CN108623560A - A kind of Quinolone acid analog derivative and its preparation method and application - Google Patents
A kind of Quinolone acid analog derivative and its preparation method and application Download PDFInfo
- Publication number
- CN108623560A CN108623560A CN201710180834.9A CN201710180834A CN108623560A CN 108623560 A CN108623560 A CN 108623560A CN 201710180834 A CN201710180834 A CN 201710180834A CN 108623560 A CN108623560 A CN 108623560A
- Authority
- CN
- China
- Prior art keywords
- group
- base
- aliphatic
- alkyl
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000002253 acid Substances 0.000 title claims abstract description 16
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title claims description 14
- -1 geometric isomer Substances 0.000 claims abstract description 231
- 150000001875 compounds Chemical class 0.000 claims abstract description 103
- 150000003839 salts Chemical class 0.000 claims abstract description 53
- 239000000203 mixture Substances 0.000 claims abstract description 41
- 239000003814 drug Substances 0.000 claims abstract description 40
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 27
- 239000012453 solvate Substances 0.000 claims abstract description 26
- 229940079593 drug Drugs 0.000 claims abstract description 24
- 230000004048 modification Effects 0.000 claims abstract description 17
- 238000012986 modification Methods 0.000 claims abstract description 17
- 239000000651 prodrug Substances 0.000 claims abstract description 13
- 229940002612 prodrug Drugs 0.000 claims abstract description 13
- 201000008827 tuberculosis Diseases 0.000 claims abstract description 9
- 230000002141 anti-parasite Effects 0.000 claims abstract description 8
- 239000003096 antiparasitic agent Substances 0.000 claims abstract 2
- 125000002619 bicyclic group Chemical group 0.000 claims description 128
- 125000001931 aliphatic group Chemical group 0.000 claims description 127
- 125000003545 alkoxy group Chemical group 0.000 claims description 91
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 83
- 125000003118 aryl group Chemical group 0.000 claims description 61
- 125000000623 heterocyclic group Chemical group 0.000 claims description 61
- 238000006467 substitution reaction Methods 0.000 claims description 54
- 125000000217 alkyl group Chemical group 0.000 claims description 53
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 53
- 125000001072 heteroaryl group Chemical group 0.000 claims description 48
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 47
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 125000001424 substituent group Chemical group 0.000 claims description 36
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 34
- 229910052760 oxygen Inorganic materials 0.000 claims description 34
- 229910052799 carbon Inorganic materials 0.000 claims description 33
- 125000003342 alkenyl group Chemical group 0.000 claims description 32
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 31
- 125000000304 alkynyl group Chemical group 0.000 claims description 30
- 229910052717 sulfur Inorganic materials 0.000 claims description 30
- 125000003282 alkyl amino group Chemical group 0.000 claims description 28
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 27
- 229910052794 bromium Inorganic materials 0.000 claims description 26
- 239000000460 chlorine Substances 0.000 claims description 26
- 229910052801 chlorine Inorganic materials 0.000 claims description 26
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 23
- 229910052731 fluorine Inorganic materials 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 125000004104 aryloxy group Chemical group 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- 229910052740 iodine Inorganic materials 0.000 claims description 19
- 229910021529 ammonia Inorganic materials 0.000 claims description 18
- 229910052805 deuterium Inorganic materials 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 17
- 201000010099 disease Diseases 0.000 claims description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
- 241000193830 Bacillus <bacterium> Species 0.000 claims description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- 125000005842 heteroatom Chemical group 0.000 claims description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 15
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 14
- 125000002252 acyl group Chemical group 0.000 claims description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 13
- 235000019441 ethanol Nutrition 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- 239000001301 oxygen Substances 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 12
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 11
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 11
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 10
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 9
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 9
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 8
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 8
- 125000002431 aminoalkoxy group Chemical group 0.000 claims description 8
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 8
- 125000002541 furyl group Chemical group 0.000 claims description 8
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 7
- 241000187492 Mycobacterium marinum Species 0.000 claims description 7
- 125000003435 aroyl group Chemical group 0.000 claims description 7
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 claims description 6
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 6
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 6
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims description 6
- 125000005936 piperidyl group Chemical group 0.000 claims description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 6
- 229920002554 vinyl polymer Polymers 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 5
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000002971 oxazolyl group Chemical group 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 4
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 4
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 4
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical compound CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 206010056377 Bone tuberculosis Diseases 0.000 claims description 4
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 4
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 4
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical class OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 4
- 241000223960 Plasmodium falciparum Species 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 4
- 125000001980 alanyl group Chemical group 0.000 claims description 4
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 claims description 4
- 125000000268 heptanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000005114 heteroarylalkoxy group Chemical group 0.000 claims description 4
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 4
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 4
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 150000003536 tetrazoles Chemical class 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 claims description 3
- YYXAMZIQDGSHJU-UHFFFAOYSA-N 2-(oxolan-2-yl)-1-benzofuran Chemical compound C1CCOC1C1=CC2=CC=CC=C2O1 YYXAMZIQDGSHJU-UHFFFAOYSA-N 0.000 claims description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 3
- 235000001258 Cinchona calisaya Nutrition 0.000 claims description 3
- 208000004554 Leishmaniasis Diseases 0.000 claims description 3
- 208000009360 Osteoarticular Tuberculosis Diseases 0.000 claims description 3
- 241000224016 Plasmodium Species 0.000 claims description 3
- 241001505293 Plasmodium ovale Species 0.000 claims description 3
- 241000223810 Plasmodium vivax Species 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- 125000004171 alkoxy aryl group Chemical group 0.000 claims description 3
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 claims description 3
- 229930101531 artemisinin Natural products 0.000 claims description 3
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 claims description 3
- 229960003677 chloroquine Drugs 0.000 claims description 3
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 claims description 3
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 claims description 3
- 125000006332 fluoro benzoyl group Chemical group 0.000 claims description 3
- 125000005241 heteroarylamino group Chemical group 0.000 claims description 3
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 201000004792 malaria Diseases 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- YWAKXRMUMFPDSH-UHFFFAOYSA-N pentene Chemical compound CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 claims description 3
- 208000008128 pulmonary tuberculosis Diseases 0.000 claims description 3
- 150000003214 pyranose derivatives Chemical class 0.000 claims description 3
- WKSAUQYGYAYLPV-UHFFFAOYSA-N pyrimethamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1 WKSAUQYGYAYLPV-UHFFFAOYSA-N 0.000 claims description 3
- 229960000611 pyrimethamine Drugs 0.000 claims description 3
- 229930183339 qinghaosu Natural products 0.000 claims description 3
- 229960000948 quinine Drugs 0.000 claims description 3
- 229910052711 selenium Inorganic materials 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 125000003860 C1-C20 alkoxy group Chemical group 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical class OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 claims description 2
- 125000005819 alkenylalkoxy group Chemical group 0.000 claims description 2
- 230000001355 anti-mycobacterial effect Effects 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 229960000285 ethambutol Drugs 0.000 claims description 2
- 229940124307 fluoroquinolone Drugs 0.000 claims description 2
- 150000004675 formic acid derivatives Chemical class 0.000 claims description 2
- 150000002402 hexoses Chemical class 0.000 claims description 2
- 125000005191 hydroxyalkylamino group Chemical group 0.000 claims description 2
- 210000003734 kidney Anatomy 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 150000002972 pentoses Chemical class 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 4
- 150000002431 hydrogen Chemical class 0.000 claims 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- NWLPAIVRIWBEIT-SEPHDYHBSA-N (e)-but-2-enedioic acid;dihydrate Chemical compound O.O.OC(=O)\C=C\C(O)=O NWLPAIVRIWBEIT-SEPHDYHBSA-N 0.000 claims 2
- YHQXBTXEYZIYOV-UHFFFAOYSA-N 3-methylbut-1-ene Chemical group CC(C)C=C YHQXBTXEYZIYOV-UHFFFAOYSA-N 0.000 claims 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims 2
- 241000222722 Leishmania <genus> Species 0.000 claims 2
- 150000004683 dihydrates Chemical class 0.000 claims 2
- 150000004682 monohydrates Chemical class 0.000 claims 2
- 238000007614 solvation Methods 0.000 claims 2
- CSIFGMFVGDBOQC-UHFFFAOYSA-N 3-iminobutanenitrile Chemical compound CC(=N)CC#N CSIFGMFVGDBOQC-UHFFFAOYSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 150000001345 alkine derivatives Chemical class 0.000 claims 1
- 235000019504 cigarettes Nutrition 0.000 claims 1
- WQPDQJCBHQPNCZ-UHFFFAOYSA-N cyclohexa-2,4-dien-1-one Chemical compound O=C1CC=CC=C1 WQPDQJCBHQPNCZ-UHFFFAOYSA-N 0.000 claims 1
- 238000004108 freeze drying Methods 0.000 claims 1
- VQTUBCCKSQIDNK-UHFFFAOYSA-N iso-butene Natural products CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 claims 1
- 150000002611 lead compounds Chemical class 0.000 claims 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 claims 1
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims 1
- 125000005425 toluyl group Chemical group 0.000 claims 1
- 150000004684 trihydrates Chemical class 0.000 claims 1
- 239000002585 base Substances 0.000 description 284
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 170
- 235000002639 sodium chloride Nutrition 0.000 description 39
- 239000012074 organic phase Substances 0.000 description 33
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 28
- 239000000243 solution Substances 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 24
- 150000001721 carbon Chemical group 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 125000004430 oxygen atom Chemical group O* 0.000 description 20
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 19
- 150000002240 furans Chemical class 0.000 description 16
- 239000000126 substance Substances 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 125000004122 cyclic group Chemical group 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 125000003277 amino group Chemical group 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 235000019253 formic acid Nutrition 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 11
- 238000005406 washing Methods 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- 150000003254 radicals Chemical class 0.000 description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- 125000005111 carboxyalkoxy group Chemical group 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000005457 ice water Substances 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 230000008859 change Effects 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000000443 aerosol Substances 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 235000019197 fats Nutrition 0.000 description 7
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 7
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 7
- 244000045947 parasite Species 0.000 description 7
- 150000003053 piperidines Chemical class 0.000 description 7
- 150000003233 pyrroles Chemical class 0.000 description 7
- NUKQMGBDWFBRSA-UHFFFAOYSA-N C(=O)OCCC.N1=CC=CC2=CC=CC=C12 Chemical class C(=O)OCCC.N1=CC=CC2=CC=CC=C12 NUKQMGBDWFBRSA-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 239000002671 adjuvant Substances 0.000 description 6
- 125000004414 alkyl thio group Chemical group 0.000 description 6
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 6
- 239000002207 metabolite Substances 0.000 description 6
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 6
- 239000000829 suppository Substances 0.000 description 6
- IZPYBIJFRFWRPR-UHFFFAOYSA-N tert-butyl pyrrole-1-carboxylate Chemical class CC(C)(C)OC(=O)N1C=CC=C1 IZPYBIJFRFWRPR-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 239000002024 ethyl acetate extract Substances 0.000 description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 229910052698 phosphorus Inorganic materials 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 125000002837 carbocyclic group Chemical group 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 150000002460 imidazoles Chemical class 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 235000021317 phosphate Nutrition 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 230000002335 preservative effect Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- XLOVPKCQAPHUKK-UHFFFAOYSA-N 1,2,3,4,4a,5,8,8a-octahydronaphthalene Chemical compound C1C=CCC2CCCCC21 XLOVPKCQAPHUKK-UHFFFAOYSA-N 0.000 description 3
- RCTLPGXYGNQCRD-UHFFFAOYSA-N 2-bromo-4-chloroquinoline Chemical class C1=CC=C2C(Cl)=CC(Br)=NC2=C1 RCTLPGXYGNQCRD-UHFFFAOYSA-N 0.000 description 3
- MHNNAWXXUZQSNM-UHFFFAOYSA-N 2-methylbut-1-ene Chemical group CCC(C)=C MHNNAWXXUZQSNM-UHFFFAOYSA-N 0.000 description 3
- GJOHLWZHWQUKAU-UHFFFAOYSA-N 5-azaniumylpentan-2-yl-(6-methoxyquinolin-8-yl)azanium;dihydrogen phosphate Chemical compound OP(O)(O)=O.OP(O)(O)=O.N1=CC=CC2=CC(OC)=CC(NC(C)CCCN)=C21 GJOHLWZHWQUKAU-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 241000792859 Enema Species 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001342 alkaline earth metals Chemical class 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940110456 cocoa butter Drugs 0.000 description 3
- 235000019868 cocoa butter Nutrition 0.000 description 3
- 238000001647 drug administration Methods 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000007920 enema Substances 0.000 description 3
- 229940095399 enema Drugs 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 125000005456 glyceride group Chemical group 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 229960003350 isoniazid Drugs 0.000 description 3
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 229960003540 oxyquinoline Drugs 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 229960005179 primaquine Drugs 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 3
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N 1-Pyrroline Chemical compound C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 2
- YOYAIZYFCNQIRF-UHFFFAOYSA-N 2,6-dichlorobenzonitrile Chemical compound ClC1=CC=CC(Cl)=C1C#N YOYAIZYFCNQIRF-UHFFFAOYSA-N 0.000 description 2
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- KNDOFJFSHZCKGT-UHFFFAOYSA-N 4-chloroquinoline Chemical compound C1=CC=C2C(Cl)=CC=NC2=C1 KNDOFJFSHZCKGT-UHFFFAOYSA-N 0.000 description 2
- DWKAQISLZUQZNU-UHFFFAOYSA-N 4-oxo-2-(1h-pyrrol-2-yl)-1h-quinoline-3-carboxylic acid Chemical compound N1C2=CC=CC=C2C(=O)C(C(=O)O)=C1C1=CC=CN1 DWKAQISLZUQZNU-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 241000790917 Dioxys <bee> Species 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 2
- 229930182566 Gentamicin Natural products 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 229920002527 Glycogen Polymers 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241001484259 Lacuna Species 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- 241000244206 Nematoda Species 0.000 description 2
- 208000030852 Parasitic disease Diseases 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- AFCIMSXHQSIHQW-UHFFFAOYSA-N [O].[P] Chemical compound [O].[P] AFCIMSXHQSIHQW-UHFFFAOYSA-N 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 239000004411 aluminium Substances 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 230000000078 anti-malarial effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 2
- 125000000131 cyclopropyloxy group Chemical group C1(CC1)O* 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 2
- 238000007876 drug discovery Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229960002518 gentamicin Drugs 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 229940096919 glycogen Drugs 0.000 description 2
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 2
- 125000001245 hexylamino group Chemical group [H]N([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 235000003642 hunger Nutrition 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 239000002917 insecticide Substances 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 125000005956 isoquinolyl group Chemical group 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 210000004324 lymphatic system Anatomy 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000013507 mapping Methods 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 150000002790 naphthalenes Chemical class 0.000 description 2
- 125000005184 naphthylamino group Chemical group C1(=CC=CC2=CC=CC=C12)N* 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 229940126701 oral medication Drugs 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 238000011287 therapeutic dose Methods 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- VCOPTHOUUNAYKQ-WBTCAYNUSA-N (3s)-3,6-diamino-n-[[(2s,5s,8e,11s,15s)-15-amino-11-[(6r)-2-amino-1,4,5,6-tetrahydropyrimidin-6-yl]-8-[(carbamoylamino)methylidene]-2-(hydroxymethyl)-3,6,9,12,16-pentaoxo-1,4,7,10,13-pentazacyclohexadec-5-yl]methyl]hexanamide;(3s)-3,6-diamino-n-[[(2s,5s,8 Chemical compound N1C(=O)\C(=C/NC(N)=O)NC(=O)[C@H](CNC(=O)C[C@@H](N)CCCN)NC(=O)[C@H](C)NC(=O)[C@@H](N)CNC(=O)[C@@H]1[C@@H]1NC(N)=NCC1.N1C(=O)\C(=C/NC(N)=O)NC(=O)[C@H](CNC(=O)C[C@@H](N)CCCN)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CNC(=O)[C@@H]1[C@@H]1NC(N)=NCC1 VCOPTHOUUNAYKQ-WBTCAYNUSA-N 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- NAOLWIGVYRIGTP-UHFFFAOYSA-N 1,3,5-trihydroxyanthracene-9,10-dione Chemical compound C1=CC(O)=C2C(=O)C3=CC(O)=CC(O)=C3C(=O)C2=C1 NAOLWIGVYRIGTP-UHFFFAOYSA-N 0.000 description 1
- XGIKILRODBEJIL-UHFFFAOYSA-N 1-(ethylamino)ethanol Chemical compound CCNC(C)O XGIKILRODBEJIL-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical class C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- OHZAHWOAMVVGEL-UHFFFAOYSA-N 2,2'-bithiophene Chemical group C1=CSC(C=2SC=CC=2)=C1 OHZAHWOAMVVGEL-UHFFFAOYSA-N 0.000 description 1
- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 1
- 125000004922 2-methyl-3-pentyl group Chemical group CC(C)C(CC)* 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- VTUDEKLZWASGON-UHFFFAOYSA-N 2-pyrazolidin-1-yl-1h-imidazole Chemical class C1CCNN1C1=NC=CN1 VTUDEKLZWASGON-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- BCZRFDKLLBFOHJ-UHFFFAOYSA-N 3-heptyl-7-methoxy-2-methyl-1h-quinolin-4-one Chemical compound COC1=CC=C2C(=O)C(CCCCCCC)=C(C)NC2=C1 BCZRFDKLLBFOHJ-UHFFFAOYSA-N 0.000 description 1
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 1
- 125000004919 3-methyl-2-pentyl group Chemical group CC(C(C)*)CC 0.000 description 1
- 125000004921 3-methyl-3-pentyl group Chemical group CC(CC)(CC)* 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical class OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- JDDQECMBPWVIRU-UHFFFAOYSA-N 4-azaspiro[2.4]heptane Chemical compound C1CC11NCCC1 JDDQECMBPWVIRU-UHFFFAOYSA-N 0.000 description 1
- 150000005653 4-chloroquinolines Chemical class 0.000 description 1
- VHWFNFITHSPBSR-UHFFFAOYSA-N 4-methyl-1,2-oxazole Chemical compound CC=1C=NOC=1 VHWFNFITHSPBSR-UHFFFAOYSA-N 0.000 description 1
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 1
- OXVJHTVSYNPXIH-UHFFFAOYSA-N 4-oxaspiro[2.4]heptane Chemical compound C1CC11OCCC1 OXVJHTVSYNPXIH-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- MSTNYGQPCMXVAQ-KIYNQFGBSA-N 5,6,7,8-tetrahydrofolic acid Chemical compound N1C=2C(=O)NC(N)=NC=2NCC1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-KIYNQFGBSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 241000585703 Adelphia <angiosperm> Species 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- RZYKUPXRYIOEME-UHFFFAOYSA-N CCCCCCCCCCCC[S] Chemical compound CCCCCCCCCCCC[S] RZYKUPXRYIOEME-UHFFFAOYSA-N 0.000 description 1
- 108010065839 Capreomycin Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 241000723346 Cinnamomum camphora Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- DYDCUQKUCUHJBH-UWTATZPHSA-N D-Cycloserine Chemical compound N[C@@H]1CONC1=O DYDCUQKUCUHJBH-UWTATZPHSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-YMDCURPLSA-N D-galactopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-YMDCURPLSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 241000222727 Leishmania donovani Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- YKFRUJSEPGHZFJ-UHFFFAOYSA-N N-trimethylsilylimidazole Chemical compound C[Si](C)(C)N1C=CN=C1 YKFRUJSEPGHZFJ-UHFFFAOYSA-N 0.000 description 1
- XIAFXLHGVUIRQG-UHFFFAOYSA-N N1=CC=CC2=CC=CC=C12.[Cl] Chemical compound N1=CC=CC2=CC=CC=C12.[Cl] XIAFXLHGVUIRQG-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 241000223821 Plasmodium malariae Species 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 1
- GZHHXOSZCDKXPZ-UHFFFAOYSA-N S1C(=NC=C1)C=1N=C(NC1)NCC Chemical class S1C(=NC=C1)C=1N=C(NC1)NCC GZHHXOSZCDKXPZ-UHFFFAOYSA-N 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical class [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 206010043774 Thyroid tuberculosis Diseases 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical group ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- DWDAZFJBSZTCCM-UHFFFAOYSA-N [O]C1CCCCC1 Chemical compound [O]C1CCCCC1 DWDAZFJBSZTCCM-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- HXHWSAZORRCQMX-UHFFFAOYSA-N albendazole Chemical compound CCCSC1=CC=C2NC(NC(=O)OC)=NC2=C1 HXHWSAZORRCQMX-UHFFFAOYSA-N 0.000 description 1
- 229960002669 albendazole Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229940061720 alpha hydroxy acid Drugs 0.000 description 1
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-N alpha-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N alpha-methyl toluene Natural products CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 239000012928 buffer substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 229930008380 camphor Natural products 0.000 description 1
- 229950005953 camsilate Drugs 0.000 description 1
- 229960004602 capreomycin Drugs 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000004567 concrete Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- MRKZAZMYXYSBDG-UHFFFAOYSA-N cyclopentyl propanoate Chemical compound CCC(=O)OC1CCCC1 MRKZAZMYXYSBDG-UHFFFAOYSA-N 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000005238 degreasing Methods 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 1
- 125000004212 difluorophenyl group Chemical group 0.000 description 1
- 102000006795 dihydrofolate reductase activity proteins Human genes 0.000 description 1
- 108040000939 dihydrofolate reductase activity proteins Proteins 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 125000005883 dithianyl group Chemical group 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical class CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 235000006694 eating habits Nutrition 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 229960001731 gluceptate Drugs 0.000 description 1
- KWMLJOLKUYYJFJ-VFUOTHLCSA-N glucoheptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-VFUOTHLCSA-N 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000003055 glycidyl group Chemical group C(C1CO1)* 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 102000057593 human F8 Human genes 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- JMANUKZDKDKBJP-UHFFFAOYSA-N imidazo[1,5-a]pyridine Chemical compound C1=CC=CC2=CN=CN21 JMANUKZDKDKBJP-UHFFFAOYSA-N 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 201000008267 intestinal tuberculosis Diseases 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 150000002545 isoxazoles Chemical class 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- OPXLLQIJSORQAM-UHFFFAOYSA-N mebendazole Chemical compound C=1C=C2NC(NC(=O)OC)=NC2=CC=1C(=O)C1=CC=CC=C1 OPXLLQIJSORQAM-UHFFFAOYSA-N 0.000 description 1
- 229960003439 mebendazole Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 238000007392 microtiter assay Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- YBFDBOCHDKHFSQ-UHFFFAOYSA-N penicinotam Chemical compound O=C1C2=CC=CC=C2N(C)C2=C1C(=O)N1C=CC=C12 YBFDBOCHDKHFSQ-UHFFFAOYSA-N 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- DLRJIFUOBPOJNS-UHFFFAOYSA-N phenetole Chemical compound CCOC1=CC=CC=C1 DLRJIFUOBPOJNS-UHFFFAOYSA-N 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical class CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229940118768 plasmodium malariae Drugs 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 125000004309 pyranyl group Chemical class O1C(C=CC=C1)* 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- RDRCCJPEJDWSRJ-UHFFFAOYSA-N pyridine;1h-pyrrole Chemical compound C=1C=CNC=1.C1=CC=NC=C1 RDRCCJPEJDWSRJ-UHFFFAOYSA-N 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 229940047431 recombinate Drugs 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940099992 seromycin Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 208000037972 tropical disease Diseases 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-M undecanoate Chemical compound CCCCCCCCCCC([O-])=O ZDPHROOEEOARMN-UHFFFAOYSA-M 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D411/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/044—Pyrrole radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of Quinolone acid analog derivatives, or non-equal amount of mixture, geometric isomer, solvate, pharmaceutically acceptable salt or the prodrug of its tautomer, stereoisomer, racemic modification, enantiomter, and the pharmaceutical composition comprising the compound.The invention also discloses this kind of compounds and its pharmaceutical composition as drug, especially as the purposes for the treatment of tuberculosis, the drug of anti parasitic.
