separazione degli enantiomeri S e R o di arricchimento della miscela racemica in uno degli enantiomeri, preferibilmente l’enantiomero S. In one embodiment of the invention the processes comprise one or more steps for separating the S and R enantiomers or for enriching the racemic mixture in one of the enantiomers, preferably the S enantiomer.
Un quarto oggetto dell’invenzione sono procedimenti di preparazione delle composizioni farmaceutiche comprendente il passaggio di miscelazione dei principi attivi con un eccipiente farmacologicamente accettabile. A fourth object of the invention are processes for the preparation of pharmaceutical compositions comprising the step of mixing the active ingredients with a pharmacologically acceptable excipient.
Un ulteriore oggetto dell’invenzione à ̈ l’uso dei composti dell’invenzione per la preparazione di un medicamento per il trattamento di infezioni da batteri Gram-positivi multi-resistenti. A further object of the invention is the use of the compounds of the invention for the preparation of a medicament for the treatment of infections by multi-resistant Gram-positive bacteria.
Vantaggi offerti dalla presente invenzione risiedono nell’ottenimento di nuovi composti antibiotici con attività equivalente o paragonabile a quella del linezolid su ceppi batterici linezolid-sensibili ma con efficacia maggiore del linezolid su ceppi batterici resistenti al linezolid e/o ad altri antibiotici. Inoltre alcune di queste sostanze presentano citotossicità paragonabile o minore di quella del linezolid. Advantages offered by the present invention reside in obtaining new antibiotic compounds with activity equivalent or comparable to that of linezolid on linezolid-sensitive bacterial strains but with greater efficacy than linezolid on bacterial strains resistant to linezolid and / or other antibiotics. Furthermore, some of these substances exhibit cytotoxicity comparable to or less than that of linezolid.
Descrizione delle Figure Description of the Figures
Figura 1. Formula del linezolid con gli elementi strutturali che la compongono e nomenclatura. Figure 1. Linezolid formula with its component structural elements and nomenclature.
Figura 2. Risultati di vitalità cellulare di cellule PK15 trattate con il composto A4b (composto 23 tabella 1) e con linezolid. Limiti di significatività : *=P<0.05; **=P<0.01. Figure 2. Cell viability results of PK15 cells treated with compound A4b (compound 23 table 1) and with linezolid. Limits of significance: * = P <0.05; ** = P <0.01.
Figura 3. Risultati di vitalità cellulare di cellule HaCaT trattate con il composto A4b e con linezolid. Limiti di significatività : *=P<0.05; **=P<0.01. Figure 3. Cell viability results of HaCaT cells treated with compound A4b and linezolid. Limits of significance: * = P <0.05; ** = P <0.01.
Figura 4. Risultati di vitalità cellulare di cellule HepG2 trattate con il composto A4b (composto 23 tabella 1) e con linezolid. Limiti di significatività : *=P<0.05; **=P<0.01. Figure 4. Cell viability results of HepG2 cells treated with compound A4b (compound 23 table 1) and with linezolid. Limits of significance: * = P <0.05; ** = P <0.01.
Figura 5. Risultati di vitalità cellulare di cellule HepG2 trattate con il composto B4b e B4a (composti 106 e 107 tabella 1) in forma dei rispettivi enantiomeri. Figure 5. Cell viability results of HepG2 cells treated with compound B4b and B4a (compounds 106 and 107 table 1) in the form of their respective enantiomers.
Figura 6: Schema 1 di sintesi chimica dei composti 1-5 e A1 Figura 7: Schema 2 di sintesi chimica dei composti A e B Figure 6: Scheme 1 of the chemical synthesis of compounds 1-5 and A1 Figure 7: Scheme 2 of the chemical synthesis of compounds A and B
Figura 8: Schema 3 di sintesi chimica dei composti di maggiore interesse A e B. Figure 8: Scheme 3 of chemical synthesis of the compounds of greatest interest A and B.
DESCRIZIONE DETTAGLIATA DELL’INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
I Composti: The Compounds:
La struttura chimica dei composti della presente invenzione [(formule (I) o (II)] si compone di un anello ossazolidinonico (anello A), di un anello fenilico (anello B), un anello eteroaromatico a cinque atomi contenente gli atomi Y, X e Z (anello C) ed una catena laterale legata al C5 (posizione 5) del nucleo ossazolidinonico (catena C5). The chemical structure of the compounds of the present invention [(formulas (I) or (II)] consists of an oxazolidinone ring (ring A), a phenyl ring (ring B), a five-atom heteroaromatic ring containing the Y atoms, X and Z (C ring) and a side chain linked to C5 (position 5) of the oxazolidinone nucleus (C5 chain).
anello C anello B anello A catena C5 ring C ring B ring A chain C5
Anello C Ring C
L’anello C à ̈ un eterociclo in cui Y, X e Z sono indipendentemente l’uno dall’altro degli atomi di N, O, S o un gruppo -CH- a condizione che l’anello contenga almeno due etero atomi. Forme di realizzazione preferite sono quelle in cui X à ̈ O, o S oppure in cui Y à ̈ N o –CH- oppure in cui Z à ̈ N o –CH-. Forme maggiormente preferite sono quelle in cui X à ̈ O e Y à ̈ N oppure in cui X à ̈ O e Z à ̈ N. Forme ancor maggiormente preferite sono quelle in cui X à ̈ O, Y à ̈ N e X à ̈ ugualmente N. The ring C is a heterocycle in which Y, X and Z are independent of each other of the atoms of N, O, S or a group -CH- provided that the ring contains at least two hetero atoms. Preferred embodiments are those where X is O, or S or where Y is N or â € “CH- or where Z is N or â €“ CH-. Most preferred forms are those in which X is O and Y is N or where X is O and Z is N. Even more preferred forms are those in which X is O, Y à ̈ N and X à ̈ likewise N.
Il radicale R sull’anello C può essere un atomo di H oppure un gruppo sostituente scelto tra: F, Cl, Br, I, metile, etile, n-propile, isopropile, n-butile, sec-butile, ter-butile, ciclopropile, ciclobutile, ciclopentile, cicloesile, eteroarile, -NH2, , NHCH3, NHC2H5, -N(CH3)2, N(CH3)(C2H5), -NC(=O)CH3, -NC(=O)C2H5, -NH(ciclopropil), NH(ciclobutil), NH(ciclopentil), NH(cicloesili), -OH, -OCH3, -OC2H5, -On-Propil, Oi-Propil, -SH, SCH3. The radical R on the C ring can be an H atom or a substituent group chosen from: F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heteroaryl, -NH2,, NHCH3, NHC2H5, -N (CH3) 2, N (CH3) (C2H5), -NC (= O) CH3, -NC (= O) C2H5, -NH (cyclopropyl), NH (cyclobutyl), NH (cyclopentyl), NH (cyclohexyl), -OH, -OCH3, -OC2H5, -On-Propyl, Oi-Propyl, -SH, SCH3.
Anello B Ring B
I gruppi R1, R2, R3,R4sono indipendentemente l’uno dall’altro H, F, Cl, Br, CH3, OH, OCH3. Almeno uno di questi à ̈ un atomo di alogeno, per esempio R1à ̈ F, Cl o Br, oppure R1e R2, sono F, Cl o Br, oppure R1,R2,e R3sono F, Cl. In una forma di realizzazione specifica l’atomo di alogeno à ̈ F ed i restanti radicali R sono atomi di H. In una forma preferita R1o R4, sono F e i restanti tra “R†sono H. The groups R1, R2, R3, R4 are independently of each other H, F, Cl, Br, CH3, OH, OCH3. At least one of these is a halogen atom, for example R1à ̈ F, Cl or Br, or R1e R2, they are F, Cl or Br, or R1, R2, and R3 are F, Cl. In a specific embodiment the halogen atom à ̈ F and the remaining radicals R are H atoms. In a preferred form R1or R4, they are F and the remainder between â € œRâ € are H.
Catena C5 C5 chain
Il sostituente R5sulla catena laterale in posizione 5 del nucleo ossazolidinonico à ̈ scelto da un gruppo comprendente i seguenti radicali: I, -N3, -NHC(=O)CH3, -NHC(=S)CH3, -NHC(=O)CH2F, -NHC(=S)CH2F, -NHC(=O)CH2Cl, -NHC(=S)CH2Cl, -NHC(=O)CH2Br, -NHC(=S)CH2Br, -NHC(=O)CHF2, -NHC(=S)CHF2, -NHC(=O)CHCl2, -NHC(=S)CHCl2, -NHC(=O)CHBr2, -NHC(=S)CHBr2, -NHC(=O)CF3, -NHC(=S)CF3, -NHC(=O)CCl3, -NHC(=S)CCl3, -NHC(=O)CBr3, -NHC(=S)CBr3,-NHC(=S)NH2, -NHC(=O)NH2, -NHC(=O)NHCH3, -NHC(=S)NHCH3, -NHC(=O)NHC2H5,-NHC(=S)NHC2H5, -NHC(=O)NH-nC3H7,-NHC(=S)NH-nC3H7, -NHC(=O)NH-iC3H7,-NHC(=S)NH-iC3H7, NHC(=S)NH-ciclopropil, -NHC(=O)NH-ciclopropil, NHC(=S)NH-ciclobutil, -NHC(=O)NH-ciclobutil, NHC(=S)NH-ciclopentil, -NHC(=O)NH-ciclopentil, NHC(=S)NH-cicloesil, -NHC(=O)NH-cicloesil, NHC(=O)NHC(=O)CH3, NHC(=S)NHC(=O)CH3NHC(=O)NHC(=O)C2H5, NHC(=O)NH-eteroaril, pirrolil, pirazolil, imidazolil, 1,2,3-triazol-1-il, 1,2,4-triazol-1-il. The substituent R5 on the side chain in position 5 of the oxazolidinone nucleus is chosen from a group comprising the following radicals: I, -N3, -NHC (= O) CH3, -NHC (= S) CH3, -NHC (= O) CH2F , -NHC (= S) CH2F, -NHC (= O) CH2Cl, -NHC (= S) CH2Cl, -NHC (= O) CH2Br, -NHC (= S) CH2Br, -NHC (= O) CHF2, - NHC (= S) CHF2, -NHC (= O) CHCl2, -NHC (= S) CHCl2, -NHC (= O) CHBr2, -NHC (= S) CHBr2, -NHC (= O) CF3, -NHC ( = S) CF3, -NHC (= O) CCl3, -NHC (= S) CCl3, -NHC (= O) CBr3, -NHC (= S) CBr3, -NHC (= S) NH2, -NHC (= O ) NH2, -NHC (= O) NHCH3, -NHC (= S) NHCH3, -NHC (= O) NHC2H5, -NHC (= S) NHC2H5, -NHC (= O) NH-nC3H7, -NHC (= S ) NH-nC3H7, -NHC (= O) NH-iC3H7, -NHC (= S) NH-iC3H7, NHC (= S) NH-cyclopropyl, -NHC (= O) NH-cyclopropyl, NHC (= S) NH -ciclobutyl, -NHC (= O) NH-cyclohexyl, NHC (= S) NH-cyclopentyl, -NHC (= O) NH-cyclopentyl, NHC (= S) NH-cyclohexyl, -NHC (= O) NH-cyclohexyl , NHC (= O) NHC (= O) CH3, NHC (= S) NHC (= O) CH3NHC (= O) NHC (= O) C2H5, NHC (= O) NH-heteroaryl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl.
In considerazione della configurazione asimmetrica dell’atomo di carbonio in posizione 5 dell’anello A, tutti i sopra identificati composti sono otticamente attivi. Per questo sono oggetto della presente invenzione sia le miscele racemiche di tali composti, sia miscele arricchite in uno degli enantiomeri, sia i singoli enantiomeri isolati. Ai fine della presente invenzione si intende per miscela racemica la miscela 50%:50% dei due enantiomeri R e S. Per miscela arricchita in un enantiomero si intende una miscela contenente più del 50% di un enantiomero (S o R) per esempio 55%, 60, 65%, 70%, 75%, o più. Per enantiomero isolato si intende un enantiomero puro, i.e. In consideration of the asymmetrical configuration of the carbon atom in position 5 of the ring A, all the compounds identified above are optically active. For this reason, both the racemic mixtures of these compounds, and mixtures enriched in one of the enantiomers, and the single isolated enantiomers, are the object of the present invention. For the purposes of the present invention, by racemic mixture we mean the mixture 50%: 50% of the two enantiomers R and S. By mixture enriched in an enantiomer we mean a mixture containing more than 50% of an enantiomer (S or R) for example 55 %, 60, 65%, 70%, 75%, or more. By isolated enantiomer we mean a pure enantiomer, i.e.
100% o una miscela fortemente arricchita di tale enantiomero, per esempio 98%, 95%, 93%, 90%, 88%, 85% 80%. Una forma di realizzazione specifica dell’invenzione implica composti che consistono o composizioni che comprendono l’enantiomero S come miscela arricchita o come enantiomero puro. Una seconda forma di realizzazione specifica dell’invenzione implica composti che consistono o composizioni che comprendono le miscele racemiche R/S. Una ulteriore forma di realizzazione, meno preferita, implica miscele arricchite dell’enantiomero R. 100% or a mixture strongly enriched with such enantiomer, for example 98%, 95%, 93%, 90%, 88%, 85% 80%. A specific embodiment of the invention involves compounds consisting of or compositions comprising the S enantiomer as an enriched mixture or as a pure enantiomer. A second specific embodiment of the invention involves compounds which consist or compositions which comprise the racemic mixtures R / S. A further, less preferred embodiment involves mixtures enriched with the R enantiomer.
