BRPI1000099B1 - POTENTIALLY ACTIVE MIMETIC PEPTIDE COMPOUNDS AGAINST HEPATITIS C VIRUSES AND PHARMACEUTICAL COMPOSITION CONTAINING SUCH COMPOUNDS - Google Patents
POTENTIALLY ACTIVE MIMETIC PEPTIDE COMPOUNDS AGAINST HEPATITIS C VIRUSES AND PHARMACEUTICAL COMPOSITION CONTAINING SUCH COMPOUNDS Download PDFInfo
- Publication number
- BRPI1000099B1 BRPI1000099B1 BRPI1000099-2A BRPI1000099A BRPI1000099B1 BR PI1000099 B1 BRPI1000099 B1 BR PI1000099B1 BR PI1000099 A BRPI1000099 A BR PI1000099A BR PI1000099 B1 BRPI1000099 B1 BR PI1000099B1
- Authority
- BR
- Brazil
- Prior art keywords
- compounds
- boc
- nmr
- mhz
- hcv
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 60
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 19
- 108090000765 processed proteins & peptides Proteins 0.000 title abstract description 13
- 241000711557 Hepacivirus Species 0.000 title 1
- 239000003001 serine protease inhibitor Substances 0.000 claims abstract description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 16
- -1 N-CBz-Valine-Phenylalanine Chemical compound 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 229940122055 Serine protease inhibitor Drugs 0.000 claims description 3
- 101710102218 Serine protease inhibitor Proteins 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 2
- 239000003963 antioxidant agent Substances 0.000 claims description 2
- 239000003443 antiviral agent Substances 0.000 claims description 2
- 239000000872 buffer Substances 0.000 claims description 2
- 239000002270 dispersing agent Substances 0.000 claims description 2
- 235000003599 food sweetener Nutrition 0.000 claims description 2
- 239000003906 humectant Substances 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 239000003755 preservative agent Substances 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 claims description 2
- 239000003765 sweetening agent Substances 0.000 claims description 2
- JXGVXCZADZNAMJ-LLVKDONJSA-N (2r)-1-phenylmethoxycarbonylpyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@H]1CCCN1C(=O)OCC1=CC=CC=C1 JXGVXCZADZNAMJ-LLVKDONJSA-N 0.000 claims 1
- 239000004475 Arginine Substances 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 241000711549 Hepacivirus C Species 0.000 abstract description 35
- 241000700605 Viruses Species 0.000 abstract description 19
- 150000001413 amino acids Chemical class 0.000 abstract description 7
- 238000005859 coupling reaction Methods 0.000 abstract description 5
- 208000006454 hepatitis Diseases 0.000 abstract description 5
- 230000008878 coupling Effects 0.000 abstract description 4
- 238000010168 coupling process Methods 0.000 abstract description 4
- 231100000283 hepatitis Toxicity 0.000 abstract description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 20
- 229940126208 compound 22 Drugs 0.000 description 20
- 239000003112 inhibitor Substances 0.000 description 17
- 101710144111 Non-structural protein 3 Proteins 0.000 description 16
- 102000035195 Peptidases Human genes 0.000 description 16
- 108091005804 Peptidases Proteins 0.000 description 16
- 239000004365 Protease Substances 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000003814 drug Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 229960002920 sorbitol Drugs 0.000 description 13
- 238000011282 treatment Methods 0.000 description 13
- 102000012479 Serine Proteases Human genes 0.000 description 11
- 108010022999 Serine Proteases Proteins 0.000 description 11
- 239000012230 colorless oil Substances 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 230000003612 virological effect Effects 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 230000002797 proteolythic effect Effects 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 229940024606 amino acid Drugs 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 7
- 208000005176 Hepatitis C Diseases 0.000 description 7
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 6
- IQQRAVYLUAZUGX-UHFFFAOYSA-N 1-butyl-3-methylimidazolium Chemical compound CCCCN1C=C[N+](C)=C1 IQQRAVYLUAZUGX-UHFFFAOYSA-N 0.000 description 6
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 6
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 6
- 241000282414 Homo sapiens Species 0.000 description 6
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 229960000329 ribavirin Drugs 0.000 description 6
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 5
- 241000710781 Flaviviridae Species 0.000 description 5
- 108010050904 Interferons Proteins 0.000 description 5
- 102000014150 Interferons Human genes 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 5
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 229940079322 interferon Drugs 0.000 description 5
- 239000002608 ionic liquid Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- NJYVEMPWNAYQQN-UHFFFAOYSA-N 5-carboxyfluorescein Chemical compound C12=CC=C(O)C=C2OC2=CC(O)=CC=C2C21OC(=O)C1=CC(C(=O)O)=CC=C21 NJYVEMPWNAYQQN-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 108010047761 Interferon-alpha Proteins 0.000 description 4
- 102000006992 Interferon-alpha Human genes 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 101800001838 Serine protease/helicase NS3 Proteins 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 150000001540 azides Chemical class 0.000 description 4
- 229940073608 benzyl chloride Drugs 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 229960002935 telaprevir Drugs 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 3
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 3
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 3
- 208000001490 Dengue Diseases 0.000 description 3
- 206010012310 Dengue fever Diseases 0.000 description 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 108060004795 Methyltransferase Proteins 0.000 description 3
- 229910020808 NaBF Inorganic materials 0.000 description 3
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 101710172711 Structural protein Proteins 0.000 description 3
- 201000006449 West Nile encephalitis Diseases 0.000 description 3
- 206010057293 West Nile viral infection Diseases 0.000 description 3
- TVRCRTJYMVTEFS-ICGCPXGVSA-N [(2r,3r,4r,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-4-hydroxy-2-(hydroxymethyl)-4-methyloxolan-3-yl] (2s)-2-amino-3-methylbutanoate Chemical compound C[C@@]1(O)[C@H](OC(=O)[C@@H](N)C(C)C)[C@@H](CO)O[C@H]1N1C(=O)N=C(N)C=C1 TVRCRTJYMVTEFS-ICGCPXGVSA-N 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 238000003149 assay kit Methods 0.000 description 3
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 3
- 229960000517 boceprevir Drugs 0.000 description 3
- 208000025729 dengue disease Diseases 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 229960002429 proline Drugs 0.000 description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- 241000725619 Dengue virus Species 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 241000710831 Flavivirus Species 0.000 description 2
- 229940124683 HCV polymerase inhibitor Drugs 0.000 description 2
- 206010019799 Hepatitis viral Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- 108010076039 Polyproteins Proteins 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 108700010756 Viral Polyproteins Proteins 0.000 description 2
- 108020000999 Viral RNA Proteins 0.000 description 2
- 208000003152 Yellow Fever Diseases 0.000 description 2
- HTJGLYIJVSDQAE-VWNXEWBOSA-N [(1s,6s,7s,8r,8ar)-1,7,8-trihydroxy-1,2,3,5,6,7,8,8a-octahydroindolizin-6-yl] butanoate Chemical compound O[C@H]1[C@H](O)[C@@H](OC(=O)CCC)CN2CC[C@H](O)[C@@H]21 HTJGLYIJVSDQAE-VWNXEWBOSA-N 0.000 description 2
- YQNQNVDNTFHQSW-UHFFFAOYSA-N acetic acid [2-[[(5-nitro-2-thiazolyl)amino]-oxomethyl]phenyl] ester Chemical compound CC(=O)OC1=CC=CC=C1C(=O)NC1=NC=C([N+]([O-])=O)S1 YQNQNVDNTFHQSW-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 241001493065 dsRNA viruses Species 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 238000000099 in vitro assay Methods 0.000 description 2
- 238000005462 in vivo assay Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 108010026228 mRNA guanylyltransferase Proteins 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 230000003362 replicative effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- NZVYCXVTEHPMHE-ZSUJOUNUSA-N thymalfasin Chemical compound CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NZVYCXVTEHPMHE-ZSUJOUNUSA-N 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 229960004799 tryptophan Drugs 0.000 description 2
- 229960004295 valine Drugs 0.000 description 2
- 229950002810 valopicitabine Drugs 0.000 description 2
- 201000001862 viral hepatitis Diseases 0.000 description 2
- SCVHJVCATBPIHN-SJCJKPOMSA-N (3s)-3-[[(2s)-2-[[2-(2-tert-butylanilino)-2-oxoacetyl]amino]propanoyl]amino]-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid Chemical compound N([C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)COC=1C(=C(F)C=C(F)C=1F)F)C(=O)C(=O)NC1=CC=CC=C1C(C)(C)C SCVHJVCATBPIHN-SJCJKPOMSA-N 0.000 description 1
- 0 *O[C@](CO[C@]12)[C@]1OC[C@]2N Chemical compound *O[C@](CO[C@]12)[C@]1OC[C@]2N 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- WTDWVLJJJOTABN-UHFFFAOYSA-N 5-cyclopropyl-2-(4-fluorophenyl)-6-[(2-hydroxyethyl)(methylsulfonyl)amino]-n-methyl-1-benzofuran-3-carboxamide Chemical compound C1=C2C(C(=O)NC)=C(C=3C=CC(F)=CC=3)OC2=CC(N(CCO)S(C)(=O)=O)=C1C1CC1 WTDWVLJJJOTABN-UHFFFAOYSA-N 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 241000218631 Coniferophyta Species 0.000 description 1
- 241001643084 Cyrtanthus elatus virus A Species 0.000 description 1
- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 description 1
- 229930182820 D-proline Natural products 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical class C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 1
- 229940122604 HCV protease inhibitor Drugs 0.000 description 1
- 108010005716 Interferon beta-1a Proteins 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 125000000415 L-cysteinyl group Chemical group O=C([*])[C@@](N([H])[H])([H])C([H])([H])S[H] 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- 125000000769 L-threonyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])[C@](O[H])(C([H])([H])[H])[H] 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 101800001020 Non-structural protein 4A Proteins 0.000 description 1
- 101800001019 Non-structural protein 4B Proteins 0.000 description 1
- GBYOBOIXWWHPKL-FDYHWXHSSA-N O[C@H](CO[C@@H]12)[C@H]1OC[C@H]2OCc1ccccc1 Chemical compound O[C@H](CO[C@@H]12)[C@H]1OC[C@H]2OCc1ccccc1 GBYOBOIXWWHPKL-FDYHWXHSSA-N 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 229940123066 Polymerase inhibitor Drugs 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 229940122277 RNA polymerase inhibitor Drugs 0.000 description 1
- 101710118046 RNA-directed RNA polymerase Proteins 0.000 description 1
- 108091030071 RNAI Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- IOYNQIMAUDJVEI-BMVIKAAMSA-N Tepraloxydim Chemical compound C1C(=O)C(C(=N/OC\C=C\Cl)/CC)=C(O)CC1C1CCOCC1 IOYNQIMAUDJVEI-BMVIKAAMSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 108010078233 Thymalfasin Proteins 0.000 description 1
- 108091023045 Untranslated Region Proteins 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003853 activation of bipolar cell growth Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 108010080374 albuferon Proteins 0.000 description 1
- 229940054685 alinia Drugs 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000005574 benzylation reaction Methods 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229950003414 celgosivir Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000011461 current therapy Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 230000000311 effect on hepatitis Effects 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 229950000234 emricasan Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000009368 gene silencing by RNA Effects 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 206010019692 hepatic necrosis Diseases 0.000 description 1
- 238000009474 hot melt extrusion Methods 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 102000011749 human hepatitis C immune globulin Human genes 0.000 description 1
- 108010062138 human hepatitis C immune globulin Proteins 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229940090438 infergen Drugs 0.000 description 1
- 108010010648 interferon alfacon-1 Proteins 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000018191 liver inflammation Diseases 0.000 description 1
- 108010046177 locteron Proteins 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 150000002678 macrocyclic compounds Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- VKHAHZOOUSRJNA-GCNJZUOMSA-N mifepristone Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@@]([C@]3(C2)C)(O)C#CC)=CC=C(N(C)C)C=C1 VKHAHZOOUSRJNA-GCNJZUOMSA-N 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 1
- 239000002088 nanocapsule Substances 0.000 description 1
- 239000002077 nanosphere Substances 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 229940038850 rebif Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000002165 resonance energy transfer Methods 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- NHKZSTHOYNWEEZ-AFCXAGJDSA-N taribavirin Chemical compound N1=C(C(=N)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NHKZSTHOYNWEEZ-AFCXAGJDSA-N 0.000 description 1
- 229950006081 taribavirin Drugs 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 229960004231 thymalfasin Drugs 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 150000004799 α-ketoamides Chemical class 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
compostos peptídeos miméticos potencialmente ativos contra vírus da hepatite c e composição farmacêutica contendo tais compostos. a presente invenção se refere à compostos peptídeo miméticos potencialmente ativos contra virus da hepatite c e composição farmacêutica contendo tais compostos, desenhados como inibidores de polimerases e serina protease do vírus da hepatite c (hcv), sintéticos, caracterizados por possuir, na porção central, uma estrutura do tipo 1,4:3,6-dianidromanitol. as porções laterais são caracterizadas por possuir ligações peptideo miméticas provenientes do acopíamento com diversos aminoácidos n-protegidos.Potentially active hepatitis C virus mimetic peptide compounds and pharmaceutical composition containing such compounds. The present invention relates to potentially active hepatitis virus mimetic peptide compounds and pharmaceutical composition containing such compounds, designed as synthetic hepatitis c virus (hcv) polymerase and serine protease inhibitors, characterized in that they have, in the central portion, a 1,4: 3,6-dianhydromanitol type structure. the side portions are characterized by having mimetic peptide bonds from the coupling with various unprotected amino acids.
Description
(54) Título: COMPOSTOS PEPTÍDEOS MIMÉTICOS POTENCIALMENTE ATIVOS CONTRA VÍRUS DA HEPATITE C E COMPOSIÇÃO FARMACÊUTICA CONTENDO TAIS COMPOSTOS (51) Int.CI.: A61K 31/00; A61K 31/04; A61K 31/33 (73) Titular(es): UNIVERSIDADE FEDERAL FLUMINENSE. UNIVERSIDADE FEDERAL DO RIO DE JANEIRO (72) Inventor(es): AMILCAR TANURI; OCTÁVIO AUGUSTO CEVA ANTUNES; ESTELA MARIS FREITAS MURI; HELENA DE SOUZA PEREIRA; JOSÉ BOULLOSA ALONSO NETO; EMMERSON CORRÊA BRASIL DA COSTA; SÉRGIO PINHEIRO; THALITA GONÇALVES BARROS; RONALDO DA SILVA MOHANA BORGES(54) Title: MIMETIC PEPTIDE COMPOUNDS POTENTIALLY ACTIVE AGAINST HEPATITIS C VIRUS AND PHARMACEUTICAL COMPOSITION CONTAINING SUCH COMPOUNDS (51) Int.CI .: A61K 31/00; A61K 4/31; A61K 31/33 (73) Holder (s): UNIVERSIDADE FEDERAL FLUMINENSE. FEDERAL UNIVERSITY OF RIO DE JANEIRO (72) Inventor (s): AMILCAR TANURI; OCTÁVIO AUGUSTO CEVA ANTUNES; ESTELA MARIS FREITAS MURI; HELENA DE SOUZA PEREIRA; JOSÉ BOULLOSA ALONSO NETO; EMMERSON CORRÊA BRASIL DA COSTA; SÉRGIO PINHEIRO; THALITA GONÇALVES BARROS; RONALDO DA SILVA MOHANA BORGES
1/311/31
Relatório Descritivo de Patente de InvençãoInvention Patent Descriptive Report
Compostos Peptídeos Miméticos Potencialmente Ativos Contra Vírus da Hepatite C e Composição Farmacêutica Contendo tais CompostosPotentially Active Mimetic Peptide Compounds Against Hepatitis C Virus and Pharmaceutical Composition Containing Such Compounds
Campo da InvençãoField of the Invention
A presente invenção se refere à COMPOSTOS PEPTÍDEO MIMÉTICOS POTENCIALMENTE ATIVOS CONTRA VÍRUS DA HEPATITE C E COMPOSIÇÃO FARMACÊUTICA CONTENDO TAIS COMPOSTOS, desenhados como inibidores de polimerases e serina protease do vírus da Hepatite C (HCV), sintéticos, caracterizados por possuir, na porção central, uma estrutura do tipo 1,4:3,6dianidromanitol. As porções laterais são caracterizadas por possuir ligações peptídeo miméticas provenientes do acoplamento com diversos aminoácidos Nprotegidos. Esses novos compostos, se ativos contra o vírus da hepatite C, poderão ser a base para a preparação de formulações antivirais capazes de cessar a proliferação do HCV responsável pela flavivirose, a Hepatite C.The present invention relates to MIMETIC PEPTIDE COMPOUNDS POTENTIALLY ACTIVE AGAINST HEPATITIS VIRUS PHARMACEUTICAL COMPOSITION CONTAINING SUCH COMPOUNDS, designed as synthetic polymerase and serine protease inhibitors of the Hepatitis C virus (HCV), characterized by having, in the central portion, structure of type 1,4: 3,6dianhydromanitol. The side portions are characterized by having mimetic peptide bonds from coupling with several N-protected amino acids. These new compounds, if active against the hepatitis C virus, could be the basis for the preparation of antiviral formulations capable of stopping the proliferation of HCV responsible for flavivirus, Hepatitis C.
Antecedentes da InvençãoBackground of the Invention
A família Flaviviridae compreende mais de 60 viroses, das quais muitas são patogênicas ao ser humano. Dentre estas viroses encontram-se aquelas relacionadas ao vírus da Hepatite C (HCV), da Febre do Oeste do Nilo (ou Febre do Nilo Ocidental), da febre amarela e da Dengue. No caso das hepatites virais, são pelo menos sete os tipos de vírus que já foram caracterizados: A, B, C, D, E, G e TT, que têm em comum o hepatotropismo e podem levar a inflamação e necrose hepática. Hepatite é o termo genérico, com origem grega hepato- (fígado) e -itis (inflamação), que designa a inflamação do fígado.The Flaviviridae family comprises more than 60 viruses, many of which are pathogenic to humans. Among these viruses are those related to the Hepatitis C virus (HCV), West Nile Fever (or West Nile Fever), yellow fever and Dengue. In the case of viral hepatitis, there are at least seven types of viruses that have already been characterized: A, B, C, D, E, G and TT, which have hepatotropism in common and can lead to liver inflammation and necrosis. Hepatitis is the generic term, with Greek origin hepato- (liver) and -itis (inflammation), which means inflammation of the liver.
As hepatites virais, particularmente, são causadas por diferentes agentes etiológicos, de distribuição global dentre eles o HCV (Craxi, A.; Laffi, G.; Zignego, A.L. Mol. Aspects Med. 2008, 29, 85-95; Manns, M.P.; Foster, G.R.; Rockstroh, J.K.; Zeuzem, S.; Zoulim, F.; Houghton, M. Nat. Rev. Drug Discov. 2007, 6, 9911000).Viral hepatitis, in particular, is caused by different etiological agents, of global distribution, among them HCV (Craxi, A .; Laffi, G .; Zignego, AL Mol. Aspects Med. 2008, 29, 85-95; Manns, MP ; Foster, GR; Rockstroh, JK; Zeuzem, S .; Zoulim, F .; Houghton, M. Nat. Rev. Drug Discov. 2007, 6, 9911000).