Description
Technical field
The invention belongs to drug fields, and more particularly to a kind of Quinolone acid analog derivative and its pharmaceutical composition and
The purposes of Quinolone acid analog derivative and its pharmaceutical composition as treating tuberculosis, anti-parasite medicine.
Background technology
The infectious diseases caused by tubercle bacillus is one of clinical most common disease, therefore anti-mycobacterium tuberculosis drug
Also just become one of widest drug of clinical application.However being on the rise with bacterial drug resistance, antibody-resistant bacterium is special
Be that more antibody-resistant bacterium continuously emerge, and immune deficiency patient increase, mycobacterium tuberculosis infection rate persistently rises.Therefore, grind
The antituberculotic for sending out new is as clinically very urgent important topic.
The tropical disease of narrow sense refers to parasitic disease, is disease caused by parasite intrusion human body.Drug can be by not
Parasite is damaged with mechanism.Such as:Pyrimethamine has the dihyrofolate reductase of plasmodium larger affinity, and can press down
Its activity is made, blocking dihydrofolate reduction is tetrahydrofolic acid, hinders the synthesis of nucleic acid;Benzimidazoles residues inhibit nematode
Intake to glucose reduces glycogen amount, reduces ATP and generates, interferes polypide growth and development;Qinghaosu can inhibit different bright ammonia
Acid incorporation Plasmodial protein, to inhibit Plasmodial protein to synthesize;The iron that chloroquine, quinine etc. are generated with parasitized erythrocyte
Porphyrin, which combines, forms compound, accumulates in the damage in parasitized erythrocyte, leading to plasmodium and parasitized erythrocyte film;Benzo
Imidazoles selectively make the micro-pipe in the body quilt and brain cell of nematode disappear, and inhibit intake of the polypide to glucose;
Glycogen amount is reduced, ATP is reduced and generates, interfere polypide growth and development.Anti-parasite medicine is still based on chemical drugs at present, but
Since pharmaceutical requirements capacity is huge, chemical drugs adverse reaction and the appearance of drug-resistant worm plant, novel anti-parasite medicine are urgently opened
It sends out and has broad application prospects.
Chinese patent CN 2009100183228 discloses piperazine Nino acid as follows(penicinoline)Compound
As insecticide.
Chinese patent CN 2009100183213 discloses piperazine Nino peace (penicinotam) compound conduct as follows
Insecticide.
In the prior art, though disclosed compound has certain similarity, general formula institute of the present invention with the compounds of this invention
The compound shown has significant difference with the prior art, and all has good treating tuberculosis, Antiparasitic Activity.
Invention content
The present invention provides a kind of Quinolone acid derivative, or its pharmaceutical composition, and its is preparing treating tuberculosis, anti-parasitism
Application in worm drug.The compound of its Quinolone acid structure, tautomer, stereoisomer, racemic modification, mapping
The non-equal amount of mixture of isomers, the solvate of geometric isomer, solvate, pharmaceutically acceptable salt or its salt.Its
It is characterized in that compound has the following structure:, wherein A, B are
Five yuan or hexa-atomic aromatic ring, hetero-aromatic ring, carbon heterocyclic;N=1,2,3 or 4;K=1,2,3 or 4;Y is O or NR5; “
" indicate singly-bound or be not present;R1, R2, R3, R4, R5Shown in being defined as follows:
Each R1, R4Can be identical or different, it is separate be hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano,
Alkyl, halogenated alkyl, alkoxy, alkylamino, alkyl acyl, hydroxy alkoxy base, Hydroxyalkylamino, hydroxyalkanoyl,
Halogenated alkoxy, halogenated alkylamino, ohaloalkanoyl, aminoalkoxy, naphthenic base, cycloalkyl oxy, naphthenic base ammonia
Base, cycloalkanoyl, alkenyl, alkenylalkoxy, alkenyl alkylamino, alkenyl alkanoyl, alkynyl, alkynyl alkoxy,
Alkynyl alkylamino, alkynyl alkanoyl, aryl, aryloxy group, aroyl, fragrant amino, alkoxy aryl, aryl alkane amino,
Heteroaryl, heteroaryloxy, 4-hetaroylpyrazol, heteroaryl amino, heteroarylalkoxy, heteroarylalkylamino, heterocycle alkane acyl
Base, Heterocyclylalkyl, heterocycle oxygroup, heterocyclylamino group, heterocyclylacyl, heterocyclylalkoxy, heterocycle alkylamino,
Heterocycle alkanoyl, azido alkoxy, condensed-bicyclic base condense miscellaneous bicyclic group, and condensed-bicyclic base aliphatic condenses
Miscellaneous bicyclic group aliphatic, condensed-bicyclic base oxygroup condense miscellaneous bicyclic group oxygroup, and condensed-bicyclic base amino condenses miscellaneous bicyclic
Base amino, condensed-bicyclic base alkoxy condense miscellaneous bicyclic group alkoxy, and condensed-bicyclic base alkylamino condenses miscellaneous bicyclic group
Alkylamino, condensed-bicyclic base oxygroup alkoxy, condensed miscellaneous bicyclic group oxygroup alkoxy, condensed-bicyclic base aminoalkoxy,
Miscellaneous bicyclic group aminoalkoxy is condensed, condensed-bicyclic base-C (=O)-, condensed-bicyclic base-C (=O) O- condense miscellaneous bicyclic group-C
(=O)-, miscellaneous bicyclic group-C (=O) O-, condensed-bicyclic base amino-C (=O)-are condensed, miscellaneous bicyclic group amino-C (=O)-is condensed,
Condensed-bicyclic base-C (=O) N (R6)-, condenses miscellaneous bicyclic group-C (=O) N (R6)-, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell, spiral shell are bicyclic
Base aliphatic, the miscellaneous bicyclic group aliphatic of spiral shell, spiral shell bicyclic group oxygroup, the miscellaneous bicyclic group oxygroup of spiral shell, spiral shell bicyclic group amino, spiral shell are miscellaneous
Bicyclic group amino, spiral shell bicyclic group alkoxy, the miscellaneous bicyclic group alkoxy of spiral shell, spiral shell bicyclic group alkylamino, the miscellaneous bicyclic group alkane ammonia of spiral shell
Base, spiral shell bicyclic group oxygroup alkoxy, the miscellaneous bicyclic group oxygroup alkoxy of spiral shell, spiral shell bicyclic group aminoalkoxy, the miscellaneous bicyclic group of spiral shell
Aminoalkoxy, spiral shell bicyclic group-C (=O)-, spiral shell bicyclic group-C (=O) O-, the miscellaneous bicyclic group-C of spiral shell (=O)-, the miscellaneous bicyclic group-of spiral shell
C (=O) O-, spiral shell bicyclic group amino-C (=O)-, the miscellaneous bicyclic group amino-C of spiral shell (=O)-, spiral shell bicyclic group-C (=O) N (R6)-, spiral shell
Miscellaneous bicyclic group-C (=O) N (R6)-, R7R6N-, -C(=O)NR6R7, -OC(=O)NR6R7, -OC(=O)OR6, -N(R6)C(=O)
NR6R7, -N(R6)C(=O)OR7, -N(R6)C(=O)-R7, R6R7N-S(=O)t-, R6S(=O)t-, R6S(=O)tN(R7)-,
R7R6N- alkyl, R6S(=O)tAlkyl, R6R7N-C (=O)-alkyl, R7R6N- alkoxies, R6S(=O)tAlkoxy,
R6R7N-C (=O)-alkoxy, aryl-(CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle-
(CH2)p-G-(CH2)m, or naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR8, S(=O), S(=O)2,C(=
O), -C(=O)N(R6)-, -OC(=O)N(R6)-, -OC(=O)-, -N(R6)C(=O)N(R6)-, -(R6)N-S(=O)t-, -
OS(=O)t, or-OS (=O)tN(R6)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;Or it is wherein fragrant
Base-(CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle-(CH2)p-G-(CH2)m, or naphthenic base-
(CH2)p-G-(CH2)mCan F, Cl, Br, I, alkyl, alkenyl, alkynyl, alkoxy or cyanogen be selected from by one or more
The substituent group of base replaces.
R2, R3, R5Separate is hydrogen, deuterium, alkyl, halogenated alkyl, alkyl acyl, hydroxyalkanoyl, halogen
For alkanoyl, naphthenic base, cycloalkanoyl, alkenyl, alkenyl alkanoyl, alkynyl, alkynyl alkanoyl, aryl, fragrant acyl
Base, heteroaryl, 4-hetaroylpyrazol, heterocycle alkanoyl, Heterocyclylalkyl, heterocyclylacyl, heterocycle alkanoyl, nitrine
Base alkyl, condensed-bicyclic base condense miscellaneous bicyclic group, and condensed-bicyclic base-C (=O)-condenses miscellaneous bicyclic group-C (=O)-, thick
Bicyclic group amino-C (=O)-is closed, miscellaneous bicyclic group amino-C (=O)-, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell, spiral shell bicyclic group are condensed
Aliphatic, the miscellaneous bicyclic group aliphatic of spiral shell, spiral shell bicyclic group-C (=O)-, the miscellaneous bicyclic group-C of spiral shell (=O)-, spiral shell bicyclic group amino-C
(=O)-, the miscellaneous bicyclic group amino-C of spiral shell (=O)-,-C (=O) NR6R7, R6R7N-S(=O)t-, R6S(=O)t-, R7R6N- alkyl,
R6S(=O)tAlkyl, R6R7N-C (=O)-alkyl, aryl-(CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m-,
Heterocycle-(CH2)p-G-(CH2)m, or naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR8, S(=O), S(=
O)2,C(=O), -C(=O)N(R6)-, -OC(=O)N(R6)-, -OC(=O)-, -N(R6)C(=O)N(R6)-, -(R6)N-S(=
O)t-, -OS(=O)t, or-OS (=O)tN(R6)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;Or
Person aryl-(CH therein2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle-(CH2)p-G-(CH2)m-,
Or naphthenic base-(CH2)p-G-(CH2)mCan by one or more be selected from F, Cl, Br, I, cyano, alkyl, alkenyl,
Alkynyl, alkoxy, aryl, heteroaryl, carbocylic radical, the substituent group substitution of heterocycle.
R8Can be identical or different, it is each independently hydrogen, R6R7NC(=O)-, R6OC(=O)-, R6C(=O)-,
R6R7NS(=O)-, R6OS(=O)-, R6S(=O)-, R6R7NS(=O)2-, R6OS(=O)2-, R6S(=O)2, aliphatic, halogen
Fat subsitutes race, hydroxyl group aliphatic, amino aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio group aliphatic,
Aromatic yl aliphat, heteroaryl aliphatic, heterocycle aliphatic, naphthenic base aliphatic, aryloxy group aliphatic, heterocyclyloxy
Base aliphatic, cycloalkyl oxy aliphatic, fragrant amino aliphatic, heterocyclylamino group aliphatic, cycloalkyl amino aliphatic,
Aryl, heteroaryl, heterocycle or carbocylic radical.
Each R6And R7It independently is hydrogen, deuterium, aliphatic, halogenated aliphatic, hydroxyl group aliphatic, amino aliphatic, alkane
Oxygroup aliphatic, alkylamino aliphatic, alkylthio group aliphatic, aromatic yl aliphat, heteroaryl aliphatic, heterocycle fat
Race, naphthenic base aliphatic, aryloxy group aliphatic, heterocycle oxygroup aliphatic, cycloalkyl oxy aliphatic, fragrant amino fat
Fat race, heterocyclylamino group aliphatic, cycloalkyl amino aliphatic, aryl, heteroaryl, heterocycle or naphthenic base;Work as R6
And R7It is connected on the same nitrogen-atoms, R6, R73-8 substituted or non-substituted membered rings can be randomly formed with nitrogen-atoms, it is thick
It is bicyclic to close bicyclic or spiral shell;The miscellaneous original in heterocycle, heteroaryl, condensed miscellaneous bicyclic group, the miscellaneous bicyclic group of spiral shell involved in above-mentioned group
Son is 1-5 hetero atom in N, O, S, Se.
Above-mentioned R1, R2, R3, R4, R5, R6, R7, R8Group can appoint by hydroxyl, methylol, carboxyl, acetyl ammonia
Base, alkyl (such as methyl, ethyl, propyl), alkoxy (such as methoxyl group, ethyoxyl, tert-butoxy), alkylamino, naphthenic base,
Alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino, azido (- N3), guanidine radicals,
Cyano, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, aryl, heteroaryl,
One or more of heterocycle replaces.
Compound of the present invention is general formula III-VI compounds represented, or compound shown in general formula III-VI
Stereoisomer geometric isomer, tautomer, nitrogen oxides, raceme, hydrate, solvate, metabolite, medicine
Acceptable salt or prodrug on:
,
Wherein T1, T2, T3, T4Separate is CR1Or N, wherein T1, T2, T3, T4At most there are two can contain N;
V1, V2, V3, V4Separate is CR4, NR9, O or S;Y is O or NR5; X1, X2, X3, X4, X5It is separate
For CR4Or N; “" indicate singly-bound or be not present;Each R1, R2, R3, R4, R5, R9As follows:
Each R1, R4Can be identical or different, it is separate be H, D, F, Cl, Br, I, hydroxyl, amino, nitro,
Cyano, C1-C20 alkyl, C1-C20 halogenated alkyls, C1-C20 alkoxies, C1-C20 alkylaminos, C1-C20 alkyl acyls,
Hydroxyl C1-C20 alkoxies, hydroxyl C1-C20 alkylaminos, hydroxyl C1-C20 alkanoyls, C1-C20 halogenated alkoxies, C1-
The halogenated alkylaminos of C20, C1-C20 ohaloalkanoyls, C1-C20 aminoalkoxies, C3-C10 naphthenic base, C3-C10 naphthenic base
Oxygroup, C3-C10 cycloalkyl aminos, C3-C10 cycloalkanoyls, C2-C8 alkenyls, C2-C8 alkynyls, C6-C10 aryl,
C6-C10 aryloxy group, C6-C10 aroyls, C6-C10 fragrant aminos, C6-C10 aryl C1-C6 alkoxies, C6-C10 aryl alkane
Amino, C5-C12 heteroaryls, C5-C12 heteroaryloxies, C5-C12 4-hetaroylpyrazols, C5-C12 heteroaryl amino, C5-C12 are miscellaneous
Aryl C1-C6 alkoxies, C5-C12 heteroaryl C1-C6 alkylaminos, C4-C12 heterocycle C1-C6 alkanoyls, C4-C12 heterocycles
Alkyl, C4-C12 heterocycle oxygroups, C4-C12 heterocyclylamino groups, C4-C12 heterocyclylacyls, C4-C12 heterocycles C1-C6
Alkoxy, C4-C12 heterocycle C1-C6 alkylaminos, C4-C12 heterocycle C1-C6 alkanoyls, R7R6N-, -C(=O)NR6R7,
-OC(=O)NR6R7, -OC(=O)OR6, -N(R6)C(=O)NR6R7, -N(R6)C(=O)OR7, -N(R6)C(=O)-R7,
R6R7N-S(=O)t-, R6S(=O)t-, R6S(=O)tN(R7)-, R7R6N-C1-C6 alkyl, R6S(=O)t- C1-C6 alkyl,
R6R7N-C (=O)-C1-C6 alkyl, R7R6N- C1-C6 alkoxies, R6S(=O)t- C1-C6 alkoxies, R6R7N-C(=O)-C1-
C6 alkoxies, C6-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m, C4-C12 heterocycles
Base-(CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR8, S(=O), S
(=O)2,C(=O), -C(=O)N(R6)-, -OC(=O)N(R6)-, -OC(=O)-, -N(R6)C(=O)N(R6)-, -(R6)N-S
(=O)t-, -OS(=O)t, or-OS (=O)tN(R6)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;
Or wherein C6-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m, C4-C12 heterocycles
Base-(CH2)p-G-(CH2)m, or C3-C1 naphthenic base-(CH2)p-G-(CH2)mCan F, Cl be selected from by one or more,
The substituent group of Br, I, alkyl, alkenyl, alkynyl, alkoxy or cyano replaces;
R2, R3, R5, R9For H, D, C1-C20 alkyl, C1-C20 halogenated alkyls, C1-C20 alkyl acyls, C1-C20 hydroxyls
Base alkanoyl, C1-C20 ohaloalkanoyls, C3-C10 naphthenic base, C3-C10 cycloalkanoyls, C2-C8 alkenyls, C2-C8
Alkenyl alkanoyl, C2-C8 alkynyls, C2-C8 alkynyl alkanoyls, C6-C10 aryl, C6-C10 aroyls, C5-C12 heteroaryls
Base, C5-C12 4-hetaroylpyrazols, C4-C12 heterocycle alkanoyls, C4-C12 Heterocyclylalkyls, C4-C12 heterocyclylacyls, C4-
C12 heterocycle C1-C6 alkanoyls, C5-C12 condensed-bicyclic bases, C5-C12 condense miscellaneous bicyclic group ,-C (=O) NR6R7,
R6R7N-S(=O)t-, R6S(=O)t-, R7R6N-C1-C6 alkyl, R6S(=O)t- C1-C6 alkyl, R6R7N-C(=O)-C1-C6
Alkyl, C6-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m, C4-C12 heterocycles-
(CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR8, S(=O), S(=
O)2,C(=O), -C(=O)N(R6)-, -OC(=O)N(R6)-, -OC(=O)-, -N(R6)C(=O)N(R6)-, -(R6)N-S(=
O)t-, -OS(=O)t, or-OS (=O)tN(R6)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;Or
Person wherein C6-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m, C4-C12 heterocycles-
(CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)mCan F, Cl, Br be selected from by one or more,
I, cyano, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, carbocylic radical, the substituent group substitution of heterocycle.