Composti preferiti aventi formula generale (II) sono elencati nella sottostante tabella 1 Preferred compounds having general formula (II) are listed in Table 1 below
R R2N R3O R R2N R3O
N O NO
N O NO
R1R1
R4R5R4R5
tabella 1 table 1
R R1 R2 R3 R4 R5 R R1 R2 R3 R4 R5
1 H H H H H NHC(=O)CH32 H F H H H NHC(=O)CH33 H F F H H NHC(=O)CH34 H F F F H NHC(=O)CH35 H F F F H NHC(=O)CH36 H Cl H H H NHC(=O)CH37 H Cl Cl H H NHC(=O)CH38 H H H H H NHC(=S)CH39 H F H H H NHC(=S)CH310 H F F H H NHC(=S)CH311 H Cl H H H NHC(=S)CH312 H Cl Cl H H NHC(=S)CH313 H F F F H NHC(=S)CH314 H Br H H H NHC(=S)CH315 CH3H H H H NHC(=O)CH3(A3a) 1 H H H H H NHC (= O) CH32 H F H H H NHC (= O) CH33 H F F H H NHC (= O) CH34 H F F F H NHC (= O) CH35 H F F F H NHC (= O) CH36 H Cl H H H NHC (= O) CH37 H Cl Cl H H NHC (= O) CH38 H H H H H NHC (= S) CH39 H F H H H NHC (= S) CH310 H F F H H NHC (= S) CH311 H Cl H H H NHC (= S) CH312 H Cl Cl H H NHC (= S) CH313 H F F F H NHC (= S ) CH314 H Br H H H NHC (= S) CH315 CH3H H H H NHC (= O) CH3 (A3a)
16 CH3F H H H NHC(=O)CH3(A3b) 16 CH3F H H H NHC (= O) CH3 (A3b)
17 CH3F F H H NHC(=O)CH318 CH3F F F H NHC(=O)CH319 CH3Cl H H H NHC(=O)CH320 CH3Cl Cl H H NHC(=O)CH321 CH3Br H H H NHC(=O)CH322 CH3H H H H NHC(=S)CH3(A4a) 17 CH3F F H H NHC (= O) CH318 CH3F F F H NHC (= O) CH319 CH3Cl H H H NHC (= O) CH320 CH3Cl Cl H H NHC (= O) CH321 CH3Br H H H NHC (= O) CH322 CH3H H H H NHC (= S) CH3 (A4a)
23 CH3F H H H NHC(=S)CH3(A4b) 23 CH3F H H H NHC (= S) CH3 (A4b)
24 CH3F F H H NHC(=S)CH325 CH3Cl H H H NHC(=S)CH326 CH3Cl Cl H H NHC(=S)CH327 CH3F F F H NHC(=S)CH328 CH3Br H H H NHC(=S)CH329 C2H5H H H H NHC(=O)CH330 C2H5F H H H NHC(=O)CH331 C2H5F F H H NHC(=O)CH332 C2H5F F F H NHC(=O)CH333 C2H5Cl H H H NHC(=O)CH334 C2H5Cl Cl H H NHC(=O)CH335 C2H5Br H H H NHC(=O)CH336 C2H5H H H H NHC(=S)CH337 C2H5F H H H NHC(=S)CH338 C2H5F F H H NHC(=S)CH339 C2H5Cl H H H NHC(=S)CH340 C2H5Cl Cl H H NHC(=S)CH341 C2H5F F F H NHC(=S)CH342 C2H5Br H H H NHC(=S)CH343 H H H H H NHC(=O)NH244 H F H H H NHC(=O)NH245 H F F H H NHC(=O)NH246 H F F F H NHC(=O)NH247 H Br H H H NHC(=O)NH248 H Cl H H H NHC(=O)NH249 H Cl Cl H H NHC(=O)NH250 H H H H H NHC(=S)NH251 H F H H H NHC(=S)NH252 H F F H H NHC(=S)NH253 H Cl H H H NHC(=S)NH254 H Cl Cl H H NHC(=S)NH255 H F F F H NHC(=S)NH256 H Br H H H NHC(=S)NH257 CH3H H H H NHC(=O)NH258 CH3F H H H NHC(=O)NH259 CH3F F H H NHC(=O)NH260 CH3F F F H NHC(=O)NH261 CH3Cl H H H NHC(=O)NH262 CH3Cl Cl H H NHC(=O)NH263 CH3Br H H H NHC(=O)NH264 CH3H H H H NHC(=S)NH2B3a 24 CH3F F H H NHC (= S) CH325 CH3Cl H H H NHC (= S) CH326 CH3Cl Cl H H NHC (= S) CH327 CH3F F F H NHC (= S) CH328 CH3Br H H H NHC (= S) CH329 C2H5H H H H NHC (= O) CH330 C2H5F H H H NHC (= O) CH331 C2H5F F H H NHC (= O) CH332 C2H5F F F H NHC (= O) CH333 C2H5Cl H H H NHC (= O) CH334 C2H5Cl Cl H H NHC (= O) CH335 C2H5Br H H H NHC (= O) CH33H H H H NHC (= S) CH337 C2H5F H H H NHC (= S) CH338 C2H5F F H H NHC (= S) CH339 C2H5Cl H H H NHC (= S) CH340 C2H5Cl Cl H H NHC (= S) CH341 C2H5F F F H NHC (= S) CH342 H C2H5Br NHC (= S) CH343 H H H H H NHC (= O) NH244 H F H H H NHC (= O) NH245 H F F H H NHC (= O) NH246 H F F F H NHC (= O) NH247 H Br H H H NHC (= O) NH248 H Cl H H H NHC (= O ) NH249 H Cl Cl H H NHC (= O) NH250 H H H H H NHC (= S) NH251 H F H H H NHC (= S) NH252 H F F H H NHC (= S) NH253 H Cl H H H NHC (= S) NH254 H Cl Cl H H NHC (= S ) NH255 H F F F H NHC (= S) NH256 H Br H H H NHC (= S) NH257 CH3H H H H NHC (= O) NH258 CH3F H H H NHC (= O) NH259 CH3F F H H NHC (= O) NH260 CH3F F F H NHC (= O) NH261 CH3Cl H H H NHC (= O) NH262 CH3Cl Cl H H NHC (= O) NH263 CH3Br H H H NHC (= O) NH264 CH3H H H H NH C (= S) NH2B3a
65 CH3F H H H NHC(=S)NH2B3b 65 CH3F H H H NHC (= S) NH2B3b
66 CH3F F H H NHC(=S)NH2CH3Cl H H H NHC(=S)NH2CH3Cl Cl H H NHC(=S)NH2CH3F F F H NHC(=S)NH2CH3Br H H H NHC(=S)NH2C2H5H H H H NHC(=O)NH2C2H5F H H H NHC(=O)NH2C2H5F F H H NHC(=O)NH2C2H5F F F H NHC(=O)NH2C2H5Cl H H H NHC(=O)NH2C2H5Cl Cl H H NHC(=O)NH2C2H5Br H H H NHC(=O)NH2C2H5H H H H NHC(=S)NH2C2H5F H H H NHC(=S)NH2C2H5F F H H NHC(=S)NH2C2H5Cl H H H NHC(=S)NH2C2H5Cl Cl H H NHC(=S)NH2C2H5F F F H NHC(=S)NH2C2H5Br H H H NHC(=S)NH2H H H H H NHC(=O)NHCH3H F H H H NHC(=O)NHCH3H F F H H NHC(=O)NHCH3H F F F H NHC(=O)NHCH3H Br H H H NHC(=O)NHCH3H Cl H H H NHC(=O)NHCH3H Cl Cl H H NHC(=O)NHCH392 H H H H H NHC(=S)NHCH393 H F H H H NHC(=S)NHCH394 H F F H H NHC(=S)NHCH395 H Cl H H H NHC(=S)NHCH396 H Cl Cl H H NHC(=S)NHCH397 H F F F H NHC(=S)NHCH398 H Br H H H NHC(=S)NHCH399 CH3H H H H NHC(=O)NHCH3100 CH3F H H H NHC(=O)NHCH3101 CH3F F H H NHC(=O)NHCH3102 CH3F F F H NHC(=O)NHCH3103 CH3Cl H H H NHC(=O)NHCH3104 CH3Cl Cl H H NHC(=O)NHCH3105 CH3Br H H H NHC(=O)NHCH3106 CH3H H H H NHC(=S)NHCH3B4a 66 CH3F F H H NHC (= S) NH2CH3Cl H H H NHC (= S) NH2CH3Cl Cl H H NHC (= S) NH2CH3F F F H NHC (= S) NH2CH3Br H H H NHC (= S) NH2C2H5H H H H NHC (= O) NH2C2C5F H H H NH ) NH2C2H5F F H H NHC (= O) NH2C2H5F F F H NHC (= O) NH2C2H5Cl H H H NHC (= O) NH2C2H5Cl Cl H H NHC (= O) NH2C2H5Br H H H NHC (= O) NH2C2H5H H H (NH2 S) ) NH2C2H5F F H H NHC (= S) NH2C2H5Cl H H H NHC (= S) NH2C2H5Cl Cl H H NHC (= S) NH2C2H5F F F H NHC (= S) NH2C2H5Br H H H NHC (= S) NH2H H H H H NHC (= O) NHH ) NHCH3H F F H H NHC (= O) NHCH3H F F F H NHC (= O) NHCH3H Br H H H NHC (= O) NHCH3H Cl H H H NHC (= O) NHCH3H Cl Cl H H NHC (= O) NHCH392 H H H H H NHC (= S) NHCH393 H F H H H NHC (= S) NHCH394 H F F H H NHC (= S) NHCH395 H Cl H H H NHC (= S) NHCH396 H Cl Cl H H NHC (= S) NHCH397 H F F F H NHC (= S) NHCH398 H Br H H H NHC (= S) NHCH399 CH3H H H H NHC (= O) NHCH3100 CH3F H H H NHC (= O) NHCH3101 CH3F F H H NHC (= O) NHCH3102 CH3F F F H NHC (= O) NHCH3103 CH3Cl H H H NHC (= O) NHCH3104 CH3Cl Cl H H NHC (= O) NHCH3105 H NHC (= O) NHCH3105 H NHC (= O) NHCH3105 H NHC = O) NHCH3106 CH3H H H H NHC (= S) NHCH3B4a
107 CH3F H H H NHC(=S)NHCH3B4b 107 CH3F H H H NHC (= S) NHCH3B4b
108 CH3F F H H NHC(=S)NHCH3109 CH3Cl H H H NHC(=S)NHCH3110 CH3Cl Cl H H NHC(=S)NHCH3111 CH3F F F H NHC(=S)NHCH3112 CH3Br H H H NHC(=S)NHCH3113 C2H5H H H H NHC(=O)NHCH3114 C2H5F H H H NHC(=O)NHCH3115 C2H5F F H H NHC(=O)NHCH3116 C2H5F F F H NHC(=O)NHCH3117 C2H5Cl H H H NHC(=O)NHCH3118 C2H5Cl Cl H H NHC(=O)NHCH3119 C2H5Br H H H NHC(=O)NHCH3120 C2H5H H H H NHC(=S)NHCH3121 C2H5F H H H NHC(=S)NHCH3122 C2H5F F H H NHC(=S)NHCH3123 C2H5Cl H H H NHC(=S)NHCH3124 C2H5Cl Cl H H NHC(=S)NHCH3125 C2H5F F F H NHC(=S)NHCH3126 C2H5Br H H H NHC(=S)NHCH3127 CH3H H H H NCS 108 CH3F F H H NHC (= S) NHCH3109 CH3Cl H H H NHC (= S) NHCH3110 CH3Cl Cl H H NHC (= S) NHCH3111 CH3F F F H NHC (= S) NHCH3112 CH3Br H H H NHC (= S) NHCH3113 C2H5H H H H NHC3 = O C2H5F H H H NHC (= O) NHCH3115 C2H5F F H H NHC (= O) NHCH3116 C2H5F F F H NHC (= O) NHCH3117 C2H5Cl H H H NHC (= O) NHCH3118 C2H5Cl Cl H H NHC (= O) NHCH3119 C2H5Br H31 H H H NHC (= S) NHCH3121 C2H5F H H H NHC (= S) NHCH3122 C2H5F F H H NHC (= S) NHCH3123 C2H5Cl H H H NHC (= S) NHCH3124 C2H5Cl Cl H H NHC (= S) NHCH3125 C2H5F C2) H NHC (= S) NHCH3125 C2H5F C2) H NHC (HH3) NHC (= S) NHCH3127 CH3H H H H NCS
B2a B2a
128 CH3F H H H NCS 128 CH3F H H H NCS
B2b B2b
129 CH3F F H H NCS 129 CH3F F H H NCS
130 CH3Cl H H H NCS 130 CH3Cl H H H NCS
131 CH3Cl Cl H H NCS 131 CH3Cl Cl H H NCS
132 CH3F F F H NCS 132 CH3F F F H NCS
133 CH3Br H H H NCS 133 CH3Br H H H NCS
134 CH3H H H H NHC(=O)NHC(=O)CH3135 CH3F H H H NHC(=O)NHC(=O)CH3136 CH3F F H H NHC(=O)NHC(=O)CH3137 CH3Cl H H H NHC(=O)NHC(=O)CH3138 CH3Cl Cl H H NHC(=O)NHC(=O)CH3139 CH3F F F H NHC(=O)NHC(=O)CH3140 CH3Br H H H NHC(=O)NHC(=O)CH3141 CH3H H H H NHC(=S)NHC(=O)CH3142 CH3F H H H NHC(=S)NHC(=O)CH3143 CH3F F H H NHC(=S)NHC(=O)CH3144 CH3Cl H H H NHC(=S)NHC(=O)CH3145 CH3Cl Cl H H NHC(=S)NHC(=O)CH3146 CH3F F F H NHC(=S)NHC(=O)CH3147 CH3Br H H H NHC(=S)NHC(=O)CH3148 CH3H H H H I 134 CH3H H H H NHC (= O) NHC (= O) CH3135 CH3F H H H NHC (= O) NHC (= O) CH3136 CH3F F H H NHC (= O) NHC (= O) CH3137 CH3Cl H H H NHC (= O) NHC (= O) CH3138 CH3Cl Cl H H NHC (= O) NHC (= O) CH3139 CH3F F F H NHC (= O) NHC (= O) CH3140 CH3Br H H H NHC (= O) NHC (= O) CH3141 CH3H H H H NHC (= S) NHC (= O) CH3142 CH3F H H H NHC (= S) NHC (= O) CH3143 CH3F F H H NHC (= S) NHC (= O) CH3144 CH3Cl H H H NHC (= S) NHC (= O) CH3145 CH3Cl Cl H H NHC ( = S) NHC (= O) CH3146 CH3F F F H NHC (= S) NHC (= O) CH3147 CH3Br H H H NHC (= S) NHC (= O) CH3148 CH3H H H H I
A1a A1a
149 CH3F H H H I 149 CH3F H H H I
A1b A1b
150 CH3F F H H I 150 CH3F F H H I
151 CH3Cl H H H I 151 CH3Cl H H H I
152 CH3Cl Cl H H I 152 CH3Cl Cl H H I
153 CH3F F F H I 153 CH3F F F H I
154 CH3Br H H H I 154 CH3Br H H H I
155 CH3H H H H 1,2,3-triazol-1-il B1a 155 CH3H H H H 1,2,3-triazol-1-yl B1a
156 CH3F H H H 1,2,3-triazol-1-il B1b 156 CH3F H H H 1,2,3-triazol-1-yl B1b
157 CH3F F H H 1,2,3-triazol-1-il 158 CH3Cl H H H 1,2,3-triazol-1-il 159 CH3 Cl Cl H H 1,2,3-triazol-1-il 160 CH3 F F F H 1,2,3-triazol-1-il 161 CH3 Br H H H 1,2,3-triazol-1-il 157 CH3F F H H 1,2,3-triazol-1-yl 158 CH3Cl H H H 1,2,3-triazol-1-yl 159 CH3 Cl Cl H H 1,2,3-triazol-1-yl 160 CH3 F F F H 1,2 , 3-triazol-1-yl 161 CH3 Br H H H 1,2,3-triazol-1-yl
Ognuno dei sopra identificati composti puntuali à ̈ inteso sia come enantiomero S che come miscela arricchita in enantiometro S o nella in miscela racemica. Each of the above identified point compounds is intended both as an S enantiomer and as a mixture enriched in the S enantiometer or in the racemic mixture.
Preparazione dei composti dell’invenzione Preparation of the compounds of the invention
Di seguito viene descritta lo schema generale di sintesi dei composti di interesse A e B e dei relativi intermedi di sintesi. I composti dell’invenzione sono sintetizzati a partire dall’anello ossadiazolico, ottenuto tramite la classica sintesi via ammidossima (Schema 1) come descritta in [9]. The general synthesis scheme of the compounds of interest A and B and of the related synthesis intermediates is described below. The compounds of the invention are synthesized starting from the oxadiazole ring, obtained through the classical synthesis via amidoxime (Scheme 1) as described in [9].
L’ammidossima 1 viene posta a reagire con l’opportuno benzoil cloruro 2, fornendo gli 1,2,4-ossadiazoli 3. Tali composti presentano una posizione para attivata verso una reazione di Sostituzione Nucleofila Aromatica, [10-13] e posti a reagire con allilammina, forniscono i composti 4. La reazione con di-(t-butil)-dicarbonato e la successiva ciclizzazione [14] dei derivati 5, fornisce gli ossazolidinoni di interesse A1 come precursori ideali per ulteriori modificazioni in catena laterale. Amidoxime 1 is reacted with the appropriate benzoyl chloride 2, providing 1,2,4-oxadiazoles 3. These compounds have a para activated position towards an Aromatic Nucleophilic Substitution reaction, [10-13] and when reacted with allylamine, they provide compounds 4. The reaction with di- (t-butyl) -dicarbonate and the subsequent cyclization [14] of the derivatives 5, provides the oxazolidinones of interest A1 as ideal precursors for further modifications in the side chain.