2/312/31
Em termos estruturais o HCV é um vírus envelopado, possuindo um genoma RNA, com aproximadamente 9.4Kb. O genoma possui uma única janela aberta de leitura que codifica três proteínas estruturais (cerne, E1, E2) e sete proteínas não estruturais (p7, NS2 a NS5B). Duas regiões não traduzidas (UTR) presentes em cada extremidade do genoma são importantes para as etapas de tradução e transcrição do genoma RNA. Foi descrita uma grande variedade na seqüência genômica do HCV. Os diferentes genótipos foram reunidos em seis grupos principais e vários subtipos. Há uma distribuição geográfica diferenciada em relação aos diferentes genótipos. No Brasil, os mais freqüentes são os genótipos 1, 2 e 3 com to incidência de 70; 2,5 e 28 %, respectivamente.In structural terms, HCV is an enveloped virus, having an RNA genome, with approximately 9.4Kb. The genome has a single open reading window that encodes three structural proteins (heartwood, E1, E2) and seven non-structural proteins (p7, NS2 to NS5B). Two untranslated regions (RTU) present at each end of the genome are important for the stages of translation and transcription of the RNA genome. A wide variety has been described in the HCV genomic sequence. The different genotypes were grouped into six main groups and several subtypes. There is a different geographical distribution in relation to the different genotypes. In Brazil, the most frequent are genotypes 1, 2 and 3 with an incidence of 70; 2.5 and 28%, respectively.
O genoma viral codifica uma única poliproteína longa de aproximadamenteThe viral genome encodes a single long polyprotein of approximately
3000 aminoácidos. Esta poliproteína é processada subseqüentemente por proteases codificadas pelo vírus e pelo hospedeiro, gerando 10 proteínas virais maduras. As proteínas de cápsula (“core”) E1 e E2 são estruturais e estão envolvidas com a montagem da partícula viral, enquanto as proteínas NS2 a NS5B são chamadas não-estruturais e estão envolvidas com a propagação do vírus. Estas proteínas nãoestruturais incluem a helicase vírus-específica NS3, a protease NS3-NS4A e a RNA polimerase RNA-dependente NS5B (RdRp, ou replicase).3000 amino acids. This polyprotein is subsequently processed by proteases encoded by the virus and the host, generating 10 mature viral proteins. Capsule proteins (“core”) E1 and E2 are structural and are involved with the assembly of the viral particle, while proteins NS2 to NS5B are called non-structural and are involved with the spread of the virus. These non-structural proteins include the NS3 virus-specific helicase, the NS3-NS4A protease and the NS5B RNA-dependent RNA polymerase (RdRp, or replicase).
A atual terapia basea-se no uso do interferon alfa combinado com ribavirina.Current therapy is based on the use of alpha interferon combined with ribavirin.
O tratamento apenas com o IFN-alfa apresenta apenas 10-19% de resposta sustentada. A Ribavirina é um análogo sintético da guanosina que tem ação direta contra vírus de RNA e DNA, por provável mecanismo de inibição da DNA polimerase vírus-dependente. A Ribavirina sozinha, no entanto, não tem qualquer efeito sobre a hepatite C. A combinação do interferon-alfa com a Ribavirina melhora a resposta virológica sustentada para 38-43%, com correspondente melhora na análise histológica (biópsia) e, possivelmente, nas complicações em longo prazo da hepatite, contudo não há estudos prospectivos convincentes (Heathcote, E.J. J. Viral Hepat. 2007, 14, Suppl 1, 82-8; Koike, K.J. Infect. Chemother. 2006, 12, 227-32; Toniutto, P.; Fabris, C.; Pirisi, M. Expert. Opin. Pharmacother. 2006, 7, 2025-35).Treatment with IFN-alpha alone shows only 10-19% of sustained response. Ribavirin is a synthetic analogue of guanosine that has a direct action against RNA and DNA viruses, by a likely mechanism of inhibition of virus-dependent DNA polymerase. Ribavirin alone, however, has no effect on hepatitis C. The combination of interferon-alpha with Ribavirin improves the sustained virological response to 38-43%, with a corresponding improvement in histological analysis (biopsy) and possibly in long-term complications of hepatitis, however there are no convincing prospective studies (Heathcote, EJJ Viral Hepat. 2007, 14, Suppl 1, 82-8; Koike, KJ Infect. Chemother. 2006, 12, 227-32; Toniutto, P. ; Fabris, C .; Pirisi, M. Expert. Opin. Pharmacother. 2006, 7, 2025-35).
Mesmo com este arsenal terapêutico, a infecção pelo HCV é responsável por mais de 80% dos transplantes de fígado no mundo, e no Brasil. (Consenso daEven with this therapeutic arsenal, HCV infection is responsible for more than 80% of liver transplants in the world, and in Brazil. (Consensus of
Sociedade Paulista de Infectologia (SPI) para Manuseio e Terapia da Hepatite C,Paulista Society of Infectious Diseases (SPI) for Hepatitis C Management and Therapy,
3/313/31
São Paulo, SP.) Diversos novos compostos têm sido avaliados para o tratamento das infecções pelo HCV. Esses compostos se encontram em fases iniciais de avaliação, ou seja, estudos in vitro ou pré-clínicos em animais. Porém, a maioria desses compostos ainda não foi analisada em fases de triagem envolvendo seres humanos (estudos clínicos). De forma geral, apenas 1 em cada 1.000 novos compostos chega a ser avaliado em etapas que envolvem seres humanos. Entre esses, somente 1 em 5 recebe a aprovação pelo Food and Drug Administration, FDA, escritório de alimentos e medicamentos do governo dos Estados Unidos da América.São Paulo, SP.) Several new compounds have been evaluated for the treatment of HCV infections. These compounds are in the initial stages of evaluation, that is, in vitro or pre-clinical studies in animals. However, most of these compounds have not yet been analyzed in screening stages involving human beings (clinical studies). In general, only 1 in 1,000 new compounds is evaluated in stages involving human beings. Among these, only 1 in 5 receives approval by the Food and Drug Administration, FDA, the United States government's food and drug office.
ío Vários esforços têm se concentrado na lista de tratamentos que tem se mostrado promissores em estudos clínicos envolvendo seres humanos. A Tabela 1 abaixo mostra alguns compostos com potencial de inibir a infecção pelo HCV e as fases clínicas que se encontram.Several efforts have focused on the list of treatments that have shown promise in clinical studies involving humans. Table 1 below shows some compounds with the potential to inhibit HCV infection and the clinical phases that are in place.
Tabela 1 - Compostos com potencial de inibição da infecção pelo HCV e suas respectivas fases clínicas. (Soriano, V.; Madejon, A.; Vispo, E.; Labarga, P.; GarciaSamaniego, J.; Martin-Carbonero, L.; Sheldon, J.; Bottecchia, M.; Tuma, P.; Barreiro, P. Expert. Op. Emerg. Drugs 2008, 13, 1-19).Table 1 - Compounds with potential to inhibit HCV infection and their respective clinical phases. (Soriano, V .; Madejon, A .; Vispo, E .; Labarga, P .; GarciaSamaniego, J .; Martin-Carbonero, L .; Sheldon, J .; Bottecchia, M .; Tuma, P .; Barreiro, P. Expert, Op. Emerg. Drugs 2008, 13, 1-19).
4/314/31
* Inibidores da RNA polimerase ** Inibidores da protease* RNA polymerase inhibitors ** Protease inhibitors
Os alvos da terapia anti-HCV estão concentrados nas diferentes etapas de replicação do RNA viral, e além desses as novas terapias estão direcionadas nas etapas de tradução (ribozimas, oligos anti-senso, RNAi), processamento proteolítico (inibidores da protease viral) e de replicação do genoma RNA (inibidores da RNA polimerase viral).The targets of anti-HCV therapy are concentrated in the different stages of viral RNA replication, and in addition to these, new therapies are targeted at the stages of translation (ribozymes, antisense oligos, RNAi), proteolytic processing (viral protease inhibitors) and replication of the RNA genome (viral RNA polymerase inhibitors).
O Valopicitabine (Idenix Pharmaceuticals), já em fase avançada de testes clínicos, se caracteriza por ser um inibidor RNA-RNA polimerase viral, e a análise envolvendo 79 pacientes mostraram em duas semanas uma redução de 90% da carga viral, sendo que a maioria desses pacientes não respondia ao tratamento com interferon. O Valopicitabine será empregado como um terceiro medicamento no tratamento, junto com o interferon e a Ribavirina, para se obter uma maior resposta terapêutica. Duas outras drogas, das quais uma deverá ser utilizada como terceira droga no tratamento são os inibidores de protease: SCH-503034 (Schering-Plough) e o VX-950 (Vertex). Em estudo realizado pela Vertex em 34 voluntários com o VX950, mostrou que após duas semanas de tratamento a diminuição da carga viral foi 250 vezes maior do que o Interferon Peguilado combinado a Ribavirina na redução da carga viral.Valopicitabine (Idenix Pharmaceuticals), already in an advanced phase of clinical tests, is characterized by being a viral RNA-RNA polymerase inhibitor, and the analysis involving 79 patients showed a 90% reduction in viral load in two weeks, the majority of which of these patients did not respond to interferon treatment. Valopicitabine will be used as a third medication in the treatment, together with interferon and Ribavirin, to obtain a greater therapeutic response. Two other drugs, of which one should be used as the third drug in the treatment, are protease inhibitors: SCH-503034 (Schering-Plow) and VX-950 (Vertex). In a study carried out by Vertex on 34 volunteers with the VX950, it showed that after two weeks of treatment the decrease in viral load was 250 times greater than that of Pegylated Interferon combined with Ribavirin in reducing viral load.
O HCV tem dois alvos potenciais para desenvolvimento de novas drogas antivirais. Um é a molécula de (NS5) RNA Polimerase RNA dependente que consegue replicar uma molécula de RNA em outra. Esta é uma atividade única dos vírus de RNA, não se encontrando essa atividade nas células hospedeiras. Dessa forma a RNA Polimerase RNA dependente é um alvo muito específico para o HCV.HCV has two potential targets for the development of new antiviral drugs. One is the RNA dependent (NS5) RNA Polymerase molecule that can replicate one RNA molecule in another. This is a unique activity of RNA viruses, and this activity is not found in host cells. Thus, RNA-dependent RNA polymerase is a very specific target for HCV.
Além da replicase viral ainda temos a NS3 (serina protease) que é responsável pelo processamento da poliproteína viral. Apesar de ser uma serina protease, a NS3 temIn addition to viral replicase, we also have NS3 (serine protease), which is responsible for processing viral polyprotein. Despite being a serine protease, NS3 has
5/31 uma estrutura molecular muito diferente das serinas proteases das células humanas, o que possibilita o desenvolvimento de inibidores específicos para esta protease.5/31 a molecular structure very different from the serine proteases of human cells, which allows the development of specific inhibitors for this protease.
O peso molecular do monômero da protease NS3 do HCV é de 70 kDa. Sua estrutura ativa é um dímero e a estrutura terciária do monômero tem uma extensão na porção N-terminal, 2 domínios com 6 “beta-barrels” (conjunto de fitas betapregueadas) cada, assim como um domínio de troca e uma alfa hélice. O sítio ativo da protease está localizado na porção N-terminal. Comparando a seqüência da NS3 de outros flavivírus podemos identificar três resíduos conservados (His-57, Asp-81, and Ser-139) que compõem o centro catalítico desta protease. O centro ativo da ío protease NS3 contém um sítio estabilizador de um oxiânion tetraédrico, intermediário da reação, “oxyanion/stabilization loop”, e uma fita E2 e precedida por uma fita E1. A NS3 cliva a poliproteína viral entre os resíduos de aminoácidos Cys/Ser (nos sítiosThe molecular weight of the HCV NS3 protease monomer is 70 kDa. Its active structure is a dimer and the tertiary structure of the monomer has an extension in the N-terminal portion, 2 domains with 6 “beta-barrels” (set of beta-folded ribbons) each, as well as an exchange domain and an alpha helix. The active site of the protease is located in the N-terminal portion. Comparing the NS3 sequence of other flaviviruses, we can identify three conserved residues (His-57, Asp-81, and Ser-139) that make up the catalytic center of this protease. The active center of the NS3 protease contains a stabilizing site of a tetrahedral oxyanion, intermediate of the reaction, “oxyanion / stabilization loop”, and an E2 ribbon and preceded by an E1 ribbon. NS3 cleaves viral polyprotein between the amino acid residues Cys / Ser (at sites
4B/5A e 5A/5B), Cys/Ala (no 4A/4B), ou Thr/Ser (no 3/4A).4B / 5A and 5A / 5B), Cys / Ala (no 4A / 4B), or Thr / Ser (no 3 / 4A).
A NS3 assume uma estrutura de dois conjuntos de fitas beta pregueadas. O primeiro localizado na porção N-terminal contém as fitas A1, B1, C1, D1, E1, e F1. O segundo barril beta é composto pelas fitas A2, B2, C2, D2, E2, e F2.NS3 takes on a structure of two sets of pleated beta tapes. The first located in the N-terminal portion contains tapes A1, B1, C1, D1, E1, and F1. The second beta barrel is composed of tapes A2, B2, C2, D2, E2, and F2.
Vários trabalhos têm sido relatados sobre inibidores de serina protease. Recentemente, derivados hexapeptídicos contendo uma função eletrofílica a-cetoamida têm sido descritos como potentes inibidores da serina protease de HCV (Arasappan, A.; Njoroge, F.G.; Chan, T.-Y.; Bennett, F.; Bogen, S.L.; Chen, K.; Gu, H.; Hong, L.; Jao, E.; Liu, Y.-T.; Lovey, R.G.; Parekh, T.; Pike, R.E.; Pinto, P.; Santhanam, B.; Venkatraman, S.; Vaccaro, H.; Wang, H.; Yang, X.; Zhu, Z.; Mckittrick, B.; Saksena, A.K.; Girijavallabhan, V.; Pichardo, J.; Butkiewicz, N.; Ingram, N.; Malcolm, B.; Prongay, A.; Yao, N.; Marten, B.; Madison, V.; Kemp, S.;Several studies have been reported on serine protease inhibitors. Recently, hexapeptide derivatives containing an electrophilic a-ketoamide function have been described as potent inhibitors of HCV serine protease (Arasappan, A .; Njoroge, FG; Chan, T.-Y .; Bennett, F .; Bogen, SL; Chen , K .; Gu, H .; Hong, L .; Jao, E .; Liu, Y.-T .; Lovey, RG; Parekh, T .; Pike, RE; Pinto, P .; Santhanam, B .; Venkatraman, S .; Vaccaro, H .; Wang, H .; Yang, X .; Zhu, Z .; Mckittrick, B .; Saksena, AK; Girijavallabhan, V .; Pichardo, J .; Butkiewicz, N .; Ingram , N .; Malcolm, B .; Prongay, A .; Yao, N .; Marten, B .; Madison, V .; Kemp, S .;
Levy, O.; Lim-Wilby, M.; Tamura, S.; Ganguly, A.K. Bioorg. Med. Chem. Lett. 2005, 15, 4180-4184). Ainda dentro da classe das α-ceto-amidas, o VX-950 e o SCH503034 (Bocepravir), já mencionados anteriormente, encontram-se em desenvolvimento clínico. O VX-950 foi capaz de reduzir a carga viral plasmática de pacientes dosados com 750mg a cada 8h, e em alguns pacientes o vírus tornou-se indetectável após 14 dias de dosagem (Chen, K.X.; Vibulbhan, B.; Yang, W.; Cheng,Levy, O .; Lim-Wilby, M .; Tamura, S .; Ganguly, A.K. Bioorg. Med. Chem. Lett. 2005, 15, 4180-4184). Still within the α-keto-amide class, VX-950 and SCH503034 (Bocepravir), mentioned above, are in clinical development. The VX-950 was able to reduce the plasma viral load of patients dosed with 750mg every 8h, and in some patients the virus became undetectable after 14 days of dosing (Chen, KX; Vibulbhan, B .; Yang, W. ; Cheng,
K-C.; Liu, R.; Pichardo, J.; Butkiewiez, N.; Njoroge, F.G. Bioorg. Med. Chem. 2008, doi:10.1016/j.bmc.2007.11.002. Perni, R.B.; Almquist, S.J.; Byrn, R.A.; Chandorkar,K-C .; Liu, R .; Pichardo, J .; Butkiewiez, N .; Njoroge, F.G. Bioorg. Med. Chem. 2008, doi: 10.1016 / j.bmc.2007.11.002. Perni, R.B .; Almquist, S.J .; Byrn, R.A .; Chandorkar,
6/316/31
G.; Chaturvedi, P.R.; Courtney, L.F.; Decker, C.J.; Dinehart, K.; Gates, C.A.; Harbeson, S.L.; Heiser, A.; Kalkeri, G.; Kolaczkowski, E.; Lin, K.; Luong, Υ-P.; Rao, B.G.; Taylor, W.P.; Thomson, J.A.; Tung, R.D.; Wei, Y.; Kwong, A.D.; Lin, C. Antimicrob. Agents Chemother. 2006, 50, 899-909).G .; Chaturvedi, P.R .; Courtney, L.F .; Decker, C.J .; Dinehart, K .; Gates, C.A .; Harbeson, S.L .; Heiser, A .; Kalkeri, G .; Kolaczkowski, E .; Lin, K .; Luong, Υ-P .; Rao, B.G .; Taylor, W.P .; Thomson, J.A .; Tung, R.D .; Wei, Y .; Kwong, A.D .; Lin, C. Antimicrob. Chemother Agents. 2006, 50, 899-909).
Na literatura patentária foram encontrados documentos relacionados à presente invenção, porém sem infringir o escopo da mesma, sendo as mais relevantes descritas a seguir:In the patent literature, documents related to the present invention were found, but without violating its scope, the most relevant of which are described below:
O documento WO2008137126 descreve um método de tratamento de infecção por HCV utilizando uma combinação terapêutica compreendendo um ío inibidor de serina protease e um de polimerase. Não sendo um composto único como inibidor de ambas serina protease e polimerase do HCV, e tais compostos descritos fazem parte do estado da técnica.WO2008137126 describes a method of treating HCV infection using a therapeutic combination comprising a serine protease inhibitor and a polymerase. Not being a single compound as an inhibitor of both serine protease and HCV polymerase, and such compounds described are part of the state of the art.
O documento W02007092616 descreve medicamentos, composições ou kits farmacêuticos e métodos, baseados em combinações de pelo menos um inibidor de protease de HCV, e um inibidor de polimerase de HCV, para serem administrados no tratamento de sintomas causados por HCV. Os compostos que atuam como inibidores de protease e polimerase também estão descritos.W02007092616 describes pharmaceutical drugs, compositions or kits and methods, based on combinations of at least one HCV protease inhibitor, and one HCV polymerase inhibitor, to be administered in the treatment of symptoms caused by HCV. The compounds that act as protease and polymerase inhibitors are also described.
O documento US7105499 descreve compostos que atuam como inibidores de polimerase do HCV.US7105499 describes compounds that act as HCV polymerase inhibitors.
O documento US2007027071 descreve compostos macrocíclicos que atuam como inibidores de protease do HCV.US2007027071 describes macrocyclic compounds that act as HCV protease inhibitors.
O documento PI0401908-3, de titularidade da UFRJ, descreve compostos inibidores de serina protease sintéticos, com um eixo de simetria C2, utilizados como base para a preparação de formulações antivirais capazes de cessar a proliferação dos vírus responsáveis pela maioria das flaviroses, como por exemplo, hepatite C, Dengue e febre do oeste do Nilo.Document PI0401908-3, held by UFRJ, describes synthetic serine protease inhibitor compounds, with a C2 axis of symmetry, used as a basis for the preparation of antiviral formulations capable of stopping the proliferation of viruses responsible for most flaviroses, such as example, hepatitis C, Dengue fever and West Nile fever.