Wherein each R8Can be identical or different, it is each independently H, D, R6R7NC(=O)-, R6OC(=O)-, R6C(=
O)-, R6R7NS(=O)-, R6OS(=O)-, R6S(=O)-, R6R7NS(=O)2-, R6OS(=O)2-, R6S(=O)2-, C1-C3
Aliphatic, C1-C3 halogenated aliphatics, C1-C3 hydroxyl group aliphatics, C1-C3 amino aliphatic, C1-C3 alkoxy C 1-C3 fat
Fat race, C1-C3 alkylamino C1-C3 aliphatic, C1-C3 alkylthio group C1-C3 aliphatic, C6-C10 aryl C1-C3 aliphatic,
C5-C9 heteroaryl C1-C3 aliphatic, C4-C10 heterocycle C1-C3 aliphatic, C3-C10 naphthenic base C1-C3 aliphatic, C6-
C10 aryloxy group C1-C3 aliphatic, C4-C10 heterocycle oxygroup C1-C3 aliphatic, C3-C10 cycloalkyl oxies C1-C3 fat
Race, C6-C10 fragrant amino C1-C3 aliphatic, C4-C10 heterocyclylamino group C1-C3 aliphatic, C3-C10 cycloalkyl aminos C1-
C3 aliphatic, C6-C10 aryl, C5-C10 heteroaryls, C4-C10 heterocycles or C3-C10 naphthenic base.
Wherein each R6And R7It independently is H, D, C1-C3 aliphatic, C1-C3 halogenated aliphatics, C1-C3 hydroxy aliphatics
Race, C1-C3 amino aliphatic, C1-C3 alkoxy C 1-C3 aliphatic, C1-C3 alkylamino C1-C3 aliphatic, C1-C3 alkane
Sulfenyl C1-C3 aliphatic, C6-C10 aryl C1-C3 aliphatic, C5-C9 heteroaryl C1-C3 aliphatic, C4-C10 heterocycles
C1-C3 aliphatic, C3-C10 naphthenic base C1-C3 aliphatic, C6-C10 aryloxy group C1-C3 aliphatic, C4-C10 heterocyclyloxies
Base C1-C3 aliphatic, C3-C10 cycloalkyl oxy C1-C3 aliphatic, C6-C10 fragrant amino C1-C3 aliphatic, C4-C10 are miscellaneous
Ring group amino C1-C3 aliphatic, C3-C10 cycloalkyl amino C1-C3 aliphatic, C6-C10 aryl, C5-C10 heteroaryls,
C4-C10 heterocycles or C3-C10 naphthenic base;Work as R6And R7It is connected on the same nitrogen-atoms, R6, R7It can be arbitrary with nitrogen-atoms
Ground forms substituted or non-substituted 3-8 membered rings.
Above-mentioned R1, R2, R3, R4, R5, R6, R7, R8, R9Group can appoint by hydroxyl, methylol, carboxyl, acetyl
Amino, alkyl (such as methyl, ethyl, propyl), alkoxy (such as methoxyl group, ethyoxyl, tert-butoxy), alkylamino, cycloalkanes
Base, alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino, azido (- N3), guanidine
Base, cyano, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, and aryl is miscellaneous
Aryl, the substitution of one or more of heterocycle.
Compound of the present invention, wherein each R1, R4Can be identical or different, it is separate be H, D, F, Cl,
Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, C5H11,
C6H13, C8H17, trifluoromethyl, hydroxymethyl, amino methyl, methoxyl group, ethyoxyl, tert-butoxy, methylamino,
Ethylamino, isopropylamino, 3- hydroxyl-propyls, acetyl group, trifluoroacetyl group, Cyanoacetyl, methylamino acetyl
Base, propiono, iso-propionyl, 2- hydroxypropanoyls, 2- aminopropionyls, 2- chlorine propionos, 2- bromine propionos, penta
Acyl group, caproyl, heptanoyl group, methacrylyl, phenyl, benzoyl, p-nitrophenyl, to methyl benzoyl,
Between fluoro benzoyl, p-benzoyl base, to methoxybenzoyl base, 2,4- dimethylbenzoyls, azido
Benzoyl, benzyl, p-chlorobenzyl, vinyl, acrylic, allyl, n-butene base, isobutenyl, n-pentene
Base, isopentene group, cyclopropyl, ring propiono, ring valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene, benzene second
Base imidazole radicals, pyridyl group, pyrrole radicals, oxazolyls, isoxazolyl, triazol radical, tetrazole base, furyl, thiophene
Base, thiazolyl, piperidyl, piperazinyl, indyl, carbazyl, benzofuranyl tetrahydrofuran base, THP trtrahydropyranyl,
Pyrimidine bases, purine bases ,-N (CH3)2,-C (C=O) NH-C1-C4 alkyl ,-OC (C=O)-NH-C1-C4 alkyl ,-OC
(O=O) O-C1-C4 alkyl ,-NHC (=O) NH-C1-C4 alkyl ,-NHC (=O) O-C1-C4 alkyl ,-NHC (=O)-C1-
C4 alkyl, C1-C4 alkyl-NH-S (=O)2, C1-C4 alkyl S (=O)2, C1-C4 alkyl S (=O)2NH-, phenyl-
(CH2)P-G-(CH2)m, difluorophenyl-(CH2)P-G-(CH2)m, thiazolyl-(CH2)p-G-(CH2)m, pyridyl group-
(CH2)p-G-(CH2)m, phenylethyl, cyclohexyl-(CH2)p-G-(CH2)m, wherein G is O, S, S (=O), S (=
O)2, C(=O);P and m is each independently 0,1,2 or 3;Or wherein C6-C10 aryl-(CH2)P-G-(CH2)mIt can be with
F, Cl, Br, I, methyl, ethyl, propyl, acetenyl, propinyl, butynyl, methoxy are selected from by one or more
The substituent group of base, ethyoxyl or cyano replaces;Or above-mentioned R1, R4It is welcome by F, Cl, Br, I, hydroxyl, hydroxyl
Base, methylol, carboxyl, acetylamino, C1-C6 alkyl(Such as methyl, ethyl, propyl), C1-C6 alkoxies, C1-C6 alkane
Amino, trifluoromethyl, trifluoroacetyl group, sulfydryl, nitro, amino, azido(-N3), guanidine radicals, cyano, tertiary fourth oxygen
Carbonyl(-Boc), carbonyl(-C=O), oxo(=O), thio(=S), sulfonyl, the substitution of one or more of phenyl.
Compound of the present invention, wherein each R2, R3, R5, R9Can be identical or different, separate is H,
D, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, C5H11, C6H13, C8H17, trifluoromethyl, hydroxyl first
Base, amino methyl, 3- hydroxyl-propyls, acetyl group, trifluoroacetyl group, Cyanoacetyl, methylamino acetyl group, third
Acyl group, iso-propionyl, 2- hydroxypropanoyls, 2- aminopropionyls, 2- chlorine propionos, 2- bromine propionos, valeryl,
Caproyl, heptanoyl group, methacrylyl, phenyl, benzoyl, p-nitrophenyl, to methyl benzoyl, fluorine
Benzoyl, p-benzoyl base, to methoxybenzoyl base, 2,4- dimethylbenzoyls, triazobenzene first
Acyl group, benzyl, p-chlorobenzyl, vinyl, acrylic, allyl, n-butene base, isobutenyl, n-pentene base,
Isopentene group, cyclopropyl, ring propiono, ring valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene, phenethyl miaow
Oxazolyl, pyridyl group, pyrrole radicals, oxazolyls, isoxazolyl, triazol radical, tetrazole base, furyl, pyranose,
Thienyl, thiazolyl, piperidyl, piperazinyl, indyl, carbazyl, benzofuranyl, tetrahydrofuran base, tetrahydrochysene
Pyranose, pyrimidine bases, purine bases, pentose base, hexose base ,-(C=O) NH-C1-C4 alkyl, C1-C4 alkane
Base-NH-S (=O)2, C1-C4 alkyl S (=O)2, phenyl-(CH2)P-G-(CH2)m, difluorophenyl-(CH2)P-G-
(CH2) m, thiazolyl-(CH2)p-G-(CH2)m, pyridyl group-(CH2)p-G-(CH2)m, phenylethyl, cyclohexyl-
(CH2)p-G-(CH2)m, wherein G is O, S, S (=O), S (=O)2, C(=O);P and m are each independently 0,1,2
Or 3;Or wherein C6-C10 aryl-(CH2)P-G-(CH2)mCan F, Cl, Br, I, first be selected from by one or more
The substituent group of base, ethyl, propyl, acetenyl, propinyl, butynyl, methoxyl group, ethyoxyl or cyano replaces;
Or above-mentioned R2, R3, R5, R9It is welcome by F, Cl, Br, I, hydroxyl, hydroxyl, methylol, carboxyl, acetyl ammonia
Base, C1-C6 alkyl (such as methyl, ethyl, propyl), C1-C6 alkoxies, C1-C6 alkylaminos, trifluoromethyl, trifluoroacetyl
Base, sulfydryl, nitro, amino, azido (- N3), guanidine radicals, cyano, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O),
Oxo (=O), thio (=S), sulfonyl, the substitution of one or more of phenyl.
In some embodiments, compound of the present invention including but not limited to following one structure or it is following it
It is the tautomer of one structure, stereoisomer, racemic modification, the non-equal amount of mixture of enantiomter, geometric isomer, molten
The solvate of agent compound, pharmaceutically acceptable salt or its salt, or prodrug:
。
The present invention includes the application of the compounds of this invention and its pharmaceutically acceptable salt, is controlled for producing medical product
Patient's disease caused by tubercle bacillus, parasite etc., including those diseases described in the invention are treated, the present invention includes medicine
Compositions, the pharmaceutical composition include the compound and at least one pharmaceutically acceptable carrier representated by general formula I-VI,
Excipient, diluent, adjuvant, effective therapeutic dose needed for the combination of medium.
On the other hand, preventing or treating to move using the compounds of this invention or its pharmaceutical composition the present invention relates to a kind of
The method for application of object or the human body various diseases caused by tubercle bacillus, parasite etc., the purposes include the change using the present invention
The pharmaceutically acceptable effective therapeutic dose for closing object or its pharmaceutical composition is administered human body or animal.
Some of embodiments are the diseases of the present invention caused by tubercle bacillus, parasite etc..The disease
By tubercle bacillus(tubercle bacillus)Or Mycobacterium marinum(Mycobacterium marinum)Caused disease,
Including diseases such as pulmonary tuberculosis, nephrophthisis, bone tuberculosis.
It is of the present invention by Plasmodium vivax(Plasmodium vivax), malariae(Plasmodium malariae), plasmodium falciparum(Plasmodium falciparum)And Plasmodium ovale(Plasmodium ovale), profit
Assorted graceful protozoon(Leishmania donovani)Caused disease, including malaria or leishmaniasis etc..
The present invention equally includes treatment or mitigates patient's disease caused by tubercle bacillus, parasite etc., or to this illness
Sensitive method, this method include to be treated to patient using the therapeutically effective amount of compound representated by general formula I-VI.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its
The content of his aspect will make more specific complete description below.
Definition and general terms
The present invention will be corresponding to the content determining materialization document list in detail, embodiment is all accompanied by structural formula
With the explanation of chemical formula.The present invention, which has, expectedly covers all choices, variant and coordinate, these possible pictures
Existing invention field is included in defined in claim like that.Those skilled in the art will identify many similar or equivalent
In method described herein and substance, these can be applied to the practice of the present invention.The present invention be limited to absolutely not method and
The description of substance.There are many documents and similar substance to distinguish or contradict with the present patent application, including but not limited to
The definition of term, the usage of term, the technology of description, or the range that is controlled as the present patent application.
The present invention will apply defined below unless other aspects show.Purpose according to the present invention, chemical element is according to member
Plain periodic table, CAS versions and chemicals handbook, 75,thEd, 1994 define.In addition, organic chemistry General Principle is shown in
“Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito:
1999, and “March's Advanced Organic Chemistry,” by Michael B. Smith and Jerry
March,John. Wiley&Sons, New York:2007, therefore all contents have all merged bibliography.
As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups,
Such as general formula compound above, or as example special inside embodiment, subclass, and one kindization that the present invention is included
Close object.It should be appreciated that this term can exchange use to " optionally replacing " this term with " substituted or non-substituted ".It is general and
Speech, term " optionally " whether it is before the term " replaced ", indicate that one or more of given structure hydrogen is former
Son is replaced by specific substituent group.Unless other aspects show, one optional substituent group can there are one substituent groups in base
The each commutable position of group is replaced.When more than one position can be by one for specific group in given structural formula
Or multiple substituent groups are replaced, then substituent group can replace at various locations identical or differently.The wherein substituent group
It can be, but be not limited to, halogenated alkyl, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy,
Alkylamino, alkylthio group, alkyl, alkenyl, alkynyl, heterocycle, sulfydryl, nitro, aryloxy group, heteroaryloxy, oxo
(=O), carboxyl, the alkoxy of hydroxyl substitution, the alkyl-C (=O)-of hydroxyl substitution, alkyl-C (=O)-, alkyl-S (=
O)-, alkyl-S (=O)2, the alkyl-S (=O)-of hydroxyl substitution, the alkyl-S (=O) of hydroxyl substitution2, Carboxyalkoxy etc.
Deng.
Terminology used in the present invention " aliphatic " or " aliphatic group " indicate straight chain(It is i.e. non-branched)Or branch, it takes
Generation or non-substituted fully saturated or containing one or more degrees of unsaturation hydrocarbon chain.Unless otherwise detailed instructions, fatty group
1-20 carbon atom is contained in group, and some of embodiments are that aliphatic group contains 1-10 carbon atom, and other is real
Applying example is, aliphatic group contains 1-8 carbon atom, and other embodiment is that it is former that aliphatic group contains 1-6 carbon
Son, other embodiment are that aliphatic group contains 1-4 carbon atom, and other embodiment is aliphatic group
Contain 1-3 carbon atom.Suitable aliphatic group is including but not limited to linear chain or branched chain is substituted or non-substituted
Alkyl, alkenyl or alkynyl, such as methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, hexyl, isobutyl group are secondary
Butyl, vinyl etc..
Terminology used in the present invention " halogenated aliphatic " indicates aliphatic group by one or more identical or different halogen
Atom is replaced, wherein aliphatic group have meaning as described in the present invention, halogen atom, that is, fluorine, chlorine, bromine or iodine, in this way
Example including but not limited to trifluoromethyl, trifluoroethyl, chloromethyl, 2- chlorovinyls etc..
Terminology used in the present invention " hydroxyl group aliphatic " indicates that aliphatic group is replaced by one or more hydroxyl groups,
Wherein aliphatic group has meaning as described in the present invention, and such example is including but not limited to ethoxy, 2- hydroxyls
Base propyl, methylol etc..
Terminology used in the present invention " amino aliphatic " indicates that aliphatic group is replaced by one or more amino groups,
Wherein aliphatic group has meaning as described in the present invention, and such example is including but not limited to amino methyl, 2-
Amino-ethyl, 2- amino isopropyls etc..
Terminology used in the present invention " alkyl " includes 1-20 carbon atom, or 1-10 carbon atom, or 1-6 carbon original
Son, or 1-4 carbon atom, or 1-3 carbon atom saturated straight chain or branch univalence hydrocarbyl, wherein alkyl can independently appoint
Selection of land is replaced by one or more substituent groups described in the invention.Alkyl more includes into one-year-old example, but and unlimited
In methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-
CH(CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu,
-CH(CH3)CH2CH3), tertiary butyl (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyls (- CH
(CH3)CH2CH2CH3), 3- amyls (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- fourths
Base (- CH (CH3)CH(CH3)2), 3- methyl-1s-butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butene base (- CH2CH(CH3)
CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2- hexyls (- CH (CH3)CH2CH2CH2CH3), 3- hexyls (- CH
(CH2CH3)(CH2CH2CH3)), 2- methyl -2- amyls (- C (CH3)2CH2CH2CH3), 3- methyl -2- amyls (- CH (CH3)CH
(CH3)CH2CH3), 4- methyl -2- amyls (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- amyls (- C (CH3)
(CH2CH3)2), 2- methyl -3- amyls (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH
(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc..Term " alkyl " and
Its prefix " alkane " uses here, all includes the saturated carbon chains of straight chain and branch.
Term " alkenyl " indicates 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or 2-4 carbon original
The monovalent hydrocarbon of sub- linear chain or branched chain, wherein at least one position are undersaturated condition, i.e., a C-C is sp2Double bond,
The group of alkenyl groups can be replaced by one or more substituent groups described in the invention individually optionally, including group
Have negation " just " or " E ∥ Z " positioning, wherein specific example is including but not limited to vinyl (- CH=CH2), alkene
Propyl (- CH2CH=CH2), etc..
Term " alkynyl " indicates 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or 2-4 carbon original
The monovalent hydrocarbon of sub- linear chain or branched chain, wherein at least one position are undersaturated condition, i.e., a C-C is tri- keys of sp, wherein
Alkynyl group can be replaced by one or more substituent groups described in the invention individually optionally, and specific example includes,
But it is not limited to, acetenyl (three CH of-C), propargyl (- CH2Tri- CH of C), etc..
Term " alkyl of hydroxyl substitution " indicates that alkyl group is replaced by one or more hydroxyl groups, wherein alkyl
Group has meaning of the present invention.Such example includes, but is not limited to methylol, ethoxy, l, 2- dihydroxies
Base ethyl etc..
Term " carbocyclic ring ", " carbocylic radical ", " naphthenic base " refer to monovalence or multivalence, non-aromatic, saturation or part insatiable hunger
And ring, and do not include hetero atom, two rings or tricyclic of monocycle or 7-12 carbon atom including 3-12 carbon atom.Tool
The bicyclic carbocyclic ring of 7-12 atom can be two rings [4.5], [5.5], [5.6] or [6.6] system, while have 9 or 10
The bicyclic carbocyclic ring of atom can be two rings [5.6] or [6.6] system.Suitable cyclic aliphatic group including but not limited to,
Naphthenic base, cycloalkenyl group and cycloalkynyl radical.The example of cyclic aliphatic group further comprises, but is not limited to, cyclopropyl, ring
Butyl, cyclopenta, 1- cyclopenta -1- alkenyls, 1- cyclopenta -2- alkenyls, 1- cyclopenta -3- alkenyls, cyclohexyl, 1- rings
Hexyl -1- alkenyls, 1- cyclohexyl -2- alkenyls, 1- cyclohexyl -3- alkenyls, cyclohexadienyl, suberyl, cyclooctyl, ring
Nonyl, cyclodecyl, ring undecyl, cyclo-dodecyl, adamantyl etc..And " carbocyclic ring ", " carbocylic radical ",
" naphthenic base " can be substituted or non-substituted, and wherein substituent group can be, but be not limited to, halogenated alkyl, hydroxyl,
Amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocycle, mercapto
Base, nitro, aryloxy group, the alkoxy of hydroxyl substitution, the alkyl-C (=O)-of hydroxyl substitution, alkyl-C (=O)-, alkyl-
S (=O)-, alkyl-S (=O)2, the alkyl-S (=O)-of hydroxyl substitution, the alkyl-S (=O) of hydroxyl substitution2, carboxyl alcoxyl
Base etc..
Term " cycloalkyl oxy " or " carbocylic radical oxygroup " include the naphthenic base optionally replaced or carbocylic radical, such as present invention
It is defined, it is connected on oxygen atom, and be connected with remaining molecule by oxygen atom, such example includes, but not
It is limited to cyclopropyl oxygroup, cyclopentyloxy, cyclohexyl oxygroup, the cyclopropyl oxygroup etc. of hydroxyl substitution.
Term " cycloalkyl amino " indicates that amino group is replaced by one or two group of naphthene base, wherein naphthenic base
With meaning as described in the present invention, such example is including but not limited to cyclopropylamino, clopentylamino, ring
Hexylamino, the cyclopropylamino of hydroxyl substitution, dicyclohexyl amino, Bicyclopropyl amino etc..
Term " cycloalkyl oxy aliphatic " indicates that aliphatic group is replaced by one or more cycloalkyl oxy groups,
Wherein aliphatic group and cycloalkyl oxy group have meaning as described in the present invention, and such example includes, but not
It is limited to cyclopropyl oxygroup methyl, cyclopropyl oxygroup ethyl, cyclopentyloxymethyl, cyclopentyloxy ethyl, cyclohexyl oxygen
Base ethyl, halogenated cyclopropyl oxygroup ethyl etc..
Term " cycloalkyl amino aliphatic " indicates that aliphatic group is replaced by one or more cycloalkylamino groups,
Wherein aliphatic group and cycloalkylamino group have meaning as described in the present invention, and such example includes, but not
It is limited to Cyclopropylaminomethyl, cyclopropylamino hexyl, clopentylamino methyl, clopentylamino ethyl, cyclohexyl ammonia
Base ethyl, halogenated cyclopropyl amino-ethyl etc..
Term " naphthenic base aliphatic " or " carbocylic radical aliphatic " indicate that aliphatic group can be by one or more naphthenic base
Group or carbocylic radical group are replaced, wherein naphthenic base, or carbocylic radical and aliphatic group have and contain as described in the present invention
Justice, such example is including but not limited to Cvclopropvlmethvl, cyclopropylethyl, Cyclopropylpropyl, cyclopentyl-methyl,
Cyclohexyl-ethyl etc..