O R2R Or R2R
R NH2Cl R3N R2R3R NH2Cl R3N R2R3
N No.
N O NO
OH R1F F OH R1F F
R4R1R4R1
123 R4123 R4
R H2N R H2N
N R2R3OO O N R2R3OO O
N R N R
O O O O O N R2O O O O O N R2
N R3N R3
R N1R O4N R N1R O4N
R1<H>R1 <H>
5 R45 R4
4 4
I2I2
R N R2R3R N R2R3
N O O N O N O O N O
R1R4I R1R4I
A1 A1
Schema 1 Scheme 1
La successive funzionalizzazione della catena laterale (Schema 2) comprende la formazione del gruppo acetammidometile A3, o gruppo equivalente, quale la formazione delle corrispondenti tioammidi A4, tiouree B4, derivati azolici A5-7, B1. I derivati A2 vengono ottenuti per reazione dei composti A1 con una fonte di azoturo. La successiva riduzione del gruppo azido, fornisce l’ammina corrispondente 6 [15]. Le ammine 6 vengono acetilate con cloruro di acetile o anidride acetica, fornendo i derivati A3. I derivati A3 vengono convertiti nelle corrispondenti tioammidi A4 per trattamento con reagenti solforanti (ad esempio Reagente di Lawesson, P2S5) (Schema 2). I derivati azolici A5-7, B1, vengono ottenuti per sostituzione nucleofila a partire dagli iododerivati A1, mentre le (tio)uree B4 vengono ottenute tramite reazione delle ammine 6 con iso(tio)cianati (Schema 2). The subsequent functionalization of the side chain (Scheme 2) comprises the formation of the acetamidomethyl group A3, or equivalent group, such as the formation of the corresponding thioamides A4, thioureas B4, azole derivatives A5-7, B1. Derivatives A2 are obtained by reaction of compounds A1 with a source of azide. The subsequent reduction of the azide group gives the corresponding amine 6 [15]. The amines 6 are acetylated with acetyl chloride or acetic anhydride, giving the derivatives A3. The A3 derivatives are converted into the corresponding A4 thioamides by treatment with sulfurizing reagents (e.g. Lawesson's Reagent, P2S5) (Scheme 2). The azole derivatives A5-7, B1, are obtained by nucleophilic substitution starting from the iododerivatives A1, while the (thio) ureas B4 are obtained through the reaction of amines 6 with iso (thio) cyanates (Scheme 2).
R R.
N R2R3O XYR R2N R2R3O XYR R2
N R O HN N N R O HN N
N N3O N N3O
O O O O
R1N O R1N O
R4I ï „ R1X A1 R4NY ZR4I ï „R1X A1 R4NY Z
N3- A5-7, B1 X, Y, Z = CH, N N3- A5-7, B1 X, Y, Z = CH, N
R N R2R3R N R2R3
N O O N O N O O N O
R1R4N3R1R4N3
A2 A2
riduzione reduction
R N R2R R N R2R
N3O CH3NCS R N3O CH3NCS R
or N R2or N R2
O R OR R
N O CH3N O CH3
3NCO N O 3NCO N O
R1O R1O
R N O R N O
4NH2R14NH2R1
6 R4HN Z 6 R4HN Z
AcCl or Ac2O HN B4 Z= O,S AcCl or Ac2O HN B4 Z = O, S
R N R2R3R N R2R3
N O O N O N O O N O
R1R4HN O R1R4HN O
A3 A3
LR or LR or
P2S5LR = Reagente di Lawesson P2S5LR = Lawesson's reagent
R N R2R3R N R2R3
N O O N O N O O N O
R1R4HN S R1R4HN S
A4 A4
Schema 2 Scheme 2
I composti così sintetizzati, in forma di miscele racemiche, sono arricchiti in uno degli isomeri o separati nei rispettivi isomeri ottici (enantiomero S e R) in accordo al seguente metodo, separazione cromatografica tramite HPLC con fase stazionaria chirale. The compounds thus synthesized, in the form of racemic mixtures, are enriched in one of the isomers or separated in the respective optical isomers (S and R enantiomer) according to the following method, chromatographic separation by HPLC with chiral stationary phase.
Le composizioni farmaceutiche The pharmaceutical compositions
Composizioni farmaceutiche idonee per la somministrazione dei composti dell’invenzione sono composizioni intese per uso orale, parenterale o topico. Pharmaceutical compositions suitable for the administration of the compounds of the invention are compositions intended for oral, parenteral or topical use.
Composizioni orali possono essere per esempio in forma di compressa, confetto, capsula rigida, capsula morbida, sciroppo, soluzione, sospensione, emulsione. Composizioni parenterali possono essere per esempio in forma di soluzione acquosa o oleosa o emulsione. Composizioni topiche possono essere per esempio in forma di pomata, crema, gel, soluzione, emulsione O/W o W/O, o sospensione. Oral compositions can be for example in the form of a tablet, a dragee, a hard capsule, a soft capsule, a syrup, a solution, a suspension, an emulsion. Parenteral compositions can be for example in the form of an aqueous or oily solution or emulsion. Topical compositions can be for example in the form of ointment, cream, gel, solution, O / W or W / O emulsion, or suspension.
Nella preparazione delle composizioni farmaceutiche uno o più composti dell’invenzione sono miscelati con vari eccipienti terapeuticamente accettabili idonei per composizioni solide, liquide o pastose. In the preparation of the pharmaceutical compositions, one or more compounds of the invention are mixed with various therapeutically acceptable excipients suitable for solid, liquid or pasty compositions.
Applicazioni terapeutiche Therapeutic applications
I composti rivendicati sono nuovi antibiotici intesi per l’uso nel trattamento di infezioni sostenute da batteri, essenzialmente da batteri Gram-positivi, estremamente resistenti. Per esempio, ma non limitati a, Staphylococcus spp, Enterococcus spp, Streptococcus spp, in particolare nel trattamento di infezioni da Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecium, Enterococcus faecalis, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis. I composti dell’invenzione si sono dimostrati attivi anche su batteri resistenti ad altri antibiotici o resistenti al composto di riferimento linezolid. Vantaggiosamente, i composti dell’invenzione sono efficaci anche su batteri resistenti a più di un antibiotico quindi su batteri multiresistenti, per esempio a due o più antibiotici scelti tra meticillina, vancomicina, penicillina o a linezolid. The claimed compounds are novel antibiotics intended for use in the treatment of bacterial-borne infections, essentially by extremely resistant Gram-positive bacteria. For example, but not limited to, Staphylococcus spp, Enterococcus spp, Streptococcus spp, particularly in the treatment of infections with Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecium, Enterococcus faecalis, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus influenzae, Haemophilus influenzae. The compounds of the invention have also been shown to be active on bacteria resistant to other antibiotics or resistant to the reference compound linezolid. Advantageously, the compounds of the invention are also effective on bacteria resistant to more than one antibiotic and therefore on multidrug-resistant bacteria, for example to two or more antibiotics selected from methicillin, vancomycin, penicillin or linezolid.
Inoltre, i nuovi composti dell’invenzione coniugano l’attività inibente o battericida su batteri sia sensibili che (multi)resistenti ad antibiotici noti ad una tossicità del tutto accettabile o addirittura minore di quella del composto di riferimento linezolid, offrendo così un profilo clinico/terapeutico del tutto vantaggioso. Furthermore, the new compounds of the invention combine the inhibitory or bactericidal activity on bacteria both sensitive and (multi) resistant to antibiotics known to a toxicity that is completely acceptable or even lower than that of the reference compound linezolid, thus offering a totally advantageous clinical / therapeutic profile.
PARTE SPERIMENTALE EXPERIMENTAL PART
Valutazione dell’attività farmacologica Evaluation of pharmacological activity
Saggi microbiologici Microbiological assays
(i) Ceppi batterici (i) Bacterial strains
Vari ceppi di Staphylococcus aureus meticillina-sensibili (MSSA) o meticillina-resistenti (MRSA) (2 MSSA e 3 MRSA) ben caratterizzati per il loro fenotipo di sensibilità agli antibiotici sono stati utilizzati per la determinazione in vitro dell'attività antibatterica dei composti studiati. In particolare, il ceppo standard di riferimento S. aureus ATCC 29213 e S. aureus M923 (ceppo da collezione) sono stati utilizzati come ceppi MSSA. Fra gli MRSA, S. aureus MU50 (ATCC 700699) ceppo di riferimento standard e due ceppi da collezione (433 e F511) sono stati utilizzati per le prove di sensibilità . Various strains of methicillin-sensitive (MSSA) or methicillin-resistant (MRSA) Staphylococcus aureus (2 MSSA and 3 MRSA) well characterized for their sensitivity phenotype to antibiotics were used for the in vitro determination of the antibacterial activity of the compounds studied. . In particular, the standard reference strain S. aureus ATCC 29213 and S. aureus M923 (collector strain) were used as MSSA strains. Among the MRSA, S. aureus MU50 (ATCC 700699) standard reference strain and two collector strains (433 and F511) were used for susceptibility tests.
(ii) Determinazione delle concentrazioni minime inibenti (MIC) L'attività antibatterica in vitro dei nuovi agenti à ̈ stata studiata determinando le concentrazioni minime inibenti (MIC) per mezzo del metodo di microdiluizione in brodo secondo le linee guida del Clinical and Laboratory Standards Institute (CLSI) [16]. In breve, diluizioni seriali di ciascun composto sono state effettuate utilizzando il brodo Cation-adjusted Mueller-Hinton (CAMHB) in piastre di microtitolazione da 96 pozzetti. Il dimetilsolfossido (DMSO) à ̈ stato utilizzato come solvente per tutti i composti sintetizzati. Un uguale volume dell'inoculo batterico normalizzato (1 x 10<6>CFU/mL) à ̈ stato aggiunto a ciascun pozzetto della piastra di microtitolazione contenente 0,05 mL delle diluizioni seriali degli sostanze da testare. La piastra di microtitolazione à ̈ stata poi incubata a 37°C per 18-24 ore, e successivamente ogni pozzetto à ̈ stato analizzato per la presenza di crescita batterica. La MIC, espressa in µg/mL, à ̈ stata definita come la più bassa concentrazione di antibiotico in grado di causare l'inibizione della crescita batterica, come mostrato dalla mancanza di torbidità del mezzo di coltura. L'attività in vitro dei nuovi composti 1,2,4-ossadiazolici linezolid-simili à ̈ stata testata e confrontata con quella del composto di riferimento per gli ossazolidinoni in uso clinico: il linezolid (Zyvox®, Pfizer). Le concentrazioni finali di DMSO sono state prese in considerazione in tutti i saggi biologici effettuati. (ii) Determination of minimum inhibitory concentrations (MIC) The in vitro antibacterial activity of the new agents was investigated by determining the minimum inhibitory concentrations (MIC) by means of the broth microdilution method according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI) [16]. Briefly, serial dilutions of each compound were made using Cation-adjusted Mueller-Hinton Broth (CAMHB) in 96-well microtiter plates. Dimethyl sulfoxide (DMSO) was used as a solvent for all synthesized compounds. An equal volume of normalized bacterial inoculum (1 x 10 <6> CFU / mL) was added to each well of the microtiter plate containing 0.05 mL of the serial dilutions of the substances to be tested. The microtiter plate was then incubated at 37 ° C for 18-24 hours, and subsequently each well was analyzed for the presence of bacterial growth. MIC, expressed in µg / mL, was defined as the lowest concentration of antibiotic capable of causing inhibition of bacterial growth, as shown by the lack of turbidity of the culture medium. The in vitro activity of the new linezolid-like 1,2,4-oxadiazole compounds was tested and compared with that of the reference compound for oxazolidinones in clinical use: linezolid (Zyvox®, Pfizer). Final DMSO concentrations were taken into consideration in all biological assays performed.
Test della Minima concentrazione inibente Minimum inhibitory concentration test
Quattordici nuovi composti in miscela racemica (gruppo A), riportati di seguito sono stati analizzati per la loro attività antibatterica contro ceppi di Staphylococcus aureus in termini di ceppi standard di riferimento e di ceppi clinici, sia sensibili alla meticillina (MSSA) che resistenti i (MRSA). Fourteen new compounds in racemic mixture (group A), listed below, were analyzed for their antibacterial activity against Staphylococcus aureus strains in terms of standard reference strains and clinical strains, both sensitive to methicillin (MSSA) and resistant i ( MRSA).
H3C H3C
N O NO
N No.
O N O OR NOT
R1R1
R2R2
A1-7a,b A1-7a, b
R1R2R1R2
A1a H I A1a H I
A1b F I A1b F I
A2a H N A2a H N
A2b F3A2b F3
N3N3
A3a H NH(C=O)CH A3a H NH (C = O) CH
A3b F3A3b F3
NH(C=O)CH NH (C = O) CH
A4a H3A4a H3
NH(C=S)CH NH (C = S) CH
A4b F3A4b F3
NH(C=S)CH NH (C = S) CH
A5a H3A5a H3
pirazol-1-il pyrazol-1-yl
A5b F pirazol-1-il A5b F pyrazol-1-yl
A6a H imidazol-1-il A6a H imidazol-1-yl
A6b F imidazol-1-il A6b F imidazol-1-yl
A7a H 1,2,4-triazol-1-il A7a H 1,2,4-triazol-1-yl
A7b F 1,2,4-triazol-1-il A7b F 1,2,4-triazol-1-yl
Le attività antimicrobiche, riassunte nella Tabella 2, sono state determinate mediante il metodo "gold standard" della brodo microdiluizione, seguendo le raccomandazioni del Clinical Laboratory Standards Institute (CLSI) (Vedasi Parte Sperimentale). Le concentrazioni minime inibenti (MIC) sono state espresse in valori µg/mL ed i test di vitalità cellulare sono stati eseguiti per valutare la tossicità antibatterica selettiva dei composti più attivi. Linezolid à ̈ stato usato come antibiotico di riferimento. Nel dettaglio i ceppi batterici saggiati sono: Staphylococcus aureus ATCC 29213, un ceppo clinico meticillino-sensibile di S. aureus (M923), S. aureus MU50 (meticillino-resistente – MRSA), e due ceppi clinici meticillinoresistenti 433 e F511. Tutti i ceppi saggiati risultavano essere linezolid-sensibili. Tra queste molecole le più attive, in forma racemica, si sono dimostrate le A4a e A4b. The antimicrobial activities, summarized in Table 2, were determined by the "gold standard" method of microdilution broth, following the recommendations of the Clinical Laboratory Standards Institute (CLSI) (See Experimental Part). Minimum inhibitory concentrations (MICs) were expressed in µg / mL values and cell viability tests were performed to evaluate the selective antibacterial toxicity of the more active compounds. Linezolid was used as a reference antibiotic. In detail, the bacterial strains tested are: Staphylococcus aureus ATCC 29213, a clinical methicillin-sensitive strain of S. aureus (M923), S. aureus MU50 (methicillin-resistant - MRSA), and two clinical methicillin-resistant strains 433 and F511. All strains tested were found to be linezolid-sensitive. Among these molecules the most active, in racemic form, are A4a and A4b.