Como pode ser observado existem diversos documentos que descrevem ou inibidores de protease ou inibidores de polimerase, ou ainda uma combinação de ambos, porém nenhum consegue descrever um composto capaz de atuar como inibidor de protease e polimerase, mais especificamente relacionado ao HCV.As can be seen, there are several documents describing either protease inhibitors or polymerase inhibitors, or even a combination of both, but none can describe a compound capable of acting as a protease and polymerase inhibitor, more specifically related to HCV.
7/317/31
Sumário da InvençãoSummary of the Invention
O primeiro objeto da presente invenção refere-se a compostos inibidores da serina protease e potencialmente inibidores de RNA e DNA polimerases de fórmula geral (I) e (II):The first object of the present invention relates to compounds that inhibit serine protease and potentially inhibitors of RNA and DNA polymerases of general formula (I) and (II):
O segundo objeto dessa invenção refere-se a uma composição farmacêutica contendo o dito composto de fórmula molecular (I),The second object of this invention relates to a pharmaceutical composition containing said compound of molecular formula (I),
assim como seus derivados e/ou seus sais farmaceuticamente aceitáveis, para a produção de um medicamento usados como inibidores de DNA e RNA polimerases e/ou serina proteases.as well as their derivatives and / or their pharmaceutically acceptable salts, for the production of a medicine used as inhibitors of DNA and RNA polymerases and / or serine proteases.
O terceiro objeto dessa invenção trata-se de uma composição farmacêutica contendo o composto de fórmula molecular (I),The third object of this invention is a pharmaceutical composition containing the compound of molecular formula (I),
(I)(I)
8/31 assim como seus derivados e/ou seus sais farmaceuticamente aceitáveis, voltados para a produção de um medicamento usado no tratamento de doenças causadas pelos vírus da família Flaviviridae em mamíferos humanos e não humanos.8/31 as well as their derivatives and / or their pharmaceutically acceptable salts, aimed at the production of a medicine used in the treatment of diseases caused by viruses of the family Flaviviridae in human and non-human mammals.
O quarto objeto dessa invenção trata-se de uma composição farmacêutica contendo o dito composto de fórmula molecular (II),The fourth object of this invention is a pharmaceutical composition containing said compound of molecular formula (II),
assim como seus derivados e/ou seus sais farmaceuticamente aceitáveis, usados para a produção de um medicamento usados como inibidores de DNA e RNA polimerases e/ou serina proteases.as well as their derivatives and / or their pharmaceutically acceptable salts, used for the production of a medicine used as inhibitors of DNA and RNA polymerases and / or serine proteases.
O último objeto dessa invenção trata-se de uma composição farmacêutica, contendo o dito composto de fórmula molecular (II),The last object of this invention is a pharmaceutical composition, containing said compound of molecular formula (II),
assim como seus derivados e/ou seus sais farmaceuticamente aceitáveis, voltados para a produção de um medicamento usado no tratamento de doenças causadas pelos vírus da família Flaviviridae em mamíferos humanos e não humanos.as well as its derivatives and / or its pharmaceutically acceptable salts, aimed at the production of a medicine used in the treatment of diseases caused by viruses of the family Flaviviridae in human and non-human mammals.
Descrição das FigurasDescription of the Figures
A Figura 1 mostra através dos gráficos A e B os resultados da inibição da protease NS3/4A do HCV. Na avaliação do potencial inibitório do composto 22 na enzima NS3pro/4A, foram realizados ensaios de IC5o% que é uma medida que indica a concentração necessária da droga para inibir 50% da atividade in vitro. Em A, está representada a curva de inibição da NS3pro/4A com o composto 22. Em B, a curvaFigure 1 shows through graphs A and B the results of inhibition of HCV NS3 / 4A protease. In assessing the inhibitory potential of compound 22 in the NS3pro / 4A enzyme, IC 5 % assays were performed, which is a measure that indicates the necessary concentration of the drug to inhibit 50% of in vitro activity. In A, the inhibition curve of NS3pro / 4A is shown with compound 22. In B, the curve
9/31 de inibição apresenta diversos pontos que representam diversas concentrações do composto (0; 7,8; 15,6; 31,2; 62,5; 125,0; 250,0; 500,0; e 1000,ΟμΜ).9/31 inhibition has several points that represent different concentrations of the compound (0; 7.8; 15.6; 31.2; 62.5; 125.0; 250.0; 500.0; and 1000, ΟμΜ) .
A Figura 2 avalia se o composto 22 promove aumento ou redução da atividade proteolítica, realizado a partir de uma nova síntese química do composto.Figure 2 assesses whether compound 22 promotes an increase or reduction in proteolytic activity, carried out from a new chemical synthesis of the compound.
Um novo lote do composto 22 foi resuspendido em DMSO a 100% e os ensaios cinéticos realizados no mesmo dia. No gráfico A, cada ponto representa diversas concentrações do composto (0; 7,8; 15,6; 31,2; 62,5; 125,0; 250,0; 500,0; e 1000,ΟμΜ). No gráfico B, curva de inibição da NS3pro/4A com o composto 22 recém sintetizado mostra em Cada ponto a média de 4 medidas independentes de 4 ío replicatas em diversas concentrações (0; 0,08; 0,16; 0,63; 1,25; 2,5; 5,0 e 10,ΟμΜ) do composto 22.A new batch of compound 22 was resuspended in 100% DMSO and the kinetic tests performed on the same day. In graph A, each point represents different concentrations of the compound (0; 7.8; 15.6; 31.2; 62.5; 125.0; 250.0; 500.0; and 1000, ΟμΜ). In graph B, the NS3pro / 4A inhibition curve with the newly synthesized compound 22 shows at each point the average of 4 independent measurements of 4 replicates in different concentrations (0; 0.08; 0.16; 0.63; 1 , 25; 2.5; 5.0 and 10, ΟμΜ) of compound 22.
Descrição Detalhada da InvençãoDetailed Description of the Invention
A presente invenção refere-se aos compostos de fórmula geral (I) e (II), desenhados como inibidores de polimerases e serina proteases.The present invention relates to the compounds of general formula (I) and (II), designed as inhibitors of polymerases and serine proteases.
Estes compostos são potencialmente ativos em vírus da família flaviviridae, preferencialmente; tais compostos são ativos na inibição da serina protease do HCV e vírus da dengue.These compounds are potentially active in viruses of the flaviviridae family, preferably; such compounds are active in inhibiting HCV serine protease and dengue virus.
Para os compostos inibidores de polimerases e serina da presente invenção de fórmula geral (I) e (II),For the polymerase and serine inhibitor compounds of the present invention of general formula (I) and (II),
X é definido como aminoácidos protegidos com grupamentos carboxi-f-butila (-Boc) e/ou carboxibenzila (-Cbz) que serão utilizados na síntese dos pseudopeptídeos. Sendo Z igual a benzila (-Bn), carboxibenzila (-Cbz) ou carboxi-f10/31 butila (-Boc); capazes de conferir rigidez ao inibidor, e que por sua natureza também podem atuar em polimerases, como DNA ou RNA polimerases, inibindo-as.X is defined as amino acids protected with carboxy-f-butyl (-Boc) and / or carboxybenzyl (-Cbz) groups that will be used in the synthesis of pseudopeptides. Z being benzyl (-Bn), carboxybenzyl (-Cbz) or carboxy-f10 / 31 butyl (-Boc); capable of giving rigidity to the inhibitor, and which by their nature can also act on polymerases, such as DNA or RNA polymerases, inhibiting them.
Os ditos compostos de fórmula molecular (I) e (II), assim como seus derivados e/ou sais farmaceuticamente aceitáveis são usados em uma composição farmacêutica como inibidores de DNA e RNA polimerases e serina proteases.Said compounds of molecular formula (I) and (II), as well as their derivatives and / or pharmaceutically acceptable salts are used in a pharmaceutical composition as inhibitors of DNA and RNA polymerases and serine proteases.
Tal composição farmacêutica apresenta uma concentração que varia na faixa de 10μΜ a 150μΜ do dito composto de fórmula molecular I e/ou II, assim como seus derivados e/ou sais farmaceuticamente aceitáveis.Such pharmaceutical composition has a concentration ranging from 10μΜ to 150μΜ of said compound of molecular formula I and / or II, as well as its derivatives and / or pharmaceutically acceptable salts.
Para fins dessa invenção os excipientes são todos aqueles compostos químicos que tem como objetivo dar forma, volume, estabilidade a composição farmacêutica. Todos os excipientes que aqui serão usados são aqueles das indústrias farmacêuticas tais como: adjuvantes, edulcorantes, solventes, estabilizantes, antioxidantes, conservantes, tampões, flavorizantes, tensoativos, umectantes, lubrificantes, dispersantes e todos aqueles conhecidos por um técnico na área.For the purposes of this invention, excipients are all those chemical compounds that aim to give shape, volume, stability to pharmaceutical composition. All excipients that will be used here are those from the pharmaceutical industries such as: adjuvants, sweeteners, solvents, stabilizers, antioxidants, preservatives, buffers, flavorings, surfactants, humectants, lubricants, dispersants and all those known to a technician in the field.
Os tais excipientes podem ser empregados em diferentes formas farmacêuticas, tais como pós, comprimidos, cápsulas, nanocápsulas, nanoesferas, processos de hot-melt extrusion, co-cristais, ampolas, soluções orais, adesivos transdérmicos, soluções injetáveis musculares ou parenterais, pomadas, cremes, géis, suspensões, emulsões, aerosóis, tinturas, elexires, pastas, pastilhas, supositórios, ugüentos, óvulos, e todas aquelas conhecidas por um técnico da arte.Such excipients can be used in different pharmaceutical forms, such as powders, tablets, capsules, nanocapsules, nanospheres, hot melt extrusion processes, co-crystals, ampoules, oral solutions, transdermal patches, injectable muscle or parenteral solutions, ointments, creams, gels, suspensions, emulsions, aerosols, tinctures, elexirs, pastes, lozenges, suppositories, ointments, eggs, and all those known to a technician in the art.
Tal composição farmacêutica que contém os compostos (I) e/ou (II), assim como seus derivados e sais farmaceuticamente aceitáveis, é empregada para a produção de um medicamento no tratamento de doenças causadas pelos vírus da família Flaviviridae, compreendendo os vírus dessa família os vírus da hepatite C, da dengue, da febre amarela, da febre do oeste ou febre do Nilo, sendo preferencialmente empregado no tratamento de doenças provocadas pelo vírus da dengue e da hepatite C. No caso da hepatite C estão compreendidos os seguintes vírus A, B, C, D, E, G e TT.Such pharmaceutical composition that contains the compounds (I) and / or (II), as well as their derivatives and pharmaceutically acceptable salts, is used for the production of a medicine in the treatment of diseases caused by the viruses of the family Flaviviridae, comprising the viruses of that family the viruses of hepatitis C, dengue, yellow fever, west fever or Nile fever, being preferably used in the treatment of diseases caused by the dengue virus and hepatitis C. In the case of hepatitis C, the following viruses A are included , B, C, D, E, G and TT.
Compostos de fórmula geral (I) e (II) foram produzidos a partir do isomanídeo como análogos dos previamente publicados pelo grupo, com a analogia adicional a pró-nucleosídios, isto é, compostos capazes de inibir polimerases. Sua analogiaCompounds of general formula (I) and (II) were produced from the isomanide as analogs of those previously published by the group, with the additional analogy to pro-nucleosides, that is, compounds capable of inhibiting polymerases. Your analogy
11/31 estrutural com dipeptídeos rígidos cíclicos o faz um excelente chassi, cerne rígido, “scaffold”. Além disto, pelo fato de apresentar um eixo C2 de simetria, pode ser homologado, em duas ou em uma posição, mantendo ou não o eixo de simetria, via reação com diferentes aminoácidos e diidroamino ácidos, por exemplo, via acoplamento direto catalisado por EDC, HOBt, e aminoácidos.Structural 11/31 with rigid cyclic dipeptides makes it an excellent chassis, rigid core, “scaffold”. In addition, because it has a C2 axis of symmetry, it can be homologated, in two or in one position, maintaining or not the axis of symmetry, via reaction with different amino acids and dihydroamino acids, for example, via direct coupling catalyzed by EDC , HOBt, and amino acids.
A partir dos dados obtidos anteriormente passou-se, então, a etapa de síntese dos inibidores da serina protease previstos.From the data obtained previously, the synthesis phase of the predicted serine protease inhibitors then passed.
A primeira etapa na obtenção dos derivados de fórmula geral I consistiu na conversão do isomanídeo (1) no derivado mono-tosilado (2) por reação com cloreto ío de p-toluenosulfonila em piridina por 12h a temperatura ambiente. O tratamento do mono-tosilado (2) com cloreto de benzila em meio básico usando TBAB como catalisador de transferência de fases forneceu o derivado benzilado (3). Este reagiu com azida de sódio em [bmim]BF4 a 120°C por 12h forneceu a azida (4), com inversão de configuração. Redução da azida (4) com paládio sobre carbono em etanol por 12h utilizando uma pressão de 40psi resultou na amina (5), que foi o substrato para a formação de novas amidas derivadas do isomanídeo (10-22) (Esquema 1).The first step in obtaining the derivatives of general formula I consisted of converting the isomanide (1) into the mono-tosylated derivative (2) by reaction with p-toluenesulfonyl chloride in pyridine for 12 hours at room temperature. Treatment of the mono-tosylate (2) with benzyl chloride in a basic medium using TBAB as a phase transfer catalyst provided the benzylated derivative (3). This reacted with sodium azide in [bmim] BF 4 at 120 ° C for 12h provided the azide (4), with an inversion of configuration. Reduction of azide (4) with palladium on carbon in ethanol for 12h using a pressure of 40psi resulted in the amine (5), which was the substrate for the formation of new amides derived from the isomanide (10-22) (Scheme 1).
Esquema 1. Síntese dos compostos intermediários para a obtenção da amina (5).Scheme 1. Synthesis of the intermediate compounds for obtaining the amine (5).
H2, 5% Pd/C EtOH quantitativoH 2 , 5% Pd / C EtOH quantitative
12/3112/31
Diferentes solventes podem ser usados na etapa de substituição nucleofílica, tais como, DMF e DMSO. Porém, o [bmim]BF4, líquido iônico, apresenta muitas vantagens em relação aos solventes orgânicos convencionais, além de ter apresentado um melhor rendimento reacional. Os líquidos iônicos não possuem pressão de vapor mensurável à temperatura ambiente, e mesmo a temperaturas bastante elevadas degradam apenas acima de 400°C, podendo ser usados em vácuo sem que haja perda de solvente.Different solvents can be used in the nucleophilic substitution step, such as, DMF and DMSO. However, [bmim] BF 4 , an ionic liquid, has many advantages over conventional organic solvents, in addition to having a better reaction yield. Ionic liquids do not have a measurable vapor pressure at room temperature, and even at very high temperatures they degrade only above 400 ° C, and can be used in a vacuum without loss of solvent.
O líquido iônico, [bmim]BF4 (9) foi sintetizado a partir do N-metil imidazol (7). Este reagiu com o 1-bromobutano formando o derivado (8) que, por troca iônica com ío NaBF4, originou (7). O líquido iônico foi purificado por coluna cromatográfica em sílica gel tendo como eluente o diclorometano, sendo obtido em 83% de rendimento como mostrado no esquema 2.The ionic liquid, [bmim] BF 4 (9) was synthesized from N-methyl imidazole (7). This reacted with the 1-bromobutane forming the derivative (8) which, by ion exchange with NaBF 4 , gave rise (7). The ionic liquid was purified by chromatographic column on silica gel having dichloromethane as eluent, being obtained in 83% yield as shown in scheme 2.
Esquema 2. Síntese do liquido iônico [Bmim]+[BF4]' \Scheme 2. Synthesis of the ionic liquid [Bmim] + [BF 4 ] '\
NN
NN
1) Bromobutano, Tolueno, 0°C1) Bromobutane, Toluene, 0 ° C
2) 110°C, 36h2) 110 ° C, 36h
NaBF4, CH2C12 24h, t.a.NaBF 4 , CH 2 C1 2 24h, ta
->->
83%83%
A síntese dos inibidores da serina protease previstos pela fórmula geral II iniciou-se pela mono benzilação do isomanídeo usando cloreto de benzila em meio básico formando o composto monobenzilado (6).The synthesis of serine protease inhibitors provided by general formula II started with the mono benzylation of the isomanide using benzyl chloride in a basic medium forming the monobenzylated compound (6).
Esquema 3. Síntese do derivado mono benzilado (6).Scheme 3. Synthesis of the mono benzylated derivative (6).
H n BnCl, TBABH n BnCl, TBAB
50% NaOH50% NaOH
CU.ASS.
o H OH 45%o H OH 45%
13/3113/31
A última etapa para obtenção dos compostos de fórmula geral I e II consistiu na reação de acoplamento da amina O-benzilada (5) e do mono benzil isomanídeo (6) com diversos amino ácidos (D- ou L-) contendo grupos de proteção N-BOC e/ou N-Cbz usando DCC como reagente de acoplamento e DMAP como catalisador em diclorometano (Esquema 4). A estrutura dos amino ácidos N-protegidos bem coma os rendimentos das reações é mostrada na tabela 1.The last step to obtain the compounds of the general formula I and II consisted of the coupling reaction of the O-benzylated amine (5) and the mono benzyl isomanide (6) with several amino acids (D- or L-) containing protecting groups N -BOC and / or N-Cbz using DCC as a coupling reagent and DMAP as a catalyst in dichloromethane (Scheme 4). The structure of the N-protected amino acids as well as the reaction yields is shown in Table 1.
Esquema 4. Síntese dos compostos (10-22) e (23-31)Scheme 4. Synthesis of compounds (10-22) and (23-31)
Tabela 1- Estruturas e rendimentos dos produtos (10-22) e (23-31)Table 1- Structures and yields of products (10-22) and (23-31)
14/3114/31
15/3115/31
A presente invenção será descrita detalhadamente através dos exemplos apresentados abaixo. É necessário frisar que a invenção não está limitada a esses exemplos e inclui variações e modificações dentro dos limites nos quais ela se aplica.The present invention will be described in detail through the examples presented below. It is necessary to emphasize that the invention is not limited to these examples and includes variations and modifications within the limits to which it applies.
Exemplo 1: Ensaio de atividade e inibição da protease recombinante NS3pro/4A do HCV.Example 1: HCV NS3pro / 4A recombinant protease activity and inhibition assay.