Term " heterocycle ", " heterocycle ", " heteroalicyclic " or " heterocycle " are used interchangeably here, all refer to list
Ring, bicyclic, or three-ring system, one or more atoms are replaced by hetero atom individually optionally in beanstalk middle ring, and ring can be with
It is fully saturated or comprising one or more degrees of unsaturation, but definitely not aromatic, is only connected to there are one tie point
Other molecules get on.One or more ring hydrogen atoms are individually optionally by one or more substituent groups described in the invention
Replaced.Some of embodiments are that " heterocycle " " heterocycle " " heteroalicyclic " or " heterocycle " group are the lists of 3-7 membered rings
Ring(1-6 carbon atom and be N, O, P, the 1-3 hetero atom of S, in this S or P optionally by one or more oxygen atom institutes
Substitution is obtained as SO, SO2, PO, PO2Group, when the ring is a three-membered ring, only one of which hetero atom),
Or 7-10 members is bicyclic(4-9 carbon atom and be N, O, P, the 1-3 hetero atom of S, in this S or P optionally by one or
Multiple oxygen atoms replace to obtain as SO, SO2, PO, PO2Group).
Heterocycle can be carbon-based or heteroatom group." heterocycle " equally also includes heterocyclic group and saturation or part insatiable hunger
With ring or heterocycle and close be formed by group.The example of heterocycle is including but not limited to, pyrrolidinyl, tetrahydrofuran base,
Dihydrofuryl, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl,
Thio-morpholinyl, thioalkyls, piperazinyl, high piperazine base, azelidinyl, oxetanylmethoxy, thietanyl,
Piperidyl, homopiperidinyl, glycidyl, azacycloheptyl, oxetane, thiocycloheptyl, 4- methoxyl groups-piperazine
Pyridine -1- bases, l, 2,3,6- tetrahydropyridine -1- bases, oxygen azatropylidene base, diazepine base, sulphur azatropylidene base, pyrroles
Quinoline -1- bases, 2- pyrrolinyls, 3- pyrrolinyls, indolinyl, dihydro pyranyl, THP trtrahydropyranyl, dioxane
Hexyl, l, 3- dioxymyls, pyrazolinyl, dithianyl, dithienyl group, dihydrothiophene, pyrazolidinyl imidazoles
Quinoline base, imidazolidinyl, l, 2,3,4- tetrahydro isoquinolyls, l, 2,6- thiadiazine alkane l, 1- dioxy -2- bases, 4- hydroxyls
Base-l, 4- azepine phosphine 4- oxide -1- bases, 2- hydroxyls -1-(Piperazine -1- bases)Ethyl ketone -4- bases, 2- hydroxyl -1- (5,6-
Dihydro-l, 2,4- triazine-l (4H)-base)Ethyl ketone -4- bases, 5,6- dihydros -4H- 1,2,4- oxadiazine -4- bases, 2- hydroxyls
Base -1- (5,6- dihydropyridines-l (2H)-base)Ethyl ketone -4- bases, 3- azabicyclos [3.1.0] hexyl, 3- azabicyclos
[4.1.0] heptyl, azabicyclo [2.2.2] hexyl, 2- methyl -5,6,7,8- tetrahydrochysenes-[1,2,4] triazole [1,5-c]
Pyrimidine -6- bases, 4,5,6,7 1 tetrahydrochysene isoxazoles [4,3-c] pyridine -5- bases, 3HIndyl 2- oxygen -5- azabicyclos
[2.2.1] heptane -5- bases, 2- oxygen -5- azabicyclos [2.2.2] octane -5- bases, quinazinyl and N- pyridyl ureas.Heterocycle
The example of group further includes l, and two carbon atoms are replaced by oxygen atom as phonetic on 1- dioxidothiomorpholinyls, and its middle ring
Pyridine diketo.And the heterocycle can be substituted or non-substituted, and wherein substituent group can be, but be not limited to, halogen
Substituted alkyl, oxo (=O), hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl,
Alkynyl, heterocycle, sulfydryl, nitro, aryloxy group, the alkoxy of hydroxyl substitution, the alkyl-C (=O)-of hydroxyl substitution, alkane
Base-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2Alkyl-the S (=O)-of hydroxyl substitution, the alkyl-S of hydroxyl substitution
(=O)2, Carboxyalkoxy etc..
Term " heterocycle aliphatic " indicates the aliphatic group of heterocycle substitution, wherein heterocycle and aliphatic group
With meaning as described in the present invention, such example is including but not limited to pyrroles's -2- methyl, piperidines -2- ethyls,
Piperazine -2- ethyls, piperidines -2- methyl etc..
Term " heterocycle oxygroup " includes that the heterocycle optionally replaced is connected to oxygen atom as defined herein
On, wherein oxygen atom is connected with the rest part of molecule, and such example is including but not limited to pyrroles's -2- oxygroups, pyrrole
Cough up -3- oxygroups, piperidines -2- oxygroups, piperidines -3- oxygroups, piperazine -2- oxygroups, piperidines -4- oxygroups etc..
Term " heterocyclylamino group " indicates that amino group is replaced by one or two heterocyclyl groups, wherein nitrogen-atoms
It is connected with the rest part of molecule, and heterocycle has meaning as described in the present invention, such example includes, but simultaneously
It is not limited to pyrroles's -2- amino, pyrroles's -3- amino, piperidines -2- amino, piperidines -3- amino, piperidines -4- amino, piperazine -
2- amino, two pyrroles's -2- amino etc..
Term " heterocycle oxygroup aliphatic " indicates that aliphatic group is replaced by one or more heterocycle oxygroup groups,
Wherein aliphatic group and heterocycle oxygroup group have meaning as described in the present invention, and such example includes, but not
It is limited to pyrroles's-2- oxygroup methyl, piperazine-3- oxygroup ethyls, piperazine-2- oxygroup ethyls, morpholine -2-oxygroup methyl, piperidines-
2- oxygroup ethyls etc..Term " heterocyclylamino group aliphatic " indicates aliphatic group by one or more heterocyclylamino group group institutes
Replace, wherein aliphatic group and heterocyclylamino group group include with meaning as described in the present invention, such example,
But pyrroles's -2- amino methyls are not limited to, piperazine -3- amino-ethyls, piperazine -2- amino-ethyls, piperidines -2- amino-ethyls,
Morpholine -2-amino methyl etc..
Term " hetero atom " indicates one or more O, S, N, P and Se, includes the shape of any oxidation state of N, S and P
Formula;The form of primary, secondary, tertiary amine and quaternary ammonium salt;Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, such as, N (as
N in 3,4- dihydro-2 h-pyrrole bases), NH (as the NH in pyrrolidinyl) or NR are (in the pyrrolidinyl replaced as N-
NR)。
Term " halogen " refers to F, Cl, Br or I.
Contain one or more degrees of unsaturation in " undersaturated " the expression part of term as used in the present invention.
Term " alkoxy " used in the present invention, is related to alkyl, as defined in the present invention, passes through oxygen original
Son(" alkoxy ")It being connected in main carbochain, such example is including but not limited to methoxyl group, ethyoxyl, and third
Oxygroup, butoxy etc..And the alkoxy can be substituted or non-substituted, and wherein substituent group can be, but and unlimited
In, hydroxyl, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, sulfydryl, nitro etc..
Term " alkoxy of hydroxyl substitution " or " hydroxy alkoxy base " indicate alkoxy base by one or more hydroxyl bases
Group is replaced, and wherein alkoxy has meaning as described in the present invention, and such example is including but not limited to hydroxyl methoxy
Base, 2- hydroxyl-oxethyls, 2- hydroxy propyloxy groups, 2- hydroxyl isopropyl oxygen etc..
Term " aminoalkoxy " indicates that alkoxy base is replaced by one or more amino groups, wherein alkoxy
With meaning as described in the present invention, such example is including but not limited to ammonia methoxyl group, 2- amino ethoxies, 2-
Amino propoxyl group, 2- amino isopropoxies etc..
Term " halogenated alkyl " " halogenated alkenyl " and " halogenated alkoxy " indicate alkyl, and alkenyl or alkoxy can be by one
The case where a or multiple halogen atoms are replaced, such example is including but not limited to trifluoromethyl, the chloro- ethylene of 2-
Base, trifluoromethoxy etc..
Term " aryl " indicates monocycle altogether containing 6-14 membered rings, bicyclic, and tricyclic carbocyclic ring system, wherein, until
Few member ring systems are aromatic, and wherein each member ring systems includes 3-7 membered rings, and only there are one attachment point and molecules
Rest part is connected.Term " aryl " can be exchanged with term " aromatic rings " and be used, if aromatic rings may include phenyl, naphthalene
And anthracene.And the aryl can be substituted or non-substituted, and wherein substituent group can be, but be not limited to, alkyl halide
Base, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl,
Heterocycle, sulfydryl, nitro, aryloxy group, the alkoxy of hydroxyl substitution, the alkyl-C (=O)-of hydroxyl substitution, alkyl-C (=
O)-, alkyl-S (=O)-, alkyl-S (=O)2, the alkyl-S (=O)-of hydroxyl substitution, alkyl-the S (=O of hydroxyl substitution
)2, Carboxyalkoxy etc..
Term " difluorophenyl " indicates that phenyl group is replaced by one or more fluorine atoms.
Term " aromatic yl aliphat " indicates that aliphatic group is replaced by one or more aryl groups, wherein aliphatic
Group and aryl group have meaning as described in the present invention, and such example is including but not limited to phenethyl, benzene first
Base, to methylphenylethyl, styryl etc..
Term " aryloxy group " or " aryloxy " include that the aryl optionally replaced is connected to as defined herein
On oxygen atom, and it is connected with molecule rest part by oxygen atom, wherein aryl group has meaning as described in the present invention,
Such example is including but not limited to phenoxy group, toloxyl, ethylbenzene oxygroup etc..
Term " fragrant amino " indicates that amino group is replaced by one or two aryl group, and wherein aryl has such as this
The invention meaning, such example is including but not limited to phenyl amino, p-fluorophenyl amino, diphenyl amino,
Xylyl amino, di-p-tolyl amino etc..
Term " aryloxy group aliphatic " indicates that aliphatic group is replaced by one or more aryloxy groups, wherein virtue
Oxygroup and aliphatic group have a meaning as described in the present invention, such example including but not limited to phenoxymethyl,
Phenoxyethyl, tolyloxyethyl, phenoxy propyl etc..
Term " heteroaryloxy aliphatic " indicates that aliphatic group is replaced by one or more heteroaryloxy groups,
Middle heteroaryloxy and aliphatic group have meaning as described in the present invention, and such example is including but not limited to furans
Oxygroup methyl, 2-pyrimidinyl oxy ethyl etc..
Term " fragrant amino aliphatic " indicates that aliphatic group is replaced by one or more fragrant amino groups,
Middle fragrant amino and aliphatic group have meaning as described in the present invention, and such example is including but not limited to phenylamino
Methyl, phenylaminoethyl, toluidino ethyl, phenylamino propyl, phenylamino allyl etc..
Term " alkoxy aryl " indicates that alkoxy base is replaced by one or more aryl, wherein aryl and alcoxyl
Base has meaning of the present invention, and for such example including but not limited to Phenylmethoxy, phenyl ethoxy is right
Methylphenylmethoxy, phenyl-propoxy etc..And the aryl can be substituted or non-substituted, and wherein substituent group can be with
It is, but is not limited to, halogenated alkyl, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkane ammonia
Base, alkyl, alkenyl, alkynyl, heterocycle, sulfydryl, nitro, aryloxy group, the alkoxy of hydroxyl substitution, hydroxyl substitution
Alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2, the alkyl-S (=O)-of hydroxyl substitution,
Alkyl-the S (=O) of hydroxyl substitution2, Carboxyalkoxy etc..
Term " aryl alkane amino " indicate alkylamino radicals replaced by one or more aryl groups, wherein aryl and
Alkoxy has meaning of the present invention, and such example is including but not limited to phenyl methylamino, phenylethylamino,
Phenylpropylamino, p-methylphenyl methylamino etc..
Term " heteroaryl " can be used alone or as most of " heteroaryl alkyl " or " heteroarylalkoxy ",
Indicate the monocycle altogether containing 5-14 membered rings, it is bicyclic, and three-ring system, wherein at least one member ring systems are aromatic, and
At least one member ring systems include one or more hetero atoms, and wherein each member ring systems includes 3-7 membered rings, and only there are one attached
Point with molecule rest part to be connected.Term " heteroaryl " can be exchanged with term " heteroaromatic " or " heteroaromatics " to be made
With.And the heteroaryl can be substituted or non-substituted, and wherein substituent group can be, but be not limited to, alkyl halide
Base, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl,
Heterocycle, sulfydryl, nitro, aryloxy group, the alkoxy of hydroxyl substitution, the alkyl-C (=O)-of hydroxyl substitution, alkyl-C (=
O)-, alkyl-S (=O)-, alkyl-S (=O)2, the alkyl-S (=O)-of hydroxyl substitution, alkyl-the S (=O of hydroxyl substitution
)2, Carboxyalkoxy etc..
Other embodiment is that heteroaromatic includes monocycle below, but is not limited to these monocycles:2- furyls,
3- furyls, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyls, 4- isoxazolyls, 5-
Isoxazolyl, 2- oxazolyls, 4- oxazolyls, 5- oxazolyls, 4- methyl-isoxazole -5- bases, N- pyrrole radicals, 2- pyrroles
Base, 3- pyrrole radicals, 2- pyridyl groups, 3- pyridyl groups, 4- pyridyl groups, 2- pyrimidine radicals, 4- pyrimidine radicals, pyrimidine -5- bases are rattled away
Piperazine base(Such as 3- pyridazinyls), 2- thiazolyls, 4- thiazolyls, 5- thiazolyls, tetrazole radical(Such as 5- tetrazole radicals), triazolyl(Such as
2- triazolyls and 5- triazolyls), 2- thienyls, 3- thienyls, pyrazolyl(Such as 2- pyrazolyls), isothiazolyl, l, 2,
3- oxadiazolyls, l, 2,5- oxadiazolyls, l, 2,4- oxadiazolyls, l, 2,3- triazolyls, l, 2,3- are thio
Di azoly, l, 3,4- thio biphosphole bases, l, 2,5- thio biphosphole bases, l, 3,4- thiadiazoles -2- bases, pyrazinyl,
Pyrazine -2- bases, l, 3,5- triazine radicals, benzothiazole -2- bases, imidazo [1,5-a] pyridine -6- bases;Also include following
It is bicyclic, but it is bicyclic to be not limited to these:Benzimidazolyl, benzofuranyl, benzothienyl, benzothiazolyl, Yin
Diindyl base(Such as 2- indyls), purine radicals, quinolyl(Such as 2- quinolyls, 3- quinolyls, 4- quinolyls), and isoquinolyl
(Such as 1- isoquinolyls, 3- isoquinolyls or 4- isoquinolyls).
Term " heteroaryl oxygroup " includes that the heteroaryl optionally replaced is connected to oxygen atom as defined herein
On, and be connected with molecule rest part by oxygen atom, wherein heteroaryl groups have meaning as described in the present invention, this
The example of sample is including but not limited to pyridine -2- oxygroups, thiazole -2- oxygroups, imidazoles -2- oxygroups, pyrimidine -2- oxygroups etc..
Term " Carboxyalkoxy " indicates that alkoxy base is replaced by one or more carboxylic groups, wherein alkoxy
There is meaning as described in the present invention with carboxylic group, such example is including but not limited to Carboxvmethoxv, carboxyl
Ethyoxyl etc..
Term " alkylthio group " includes that the alkyl of Cl-C10 linear chain or branched chains is connected on the sulphur atom of divalent.It is some of real
Applying example is, alkylthio group is the C1-C3 alkylthio groups of lower level, and such example is including but not limited to methyl mercapto(CH3S-).
Term " halogenated alkylthio " includes that the halogenated alkyl of Cl-C10 is connected on bivalent sulfur atom.Some of embodiments are, halogenated
Alkylthio group is the C1-C3 halogenated alkylthios of lower level, and such example is including but not limited to trifluoromethylthio.
Term " alkyl amino ", or " alkylamino ", including " N- alkyl aminos " and " N, N- dialkyl amido ", wherein
Amine groups separately drive generation by one or two alkyl group.Some of embodiments are, alkyl amino be one or
Two C1-C6 alkyl are connected to the alkylamino group of the lower level on nitrogen-atoms.Other embodiment is alkyl amino
It is the alkylamino group of the lower level of C1-C3.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido,
Such example is including but not limited to, N- methylaminos, N- ethylaminos, N, N- dimethylaminos, N, N- lignocaines
Etc..
Term " heteroaryl amino " indicates that amine groups are replaced by one or two heteroaryl, and wherein heteroaryl has this
The invention meaning, such example is including but not limited to N- thienyl amino etc..Some of embodiments are, miscellaneous
Hetero-aromatic ring on arylamino can be further substituted.
Term " heteroaryl aliphatic " indicates that aliphatic group is replaced by one or more heteroaryls, wherein heteroaryl
There is meaning of the present invention with aliphatic group, such example is including but not limited to thiophene -2- acrylic, pyrrole
Pyridine -4- ethyls, imidazoles -2- methyl, furans -2- ethyls, indoles -3- methyl etc..
Term " heteroaryl alkyl " indicates that alkyl group is replaced by one or more heteroaryls, wherein heteroaryl and alkane
There is base group meaning of the present invention, such example to include but be not limited to imidazoles -2- methyl, furans -2- second
Base, indoles -3- methyl etc..
Term " heteroarylalkylamino " includes that the heteroarylalkyl group containing nitrogen-atoms is connected to other by nitrogen-atoms
On group, wherein heteroaryl alkyl has meaning as described in the present invention, and such example is including but not limited to pyridine-
2- base methylaminos, thiazol-2-yl ethylamino, imidazoles -2- base ethylaminos, the third amino of pyrimidine -2-base, pyrimidine -2-base first ammonia
Base etc..
Term " heteroarylalkoxy " includes that the heteroarylalkyl group containing oxygen atom is connected to other by oxygen atom
On group, wherein heteroaryl alkyl has meaning as described in the present invention, and such example is including but not limited to pyridine-
2- ylmethoxies, thiazol-2-yl ethyoxyl, imidazoles -2- base oxethyls, pyrimidine -2-base propoxyl group, pyrimidine -2-base first ammonia
Base.
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base ", " condensed ring radical " indicate saturated or unsaturated condensed ring
System is related to the bicyclic system of non-aromatic.Such system can include independent or conjugation undersaturated condition, but
Its nuclear structure does not include aromatic rings or heteroaromatic(But aromatic series can be as substituent group thereon).It is every in condensed-bicyclic
One ring is either carbocyclic ring or is heteroalicyclic, and such example is including but not limited to, hexahydro furyl simultaneously [3,2-
B] furans, 2,3,3a, 4,7,6- hexahydros -1HIndenes, 7- azabicyclos [2.3.0] heptane, condensed-bicyclic [3.3.0]
Octane, condensed-bicyclic [3.1.0] hexane, l, 2,3,4,4a, 5,8,8a- octahydro naphthalenes, these are included in condensed
Within bicyclic system.And the condensed-bicyclic base can be substituted or non-substituted, and wherein substituent group can be, but simultaneously
It is not limited to, halogenated alkyl, oxo (=O), hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkane
Amino, alkyl, alkenyl, alkynyl, heterocycle, sulfydryl, nitro, aryloxy group, the alkoxy of hydroxyl substitution, hydroxyl take
Alkyl-the C (=O)-in generation, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2, hydroxyl substitution alkyl-S (=
O)-, the alkyl-S (=O) of hydroxyl substitution2, Carboxyalkoxy etc..
Term " condensing miscellaneous bicyclic group " indicates saturated or unsaturated fused ring system, is related to the bicyclic body of non-aromatic
System.Such system can include independent or conjugation undersaturated condition, but its nuclear structure does not include aromatic rings or virtue is miscellaneous
Ring(But aromatic series can be as substituent group thereon).And at least one member ring systems include one or more hetero atoms, wherein
Each member ring systems include 3-7 membered rings, that is, include 1-6 carbon atom and be N, O, P, the 1-3 hetero atom of S, in this S
Or P optionally is replaced to obtain as SO, SO by one or more oxygen atoms2, PO, PO2Group, such example includes,
But it is not limited to hexahydro furyl simultaneously [3,2-b] furans, 7- azabicyclos [2.3.0] heptane etc..And it is described condensed miscellaneous bicyclic
Base can be substituted or non-substituted, and wherein substituent group can be, but be not limited to, halogenated alkyl, oxo (=O), hydroxyl
Base, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocycle,
Sulfydryl, nitro, aryloxy group, the alkoxy of hydroxyl substitution, the alkyl-C (=O)-of hydroxyl substitution, alkyl-C (=O)-, alkane
Base-S (=O)-, alkyl-S (=O)2, the alkyl-S (=O)-of hydroxyl substitution, the alkyl-S (=O) of hydroxyl substitution2, carboxyl
Alkoxy etc..
