SK8892002A3 - Novel bisamidate phosphonate prodrugs, process for their preparation and use thereof - Google Patents

Info

Publication number

SK8892002A3

SK8892002A3 SK889-2002A SK8892002A SK8892002A3 SK 8892002 A3 SK8892002 A3 SK 8892002A3 SK 8892002 A SK8892002 A SK 8892002A SK 8892002 A3 SK8892002 A3 SK 8892002A3

Authority

SK

Slovakia

Prior art keywords

group

alkyl

hydrogen

aryl

atom

Prior art date

1999-12-22

Links

• Espacenet
• Global Dossier
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• 238000000034 method Methods 0.000 title claims description 125
• 239000000651 prodrug Substances 0.000 title abstract description 46
• 229940002612 prodrug Drugs 0.000 title abstract description 46
• UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 title abstract description 33
• 238000002360 preparation method Methods 0.000 title description 71
• 230000008569 process Effects 0.000 title description 4
• 239000003112 inhibitor Substances 0.000 claims abstract description 13
• 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 claims abstract description 9
• 239000008280 blood Substances 0.000 claims abstract description 9
• 210000004369 blood Anatomy 0.000 claims abstract description 9
• 239000008103 glucose Substances 0.000 claims abstract description 9
• 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 7
• 101710099475 3'-phosphoadenosine 5'-phosphate phosphatase Proteins 0.000 claims abstract 2
• 101710196411 Fructose-1,6-bisphosphatase Proteins 0.000 claims abstract 2
• 101710186733 Fructose-1,6-bisphosphatase, chloroplastic Proteins 0.000 claims abstract 2
• 101710109119 Fructose-1,6-bisphosphatase, cytosolic Proteins 0.000 claims abstract 2
• 101710198902 Fructose-1,6-bisphosphate aldolase/phosphatase Proteins 0.000 claims abstract 2
• 125000000217 alkyl group Chemical group 0.000 claims description 351
• 150000001875 compounds Chemical class 0.000 claims description 298
• 125000003118 aryl group Chemical group 0.000 claims description 251
• 229910052739 hydrogen Inorganic materials 0.000 claims description 251
• CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 236
• 239000001257 hydrogen Substances 0.000 claims description 216
• -1 perhaloalkyl Chemical group 0.000 claims description 167
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 151
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 146
• 125000002723 alicyclic group Chemical group 0.000 claims description 127
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 120
• 229910052736 halogen Inorganic materials 0.000 claims description 118
• 150000002367 halogens Chemical class 0.000 claims description 113
• 229910052757 nitrogen Inorganic materials 0.000 claims description 111
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 105
• 125000004429 atom Chemical group 0.000 claims description 96
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 91
• 125000005842 heteroatom Chemical group 0.000 claims description 83
• 125000004432 carbon atom Chemical group C* 0.000 claims description 81
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 80
• 125000004122 cyclic group Chemical group 0.000 claims description 70
• 229910052717 sulfur Chemical group 0.000 claims description 70
• 229910052799 carbon Inorganic materials 0.000 claims description 66
• 229910052760 oxygen Inorganic materials 0.000 claims description 63
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 62
• 239000001301 oxygen Substances 0.000 claims description 62
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 53
• 239000011593 sulfur Chemical group 0.000 claims description 53
• 125000003342 alkenyl group Chemical group 0.000 claims description 52
• 125000000304 alkynyl group Chemical group 0.000 claims description 49
• 125000000623 heterocyclic group Chemical group 0.000 claims description 47
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 45
• 125000001072 heteroaryl group Chemical group 0.000 claims description 41
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
• 125000005843 halogen group Chemical group 0.000 claims description 34
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 33
• 229910052698 phosphorus Inorganic materials 0.000 claims description 31
• 125000006165 cyclic alkyl group Chemical group 0.000 claims description 30
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
• CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 30
• 150000003839 salts Chemical class 0.000 claims description 29
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 27
• 150000002148 esters Chemical class 0.000 claims description 26
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 26
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 26
• 125000004437 phosphorous atom Chemical group 0.000 claims description 26
• XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 25
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 22
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 20
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 20
• 102000012195 Fructose-1,6-bisphosphatases Human genes 0.000 claims description 19
• 108010017464 Fructose-Bisphosphatase Proteins 0.000 claims description 19
• 125000001543 furan-2,5-diyl group Chemical group O1C(=CC=C1*)* 0.000 claims description 19
• 125000001041 indolyl group Chemical group 0.000 claims description 18
• 125000001424 substituent group Chemical group 0.000 claims description 18
• 125000003545 alkoxy group Chemical group 0.000 claims description 17
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 16
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 16
• 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 16
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
• 125000001188 haloalkyl group Chemical group 0.000 claims description 15
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 14
• BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims description 13
• 125000004414 alkyl thio group Chemical group 0.000 claims description 13
• 239000004202 carbamide Substances 0.000 claims description 13
• 229910052711 selenium Inorganic materials 0.000 claims description 13
• 150000001721 carbon Chemical group 0.000 claims description 12
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 12
• 239000011669 selenium Substances 0.000 claims description 12
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 11
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 11
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
• 239000000460 chlorine Substances 0.000 claims description 11
• 125000004434 sulfur atom Chemical group 0.000 claims description 11
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 10
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
• 125000005343 heterocyclic alkyl group Chemical group 0.000 claims description 10
• 125000004076 pyridyl group Chemical group 0.000 claims description 10
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 9
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
• 229910052794 bromium Inorganic materials 0.000 claims description 9
• 229910052801 chlorine Inorganic materials 0.000 claims description 8
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 8
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 7
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 7
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical group NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 6
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
• 125000001246 bromo group Chemical group Br* 0.000 claims description 6
• 229910052731 fluorine Inorganic materials 0.000 claims description 6
• 238000001727 in vivo Methods 0.000 claims description 6
• 230000002401 inhibitory effect Effects 0.000 claims description 6