A avaliação da atividade proteolítica do HCV foi realizada com o kit SensoLyte®520 HCV Protease Assay Kit *Fluorímetríc* (AnaSpec,CA,USA). Este ensaio possibilita realizar a triagem de inibidores anti-HCV-NS3pro/4A com maior eficiência e sensibilidade, baseado no fenômeno de FRET (fluorecence ressonance energy transfer), no qual o peptídeo derivado do sítio de divagem NS4A/NS4B encontra-se marcado com fluoróforo 5-FAM/QXL™520, sendo a fluorescência do 5FAM suprimida pela QXL™520. A quantificação da atividade proteolítica ocorre quando o peptídeo FRET sofre a divagem em dois fragmentos pela NS3pro/4A, com isso, a fluorescência do 5-FAM pode ser monitorada em excitação/emissão igual a 490nm/520nm. A grande vantagem na utilização do peptídeo marcado com 5-FAM, é que a emissão de fluorescência ocorre em longo comprimento de onda, sofrendo menos interferência da autofluorescência dos compostos testados.The assessment of HCV proteolytic activity was carried out with the SensoLyte®520 HCV Protease Assay Kit * Fluorimetric * (AnaSpec, CA, USA). This assay makes it possible to screen anti-HCV-NS3pro / 4A inhibitors with greater efficiency and sensitivity, based on the phenomenon of FRET (fluorecence resonance energy transfer), in which the peptide derived from the dividing site NS4A / NS4B is marked with fluorophore 5-FAM / QXL ™ 520 , the fluorescence of 5FAM being suppressed by QXL ™ 520 . The quantification of proteolytic activity occurs when the FRET peptide divides into two fragments by NS3pro / 4A, thus, the fluorescence of 5-FAM can be monitored in excitation / emission equal to 490nm / 520nm. The great advantage of using the 5-FAM-labeled peptide is that the fluorescence emission occurs over a long wavelength, suffering less interference from the autofluorescence of the tested compounds.
Exemplo 2: Metodologia utilizada na dosagem da capacidade inibitória dos compostos inibidores de polimerases e serina proteasesExample 2: Methodology used to measure the inhibitory capacity of polymerase-inhibiting compounds and serine proteases
Os compostos liofilizados foram resuspendidos em DMSO (100%) a uma concentração de 20mM . Posteriormente, 100μΜ dos compostos foram préincubados a 25°C por 15 min com 10ng da enzima HCV-NS3pro/4A em volume final de 50μΙ_ do tampão de reação do kit SensoLyte®520 HCV Protease Assay Kit *Fluorimetric* (AnaSpec,CA,USA), seguindo o protocolo do fabricante. A reação foi iniciada com a adição do substrato Peptídeo 5-FAM/QXL™520 FRET, cuja divagem do peptídeo foi monitorada no leitor de placas SpectraMax M2e (Molecular Devices) enn excitação/emissão igual a 490nm/520nm medindo a fluorescência gerada a cada 30 segundos por 60 min.The lyophilized compounds were resuspended in DMSO (100%) at a concentration of 20mM. Subsequently, 100μΜ of the compounds were pre-incubated at 25 ° C for 15 min with 10ng of the HCV-NS3pro / 4A enzyme in a final volume of 50μΙ_ of the reaction buffer of the SensoLyte®520 HCV Protease Assay Kit * Fluorimetric * (AnaSpec, CA, USA ), following the manufacturer's protocol. The reaction was initiated with the addition of the substrate Peptide 5-FAM / QXL ™ 520 FRET, whose peptide dividing was monitored in the SpectraMax M2 plate reader and (Molecular Devices) enn excitation / emission equal to 490nm / 520nm measuring the fluorescence generated at every 30 seconds for 60 min.
Os parâmetros cinéticos de velocidade inicial (Vi) das reações foram calculados por regressões linear e/ou polinomial de 3a ordem utilizando-se oThe kinetic parameters of initial speed (Vi) of the reactions were calculated by linear regression and / or 3 rd order polynomial using it
16/31 programa SigmaPlot versão 10.0 e Excel 2007, respectivamente, sendo os valores de Vi convertidos em atividade residual (%).16/31 SigmaPlot program version 10.0 and Excel 2007, respectively, with Vi values converted into residual activity (%).
O teste cinético de 22 compostos (10 a 31) está mostrado na Tabela 3. Podemos verificar que os compostos 19, 20, 21, 22, e 23 tiveram atividade inibitória para a protease NS3/4A do HCV, sendo que o composto 22 foi o mais ativo, com uma capacidade inibitória de 64%.The kinetic test of 22 compounds (10 to 31) is shown in Table 3. We can see that compounds 19, 20, 21, 22, and 23 had inhibitory activity for HCV NS3 / 4A protease, with compound 22 being the most active, with a 64% inhibitory capacity.
A inibição parcial da NS3pro/4A em altas concentrações do composto 22, pode ser explicada devido a ausência do domínio helicase da NS3 e/ou do complexo replicativo (ensaio in vitro). Eles podem estar contribuindo para a correta orientação ío da molécula e/ou acentuando a interação do composto 22 com a protease NS3/4A (ensaio in vivo). Na Figura 1A ocorreu uma completa inibição da NS3pro/4A com o inibidor padrão (IC5o°/0=0,80±0,37pl\/l). Entretanto, o composto 22 em altas concentrações inibiu parcialmente (~45%) a atividade proteolítica da NS3/4A.The partial inhibition of NS3pro / 4A at high concentrations of compound 22, can be explained due to the absence of the NS3 helicase domain and / or the replicative complex (in vitro assay). They may be contributing to the correct orientation of the molecule and / or enhancing the interaction of compound 22 with protease NS3 / 4A (in vivo assay). In Figure 1A there was a complete inhibition of NS3pro / 4A with the standard inhibitor (IC 5 ° / 0 = 0.80 ± 0.37 ppl / l). However, compound 22 in high concentrations partially inhibited (~ 45%) the proteolytic activity of NS3 / 4A.
A inibição parcial da NS3pro/4A em altas concentrações do composto 22, pode ser explicada devido a ausência do domínio helicase da NS3 e/ou do complexo replicativo (ensaio in vitro). Eles podem estar contribuindo para a correta orientação da molécula e/ou acentuando a interação do composto 22 com a protease NS3/4A (ensaio in vivo). Contudo, quando realizamos os ensaios in vitro com o composto 22 armazenado a -20°C não observamos essa ativação (Figura 1A). Esses dados sugerem que o composto 22 não seja estável quando armazenado a 4°C, e que seu produto aumente a atividade proteolítica da NS3/4A.The partial inhibition of NS3pro / 4A at high concentrations of compound 22, can be explained due to the absence of the NS3 helicase domain and / or the replicative complex (in vitro assay). They may be contributing to the correct orientation of the molecule and / or accentuating the interaction of compound 22 with protease NS3 / 4A (in vivo assay). However, when we performed the in vitro tests with compound 22 stored at -20 ° C, we did not observe this activation (Figure 1A). These data suggest that compound 22 is not stable when stored at 4 ° C, and that its product increases the proteolytic activity of NS3 / 4A.
É importante ressaltar que quando iniciamos a avaliar, in vitro, a atividade inibitória do composto 22 armazenada a 4°C, observamos que o mesmo em baixas concentrações, aumentava a atividade proteolítica da NS3/4A em 2,5X(Figura 2A).It is important to note that when we started to evaluate, in vitro, the inhibitory activity of compound 22 stored at 4 ° C, we observed that it at low concentrations, increased the proteolytic activity of NS3 / 4A by 2.5X (Figure 2A).
Contudo, quando realizamos os ensaios in vitro com o composto 22 armazenado a 20°C não observamos essa ativação (Figura 1A). Esses dados sugerem que o composto 22 não seja estável quando armazenado a 4°C, e que seu produto aumente a atividade proteolítica da NS3/4A.However, when we performed the in vitro tests with compound 22 stored at 20 ° C, we did not observe this activation (Figure 1A). These data suggest that compound 22 is not stable when stored at 4 ° C, and that its product increases the proteolytic activity of NS3 / 4A.
Com o objetivo de avaliar se o composto 22 promove aumento ou redução da atividade proteolítica, foi realizada uma nova síntese química do composto. Esse novo lote do composto 22 foi resuspendido em DMSO a 100% e os ensaios cinéticos realizados no mesmo dia. Nossos dados revelam que em baixas concentrações doIn order to assess whether compound 22 promotes an increase or reduction in proteolytic activity, a new chemical synthesis of the compound was performed. This new batch of compound 22 was resuspended in 100% DMSO and the kinetic tests performed on the same day. Our data reveal that in low concentrations of
17/31 composto 22 (recém sintetizado) a atividade proteolítica da NS3/4A aumentou aproximadamente 15% (Figura 2B).17/31 compound 22 (newly synthesized) the proteolytic activity of NS3 / 4A increased approximately 15% (Figure 2B).
Tabela 3 - Atividade inibitória dos 22 compostos da patente frente à protease 5 NS3/4A do HCV numa reação in vitro com o kit SensoLyte® 520 HCV ProteaseTable 3 - Inhibitory activity of the 22 patent compounds against HCV protease 5 NS3 / 4A in an in vitro reaction with the SensoLyte® 520 HCV Protease kit
Assay Kit (Anaspec, CA, USA).Assay Kit (Anaspec, CA, USA).
ío Exemplo 3: Obtenção do 1,4:3,6-dianidro-mono(4-metillbenzenosulfonato)-Dmanitol (2)Example 3: Obtaining 1,4: 3,6-dianhydro-mono (4-methylbenzenesulfonate) -Dmanitol (2)
A uma solução do isomanideo (1g, 6mmol) e piridina (1,10ml_) em CH2CI2 (10mL) foi adicionado cloreto de p-toluenosulfonila (1,49g, 7mmol) a 0°C. A reação foi agitada a temperatura ambiente por 12h e após foi diluída com CH2CI2 (20mL). A solução foi lavada com água, HCl 1N e solução saturada de cloreto de sódio. ApósTo a solution of isomanide (1g, 6mmol) and pyridine (1.10ml_) in CH2Cl2 (10mL) was added p-toluenesulfonyl chloride (1.49g, 7mmol) at 0 ° C. The reaction was stirred at room temperature for 12h and then it was diluted with CH 2 CI 2 (20mL). The solution was washed with water, 1N HCl and saturated sodium chloride solution. After
18/31 evaporação do solvente, o sólido foi recristalizado com uma mistura de metanol/isopropanol fornecendo o produto como um sólido branco em 40% de rendimento. PF: 103-104°C.18/31 evaporation of the solvent, the solid was recrystallized with a methanol / isopropanol mixture providing the product as a white solid in 40% yield. Mp: 103-104 ° C.
RMN1H δ ppm (CDCI3, 300MHz): 7,84 (d, 2H, J = 8,1 Hz); 7,34 (d, 2H, J = 8,1 Hz); 1 H NMR δ ppm (CDCI 3 , 300MHz): 7.84 (d, 2H, J = 8.1 Hz); 7.34 (d, 2H, J = 8.1 Hz);
4,91 (dd, 1H, J = 6,6/ 5,5 Hz); 4,42 (t, 1H, J = 5,1 Hz); 4,49 (t, 1H, J = 4,8 Hz); 4,294,25 (m, 1H); 4,04-3,95 (m, 2H); 3,79 (t, 1H, J = 7,8 Hz); 3,55 (dd, 1H, J = 7,2/1,8 Hz); 2,46 (s, 3H).4.91 (dd, 1H, J = 6.6 / 5.5 Hz); 4.42 (t, 1H, J = 5.1 Hz); 4.49 (t, 1H, J = 4.8 Hz); 4.294.25 (m, 1H); 4.04-3.95 (m, 2H); 3.79 (t, 1H, J = 7.8 Hz); 3.55 (dd, 1H, J = 7.2 / 1.8 Hz); 2.46 (s, 3H).
IV v cm'1(KBr): 3526, 2933, 2866, 1596, 1359, 1189, 1173, 1050, 1019, 818, 663.IV v cm -1 (KBr): 3526, 2933, 2866, 1596, 1359, 1189, 1173, 1050, 1019, 818, 663.
Exemplo 4: Obtenção do 1,4:3,6-dianidro-5-O-(benzil)-2-(4ío metilbenzenosulfonato)-D-manitol (3)Example 4: Obtaining 1,4: 3,6-dianhydro-5-O- (benzyl) -2- (4-methylbenzenesulfonate) -D-mannitol (3)
A uma solução de (2) (1 Og, 33mmol), solução aquosa de KOH 50% e TBAB (0,322g, 1mmol) em CH2CI2 (80mL), foi adicionado cloreto de benzila (6,54g, 38mmol). Após agitação por 12h, a mistura foi diluída com água (10mL) e a fase orgânica foi separada. A fase aquosa foi extraída com CH2CI2 e seca com Na2SO4. O produto foi purificado por coluna cromatográfica em sílica gel tendo como eluente uma mistura de hexano e acetato de etila, fornecendo o produto como um óleo incolor em 75% de rendimento.To a solution of (2) (1 Og, 33mmol), aqueous solution of KOH 50% and TBAB (0.322g, 1mmol) in CH2 Cl2 (80mL), was added benzyl chloride (6.54g, 38mmol). After stirring for 12h, the mixture was diluted with water (10mL) and the organic phase was separated. The aqueous phase was extracted with CH 2 CI 2 and dried with Na 2 SO 4 . The product was purified by chromatographic column on silica gel with a mixture of hexane and ethyl acetate as eluent, providing the product as a colorless oil in 75% yield.
RMN1H δ ppm (CDCI3, 300MHz): 7,81 (d, 2H, J = 8,4 Hz); 7,35-7,32 (m, 7H); 4,9120 4,89 (m, 1H); 4,69 (d, 1H, J= 12,0 Hz); 4,50 (d, 1H, J = 12,0 Hz); 4,47 (t, 2H, J= 2,1 1 H NMR δ ppm (CDCI 3 , 300MHz): 7.81 (d, 2H, J = 8.4 Hz); 7.35-7.32 (m, 7H); 4.9120 4.89 (m, 1H); 4.69 (d, 1H, J = 12.0 Hz); 4.50 (d, 1H, J = 12.0 Hz); 4.47 (t, 2H, J = 2.1
Hz); 4,04-3,79 (m, 4H); 3,62 (t, 1H, J= 8,4 Hz); 2,44 (s, 3H).Hz); 4.04-3.79 (m, 4H); 3.62 (t, 1H, J = 8.4 Hz); 2.44 (s, 3H).
IV v cm'1(filme): 3063, 2977, 2950, 2879, 1598, 1454, 1366, 1190, 1178, 1141, 1027, 853.IV v cm -1 (film): 3063, 2977, 2950, 2879, 1598, 1454, 1366, 1190, 1178, 1141, 1027, 853.
ccd 20 = +98 (c, 0.1) DMSO.cc d 20 = +98 (c, 0.1) DMSO.
Exemplo 5: Obtenção do 1,4:3,6-dianidro-2-azido-2-deoxi-5-O-(benzil)-DGlucitol (4)Example 5: Obtaining 1,4: 3,6-dianhydro-2-azido-2-deoxy-5-O- (benzyl) -DGlucitol (4)
Uma mistura de (3) (1,86g, 4mmol), [bmim]+[BF4]' previamente seco sob vácuo a 90°C (4,8mL, 23mmol) e NaN3 (0,93g, 14mmol) foi aquecida a 120°C porA mixture of (3) (1.86g, 4mmol), [bmim] + [BF 4 ] 'previously vacuum dried at 90 ° C (4.8mL, 23mmol) and NaN 3 (0.93g, 14mmol) was heated at 120 ° C for
12h. Adicionou-se água e a fase aquosa foi extraída com éter etílico. O produto foi12h. Water was added and the aqueous phase was extracted with ethyl ether. The product was
19/31 purificado por coluna cromatográfica flash (hexano/acetato de etila), obtendo um óleo amarelo claro em 73% de rendimento.19/31 purified by flash chromatographic column (hexane / ethyl acetate), obtaining a light yellow oil in 73% yield.
RMN1H δ ppm (CDCI3, 300MHz): 7,36-7,26 (m, 5H); 4,75 (d, 1H, J = 11,7 Hz); 4,66 (t, 1H, J = 4,5 Hz); 4,54 (d, 1H, J= 11,7 Hz); 4,48 (d, 1H, J = 4,2 Hz); 4,15-4,00 (m, 1 H NMR δ ppm (CDCI 3 , 300MHz): 7.36-7.26 (m, 5H); 4.75 (d, 1H, J = 11.7 Hz); 4.66 (t, 1H, J = 4.5 Hz); 4.54 (d, 1H, J = 11.7 Hz); 4.48 (d, 1H, J = 4.2 Hz); 4.15-4.00 (m,
4H); 3,86 (dd, 1H, J = 6,3/2,7 Hz); 3,66 (t, 1H, J = 7,8 Hz).4H); 3.86 (dd, 1H, J = 6.3 / 2.7 Hz); 3.66 (t, 1H, J = 7.8 Hz).
RMN 13C δ ppm (CDCI3, 75,4 MHz): 137,4 (-C), 128,3 (-CH), 127,8 (-CH), 127,7 (CH), 86,4 (-CH), 80,5 (-CH), 78,8 (-CH), 72,6 (-CH2), 72,4 (-CH2), 70,7 (-CH2), 66,2 (CH). 13 C δ ppm NMR (CDCI 3 , 75.4 MHz): 137.4 (-C), 128.3 (-CH), 127.8 (-CH), 127.7 (CH), 86.4 ( -CH), 80.5 (-CH), 78.8 (-CH), 72.6 (-CH 2 ), 72.4 (-CH 2 ), 70.7 (-CH 2 ), 66.2 (CH).
IV v cm’1 (filme): 3063, 3031, 2946, 2878, 2102, 1455, 1320, 1256, 1135, 1100,IV v cm ' 1 (film): 3063, 3031, 2946, 2878, 2102, 1455, 1320, 1256, 1135, 1100,
1083,1021,739.1083,1021,739.
HRMS calculada para Ci3H15N3O3Na, 284,1011; encontrada, 284,1025. aD 20 = +92 (c, 0.1) DMSO.HRMS calculated for Ci3H 15 N 3 O 3 Na, 284.1011; found, 284.1025. a D 20 = +92 (c, 0.1) DMSO.
Exemplo 6: Obtenção do 1,4:3,6-dianidro-2-amino-2-deoxi-5-O-(benzil)-D15 Glucitol (5)Example 6: Obtaining 1,4: 3,6-dianhydro-2-amino-2-deoxy-5-O- (benzyl) -D15 Glucitol (5)
A uma solução de (4) (0,870g, 3mmol) em etanol (25ml_) foi adicionado Pd/C 5% (0,3mmol) e a mistura foi hidrogenada sob 40psi for 5h. Após esse tempo a suspensão foi filtrada em XAD-4 e lavada com etanol. Evaporado o solvente obteve20 se um óleo incolor em rendimento quantitativo.To a solution of (4) (0.870g, 3mmol) in ethanol (25ml_) was added 5% Pd / C (0.3mmol) and the mixture was hydrogenated under 40psi for 5h. After that time the suspension was filtered over XAD-4 and washed with ethanol. Evaporated the solvent obtained 20 if a colorless oil in quantitative yield.
RMN1H δ ppm (CDCI3, 300MHz): 7,37-7,35 (m, 5H); 4,76 (d, 1H, J = 11,4 Hz); 4,68 (t, 1H, J = 4,2 Hz); 4,54 (d, 1H, J = 12,0 Hz); 4,27 (d, 1H, J = 4,2 Hz); 4,06-4,02 (m, 1H); 3,85 (dd, 1H, J = 6,3/2,4 Hz); 3,76 (d, 1H, J = 9,3 Hz); 3,64 (t, 1H, J = 7,8 Hz); 3,53 (d, 1H, J = 4,2 Hz); 3,45 (s, 1H). 1 H NMR δ ppm (CDCI 3 , 300MHz): 7.37-7.35 (m, 5H); 4.76 (d, 1H, J = 11.4 Hz); 4.68 (t, 1H, J = 4.2 Hz); 4.54 (d, 1H, J = 12.0 Hz); 4.27 (d, 1H, J = 4.2 Hz); 4.06-4.02 (m, 1H); 3.85 (dd, 1H, J = 6.3 / 2.4 Hz); 3.76 (d, 1H, J = 9.3 Hz); 3.64 (t, 1H, J = 7.8 Hz); 3.53 (d, 1H, J = 4.2 Hz); 3.45 (s, 1H).