Tabella 2 Table 2
MIC (ï g/mL) MIC (ï g / mL)
ATCC MSSA MRSA MRSA MRSA ATCC MSSA MRSA MRSA MRSA
Comp. A Comp. A
29213 M923 MU50 433 F511 A1a >50 >50 50 25 50 A1b >50 >50 50 50 >50 A2a >50 >50 >50 >50 >50 A2b >50 >50 >50 >50 >50 A3a 12.5 6.25 6.25 1.6 12.5 A3b 12.5 6.25 6.25 1.6 12.5 A4a 3.13 1.6 <0.4 1.6 1.6 A4b 1.6 1.6 <0.4 0.8 1.6 A5a >50 >50 >50 >50 >50 A5b >50 >50 >50 >50 >50 A6a >50 >50 >50 >50 >50 A6b >50 >50 >50 >50 >50 A7a >50 >50 >50 >50 >50 A7b >50 >50 >50 >50 >50 Linezolid <0.4 3.13 0.8 1.6 3.13 I composti A3a, A3b, A4a, A4b, A1a, A1b corrispondono ai composti 15, 16, 22, 23, 148 e 149 della Tabella 1 Quattro dei quattordici composti in esame (cfr. tabella 2) hanno mostrato valori di MIC, sia contro ceppi di MSSA che ceppi di MRSA con potenza paragonabile o superiore a quella di linezolid. Inoltre, una migliore attività contro MSSA e MRSA rispetto a linezolid à ̈ stata mostrata dai derivati contenenti zolfo A4a e A4b, mentre i composti A3a, e A3b si sono rilevati meno attivi del linezolid, tranne che per il ceppo MRSA 433. Il paragone con il linezolid deve tener conto del fatto che i composti testati sono stati usati come miscela racemica, quindi l'attività antibatterica per A3a, A3b, A4a e A4b si presume sia sottostimata rispetto alla potenza dell’enantiomero puro più attivo. 29213 M923 MU50 433 F511 A1a> 50> 50 50 25 50 A1b> 50> 50 50 50> 50 A2a> 50> 50> 50> 50> 50 A2b> 50> 50> 50> 50> 50 A3a 12.5 6.25 6.25 1.6 12.5 A3b 12.5 6.25 6.25 1.6 12.5 A4a 3.13 1.6 <0.4 1.6 1.6 A4b 1.6 1.6 <0.4 0.8 1.6 A5a> 50> 50> 50> 50> 50 A5b> 50> 50> 50> 50> 50 A6a> 50> 50> 50> 50> 50 A6b> 50> 50> 50> 50> 50 A7a> 50> 50> 50> 50> 50 A7b> 50> 50> 50> 50> 50 Linezolid <0.4 3.13 0.8 1.6 3.13 Compounds A3a, A3b, A4a , A4b, A1a, A1b correspond to compounds 15, 16, 22, 23, 148 and 149 of Table 1 Four of the fourteen compounds under examination (see Table 2) showed MIC values, both against MSSA and MRSA strains with potency comparable to or greater than that of linezolid. Furthermore, better activity against MSSA and MRSA than linezolid was shown by sulfur-containing derivatives A4a and A4b, while compounds A3a, and A3b were less active than linezolid, except for the MRSA 433 strain. linezolid must take into account the fact that the compounds tested were used as a racemic mixture, therefore the antibacterial activity for A3a, A3b, A4a and A4b is assumed to be underestimated compared to the potency of the more active pure enantiomer.
Di altri composti (gruppo B), riportati sotto, sono state valutate le attività sia della miscela racemica che degli enantiomeri S e R isolati. Of other compounds (group B), reported below, the activities of both the racemic mixture and the isolated S and R enantiomers were evaluated.
H3C H3C
N O NO
N O N O NINTH
R1R2R1R2
B1-4a,b B1-4a, b
R1R2R1R2
B1a H 1,2,3-triazol-1-il B1a H 1,2,3-triazol-1-yl
B1b F 1,2,3-triazol-1-il B1b F 1,2,3-triazol-1-yl
B2a H NCS B2a H NCS
B2b F NCS B2b F NCS
B3a H NH(C=S)NH B3a H NH (C = S) NH
B3b F2B3b F2
NH(C=S)NH2NH (C = S) NH2
B4a H NH(C=S)NHCH3B4a H NH (C = S) NHCH3
B4b F NH(C=S)NHCH3B4b F NH (C = S) NHCH3
Le attività antimicrobiche, riassunte nella Tabella 3, sono state determinate mediante il metodo "gold standard" della brodo microdiluizione, seguendo le raccomandazioni del Clinical Laboratory Standards Institute (CLSI) (Vedasi Parte Sperimentale). Le concentrazioni minime inibenti (MIC) sono state espresse in valori µg/mL. Linezolid à ̈ stato usato come antibiotico di riferimento. Nel dettaglio i ceppi batterici saggiati sono: Staphylococcus aureus ATCC 29213, un ceppo clinico meticillino-sensibile di S. aureus (M923), S. aureus MU50 (meticillino-resistente – MRSA), e due ceppi clinici meticillino-resistenti 433 e F511. Tutti i ceppi saggiati risultavano essere linezolid-sensibili. Tra queste molecole le più attive, in forma racemica, si sono dimostrate le B4a e B4b, seguite da B1a e B1b con una discreta attività (Tabella 3). The antimicrobial activities, summarized in Table 3, were determined by the "gold standard" method of microdilution broth, following the recommendations of the Clinical Laboratory Standards Institute (CLSI) (See Experimental Part). Minimum inhibitory concentrations (MICs) were expressed in µg / mL values. Linezolid was used as a reference antibiotic. In detail, the bacterial strains tested are: Staphylococcus aureus ATCC 29213, a clinical methicillin-sensitive strain of S. aureus (M923), S. aureus MU50 (methicillin-resistant - MRSA), and two clinical methicillin-resistant strains 433 and F511. All strains tested were found to be linezolid-sensitive. Among these molecules the most active, in racemic form, proved to be B4a and B4b, followed by B1a and B1b with a moderate activity (Table 3).
Tabella 3 Table 3
MIC (ï g/mL) MIC (ï g / mL)
ATCC MSSA MRSA MRSA MRSA ATCC MSSA MRSA MRSA MRSA
Comp. B Comp. B
29213 M923 MU50 433 F511 B1a 25 25 3,125 12,5 12,5 B1b 25 25 1,6 6,25 12,5 B2a >50 >50 >50 >50 50 B2b >50 >50 >50 >50 >50 B3a >50 >50 >50 >50 >50 29213 M923 MU50 433 F511 B1a 25 25 3.125 12.5 12.5 B1b 25 25 1.6 6.25 12.5 B2a> 50> 50> 50> 50 50 B2b> 50> 50> 50> 50> 50 B3a> 50> 50> 50> 50> 50
B3b >50 >50 >50 >50 >50 B3b> 50> 50> 50> 50> 50
B4a 6,25 6,25 1,6 3,125 6,25 B4a 6.25 6.25 1.6 3.125 6.25
B4b 6,25 6,25 1,6 3,125 6,25 B4b 6.25 6.25 1.6 3.125 6.25
Linezolid <0.4 3.125 0.8 1.6 3.125 Linezolid <0.4 3.125 0.8 1.6 3.125
Tra questi, i composti B4a e B4b (corrispondenti ai composti 106 e 107 della Tabella 1) hanno mostrato una attività molto simile a quella del linezolid su ceppi di S. aureus linezolid-sensibili. Among these, compounds B4a and B4b (corresponding to compounds 106 and 107 of Table 1) showed activity very similar to that of linezolid on linezolid-sensitive strains of S. aureus.
In maniera del tutto sorprendente, gli stessi composti, risolti nei loro enantiomeri, hanno dimostrato un’efficacia dalle 4 alle 8 volte superiore al linezolid su ceppi di Staphylococcus spp. linezolidresistenti. I risultati sono riportati in Tabella 4. In un caso si à ̈ totalmente ribaltata la resistenza al linezolid in sensibilità . Di queste molecole le separazioni enantiomeriche hanno permesso di attribuire tale potenza all’enantiomero S, mentre l’R si dimostrava inattivo (vedi Tabella 4). Surprisingly, the same compounds, resolved in their enantiomers, have shown an efficacy from 4 to 8 times higher than linezolid on strains of Staphylococcus spp. linezolidresistenti. The results are reported in Table 4. In one case the resistance to linezolid was completely overturned in sensitivity. The enantiomeric separations of these molecules made it possible to attribute this power to the S enantiomer, while the R proved to be inactive (see Table 4).
I composti B4b e B4a corrispondono alle miscele racemiche dei due composti B4b e B4a, i composti B4bS e B4bR e B4aS e B4aR sono gli enantiomeri S e R isolati. Compounds B4b and B4a correspond to the racemic mixtures of the two compounds B4b and B4a, compounds B4bS and B4bR and B4aS and B4aR are the isolated S and R enantiomers.
Tabella 4 Table 4
Viabilità cellulare (citotossicità ) Cell viability (cytotoxicity)
Per valutare se l’effetto ottenuto su cellule batteriche era dovuto ad una tossicità selettiva o generale, à ̈ stato eseguito un saggio di vitalità in differenti tipi di linee cellulari eucariotiche, per selezionare le nuove molecole in base alla loro attività citotossica generale. To evaluate whether the effect obtained on bacterial cells was due to selective or general toxicity, a viability assay was performed in different types of eukaryotic cell lines, to select the new molecules on the basis of their general cytotoxic activity.
Saggio di citotossicità Cytotoxicity assay
Gli effetti dei composti A4b, (composto 23 in Tabella 1) B4b (composto 107 Tabella 1) e B4a (composto 106 Tabella 1) e Linezolid sulla vitalità cellulare sono stati studiati in vitro in linee cellulari PK15 (epitelio di rene di maiale), HaCaT (cheratinociti umani) e HepG2 (carcinoma epatocellulare umano o epatoma) [17 19]. HepG2 e HaCaT sono state coltivate in terreno Dulbecco’s modified eagles medium (DMEM) mentre le cellule PK15 in DMEM/M199 (1:1). Tutti i terreni sono stati addizionati del 10% di siero bovino fetale (FBS) inattivato con il calore, L-glutammina alla concentrazione finale di 2mM, 100 unità /mL di penicillina streptomicina e 100 µg/mL di streptomicina. Le cellule sono state mantenute a 37°C in atmosfera con 5% CO2. Tutti i reagenti per le colture cellulari provengono da Euroclone (Pero, Italia). The effects of compounds A4b, (compound 23 in Table 1) B4b (compound 107 Table 1) and B4a (compound 106 Table 1) and Linezolid on cell viability were studied in vitro in PK15 cell lines (pig kidney epithelium), HaCaT (human keratinocytes) and HepG2 (human hepatocellular carcinoma or hepatoma) [17 19]. HepG2 and HaCaT were cultured in Dulbecco's modified eagles medium (DMEM) while PK15 cells in DMEM / M199 (1: 1). All media were spiked with 10% heat inactivated fetal bovine serum (FBS), 2mM final concentration L-glutamine, 100 units / mL penicillin streptomycin and 100 µg / mL streptomycin. The cells were kept at 37 ° C in an atmosphere with 5% CO2. All cell culture reagents come from Euroclone (Pero, Italy).
La vitalità cellulare à ̈ stata valutata mediante il saggio MTT [20]. Brevemente, una soluzione di MTT [3-(4,5-Dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide] (5 mg/mL) à ̈ stata aggiunta ad ogni pozzetto alla concentrazione finale di 1.2 mM, e le cellule sono state incubate per 1 ora e 30 minuti a 37°C. Dopo aver eliminato la soluzione di MTT, la reazione à ̈ stata bloccata aggiungendo etanolo al 90%. Le cellule sono state risospese e centrifugate 10 minuti a 800 x g. L’assorbanza à ̈ stata misurata utilizzando uno spettrofotometro multifunzione Victor3 (Perkin Elmer, Turku, Finlandia) alla lunghezza d’onda di 570 nm. I risultati rappresentano la media ± S.E. di 3 esperimenti separati eseguiti in triplo. Cell viability was assessed by the MTT assay [20]. Briefly, a solution of MTT [3- (4,5-Dimethythiazol-2-yl) -2,5-diphenyltetrazolium bromide] (5 mg / mL) was added to each well at the final concentration of 1.2 mM, and the cells were incubated for 1 hour and 30 minutes at 37 ° C. After removing the MTT solution, the reaction was stopped by adding 90% ethanol. The cells were resuspended and centrifuged for 10 minutes at 800 x g. The absorbance was measured using a Victor3 multifunction spectrophotometer (Perkin Elmer, Turku, Finland) at a wavelength of 570 nm. The results represent the mean ± S.E. of 3 separate experiments performed in triplicate.
Analisi statistica Statistic analysis
La significatività statistica à ̈ stata ottenuta con il test Student's t rispetto ai controlli * = p <0.05, ** = p <0.001. I dati sono medie ± D.S. di tre esperimenti separati condotti in triplicato. Statistical significance was obtained with Student's t test compared to controls * = p <0.05, ** = p <0.001. Data are means ± D.S. of three separate experiments conducted in triplicate.
Tutte le linee cellulari analizzate sono state sottoposte a trattamento con concentrazioni crescenti (5-400 µg/mL) di A4b, e linezolid utilizzato come molecola di riferimento. Inoltre come ulteriore controllo le cellule sono state trattate con DMSO, adoperato come solvente. All the cell lines analyzed were subjected to treatment with increasing concentrations (5-400 µg / mL) of A4b, and linezolid used as the reference molecule. Furthermore, as a further control, the cells were treated with DMSO, used as a solvent.
La molecola A4b ha indotto una moderata riduzione della vitalità (meno del 10%) nella linea cellulare PK15, con significatività statistica alle concentrazioni 25 (P<0.01), 50 (P<0.05) e 200 µg/mL (P<0.05) rispettivamente (Figura 2). Questo andamento à ̈ comparabile a quello ottenuto con il linezolid alle stesse concentrazioni. Molecule A4b induced a moderate reduction in viability (less than 10%) in the PK15 cell line, with statistical significance at concentrations 25 (P <0.01), 50 (P <0.05) and 200 µg / mL (P <0.05) respectively. (Figure 2). This trend is comparable to that obtained with linezolid at the same concentrations.
La riduzione della vitalità cellulare provocata dalla molecola A4b à ̈ risultata poco più evidente nella linea cellulare HaCaT, raggiungendo livelli di mortalità statisticamente significativi rispetto ai valori ottenuti con linezolid solo alla concentrazione di 400 µg/mL (P<0.01; Figura 3). The reduction in cell viability caused by the A4b molecule was slightly more evident in the HaCaT cell line, reaching statistically significant mortality levels compared to the values obtained with linezolid only at the concentration of 400 µg / mL (P <0.01; Figure 3).
Le cellule HepG2 hanno mostrato una riduzione della viabilità a partire da 50 µg/mL della sostanza A4b (Figura 4). HepG2 cells showed a reduction in viability starting from 50 µg / mL of substance A4b (Figure 4).
Sono stati poi valutati in vitro gli effetti delle molecole B4b e B4a sulla vitalità cellulare sulla linea cellulare di epatoma umano, HepG2 e confronto con citotossicità indotta dal linezolid (controllo negativo). Le cellule sono coltivate in terreno Dulbecco’s modified eagles medium (DMEM) addizionato del 10% di siero bovino fetale (FBS) inattivato con il calore, L-glutammina alla concentrazione finale di 2mM, 100 unità /mL di penicillina e 100 µg/mL di streptomicina. Le cellule sono mantenute a 37°C in atmosfera con 5% CO2. Trattamento citotossico: le cellule, piastrate alla densità di 40.000 cell/cm<2>e mantenute in coltura per due giorni, sono state sottoposte a trattamento per 48 ore con concentrazioni crescenti (25-100ï g/mL) di entrambi gli enantiomeri delle sostanze B4b e B4a. The effects of molecules B4b and B4a on cell viability on the human hepatoma cell line, HepG2, and comparison with linezolid-induced cytotoxicity (negative control) were then evaluated in vitro. Cells are cultured in Dulbecco's modified eagles medium (DMEM) supplemented with 10% heat inactivated fetal bovine serum (FBS), L-glutamine at the final concentration of 2mM, 100 units / mL of penicillin and 100 µg / mL of streptomycin. The cells are kept at 37 ° C in an atmosphere with 5% CO2. Cytotoxic treatment: the cells, plated at a density of 40,000 cells / cm <2> and kept in culture for two days, were subjected to treatment for 48 hours with increasing concentrations (25-100ïg / mL) of both enantiomers of the substances B4b and B4a.