Term " condensed-bicyclic base aliphatic " indicates that aliphatic group is replaced by one or more condensed-bicyclic base groups,
Wherein aliphatic group and condensed-bicyclic base group have meaning as described in the present invention, and such example includes, but not
It is limited to l, 2,3,4,4a, 5,8,8a- octahydro naphtylethyl groups, l, 2,3,4,4a, 5,8,8a- octahydro naphthalenes
Methyl, l, 2,3,4,4a, 5,8,8a- octahydro naphthylpropyls, condensed-bicyclic [3.3.0] octane ylmethyl condense
Bicyclic [3.1.0] hexyl ethyl etc..
Term " condensing miscellaneous bicyclic group aliphatic " indicates that aliphatic group condenses miscellaneous bicyclic group group institute by one or more
Replace, wherein aliphatic group and condensed miscellaneous bicyclic group group include with meaning as described in the present invention, such example,
But hexahydro furyl simultaneously [3,2-b] furans -2- base ethyls are not limited to, hexahydro furyl simultaneously [3,2-b] furans -2- ylmethyls,
7- azabicyclos [2.3.0] heptane -2- ylmethyls, 7- azabicyclos [2.3.0] heptane -2- base ethyls, 7- azabicyclos
[2.3.0] heptane -4- ylmethyls etc..
Term " condensed-bicyclic base oxygroup " includes the condensed-bicyclic base optionally replaced, as defined in the present invention, connection
It is connected with molecule rest part onto oxygen atom, and by oxygen atom, such example is including but not limited to l, and 2,
3,4,4a, 5,8,8a- octahydro naphthalene oxygroup, condensed-bicyclic [3.3.0] octane -2- oxygroups, condensed-bicyclic [3.1.0]
Hexane -2- oxygroups etc..
Term " condensing miscellaneous bicyclic group oxygroup " includes the condensed miscellaneous bicyclic group optionally replaced, as defined in the present invention,
It is connected on oxygen atom, and is connected with molecule rest part by oxygen atom, such example is including but not limited to six
Hydrogen-furans simultaneously [3,2-b] furans -2- base oxygroups, 7- azabicyclos [2.3.0] heptane -2- base oxygroups, 7- azabicyclos
[2.3.0] heptane -4- base oxygroups etc..
Term " condensed-bicyclic base amino " indicates that amino group is replaced by one or two condensed-bicyclic base, wherein thick
Closing bicyclic group has meaning as described in the present invention, such example including but not limited to l, 2,3,4,4a, 5,
8,8a- octahydro naphthyl-aminos, two(1,2,3,4,4a, 5,8,8a- octahydro naphthalene)Amino, condensed-bicyclic
[3.3.0] octyl amino, condensed-bicyclic [3.1.0] hexyl amino etc..
Term " condensing miscellaneous bicyclic group amino " indicates that amino group condenses miscellaneous bicyclic group by one or two and replaces,
In condense miscellaneous bicyclic group have meaning as described in the present invention, such example including but not limited to hexahydro-furans simultaneously
[3,2-b] furans -2- base amino, -2 base amino of 7- azabicyclos [2.3.0] heptane, 7- azabicyclos [2.3.0] heptane -
4- base amino etc..
Term " condensed-bicyclic base alkylamino " indicates that alkylamino radicals are replaced by one or more condensed-bicyclic bases,
Middle condensed-bicyclic base has meaning as described in the present invention, such example including but not limited to l, 2,3,4,4a,
5,8,8a- octahydro napthylmethylaminos, two(1,2,3,4,4a, 5,8,8a- octahydro naphthalene)Methylamino condenses double
Ring [3.3.0] octyl methylamino, condensed-bicyclic [3.1.0] hexyl methylamino etc..
Term " condensing miscellaneous bicyclic group alkylamino " indicates that alkylamino radicals condense miscellaneous bicyclic group by one or more and replace,
Wherein condense miscellaneous bicyclic group have meaning as described in the present invention, such example including but not limited to hexahydro-furans simultaneously
[3,2-b] furans -2- base methylaminos, 7- azabicyclos [2.3.0] heptane -2- base methylaminos, 7- azabicyclos [2.3.0]
Heptane -4- base methylaminos etc..
Term " condensed-bicyclic base alkoxy " indicates that alkoxy is replaced by one or more condensed-bicyclic base groups,
Middle alkoxy and condensed-bicyclic base have a meaning as described in the present invention, and such example is including but not limited to l, and 2,
3,4,4a, 5,8,8a- octahydro naphthylmethoxy, l, 2,3,4,4a, 5,8,8a- octahydro naphthalene ethyoxyls,
Condensed-bicyclic [3.3.0] octane ethyoxyl, condensed-bicyclic [3.1.0] hexane-propoxyl group etc..
Term " condensing miscellaneous bicyclic group alkoxy " indicates that alkoxy condenses miscellaneous bicyclic group group by one or more and replaces,
Wherein alkoxy and condensed miscellaneous bicyclic group has meaning as described in the present invention, and such example color includes, but is not limited to six
Simultaneously [3,2-b] furans -2- base propoxyl group, 7- azabicyclos [2.2.1] heptane -2- base oxethyls, 7- azepines are double for hydrogen-furans
Ring [2.3.0] heptane -4- base propoxyl group, hexahydro-furans simultaneously [3,2-b] furans -2- base oxethyls, 7- azabicyclos
[2.3.0] heptane -2- base propoxyl group, 7- azabicyclos [2.3.0] heptane -4- base oxethyls etc..
Term " condensed-bicyclic base oxygroup alkoxy " indicates alkoxy by one or more condensed-bicyclic base oxygroup groups institute
Replace, wherein alkoxy and condensed-bicyclic base oxygroup include with meaning as described in the present invention, such example, but simultaneously
It is not limited to l, 2,3,4,4a, 5,8,8a- octahydro naphthalene Oxymethoxies, l, 2,3,4,4a, 5,8,8a-
Octahydro naphthalene oxygroup ethyoxyl, condensed-bicyclic [3.3.0] octane -2- oxygroup ethyoxyls, condensed-bicyclic [3.1.0] hexane -2-
Oxygroup propoxyl group etc..
Term " condensing miscellaneous bicyclic group oxygroup alkoxy " indicates that alkoxy condenses miscellaneous bicyclic group oxygroup base by one or more
Group is replaced, and wherein alkoxy and condensed miscellaneous bicyclic group oxygroup include with meaning as described in the present invention, such example,
But it is not limited to hexahydro-furans simultaneously [3,2-b] furans -2- base oxygroup propoxyl group, 7- azabicyclos [2.2.1] heptane -2- bases
Oxygroup ethyoxyl, 7- azabicyclos [2.3.0] heptane -4- base oxygroup propoxyl group, hexahydro-furans simultaneously [3,2-b] furans -2-
Base oxygroup ethyoxyl, 7- azabicyclos [2.3.0] heptane -2- base oxygroup propoxyl group, 7- azabicyclos [2.3.0] heptane -4-
Base oxygroup ethyoxyl etc..
Term " condensed-bicyclic base aminoalkoxy " indicates that alkoxy is replaced by one or more condensed-bicyclic base amino,
Wherein alkoxy and condensed-bicyclic base amino have meaning as described in the present invention, such example including but not limited to
L, 2,3,4,4a, 5,8,8a- octahydro naphthyl-amino ethyoxyl, l, 2,3,4,4a, 5,8,8a- octahydro naphthalenes
Base amino propoxyl group, two(1,2,3,4,4a, 5,8,8a- octahydro naphthalene)Amino propoxyl group, condensed-bicyclic
[3.3.0] octane -2- amino ethoxies, condensed-bicyclic [3.1.0] hexane -2- amino propoxyl group etc..
Term " condensing miscellaneous bicyclic group aminoalkoxy " indicates that alkoxy condenses miscellaneous bicyclic group amino institute by one or more
Replace, wherein alkoxy and condensed miscellaneous bicyclic group amino include with meaning as described in the present invention, such example, but
It is not limited to 7- azabicyclos [2.2.1] heptane -2- base amino ethoxies, 7- azabicyclos [2.3.0] heptane -4- base amino
Propoxyl group, hexahydro-furans simultaneously [3,2-b] furans -2- base amino ethoxies, hexahydro-furans simultaneously [3,2-b] furans -2- bases
Amino propoxyl group, hexahydro-furans simultaneously [3,2-b] furans -2- base aminomethoxies etc..
Term " loop coil base ", " loop coil ", " spiral shell bicyclic group ", " spiral shell is bicyclic " indicate a ring originating from another ring
Particularly ring-shaped carbon.Such as disclosed below, the bridged-ring system of a saturation(Ring B and B ')It is referred to as " condensed double
Ring ", otherwise a shared carbon atom in the member ring systems that be saturateds at two of ring A and ring B, then be referred to as " loop coil ".Inside loop coil
Each ring be either carbocyclic ring or be heteroalicyclic.Such example is including but not limited to 2,7- diaza spiros
[4.4] nonane -2- bases, 7- oxygen -2- azaspiros [4.5] decane -2- bases, 4- azaspiros [2.4] heptane -5- bases, 4- oxaspiros
[2.4] heptane -5- bases, 5- azaspiros [2.4] heptane -5- bases, spiral shell [2.4] heptane base, spiral shell [4.4] nonyl, 7- hydroxyls -
5- azaspiros [2.4] heptane -5- bases etc..And the spiral shell bicyclic group can be substituted or non-substituted, and wherein substituent group can be with
It is, but is not limited to, halogenated alkyl, oxo (=O), hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkane
Oxygroup, alkylamino, alkyl, alkenyl, alkynyl, heterocycle, sulfydryl, nitro, aryloxy group, the alkoxy of hydroxyl substitution,
Alkyl-the C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O) of hydroxyl substitution2, the alkane of hydroxyl substitution
Base-S (=O)-, the alkyl-S (=O) of hydroxyl substitution2, Carboxyalkoxy etc..
Term " the miscellaneous bicyclic group of spiral shell " indicates a ring originating from particularly ring-shaped carbon on another ring.Such as institute above
Description, the bridged-ring system of a saturation(Ring B and B ')It is referred to as " condensed-bicyclic ", on the contrary what ring A and ring B was saturated at two
A carbon atom is shared in member ring systems, then is referred to as " loop coil ".And at least one member ring systems include one or more hetero atoms,
Wherein each member ring systems include 3-7 membered rings, that is, include 1-6 carbon atom and be N, O, P, the 1-3 hetero atom of S,
This S or P optionally is replaced to obtain as SO, SO by one or more oxygen atoms2, PO, PO2, group, such example
Including but not limited to 4- azaspiros [2.4] heptane -5- bases, 4- oxaspiros [2.4] heptane -5- bases, 5- azaspiros [2.4]
Heptane -5- bases, 7- hydroxyl -5- azaspiros [2.4] heptane -5- bases etc..And the miscellaneous bicyclic group of spiral shell can be substitution or non-take
Generation, wherein substituent group can be, but be not limited to, halogenated alkyl, oxo (=O), hydroxyl, amino, halogen, cyanogen
Base, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocycle, sulfydryl, nitro, fragrant oxygen
Base, the alkoxy of hydroxyl substitution, the alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S of hydroxyl substitution
(=O)2, the alkyl-S (=O)-of hydroxyl substitution, the alkyl-S (=O) of hydroxyl substitution2, Carboxyalkoxy etc..
Term " spiral shell bicyclic group aliphatic " indicates that aliphatic group is replaced by one or more spiral shell bicyclic group groups,
Middle aliphatic group and spiral shell bicyclic group group have a meaning as described in the present invention, such example including but not limited to
Spiral shell [2.4] heptane ylmethyl, spiral shell [2.4] heptane base ethyl, spiral shell [2.4] heptane base propyl, spiral shell [4.4] nonane ylmethyl,
Spiral shell 4.4] nonyl ethyl, 4- azaspiros [2.4] heptane -5- ylmethyls, 4- azaspiros [2.4] heptane -5- base ethyls, 4-
Oxaspiro [2.4] heptane -5- base ethyls, 5- azaspiros [2.4] heptane -5- base propyl, 7- hydroxyl -5- azaspiros [2.4] heptan
Alkane -5- base propyl etc..
Term " the miscellaneous bicyclic group aliphatic of spiral shell " indicates that aliphatic group is replaced by the miscellaneous bicyclic group group of one or more spiral shells,
Wherein the miscellaneous bicyclic group group of aliphatic group and spiral shell has meaning as described in the present invention, and such example includes, but not
It is limited to 4- azaspiros [2.4] heptane -5- ylmethyls, 4- azaspiros [2.4] heptane -5- base ethyls, 4- oxaspiros [2.4] heptan
Alkane -5- base ethyls, 5- azaspiros [2.4] heptane -5- base propyl, 7- hydroxyl -5- azaspiros [2.4] heptane -5- base propyl etc..
Term " spiral shell bicyclic group oxygroup " includes that the spiral shell bicyclic group optionally replaced is connected to oxygen as defined in the present invention
On atom, and it is connected with molecule rest part by oxygen atom, such example is including but not limited to spiral shell [2.4] heptan
Alkane -2- oxygroups, spiral shell [2.4] heptane -3- oxygroups, spiral shell [2.4] heptane -4- oxygroups, spiral shell [4.4] nonane -2- oxygroups, spiral shell
[4.4] nonane -4- oxygroups, 4- azaspiros [2.4] heptane -5- oxygroups etc..
Term " the miscellaneous bicyclic group oxygroup of spiral shell " includes the miscellaneous bicyclic group of spiral shell optionally replaced, as defined in the present invention, connection
It is connected with molecule rest part onto oxygen atom, and by oxygen atom, such example is including but not limited to 4- azepines
Spiral shell [2.4] heptane -5- base oxygroups, 4- oxaspiros [2.4] heptane -5- base oxygroups, 5- azaspiros [2.4] heptane -5- base oxygroups
Deng.
Term " spiral shell bicyclic group amino " indicates that amino group is replaced by one or two spiral shell bicyclic group group, wherein spiral shell
Bicyclic group has meaning as described in the present invention, such example including but not limited to spiral shell [2.4] heptane -2- amino,
Spiral shell [2.4] heptane -3- amino, spiral shell [2.4] heptane -4- amino, spiral shell [4.4] nonane -2- amino, spiral shell [4.4] nonane -4- ammonia
Base, 4- azaspiros [2.4] heptane -5- amino etc..
Term " the miscellaneous bicyclic group amino of spiral shell " indicates that amino group is replaced by the miscellaneous bicyclic group group of one or two spiral shell,
The middle miscellaneous bicyclic group of spiral shell has meaning as described in the present invention, and such example is including but not limited to 4- azaspiros [2.4] heptan
Alkane -5- base amino, 4- azaspiros [2.4] heptane -2- base amino, 4- oxaspiros [2.4] heptane -5- base amino, 5- azaspiros
[2.4] heptane -5- bases amino etc..
Term " spiral shell bicyclic group alkoxy " indicates that alkoxy base is replaced by one or more spiral shell bicyclic groups, wherein spiral shell
Bicyclic group and alkoxy base have meaning as described in the present invention, and such example is including but not limited to spiral shell [2.4] heptan
Alkane -2- methoxyl groups, spiral shell [2.4] heptane -3- ethyoxyls, spiral shell [2.4] heptane -4- ethyoxyls, spiral shell [4.4] nonane -2- methoxies
Base, spiral shell [4.4] nonane -4- propoxyl group, 4- azaspiros [2.4] heptane -5- methoxyl groups etc..
Term " the miscellaneous bicyclic group alkoxy of spiral shell " indicates that alkoxy base is replaced by the miscellaneous bicyclic group of one or more spiral shells,
The miscellaneous bicyclic group of middle spiral shell and alkoxy base have meaning as described in the present invention, and such example is including but not limited to 4-
Azaspiro [2.4] heptane -5- ylmethoxies, 4- azaspiros [2.4] heptane -2- base oxethyls, 4- oxaspiros [2.4] heptane -
5- base oxethyls, 5- azaspiros [2.4] heptane -5- base propoxyl group etc..
Term " spiral shell bicyclic group alkylamino " indicates that alkylamino radicals are replaced by one or more spiral shell bicyclic groups, wherein spiral shell
Bicyclic group and alkylamino radicals have meaning as described in the present invention, and such example is including but not limited to spiral shell [2.4] heptan
Alkane -2- methylaminos, spiral shell [2.4] heptane -3- ethylaminos, spiral shell [2.4] heptane -4- ethylaminos, spiral shell [4.4] nonane -2- first ammonia
Base, spiral shell [4.4] third amino of nonane -4-, 4- azaspiros [2.4] heptane -5- methylaminos etc..
Term " the miscellaneous bicyclic group alkylamino of spiral shell " alkylamino radicals are replaced by the miscellaneous bicyclic group of one or more spiral shells, wherein spiral shell
Miscellaneous bicyclic group and alkylamino radicals have meaning as described in the present invention, and such example is including but not limited to 4- azepines
Spiral shell [2.4] heptane -5- base methylaminos, 4- azaspiros [2.4] heptane -2- base ethylaminos, 4- oxaspiros [2.4] heptane -5- bases
Ethylamino, 5- azaspiros [2.4] heptane -5- third amino of base etc..
Term " spiral shell bicyclic group oxygroup alkoxy " indicates that alkoxy is replaced by one or more spiral shell bicyclic group oxygroup groups,
Wherein spiral shell bicyclic group oxygroup and alkoxy base have meaning as described in the present invention, and such example includes, but and unlimited
In spiral shell [2.4] heptane -2- oxygroup ethyoxyls, spiral shell [2.4] heptane -3- oxygroup propoxyl group, spiral shell [2.4] heptane -4- the third oxygen of oxygroup
Base, spiral shell [4.4] nonane -2- oxygroup ethyoxyls, spiral shell [4.4] nonane -4- oxygroup propoxyl group, 4- azaspiros [2.4] heptane -5-
Oxygroup propoxyl group etc..
Term " the miscellaneous bicyclic group oxygroup alkoxy of spiral shell " indicates alkoxy by the miscellaneous bicyclic group oxygroup group institute of one or more spiral shells
Replace, wherein the miscellaneous bicyclic group oxygroup of spiral shell and alkoxy base include with meaning as described in the present invention, such example,
But 4- azaspiros [2.4] heptane -5- base oxygroup ethyoxyls are not limited to, 4- oxaspiros [2.4] heptane -5- base oxygroup ethyoxyls,
5- azaspiros [2.4] heptane -5- base oxygroup ethyoxyls, 4- azaspiros [2.4] heptane -5- base oxygroup propoxyl group, 4- oxaspiros
[2.4] heptane -5- bases oxygroup propoxyl group, 5- azaspiros [2.4] heptane -5- base oxygroup propoxyl group etc..
Term " spiral shell bicyclic group aminoalkoxy " indicates that alkoxy is replaced by one or more spiral shell bicyclic group amino,
Middle alkoxy and spiral shell bicyclic group amino have meaning as described in the present invention, and such example is including but not limited to spiral shell
[2.4] heptane -2- amino ethoxies, spiral shell [2.4] heptane -3- amino propoxyl group, spiral shell [2.4] heptane -4- amino ethoxies,
Spiral shell [4.4] nonane -2- amino ethoxies, spiral shell [4.4] nonane -4- amino propoxyl group, 4- azaspiros [2.4] heptane -5- amino
Propoxyl group etc..
Term " the miscellaneous bicyclic group aminoalkoxy of spiral shell " indicates that alkoxy is replaced by the miscellaneous bicyclic group amino of one or more spiral shells,
Wherein the miscellaneous bicyclic group amino of alkoxy and spiral shell have meaning as described in the present invention, such example including but not limited to
4- azaspiros [2.4] heptane -5- base amino ethoxies, two oxygroup of 4- azaspiros [2.4] heptane -2- bases amino, 4- oxaspiros
[2.4] heptane -5- bases amino ethoxy, 5- azaspiros [2.4] heptane -5- base amino propoxyl group etc..
Unless other aspects show that structural formula described in the invention includes all isomeric forms(As mapping is different
Structure, diastereo-isomerism, and geometrical isomerism(Or conformational isomerism)):Such as R, S configuration containing asymmetric center, double bond
(Z), (E) isomers, and (Z), (E) rotamer.Therefore, the single three-dimensional chemical isomer of the compound of the present invention
Or its enantiomter, diastereoisomer, or geometric isomer(Or rotamer)Mixture belong to the present invention
Range.
Term " prodrug " used in the present invention represents a compound and is converted into chemical combination shown in Formulas I-VI in vivo
Object.Such conversion is hydrolyzed by pro-drug or is influenced for precursor structure through enzymatic conversion in blood or tissue in blood.
Pro-drug compounds of the present invention can be ester, and ester can have phenyl ester class as pro-drug in existing invention,
Aliphatic (C1-C24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as this hair
A compound in bright includes hydroxyl, can be acylated to obtain the compound of prodrug form.Other precursor medicines
Object form includes phosphate, if these phosphate compounds are being obtained through the di on parent.About precursor medicine
Object, which completely discusses, can refer to following documents:T. Higuchi and V.Stella, Pro-drugsas Novel
Delivery Systems, Vol. 14 of the A.C.S.Symposium Series, Edward B. Roche,
ed., Bioreversible Carriers in Drug Design, American Pharmaceutical
Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and
Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and
S.J. Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.
Unless other aspects show, all tautomeric forms of the compound of the present invention be included in the scope of the present invention it
It is interior.In addition, unless other aspects show, the structural formula of compound described in the invention includes one or more different originals
The enriched isotope of son.
" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change
Closing the metabolite of object can be identified that activity can pass through institute such as of the present invention by technology well-known in the art
It adopts as description and is experimentally characterized.Such product can be by, by aoxidizing, being gone back to drug compound
Original, hydrolysis, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, this hair
The bright metabolite for including compound, including the compound of the present invention and mammal were come into full contact with produced by a period of time
Metabolite.
The compound of the present invention can include asymmetric center or chiral centre, therefore there are different stereoisomers.
All stereoisomeric forms in any ratio of the compound of the present invention, including but not limited to, diastereomer, enantiomter, resistance turn
Isomers, and their mixture, such as racemic mixture constitute the part of the present invention.Many organic compounds are all
Exist with optical active forms, i.e. the plane of their capable Plane of rotation polarised lights.When describing optically active compound,
Prefix D, L or R, S are used for indicating the absolute configuration at molecular chiral center.Prefix D, L or(+)、(-)For naming chemical combination object plane
The symbol of polarised light rotation,(-)Or it is left-handed, prefix that L, which refers to compound,(+)Or it is dextrorotation that D, which refers to compound,.These
The chemical constitution of stereoisomer is identical, but their stereochemical structure is different.Specifically stereoisomer can be
The mixture of enantiomer, isomers is commonly referred to as enantiomeric mixture.50:50 mixture of enantiomers is referred to as outer disappear
Mixture or racemic modification are revolved, this may lead to do not have stereoselectivity or stereoselectivity in chemical reaction process.Term
" racemic mixture " and " racemic modification " refers to the mixture of equimolar two enantiomters, lacks optical activity.
Term " tautomer " or " tautomeric form " refer to that the isomer of the structure of different-energy can be with
Pass through the mutual inversion of phases of low energy barrier.Such as proton tautomer(I.e. prototropic tautomer)Including passing through proton transfer
Change, such as the isomerization of keto-enol and imine-enamine.Valence(Chemical valence)Tautomer includes
Recombinate the change of bonding electrons.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine
Acceptable salt is known to us in fields on, such as document:S. M. Berge et al., describe
pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences,
66:1-19,1977. recorded.The salt that pharmaceutically acceptable nontoxic acid is formed is including but not limited to ammonia
Base group, which reacts the inorganic acid salt to be formed, a hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and organic
Hydrochlorate, such as acetate, oxalates, maleate, tartrate, citrate, succinate, malonate, or
These salt are obtained by other methods described in the books or literature such as ion-exchange.Other pharmaceutically acceptable salt packets
It includes:Adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate,
Borate, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulphur
Hydrochlorate, esilate, formates, fumarate, gluceptate, glycerophosphate, gluconate, half
Sulfate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonate salts, lactobionate, lactate, lauric acid
Salt, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate,
Oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, picrate, pivalic acid
Salt, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..By appropriate
The obtained salt of alkali include alkali metal, alkaline-earth metal, ammonium and N+(C1-C4 alkyl)4Salt.The present invention is also intended to contemplate any
The compound of the group of included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be turned by quaternary ammonium
With obtaining.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt is further
Including appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylic
Compound, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-C8 azochlorosulfonate acid compounds and aromatic sulphonic acid compound.
The salt of part of compounds of the present invention can be as follows the salt of particular compound illustrate, but not
Limit the present invention.
" solvate " of the present invention refers to that one or more solvent molecules are formed by associated matter with the compound of the present invention.Shape
The solvent of solvate is including but not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate,
Acetic acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
The solvate of part of compounds or the solvate of its salt of the present invention can use the specific chemical combination listed as follows
The salt of object illustrates, but is not limited to the present invention:
The salt of the compound of the present invention further includes being used to prepare or purifying the intermediate of compound or general formula I- shown in general formula I-VI
The salt of the enantiomter of the separation of compound shown in VI, but it is not necessarily pharmaceutically acceptable salt.
If the compound of the present invention is alkaline, then conceivable salt can be by provided in the literature any suitable
Method be prepared, for example with inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid etc..Or make
With organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, hydroxyl second
Acid and salicylic acid;Pyrans saccharic acid, such as glucuronic acid and galacturonic acid;Alpha-hydroxy acid, such as citric acid and tartaric acid;Ammonia
Base acid, such as asparatate and glutamic acid;Aromatic acid, such as benzoic acid and cinnamic acid;Sulfonic acid, such as p-methyl benzenesulfonic acid,
Ethanesulfonic acid, etc..
If the compound of the present invention is acid, then conceivable salt can be prepared by suitable method,
Such as, using inorganic base or organic base, such as ammonia(Primaquine, parahelium, tertiary ammonia), alkali metal hydroxide or alkaline-earth metal hydrogen-oxygen
Compound, etc..Suitable salt includes but is not limited to organic salt obtained from amino acids, such as glycine and arginine,
Ammonia, such as primaquine, parahelium and tertiary ammonia, and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium,
Manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salts.
According on the other hand, the characteristics of pharmaceutical composition of the invention includes the compound of general formula I-VI, institute of the present invention
The compound listed, or embodiment compound represented, and pharmaceutically acceptable carrier, adjuvant, or excipient.This hair
Patient effectively can detectably be treated or be mitigated to the amount of compound caused by tubercle bacillus, parasite etc. in bright composition
Disease.
There are free forms for the compound of the present invention, or it is suitable, as pharmaceutically acceptable derivates.According to this
Invention, pharmaceutically acceptable derivates include but is not limited to pharmaceutically acceptable prodrug, salt, ester, esters
Salt, or other any adducts or derivative that can be directly or indirectly administered according to the needs of patient, its other party of the invention
Compound described in face, metabolite or his residue.
As described in the invention, the pharmaceutically acceptable composition of the present invention further includes pharmaceutically acceptable
Carrier, adjuvant, or excipient, these are applied as the present invention, including any solvent, diluent, or other liquid
Excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid adhesion
Agent or lubricant etc. are suitable for distinctive target formulation.As described in following documents:In Remington: The
Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy,
Lippincott Williams Wilkins, Phil adelphia, and Encyclopedia of
Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999,
Marcel Dekker, New York, the content of comprehensive document herein, show that different carriers can be applied to pharmaceutically connect
The preparation for the composition received and their well known preparation methods.Not in addition to any conventional carrier medium and the compound of the present invention
Compatible range, for example, caused by any undesirable biological effect or any other with pharmaceutically acceptable composition
The interaction that component generates in harmful manner, their purposes are also the range that the present invention is considered.
The substance that can be used as pharmaceutically acceptable carrier includes but is not limited to ion-exchanger, aluminium, aluminum stearate,
Lecithin, haemocyanin, such as human albumin, buffer substance such as phosphate, glycine, sorbic acid, potassium sorbate,
The partial glyceride mixtures of saturated vegetable fatty acid, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate,
Potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax gather
Ethylene-polyoxypropylene-block condensate, lanolin, sugar, such as lactose, dextrose and saccharose;Starch such as cornstarch and
Potato starch;Cellulose and its derivative such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate;Gum powder;
Malt;Gelatin;Talcum powder;Auxiliary material such as cocoa butter and suppository wax;Oil such as peanut oil, cotton seed oil, safflower oil,
Sesame oil, olive oil, corn oil and soya-bean oil;Glycol compound, such as propylene glycol and polyethylene glycol;Esters such as ethyl oleate
Ester and ethyl laurate;Agar;Buffer such as magnesium hydroxide and aluminium hydroxide;Alginic acid;Pyrogen-free water;It is isotonic
Salt;Lin Ge(Family name)Solution;Ethyl alcohol, phosphate buffer solution, and other nontoxic suitable lubricant such as Sodium Laurylsulfates and
Magnesium stearate, colorant, releasing agent, coating agents, sweetener, flavoring agent and fragrance, preservative and antioxidant.
The pharmaceutical composition of the present invention can be oral medication, drug administration by injection, Aerosol inhalation, local administration, warp
Rectally, nose administration, buccal administration or are administered vagina administration by implantable medicine box.Can be capsule, tablet,
Pill, pulvis, granula and water suspension or solution.Oral medication can use following form:Tablet, capsule, can divide pill
Scattered powder, particle or suspension, syrup and elixir, or be administered in a manner of external application:Ointment, gel, drug containing adhesive plaster etc.,
Or parenteral routes are carried out with sterile injectable solution or suspension form.The compounds of this invention also can parenteral or intraperitoneal
Administration.Also surfactant can properly mixed(Such as hydroxypropyl cellulose, polyvinylpyrrolidone)Water in prepare these
Reactive compound(As free alkali or pharmaceutically acceptable salt)Solution or suspension.It can also be in glycerine, liquid, poly- second two
Dispersion liquid is prepared in alcohol and its mixture in the oil.Under conventional storage and use condition, contain preservative in these preparations
To prevent microorganism from growing.
Medicament forms suitable for injection include:Aseptic aqueous solution or dispersion liquid and aseptic powder(It is noted for extemporaneous preparation of sterile
Penetrate solution or dispersion liquid).In all cases, these forms must be sterile and must be that fluid is arranged with being easy to syringe
Go out fluid.It must be stable under conditions of manufacture and storage, and must be able to prevent microorganism(Such as bacterium and fungi)Pollution
It influences.Carrier can be solvent or decentralized medium, wherein containing such as water, alcohol(Such as glycerine, propylene glycol and liquid polyethylene glycol)、
They properly mix object and vegetable oil.
Compound can be applied with local mode, without being applied with system mode.Such as usually to dilute preparation or continue
The form of delivery formulations will be in compound direct injection to organ.In addition, the pharmaceutical composition containing the compounds of this invention can be with
It uses in targeted drug delivery system, such as is delivered in the liposome being coated with organ specific antibody.The liposome
The organ will be targeted and absorbed by the Organic selection.In addition, the composition containing the compounds of this invention can be with fast quick-release
The form for putting preparation, timed release preparations or IR formulation provides.
Sucking is applied, the compound of the present invention can be aerosol, aerosol or powder type.Chemical combination of the present invention
The pharmaceutical composition of object can be delivered easily in the form of aerosol spray, and the aerosol spray can be mounted in pressure
In container or atomizer, suitable propellant such as dicholorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, dioxy are used
Change carbon or other suitable gases.In the case of pressurized aerosol, dosage unit can be determined by valve to deliver
Metered amount.Such as by taking capsule and cylindrantherae as an example, it can be prepared as containing describedization for the gelatin of inhalator or insufflator
Close the mixture of powders of object and appropriate powdered substrate such as lactose or starch.
The compounds of this invention can also be prepared as rectal compositions such as enema, Gel in rectal administered, rectal foams agent, straight
Intestines aerosol, suppository, gel suppository (gel suppository) or enema,retention (retention enema), wherein containing
There is conventional suppository base such as cocoa butter or other glyceride and synthetic polymer such as polyvinylpyrrolidone, PEG.
In the suppository form of composition, it is optionally first with the mixture of cocoa butter that low melt wax is such as, but not limited to fatty glyceride
First it is melted.
In addition, the compounds of this invention can be also combined with other treating tuberculosis, anti-parasite medicine.It is specifically including but not limited to,
Fluoroquinolones medicine, isoniazid, ethambutol, PAS, pyrazinamide, 2-ethylisonicotinthionamide, aminoglycoside antibiosis
Element, rifamycinoid antibiotics, seromycin, capreomycin, qinghaosu, pyrimethamine, primaquine, albendazole, quinine, chlorine
Quinoline, mebendazole etc..
Pharmaceutical composition can be prepared according to the usual manner acceptable carrier of one or more physiology, wherein wrapping
Include the excipient and adjuvant that can help that reactive compound is processed as to pharmaceutical preparations.Selected administration method determines appropriate
Dosage form.Technology, carrier and excipient known to any can understand use appropriate according in the prior art.Contain this hair
The pharmaceutical composition of bright compound can be prepared according to conventional methods, for example, by conventional mixing, dissolving, pelletize, ingot processed,
It is prepared by grinding, emulsification, packing, encapsulating or pressing process.
Pharmaceutical composition will include at least one pharmaceutical acceptable carrier, diluent or excipient and free acid, free alkali or can
The compound of the present invention of acceptable salt is as active constituent.In addition, pharmaceutical composition may also include other medicine or pharmacy
Activating agent, carrier, adjuvant, such as preservative, stabilizer, wetting agent or emulsifier, dissolution accelerator, adjust osmotic pressure salt or
Buffer.In addition, pharmaceutical composition also contains other substances for having therapeutic value.
The preparation method of composition containing compound described herein include by compound with it is one or more it is inert can
Pharmaceutical excipient or carrier are prepared as solid, semisolid or liquid form together.Solid composite includes but not limited to powder, piece
Agent, dispersible granule, capsule, cachet and suppository.Liquid composition includes wherein being dissolved with the solution of compound, containing
Emulsion, the solution containing the liposome comprising compound disclosed herein, micelle or nano-particle for having compound.Semisolid group
It includes but not limited to gelling agent, suspension and cream to close object.Composition can be aqueous agent or suspended form, be suitble to
In the solid form or emulsion form that are dissolved or suspended in before use in liquid.These compositions can also contain a small amount of nontoxic
Adjuvant, such as wetting agent or emulsifier, pH buffer etc..
The compound of the present invention is preferably prepared into dosage unit form to mitigate the equal of dosage and dosage by pharmaceutical formulation
Even property.Term " dosage " unit type " obtains suitably treating the physical dispersion unit of required drug referred to herein as patient.However
It should be appreciated that the compound of the present invention or the daily total usage of composition will be judged by attending physician according to reliable medicine range
To determine.Specific effective dose level will include quilt depending on many factors for any one special patient or organism
The illness for the treatment of and the seriousness of illness, the activity of particular compound, concrete composition used, the age of patient, body
Weight, health status, gender and eating habit, administration time, the discharge rate of administration route and particular compound used are controlled
The duration for the treatment of, medicinal application is combined in drug combination or with specific compound, and some other pharmaceutical field
Well known factor.
The compounds of this invention can be modified by the functional group of additional suitable to improve selectivity organism characteristic.This
The modification of sample is that this field is known and include to biological lacuna(Such as blood, lymphatic system, central nervous system)Infiltration,
It improves Oral Availability, improve dissolubility so as to which the modification of excretion is metabolized and changed by drug administration by injection, change.It can incite somebody to action
The compounds of this invention is modified by the functional group of additional suitable to improve selectivity organism characteristic.Such modification is ability
Domain is known and includes to biological lacuna(Such as blood, lymphatic system, central nervous system)Infiltration, raising are oral effective
Property, improve dissolubility so as to pass through drug administration by injection, change metabolism and change excretion modification.
The disease of the present invention caused by tubercle bacillus, Mycobacterium marinum etc., including pulmonary tuberculosis, intestinal tuberculosis, kidney knot
Core, bone tuberculosis, laryngophthisis, tuberculosis of thyroid gland, tuberculosis of spine etc..
The disease of the present invention caused by parasite, including malaria, leishmaniasis etc..
General, the compound of the present invention described method can be prepared through the invention, unless there are into one
The explanation of step, the wherein definition of substituent group are as shown in general formula I-VI, and reaction scheme and embodiment below is for further lifting
Example illustrates present disclosure.
Those skilled in the art will realize that:Chemical reaction described in the invention can be used for suitable prepare originally
Other compounds of invention, and other methods for the preparation of the compounds of the present invention are considered as in the scope of the present invention
Within.Such as can successfully it be led to by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention
Method of modifying completion, such as protection interference group appropriate are crossed, by using other known reagent in addition to described in the invention
, or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also public
That recognizes is suitable for the preparation of other compounds of the invention.
Solvent for use of the present invention, such as anhydrous tetrahydro furan, dioxane, toluene, ether are dry by sodium metal reflux
It is dry to obtain.Anhydrous methylene chloride and chloroform are dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, N, N-
Dimethylacetylamide and N,N-dimethylformamide are used by anhydrous sodium sulfate is dry in advance.The protics such as methanol, ethyl alcohol
Solvent is used after being dried again with anhydrous sodium sulfate after being repeatedly evaporated under reduced pressure.
Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents below(Unless other aspects
Show), reaction bulb all by syringe squeezed into beyond the Great Wall by suitable rubber band, substrate.Glassware is by dry.
Embodiment
Embodiment 1.1- (3- aminopropyls) -4- oxygen -2- (1HPyrroles -2- bases) -1,4- dihydroquinoline -3- carboxylic acids
Step(1)4- hydroxyls -2- hydrogen-quinoline -3- Ethyl formates
Weigh aniline (0. 011 mol) and diethyl ethoxymethylenemalonate(0.012 mol)It is added in 20 mL ethyl alcohol,
90oC is heated three hours, is cooled to room temperature, the phenetole of 40 mL is added, 100o30 min are heated under C, are cooled to
Ice water is added after reaction in room temperature, and ethyl acetate extracts (100 mL × 2), merges organic phase, organic phase saturation
Brine It, anhydrous sodium sulfate drying, filtering, organic phase concentration, residue obtain 4- hydroxyls -2- through silica gel column chromatography
Hydrogen-quinoline -3- Ethyl formates(66% yield);
Step(2)4- chloroquinoline -3- Ethyl formates
Claim disubstituted-4-hydroxy -2- hydrogen-quinoline -3- Ethyl formates(7.3 mmol)It is dissolved in 100 mL dioxane, is then added
Phosphorus oxychloride(7.4 mmol)After mixing, 80oC is heated one hour, after reaction pours into reaction solution in ice water, is used
Saturated sodium carbonate solution adjusts pH to neutrality, and ethyl acetate extracts (100 mL × 2), merges organic phase, organic phase saturation
Brine It, anhydrous sodium sulfate drying, filtering, organic phase concentration, residue obtain 4- chloroquinolines -3- through silica gel column chromatography
Ethyl formate(58% yield);
Step(3)The bromo- 4- chloroquinolines -3- Ethyl formates of 2-
It weighs 4- chloroquinoline -3- Ethyl formates (4.7 mmol) and is dissolved in chloroform (20 mL), peroxide benzene is added in room temperature thereto
It is stirred at room temperature 4 hours after formic acid (6.8 mmol), the chloroformic solution (20 of tribromo oxygen phosphorus (6.9 mmol) is added toward reaction solution
ML it) stirs 1 hour, after reaction pours into reaction solution in ice water, with saturated sodium carbonate solution tune pH value to 8, acetic acid afterwards
Ethyl ester extracts (100 mL × 2), merges organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, mistake
Filter, organic phase concentration, residue is through column chromatography (EtOAc: PET = 1 :60) the bromo- 4- chloroquinolines -3- formic acid second of 2- is obtained
Ester (62% yield);
Step(4)2- (1- (tertbutyloxycarbonyl) -1HPyrroles -2- bases) -4- chloroquinoline -3- Ethyl formates
Weigh the bromo- 4- chloroquinolines -3- Ethyl formates of 2- (3.2 mmol) and (1- (tertbutyloxycarbonyl) -1HPyrroles -2- bases) boric acid
(3.3 mmol) is dissolved in 1,4- dioxane (15 mL), and potassium carbonate (6.5 mmol) and palladium (0.3 are added thereto
), mmol reaction solution is 50oIt is stirred 3 hours under C, reaction solution is poured into ice water after reaction, is extracted with ethyl acetate
(100 mL×2).Merge organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, filtering, organic phase
Concentration, residue obtain 2- (1- (tertbutyloxycarbonyl) -1 through column chromatographyHPyrroles -2- bases) -4- chloroquinoline -3- Ethyl formates
(43% yield);
Step(5)4- oxos -2- (1HPyrroles -2- bases) -1,4- dihydroquinoline -3- Ethyl formates
By 2- (1- (tertbutyloxycarbonyl) -1HPyrroles -2- bases) -4- chloroquinoline -3- Ethyl formates (1.7 mmol) are dissolved in acetic acid
(10 mL), ethyl alcohol (6 mL), water(5 ml)After be warming up to 75oC reacts 18 hours, vacuum distillation removing acetic acid, ethyl alcohol,
Gained residue is diluted with water, and is adjusted to neutrality with saturated sodium carbonate solution, ethyl acetate extracts (100 mL × 2), is associated with
Machine phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, filtering, organic phase concentration.Residue is through column chromatography
(EtOAc: PET = 2:1) 4- oxos -2- (1 is obtainedHPyrroles -2- bases) (36% receives -1,4- dihydroquinoline -3- Ethyl formates
Rate);
Step(6)4- oxos -2- (1HPyrroles -2- bases) -1,4- dihydroquinoline -3- formic acid
By 4- oxos -2- (1HPyrroles -2- bases) -1,4- dihydroquinoline -3- Ethyl formates (0.18 mmol) are dissolved in methanol (10
ML it in), is stirred at room temperature 5 hours after sodium hydrate aqueous solution (10 mL) is added, hydrochloric acid is added into reaction solution(1 mL)It neutralizes
And (50 mL × 2) are extracted with ethyl acetate, organic phase saturated common salt water washing, anhydrous sodium sulfate drying is filtered, rotation
Dry, residue obtains 4- oxos -2- (1 through silica gel column chromatographyHPyrroles -2- bases) (55% receives -1,4- dihydroquinoline -3- formic acid
Rate).
