CA2842838C - 9-aminomethyl substituted tetracycline compounds - Google Patents
9-aminomethyl substituted tetracycline compounds Download PDFInfo
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- CA2842838C CA2842838C CA2842838A CA2842838A CA2842838C CA 2842838 C CA2842838 C CA 2842838C CA 2842838 A CA2842838 A CA 2842838A CA 2842838 A CA2842838 A CA 2842838A CA 2842838 C CA2842838 C CA 2842838C
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- 6alkyl
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- -1 tetracycline compounds Chemical class 0.000 title abstract description 101
- 239000004098 Tetracycline Substances 0.000 title abstract description 17
- 235000019364 tetracycline Nutrition 0.000 title abstract description 16
- 229960002180 tetracycline Drugs 0.000 title abstract description 13
- 229930101283 tetracycline Natural products 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 189
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 239000012453 solvate Substances 0.000 claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 46
- 239000001257 hydrogen Substances 0.000 claims description 44
- 229920006395 saturated elastomer Polymers 0.000 claims description 37
- 229910052757 nitrogen Inorganic materials 0.000 claims description 28
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 125000002393 azetidinyl group Chemical group 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 208000015181 infectious disease Diseases 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 3
- 125000005843 halogen group Chemical group 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 36
- 239000003814 drug Substances 0.000 abstract description 18
- 238000000034 method Methods 0.000 abstract description 13
- 150000003522 tetracyclines Chemical class 0.000 abstract description 9
- 238000011282 treatment Methods 0.000 abstract description 6
- 229940040944 tetracyclines Drugs 0.000 abstract description 4
- 230000006806 disease prevention Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 84
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 61
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 54
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 53
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- 238000006243 chemical reaction Methods 0.000 description 33
- 239000000203 mixture Substances 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 239000007787 solid Substances 0.000 description 31
- 125000004429 atom Chemical group 0.000 description 29
- SOVUOXKZCCAWOJ-HJYUBDRYSA-N (4s,4as,5ar,12ar)-9-[[2-(tert-butylamino)acetyl]amino]-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=C(NC(=O)CNC(C)(C)C)C(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O SOVUOXKZCCAWOJ-HJYUBDRYSA-N 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 229940126062 Compound A Drugs 0.000 description 22
- 230000000844 anti-bacterial effect Effects 0.000 description 21
- 229960004089 tigecycline Drugs 0.000 description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
- 238000012360 testing method Methods 0.000 description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- 239000003208 petroleum Substances 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 229940079593 drug Drugs 0.000 description 16
- 229910002091 carbon monoxide Inorganic materials 0.000 description 15
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Substances CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- 150000002367 halogens Chemical group 0.000 description 14
- 150000002431 hydrogen Chemical group 0.000 description 14
- 239000005457 ice water Substances 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 14
- 241000894006 Bacteria Species 0.000 description 13
- PSCMQHVBLHHWTO-UHFFFAOYSA-K indium(iii) chloride Chemical compound Cl[In](Cl)Cl PSCMQHVBLHHWTO-UHFFFAOYSA-K 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- 238000004809 thin layer chromatography Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 12
- 238000010241 blood sampling Methods 0.000 description 12