La vitalità cellulare à ̈ stata valutata mediante saggio PrestoBlue® Cell Viability Reagent, una soluzione contenente resazurina che permea nelle cellule e ne sfrutta il potere riducente quando sono vive e metabolicamente attive. Brevemente, la soluzione PrestoBlue® viene somministrata direttamente al terreno delle cellule in coltura seguendo le istruzioni dell’industria che ha fornito il prodotto. Le cellule sono incubate per 1 ora a 37°C, tempo in cui la soluzione PrestoBlue®, metabolizzata dalle cellule vive vira la colorazione da blu al rosso. L’assorbanza à ̈ misurata utilizzando uno spettrofotometro multifunzione Victor3 (Perkin Elmer, Turku, Finland) alla lunghezza d’onda di 570 nm. I risultati ottenuti e rappresentati in grafico corrispondono alla media ± S.E. di esperimenti separati eseguiti in triplo. Cell viability was evaluated using the PrestoBlue® Cell Viability Reagent, a solution containing resazurin that permeates cells and exploits their reducing power when they are alive and metabolically active. Briefly, the PrestoBlue® solution is administered directly to the medium of the cultured cells following the instructions of the industry that supplied the product. The cells are incubated for 1 hour at 37 ° C, time in which the PrestoBlue® solution, metabolized by living cells, changes the color from blue to red. The absorbance is measured using a Victor3 multifunction spectrophotometer (Perkin Elmer, Turku, Finland) at a wavelength of 570 nm. The results obtained and represented in the graph correspond to the mean ± S.E. of separate experiments performed in triplicate.
La linea cellulare HepG2 à ̈ stata sottoposta a trattamento con concentrazioni crescenti (25-100 µg /mL) di entrambi gli enantiomeri delle molecole B4b e B4a. Il linezolid à ̈ utilizzato come molecola di riferimento solo alla concentrazione finale di 100 µg/mL. Inoltre come ulteriore controllo le cellule sono trattate anche con DMSO 0,9%, adoperato come solvente delle sostanze. The HepG2 cell line was subjected to treatment with increasing concentrations (25-100 µg / mL) of both the enantiomers of the molecules B4b and B4a. Linezolid is used as a reference molecule only at the final concentration of 100 µg / mL. Furthermore, as a further control, the cells are also treated with 0.9% DMSO, used as a solvent for the substances.
Entrambi gli enantiomeri della molecola B4b hanno indotto una moderata riduzione della vitalità (ï‚£ del 12%) nella linea cellulare HepG2 a tutte le concentrazioni testate (Figura 5). Both enantiomers of the B4b molecule induced a moderate reduction in viability (ï ‚£ by 12%) in the HepG2 cell line at all concentrations tested (Figure 5).
L’enantiomero S della molecola B4a ha un lieve effetto citotossico concentrazione-indipendente sulle cellule HepG2 (evidente solo a 25 µg/mL), mentre l’enantiomero R non determina una riduzione apparente della vitalità cellulare. Le cellule HepG2, come atteso, sono soggette ad una mortalità del 20% dopo trattamento con 100 µg /mL di linezolid. The S enantiomer of the B4a molecule has a mild concentration-independent cytotoxic effect on HepG2 cells (evident only at 25 µg / mL), while the R enantiomer does not cause an apparent reduction in cell viability. HepG2 cells, as expected, are subject to a mortality rate of 20% after treatment with 100 µg / mL of linezolid.
Sintesi dei composti Synthesis of compounds
I punti di fusione sono stati determinati tramite un apparato Reichart-Thermovar hotstage. Gli spettri IR (Nujol) sono stati registrati con uno Shimadzu FTIR-8300; GLi spettri NMR sono stati registrati con un spettrometro Bruker 300 Avance utilizzando TMS come standard interno. Le separazioni cromatografiche sono state effettuate con gel di silice (0.040–0.063 mm) e miscele di acetato d’etile ed etere di petrolio (40–60 °C) in varie proporzioni. La purezza di tutti i composti à ̈ stata determinata tramite NMR e HPLC e in tutti i casi si à ̈ rivelata maggiore del 95%. Le separazioni delle miscele racemiche sono state effettuate tramite HPLC con fase stazionaria chirale (Daicel, Chiralpak-IA), utilizzando esano-iPrOH (70:30) come fase mobile, impiegando un flusso di 1 mL/min. In ogni caso si ottiene un ee>99%. The melting points were determined using a Reichart-Thermovar hotstage apparatus. IR (Nujol) spectra were recorded with a Shimadzu FTIR-8300; NMR spectra were recorded with a Bruker 300 Avance spectrometer using TMS as an internal standard. The chromatographic separations were carried out with silica gel (0.040â € “0.063 mm) and mixtures of ethyl acetate and petroleum ether (40â €“ 60 ° C) in various proportions. The purity of all compounds was determined by NMR and HPLC and in all cases it was found to be greater than 95%. The separations of the racemic mixtures were carried out by HPLC with chiral stationary phase (Daicel, Chiralpak-IA), using hexane-iPrOH (70:30) as the mobile phase, using a flow of 1 mL / min. In any case, an ee> 99% is obtained.
I composti di maggiore interesse: The compounds of greatest interest:
A1a (composto 148 tabella 1), A1b (composto 149 tabella 1), A3a (composto 15 tabella 1), A3b (composto 16 tabella 1), A4a (composto 22 tabella 1), A4b (composto 23 tabella 1), B1a (composto 155 tabella 1), B1b (composto 156 tabella 1), B4a (composto 106 tabella 1), B4b (composto 107 tabella 1); riportati in tabella 2 (gruppo A) e 3 (gruppo B) e i relativi intermedi 1-6, sono stati ottenuti secondo le metodologie generali riportate negli schemi 1 e 2, secondo le specifiche di seguito indicate e riassunte nello schema 3. A1a (compound 148 table 1), A1b (compound 149 table 1), A3a (compound 15 table 1), A3b (compound 16 table 1), A4a (compound 22 table 1), A4b (compound 23 table 1), B1a ( compound 155 table 1), B1b (compound 156 table 1), B4a (compound 106 table 1), B4b (compound 107 table 1); shown in table 2 (group A) and 3 (group B) and the relative intermediates 1-6, were obtained according to the general methodologies reported in diagrams 1 and 2, according to the specifications indicated below and summarized in diagram 3.
O H3C Or H3C
a: R H3C NH2Cl 1) K2CO3/acetone N a: R H3C NH2Cl 1) K2CO3 / acetone N
= H N = H N
b: R1b: R1
1= F N 1 = F N
OH R12)ï „ O F R1OH R12) ï „O F R1
1 2a,b3a,b H2N K 1 2a, b3a, b H2N K
H3C2CO3H3C2CO3
NOO O H3C NOO OR H3C
N No.
N O N O O O O N O N O N O O O O N O
R N R N
1DMAP /MeCNR1<H>5a,b4a,b 1DMAP / MeCNR1 <H> 5a, b4a, b
I2DCM I2DCM
H3C H3C
N N H3C N N N H3C N
N O N NOT
O N O NH N O O N O NH N O
O OR
R1N O R1N O
I R1N A1a,b NNB1a,b I R1N A1a, b NNB1a, b
H3C NaN3DMF H3C NaN3DMF
N N O O N O N N O O N O
R1R1
A2a,b N3A2a, b N3
Ph Ph
H3C3P THF H3C H3C3P THF H3C
N No.
N O N NOT
O N O OR NOT
N O CH3NCS O N O CH3NCS O
R1TEA/THF N O NH2R1HN 6a,b B4a,b S NH CH3COCl Py/DCM R1TEA / THF N O NH2R1HN 6a, b B4a, b S NH CH3COCl Py / DCM
H3C H3C
N H3C N H3C
N No.
N O O N O O
O LR N O LR N
N O O N O N O O N O
R1H HF R1H A3a,b N T R1H HF R1H A3a, b N T
<O>A4a,b N<S><O> A4a, b N <S>
Schema 3 Scheme 3
Procedura generale per la preparazione dei composti 3a,b General procedure for the preparation of compounds 3a, b
Ad una soluzione di idrossilammina cloridrato (1.00 g, 14.4 mmol) ed NaOH (0.57 g, 14.4 mmol) in acqua (5 mL) vengono aggiunti 15 mL di CH3CN nell’arco di 15 minuti. La miscela di reazione viene lasciata ad agitare a temperatura ambiente per 24 ore. Il solvente viene rimosso a pressione ridotta ed il residuo trattato con etanolo; la sospensione risultante viene filtrate ed il solvente rimosso a pressione ridotta, fornendo 1.659 g di acetammidossima 1 (77%). Ad una soluzione di 1 (1.00 g; 13.5 mmol) in Acetone (35 mL) contenente anche K2CO3(2.05 g, 14.8 mmol) viene aggiunto 4-fluorobenzoil cloruro (2a) o 2,4-difluorobenzoil cloruro (2b) (14.8 mmol). La miscela viene posta sotto agitazione a temperature ambiente per 90 minuti, dopo i quali il solvente viene rimosso a pressione ridotta. Il residuo viene trattato con acqua ed il precipitato viene raccolto per filtrazione. La O-acilammidossima ottenuta, senza ulteriori purificazioni, viene scaldata a 130°C. per 90 minuti. in tubo chiuso. Il residuo ottenuto viene cromatografato fornendo i corrispondenti 1,2,4-ossadiazoli 3a e 3b. 15 mL of CH3CN is added to a solution of hydroxylamine hydrochloride (1.00 g, 14.4 mmol) and NaOH (0.57 g, 14.4 mmol) in water (5 mL) over a period of 15 minutes. The reaction mixture is left to stir at room temperature for 24 hours. The solvent is removed under reduced pressure and the residue treated with ethanol; the resulting suspension is filtered and the solvent removed under reduced pressure, providing 1,659 g of acetamidoxime 1 (77%). To a solution of 1 (1.00 g; 13.5 mmol) in Acetone (35 mL) also containing K2CO3 (2.05 g, 14.8 mmol) is added 4-fluorobenzoyl chloride (2a) or 2,4-difluorobenzoyl chloride (2b) (14.8 mmol ). The mixture is stirred at room temperature for 90 minutes, after which the solvent is removed under reduced pressure. The residue is treated with water and the precipitate is collected by filtration. The obtained O-acylamide oxime, without further purification, is heated to 130 ° C. for 90 minutes. in closed tube. The obtained residue is chromatographed giving the corresponding 1,2,4-oxadiazoles 3a and 3b.
3-metil-5-(4’-fluorofenil)-1,2,4-ossadiazolo (3a): Resa (72 %); Pf 80.0-81.0°C;<1>H NMR (300 MHz; CDCl3) Î ́ 2.45 (s, 3H, Me); 7.16-7.23 (m, 2H, Ar); 8.08-8.14 (m, 2H, Ar). Anal. Found (calc) for C9H7FN2O (%): C, 60.65 (60.67); H, 3.90 (3.96); N, 15.70 (15.72). 3-methyl-5- (4â € ™ -fluorophenyl) -1,2,4-oxadiazole (3a): Yield (72%); Pf 80.0-81.0 ° C; <1> H NMR (300 MHz; CDCl3) Î ́ 2.45 (s, 3H, Me); 7.16-7.23 (m, 2H, Ar); 8.08-8.14 (m, 2H, Ar). Anal. Found (calc) for C9H7FN2O (%): C, 60.65 (60.67); H, 3.90 (3.96); N, 15.70 (15.72).
3-metil-5-(2’,4’-difluorofenil)-1,2,4-ossadiazolo (3b): Resa (72 %); Pf 57.0-60.0°C;<1>H-NMR (300 MHz; CDCl3) Î ́ 2.46 (s, 3H, Me); 6.95 7.07 (m, 2H, Ar); 8.04-8.14 (m, 1H, Ar). Anal. Found (calc) for C9H6F2N2O (%): C, 55.15 (55.11); H, 3.10 (3.08); N, 14.25 (14.28). 3-methyl-5- (2â € ™, 4â € ™ -difluorophenyl) -1,2,4-oxadiazole (3b): Yield (72%); Pf 57.0-60.0 ° C; <1> H-NMR (300 MHz; CDCl3) Î ́ 2.46 (s, 3H, Me); 6.95 7.07 (m, 2H, Ar); 8.04-8.14 (m, 1H, Ar). Anal. Found (calc) for C9H6F2N2O (%): C, 55.15 (55.11); H, 3.10 (3.08); N, 14.25 (14.28).
Preparazione della N-allil-4-(3’-metil-1,2,4-ossadiazol-5’-il)-anilina 4a. Preparation of N-allyl-4- (3â € ™ -methyl-1,2,4-oxadiazol-5â € ™ -yl) -aniline 4a.
Il composto 3a (0.61g; 3.43 mmol) viene solubilizzato in allilammina (3.0 mL; 2.28 g; 40.0 mmol) in presenza di K2CO3(2.00 g; 14.5 mmol), e riscaldato a 60°C per 8 giorni. La miscela di reazione viene trattata con acqua ed estratta con EtOAc. La fase organica viene seccata su Na2SO4anidro, filtrata ed il solvente rimosso. Il residuo viene cromatografato fornendo il composto 4a: Resa (54%); Pf 63.9-65.5°C; IR (Nujol) 3335 (NH), 1607 (C=N) cm<-1>;<1>H-NMR (300 MHz; DMSO-d6) Î ́ 2.31 (s, 3H, Me); 3.76-3.79 (m, 2H, CH2); 5.12 (dd, 1H, J1= 10.5 Hz, J2= 1.8 Hz, -CH=CH2); 5.22 (dd, 1H, J1= 17.1 Hz, J2= 1.8 Hz, -CH=CH2); 5.82-5.93 (m, 1H, -CH=CH2); 6.68 (d, 2H, J = 9.0 Hz, Ar); 6.87 (t, 1H, J = 5.7 Hz, NH, exch. with D2O); 7.76 (d, 2H, J = 9.0 Hz, Ar). Anal. Found (calc) for C12H13N3O (%): C, 66.95 (66.96); H, 6.10 (6.09); N, 19.45 (19.52). Compound 3a (0.61g; 3.43 mmol) is solubilized in allylamine (3.0 mL; 2.28 g; 40.0 mmol) in the presence of K2CO3 (2.00 g; 14.5 mmol), and heated at 60 ° C for 8 days. The reaction mixture is treated with water and extracted with EtOAc. The organic phase is dried on anhydrous Na2SO4, filtered and the solvent removed. The residue is chromatographed giving the compound 4a: Yield (54%); Pf 63.9-65.5 ° C; IR (Nujol) 3335 (NH), 1607 (C = N) cm <-1>; <1> H-NMR (300 MHz; DMSO-d6) Î ́ 2.31 (s, 3H, Me); 3.76-3.79 (m, 2H, CH2); 5.12 (dd, 1H, J1 = 10.5 Hz, J2 = 1.8 Hz, -CH = CH2); 5.22 (dd, 1H, J1 = 17.1 Hz, J2 = 1.8 Hz, -CH = CH2); 5.82-5.93 (m, 1H, -CH = CH2); 6.68 (d, 2H, J = 9.0 Hz, Ar); 6.87 (t, 1H, J = 5.7 Hz, NH, exch. With D2O); 7.76 (d, 2H, J = 9.0 Hz, Ar). Anal. Found (calc) for C12H13N3O (%): C, 66.95 (66.96); H, 6.10 (6.09); N, 19.45 (19.52).