RMN 13C δ ppm (CDCI3, 75,4 MHz): 137,9 (-C), 128,6 (-CH), 128,0 (-CH), 127,8 (CH), 90,0 (-CH), 80,1 (-CH), 79,4 (-CH), 76,3 (-CH2), 72,6 (-CH2), 70,5 (-CH2), 58,8 (CH). 13 C δ ppm NMR (CDCI 3 , 75.4 MHz): 137.9 (-C), 128.6 (-CH), 128.0 (-CH), 127.8 (CH), 90.0 ( -CH), 80.1 (-CH), 79.4 (-CH), 76.3 (-CH 2 ), 72.6 (-CH 2 ), 70.5 (-CH 2 ), 58.8 (CH).
IV vem’1 (filme): 3360, 2876, 1605, 1455, 1369, 1209, 1065, 1017, 751,700.IV comes' 1 (film): 3360, 2876, 1605, 1455, 1369, 1209, 1065, 1017, 751,700.
HRMS calculada para Ci3Hi7NO3Na, 236,1287; encontrada, 236,1284.HRMS calculated for Ci 3 Hi7NO 3 Na, 236.1287; found, 236.1284.
Exemplo 7: Obtenção do 1,4:3,6-diamdro-5-O-(benzil)-2-(hidroxi)-D-manitol (6)Example 7: Obtaining 1,4: 3,6-diamdro-5-O- (benzyl) -2- (hydroxy) -D-mannitol (6)
20/3120/31
Uma mistura de isomanideo (1g, 6,85 mmol), KOH (0,44g, 6,85 mmol) e água (3,5 mL) foi refluxada por 20min. Após esse tempo a reação foi resfriada a temperatura ambiente e foi adicionado cloreto de benzila (0,78 mL, 6,85 mmol). A mistura foi refluxada por 3h. Ao final desse tempo, foi adicionado HCI 2N (4 mL) e o produto foi extraído com acetato de etila. O produto foi obtido em 45% de rendimento após purificação por coluna cromatográfica. Pf = 93°C.A mixture of isomanide (1g, 6.85 mmol), KOH (0.44g, 6.85 mmol) and water (3.5 ml) was refluxed for 20min. After that time the reaction was cooled to room temperature and benzyl chloride (0.78 mL, 6.85 mmol) was added. The mixture was refluxed for 3 hours. At the end of that time, 2N HCI (4 mL) was added and the product was extracted with ethyl acetate. The product was obtained in 45% yield after purification by chromatographic column. Mp = 93 ° C.
RMN1H (300MHz, CDCI3): 7,36-7,27 (m, 5H); 4,79 (d, 1H, J= 12,0 Hz); 4,58 (d, 1H, J = 12,0 Hz); 4,57-4,53 (m, 1H); 4,48 (t, 1H, J= 5,1 Hz); 4,27 (br s, 1H); 4,11-3,95 (m, 3H); 3,76-3,68 (m, 2H); 2,82 (br s, 1H). 1 H NMR (300MHz, CDCI 3 ): 7.36-7.27 (m, 5H); 4.79 (d, 1H, J = 12.0 Hz); 4.58 (d, 1H, J = 12.0 Hz); 4.57-4.53 (m, 1H); 4.48 (t, 1H, J = 5.1 Hz); 4.27 (br s, 1H); 4.11 - 3.95 (m, 3H); 3.76-3.68 (m, 2H); 2.82 (br s, 1H).
ío RMN13C (50 MHz, CDCI3): 137,5; 128,4; 127,9; 127,8; 81,7; 80,6; 78,9; 74,7; 72,5; 72,2; 71,3. 13 C NMR (50 MHz, CDCl 3 ): 137.5; 128.4; 127.9; 127.8; 81.7; 80.6; 78.9; 74.7; 72.5; 72.2; 71.3.
IV v (cm'1) (KBr): 3459, 3404, 2920, 2865, 1459, 1419, 1329, 1266, 1200, 1118, 1068, 1021, 820.IV v (cm -1 ) (KBr): 3459, 3404, 2920, 2865, 1459, 1419, 1329, 1266, 1200, 1118, 1068, 1021, 820.
Exemplo 8: Obtenção do Líquido lônico [Bmim]*BF4* (composto 9).Example 8: Obtaining the tonic liquid [Bmim] * BF 4 * (compound 9).
A uma solução de N-metil imidazol (200mmol, 16mL) em tolueno (25mL), a 0°C, foi adicionado 1-Bromobutano (230mmol, 25mL) lentamente e com agitação. A mistura foi deixada em refluxo (110°C) por 36 h. Foram formadas duas fases: a mais densa (viscosa) e a mais leve. Elas foram separadas. A fase viscosa foi lavada com éter etílico (3 x 50mL) e acetato de etila (3x50mL). Logo após, foi adicionado CH2CI2 (150mL) e NaBF4 (164mmol, 18g). A mistura ficou agitando por 24h à temperatura ambiente. Após este tempo, a mistura foi filtrada 2 vezes, adicionado o carvão ativo e deixada por mais 24h sob agitação. Ao final, a mistura foi filtrada, evaporada e por fim filtrada em alumina neutra lavando bem com CH2CI2. O produto foi obtido como um óleo amarelo claro em 83% de rendimento.To a solution of N-methyl imidazole (200mmol, 16mL) in toluene (25mL), at 0 ° C, was added 1-Bromobutane (230mmol, 25mL) slowly and with stirring. The mixture was left at reflux (110 ° C) for 36 h. Two phases were formed: the densest (viscous) and the lightest. They were separated. The viscous phase was washed with ethyl ether (3 x 50mL) and ethyl acetate (3x50mL). Soon after, CH2Cl2 (150mL) and NaBF 4 (164mmol, 18g) were added. The mixture was stirred for 24 hours at room temperature. After this time, the mixture was filtered 2 times, the active charcoal was added and left for another 24 hours with stirring. At the end, the mixture was filtered, evaporated and finally filtered over neutral alumina washing well with CH 2 CI 2 . The product was obtained as a light yellow oil in 83% yield.
RMN 1H δ ppm (CDCI3, 300 MHz): 9,27 (s, 1H); 7,38 (s, 1H); 7,32 (s, 1H); 4,22 (t, 2H, J = 7,2 Hz); 3,99 (s, 3H); 1,91-1,80 (m, 2H); 1,43-1,30 (m, 2H); 0,94 (t, 3H, J = 1 H NMR δ ppm (CDCI 3 , 300 MHz): 9.27 (s, 1H); 7.38 (s, 1H); 7.32 (s, 1H); 4.22 (t, 2H, J = 7.2 Hz); 3.99 (s, 3H); 1.91 - 1.80 (m, 2H); 1.43-1.30 (m, 2H); 0.94 (t, 3H, J =
7,2 Hz).7.2 Hz).
IV vcm'1(KBr): 3606, 3418, 3161, 3119, 2964, 2939, 2877, 1634, 1574, 1467, 1385,IV vcm ' 1 (KBr): 3606, 3418, 3161, 3119, 2964, 2939, 2877, 1634, 1574, 1467, 1385,
1338, 1286, 1170, 1062, 848, 754, 623.1338, 1286, 1170, 1062, 848, 754, 623.
21/3121/31
Exemplo 9: Processo geral para obtenção das amidas (10-22) e ésteres (23-31)Example 9: General process for obtaining amides (10-22) and esters (23-31)
A uma solução da amina benzilada (5) ou isomanideo mono benzilado (6) (1,27 mmol) em CH2CI2 (10 mL) foram adicionados o respectivo aminoácido Nprotegido (1,27 mmol), e a 0°C, DCC (1,27 mmol) e DMAP (0,12 mmol). Após agitação por 12h a temperatura ambiente, a mistura foi filtrada e o filtrado foi seco em vácuo. O produto foi purificado por coluna cromatográfica usando hexano e acetato de etila como solvente.To a solution of the benzylated amine (5) or mono-benzylated isomanide (6) (1.27 mmol) in CH2 Cl2 (10 mL) was added the respective N-protected amino acid (1.27 mmol), and at 0 ° C, DCC (1 , 27 mmol) and DMAP (0.12 mmol). After stirring for 12 hours at room temperature, the mixture was filtered and the filtrate was dried in vacuo. The product was purified by column chromatography using hexane and ethyl acetate as solvent.
Exemplo 10: Obtenção do 1,4:3,6-dianidro-5-O-(benzil)-2-N-(N-f-butoxicarbonil10 L-prolina)-D-glucitol (10)Example 10: Obtaining 1,4: 3,6-dianhydro-5-O- (benzyl) -2-N- (N-f-butoxycarbonyl10 L-proline) -D-glucitol (10)
RMN 1H δ ppm (CDCI3, 300 MHz): 7,40-7,25 (m, 5H); 4,77-4,74 (m, 1H); 4,66 (t, 1H, J = 4,8 Hz); 4,57 (d, 1H, J = 11,4 Hz); 4,41-4,40 (m, 1H); 4,25-4,24 (m, 1H); 4,164,12 (m, 2H); 4,10-4,01 (m, 1H); 3,87-3,82 (m, 1H); 2,21-1,92 (m, 2H); 1,92-1,86 (m, 2H); 1,41 (s, 9H). 1 H NMR δ ppm (CDCl3, 300 MHz): 7.40-7.25 (m, 5H); 4.77-4.74 (m, 1H); 4.66 (t, 1H, J = 4.8 Hz); 4.57 (d, 1H, J = 11.4 Hz); 4.41 - 4.40 (m, 1H); 4.25-4.24 (m, 1H); 4,164.12 (m, 2H); 4.10-4.01 (m, 1H); 3.87-3.82 (m, 1H); 2.21 - 1.92 (m, 2H); 1.92-1.86 (m, 2H); 1.41 (s, 9H).
RMN13C (50 MHz, CDCI3): 175,7; 155,9; 139,4; 129,4; 129,0; 128,8; 88,4; 81,9; 81,4; 80,7; 74,0; 73,5; 71,7; 61,4; 58,5; 32,6; 28,7; 25,4; 24.7. 13 C NMR (50 MHz, CDCl 3): 175.7; 155.9; 139.4; 129.4; 129.0; 128.8; 88.4; 81.9; 81.4; 80.7; 74.0; 73.5; 71.7; 61.4; 58.5; 32.6; 28.7; 25.4; 24.7.
IV v (cm'1) filme (CH2CI2): 3055, 2986, 1684, 1604, 1423, 1159, 987, 896, 741. α.ϋ2θ= +91 (c 0,1 DMSO). Aspecto: óleo incolor.IV v (cm ' 1 ) film (CH 2 CI 2 ): 3055, 2986, 1684, 1604, 1423, 1159, 987, 896, 741. α.ϋ 2θ = +91 (c 0.1 DMSO). Appearance: colorless oil.
HRMS calculada para C23H32N2O6Na, 455,2158; Encontrada, 455,2164.HRMS calculated for C 23 H 32 N 2 O6Na, 455.2158; Found, 455.2164.
Exemplo 11: Obtenção do 1,4:3,6-dianidro-5-O-(benzil)-2-N-(N-í-butoxicarbonilL-valina)-D-glucitol (11)Example 11: Obtaining 1,4: 3,6-dianhydro-5-O- (benzyl) -2-N- (N-i-butoxycarbonylL-valine) -D-glucitol (11)
RMN 1H δ ppm (CDCI3, 300 MHz): 7,38-7,24 (m, 5H); 6,23 (br s, 1H); 5,01 (br s, 1H); 1 H NMR δ ppm (CDCI 3 , 300 MHz): 7.38-7.24 (m, 5H); 6.23 (br s, 1H); 5.01 (br s, 1H);
4,76 (d, 1H, J = 11,7 Hz); 4,60-4,53 (m, 2H); 4,42 (q, 2H, J = 3,9 Hz); 4,08-4,02 (m, 2H); 3,88-3,81 (m 3H); 3,69-3,63 (m, 1H); 2,15-2,09 (m, 1H); 1,44 (s, 9H); 0,95 (d,4.76 (d, 1H, J = 11.7 Hz); 4.60-4.53 (m, 2H); 4.42 (q, 2H, J = 3.9 Hz); 4.08-4.02 (m, 2H); 3.88-3.81 (m 3H); 3.69-3.63 (m, 1H); 2.15-2.09 (m, 1H); 1.44 (s, 9H); 0.95 (d,
3H, J = 6,9 Hz); 0,91 (d, 3H, J = 6,9 Hz).3H, J = 6.9 Hz); 0.91 (d, 3H, J = 6.9 Hz).
RMN13C (50 MHz, CDCI3): 171,4; 155,9; 137,6; 128,4; 127,9; 127,8; 86,9; 80,3; 80,2; 80,0; 79,0; 72,5; 70,8; 59,9; 56,8; 30,6; 28,2; 19,3; 17.8. 13 C NMR (50 MHz, CDCI 3 ): 171.4; 155.9; 137.6; 128.4; 127.9; 127.8; 86.9; 80.3; 80.2; 80.0; 79.0; 72.5; 70.8; 59.9; 56.8; 30.6; 28.2; 19.3; 17.8.
IV v (cm‘1) KBr: 3335, 2968, 2934, 2879, 1687, 1654, 1529, 1461, 1368, 1299, 1250, 1169, 1092, 1052, 1018, 738.IV v (cm -1 ) KBr: 3335, 2968, 2934, 2879, 1687, 1654, 1529, 1461, 1368, 1299, 1250, 1169, 1092, 1052, 1018, 738.
PF = 102-103°C ao20= +67 (c 0,1 DMSO). Aspecto: sólido branco.PF = 102-103 ° C at 20 = +67 (c 0.1 DMSO). Appearance: white solid.
HRMS calculada para C23H34N2O6Na, 457,2315; Encontrada, 457,2324.HRMS calculated for C 23 H 3 4N 2 O 6 Na, 457.2315; Found, 457.2324.
22/3122/31
Exemplo 12: Obtenção do 1,4:3,6-dianidro-5-O-(benzil)-2-N-(N-f-butoxicarbonilO-benzil-L-serina)-D-glucitol (12)Example 12: Obtaining 1,4: 3,6-dianhydro-5-O- (benzyl) -2-N- (N-f-butoxycarbonylO-benzyl-L-serine) -D-glucitol (12)
RMN 1H δ ppm (CDCfe, 300 MHz): 7,35-7,27 (m, 10H); 4,73 (d, 1H, J = 12 Hz); 4,544,45 (m, 3H); 4,40-4,38 (m, 2H); 4,32-4,31 (m, 1H); 4,23-4,21 (m, 1H); 4,05-3,95 (m, 2H); 3,91-3,81 (m, 3H); 3,67-3,57 (m, 1H); 3,64 (dd, 1H, J = 7,5; 8,7 Hz); 3,61-3,54 (m, 1H); 1,44 (s, 9H). 1 H NMR δ ppm (CDCfe, 300 MHz): 7.35-7.27 (m, 10H); 4.73 (d, 1H, J = 12 Hz); 4,544.45 (m, 3H); 4.40-4.38 (m, 2H); 4.32-4.31 (m, 1H); 4.23-4.21 (m, 1H); 4.05-3.95 (m, 2H); 3.91 - 3.81 (m, 3H); 3.67-3.57 (m, 1H); 3.64 (dd, 1H, J = 7.5; 8.7 Hz); 3.61 - 3.54 (m, 1H); 1.44 (s, 9H).
RMN13C (50 MHz, CDCfe): RMN13C: 169,9; 155,7; 137,6; 137,3; 128,5; 128,4; 128,0; 127,9; 127,8; 86,8; 80,4; 80,1; 79,1; 73,5; 73,2; 72,4; 70,7; 69,8; 56,8; 51,9; 28,2. 13 C NMR (50 MHz, CDCfe): 13 C NMR: 169.9; 155.7; 137.6; 137.3; 128.5; 128.4; 128.0; 127.9; 127.8; 86.8; 80.4; 80.1; 79.1; 73.5; 73.2; 72.4; 70.7; 69.8; 56.8; 51.9; 28.2.
IV v (cm’1) KBr: 3289, 2968, 2974, 2873, 1690, 1650, 1553, 1511, 1299, 1310, 1243, 1168, 1133, 1049, 864, 742.IV v (cm -1 ) KBr: 3289, 2968, 2974, 2873, 1690, 1650, 1553, 1511, 1299, 1310, 1243, 1168, 1133, 1049, 864, 742.
PF = 116-117°C αο2θ= +57 (c 0,1 DMSO). Aspecto: sólido branco.PF = 116-117 ° C αο 2θ = +57 (c 0.1 DMSO). Appearance: white solid.
HRMS calculada para C28H36N2O7Na, 535,2420; Encontrada, 535,2400.HRMS calculated for C28H 3 6N2O 7 Na, 535.2420; Found, 535.2400.
Exemplo 13: Obtenção do 1,4:3,6-dianidro-5-O-(benzil)-2-N-(N-f-butoxicarbonilL-metionina)-D-glucitol (13)Example 13: Obtaining 1,4: 3,6-dianhydro-5-O- (benzyl) -2-N- (N-f-butoxycarbonylL-methionine) -D-glucitol (13)
RMN 1H δ ppm (CDCfe, 300 MHz): 7,35-7,30 (m, 5H); 6,55 (brs, 1H); 5,16 (brs, 1H); 1 H NMR δ ppm (CDCfe, 300 MHz): 7.35-7.30 (m, 5H); 6.55 (brs, 1H); 5.16 (brs, 1H);
4,77 (d, 1H, J = 12 Hz); 4,59-4,52 (m, 2H); 4,42-4,38 (m, 2H); 4,24-4,17 (m, 1H); 4,08-4,02 (m 2H); 3,87-3,82 (m, 2H); 3,67 (dd, 1H, J = 7,5; 9,0 Hz); 2,55-2,52 (m, 2H); 2,10 (s, 3H); 2,06-2,03 (m, 2H); 1,44 (s, 9H).4.77 (d, 1H, J = 12 Hz); 4.59-4.52 (m, 2H); 4.42-4.38 (m, 2H); 4.24-4.17 (m, 1H); 4.08-4.02 (m 2H); 3.87-3.82 (m, 2H); 3.67 (dd, 1H, J = 7.5; 9.0 Hz); 2.55-2.52 (m, 2H); 2.10 (s, 3H); 2.06-2.03 (m, 2H); 1.44 (s, 9H).
RMN13C (50 MHz, CDCfe): 171,3; 155,6; 137,6; 128,4; 127,8; 127,8; 86,9; 80,4; 80,2; 73,2; 72,4; 70,8; 56,8; 53,4; 31,2; 30,2; 28,2; 15.2. 13 C NMR (50 MHz, CDCfe): 171.3; 155.6; 137.6; 128.4; 127.8; 127.8; 86.9; 80.4; 80.2; 73.2; 72.4; 70.8; 56.8; 53.4; 31.2; 30.2; 28.2; 15.2.
IV v (cm'1) KBr: 3297, 2974, 2931, 2873, 1660, 1650, 1530, 1452, 1368, 1249, 1168, 1092, 860, 742.IV v (cm -1 ) KBr: 3297, 2974, 2931, 2873, 1660, 1650, 1530, 1452, 1368, 1249, 1168, 1092, 860, 742.