- 229940125833 compound 23 Drugs 0.000 description 12
- 238000004237 preparative chromatography Methods 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- JEECQCWWSTZDCK-IQZGDKDPSA-N omadacycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=C(CNCC(C)(C)C)C(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O JEECQCWWSTZDCK-IQZGDKDPSA-N 0.000 description 11
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 11
- 229910052717 sulfur Inorganic materials 0.000 description 11
- 210000000689 upper leg Anatomy 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 241000700159 Rattus Species 0.000 description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 9
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 125000000753 cycloalkyl group Chemical group 0.000 description 9
- 125000000623 heterocyclic group Chemical group 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 229940125782 compound 2 Drugs 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 8
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- BMSQWGFRHCENRR-UHFFFAOYSA-N 4-azaspiro[2.4]heptane;2,2,2-trifluoroacetic acid Chemical compound C1CC11NCCC1.OC(=O)C(F)(F)F BMSQWGFRHCENRR-UHFFFAOYSA-N 0.000 description 7
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 7
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 239000002274 desiccant Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 239000012086 standard solution Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 229940125810 compound 20 Drugs 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)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)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 6
- 244000052769 pathogen Species 0.000 description 6
- 230000036470 plasma concentration Effects 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 229940072172 tetracycline antibiotic Drugs 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 241000191967 Staphylococcus aureus Species 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- 229940126214 compound 3 Drugs 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- ZYTYWJHGVSRYNU-UHFFFAOYSA-N (3-methylidenecyclobutyl)methanamine Chemical compound NCC1CC(=C)C1 ZYTYWJHGVSRYNU-UHFFFAOYSA-N 0.000 description 4
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 4
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 4
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 4
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 4
- MMAJXKGUZYDTHV-UHFFFAOYSA-N 1-benzhydrylazetidin-3-ol Chemical compound C1C(O)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 MMAJXKGUZYDTHV-UHFFFAOYSA-N 0.000 description 4
- PXFUWRWCKSLCLS-UHFFFAOYSA-N 3-fluoroazetidine;hydron;chloride Chemical compound Cl.FC1CNC1 PXFUWRWCKSLCLS-UHFFFAOYSA-N 0.000 description 4
- PCYZDTILOPUMBA-UHFFFAOYSA-N 4-methylidenecyclohexane-1-carboxamide Chemical compound NC(=O)C1CCC(=C)CC1 PCYZDTILOPUMBA-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 4
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 description 4
- 229960001667 alogliptin Drugs 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- AJAGMFCWJWROHI-UHFFFAOYSA-N benzyl n-(spiro[2.5]octan-6-ylmethyl)carbamate Chemical compound C=1C=CC=CC=1COC(=O)NCC(CC1)CCC21CC2 AJAGMFCWJWROHI-UHFFFAOYSA-N 0.000 description 4
- IGDGPICWQHOKSY-UHFFFAOYSA-N benzyl n-[(2-oxospiro[3.3]heptan-6-yl)methyl]carbamate Chemical compound C=1C=CC=CC=1COC(=O)NCC(C1)CC21CC(=O)C2 IGDGPICWQHOKSY-UHFFFAOYSA-N 0.000 description 4
- UESKTWIDKNXQFE-UHFFFAOYSA-N benzyl n-[(3-methylidenecyclobutyl)methyl]carbamate Chemical compound C1C(=C)CC1CNC(=O)OCC1=CC=CC=C1 UESKTWIDKNXQFE-UHFFFAOYSA-N 0.000 description 4
- BLXAWWJAHRZFPX-UHFFFAOYSA-N benzyl n-[(4-methylidenecyclohexyl)methyl]carbamate Chemical compound C1CC(=C)CCC1CNC(=O)OCC1=CC=CC=C1 BLXAWWJAHRZFPX-UHFFFAOYSA-N 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- 229940125773 compound 10 Drugs 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000000945 filler Substances 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 4