Step(7)1- (3- aminopropyls) -4- oxos -2- (1HPyrroles -2- bases) -1,4- dihydroquinoline -3- formic acid
By 4- oxos -2- (1HPyrroles -2- bases) -1,4- dihydroquinoline -3- formic acid(1.2 mmol)With 3- N-Propyl Bromide -1- amine
(0.9 mmol)It is dissolved in DMSO (10 mL), potassium carbonate (6.5 mmol) is added thereto, reaction solution is stirred at room temperature 1
Hour, reaction solution is poured into ice water after reaction, is extracted with ethyl acetate (100 mL × 2).Merge organic phase, has
Machine mutually uses saturated common salt water washing, and anhydrous sodium sulfate drying, filtering, organic phase concentration, residue is through column chromatography (EtOAc:
PET = 1:30) 1- (3- aminopropyls) -4- oxos -2- (1 is obtainedHPyrroles -2- bases) -1,4- dihydroquinoline -3- formic acid (25%,
Yield);
ESI-MS (m/z):313.13 [M+H]+。
Embodiment 2.1- (3- hydroxypropyls) -4- oxos -2- (1HPyrroles -2- bases) -1,4- dihydroquinoline -3- formic acid
By 4- oxos -2- (1HPyrroles -2- bases) -1,4- dihydroquinoline -3- formic acid(1.2 mmol)With 3- N-Propyl Bromide -1- alcohol
(0.9 mmol)It is dissolved in DMSO (10 mL), potassium carbonate (6.5 mmol) is added thereto, reaction solution is stirred at room temperature 1
Hour, reaction solution is poured into ice water after reaction, is extracted with ethyl acetate (100 mL × 2).Merge organic phase, has
Machine mutually uses saturated common salt water washing, anhydrous sodium sulfate drying to filter, and organic phase concentration, residue obtains 1- (3- through column chromatography
Hydroxypropyl) -4- oxos -2- (1HPyrroles -2- bases) -1,4- dihydroquinoline -3- formic acid (5%, yield);
ESI-MS (m/z): 313.11 [M+H]+。
Embodiment 3.7- (3- fluorophenoxies) -4- oxos -2- (1HPyrroles -2- bases) -1,4- dihydroquinoline -3- formic acid third
Ester
Step(1)7- (3- fluorophenoxies) -4- oxyquinoline -3- propyl formates
Weigh 3- (3- fluorophenoxies) aniline (0. 011 mol) and(E)-2-(Ethoxymeyhylene)Malonic acid 1- ethyls 3- third
Base ester(0.012 mol)It is added in 20 mL ethyl alcohol, 100oC is heated three hours, is cooled to room temperature, and the benzene of 40 mL is added
Ether, 100o30 min are heated under C, are cooled to room temperature, and after reaction, ice water, ethyl acetate extraction are added
(100 mL × 2) merge organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, filtering, organic phase
Concentration, residue obtain 7- (3- fluorophenoxies) -4- oxyquinoline -3- propyl formates through silica gel column chromatography(66% yield);
Step(2)7- (3- fluorophenoxies) -4- chloroquinoline -3- propyl formates
Weigh 7- (3- fluorophenoxies) -4- oxyquinoline -3- propyl formates(7.3 mmol)It is dissolved in 100 mL dioxane,
Then phosphorus oxychloride is added(7.4 mmol)After mixing, 80oC is heated one hour, and reaction solution is poured into ice after reaction
In water, pH is adjusted to neutrality with saturated sodium carbonate solution, ethyl acetate extracts (100 mL × 2), merges organic phase, organic
Saturated common salt water washing, anhydrous sodium sulfate drying is mutually used to filter, organic phase concentration, residue obtains 7- through silica gel column chromatography
(3- fluorophenoxies) -4- chloroquinoline -3- propyl formates(58% yield);
Step(3)The chloro- 7- of the bromo- 4- of 2- (3- fluorophenoxies) quinoline -3- propyl formates
It weighs 7- (3- fluorophenoxies) -4- chloroquinoline -3- propyl formates (4.7 mmol) and is dissolved in tetrahydrofuran (20 mL), room
Temperature is stirred at room temperature 4 hours after 85% benzoyl hydroperoxide (6.8 mmol) is added thereto, and tribromo oxygen phosphorus is added toward reaction solution
(6.9 mmol) is stirred 1 hour afterwards, is after reaction poured into reaction solution in ice water, extremely with saturated sodium carbonate solution tune pH value
8, ethyl acetate extracts (100 mL × 2), merges organic phase, organic phase saturated common salt water washing, and anhydrous sodium sulfate is done
Dry, filtering, organic phase concentrates, and residue obtains the bromo- 4- of 2- chloro- 7- (3- fluorophenoxies) quinoline -3- propyl formates through column chromatography
(62% yield);
Step(4)2- (1- (tertbutyloxycarbonyl) -1HPyrroles -2- bases) the chloro- 7- of -4- (3- fluorophenoxies) quinoline -3- propyl formates
Weigh the bromo- 4- of 2- chloro- 7- (3- fluorophenoxies) quinoline -3- propyl formates (3.2 mmol) and (1- (tertbutyloxycarbonyl) -
1HPyrroles -2- bases) boric acid (3.3 mmol) is dissolved in 1,4- dioxane (15 mL), potassium carbonate (6.5 is added thereto
) and palladium (0.3 mmol), mmol reaction solution is 50oIt is stirred 3 hours under C, reaction solution is poured into ice water after reaction
In, it is extracted with ethyl acetate (100 mL × 2).Merge organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate
Dry, filtering, organic phase concentrates, and residue obtains 2- (1- (tertbutyloxycarbonyl) -1 through column chromatographyHPyrroles -2- bases) -4- is chloro-
7- (3- fluorophenoxies) quinoline -3- propyl formates (43% yield);
Step(5)7- (3- fluorophenoxies) -4- oxos -2- (1HPyrroles -2- bases) -1,4- dihydroquinoline -3- propyl formates
By 2- (1- (tertbutyloxycarbonyl) -1HPyrroles -2- bases) the chloro- 7- of -4- (3- fluorophenoxies) quinoline -3- propyl formates (1.7
Mmol) it is dissolved in acetic acid (10 mL), ethyl alcohol (6 mL), water(5 ml)After be warming up to 75oC reacts 18 hours, and vacuum distillation removes
It goes acetic acid, ethyl alcohol, gained residue to be diluted with water, neutrality, ethyl acetate extraction (100 is adjusted to saturated sodium carbonate solution
ML × 2), merge organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, filtering, organic phase concentration.
Residue obtains 7- (3- fluorophenoxies) -4- oxos -2- (1 through column chromatographyHPyrroles -2- bases) -1,4- dihydroquinoline -3- formic acid third
Ester (36% yield);
ESI-MS (m/z): 407.13 [M+H]+。
Embodiment 4
Tubercle bacillus resistant activity is tested
Tubercle bacillus resistant activity test method bibliography Palomino, J.C., Martin, A., Camacho, M.,
Guerra, H., Swings, J. Portaels, F. Resazurin microtiter assay plate: simple
and inexpensive method for detection of drug resistance in Mycobacterium
tuberculosis. Antimicrob. Agents Chemother.2002,46,2720-2722. with isoniazid be sun
Property drug.
Anti- 2012. Plant of Mycobacterium marinum activity test method bibliography Cechinel-Filho V.
Bioactives and Drug Discovery: Principles, Practice, and Perspectives. John
Wiley & Sons, Inc., Hoboken, New Jersey. are using gentamicin as positive control.
Active testing data
Compound number | To the MIC of tubercle bacillus(μg/mL) | To the MIC of Mycobacterium marinum(μg/mL) |
1 | ++ | ++ |
2 | ++ | ++ |
7 | ++ | + |
10 | + | + |
12 | ++ | + |
18 | ++ | + |
21 | + | ++ |
23 | ++ | ++ |
26 | ++ | + |
31 | + | ++ |
35 | ++ | + |
37 | ++ | ++ |
40 | + | ++ |
42 | + | ++ |
44 | ++ | + |
48 | ++ | + |
50 | ++ | ++ |
Isoniazid | ++ | / |
Gentamicin | / | + |
" ++++" indicates MIC between 0-5 in table, and " +++ " indicates MIC between 5-10, " ++ " indicate MIC 10-20 it
Between, "+" indicates MIC between 20-50.
Active testing shows:The compounds of this invention tubercle bacillus resistant activity is better than positive drug or suitable with positive drug, display
Go out preferable application value.
Embodiment 5
Antimalarial active test method bibliography Cross, R. Matthew; Monastyrskyi, Andrii; Mutka,
Tina S.; Burrows, Jeremy N.; Kyle, Dennis E.; Manetsch, Roman. Endochin
Optimization: Structure-Activity and Structure-Property Relationship Studies
of 3-Substituted 2-Methyl-4(1H)-quinolones with Antimalarial Activity.Journal of Medicinal Chemistry(2010), 53 (19), 7076-7094. is using chloroquine as positive drug.
Active testing data
In table " ++++" indicate EC50Between 1-20, " +++ " indicates EC50Between 20-100, " ++ " indicates EC50In 100-
Between 1000, "+" indicates EC50Between 1000-10000.
Active testing shows:The compounds of this invention antimalarial active is better than positive drug or suitable with positive drug, shows preferably
Application prospect.
Claims (13)
1. the Quinolone acid analog derivative of a kind of Formulas I and Formula II structure, tautomer, stereoisomer, racemic modification,
The non-equal amount of mixture of enantiomter, the solvation of geometric isomer, solvate, pharmaceutically acceptable salt or its salt
Object, it is characterised in that compound has the following structure:, wherein A,
B is five yuan or hexa-atomic aromatic ring, hetero-aromatic ring, carbon heterocyclic;N=1,2,3 or 4;K=1,2,3 or 4;Y is O or NR5; “" indicate singly-bound or be not present; R1, R2, R3, R4, R5Shown in being defined as follows:
Each R1, R4Can be identical or different, it is separate be hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano,
Alkyl, halogenated alkyl, alkoxy, alkylamino, alkyl acyl, hydroxy alkoxy base, Hydroxyalkylamino, hydroxyalkanoyl,
Halogenated alkoxy, halogenated alkylamino, ohaloalkanoyl, aminoalkoxy, naphthenic base, cycloalkyl oxy, naphthenic base ammonia
Base, cycloalkanoyl, alkenyl, alkenylalkoxy, alkenyl alkylamino, alkenyl alkanoyl, alkynyl, alkynyl alkoxy,
Alkynyl alkylamino, alkynyl alkanoyl, aryl, aryloxy group, aroyl, fragrant amino, alkoxy aryl, aryl alkane amino,
Heteroaryl, heteroaryloxy, 4-hetaroylpyrazol, heteroaryl amino, heteroarylalkoxy, heteroarylalkylamino, heterocycle alkane acyl
Base, Heterocyclylalkyl, heterocycle oxygroup, heterocyclylamino group, heterocyclylacyl, heterocyclylalkoxy, heterocycle alkylamino,
Heterocycle alkanoyl, azido alkoxy, condensed-bicyclic base condense miscellaneous bicyclic group, and condensed-bicyclic base aliphatic condenses
Miscellaneous bicyclic group aliphatic, condensed-bicyclic base oxygroup condense miscellaneous bicyclic group oxygroup, and condensed-bicyclic base amino condenses miscellaneous bicyclic
Base amino, condensed-bicyclic base alkoxy condense miscellaneous bicyclic group alkoxy, and condensed-bicyclic base alkylamino condenses miscellaneous bicyclic group
Alkylamino, condensed-bicyclic base oxygroup alkoxy, condensed miscellaneous bicyclic group oxygroup alkoxy, condensed-bicyclic base aminoalkoxy,
Miscellaneous bicyclic group aminoalkoxy is condensed, condensed-bicyclic base-C (=O)-, condensed-bicyclic base-C (=O) O- condense miscellaneous bicyclic group-C
(=O)-, miscellaneous bicyclic group-C (=O) O-, condensed-bicyclic base amino-C (=O)-are condensed, miscellaneous bicyclic group amino-C (=O)-is condensed,
Condensed-bicyclic base-C (=O) N (R6)-, condenses miscellaneous bicyclic group-C (=O) N (R6)-, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell, spiral shell are bicyclic
Base aliphatic, the miscellaneous bicyclic group aliphatic of spiral shell, spiral shell bicyclic group oxygroup, the miscellaneous bicyclic group oxygroup of spiral shell, spiral shell bicyclic group amino, spiral shell are miscellaneous
Bicyclic group amino, spiral shell bicyclic group alkoxy, the miscellaneous bicyclic group alkoxy of spiral shell, spiral shell bicyclic group alkylamino, the miscellaneous bicyclic group alkane ammonia of spiral shell
Base, spiral shell bicyclic group oxygroup alkoxy, the miscellaneous bicyclic group oxygroup alkoxy of spiral shell, spiral shell bicyclic group aminoalkoxy, the miscellaneous bicyclic group of spiral shell
Aminoalkoxy, spiral shell bicyclic group-C (=O)-, spiral shell bicyclic group-C (=O) O-, the miscellaneous bicyclic group-C of spiral shell (=O)-, the miscellaneous bicyclic group-of spiral shell
C (=O) O-, spiral shell bicyclic group amino-C (=O)-, the miscellaneous bicyclic group amino-C of spiral shell (=O)-, spiral shell bicyclic group-C (=O) N (R6)-, spiral shell
Miscellaneous bicyclic group-C (=O) N (R6)-, R7R6N-, -C(=O)NR6R7, -OC(=O)NR6R7, -OC(=O)OR6, -N(R6)C(=O)
NR6R7, -N(R6)C(=O)OR7, -N(R6)C(=O)-R7, R6R7N-S(=O)t-, R6S(=O)t-, R6S(=O)tN(R7)-,
R7R6N- alkyl, R6S(=O)tAlkyl, R6R7N-C (=O)-alkyl, R7R6N- alkoxies, R6S(=O)tAlkoxy,
R6R7N-C (=O)-alkoxy, aryl-(CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle-(CH2)p-
G-(CH2)m, or naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR8, S(=O), S(=O)2,C(=O), -C
(=O)N(R6)-, -OC(=O)N(R6)-, -OC(=O)-, -N(R6)C(=O)N(R6)-, -(R6)N-S(=O)t-, -OS(=
O)t, or-OS (=O)tN(R6)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;Or wherein aryl-
(CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle-(CH2)p-G-(CH2)m, or naphthenic base-
(CH2)p-G-(CH2)mCan F, Cl, Br, I, alkyl, alkenyl, alkynyl, alkoxy or cyanogen be selected from by one or more
The substituent group of base replaces;
R2, R3, R5Separate is hydrogen, deuterium, alkyl, halogenated alkyl, alkyl acyl, hydroxyalkanoyl, alkyl halide
Acyl group, naphthenic base, cycloalkanoyl, alkenyl, alkenyl alkanoyl, alkynyl, alkynyl alkanoyl, aryl, aroyl,
Heteroaryl, 4-hetaroylpyrazol, heterocycle alkanoyl, Heterocyclylalkyl, heterocyclylacyl, heterocycle alkanoyl, azido alkane
Base, condensed-bicyclic base condense miscellaneous bicyclic group, and condensed-bicyclic base-C (=O)-condenses miscellaneous bicyclic group-C (=O)-, condense double
Ring group amino-C (=O)-condenses miscellaneous bicyclic group amino-C (=O)-, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell, spiral shell bicyclic group fat
Race, the miscellaneous bicyclic group aliphatic of spiral shell, spiral shell bicyclic group-C (=O)-, the miscellaneous bicyclic group-C of spiral shell (=O)-, spiral shell bicyclic group amino-C (=
O)-, the miscellaneous bicyclic group amino-C of spiral shell (=O)-,-C (=O) NR6R7, R6R7N-S(=O)t-, R6S(=O)t-, R7R6N- alkyl,
R6S(=O)tAlkyl, R6R7N-C (=O)-alkyl, aryl-(CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m-,
Heterocycle-(CH2)p-G-(CH2)m, or naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR8, S(=O), S(=
O)2,C(=O), -C(=O)N(R6)-, -OC(=O)N(R6)-, -OC(=O)-, -N(R6)C(=O)N(R6)-, -(R6)N-S(=
O)t-, -OS(=O)t, or-OS (=O)tN(R6)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;Or
Aryl-(CH therein2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle-(CH2)p-G-(CH2)m, or
Naphthenic base-(CH2)p-G-(CH2)mCan F, Cl, Br, I, cyano, alkyl, alkenyl, alkynes be selected from by one or more
Base, alkoxy, aryl, heteroaryl, carbocylic radical, the substituent group substitution of heterocycle;
R8Can be identical or different, separate is hydrogen, R6R7NC(=O)-, R6OC(=O)-, R6C(=O)-, R6R7NS(=
O)-, R6OS(=O)-, R6S(=O)-, R6R7NS(=O)2-, R6OS(=O)2-, R6S(=O)2, aliphatic, halogenated aliphatic
Race, hydroxyl group aliphatic, amino aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio group aliphatic, aryl fat
Fat race, heteroaryl aliphatic, heterocycle aliphatic, naphthenic base aliphatic, aryloxy group aliphatic, heterocycle oxygroup fat
Race, cycloalkyl oxy aliphatic, fragrant amino aliphatic, heterocyclylamino group aliphatic, cycloalkyl amino aliphatic, aryl,
Heteroaryl, heterocycle or carbocylic radical;
Each R6And R7It is independently hydrogen, deuterium, aliphatic, halogenated aliphatic, hydroxyl group aliphatic, amino aliphatic, alkoxy
Aliphatic, alkylamino aliphatic, alkylthio group aliphatic, aromatic yl aliphat, heteroaryl aliphatic, heterocycle aliphatic,
Naphthenic base aliphatic, aryloxy group aliphatic, heterocycle oxygroup aliphatic, cycloalkyl oxy aliphatic, fragrant amino aliphatic,
Heterocyclylamino group aliphatic, cycloalkyl amino aliphatic, aryl, heteroaryl, heterocycle or naphthenic base;Work as R6And R7It is connected in
On the same nitrogen-atoms, R6, R7Can be randomly formed substituted or non-substituted 3-8 membered rings with nitrogen-atoms, condensed-bicyclic or
Spiral shell is bicyclic;The hetero atom in heterocycle, heteroaryl, condensed miscellaneous bicyclic group, the miscellaneous bicyclic group of spiral shell involved in above-mentioned group is independent
1-5 hetero atom of the ground in N, O, S, Se;
Above-mentioned R1, R2, R3, R4, R5, R6, R7, R8Group can appoint by hydroxyl, methylol, carboxyl, acetylamino, alkane
Base (such as methyl, ethyl, propyl), alkoxy (such as methoxyl group, ethyoxyl, tert-butoxy), alkylamino, naphthenic base, alkenyl,
Alkynyl, trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino, azido (- N3), guanidine radicals, cyano,
Tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, aryl, heteroaryl, heterocycle
One or more of base replaces.