PF = 91-93°C ccd20= +34 (c 0,1 CH2CI2). Aspecto: sólido branco.PF = 91-93 ° C ccd 20 = +34 (c 0.1 CH2 Cl2). Appearance: white solid.
HRMS calculada para C23H32N2O6NaS, 489,2035; Encontrada, 489,2038.HRMS calculated for C 2 3H32N2O6NaS, 489.2035; Found, 489.2038.
Exemplo 14: Obtenção do 1,4:3,6-dianidro-5-O-(benzil)-2-N-(N-f-butoxicarbonilExample 14: Obtaining 1,4: 3,6-dianhydro-5-O- (benzyl) -2-N- (N-f-butoxycarbonyl
L-triptofano)-D-glucitol (14)L-tryptophan) -D-glucitol (14)
23/3123/31
RMN 1H δ ppm (CDCI3, 300 MHz): 8,24 (brs, 1H); 7,64 (d, 1H, J= 7,8 Hz); 7,36-7,29 (m, 6H); 7,19-7,07 (m, 3H); 5,70 (br s, 1H); 5,29 (br s, 1H); 4,48 (q, 1H, J = 12 Hz); 4,39-4,36 (m, 1H); 4,23-4,21 (m, 1H); 3,84-3,65 (m, 5H); 3,55-3,49 (m 3H); 3,29 (dd, 1H, *7= 5,7; 14,4 Hz); 3,10 (dd, 1H, J=8,4; 14,4 Hz); 1,44 (s, 9H). 1 H NMR δ ppm (CDCI 3 , 300 MHz): 8.24 (brs, 1H); 7.64 (d, 1H, J = 7.8 Hz); 7.36-7.29 (m, 6H); 7.19-7.07 (m, 3H); 5.70 (br s, 1H); 5.29 (br s, 1H); 4.48 (q, 1H, J = 12 Hz); 4.39-4.36 (m, 1H); 4.23-4.21 (m, 1H); 3.84-3.65 (m, 5H); 3.55-3.49 (m 3H); 3.29 (dd, 1H, * 7 = 5.7; 14.4 Hz); 3.10 (dd, 1H, J = 8.4; 14.4 Hz); 1.44 (s, 9H).
RMN13C (50 MHz, CDCI3): 171,4; 155,4; 137,6; 136,1; 128,4; 127,9; 127,7; 127,3; 123,2; 122,2; 119,7; 118,9; 111,2; 110,6; 86,3; 80,1; 79,6; 79,0; 72,6; 72,3; 70,4; 13 C NMR (50 MHz, CDCI 3 ): 171.4; 155.4; 137.6; 136.1; 128.4; 127.9; 127.7; 127.3; 123.2; 122.2; 119.7; 118.9; 111.2; 110.6; 86.3; 80.1; 79.6; 79.0; 72.6; 72.3; 70.4;
56,4; 55,6; 28,6; 28,3.56.4; 55.6; 28.6; 28.3.
IV v (cm'1) KBr: 3321, 2974, 2933, 2881, 1685, 1646, 1523, 1455, 1366, 1250, 1169, 1095, 1018, 863, 743.IV v (cm -1 ) KBr: 3321, 2974, 2933, 2881, 1685, 1646, 1523, 1455, 1366, 1250, 1169, 1095, 1018, 863, 743.
PF = 161-162°C αο2θ= +44 (c 0,1 CH2CI2). Aspecto: sólido branco.PF = 161-162 ° C αο 2θ = +44 (c 0.1 CH2 Cl2). Appearance: white solid.
HRMS calculada para C2oH35N3C>6Na, 544,2424; Encontrada, 544,2408.HRMS calculated for C 2 oH 3 5N 3 C> 6Na, 544.2424; Found, 544.2408.
Exemplo 15: Obtenção do 1,4:3,6-dianidro-5-O-(benzil)-2-N-(N-carbobenziloxiprolina-fenilalanina)-D-glucitol (15)Example 15: Obtaining 1,4: 3,6-dianhydro-5-O- (benzyl) -2-N- (N-carbobenzyloxyproline-phenylalanine) -D-glucitol (15)
RMN 1H δ ppm (CDCI3, 300 MHz): 7,27-7,02 (m, 15H); 6,61 (br s, 1H); 6,29 (br s, 1H); 5,06-4,90 (m, 2H); 4,66 (d, 2H, J= 12 Hz); 4,45 (d, 2H, J= 12 Hz); 4,31-4,27 (m, 2H); 4,18-4,15 (m, 1H); 3,99-3,91 (m, 2H); 3,78-3,72 (m, 2H); 3,56 (t, 1H, J= 8,1 Hz); 3,44-3,30 (m, 3H); 3,10-3,03 (m 1H); 1,93-1,60 (m, 4H). 1 H NMR δ ppm (CDCI 3 , 300 MHz): 7.27-7.02 (m, 15H); 6.61 (br s, 1H); 6.29 (br s, 1H); 5.06-4.90 (m, 2H); 4.66 (d, 2H, J = 12 Hz); 4.45 (d, 2H, J = 12 Hz); 4.31 - 4.27 (m, 2H); 4.18-4.15 (m, 1H); 3.99-3.91 (m, 2H); 3.78-3.72 (m, 2H); 3.56 (t, 1H, J = 8.1 Hz); 3.44-3.30 (m, 3H); 3.10-3.03 (m 1H); 1.93-1.60 (m, 4H).
RMN13C (50 MHz, CDCI3): 171,2; 170,2; 155,9; 137,6; 136,4; 135,9; 129,0; 128,6; 128,5; 128,3; 128,2; 127,7; 127,0; 86,8; 80,1; 79,0; 73,4; 72,3; 70,4; 67,5; 61,2; 57,0; 13 C NMR (50 MHz, CDCI 3 ): 171.2; 170.2; 155.9; 137.6; 136.4; 135.9; 129.0; 128.6; 128.5; 128.3; 128.2; 127.7; 127.0; 86.8; 80.1; 79.0; 73.4; 72.3; 70.4; 67.5; 61.2; 57.0;
53,4; 47,0; 37,3; 29,3; 24,3.53.4; 47.0; 37.3; 29.3; 24.3.
IVv (cm'1) KBr: 3279, 3069, 2949, 2878, 1704, 1649, 1554, 1448, 1415, 1355, 1247, 1093, 1023, 914, 743.IVv (cm -1 ) KBr: 3279, 3069, 2949, 2878, 1704, 1649, 1554, 1448, 1415, 1355, 1247, 1093, 1023, 914, 743.
PF = 141-143°C aD 20 = -15 (c 0,1 CH2CI2). Aspecto: sólido branco.PF = 141-143 ° C to D 20 = -15 (c 0.1 CH 2 CI 2 ). Appearance: white solid.
HRMS calculada para C35H3gN3O7Na, 636,2686; Encontrada, 636,2697.HRMS calculated for C 3 5H 3 gN 3 O 7 Na, 636.2686; Found, 636.2697.
Exemplo 16: Obtenção do 1,4:3,6-dianidro-5-O-(benzil)-2-N-(N-carbobenziloxi30 D-prolina)-D-glucitol (16)Example 16: Obtaining 1,4: 3,6-dianhydro-5-O- (benzyl) -2-N- (N-carbobenzyloxy30 D-proline) -D-glucitol (16)
24/3124/31
RMN 1H δ ppm (CDCI3, 300 MHz): 7,36-7,26 (m, 6H); 5,15-5,13 (m, 2H); 4,75 (d, 1H, J= 11,7 Hz); 4,56 (d, 1H, J= 12 Hz); 4,30-4,26 (m, 2H); 4,00-3,91 (m, 2H); 3,85-3,80 (m, 2H); 3,66-3,62 (m, 1H); 3,61-3,44 (m, 4H); 2,34-1,85 (m, 4H). 1 H NMR δ ppm (CDCI 3 , 300 MHz): 7.36-7.26 (m, 6H); 5.15-5.13 (m, 2H); 4.75 (d, 1H, J = 11.7 Hz); 4.56 (d, 1H, J = 12 Hz); 4.30-4.26 (m, 2H); 4.00-3.91 (m, 2H); 3.85-3.80 (m, 2H); 3.66-3.62 (m, 1H); 3.61 - 3.44 (m, 4H); 2.34-1.85 (m, 4H).
RMN13C (50 MHz, CDCI3): 171,1; 156,5; 137,6; 136,4; 128,5; 128,4; 128,1; 127,8; 86,9; 80,1; 78,9; 73,4; 72,4; 70,6; 67,3; 60,2; 56,8; 47,0; 27,9; 24,6. 13 C NMR (50 MHz, CDCI 3 ): 171.1; 156.5; 137.6; 136.4; 128.5; 128.4; 128.1; 127.8; 86.9; 80.1; 78.9; 73.4; 72.4; 70.6; 67.3; 60.2; 56.8; 47.0; 27.9; 24.6.
IV v (cm'1) KBr: 3345, 3034, 2974, 2926, 2873, 1679, 1531, 1451, 1421, 1356, 1253, 1208, 1122, 1091, 952, 866, 758.IV v (cm -1 ) KBr: 3345, 3034, 2974, 2926, 2873, 1679, 1531, 1451, 1421, 1356, 1253, 1208, 1122, 1091, 952, 866, 758.
PF = 89-90°C ctD20= +94 (c 0,1 CH2CI2). Aspecto: sólido branco.PF = 89-90 ° C ctD 20 = +94 (c 0.1 CH2 Cl2). Appearance: white solid.
HRMS calculada para C26H3oN206Na, 489,2002; Encontrada, 489,2011.HRMS calculated for C 2 6H 3 oN 2 06Na, 489.2002; Found, 489,2011.
Exemplo 17: Obtenção do 1,4:3,6-dianidro-5-O-(benzil)-2-N-(Na-f-butoxicarbonilN,-carbobenziloxi-L-lisina)-D-glucitol(17)Example 17: Obtaining 1,4: 3,6-dianhydro-5-O- (benzyl) -2-N- (N a -f-butoxycarbonylN, -carbobenzyloxy-L-lysine) -D-glucitol (17)
RMN 1H δ ppm (CDCI3, 300 MHz): 7,34-7,30 (m, 10H); 6,55 (br s, 1H); 5,29 (s, 2H); 5,09-5,02 (m, 1H); 4,75 (d, 1H, J = 11,7 Hz); 4,58 (t, 1H, J = 4,5 Hz); 4,51 (d, 1H, J = 12 Hz); 4,41-4,36 (m, 2H); 4,07-4,00 (m, 2H); 3,86-3,81 (m, 2H); 3,65 (dd, 1H, J = 7,5; 8,7 Hz); 3,17 (q, 2H, J = 6,0 Hz); 1,84-1,82 (m, 2H); 1,64-1,50 (m, 2H); 1,43 (s, 9H); 1,39-1,34 (m, 2H). 1 H NMR δ ppm (CDCI 3 , 300 MHz): 7.34-7.30 (m, 10H); 6.55 (br s, 1H); 5.29 (s, 2H); 5.09-5.02 (m, 1H); 4.75 (d, 1H, J = 11.7 Hz); 4.58 (t, 1H, J = 4.5 Hz); 4.51 (d, 1H, J = 12 Hz); 4.41 - 4.36 (m, 2H); 4.07-4.00 (m, 2H); 3.86-3.81 (m, 2H); 3.65 (dd, 1H, J = 7.5; 8.7 Hz); 3.17 (q, 2H, J = 6.0 Hz); 1.84-1.82 (m, 2H); 1.64-1.50 (m, 2H); 1.43 (s, 9H); 1.39-1.34 (m, 2H).
RMN13C (50 MHz, CDCI3): 172,0; 156,6; 155,8; 137,6; 136,5; 128,4; 128,3; 128,0; 127,9; 127,8; 86,9; 80,2; 80,1; 79,0; 73,2; 72,4; 70,7; 66,6; 56,8; 54,3; 40,1; 31,5; 13 C NMR (50 MHz, CDCI 3 ): 172.0; 156.6; 155.8; 137.6; 136.5; 128.4; 128.3; 128.0; 127.9; 127.8; 86.9; 80.2; 80.1; 79.0; 73.2; 72.4; 70.7; 66.6; 56.8; 54.3; 40.1; 31.5;
29,4; 28,2; 22,4.29.4; 28.2; 22.4.
IVv (cm'1) KBr: 3360, 2972, 2937, 2879, 1694, 1659, 1459, 1366, 1254, 1168, 1087, 1015, 908, 749.IVv (cm -1 ) KBr: 3360, 2972, 2937, 2879, 1694, 1659, 1459, 1366, 1254, 1168, 1087, 1015, 908, 749.
PF = 62-63°C aD 20= +23 (c 0,1 CH2CI2). Aspecto: sólido branco.PF = 62-63 ° C to D 20 = +23 (c 0.1 CH 2 CI 2 ). Appearance: white solid.
HRMS calculada para C32H43N3O8Na, 620,2948; Encontrada, 620,2958.HRMS calculated for C 32 H 43 N 3 O8Na, 620.2948; Found, 620.2958.
Exemplo 18: Obtenção do 1,4:3,6-dianidro-5-O-(benzil)-2-N-(Na-f-butoxicarbonilNCj-tosil-L-histidina)-D-glucitol (18)Example 18: Obtaining 1,4: 3,6-dianhydro-5-O- (benzyl) -2-N- (N a -f-butoxycarbonylN Cj -tosyl-L-histidine) -D-glucitol (18)
RMN 1H δ ppm (CDCI3, 300 MHz): 7,93 (s, 1H); 7,81 (d, 2H, J = 8,4 Hz); 7,35-7,29 (m, 7H); 7,08 (s, 1H); 6,77 (br s, 1H); 5,87 (br s, 1H); 4,71 (d, 1H, J = 11,7 Hz); 4,55 (d, 1H, J = 11,7 Hz); 4,46 (t, 1H, J = 4,5 Hz); 4,34-4,23 (m, 3H), 4,04 (q, 1H, J = 6,9 1 H NMR δ ppm (CDCI 3 , 300 MHz): 7.93 (s, 1H); 7.81 (d, 2H, J = 8.4 Hz); 7.35-7.29 (m, 7H); 7.08 (s, 1H); 6.77 (br s, 1H); 5.87 (br s, 1H); 4.71 (d, 1H, J = 11.7 Hz); 4.55 (d, 1H, J = 11.7 Hz); 4.46 (t, 1H, J = 4.5 Hz); 4.34-4.23 (m, 3H), 4.04 (q, 1H, J = 6.9
25/3125/31
Hz); 3,92-3,80 (m, 2H); 3,65-3,59 (m, 2H); 3,04 (dd, 1H, J= 5,1; 14,7 Hz); 2,85 (dd, 1H, J = 6,3; 14,7 Hz); 2,42 (s, 3H); 1,42 (s, 9H).Hz); 3.92-3.80 (m, 2H); 3.65-3.59 (m, 2H); 3.04 (dd, 1H, J = 5.1; 14.7 Hz); 2.85 (dd, 1H, J = 6.3; 14.7 Hz); 2.42 (s, 3H); 1.42 (s, 9H).
RMN13C (50 MHz, CDCI3): 170,8; 155,4; 146,4; 140,4; 137,6; 134,5; 130,4; 128,3; 127,8; 127,3; 114,9; 86,7; 81,7; 80,1; 79,1; 72,9; 72,4; 70,7; 56,6; 53,9; 30,4; 28,2; 13 C NMR (50 MHz, CDCI 3 ): 170.8; 155.4; 146.4; 140.4; 137.6; 134.5; 130.4; 128.3; 127.8; 127.3; 114.9; 86.7; 81.7; 80.1; 79.1; 72.9; 72.4; 70.7; 56.6; 53.9; 30.4; 28.2;
21,6.21.6.
IV v (cm'1) KBr: 3290, 3073, 2974, 2934, 2879, 1661, 1527, 1376, 1300, 1248, 1174, 1088, 814, 744.IV v (cm -1 ) KBr: 3290, 3073, 2974, 2934, 2879, 1661, 1527, 1376, 1300, 1248, 1174, 1088, 814, 744.
PF = 91-93°C ccd2°= +55 (c 0,1 CH2CI2). Aspecto: sólido branco.PF = 91-93 ° C ccd 2 ° = +55 (c 0.1 CH2 Cl2). Appearance: white solid.
HRMS calculada para C3iH38N4O8NaS, 649,2308; Encontrada, 649,2321.HRMS calculated for C 3 iH 38 N4O8NaS, 649.2308; Found, 649.2321.
Exemplo 19: Obtenção do 1,4:3,6-dianidro-5-O-(benzil)-2-N-(N-carbobenziloxivalina-fenilalanina)-D-glucitol (19)Example 19: Obtaining 1,4: 3,6-dianhydro-5-O- (benzyl) -2-N- (N-carbobenzyloxivaline-phenylalanine) -D-glucitol (19)
RMN 1H δ ppm (CDCI3, 300 MHz): 7,33-7,12 (m, 15H); 6,77 (br s, 1H); 5,59-5,57 (m, 1H); 5.12-5,01 (m, 2H); 4,80 (q, 1H, J = 7,8 Hz); 4,65 (dd, 1H, J = 4,5; 12 Hz); 4,454,38 (m, 1H); 4,32-4,27 (m, 2H); 4,01-3,80 (m, 3H); 3,77-3,70 (m, 2H); 3,66-3,57 (m, 1H); 3,10-2,98 (m, 2H); 2,11-1,95 (m, 1H); 0,91 (d, 3H, J = 6,6 Hz); 0,84 (d, 3H, J = 6,6 Hz). 1 H NMR δ ppm (CDCI 3 , 300 MHz): 7.33-7.12 (m, 15H); 6.77 (br s, 1H); 5.59-5.57 (m, 1H); 5.12-5.01 (m, 2H); 4.80 (q, 1H, J = 7.8 Hz); 4.65 (dd, 1H, J = 4.5; 12 Hz); 4,454.38 (m, 1H); 4.32-4.27 (m, 2H); 4.01-3.80 (m, 3H); 3.77-3.70 (m, 2H); 3.66-3.57 (m, 1H); 3.10-2.98 (m, 2H); 2.11 - 1.95 (m, 1H); 0.91 (d, 3H, J = 6.6 Hz); 0.84 (d, 3H, J = 6.6 Hz).
RMN13C (50 MHz, CDCI3): 171,6; 170,5; 156,6; 137,8; 136,3; 136,2; 129,4; 129,3; 128,5; 128,4; 128,3; 128,1; 127,7; 126,9; 126,7; 87,0; 80,3; 78,9; 72,9; 72,2; 70,8; 13 C NMR (50 MHz, CDCI 3 ): 171.6; 170.5; 156.6; 137.8; 136.3; 136.2; 129.4; 129.3; 128.5; 128.4; 128.3; 128.1; 127.7; 126.9; 126.7; 87.0; 80.3; 78.9; 72.9; 72.2; 70.8;
67,1; 60,7; 56,6; 53,7; 39,2; 31,2; 19,3; 18,1.67.1; 60.7; 56.6; 53.7; 39.2; 31.2; 19.3; 18.1.
IV v (cm'1) KBr: 3290, 3066, 2962, 1708, 1646, 1544, 1393, 1241, 1132, 1091, 1023, 914, 741.IV v (cm -1 ) KBr: 3290, 3066, 2962, 1708, 1646, 1544, 1393, 1241, 1132, 1091, 1023, 914, 741.