Preparazione della N-allil-3-fluoro-4-(3’-metil-1,2,4-ossadiazol-5’-il)-anilina (4b) Preparation of N-allyl-3-fluoro-4- (3â € ™ -methyl-1,2,4-oxadiazol-5â € ™ -yl) -aniline (4b)
Ad una soluzione di 3b (0,86g; 4.38 mmol) in DMF (2.0 mL) viene aggiunta allilammina (1.64 mL; 1.25 g; 22.0 mmol). La miscela di reazione viene posta sotto agitazione per 2 giorni a temperatura ambiente. La miscela di reazione viene trattata con acqua ed estratta con EtOAc. La fase organica viene seccata su Na2SO4anidro, filtrata ed il solvente rimosso. Il residuo viene cromatografato fornendo il composto 4b: Resa (49%); Pf 57.9-59.9°C; IR (Nujol) 3335 (NH), 1626 (C=N) cm<-1>;<1>H-NMR (300 MHz; DMSO-d6) Î ́ 2.34 (s, 3H, Me); 3.77-3.81 (m, 2H, CH2); 5.13 (dd, 1H, J1= 13.2 Hz, J2= 1.2 Hz,-CH=CH2); 5.23 (dd, 1H, J1= 17.4 Hz, J2= 1.2 Hz,-CH=CH2); 5.81-5.93 (m, 1H,-CH=CH2); 6.46 (dd, 1H, J1= 14.4 Hz, J2= 1.8 Hz, Ar); 6.56 (dd, 1H, J1= 8.7 Hz, J2= 1.8 Hz, Ar); 7.17-7.21 (bs, 1H, NH, exch. with D2O); 7.72-7.77 (m, 1H, Ar). Anal. Found (calc) for C12H12FN3O (%): C, 61.80 (61.79); H, 5.10 (5.19); N, 18.15 (18.02). Allylamine (1.64 mL; 1.25 g; 22.0 mmol) is added to a solution of 3b (0.86g; 4.38 mmol) in DMF (2.0 mL). The reaction mixture is stirred for 2 days at room temperature. The reaction mixture is treated with water and extracted with EtOAc. The organic phase is dried on anhydrous Na2SO4, filtered and the solvent removed. The residue is chromatographed giving compound 4b: Yield (49%); Pf 57.9-59.9 ° C; IR (Nujol) 3335 (NH), 1626 (C = N) cm <-1>; <1> H-NMR (300 MHz; DMSO-d6) Î ́ 2.34 (s, 3H, Me); 3.77-3.81 (m, 2H, CH2); 5.13 (dd, 1H, J1 = 13.2 Hz, J2 = 1.2 Hz, -CH = CH2); 5.23 (dd, 1H, J1 = 17.4 Hz, J2 = 1.2 Hz, -CH = CH2); 5.81-5.93 (m, 1H, -CH = CH2); 6.46 (dd, 1H, J1 = 14.4 Hz, J2 = 1.8 Hz, Ar); 6.56 (dd, 1H, J1 = 8.7 Hz, J2 = 1.8 Hz, Ar); 7.17-7.21 (bs, 1H, NH, exch. With D2O); 7.72-7.77 (m, 1H, Ar). Anal. Found (calc) for C12H12FN3O (%): C, 61.80 (61.79); H, 5.10 (5.19); N, 18.15 (18.02).
Procedura Generale per la sintesi dei composti 5a,b General procedure for the synthesis of compounds 5a, b
Il composto 4 (2.15 mmol) viene solubilizzato in CH3CN (25 mL); vengoni quindi aggiunti 4-dimetilaminopiridina (0.29 g; 2.36 mmol) e di-(t-butil)-dicarbonato (0.51 g; 2.36 mmol) e la reazione viene posta sotto agitazione a temperatura ambiente fino scomparsa del composto 4 (via TLC). Il solvente viene rimosso a pressione ridotta ed il residuo ottenuto cromatografato fornendo il corrispondente composto 5a o 5b. Compound 4 (2.15 mmol) is solubilized in CH3CN (25 mL); 4-dimethylaminopyridine (0.29 g; 2.36 mmol) and di- (t-butyl) -dicarbonate (0.51 g; 2.36 mmol) are then added and the reaction is stirred at room temperature until compound 4 disappears (via TLC). The solvent is removed under reduced pressure and the obtained residue is chromatographed giving the corresponding compound 5a or 5b.
tert-butil N-allil-(4-(3’-metil-1,2,4-ossadiazol-5’-il)-fenil)-carbammato (5a): Resa (73%); olio; IR (Nujol) 1711 (NCO2), 1614 (C=N) cm<-1>;<1>H-NMR (300 MHz; CDCl3) Î ́ 1.27 (s, 9H, t-Bu); 2.25 (s, 3H, Me); 4.10 (d, 2H, J = 5.1 Hz, CH2); 4.95-4.97 (m, 1H,-CH=CH2); 4.99-5.01 (m, 1H,-CH=CH2); 5.67-5.78 (m, 1H,-CH=CH2); 7.23 (d, 2H, J = 9.0 Hz, Ar); 7.84 (d, 2H, J = 9.0 Hz, Ar). Anal. Found (calc) for C17H21N3O3(%): C, 64.70 (64.74); H, 6.80 (6.71); N, 13.35 (13.32). tert-butyl N-allyl- (4- (3â € ™ -methyl-1,2,4-oxadiazol-5â € ™ -yl) -phenyl) -carbamate (5a): Yield (73%); oil; IR (Nujol) 1711 (NCO2), 1614 (C = N) cm <-1>; <1> H-NMR (300 MHz; CDCl3) Î ́ 1.27 (s, 9H, t-Bu); 2.25 (s, 3H, Me); 4.10 (d, 2H, J = 5.1 Hz, CH2); 4.95-4.97 (m, 1H, -CH = CH2); 4.99-5.01 (m, 1H, -CH = CH2); 5.67-5.78 (m, 1H, -CH = CH2); 7.23 (d, 2H, J = 9.0 Hz, Ar); 7.84 (d, 2H, J = 9.0 Hz, Ar). Anal. Found (calc) for C17H21N3O3 (%): C, 64.70 (64.74); H, 6.80 (6.71); N, 13.35 (13.32).
tert-butil N-allil-(3-fluoro-4-(3’-metil-1,2,4-ossadiazol-5’-il)-fenil)-carbammato (5b): Resa (72%); olio; IR (Nujol) 1713 (NCO2), 1615 (C=N) cm<-1>;<1>H-NMR (300 MHz; CDCl3) Î ́ 1.53 (s, 9H, t-Bu); 2.53 (s, 3H, Me); 4.36 (d, 2H, J = 5.1 Hz, CH2); 5.21-5.28 (m, 2H, -CH=CH2); 5.91-6.02 (m, 1H,-CH=CH2); 7.28-7.36 (m, 2H, Ar); 8.02-8.08 (m, 1H, Ar).Anal. Found (calc) for C17H20FN3O3(%): C, 61.25 (61.25); H, 6.10 (6.05); N, 12.65 (12.61). tert-butyl N-allyl- (3-fluoro-4- (3â € ™ -methyl-1,2,4-oxadiazol-5â € ™ -yl) -phenyl) -carbamate (5b): Yield (72%); oil; IR (Nujol) 1713 (NCO2), 1615 (C = N) cm <-1>; <1> H-NMR (300 MHz; CDCl3) Î ́ 1.53 (s, 9H, t-Bu); 2.53 (s, 3H, Me); 4.36 (d, 2H, J = 5.1 Hz, CH2); 5.21-5.28 (m, 2H, -CH = CH2); 5.91-6.02 (m, 1H, -CH = CH2); 7.28-7.36 (m, 2H, Ar); 8.02-8.08 (m, 1H, Ar) .Anal. Found (calc) for C17H20FN3O3 (%): C, 61.25 (61.25); H, 6.10 (6.05); N, 12.65 (12.61).
Procedura Generale per la sintesi dei composti A1a,b General procedure for the synthesis of compounds A1a, b
Ad una soluzione del composto 5 (1.70 mmol) in CH2Cl2(10 mL) viene aggiunto I2(1.29 g; 5.10 mmol). La soluzione viene agitata a temperatura ambiente per 24 ore, dopo le quali la soluzione viene lavata con una soluzione satura di Na2S2O3; la fase organica viene seccata su Na2SO4anidro, filtrata ed il solvente rimosso. Il residuo viene cromatografato fornendo i composti A1a o A1b. I2 (1.29 g; 5.10 mmol) is added to a solution of compound 5 (1.70 mmol) in CH2Cl2 (10 mL). The solution is stirred at room temperature for 24 hours, after which the solution is washed with a saturated solution of Na2S2O3; the organic phase is dried over anhydrous Na2SO4, filtered and the solvent removed. The residue is chromatographed giving the compounds A1a or A1b.
3-(4’-(3’’-metil-1,2,4-ossadiazol-5’’-il)-fenil)-5-(iodometil)-ossazolidin-2-one (A1a): Resa (89%); Pf 145.0-147.0 °C; IR (Nujol) 1763 (NCO2), 1618 (C=N) cm<-1>;<1>H-NMR (300 MHz; DMSO-d6) Î ́ 2.47 (s, 3H, Me); 3.62-3.73 (m, 2H, CH2-I); 3.80 (dd, 1H, J1= 9.3 Hz, J2= 6.0 Hz, C4-H); 4.34 (dd, 1H, J1= 9.3 Hz, J2= 9.0 Hz,C4-H); 4.81-4.90 (m, 1H, C5-H); 7.88 (d, 2H, J = 9.0 Hz, Ar); 8.17 (d, 2H, J = 9.0 Hz, Ar).Anal. Found (calc) for C13H12IN3O3(%): C, 40.55 (40.54); H, 3.15 (3.14); N, 10.85 (10.91). 3- (4â € ™ - (3â € ™ â € ™ -methyl-1,2,4-oxadiazol-5â € ™ â € ™ -yl) -phenyl) -5- (iodomethyl) -oxazolidin-2-one ( A1a): Yield (89%); Pf 145.0-147.0 ° C; IR (Nujol) 1763 (NCO2), 1618 (C = N) cm <-1>; <1> H-NMR (300 MHz; DMSO-d6) Î ́ 2.47 (s, 3H, Me); 3.62-3.73 (m, 2H, CH2-I); 3.80 (dd, 1H, J1 = 9.3 Hz, J2 = 6.0 Hz, C4-H); 4.34 (dd, 1H, J1 = 9.3 Hz, J2 = 9.0 Hz, C4-H); 4.81-4.90 (m, 1H, C5-H); 7.88 (d, 2H, J = 9.0 Hz, Ar); 8.17 (d, 2H, J = 9.0 Hz, Ar) .Anal. Found (calc) for C13H12IN3O3 (%): C, 40.55 (40.54); H, 3.15 (3.14); N, 10.85 (10.91).
3-(3’-fluoro-4’-(3’’-metil-1,2,4-ossadiazol-5’’-il)-fenil)-5-(iodometil)-ossazolidin-2-one (A1b): Resa (76%); Pf 148.0-149.0 °C; IR (Nujol) 1743 (NCO2), 1637 (C=N) cm<-1>;<1>H-NMR (300 MHz; DMSO-d6) Î ́2.48 (s, 3H, Me); 3.61-3.72 (m, 2H, CH2-I); 3.81 (dd, 1H, J1= 9.6 Hz, J2= 6.0 Hz, C4-H); 4.33 (dd, 1H, J1= 9.6 Hz, J2= 9.0 Hz, C4-H); 4.83-4.93 (m, 1H, C5-H); 7.68 (dd, 1H, J1= 8.7 Hz, J2= 2.1 Hz, Ar); 7.80 (dd, 1H, J1= 13.8 Hz, J2= 2.1 Hz, Ar); 8.16 (dd, 1H, J1= 8.7 Hz, J2= 8.5 Hz, Ar).Anal. Found (calc) for C13H11FIN3O3(%): C, 38.75 (38.73); H, 2.55 (2.75); N, 10.35 (10.42). 3- (3â € ™ -fluoro-4â € ™ - (3â € ™ â € ™ -methyl-1,2,4-oxadiazol-5â € ™ â € ™ -yl) -phenyl) -5- (iodomethyl) - oxazolidin-2-one (A1b): Yield (76%); Pf 148.0-149.0 ° C; IR (Nujol) 1743 (NCO2), 1637 (C = N) cm <-1>; <1> H-NMR (300 MHz; DMSO-d6) Î ́2.48 (s, 3H, Me); 3.61-3.72 (m, 2H, CH2-I); 3.81 (dd, 1H, J1 = 9.6 Hz, J2 = 6.0 Hz, C4-H); 4.33 (dd, 1H, J1 = 9.6 Hz, J2 = 9.0 Hz, C4-H); 4.83-4.93 (m, 1H, C5-H); 7.68 (dd, 1H, J1 = 8.7 Hz, J2 = 2.1 Hz, Ar); 7.80 (dd, 1H, J1 = 13.8 Hz, J2 = 2.1 Hz, Ar); 8.16 (dd, 1H, J1 = 8.7 Hz, J2 = 8.5 Hz, Ar). Found (calc) for C13H11FIN3O3 (%): C, 38.75 (38.73); H, 2.55 (2.75); N, 10.35 (10.42).
Procedura Generale per la sintesi dei composti A2a,b General procedure for the synthesis of A2a compounds, b
Ad una soluzione di composto A1 (0.75 mmol) in DMF (6 mL) viene aggiunta NaN3(0.39 g; 6.00 mmol). La miscela di reazione viene trattata con acqua ed estratta con EtOAc. La fase organica viene seccata su Na2SO4anidro, filtrata ed il solvente rimosso. Il residuo viene cromatografato fornendo il corrispondente composto A2a o A2b. NaN3 (0.39 g; 6.00 mmol) is added to a solution of compound A1 (0.75 mmol) in DMF (6 mL). The reaction mixture is treated with water and extracted with EtOAc. The organic phase is dried on anhydrous Na2SO4, filtered and the solvent removed. The residue is chromatographed yielding the corresponding compound A2a or A2b.
3-(4’-(3’’-metil-1,2,4-ossadiazol-5-il)-fenil)-5-(azidometil)-ossazolidin-2-one (A2a): Resa (94%); Pf 133.9-135.0 °C; IR (Nujol) 2095 (N3), 1765(NCO2), 1727(NCO2), 1618 (C=N) cm<-1>;<1>H-NMR (300 MHz; DMSO-d6) Î ́ 2.46 (s, 3H, Me); 3.75-3.88 (m, 2H, CH2-N3); 3.92 (dd, 1H, J1= 9.3 Hz, J2= 6.0 Hz, C4-H); 4.28 (t, 1H, J = 9.3 Hz, C4-H); 4.96-5.03 (m, 1H,C5-H); 7.86 (d, 2H, J = 9.0 Hz, Ar); 8.16 (d, 2H, J = 9.0 Hz, Ar). Anal. Found (calc) for C13H12N6O3(%): C, 52.05 (52.00); H, 4.10 (4.03); N, 27.85 (27.99). 3- (4â € ™ - (3â € ™ â € ™ -methyl-1,2,4-oxadiazol-5-yl) -phenyl) -5- (azidomethyl) -oxazolidin-2-one (A2a): Yield ( 94%); Pf 133.9-135.0 ° C; IR (Nujol) 2095 (N3), 1765 (NCO2), 1727 (NCO2), 1618 (C = N) cm <-1>; <1> H-NMR (300 MHz; DMSO-d6) Î ́ 2.46 (s , 3H, Me); 3.75-3.88 (m, 2H, CH2-N3); 3.92 (dd, 1H, J1 = 9.3 Hz, J2 = 6.0 Hz, C4-H); 4.28 (t, 1H, J = 9.3 Hz, C4-H); 4.96-5.03 (m, 1H, C5-H); 7.86 (d, 2H, J = 9.0 Hz, Ar); 8.16 (d, 2H, J = 9.0 Hz, Ar). Anal. Found (calc) for C13H12N6O3 (%): C, 52.05 (52.00); H, 4.10 (4.03); N, 27.85 (27.99).