2. compound according to claim 1 is general formula III-VI compounds represented, or general formula III-VI shownization
It closes the stereoisomer geometric isomer of object, tautomer, nitrogen oxides, raceme, hydrate, solvate, be metabolized production
Object, pharmaceutically acceptable salt or prodrug:
,
Wherein T1, T2, T3, T4Separate is CR1Or N, wherein T1, T2, T3, T4At most there are two can contain N;
V1, V2, V3, V4Separate is CR4, NR9, O or S;Y is O or NR5; X1, X2, X3, X4, X5It is separate
For CR4Or N; “" indicate singly-bound or be not present;Each R1, R2, R3, R4, R5, R9As follows:
Each R1, R4Can be identical or different, it is separate be H, D, F, Cl, Br, I, hydroxyl, amino, nitro,
Cyano, C1-C20 alkyl, C1-C20 halogenated alkyls, C1-C20 alkoxies, C1-C20 alkylaminos, C1-C20 alkyl acyls,
Hydroxyl C1-C20 alkoxies, hydroxyl C1-C20 alkylaminos, hydroxyl C1-C20 alkanoyls, C1-C20 halogenated alkoxies, C1-
The halogenated alkylaminos of C20, C1-C20 ohaloalkanoyls, C1-C20 aminoalkoxies, C3-C10 naphthenic base, C3-C10 naphthenic base
Oxygroup, C3-C10 cycloalkyl aminos, C3-C10 cycloalkanoyls, C2-C8 alkenyls, C2-C8 alkynyls, C6-C10 aryl,
C6-C10 aryloxy group, C6-C10 aroyls, C6-C10 fragrant aminos, C6-C10 aryl C1-C6 alkoxies, C6-C10 aryl alkane
Amino, C5-C12 heteroaryls, C5-C12 heteroaryloxies, C5-C12 4-hetaroylpyrazols, C5-C12 heteroaryl amino, C5-C12 are miscellaneous
Aryl C1-C6 alkoxies, C5-C12 heteroaryl C1-C6 alkylaminos, C4-C12 heterocycle C1-C6 alkanoyls, C4-C12 heterocycles
Alkyl, C4-C12 heterocycle oxygroups, C4-C12 heterocyclylamino groups, C4-C12 heterocyclylacyls, C4-C12 heterocycles C1-C6
Alkoxy, C4-C12 heterocycle C1-C6 alkylaminos, C4-C12 heterocycle C1-C6 alkanoyls, R7R6N-, -C(=O)NR6R7,
-OC(=O)NR6R7, -OC(=O)OR6, -N(R6)C(=O)NR6R7, -N(R6)C(=O)OR7, -N(R6)C(=O)-R7,
R6R7N-S(=O)t-, R6S(=O)t-, R6S(=O)tN(R7)-, R7R6N- C1-C6 alkyl, R6S(=O)t- C1-C6 alkyl,
R6R7N-C (=O)-C1-C6 alkyl, R7R6N- C1-C6 alkoxies, R6S(=O)t- C1-C6 alkoxies, R6R7N-C(=O)-
C1-C6 alkoxies, C6-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m-, C4-C12
Heterocycle-(CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR8, S(=
O), S(=O)2,C(=O), -C(=O)N(R6)-, -OC(=O)N(R6)-, -OC(=O)-, -N(R6)C(=O)N(R6)-, -
(R6)N-S(=O)t-, -OS(=O)t, or-OS (=O)tN(R6)-;T is l or 2;P and m be each independently 0, l, 2,3 or
4;Or wherein C6-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m, C4-C12 heterocycles
Base-(CH2)p-G-(CH2)m, or C3-C1 naphthenic base-(CH2)p-G-(CH2)mCan F, Cl be selected from by one or more,
The substituent group of Br, I, alkyl, alkenyl, alkynyl, alkoxy or cyano replaces;
R2, R3, R5, R9For H, D, C1-C20 alkyl, C1-C20 halogenated alkyls, C1-C20 alkyl acyls, C1-C20 hydroxyls
Base alkanoyl, C1-C20 ohaloalkanoyls, C3-C10 naphthenic base, C3-C10 cycloalkanoyls, C2-C8 alkenyls, C2-C8
Alkenyl alkanoyl, C2-C8 alkynyls, C2-C8 alkynyl alkanoyls, C6-C10 aryl, C6-C10 aroyls, C5-C12 heteroaryls
Base, C5-C12 4-hetaroylpyrazols, C4-C12 heterocycle alkanoyls, C4-C12 Heterocyclylalkyls, C4-C12 heterocyclylacyls, C4-
C12 heterocycle C1-C6 alkanoyls, C5-C12 condensed-bicyclic bases, C5-C12 condense miscellaneous bicyclic group ,-C (=O) NR6R7,
R6R7N-S(=O)t-, R6S(=O)t-, R7R6N-C1-C6 alkyl, R6S(=O)t- C1-C6 alkyl, R6R7N-C(=O)-C1-C6
Alkyl, C6-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m, C4-C12 heterocycles-
(CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR8, S(=O), S(=
O)2,C(=O), -C(=O)N(R6)-, -OC(=O)N(R6)-, -OC(=O)-, -N(R6)C(=O)N(R6)-, -(R6)N-S(=
O)t-, -OS(=O)t, or-OS (=O)tN(R6)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;Or its
Middle C6-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m, C4-C12 heterocycles-
(CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)mCan F, Cl, Br be selected from by one or more,
I, cyano, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, carbocylic radical, the substituent group substitution of heterocycle;
Wherein each R8Can be identical or different, separate is H, D, R6R7NC(=O)-, R6OC(=O)-, R6C(=O)-,
R6R7NS(=O)-, R6OS(=O)-, R6S(=O)-, R6R7NS(=O)2-, R6OS(=O)2-, R6S(=O)2, C1-C3 fat
Race, C1-C3 halogenated aliphatics, C1-C3 hydroxyl group aliphatics, C1-C3 amino aliphatic, C1-C3 alkoxy Cs 1-C3 fat
Race, C1-C3 alkylamino C1-C3 aliphatic, C1-C3 alkylthio group C1-C3 aliphatic, C6-C10 aryl C1-C3 aliphatic,
C5-C9 heteroaryl C1-C3 aliphatic, C4-C10 heterocycle C1-C3 aliphatic, C3-C10 naphthenic base C1-C3 aliphatic, C6-
C10 aryloxy group C1-C3 aliphatic, C4-C10 heterocycle oxygroup C1-C3 aliphatic, C3-C10 cycloalkyl oxies C1-C3 fat
Race, C6-C10 fragrant amino C1-C3 aliphatic, C4-C10 heterocyclylamino group C1-C3 aliphatic, C3-C10 cycloalkyl aminos C1-
C3 aliphatic, C6-C10 aryl, C5-C10 heteroaryls, C4-C10 heterocycles or C3-C10 naphthenic base;
Wherein each R6And R7It independently is H, D, C1-C3 aliphatic, C1-C3 halogenated aliphatics, C1-C3 hydroxyl group aliphatics,
C1-C3 amino aliphatic, C1-C3 alkoxy C 1-C3 aliphatic, C1-C3 alkylamino C1-C3 aliphatic, C1-C3 alkylthio groups
C1-C3 aliphatic, C6-C10 aryl C1-C3 aliphatic, C5-C9 heteroaryl C1-C3 aliphatic, C4-C10 heterocycles C1-C3
Aliphatic, C3-C10 naphthenic base C1-C3 aliphatic, C6-C10 aryloxy group C1-C3 aliphatic, C4-C10 heterocycle oxygroups C1-
C3 aliphatic, C3-C10 cycloalkyl oxy C1-C3 aliphatic, C6-C10 fragrant amino C1-C3 aliphatic, C4-C10 heterocycles
Amino C1-C3 aliphatic, C3-C10 cycloalkyl amino C1-C3 aliphatic, C6-C10 aryl, C5-C10 heteroaryls, C4-
C10 heterocycles or C3-C10 naphthenic base;Work as R6And R7It is connected on the same nitrogen-atoms, R6, R7It can arbitrary landform with nitrogen-atoms
At substituted or non-substituted 3-8 membered rings;
Above-mentioned R1, R2, R3, R4, R5, R6, R7, R8, R9Group can appoint by hydroxyl, methylol, carboxyl, acetyl ammonia
Base, alkyl (such as methyl, ethyl, propyl), alkoxy (such as methoxyl group, ethyoxyl, tert-butoxy), alkylamino, naphthenic base,
Alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino, azido(-N3), guanidine radicals,
Cyano, tertbutyloxycarbonyl(-Boc), carbonyl(-C=O), oxo(=O), thio(=S), sulfonyl, aryl, heteroaryl,
One or more of heterocycle replaces.
3. according to compound described in claim 1-2, wherein each R1, R4Can be identical or different, it is separate be H, D,
F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl,
C5H11, C6H13, C8H17, trifluoromethyl, hydroxymethyl, amino methyl, methoxyl group, ethyoxyl, tert-butoxy, first
Amino, ethylamino, isopropylamino, 3- hydroxyl-propyls, acetyl group, trifluoroacetyl group, Cyanoacetyl, methylamino
Acetyl group, propiono, iso-propionyl, 2- hydroxypropanoyls, 2- aminopropionyls, 2- chlorine propionos, 2- bromine propionos,
Valeryl, caproyl, heptanoyl group, methacrylyl, phenyl, benzoyl, p-nitrophenyl, to toluyl
Base, fluoro benzoyl, p-benzoyl base, to methoxybenzoyl base, 2,4- dimethylbenzoyls are folded
Nitrogen base benzoyl, benzyl, p-chlorobenzyl, vinyl, acrylic, allyl, n-butene base, isobutenyl, just
Pentenyl, isopentene group, cyclopropyl, ring propiono, ring valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene,
Phenethyl imidazole radicals, pyridyl group, pyrrole radicals, oxazolyls, isoxazolyl, triazol radical, tetrazole base, furyl,
Thienyl, thiazolyl, piperidyl, piperazinyl, indyl, carbazyl, benzofuranyl tetrahydrofuran base, tetrahydrochysene pyrrole
It mutters base, pyrimidine bases, purine bases ,-N (CH3)2,-C (C=O) NH-C1-C4 alkyl ,-OC (C=O)-NH-C1-C4 alkane
Base ,-OC (O=O) O-C1-C4 alkyl ,-NHC (=O) NH-C1-C4 alkyl ,-NHC (=O) O-C1-C4 alkyl ,-NHC (=
O)-C1-C4 alkyl, C1-C4 alkyl-NH-S (=O)2, C1-C4 alkyl S (=O)2, C1-C4 alkyl S (=O)2NH-, benzene
Base-(CH2)P-G-(CH2)m, difluorophenyl-(CH2)P-G-(CH2)m, thiazolyl-(CH2)p-G-(CH2)m, pyridyl group-
(CH2)p-G-(CH2)m, phenylethyl, cyclohexyl-(CH2)p-G-(CH2)m, wherein G is O, S, S (=O), S (=
O)2, C(=O);P and m is each independently 0,1,2 or 3;Or wherein C6-C10 aryl-(CH2)P-G-(CH2)mIt can be with
F, Cl, Br, I, methyl, ethyl, propyl, acetenyl, propinyl, butynyl, methoxy are selected from by one or more
The substituent group of base, ethyoxyl or cyano replaces;Or above-mentioned R1, R4It is welcome by F, Cl, Br, I, hydroxyl, hydroxyl
Base, methylol, carboxyl, acetylamino, C1-C6 alkyl(Such as methyl, ethyl, propyl), C1-C6 alkoxies, C1-C6 alkane
Amino, trifluoromethyl, trifluoroacetyl group, sulfydryl, nitro, amino, azido(-N3), guanidine radicals, cyano, tertiary fourth oxygen
Carbonyl(-Boc), carbonyl(-C=O), oxo(=O), thio(=S), sulfonyl, the substitution of one or more of phenyl;
Wherein each R2, R3, R5, R9Can be identical or different, separate is H, D, methyl, ethyl, propyl, isopropyl
Base, butyl, tertiary butyl, C5H11, C6H13, C8H17, trifluoromethyl, hydroxymethyl, amino methyl, 3- hydroxyls-the third
Base, acetyl group, trifluoroacetyl group, Cyanoacetyl, methylamino acetyl group, propiono, iso-propionyl, 2- hydroxyls
Propiono, 2- aminopropionyls, 2- chlorine propionos, 2- bromine propionos, valeryl, caproyl, heptanoyl group, isobutene
Acyl group, phenyl, benzoyl, p-nitrophenyl, to methyl benzoyl, fluoro benzoyl, p-benzoyl
Base, to methoxybenzoyl base, 2,4- dimethylbenzoyls, azidobenzoyl, benzyl, p-chlorobenzyl,
Vinyl, acrylic, allyl, n-butene base, isobutenyl, n-pentene base, isopentene group, cyclopropyl, ring third
Acyl group, ring valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene, phenethyl imidazole radicals, pyridyl group, pyrrole radicals,
Oxazolyl, isoxazolyl, triazol radical, tetrazole base, furyl, pyranose, thienyl, thiazolyl, piperidyl,
Piperazinyl, indyl, carbazyl, benzofuranyl tetrahydrofuran base, THP trtrahydropyranyl, pyrimidine bases, purine bases,
Pentose base, hexose base ,-(C=O) NH-C1-C4 alkyl, C1-C4 alkyl-NH-S (=O)2, C1-C4 alkyl S (=O
)2, phenyl-(CH2)P-G-(CH2)m, difluorophenyl-(CH2)P-G-(CH2) m, thiazolyl-(CH2)p-G-(CH2)m-,
Pyridyl group-(CH2)p-G-(CH2)m, phenylethyl, cyclohexyl-(CH2)p-G-(CH2)m, wherein G is O, S, S (=
O), S (=O)2, C(=O);P and m is each independently 0,1,2 or 3;Or wherein C6-C10 aryl-(CH2)P-G-
(CH2)mCan F, Cl, Br, I, methyl, ethyl, propyl, acetenyl, propinyl, fourth be selected from by one or more
The substituent group of alkynyl, methoxyl group, ethyoxyl or cyano replaces;Or above-mentioned R2, R3, R5, R9It is welcome by F,
Cl, Br, I, hydroxyl, hydroxyl, methylol, carboxyl, acetylamino, C1-C6 alkyl(Such as methyl, ethyl, propyl),
C1-C6 alkoxies, C1-C6 alkylaminos, trifluoromethyl, trifluoroacetyl group, sulfydryl, nitro, amino, azido(-
N3), guanidine radicals, cyano, tertbutyloxycarbonyl(-Boc), carbonyl(-C=O), oxo(=O), thio(=S), sulfonyl, benzene
One or more of base replaces.
4. according to compound described in claim 1-3, structure or following one structure including but not limited to following one it is mutual
Non- equal amount of mixture, geometric isomer, solvate, the medicine of tautomeric, stereoisomer, racemic modification, enantiomter
The solvate of acceptable salt or its salt on, or prodrug:
。
5. claim 1-4 any one of them pharmaceutically acceptable salts are selected from:Hydrochloride, sulfate, phosphate, oxalic acid
Salt, maleate, methane sulfonates, succinate, citrate, fumarate, glucuronate salt, formates, acetate,
Succinate;The solvate of solvate or salt is selected from:Monohydrate, dihydrate, trihydrate, a methanol solvate, two
Methanol solvate, an acetonitrile close object, diacetonitrile closes object, acetone conjunction object, two acetone close object, hemifumarate monohydrate, rich horse
Hydrochlorate dihydrate, one ethanolates of fumarate;It is preferred that monohydrate, fumarate dihydrate, one ethyl alcohol of fumarate
Close object.
6. a kind of pharmaceutical composition, it includes according to a kind of compound of claim 1-5 any one of them or several compounds
Or the non-equal amount of mixture of its tautomer, stereoisomer, racemic modification, enantiomter, geometric isomer, solvation
Any one or a few in the solvate of object, pharmaceutically acceptable salt or its salt is as active ingredient.
7. the pharmaceutical composition described in claim 6, it is characterised in that the pharmaceutical composition also includes that at least one pharmaceutically may be used
Carrier, diluent or the excipient of receiving.
8. the pharmaceutical composition described in claim 7, it is characterised in that the pharmaceutical composition also includes other at least one resistive connections
Core, anti-parasite medicine, be specifically including but not limited to fluoroquinolones medicine, qinghaosu, chloroquine, quinine, pyrimethamine, cigarette hydrazine,
Streptomysin, Ethambutol, Rimactazid etc.;The pharmaceutical composition optimizing injection, freeze drying powder injection, is hanged at oral preparation
Floating agent etc..
9. compound or its tautomer, its stereoisomer, its racemic modification described in any one of claim 1-5,
The non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt
Pharmaceutical composition described in any one of solvate or claim 6-8 is in preparing the drugs such as treating tuberculosis, anti parasitic
Purposes.
10. compound or its tautomer, its stereoisomer, its racemic modification described in any one of claim 1-5,
The non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt
Pharmaceutical composition described in any one of solvate or claim 6-8 is preparing treatment and/or is preventing by tubercle bacillus, sea
Application in the drug of disease caused by mycobacteria, plasmodium, Leishmania etc.;The disease includes pulmonary tuberculosis, kidney knot
The diseases such as core, bone tuberculosis, malaria or leishmaniasis.
11. compound or its tautomer, its stereoisomer, its racemic modification described in any one of claim 1-5,
The non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt
The purposes of pharmaceutical composition in medicine preparation described in any one of solvate or claim 6-8, the drug are used for
Treat tubercle bacillus or Mycobacterium marinum, Plasmodium vivax, malariae, plasmodium falciparum and Plasmodium ovale, Li Shiman
Disease caused by protozoon etc..
12. compound or its tautomer, its stereoisomer, its racemic modification described in any one of claim 1-5,
The non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt
Solvate answering in the lead compound such as anti-mycobacterium tuberculosis or Mycobacterium marinum, plasmodium falciparum, Leishmania
With.
13. the preparation method of compound described in claim 1 is following reaction scheme:
Wherein R1, R2, R3, R4, A, B, Y, n, k, “" definition with any of the above-described place of the present invention to R1, R2,
R3, R4, A, B, Y, n, k, “" definition.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710180834.9A CN108623560A (en) | 2017-03-24 | 2017-03-24 | A kind of Quinolone acid analog derivative and its preparation method and application |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710180834.9A CN108623560A (en) | 2017-03-24 | 2017-03-24 | A kind of Quinolone acid analog derivative and its preparation method and application |
Publications (1)
Publication Number | Publication Date |
---|---|
CN108623560A true CN108623560A (en) | 2018-10-09 |
Family
ID=63707505
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710180834.9A Pending CN108623560A (en) | 2017-03-24 | 2017-03-24 | A kind of Quinolone acid analog derivative and its preparation method and application |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108623560A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114989177A (en) * | 2022-07-11 | 2022-09-02 | 江西瑞威尔生物科技有限公司 | Preparation process of imidazopyrazine compound |
US11820747B2 (en) | 2021-11-02 | 2023-11-21 | Flare Therapeutics Inc. | PPARG inverse agonists and uses thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1081138A1 (en) * | 1999-08-30 | 2001-03-07 | Maruishi Pharmaceutical Co., Ltd. | 1,2-disubstituted 1,4-dihydro-4-oxoquinoline compounds |
US20050032832A1 (en) * | 2003-08-08 | 2005-02-10 | China Medical University | Substituted 2-phenyl-4-quinolone-3-carboxylic acid compounds and their use as antitumor agents |
CN101643468A (en) * | 2009-08-25 | 2010-02-10 | 中国海洋大学 | Quinolinone alkaloid derivant as well as preparation method and application thereof |
JP2012012388A (en) * | 2010-06-04 | 2012-01-19 | Otsuka Pharmaceut Co Ltd | Pharmaceutical agent |
-
2017
- 2017-03-24 CN CN201710180834.9A patent/CN108623560A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1081138A1 (en) * | 1999-08-30 | 2001-03-07 | Maruishi Pharmaceutical Co., Ltd. | 1,2-disubstituted 1,4-dihydro-4-oxoquinoline compounds |
US20050032832A1 (en) * | 2003-08-08 | 2005-02-10 | China Medical University | Substituted 2-phenyl-4-quinolone-3-carboxylic acid compounds and their use as antitumor agents |
CN101643468A (en) * | 2009-08-25 | 2010-02-10 | 中国海洋大学 | Quinolinone alkaloid derivant as well as preparation method and application thereof |
JP2012012388A (en) * | 2010-06-04 | 2012-01-19 | Otsuka Pharmaceut Co Ltd | Pharmaceutical agent |
Non-Patent Citations (8)
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11820747B2 (en) | 2021-11-02 | 2023-11-21 | Flare Therapeutics Inc. | PPARG inverse agonists and uses thereof |
CN114989177A (en) * | 2022-07-11 | 2022-09-02 | 江西瑞威尔生物科技有限公司 | Preparation process of imidazopyrazine compound |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN108658972A (en) | A kind of substituted lactams compounds and its preparation method and application | |
CN106854205B (en) | Inhibitors of influenza viruses replication and its application method and purposes | |
CN105384687B (en) | Quinolinones compound and its applied in medicine | |
CN109641868A (en) | Inhibitors of influenza viruses replication and its application method and purposes | |
CN104513252B (en) | Substituted urea derivative and its application in medicine | |
CN104755085B (en) | Heteroaromatic compounds and its application method and purposes as PI3 kinase modulators | |
CN103565653B (en) | Substituted pyrazolone compound as well as using method and application of pyrazolone compound | |
CN108658974A (en) | A kind of lactam analog compound and its preparation method and application | |
CN104974162B (en) | Bicyclic pyrazolone compounds and its application method and purposes | |
CN110511219A (en) | The dihydronaphthridine class compound and application thereof that phenyl replaces | |
CN104725249B (en) | Benzylamine analog derivative and its application on drug | |
CN108218873A (en) | Inhibitors of influenza viruses replication and application thereof | |
CN104163813A (en) | Substituted indole compound, and preparation method and use thereof | |
CN103965199B (en) | A kind of heteroaromatic compounds, the medical composition and its use comprising it | |
US9562046B2 (en) | Means and method for treating solid tumors | |
CN109988106A (en) | The aminated compounds for inhibiting SSAO/VAP-1 and its application in medicine | |
CN106317072A (en) | Heterocyclic compound for treatment of mycobacterial infections and use thereof | |
CN108623560A (en) | A kind of Quinolone acid analog derivative and its preparation method and application | |
CN108658937A (en) | A kind of bicyclic alkaloid compound and its preparation method and application | |
CN107334767B (en) | A kind of application of pyridazinone compound in oncotherapy | |
CN106349228B (en) | Substituted quianzolinones and its preparation method and application | |
CN105367582B (en) | Bilobalide B derivates and its application in drug | |
CN108658854A (en) | A kind of alkaloid compound and preparation method thereof and application as marine antifoulant | |
CN108658855A (en) | A kind of nitrogenous dicyclic compound and its preparation method and application | |
CN108069952A (en) | It quinolinones compound and its is applied in drug |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WD01 | Invention patent application deemed withdrawn after publication | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20181009 |