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 125000000168 pyrrolyl group Chemical group 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- OHYFIZIPLBFBCM-UHFFFAOYSA-N spiro[2.3]hexan-5-amine;2,2,2-trifluoroacetic acid Chemical compound C1C(N)CC11CC1.OC(=O)C(F)(F)F OHYFIZIPLBFBCM-UHFFFAOYSA-N 0.000 description 4
- COQGAGRRZZQWTI-UHFFFAOYSA-N spiro[2.5]octan-6-ylmethanamine;hydrochloride Chemical compound Cl.C1CC(CN)CCC11CC1 COQGAGRRZZQWTI-UHFFFAOYSA-N 0.000 description 4
- IYNOQFFDELCIEP-UHFFFAOYSA-N spiro[3.3]heptan-2-ylmethanamine Chemical compound C1C(CN)CC11CCC1 IYNOQFFDELCIEP-UHFFFAOYSA-N 0.000 description 4
- UKVCZCZNTKQCCW-UHFFFAOYSA-N tert-butyl n-(3-methylidenecyclobutyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CC(=C)C1 UKVCZCZNTKQCCW-UHFFFAOYSA-N 0.000 description 4
- RORBKRGGCPRUPV-UHFFFAOYSA-N tert-butyl n-(4-methylidenecyclohexyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CCC(=C)CC1 RORBKRGGCPRUPV-UHFFFAOYSA-N 0.000 description 4
- VNRBABCQWLWVGU-UHFFFAOYSA-N tert-butyl n-spiro[2.3]hexan-5-ylcarbamate Chemical compound C1C(NC(=O)OC(C)(C)C)CC11CC1 VNRBABCQWLWVGU-UHFFFAOYSA-N 0.000 description 4
- VULFXNPHEOFQMP-UHFFFAOYSA-N tert-butyl n-spiro[2.5]octan-6-ylcarbamate Chemical compound C1CC(NC(=O)OC(C)(C)C)CCC11CC1 VULFXNPHEOFQMP-UHFFFAOYSA-N 0.000 description 4
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- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
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- SRILPABKELGUEB-UHFFFAOYSA-N spiro[2.5]octan-6-amine;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1CC(N)CCC11CC1 SRILPABKELGUEB-UHFFFAOYSA-N 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QIYOMZXJQAKHEK-UHFFFAOYSA-N tert-butyl n-(3-azabicyclo[3.1.0]hexan-6-yl)carbamate Chemical compound C1NCC2C(NC(=O)OC(C)(C)C)C21 QIYOMZXJQAKHEK-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 1
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- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 1
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- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
- C07C237/26—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/65—Tetracyclines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
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- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/66—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems and singly-bound oxygen atoms, bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/12—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/54—Spiro-condensed
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/20—Spiro-condensed ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D305/06—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
- C07C2602/40—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing six carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
- C07C2603/42—Ortho- or ortho- and peri-condensed systems containing four condensed rings containing only six-membered rings
- C07C2603/44—Naphthacenes; Hydrogenated naphthacenes
- C07C2603/46—1,4,4a,5,5a,6,11,12a- Octahydronaphthacenes, e.g. tetracyclines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/93—Spiro compounds
- C07C2603/94—Spiro compounds containing "free" spiro atoms
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Applications Claiming Priority (3)
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CN201110222016 | 2011-07-26 | ||
CN201110222016.3 | 2011-07-26 | ||
PCT/CN2012/001001 WO2013013505A1 (zh) | 2011-07-26 | 2012-07-26 | 9-氨基甲基取代的四环素类化合物 |
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CA2842838A1 CA2842838A1 (en) | 2013-01-31 |
CA2842838C true CA2842838C (en) | 2017-04-25 |
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CA2842838A Active CA2842838C (en) | 2011-07-26 | 2012-07-26 | 9-aminomethyl substituted tetracycline compounds |
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US8193182B2 (en) | 2008-01-04 | 2012-06-05 | Intellikine, Inc. | Substituted isoquinolin-1(2H)-ones, and methods of use thereof |