3-(3’-fluoro-4’-(3’’-metil-1,2,4-ossadiazol-5-il)-fenil)-5-(azidometil)-ossazolidin-2-one (A2b): Resa (99%); Pf 126.2-127.7 °C; IR (Nujol) 2107 (N3), 1758 (NCO2), 1743 (NCO2), 1630 (C=N) cm<-1>;<1>H-NMR (300 MHz; DMSO-d6) Î ́ 2.41 (s, 3H, Me); 3.69-3.82 (m, 2H, CH2-N3); 3.86 (dd, 1H, J1= 9.3 Hz, J2= 6.0 Hz,C4-H); 4.21 (t, 1H, J = 9.3 Hz,C4-H); 4.91-4.99 (m, 1H,C5-H); 7.60 (dd, 1H, J1= 9.0 Hz, J2= 1.8 Hz, Ar); 7.72 (dd, 1H, J1= 13.5 Hz, J2= 1.8 Hz, Ar); 8.08-8.14 (m, 1H, Ar).Anal. Found (calc) for C13H11FN6O3(%): C, 49.10 (49.06); H, 3.50 (3.48); N, 26.45 (26.41). 3- (3â € ™ -fluoro-4â € ™ - (3â € ™ â € ™ -methyl-1,2,4-oxadiazol-5-yl) -phenyl) -5- (azidomethyl) -oxazolidin-2-one (A2b): Yield (99%); Pf 126.2-127.7 ° C; IR (Nujol) 2107 (N3), 1758 (NCO2), 1743 (NCO2), 1630 (C = N) cm <-1>; <1> H-NMR (300 MHz; DMSO-d6) Î ́ 2.41 (s , 3H, Me); 3.69-3.82 (m, 2H, CH2-N3); 3.86 (dd, 1H, J1 = 9.3 Hz, J2 = 6.0 Hz, C4-H); 4.21 (t, 1H, J = 9.3 Hz, C4-H); 4.91-4.99 (m, 1H, C5-H); 7.60 (dd, 1H, J1 = 9.0 Hz, J2 = 1.8 Hz, Ar); 7.72 (dd, 1H, J1 = 13.5 Hz, J2 = 1.8 Hz, Ar); 8.08-8.14 (m, 1H, Ar) .Anal. Found (calc) for C13H11FN6O3 (%): C, 49.10 (49.06); H, 3.50 (3.48); N, 26.45 (26.41).
Procedura Generale per la sintesi dei composti 6a,b General procedure for the synthesis of compounds 6a, b
Ad una soluzione del composto A2 (0.45 mmol) in THF (15 mL) viene aggiunta PPh3(0.16 g; 0.60 mmol). La soluzione viene agitata per 90 minuti, passati i quali vengono aggiunti 100 Î1⁄4l di acqua e la miscela posta a riflusso per 4 ore. Il THF viene rimosso a pressione ridotta ed il residuo risultante viene trattato con HCl diluito ed estratto con EtOAc. Alla fase acquosa viene quindi aggiunto NaOH (pH~9), e nuovamente il tutto estratto con EtOAc; la fase organica viene seccata su Na2SO4anidro, filtrata ed il solvente rimosso. Il residuo viene cromatografato fornendo il corrispondente composto 6a o 6b. PPh3 (0.16 g; 0.60 mmol) is added to a solution of compound A2 (0.45 mmol) in THF (15 mL). The solution is stirred for 90 minutes, after which 100 Î1⁄4l of water are added and the mixture refluxed for 4 hours. The THF is removed under reduced pressure and the resulting residue is treated with diluted HCl and extracted with EtOAc. NaOH (pH ~ 9) is then added to the aqueous phase, and the whole is extracted again with EtOAc; the organic phase is dried over anhydrous Na2SO4, filtered and the solvent removed. The residue is chromatographed yielding the corresponding compound 6a or 6b.
3-(4’-(3’’-metil-1,2,4-ossadiazol-5-il)-fenil)-5-(amminometil)-ossazolidin-2-one (6a): Resa (66%); Pf 139.3-141.3 °C; IR (Nujol) 3390 (NH), 3361 (NH), 1748 (NCO2), 1616 (C=N) cm<-1>;<1>H-NMR (300 MHz; DMSO-d6) Î ́2.22 (bs, 2H, NH2, exch. with D2O); 2.39 (s, 3H, Me); 2.77-2.91 (m, 2H, CH2-NH2); 3.94 (dd, 1H, J1= 9.0 Hz, J2= 6.3 Hz, C4-H); 4.13 (t, 1H, J = 9.0 Hz, C4-H); 4.61-4.70 (m, 1H,C5-H); 7.80 (d, 2H, J = 9.0 Hz, Ar); 8.09 (d, 2H, J = 9.0 Hz, Ar). Anal. Found (calc) for C13H14N4O3(%): C, 56.90 (56.93); H, 5.15 (5.14); N, 20.45 (20.43). 3- (4â € ™ - (3â € ™ â € ™ -methyl-1,2,4-oxadiazol-5-yl) -phenyl) -5- (aminomethyl) -oxazolidin-2-one (6a): Yield ( 66%); Pf 139.3-141.3 ° C; IR (Nujol) 3390 (NH), 3361 (NH), 1748 (NCO2), 1616 (C = N) cm <-1>; <1> H-NMR (300 MHz; DMSO-d6) Î ́2.22 ( bs, 2H, NH2, exch. with D2O); 2.39 (s, 3H, Me); 2.77-2.91 (m, 2H, CH2-NH2); 3.94 (dd, 1H, J1 = 9.0 Hz, J2 = 6.3 Hz, C4-H); 4.13 (t, 1H, J = 9.0 Hz, C4-H); 4.61-4.70 (m, 1H, C5-H); 7.80 (d, 2H, J = 9.0 Hz, Ar); 8.09 (d, 2H, J = 9.0 Hz, Ar). Anal. Found (calc) for C13H14N4O3 (%): C, 56.90 (56.93); H, 5.15 (5.14); N, 20.45 (20.43).
3-(3’-fluoro-4’-(3’’-metil-1,2,4-ossadiazol-5-il)-fenil)-5-(amminometil)-ossazolidin-2-one (6b): Resa (88%); Pf 137.0-140.0 °C; IR (Nujol) 3372 (NH), 1743 (NCO2), 1630(C=N) cm<-1>;<1>H-NMR (300 MHz; DMSO-d6) Î ́2.21 (bs, 2H, NH2, exch. with D2O); 2.41 (s, 3H, Me); 2.77-2.91 (m, 2H, CH2-NH2); 3.93 (dd, 1H, J1= 9.3 Hz, J2= 6.3 Hz, C4-H); 4.13 (t, 1H, J = 9.0 Hz,C4-H); 4.63-4.71 (m, 1H,C5-H); 7.60 (dd, 1H, J1= 9.0 Hz, J2= 2.1 Hz, Ar); 7.73 (dd, 1H, J1= 10.8 Hz, J2= 2.1 Hz, Ar); 8.08-8.14 (m, 1H, Ar).Anal. Found (calc) for C13H13FN4O3(%): C, 53.40 (53.42); H, 4.45 (4.48); N, 19.25 (19.17). 3- (3â € ™ -fluoro-4â € ™ - (3â € ™ â € ™ -methyl-1,2,4-oxadiazol-5-yl) -phenyl) -5- (aminomethyl) -oxazolidin-2-one (6b): Yield (88%); Pf 137.0-140.0 ° C; IR (Nujol) 3372 (NH), 1743 (NCO2), 1630 (C = N) cm <-1>; <1> H-NMR (300 MHz; DMSO-d6) Î ́2.21 (bs, 2H, NH2 , exch. with D2O); 2.41 (s, 3H, Me); 2.77-2.91 (m, 2H, CH2-NH2); 3.93 (dd, 1H, J1 = 9.3 Hz, J2 = 6.3 Hz, C4-H); 4.13 (t, 1H, J = 9.0 Hz, C4-H); 4.63-4.71 (m, 1H, C5-H); 7.60 (dd, 1H, J1 = 9.0 Hz, J2 = 2.1 Hz, Ar); 7.73 (dd, 1H, J1 = 10.8 Hz, J2 = 2.1 Hz, Ar); 8.08-8.14 (m, 1H, Ar) .Anal. Found (calc) for C13H13FN4O3 (%): C, 53.40 (53.42); H, 4.45 (4.48); N, 19.25 (19.17).
Procedura Generale per la sintesi dei composti A3a,b General procedure for the synthesis of compounds A3a, b
Cloruro di acetile (40 l; 44 mg; 0.56 mmol) viene aggiunto ad una soluzione del composto 8 (0.28 mmol) in CH2Cl2(3 mL) e piridina (1 mL; 0.97 g; 12.3 mmol). La soluzione viene posta ad agitare a temperatura ambiente per 30 minuti, dopo i quali il solvent viene rimosso ed il residuo trattato con HCl 1M (20 mL) ed estratto con EtOAc; la fase organica viene seccata su Na2SO4anidro, filtrata ed il solvente rimosso. Il residuo viene cromatografato fornendo il corrispondente composto A3a o A3b. Acetyl chloride (40 l; 44 mg; 0.56 mmol) is added to a solution of compound 8 (0.28 mmol) in CH2Cl2 (3 mL) and pyridine (1 mL; 0.97 g; 12.3 mmol). The solution is stirred at room temperature for 30 minutes, after which the solvent is removed and the residue treated with 1M HCl (20 mL) and extracted with EtOAc; the organic phase is dried over anhydrous Na2SO4, filtered and the solvent removed. The residue is chromatographed yielding the corresponding compound A3a or A3b.
3-(4’-(3’’-metil-1,2,4-ossadiazol-5-il)-fenil)-5-(N-acetilamminometil)-ossazolidin-2-one (A3a): Resa (58%); Pf 214.0-216.0 °C; IR (Nujol) 3257 (NH), 1751(NCO2), 1646 (amide),1616 (C=N) cm<-1>;<1>H-NMR (300 MHz; DMSO-d6) Î ́ 1.89 (s, 3H, COMe); 2.46 (s, 3H, Me); 3.50 (t, 2H, J = 5.7 Hz, CH2-NHCOMe); 3.88 (dd, 1H, J1= 9.0 Hz, J2= 6.6 Hz,C4-H); 4.25 (t, 1H, J = 9.0 Hz,C4-H); 4.79-4.87 (m, 1H,C5-H); 7.84 (d, 2H, J = 8.7 Hz, Ar); 8.16 (d, 2H, J = 8.7 Hz, Ar); 8.32 (t, 1H, J = 5.7 Hz, NH, exch. with D2O);<13>C-NMR (75 MHz; DMSO-d6) Î ́ 11.4, 22.6, 41.5, 47.2, 72.0, 118.1, 128.9, 142.6, 154.1, 167.7, 170.2, 174.5. Anal. Found (calc) for C15H16N4O4(%): C, 56.95 (56.96); H, 5.05 (5.10); N, 17.85 (17.71). 3- (4â € ™ - (3â € ™ â € ™ -methyl-1,2,4-oxadiazol-5-yl) -phenyl) -5- (N-acetylaminomethyl) -oxazolidin-2-one (A3a): Yield (58%); Pf 214.0-216.0 ° C; IR (Nujol) 3257 (NH), 1751 (NCO2), 1646 (amide), 1616 (C = N) cm <-1>; <1> H-NMR (300 MHz; DMSO-d6) Î ́ 1.89 (s , 3H, COMe); 2.46 (s, 3H, Me); 3.50 (t, 2H, J = 5.7 Hz, CH2-NHCOMe); 3.88 (dd, 1H, J1 = 9.0 Hz, J2 = 6.6 Hz, C4-H); 4.25 (t, 1H, J = 9.0 Hz, C4-H); 4.79-4.87 (m, 1H, C5-H); 7.84 (d, 2H, J = 8.7 Hz, Ar); 8.16 (d, 2H, J = 8.7 Hz, Ar); 8.32 (t, 1H, J = 5.7 Hz, NH, exch. With D2O); <13> C-NMR (75 MHz; DMSO-d6) Î ́ 11.4, 22.6, 41.5, 47.2, 72.0, 118.1, 128.9, 142.6 , 154.1, 167.7, 170.2, 174.5. Anal. Found (calc) for C15H16N4O4 (%): C, 56.95 (56.96); H, 5.05 (5.10); N, 17.85 (17.71).
3-(3’-fluoro-4’-(3’’-metil-1,2,4-ossadiazol-5-il)-fenil)-5-(N-acetilamminometil)-ossazolidin-2-one (A3b): Resa (62%); Pf 184.0-186.0 °C; IR (Nujol) 3343 (NH), 1751 (NCO2), 1666 (amide), 1628 (C=N) cm<-1>;<1>H-NMR (300 MHz; DMSO-d6) Î ́ 1.89 (s, 3H, COMe); 2.48 (s, 3H, Me); 3.50 (t, 2H, J = 5.4 Hz, CH2-NHCOMe); 3.88 (dd, 1H, J1= 9.3 Hz, J2= 6.3 Hz, C4-H); 4.25 (t, 1H, J = 9.0 Hz, C4-H); 4.81-4.88 (m, 1H, C5-H); 7.64 (dd, 1H, J1= 9.0 Hz, J2= 1.8 Hz, Ar); 7.77 (dd, 1H, J1= 13.8 Hz, J2= 1.8 Hz, Ar); 8.15-8.21 (m, 1H, Ar), 8.31 (m, 1H, NH, exch. with D2O);<13>C-NMR (75 MHz; DMSO-d6) Î ́ 11.32, 22.6, 41.5, 47.3, 72.2, 105.7 (d, JC-F= 32 Hz), 106.2 (d, JC-F= 14 Hz), 114.1, 131.4, 144.3 (d, JC-F= 14 Hz), 153.9, 160.4 (d, JC-F= 305 Hz), 167.5, 170.2, 171.6.Anal. Found (calc) for C15H15FN4O4(%): C, 53.90 (53.89); H, 4.65 (4.52); N, 16.65 (16.76). 3- (3â € ™ -fluoro-4â € ™ - (3â € ™ â € ™ -methyl-1,2,4-oxadiazol-5-yl) -phenyl) -5- (N-acetylaminomethyl) -oxazolidin-2 -one (A3b): Yield (62%); Pf 184.0-186.0 ° C; IR (Nujol) 3343 (NH), 1751 (NCO2), 1666 (amide), 1628 (C = N) cm <-1>; <1> H-NMR (300 MHz; DMSO-d6) Î ́ 1.89 (s , 3H, COMe); 2.48 (s, 3H, Me); 3.50 (t, 2H, J = 5.4 Hz, CH2-NHCOMe); 3.88 (dd, 1H, J1 = 9.3 Hz, J2 = 6.3 Hz, C4-H); 4.25 (t, 1H, J = 9.0 Hz, C4-H); 4.81-4.88 (m, 1H, C5-H); 7.64 (dd, 1H, J1 = 9.0 Hz, J2 = 1.8 Hz, Ar); 7.77 (dd, 1H, J1 = 13.8 Hz, J2 = 1.8 Hz, Ar); 8.15-8.21 (m, 1H, Ar), 8.31 (m, 1H, NH, exch. With D2O); <13> C-NMR (75 MHz; DMSO-d6) Î ́ 11.32, 22.6, 41.5, 47.3, 72.2 , 105.7 (d, JC-F = 32 Hz), 106.2 (d, JC-F = 14 Hz), 114.1, 131.4, 144.3 (d, JC-F = 14 Hz), 153.9, 160.4 (d, JC-F = 305 Hz), 167.5, 170.2, 171.6.Anal. Found (calc) for C15H15FN4O4 (%): C, 53.90 (53.89); H, 4.65 (4.52); N, 16.65 (16.76).