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
• 125000005647 linker group Chemical group 0.000 claims description 6
• 125000002757 morpholinyl group Chemical group 0.000 claims description 6
• 125000002971 oxazolyl group Chemical group 0.000 claims description 6
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
• 150000001409 amidines Chemical class 0.000 claims description 5
• 150000001413 amino acids Chemical class 0.000 claims description 5
• 239000011737 fluorine Substances 0.000 claims description 5
• 230000004110 gluconeogenesis Effects 0.000 claims description 5
• 125000006366 methylene oxy carbonyl group Chemical group [H]C([H])([*:1])OC([*:2])=O 0.000 claims description 5
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
• 150000003462 sulfoxides Chemical class 0.000 claims description 5
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
• 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 claims description 4
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
• ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 4
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 4
• 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 4
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 4
• 125000002883 imidazolyl group Chemical group 0.000 claims description 4
• 238000000338 in vitro Methods 0.000 claims description 4
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
• 102000004190 Enzymes Human genes 0.000 claims description 3
• 108090000790 Enzymes Proteins 0.000 claims description 3
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 3
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
• 125000000335 thiazolyl group Chemical group 0.000 claims description 3
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
• 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 claims description 2
• 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 2
• CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 2
• 229910018828 PO3H2 Inorganic materials 0.000 claims description 2
• SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 2
• 125000001153 fluoro group Chemical group F* 0.000 claims description 2
• 208000007345 glycogen storage disease Diseases 0.000 claims description 2
• 125000001475 halogen functional group Chemical group 0.000 claims description 2
• 210000004185 liver Anatomy 0.000 claims description 2
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
• 241001465754 Metazoa Species 0.000 claims 15
• 125000000218 acetic acid group Chemical class C(C)(=O)* 0.000 claims 4
• 150000002688 maleic acid derivatives Chemical class 0.000 claims 4
• JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 claims 2
• 125000006726 (C1-C5) alkenyl group Chemical group 0.000 claims 2
• 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims 2
• 150000007970 thio esters Chemical class 0.000 claims 2
• 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 1
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 1
• 125000006730 (C2-C5) alkynyl group Chemical group 0.000 claims 1
• 125000004530 1,2,4-triazinyl group Chemical group N1=NC(=NC=C1)* 0.000 claims 1
• 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 claims 1
• 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims 1
• 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 claims 1
• 125000003363 1,3,5-triazinyl group Chemical group N1=C(N=CN=C1)* 0.000 claims 1
• FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims 1
• NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims 1
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
• 125000002541 furyl group Chemical group 0.000 description 262
• 238000000921 elemental analysis Methods 0.000 description 143
• 229910000042 hydrogen bromide Inorganic materials 0.000 description 115
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 104
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 93
• 239000000243 solution Substances 0.000 description 88
• 239000004793 Polystyrene Substances 0.000 description 78
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 63
• 238000006243 chemical reaction Methods 0.000 description 61
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 52
• YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 48
• 238000003786 synthesis reaction Methods 0.000 description 47
• 238000004587 chromatography analysis Methods 0.000 description 45
• 239000007787 solid Substances 0.000 description 42
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 40
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
• 125000002947 alkylene group Chemical group 0.000 description 39
• 230000015572 biosynthetic process Effects 0.000 description 39
• ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 37
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
• 239000011541 reaction mixture Substances 0.000 description 36
• 238000000605 extraction Methods 0.000 description 34
• 239000000203 mixture Substances 0.000 description 34
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 28
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 26
• 229910001868 water Inorganic materials 0.000 description 25
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 23
• 238000001704 evaporation Methods 0.000 description 23
• 230000008020 evaporation Effects 0.000 description 23
• 239000003921 oil Substances 0.000 description 21
• 235000019198 oils Nutrition 0.000 description 21
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 21
• KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 20
• 239000004480 active ingredient Substances 0.000 description 19
• 238000002844 melting Methods 0.000 description 19
• 230000008018 melting Effects 0.000 description 19
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 16
• 239000003814 drug Substances 0.000 description 15
• 229940079593 drug Drugs 0.000 description 14
• 239000002585 base Substances 0.000 description 13
• 238000009833 condensation Methods 0.000 description 13
• 230000005494 condensation Effects 0.000 description 13
• 235000019439 ethyl acetate Nutrition 0.000 description 13
• 239000000725 suspension Substances 0.000 description 13
• 238000013459 approach Methods 0.000 description 12
• 150000003557 thiazoles Chemical class 0.000 description 12
• UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 12
• 150000001299 aldehydes Chemical class 0.000 description 11
• 239000003795 chemical substances by application Substances 0.000 description 11
• 239000000543 intermediate Substances 0.000 description 11
• 230000004048 modification Effects 0.000 description 11
• 238000012986 modification Methods 0.000 description 11
• 238000010992 reflux Methods 0.000 description 11
• 238000007363 ring formation reaction Methods 0.000 description 11
• PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 10
• 201000010099 disease Diseases 0.000 description 10
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
• 150000002240 furans Chemical class 0.000 description 10
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 10
• 239000002243 precursor Substances 0.000 description 10
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 9
• 229960000583 acetic acid Drugs 0.000 description 9
• IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 9
• 150000003222 pyridines Chemical class 0.000 description 9
• 150000003230 pyrimidines Chemical class 0.000 description 9
• 239000003826 tablet Substances 0.000 description 9
• XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 description 8
• ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 8
• 238000005804 alkylation reaction Methods 0.000 description 8
• 229940024606 amino acid Drugs 0.000 description 8
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