PF = 81-83°C ocd20= +26 (c 0,1 CH2CI2). Aspecto: sólido branco.PF = 81-83 ° C ocd 20 = +26 (c 0.1 CH 2 CI 2 ). Appearance: white solid.
HRMS calculada para C35H4iN7O7Na, 638,2842; Encontrada, 638,2862.HRMS calculated for C 3 5H4iN 7 O 7 Na, 638.2842; Found, 638.2862.
Exemplo 20: Obtenção do 1,4:3,6-dianidro-5-O-(benzil)-2-N-(N-f-butoxicarbonilL-isoserina)-D-glucitol (20)Example 20: Obtaining 1,4: 3,6-dianhydro-5-O- (benzyl) -2-N- (N-f-butoxycarbonylL-isoserine) -D-glucitol (20)
RMN 1H δ ppm (CDCI3, 300 MHz): 7,36-7,18 (m, 5H); 5,37 (brs, 1H); 5,20 (brs, 1H); 1 H NMR δ ppm (CDCI 3 , 300 MHz): 7.36-7.18 (m, 5H); 5.37 (brs, 1H); 5.20 (brs, 1H);
4,77 (d, 1H, J = 12 Hz); 4,64 (t, 1H, J = 4,5 Hz); 4,53 (d, 1H, J = 12 Hz); 4,43-4,414.77 (d, 1H, J = 12 Hz); 4.64 (t, 1H, J = 4.5 Hz); 4.53 (d, 1H, J = 12 Hz); 4.43-4.41
26/31 (m, 2H); 4,17 (br s, 1H); 4,11-4,02 (m, 2H); 3,88-3,81 (m, 2H); 3,70-3,64 (m, 1H); 3,61-3,44 (m, 2H); 1,74 (brs, 1H); 1,43 (s, 9H).26/31 (m, 2H); 4.17 (br s, 1H); 4.11 - 4.02 (m, 2H); 3.88-3.81 (m, 2H); 3.70-3.64 (m, 1H); 3.61 - 3.44 (m, 2H); 1.74 (brs, 1H); 1.43 (s, 9H).
RMN13C (50 MHz, CDCI3): 171,8; 158,9; 137,6; 128,4; 127,8; 87,0; 80,7; 80,3; 79,0; 73,6; 73,4; 72,4; 70,7; 56,5; 44,7; 28,2. 13 C NMR (50 MHz, CDCl 3): 171.8; 158.9; 137.6; 128.4; 127.8; 87.0; 80.7; 80.3; 79.0; 73.6; 73.4; 72.4; 70.7; 56.5; 44.7; 28.2.
IV v (cm'1) KBr: 3398, 3315, 2975, 2936, 2889, 1708, 1640, 1547, 1515, 1399, 1325, 1256, 1171, 1110, 1043, 882, 731.IV v (cm -1 ) KBr: 3398, 3315, 2975, 2936, 2889, 1708, 1640, 1547, 1515, 1399, 1325, 1256, 1171, 1110, 1043, 882, 731.
PF = 133-134°C ccd20= +4 (c 0,1 CH2CI2). Aspecto: sólido branco.PF = 133-134 ° C ccd 20 = +4 (c 0.1 CH2 Cl2). Appearance: white solid.
HRMS calculada para C2iH3oN207Na, 445,1951; Encontrada, 445,1947.HRMS calculated for C 2 iH 3 oN 2 07Na, 445.1951; Found, 445.1947.
Exemplo 21: Obtenção do 1,4:3,6-dianidro-5-O-(benzil)-2-N-(N-f-butoxicarbonilL-treonina)-D-glucitol (21)Example 21: Obtaining 1,4: 3,6-dianhydro-5-O- (benzyl) -2-N- (N-f-butoxycarbonylL-threonine) -D-glucitol (21)
RMN 1H δ ppm (CDCI3, 300 MHz): 7,35-7,29 (m, 5H); 6,92 (brs, 1H); 5,51 (brs, 1H); 4,73 (d, 1H, J= 12 Hz); 4,63-4,61 (m, 1H); 4,56 (d, 1H, J= 12 Hz); 4,43-4,35 (m, 3H); 1 H NMR δ ppm (CDCl3, 300 MHz): 7.35-7.29 (m, 5H); 6.92 (brs, 1H); 5.51 (brs, 1H); 4.73 (d, 1H, J = 12 Hz); 4.63-4.61 (m, 1H); 4.56 (d, 1H, J = 12 Hz); 4.43-4.35 (m, 3H);
4,08-4,04 (m, 2H); 4,00 (dd, 1H, J= 2,1; 8,1 Hz); 3,88-3,81 (m, 2H); 3,67 (dd, 1H, J =4.08-4.04 (m, 2H); 4.00 (dd, 1H, J = 2.1; 8.1 Hz); 3.88-3.81 (m, 2H); 3.67 (dd, 1H, J =
7,5; 9,0 Hz); 1,46 (s, 9H); 1,17 (d, 3H, J = 6,3 Hz).7.5; 9.0 Hz); 1.46 (s, 9H); 1.17 (d, 3H, J = 6.3 Hz).
RMN13C (50 MHz, CDCI3): 171,2; 156,6; 137,6; 128,4; 127,9; 127,8; 86,9; 80,5; 80,3; 78,9; 73,2; 72,4; 70,5; 66,6; 58,2; 56,9; 28,2; 18,3. 13 C NMR (50 MHz, CDCl 3): 171.2; 156.6; 137.6; 128.4; 127.9; 127.8; 86.9; 80.5; 80.3; 78.9; 73.2; 72.4; 70.5; 66.6; 58.2; 56.9; 28.2; 18.3.
IV v (cm'1) film (CH2CI2): 3944, 3755, 3691, 3056, 2987, 1682, 1604, 1424, 1265,IV v (cm ' 1 ) film (CH 2 CI 2 ): 3944, 3755, 3691, 3056, 2987, 1682, 1604, 1424, 1265,
1159,986,896,742.1159,986,896,742.
ocd20= +6 (c 0,1 CH2CI2). Aspecto: óleo incolor.ocd 20 = +6 (c 0.1 CH 2 CI 2 ). Appearance: colorless oil.
HRMS calculada para C22H32N2O7Na, 459,2107; Encontrada, 459,2085.HRMS calculated for C 22 H3 2 N 2 O7Na, 459.2107; Found, 459.2085.
Exemplo 22: Obtenção do 1,4:3,6-dianidro-5-O-(benzil)-2-N-(Na-f-butoxicarbonil25 Ng.Nco-di-carbobenziloxi-L-argininaj-D-glucitol (22)Example 22: Obtaining 1,4: 3,6-dianhydro-5-O- (benzyl) -2-N- (N a -f-butoxycarbonyl25 Ng.Nco-di-carbobenzyloxy-L-argininej-D-glucitol ( 22)
RMN 1H δ ppm (CDCI3, 300 MHz): 9,42 (br s, 1H); 7,43-7,29 (m, 15H); 6,68 (br s, 1H); 5,64 (brs, 1H); 5,29 (s, 2H); 5,24 (s, 2H); 5,19-5,10 (m, 2H); 4,73 (d, 1H, J = 12 Hz); 4,52 (d, 1H, J = 12 Hz); 4,33-4,20 (m, 3H); 3,96-3,90 (m, 2H); 3,78 (dd, 1H, J = 7,5; 9,0 Hz); 3,63-3,57 (m, 1H); 1,94-1,70 (m, 2H); 1,68-1,58 (m, 4H); 1,43 (s, 9H). 1 H NMR δ ppm (CDCI 3 , 300 MHz): 9.42 (br s, 1H); 7.43-7.29 (m, 15H); 6.68 (br s, 1H); 5.64 (brs, 1H); 5.29 (s, 2H); 5.24 (s, 2H); 5.19-5.10 (m, 2H); 4.73 (d, 1H, J = 12 Hz); 4.52 (d, 1H, J = 12 Hz); 4.33-4.20 (m, 3H); 3.96-3.90 (m, 2H); 3.78 (dd, 1H, J = 7.5; 9.0 Hz); 3.63-3.57 (m, 1H); 1.94-1.70 (m, 2H); 1.68-1.58 (m, 4H); 1.43 (s, 9H).
RMN13C (50 MHz, CDCI3): 171,8; 163,4; 160,7; 155,8; 155,6; 137,7; 136,6; 134,5; 13 C NMR (50 MHz, CDCl 3): 171.8; 163.4; 160.7; 155.8; 155.6; 137.7; 136.6; 134.5;
128,8; 128,7; 128,5; 128,4; 128,3; 127,9; 127,8; 127,7; 86,9; 80,0; 79,9; 78,9; 72,9;128.8; 128.7; 128.5; 128.4; 128.3; 127.9; 127.8; 127.7; 86.9; 80.0; 79.9; 78.9; 72.9;
72,3; 70,4; 68,9; 67,0; 56,9; 49,0; 43,9; 28,4; 25,5; 24,7.72.3; 70.4; 68.9; 67.0; 56.9; 49.0; 43.9; 28.4; 25.5; 24.7.
27/3127/31
IV v (cm'1) KBr: 3387, 3328, 2929, 2857, 1717, 1656, 1615, 1510, 1451, 1376, 1252, 1093, 744.IV v (cm -1 ) KBr: 3387, 3328, 2929, 2857, 1717, 1656, 1615, 1510, 1451, 1376, 1252, 1093, 744.
PF = 81-83°C ccd 20= +34 (c 0,1 CH2CI2). Aspecto: sólido branco.PF = 81-83 ° C cc d 20 = +34 (c 0.1 CH 2 CI 2 ). Appearance: white solid.
HRMS calculada para C^FLgNsOioNa, 782,3377; Encontrada, 782,3405.HRMS calculated for C4 FLgNsOioNa, 782.3377; Found, 782.3405.
Exemplo 23: Obtenção do 1,4:3,6-dianidro-5-O-(benzil)-2-O-(N-f-butoxicarbonilL-prolina)-D-manitol (23)Example 23: Obtaining 1,4: 3,6-dianhydro-5-O- (benzyl) -2-O- (N-f-butoxycarbonylL-proline) -D-mannitol (23)
RMN 1H δ ppm (CDCI3, 300 MHz): 7,30-7,21 (m, 5H); 5,06-4,95 (m, 1H); 4,76-4,68 ío (m, 2H); 4,57 (s, 1H); 4,53-4,46 (m, 1H); 4,39-4,30 (m, 1H); 4,07-3,99 (m, 1H); 3,953,84 (m, 2H); 3,51-3,35 (m, 2H); 2,23-2,19 (m, 2H); 2,04-1,86 (m, 2H); 1,40 (s, 9H). RMN13C (50 MHz, CDCI3): 172,5; 153,7; 137,5; 128,4; 127,9; 80,6; 80,4; 79,9; 78,8; 74,3; 72,5; 70,8; 70,5; 59,0; 46,5; 30,9; 28,3; 24,2. 1 H NMR δ ppm (CDCl3, 300 MHz): 7.30-7.21 (m, 5H); 5.06-4.95 (m, 1H); 4.76-4.68 (m, 2H); 4.57 (s, 1H); 4.53-4.46 (m, 1H); 4.39-4.30 (m, 1H); 4.07-3.99 (m, 1H); 3,953.84 (m, 2H); 3.51-3.35 (m, 2H); 2.23-2.19 (m, 2H); 2.04-1.86 (m, 2H); 1.40 (s, 9H). 13 C NMR (50 MHz, CDCl 3): 172.5; 153.7; 137.5; 128.4; 127.9; 80.6; 80.4; 79.9; 78.8; 74.3; 72.5; 70.8; 70.5; 59.0; 46.5; 30.9; 28.3; 24.2.
IV v (cm'1) filme (CH2CI2): 2974, 2880, 1746, 1697, 1454, 1398, 1261, 1128, 1090, 15 1028,885,819.IV v (cm -1 ) film (CH 2 CI 2 ): 2974, 2880, 1746, 1697, 1454, 1398, 1261, 1128, 1090, 15 1028,885,819.
ccd20= +91 (c, 0.1 DMSO). Aspecto: óleo incolor.ccd 20 = +91 (c, 0.1 DMSO). Appearance: colorless oil.
HRMS calculada para C23H3iNO7Na, 456,1998; Encontrada, 456,2009.HRMS calculated for C 23 H 3 iNO 7 Na, 456.1998; Found, 456,2009.
Exemplo 24: Obtenção do 1,4:3,6-dianidro-5-O-(benzil)-2-O-(N-f-butoxicarbonil20 L-valina)-D-manitol (24)Example 24: Obtaining 1,4: 3,6-dianhydro-5-O- (benzyl) -2-O- (N-f-butoxycarbonyl20 L-valine) -D-mannitol (24)
RMN 1H δ ppm (CDCI3, 300 MHz): 7,40-7,25 (m, 5H); 5,14 (q, 1H, J = 6,0 Hz); 5,014,98 (m, 1H); 4,76-4,68 (m, 2H); 4,58 (s, 1H); 4,49 (t, 1H, J = 4,8 Hz); 4,31-4,26 (m, 1H); 4,13-4,00 (m, 2H); 3,95-3,90 (m, 2H); 3,62 (t, 1H, J= 8,5 Hz); 1,44 (s, 9H); 0,98 (d, 3H, J = 6,9 Hz); 0,90 (d, 3H, J = 6,9 Hz). 1 H NMR δ ppm (CDCI 3 , 300 MHz): 7.40-7.25 (m, 5H); 5.14 (q, 1H, J = 6.0 Hz); 5.014.98 (m, 1H); 4.76-4.68 (m, 2H); 4.58 (s, 1H); 4.49 (t, 1H, J = 4.8 Hz); 4.31 - 4.26 (m, 1H); 4.13-4.00 (m, 2H); 3.95-3.90 (m, 2H); 3.62 (t, 1H, J = 8.5 Hz); 1.44 (s, 9H); 0.98 (d, 3H, J = 6.9 Hz); 0.90 (d, 3H, J = 6.9 Hz).
RMN13C (50 MHz, CDCI3): 171,7; 155,5; 137,5; 128,4; 127,9; 80,5; 80,3; 79,7; 78,7; 74,8; 72,5; 71,0; 70,5; 58,5; 31,2; 28,3; 18,9; 17,4. 13 C NMR (50 MHz, CDCI 3 ): 171.7; 155.5; 137.5; 128.4; 127.9; 80.5; 80.3; 79.7; 78.7; 74.8; 72.5; 71.0; 70.5; 58.5; 31.2; 28.3; 18.9; 17.4.
IV v (cm'1) filme (CH2CI2): 3350, 2970, 2880, 1713, 1502, 1461, 1367, 1251, 1161, 1090, 1023, 866, 740.IV v (cm -1 ) film (CH 2 CI 2 ): 3350, 2970, 2880, 1713, 1502, 1461, 1367, 1251, 1161, 1090, 1023, 866, 740.
ccd20= +107 (c, 0.1 DMSO). Aspecto: óleo incolor.ccd 20 = +107 (c, 0.1 DMSO). Appearance: colorless oil.
HRMS calculada para C23H33NO7Na, 458,2155; Encontrada, 458,2163.HRMS calculated for C 23 H 33 NO 7 Na, 458.2155; Found, 458.2163.
28/3128/31
Exemplo 25: Obtenção do 1,4:3,6-dianidro-5-O-(benzil)-2-O-(N-f-butoxicarbonil0-benzil-L-serina)-D-manitol (25)Example 25: Obtaining 1,4: 3,6-dianhydro-5-O- (benzyl) -2-O- (N-f-butoxycarbonyl0-benzyl-L-serine) -D-mannitol (25)
RMN 1H δ ppm (CDCb, 300 MHz): 7,36-7,27 (m, 10H); 5,43-5,40 (m, 1H); 5,13 (q, 1H, J = 5,7 Hz); 4,74-4,70 (m, 2H); 4,57-4,43 (m, 4H); 4,04-3,88 (m, 5H); 3,86-3,60 (m, 1H); 3,51-3,46 (m, 1H), 1,44 (s, 9H). 1 H NMR δ ppm (CDCb, 300 MHz): 7.36-7.27 (m, 10H); 5.43-5.40 (m, 1H); 5.13 (q, 1H, J = 5.7 Hz); 4.74-4.70 (m, 2H); 4.57-4.43 (m, 4H); 4.04-3.88 (m, 5H); 3.86-3.60 (m, 1H); 3.51-3.46 (m, 1H), 1.44 (s, 9H).
RMN13C (50 MHz, CDCb): 170,1; 155,3; 137,5; 137,4; 128,4; 128,3; 127,9; 127,8; 127,7; 127,6; 80,5; 80,3; 79,9; 78,7; 75,1; 73,2; 72,5; 71,0; 70,4; 69,8; 53,9; 28,3. 13 C NMR (50 MHz, CDCb): 170.1; 155.3; 137.5; 137.4; 128.4; 128.3; 127.9; 127.8; 127.7; 127.6; 80.5; 80.3; 79.9; 78.7; 75.1; 73.2; 72.5; 71.0; 70.4; 69.8; 53.9; 28.3.
IV v (cm'1) filme (CH2CI2): 3328, 2974, 2928, 2876, 1749, 1713, 1499, 1363, 1245, 1166, 1098, 1028, 859, 742.IV v (cm -1 ) film (CH 2 CI 2 ): 3328, 2974, 2928, 2876, 1749, 1713, 1499, 1363, 1245, 1166, 1098, 1028, 859, 742.
ccd20= +92 (c, 0.1 DMSO). Aspecto: óleo incolor.ccd 20 = +92 (c, 0.1 DMSO). Appearance: colorless oil.
HRMS calculada para C28H35NO8Na, 536,2260; Encontrada, 536,2278.HRMS calculated for C 2 8H 35 NO8Na, 536.2260; Found, 536.2278.
Exemplo 26: Obtenção do 1,4:3,6-dianidro-5-O-(benzil)-2-O-(N-í-butoxicarbonilL-metionina)-D-manitol (26)Example 26: Obtaining 1,4: 3,6-dianhydro-5-O- (benzyl) -2-O- (N-i-butoxycarbonylL-methionine) -D-mannitol (26)
RMN 1H δ ppm (CDCb, 300 MHz): 7,36-7,32 (m, 5H); 5,13 (q, 2H, J = 5,7 Hz); 4,764,69 (m, 2H); 4,59 (s, 1H); 4,49-4,46 (m, 1H); 4,07-4,04 (m, 3H); 3,95-3,90 (m, 1H); 3,60 (t, 1H, J = 8,5 Hz); 2,57-2,51 (m, 2H); 2,10-2,05 (m, 2H); 2,08 (s, 3H); 1,44 (s, 9H). 1 H NMR δ ppm (CDCb, 300 MHz): 7.36-7.32 (m, 5H); 5.13 (q, 2H, J = 5.7 Hz); 4,764.69 (m, 2H); 4.59 (s, 1H); 4.49-4.46 (m, 1H); 4.07-4.04 (m, 3H); 3.95-3.90 (m, 1H); 3.60 (t, 1H, J = 8.5 Hz); 2.57-2.51 (m, 2H); 2.10-2.05 (m, 2H); 2.08 (s, 3H); 1.44 (s, 9H).
RMN13C (50 MHz, CDCb): 171,5; 155,1; 137,4; 128,4; 127,9; 127,8; 80,5; 80,3; 79,9; 13 C NMR (50 MHz, CDCb): 171.5; 155.1; 137.4; 128.4; 127.9; 127.8; 80.5; 80.3; 79.9;
78,6; 75,0; 72,5; 71,1; 70,4; 52,8; 32,0; 29,7; 28,2; 15,4.78.6; 75.0; 72.5; 71.1; 70.4; 52.8; 32.0; 29.7; 28.2; 15.4.