KR101897881B1 (ko) | 2008-01-04 | 2018-09-12 | 인텔리카인, 엘엘씨 | 특정 화학 물질, 조성물 및 방법 |
PH12013501465A1 (en) | 2011-01-10 | 2013-09-09 | Infinity Pharmaceuticals Inc | Processes for preparing isoquinolinones and solid forms of isoquinolinones |
NO2738156T3 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) | 2011-07-26 | 2018-06-02 | ||
US8828998B2 (en) | 2012-06-25 | 2014-09-09 | Infinity Pharmaceuticals, Inc. | Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors |
IL291945B1 (en) | 2012-11-01 | 2025-07-01 | Infinity Pharmaceuticals Inc | Treatment of cancers using pi3 kinase isoform modulators |
CN103073481A (zh) * | 2013-02-06 | 2013-05-01 | 上海药明康德新药开发有限公司 | 一种4-氮杂螺[2.4]庚烷盐酸盐的制备方法 |
US9580758B2 (en) | 2013-11-12 | 2017-02-28 | Luc Montagnier | System and method for the detection and treatment of infection by a microbial agent associated with HIV infection |
US20150320755A1 (en) | 2014-04-16 | 2015-11-12 | Infinity Pharmaceuticals, Inc. | Combination therapies |
CN105384673B (zh) * | 2015-11-09 | 2017-11-14 | 南京富润凯德生物医药有限公司 | 3‑氟代‑氮杂环丁烷衍生物的合成方法 |
EP3476831B8 (en) * | 2016-06-22 | 2021-12-29 | Kbp Biosciences Pte. Ltd. | Crystal form of 9-aminomethyl substituted tetracycline compounds and preparation method therefor |
CN109640999A (zh) | 2016-06-24 | 2019-04-16 | 无限药品股份有限公司 | 组合疗法 |
CN106883138B (zh) * | 2017-03-01 | 2018-07-10 | 郑州大学第一附属医院 | 老虎素的制备方法 |
WO2019192614A1 (en) * | 2018-04-06 | 2019-10-10 | Paratek Pharmaceuticals, Inc. | Process for making sarecycline hydrochloride |
CN113164456A (zh) | 2018-09-04 | 2021-07-23 | 帕拉特克药品公司 | 使用四环素化合物治疗分枝杆菌感染的方法 |
CN115057775A (zh) * | 2022-07-22 | 2022-09-16 | 临海市建新化工有限公司 | 一种2,2-二甲基丙二酸二甲酯的制备方法 |
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SI1301467T1 (sl) * | 2000-07-07 | 2007-02-28 | Tufts College | 9-substituirane minociklinske spojine |
AU2002354619A1 (en) * | 2001-07-13 | 2003-01-29 | Centillium Communications, Inc. | Application of metering tones to a dsl and voice communications system |
EP2316450A1 (en) * | 2002-03-08 | 2011-05-04 | Paratek Pharmaceuticals, Inc. | Amino-methyl substituted tetracycline compounds |
EP2277504A1 (en) | 2002-10-24 | 2011-01-26 | Paratek Pharmaceuticals, Inc. | Substituted tetracycline compounds for the treatment of malaria |
WO2004064728A2 (en) * | 2003-01-16 | 2004-08-05 | Paratek Pharmaceuticals, Inc. | Use of specific tetracycline compounds in therapy |
CA2531728A1 (en) * | 2003-07-09 | 2005-02-03 | Paratek Pharmaceuticals, Inc. | Substituted tetracycline compounds |
EP2450347B1 (en) * | 2006-12-21 | 2015-06-24 | Paratek Pharmaceuticals, Inc. | Tetracycline derivatives for the treatment of bacterial, viral and parasitic infections |
CN101759604A (zh) * | 2008-09-12 | 2010-06-30 | 山东轩竹医药科技有限公司 | 胍基取代的四环素衍生物 |
NO2738156T3 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) | 2011-07-26 | 2018-06-02 |
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- 2012-07-26 SI SI201231256T patent/SI2738156T1/en unknown
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ES2664516T3 (es) | 2018-04-19 |
HRP20180444T1 (hr) | 2018-05-04 |
EP2738156A1 (en) | 2014-06-04 |
LT2738156T (lt) | 2018-05-25 |
US20140179638A1 (en) | 2014-06-26 |
PT2738156T (pt) | 2018-03-28 |
WO2013013505A1 (zh) | 2013-01-31 |
HK1191931A1 (zh) | 2014-08-08 |
CN103717571B8 (zh) | 2017-05-17 |
EP2738156B1 (en) | 2018-01-03 |
JP5792902B2 (ja) | 2015-10-14 |
NO2738156T3 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) | 2018-06-02 |
KR101732084B1 (ko) | 2017-05-02 |
BR112014001798A2 (pt) | 2017-02-21 |
PL2738156T3 (pl) | 2018-06-29 |
DK2738156T3 (en) | 2018-03-26 |
US9365499B2 (en) | 2016-06-14 |
CN103717571B (zh) | 2016-01-13 |
JP2014529342A (ja) | 2014-11-06 |
SI2738156T1 (en) | 2018-05-31 |
CA2842838A1 (en) | 2013-01-31 |
KR20140050694A (ko) | 2014-04-29 |
EP2738156A4 (en) | 2015-01-07 |
CN103717571A (zh) | 2014-04-09 |
HUE036696T2 (hu) | 2018-07-30 |
BR112014001798B1 (pt) | 2021-07-27 |
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