Procedura Generale per la sintesi dei composti A4a,b General procedure for the synthesis of compounds A4a, b
Ad una soluzione di composto A3 (0.49 mmol) in THF (14 mL) viene aggiunto il reagente di Lawesson (0.2 g; 0.49 mmol). La miscela viene posta a riflusso per 2 ore, passate le quali il solvente viene rimosso a pressione ridotta. Il residuo viene cromatografato fornendo il corrispondente composto A4a o A4b. Lawesson's reagent (0.2 g; 0.49 mmol) is added to a solution of compound A3 (0.49 mmol) in THF (14 mL). The mixture is refluxed for 2 hours, after which the solvent is removed under reduced pressure. The residue is chromatographed yielding the corresponding compound A4a or A4b.
3-(4’-(3’’-metil-1,2,4-ossadiazol-5-il)-fenil)-5-(N-tioacetilamminometil)-ossazolidin-2-one (A4a): Resa (77%); Pf 199.4-201.0°C; IR (Nujol) 3217 (NH), 1721 (NCO2), 1618(tioammide) cm<-1>;<1>H-NMR (300MHz; DMSO-d6) Î ́ 2.47 (s, 3H, Me); 2.51 (s, 3H, CSMe); 3.95-4.03 (m, 3H); 4.28-4.34 (m, 1H, C4-H); 5.01-5.11 (m, 1H, C5-H); 7.85 (d, 2H, J = 9.0 Hz, Ar); 8.18 (d, 2H, J = 9.0 Hz, Ar); 10.45 (bs, 1H, NH, exch. with D2O).Anal. Found (calc) for C15H16N4O3S (%): C, 54.15 (54.20); H, 4.85 (4.85); N, 16.90 (16.86). 3- (4â € ™ - (3â € ™ â € ™ -methyl-1,2,4-oxadiazol-5-yl) -phenyl) -5- (N-thioacetylaminomethyl) -oxazolidin-2-one (A4a): Yield (77%); Pf 199.4-201.0 ° C; IR (Nujol) 3217 (NH), 1721 (NCO2), 1618 (thioamide) cm <-1>; <1> H-NMR (300MHz; DMSO-d6) Î ́ 2.47 (s, 3H, Me); 2.51 (s, 3H, CSMe); 3.95-4.03 (m, 3H); 4.28-4.34 (m, 1H, C4-H); 5.01-5.11 (m, 1H, C5-H); 7.85 (d, 2H, J = 9.0 Hz, Ar); 8.18 (d, 2H, J = 9.0 Hz, Ar); 10.45 (bs, 1H, NH, exch. With D2O). Found (calc) for C15H16N4O3S (%): C, 54.15 (54.20); H, 4.85 (4.85); N, 16.90 (16.86).
3-(3’-fluoro-4’-(3’’-metil-1,2,4-ossadiazol-5-il)-fenil)-5-(N-tioacetilamminometil)-ossazolidin-2-one (A4b): Resa (93%); Pf 166.5-167.7°C; IR (Nujol) 3262 (NH), 1746 (NCO2),1633(thioamide) cm<-1>;<1>H-NMR (300MHz; DMSO-d6)Î ́ 2.48 (s, 3H, Me); 2.51 (s, 3H, CSMe); 3.94-4.00 (m, 3H); 4.28-4.34 (m, 1H, C4-H); 5.04-5.12 (m, 1H,C5-H); 7.65 (dd, 1H, J1= 9 Hz, J2= 1.8 Hz, Ar); 7.78 (dd, 1H, J1= 13.5 Hz, J2= 1.8 Hz, Ar); 8.16-8.22 (m, 1H, Ar); 10.45 (bs, 1H, NH exch. with D2O).Anal. Found (calc) for C15H14FN4O3S (%): C, 51.35 (51.42); H, 4.30 (4.32); N, 16.05 (15.99). 3- (3â € ™ -fluoro-4â € ™ - (3â € ™ â € ™ -methyl-1,2,4-oxadiazol-5-yl) -phenyl) -5- (N-thioacetylaminomethyl) -oxazolidin-2 -one (A4b): Yield (93%); Pf 166.5-167.7 ° C; IR (Nujol) 3262 (NH), 1746 (NCO2), 1633 (thioamide) cm <-1>; <1> H-NMR (300MHz; DMSO-d6) Î ́ 2.48 (s, 3H, Me); 2.51 (s, 3H, CSMe); 3.94-4.00 (m, 3H); 4.28-4.34 (m, 1H, C4-H); 5.04-5.12 (m, 1H, C5-H); 7.65 (dd, 1H, J1 = 9 Hz, J2 = 1.8 Hz, Ar); 7.78 (dd, 1H, J1 = 13.5 Hz, J2 = 1.8 Hz, Ar); 8.16-8.22 (m, 1H, Ar); 10.45 (bs, 1H, NH exch. With D2O). Found (calc) for C15H14FN4O3S (%): C, 51.35 (51.42); H, 4.30 (4.32); N, 16.05 (15.99).
Procedura generale per la preparazione dei composti B1a,b General procedure for the preparation of compounds B1a, b
In un tubo di vetro, a 0.45 mmol di composto A1a o A1b, viene aggiunto 1,2,3-triazolo (0.124 g; 1.8 mmol). La miscela viene posta a riflusso fino a scomparsa del reagente iniziale (TLC). Il residuo viene cromatografato fornendo il corrispondente derivato B1a o B1b. In a glass tube, 1,2,3-triazole (0.124 g; 1.8 mmol) is added to 0.45 mmol of compound A1a or A1b. The mixture is refluxed until the initial reagent (TLC) disappears. The residue is chromatographed giving the corresponding derivative B1a or B1b.
((3-(4-(3-metil-1,2,4-ossadiazol-5-il)fenil)-ossazolidin-2-on-5-il)metil)-1H-1,2,3-triazolo (B1a): Resa (73%); Pf 208-210 °C; IR (Nujol) Î1⁄2 1751 cm<-1>;<1>H-NMR (300MHz; CDCl3) Î ́ 2.46 (s, 3H), 4.03 (dd, J1= 6.3 Hz, J2= 9.3 Hz, 1H), 4.25 (dd, J1= 9.3 Hz, J2= 9.0 Hz, 1H), 4.82-4.83 (m, 2H), 5.08-5.14 (m, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.75 (s, 1H), 7.80 (s, 1H), 8.08 (d, J = 9.0 Hz, 1H); Anal. Found (calc) for C15H14N6O3(%): C, 55.30 (55.21); H, 4.39 (4.32); N, 25.69 (25.75). ((3-(3-fluoro-4-(3-metil-1,2,4-ossadiazol-5-il)fenil)-ossazolidin-2-on-5-il)metil)-1H-1,2,3-triazolo (B1b): Resa (64%); Pf 176.2-177.8 °C; IR (Nujol) Î1⁄2 1751 cm<-1>;<1>H-NMR (300MHz; CDCl3) Î ́ 2.48 (s, 3H), 4.03 (dd, J1= 9.3 Hz, J2= 6.0 Hz, 1H), 4.25 (dd, J1= 9.6 Hz, J2= 9.0 Hz, 1H), 4.82-4.83 (m, 2H), 5.15-5.30 (m,1H), 7.27 (dd, J1= 8.3 Hz, J2= 1.8 Hz, 1H), 7.56 (dd, J1= 12.6 Hz, J2= 1.8 Hz, 1H), 7.75 (s, 1H), 7.79 (s, 1H), 8.02 (t, J = 8.3 Hz, 1H); Anal. Found (calc) for C15H13FN6O3(%): C, 52.37 (52.33); H, 3.85 (3.81); N, 24.47 (24.41). ((3- (4- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl) -oxazolidin-2-on-5-yl) methyl) -1H-1,2,3-triazole ( B1a): Yield (73%); Pf 208-210 ° C; IR (Nujol) Î1⁄2 1751 cm <-1>; <1> H-NMR (300MHz; CDCl3) Î ́ 2.46 (s, 3H), 4.03 (dd, J1 = 6.3 Hz, J2 = 9.3 Hz, 1H) , 4.25 (dd, J1 = 9.3 Hz, J2 = 9.0 Hz, 1H), 4.82-4.83 (m, 2H), 5.08-5.14 (m, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.75 ( s, 1H), 7.80 (s, 1H), 8.08 (d, J = 9.0 Hz, 1H); Anal. Found (calc) for C15H14N6O3 (%): C, 55.30 (55.21); H, 4.39 (4.32); N, 25.69 (25.75). ((3- (3-fluoro-4- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl) -oxazolidin-2-on-5-yl) methyl) -1H-1,2, 3-triazole (B1b): Yield (64%); Pf 176.2-177.8 ° C; IR (Nujol) Î1⁄2 1751 cm <-1>; <1> H-NMR (300MHz; CDCl3) Î ́ 2.48 (s, 3H), 4.03 (dd, J1 = 9.3 Hz, J2 = 6.0 Hz, 1H) , 4.25 (dd, J1 = 9.6 Hz, J2 = 9.0 Hz, 1H), 4.82-4.83 (m, 2H), 5.15-5.30 (m, 1H), 7.27 (dd, J1 = 8.3 Hz, J2 = 1.8 Hz, 1H), 7.56 (dd, J1 = 12.6 Hz, J2 = 1.8 Hz, 1H), 7.75 (s, 1H), 7.79 (s, 1H), 8.02 (t, J = 8.3 Hz, 1H); Anal. Found (calc) for C15H13FN6O3 (%): C, 52.37 (52.33); H, 3.85 (3.81); N, 24.47 (24.41).
Procedura generale per la preparazione dei composti B4a,b General procedure for the preparation of compounds B4a, b
Ad una soluzione di ammina 8 (0.55 mmol) in THF (5 mL) viene aggiunto CH3NCS (0.041 mL; 0.60 mmol) e trietilammina (0.084 mL; 0.60 mmol). La soluzione viene posta sotto agitazione per 3 ore a temperatura ambiente. Il solvente viene rimosso a pressione ridotta ed il residuo cromatografato, fornendo i composti B4a o B4b. CH3NCS (0.041 mL; 0.60 mmol) and triethylamine (0.084 mL; 0.60 mmol) are added to a solution of amine 8 (0.55 mmol) in THF (5 mL). The solution is stirred for 3 hours at room temperature. The solvent is removed under reduced pressure and the residue is chromatographed, giving the compounds B4a or B4b.
1-((3-(4-(3-metil-1,2,4-ossadiazol-5-il)fenil)-ossazolidin-2-one-5-il)metil)-3-metiltiourea (B4a): Resa (80%); Pf 189.4-191.8 °C; IR (Nujol) Î1⁄2 3364, 1732 cm<-1>;<1>H-NMR (300MHz; CDCl3) Î ́ 2.39 (s, 3H), 2.82 (bs, 3H), 3.82-4.00 (m, 3H), 4.20 (dd, J1= 8.7 Hz, J2= 6.0 Hz, 1H), 4.91 (bs, 1H), 7.77-7.80 (m, 3H), 8.09 (d, J = 6.9 Hz, 2H); Anal. Found (calc) for C15H17N5O3S (%): C, 51.91 (51.86); H, 5.00 (4.93); N, 20.20 (20.16). 1 - ((3- (4- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl) -oxazolidin-2-one-5-yl) methyl) -3-methylthiourea (B4a): Yield (80%); Pf 189.4-191.8 ° C; IR (Nujol) Î1⁄2 3364, 1732 cm <-1>; <1> H-NMR (300MHz; CDCl3) Î ́ 2.39 (s, 3H), 2.82 (bs, 3H), 3.82-4.00 (m, 3H ), 4.20 (dd, J1 = 8.7 Hz, J2 = 6.0 Hz, 1H), 4.91 (bs, 1H), 7.77-7.80 (m, 3H), 8.09 (d, J = 6.9 Hz, 2H); Anal. Found (calc) for C15H17N5O3S (%): C, 51.91 (51.86); H, 5.00 (4.93); N, 20.20 (20.16).
1-((3-(3-fluoro-4-(3-metil-1,2,4-ossadiazol-5-il)fenil)-ossazolidin-2-one-5-il)metil)-3-metiltiourea (B4b): Resa (88%); Pf 170.7-172.4 °C; IR (Nujol) Î1⁄2 3370, 1739 cm<-1>;<1>H-NMR (300MHz, DMSO) Î ́ 2.48 (s, 3H), 2.89 (bs, 3H), 3.89-4.07 (m, 3H), 4.24-4.30 (m, 1H), 4.89 (bs, 1H), 7.74 (s, 1H), 7.79 (dd, J1= 13.5 Hz, J2= 2.1 Hz, 2H), 8.20 (t, J = 9.0 Hz, 2H); Anal. Found (calc) for C15H16FN5O3S (%): C, 49.21 (49.31); H, 4.35 (4.41); N, 19.10 (19.17). 1 - ((3- (3-fluoro-4- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl) -oxazolidin-2-one-5-yl) methyl) -3-methylthiourea ( B4b): Yield (88%); Pf 170.7-172.4 ° C; IR (Nujol) Î1⁄2 3370, 1739 cm <-1>; <1> H-NMR (300MHz, DMSO) Î ́ 2.48 (s, 3H), 2.89 (bs, 3H), 3.89-4.07 (m, 3H ), 4.24-4.30 (m, 1H), 4.89 (bs, 1H), 7.74 (s, 1H), 7.79 (dd, J1 = 13.5 Hz, J2 = 2.1 Hz, 2H), 8.20 (t, J = 9.0 Hz , 2H); Anal. Found (calc) for C15H16FN5O3S (%): C, 49.21 (49.31); H, 4.35 (4.41); N, 19.10 (19.17).
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| CA2907032A CA2907032C (en) | 2013-03-15 | 2014-03-17 | 1, 2, 4-oxadiazol compounds active against gram-positive pathogens |
| US14/777,508 US9920039B2 (en) | 2013-03-15 | 2014-03-17 | 1,2,4-Oxadiazol compounds active against gram-positive pathogens |
| PCT/IB2014/059896 WO2014141218A1 (en) | 2013-03-15 | 2014-03-17 | Novel 1, 2, 4-oxadiazol compounds active against gram-positive pathogens |
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| ES14718750T ES2753244T3 (en) | 2013-03-15 | 2014-03-17 | Novel Compounds 1,2,4 Oxadiazole Active Against Gram Positive Pathogens |
| CN201480015509.1A CN105209458B (en) | 2013-03-15 | 2014-03-17 | It is novel that there is the active 1,2,4- oxadiazole compound of resisting gram-positive pathogen |
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| EP0352781A2 (en) * | 1988-07-29 | 1990-01-31 | The Du Pont Merck Pharmaceutical Company | Aminomethyloxooxazolidinyl arylbenzene derivatives useful as antibacterial agents |
| WO1999002525A1 (en) * | 1997-07-11 | 1999-01-21 | Pharmacia & Upjohn Company | Thiadiazolyl and oxadiazolyl phenyl oxazolidinone antibacterial agents |
| WO2003035648A1 (en) * | 2001-10-25 | 2003-05-01 | Astrazeneca Ab | Aryl substituted oxazolidinones with antibacterial activity |
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| EP0352781A2 (en) * | 1988-07-29 | 1990-01-31 | The Du Pont Merck Pharmaceutical Company | Aminomethyloxooxazolidinyl arylbenzene derivatives useful as antibacterial agents |
| WO1999002525A1 (en) * | 1997-07-11 | 1999-01-21 | Pharmacia & Upjohn Company | Thiadiazolyl and oxadiazolyl phenyl oxazolidinone antibacterial agents |
| WO2003035648A1 (en) * | 2001-10-25 | 2003-05-01 | Astrazeneca Ab | Aryl substituted oxazolidinones with antibacterial activity |
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| LISA M THOMASCO ET AL: "The synthesis and antibacterial activity of 1,3,4-Thiadiazole phenyl oxazolidinone analogues", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 13, no. 23, 1 December 2003 (2003-12-01), pages 4193 - 4196, XP055066018, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2003.07.018 * |
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