IV v (cm'1) filme (CH2CI2): 3339, 2974, 2923, 2876, 1710, 1509, 1450, 1366, 1253IV v (cm ' 1 ) film (CH 2 CI 2 ): 3339, 2974, 2923, 2876, 1710, 1509, 1450, 1366, 1253
1166, 1069, 1028, 864, 743.1166, 1069, 1028, 864, 743.
ccd20= +116 (c 0,1 CH2CI2). Aspecto: óleo incolor.ccd 20 = +116 (c 0.1 CH 2 CI 2 ). Appearance: colorless oil.
HRMS calculada para C22H33NO7NaS, 490,1875; Encontrada, 490,1895.HRMS calculated for C 22 H 33 NO 7 NaS, 490.1875; Found, 490.1895.
Exemplo 27: Obtenção do 1,4:3,6-dianidro-5-O-(benzil)-2-O-(N-f-butoxicarbonil L-triptofano)-D-manitol (27)Example 27: Obtaining 1,4: 3,6-dianhydro-5-O- (benzyl) -2-O- (N-f-butoxycarbonyl L-tryptophan) -D-mannitol (27)
RMN 1H δ ppm (CDCb, 300 MHz): 7,56 (d, 1H); 7,35-7,25 (m, 7H); 7,17-7,02 (m 2H); 4,99 (q, 1H, J = 5,7 Hz); 4,75-4,46 (m, 5H); 4,13-4,01 (m, 1H); 3,90-3,85 (m 2H); 3,80-3,67 (m, 1H); 3,58 (t, 1H, J = 8,4 Hz); 3,31-3,90 (m, 2H); 1,42 (s, 9H). 1 H NMR δ ppm (CDCb, 300 MHz): 7.56 (d, 1H); 7.35-7.25 (m, 7H); 7.17-7.02 (m 2H); 4.99 (q, 1H, J = 5.7 Hz); 4.75-4.46 (m, 5H); 4.13-4.01 (m, 1H); 3.90-3.85 (m 2H); 3.80-3.67 (m, 1H); 3.58 (t, 1H, J = 8.4 Hz); 3.31 - 3.90 (m, 2H); 1.42 (s, 9H).
29/3129/31
RMN13C (50 MHz, CDCIs): 171,7; 155,0; 137,5; 135,9; 128,4; 127,9; 127,6; 127,5; 122,9; 121,9; 119,4; 118,6; 111,1; 110,0; 81,7; 80,6; 80,5; 80,2; 79,7; 78,6; 74,9; 13 C NMR (50 MHz, CDCIs): 171.7; 155.0; 137.5; 135.9; 128.4; 127.9; 127.6; 127.5; 122.9; 121.9; 119.4; 118.6; 111.1; 110.0; 81.7; 80.6; 80.5; 80.2; 79.7; 78.6; 74.9;
72,5; 60,3; 54,3; 28,2.72.5; 60.3; 54.3; 28.2.
IV v (cm'1) filme (CH2CI2): 3344, 2974, 2933, 2876, 1740, 1706, 1500, 1455, 1366,IV v (cm ' 1 ) film (CH 2 CI 2 ): 3344, 2974, 2933, 2876, 1740, 1706, 1500, 1455, 1366,
1247, 1166, 1068, 1023, 858, 743.1247, 1166, 1068, 1023, 858, 743.
ocd20= +114 (c 0,1 CH2CI2). Aspecto: óleo incolor.ocd 20 = +114 (c 0.1 CH 2 CI 2 ). Appearance: colorless oil.
HRMS calculada para C29H34N2O7Na, 545,2264; Encontrada, 545,2283.HRMS calculated for C 2 9H 3 4N 2 O7Na, 545.2264; Found, 545.2283.
íoio
Exemplo 28: Obtenção do 1,4:3,6-dianidro-5-O-(benzil)-2-O-(N-carbobenziloxiprolina-fenilalanina)-D-manitol (28)Example 28: Obtaining 1,4: 3,6-dianhydro-5-O- (benzyl) -2-O- (N-carbobenzyloxyproline-phenylalanine) -D-mannitol (28)
RMN 1H δ ppm (CDCI3, 300 MHz): 7,40-7,00 (m, 15H); 5,12-5,09 (m, 2H); 4,90 (q, 1H, J = 7,2 Hz); 4,75-4,72 (m, 2H); 4,54-4,46 (m, 2H); 4,35-4,29 (m, 1H); 4,07-3,90 (m, 4H); 3,70-3,60 (m, 1H); 3,49-3,38 (m, 3H); 3,20-3,02 (m, 2H); 1,90-1,65 (m, 4H). RMN13C (50 MHz, CDCI3): 171,0; 170,7; 155,9; 137,4; 136,3; 135,9; 129,2; 128,4; 127,8; 126,9; 126,8; 80,3; 80,1; 78,6; 74,9; 72,4; 70,9; 70,7; 70,4; 67,2; 60,1; 53,0; 1 H NMR δ ppm (CDCl3, 300 MHz): 7.40-7.00 (m, 15H); 5.12-5.09 (m, 2H); 4.90 (q, 1H, J = 7.2 Hz); 4.75-4.72 (m, 2H); 4.54-4.46 (m, 2H); 4.35-4.29 (m, 1H); 4.07-3.90 (m, 4H); 3.70-3.60 (m, 1H); 3.49-3.38 (m, 3H); 3.20-3.02 (m, 2H); 1.90-1.65 (m, 4H). 13 C NMR (50 MHz, CDCl 3): 171.0; 170.7; 155.9; 137.4; 136.3; 135.9; 129.2; 128.4; 127.8; 126.9; 126.8; 80.3; 80.1; 78.6; 74.9; 72.4; 70.9; 70.7; 70.4; 67.2; 60.1; 53.0;
46,7; 37,7; 27,7; 23,3.46.7; 37.7; 27.7; 23.3.
IV v (cm'1) filme (CH2CI2): 3413, 3316, 3060, 2952, 2881, 1744, 1694, 1524, 1448, 1416, 1355, 1200, 1122, 1029, 918, 738. ccd20= +53 (c 0,1 CH2CI2). Aspecto: óleo incolor.IV v (cm ' 1 ) film (CH2 Cl2): 3413, 3316, 3060, 2952, 2881, 1744, 1694, 1524, 1448, 1416, 1355, 1200, 1122, 1029, 918, 738. ccd 20 = +53 ( and 0.1 CH 2 Cl 2 ). Appearance: colorless oil.
HRMS calculada para C35H38N2O8Na, 637,2526; Encontrada, 637,2542.HRMS calculated for C 35 H 3 8N 2 O8Na, 637.2526; Found, 637.2542.
Exemplo 29: Obtenção do 1,4:3,6-dianidro-5-O-(benzil)-2-O-(N-carbobenziloxiD-prolina)-D-manitol (29)Example 29: Obtaining 1,4: 3,6-dianhydro-5-O- (benzyl) -2-O- (N-carbobenzyloxyD-proline) -D-mannitol (29)
RMN 1H δ ppm (CDCI3, 300 MHz): 7,36-7,29 (m, 10H); 5,18-5,07 (m, 1H); 4,98 (q, 1H, J= 5,7 Hz); 4,79-4,64 (m, 2H); 4,54 (dd, 1H, J= 2,4; 11,7 Hz); 4,49-4,42 (m, 1H); 4,38 (dd, 1H, J = 3,9; 8,4 Hz); 4,06-3,89 (m, 2H); 3,88-3,80 (m, 2H); 3,70-3,45 (m, 4H); 2,19-1,96 (m, 2H); 1,94-1,68 (m, 2H). 1 H NMR δ ppm (CDCI 3 , 300 MHz): 7.36-7.29 (m, 10H); 5.18-5.07 (m, 1H); 4.98 (q, 1H, J = 5.7 Hz); 4.79-4.64 (m, 2H); 4.54 (dd, 1H, J = 2.4; 11.7 Hz); 4.49-4.42 (m, 1H); 4.38 (dd, 1H, J = 3.9; 8.4 Hz); 4.06-3.89 (m, 2H); 3.88-3.80 (m, 2H); 3.70-3.45 (m, 4H); 2.19-1.96 (m, 2H); 1.94-1.68 (m, 2H).
RMN13C (50 MHz, CDCI3): 172,3; 160,1; 137,5; 136,6 128,5; 138,4; 128,3; 127,9; 127,8; 127,7; 80,6; 80,2; 78,6; 74,5; 72,5; 71,4; 70,1; 66,9; 58,8; 46,4; 30,8; 23,4. 13 C NMR (50 MHz, CDCI 3 ): 172.3; 160.1; 137.5; 136.6 128.5; 138.4; 128.3; 127.9; 127.8; 127.7; 80.6; 80.2; 78.6; 74.5; 72.5; 71.4; 70.1; 66.9; 58.8; 46.4; 30.8; 23.4.
IV v (cm'1) (KBr): 3405, 2964, 2869, 1739, 1708, 1465, 1411, 1351, 1197, 1124, 1071, 880, 746.IV v (cm -1 ) (KBr): 3405, 2964, 2869, 1739, 1708, 1465, 1411, 1351, 1197, 1124, 1071, 880, 746.
Pf = 71-72°C.Mp = 71-72 ° C.
aD 20= + 158 (c 0,1 CH2CI2). Aspecto: sólido branco.a D 20 = + 158 (c 0.1 CH 2 CI 2 ). Appearance: white solid.
31/3131/31
RMN 1Η δ ppm (CDCI3, 300 MHz): 7,36-7,31 (m, 10H); 5,51 (d, 1H, J=8,1 Hz); 5,115,06 (m, 3H); 4,75 (d, 1H, J = 12 Hz); 4,70-4,61 (m, 2H); 4,57 (d, 1H, J = 11,7 Hz); 4,53 (t, 1H, J = 4,8 Hz); 4,05-3,99 (m, 1H); 3,93-3,81 (m, 3H); 3,56 (t, 1H, J = 8,4 Hz); 3,02 (dd, 1H, J = 4,5; 17 Hz); 2,93 (dd, 1H, J = 4,5; 17 Hz); 1,43 (s, 9H).NMR 1 δ δ ppm (CDCI 3 , 300 MHz): 7.36-7.31 (m, 10H); 5.51 (d, 1H, J = 8.1 Hz); 5,115.06 (m, 3H); 4.75 (d, 1H, J = 12 Hz); 4.70-4.61 (m, 2H); 4.57 (d, 1H, J = 11.7 Hz); 4.53 (t, 1H, J = 4.8 Hz); 4.05-3.99 (m, 1H); 3.93-3.81 (m, 3H); 3.56 (t, 1H, J = 8.4 Hz); 3.02 (dd, 1H, J = 4.5; 17 Hz); 2.93 (dd, 1H, J = 4.5; 17 Hz); 1.43 (s, 9H).
RMN13C (50 MHz, CDCI3): 170,0; 170,4; 155,2; 137,5; 135,4; 128,5; 128,4; 128,3; 128,2; 127,9; 127,8; 80,5; 80,2; 80,0; 78,6; 75,2; 72,5; 70,9; 70,3; 66,7; 49,8; 36,7; 13 C NMR (50 MHz, CDCI 3 ): 170.0; 170.4; 155.2; 137.5; 135.4; 128.5; 128.4; 128.3; 128.2; 127.9; 127.8; 80.5; 80.2; 80.0; 78.6; 75.2; 72.5; 70.9; 70.3; 66.7; 49.8; 36.7;
28,2.28.2.
IV v (cm'1) filme (CH2CI2): 3361, 2975, 2881, 1732, 1501, 1457, 1362, 1212, 1158, 1089, 1065, 1028, 859, 744. ccd20= (c,). Aspecto: óleo incolor.IV v (cm ' 1 ) film (CH 2 CI 2 ): 3361, 2975, 2881, 1732, 1501, 1457, 1362, 1212, 1158, 1089, 1065, 1028, 859, 744. ccd 20 = (c,) . Appearance: colorless oil.
HRMS calculada para C29H35NO7Na, 564,2210; Encontrada, 564,2190.HRMS calculated for C 2 9H 35 NO 7 Na, 564.2210; Found, 564.2190.
A descrição acima da presente invenção bem como os exemplos que foram apresentados atua com o propósito de ilustração e não limitam a invenção à forma aqui revelada e exemplificada. Em conseqüência; variações e modificações compatíveis com os ensinamentos acima; e a habilidade ou conhecimento da técnica relevante; estão dentro do escopo da presente invenção. As modalidades acima descritas e exemplificadas têm a intenção de melhor explicar os modos conhecidos para a prática da invenção e para permitir que os técnicos na área utilizem a invenção em tais; ou outras; modalidades e com várias modificações necessárias pelas aplicações específicas ou usos da presente invenção. É a intenção que a presente invenção inclua todas as modificações e variações da mesma; dentro do escopo descrito no relatório e nas reivindicações anexas.The above description of the present invention as well as the examples that have been presented acts for the purpose of illustration and does not limit the invention to the form disclosed and exemplified herein. In consequence; variations and modifications compatible with the above teachings; and the skill or knowledge of the relevant technique; are within the scope of the present invention. The above described and exemplified modalities are intended to better explain the known methods for practicing the invention and to allow those skilled in the art to use the invention in such; or others; modalities and with several modifications necessary for the specific applications or uses of the present invention. It is the intention that the present invention includes all modifications and variations thereof; within the scope described in the report and the appended claims.
Claims (6)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BRPI1000099-2A BRPI1000099B1 (en) | 2010-01-27 | 2010-01-27 | POTENTIALLY ACTIVE MIMETIC PEPTIDE COMPOUNDS AGAINST HEPATITIS C VIRUSES AND PHARMACEUTICAL COMPOSITION CONTAINING SUCH COMPOUNDS |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BRPI1000099-2A BRPI1000099B1 (en) | 2010-01-27 | 2010-01-27 | POTENTIALLY ACTIVE MIMETIC PEPTIDE COMPOUNDS AGAINST HEPATITIS C VIRUSES AND PHARMACEUTICAL COMPOSITION CONTAINING SUCH COMPOUNDS |
Publications (2)
Publication Number | Publication Date |
---|---|
BRPI1000099A2 BRPI1000099A2 (en) | 2011-09-27 |
BRPI1000099B1 true BRPI1000099B1 (en) | 2018-06-12 |
Family
ID=44653749
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
BRPI1000099-2A BRPI1000099B1 (en) | 2010-01-27 | 2010-01-27 | POTENTIALLY ACTIVE MIMETIC PEPTIDE COMPOUNDS AGAINST HEPATITIS C VIRUSES AND PHARMACEUTICAL COMPOSITION CONTAINING SUCH COMPOUNDS |
Country Status (1)
Country | Link |
---|---|
BR (1) | BRPI1000099B1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102822175A (en) | 2009-12-18 | 2012-12-12 | 埃迪尼克斯医药公司 | 5,5-fused arylene or heteroarylene hepatitis C virus inhibitors |
US9540391B2 (en) | 2013-01-17 | 2017-01-10 | Sanofi | Isomannide derivatives as inhibitors of soluble epoxide hydrolase |
-
2010
- 2010-01-27 BR BRPI1000099-2A patent/BRPI1000099B1/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
BRPI1000099A2 (en) | 2011-09-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2010330862B2 (en) | 5,5-fused arylene or heteroarylene hepatitis C virus inhibitors | |
AU2009210789B2 (en) | Macrocyclic serine protease inhibitors | |
EP2812331B1 (en) | Piperidino-pyrimidine derivatives for the treatment of viral infections | |
ES2726998T3 (en) | Modified fluorinated nucleoside analogs | |
AU2020203892A1 (en) | Methods for treating Filoviridae virus infections | |
CA2799501C (en) | Oligonucleotide analogues having modified intersubunit linkages and/or terminal groups | |
EP2461811B1 (en) | Macrocyclic serine protease inhibitors useful against viral infections, particularly hcv | |
EP2417134B1 (en) | Macrocyclic serine protease inhibitors | |
ES2357076T3 (en) | COMPOUNDS FOR THE TREATMENT OF HEPATITIS C. | |
Shao et al. | Design, synthesis, and evaluation of trifluoromethyl ketones as inhibitors of SARS-CoV 3CL protease | |
AU6213899A (en) | Antiviral purine derivatives | |
AU2012236377A1 (en) | Methods for treating drug-resistant hepatitis C virus infection with a 5,5-fused arylene or heteroarylene hepatitis C virus inhibitor | |
AU2011367230A1 (en) | Peptide oligonucleotide conjugates | |
BR112020008762A2 (en) | innovative highly active substituted indole-2-carboxamides amino-thiazole active against hepatitis b virus (hbv) | |
WO2015042375A1 (en) | Hepatitis c virus inhibitors | |
BRPI1000099B1 (en) | POTENTIALLY ACTIVE MIMETIC PEPTIDE COMPOUNDS AGAINST HEPATITIS C VIRUSES AND PHARMACEUTICAL COMPOSITION CONTAINING SUCH COMPOUNDS | |
WO2022008025A1 (en) | 2-hydroxyiminopyrimidine nucleosides and derivitives and antiviral uses thereto | |
ES2416062T3 (en) | Indolobenzadiazepine HCV NS5B inhibitors fused to pyrrolidine | |
BR102012020638A2 (en) | MIMETIC PEPTIDE COMPOUNDS DERIVED FROM TARTARIC ACID POTENTIALLY ACTIVE AGAINST HEPATITIS C VIRUS AND PHARMACEUTICAL COMPOSITION CONTAINING SUCH COMPOUNDS | |
RU2807057C2 (en) | Method for preparing a thio derivative of pyrrolidine-2,5-dione with a quinazoline fragment | |
BRPI0902520A2 (en) | serine protease inhibiting pseudopeptide compounds, serine protease inhibiting compositions and pharmaceutical compositions containing such compounds | |
JP2023528456A (en) | Spirolactam compounds and methods of treating viral infections | |
CN109846883A (en) | Benzofuran derivatives and TMC435 combination medicine | |
CN106138080A (en) | Nucleoside compound catches the application of medicine in preparation treatment hepatitis C virus (HCV) | |
CN105985356A (en) | Imidazole [2, 1-b] thiazole derivative as well as preparation method and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
B03A | Publication of a patent application or of a certificate of addition of invention [chapter 3.1 patent gazette] | ||
B65X | Notification of requirement for priority examination of patent application | ||
B65Y | Grant of priority examination of the patent application (request complies with dec. 132/06 of 20061117) | ||
B07D | Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette] | ||
B07E | Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette] |
Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
|
B08F | Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette] |
Free format text: REFERENTE A 6A ANUIDADE. |
|
B08G | Application fees: restoration [chapter 8.7 patent gazette] | ||
B08F | Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette] | ||
B08G | Application fees: restoration [chapter 8.7 patent gazette] | ||
B06A | Patent application procedure suspended [chapter 6.1 patent gazette] | ||
B09A | Decision: intention to grant [chapter 9.1 patent gazette] | ||
B16A | Patent or certificate of addition of invention granted [chapter 16.1 patent gazette] | ||
B21F | Lapse acc. art. 78, item iv - on non-payment of the annual fees in time |
Free format text: REFERENTE A 14A ANUIDADE. |
|
B24D | Patent annual fee: restoration after fee payment |