SK8892002A3 - Novel bisamidate phosphonate prodrugs, process for their preparation and use thereof - Google Patents
Novel bisamidate phosphonate prodrugs, process for their preparation and use thereof Download PDFInfo
- 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
Links
- 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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- HTGMMEYONMZOCC-UHFFFAOYSA-N methyl 5-(ethylamino)-2-methylsulfanyl-1,3-thiazole-4-carboxylate Chemical compound CCNC=1SC(SC)=NC=1C(=O)OC HTGMMEYONMZOCC-UHFFFAOYSA-N 0.000 description 1
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- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
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- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
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- QWINLXGDCJBZIP-UHFFFAOYSA-N tert-butyl n-(4-carbonochloridoyl-1,3-thiazol-2-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=NC(C(Cl)=O)=CS1 QWINLXGDCJBZIP-UHFFFAOYSA-N 0.000 description 1
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- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- 125000004306 triazinyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 150000008648 triflates Chemical class 0.000 description 1
- ZPFMGRNFKOVOQZ-UHFFFAOYSA-N trifluoromethylsulfonyloxymethylphosphonic acid Chemical compound OP(O)(=O)COS(=O)(=O)C(F)(F)F ZPFMGRNFKOVOQZ-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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Classifications
-
- 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
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
-
- 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
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/44—Amides thereof
- C07F9/4461—Amides thereof the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4465—Amides thereof the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
-
- 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
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Emergency Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
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US17186299P | 1999-12-22 | 1999-12-22 | |
PCT/IB2000/002071 WO2001047935A2 (en) | 1999-12-22 | 2000-12-22 | Novel bisamidate phosphonate prodrugs |
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Family Applications (1)
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SK889-2002A SK8892002A3 (en) | 1999-12-22 | 2000-12-22 | Novel bisamidate phosphonate prodrugs, process for their preparation and use thereof |
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US (3) | US6965033B2 (ja) |
EP (1) | EP1240174A2 (ja) |
JP (1) | JP2003519154A (ja) |
KR (1) | KR100875335B1 (ja) |
CN (2) | CN100595204C (ja) |
AU (1) | AU784370B2 (ja) |
BR (1) | BR0017048A (ja) |
CA (1) | CA2396713A1 (ja) |
CZ (1) | CZ301401B6 (ja) |
HK (1) | HK1049841A1 (ja) |
HU (1) | HUP0204092A3 (ja) |
IL (1) | IL149887A0 (ja) |
MX (1) | MXPA02006156A (ja) |
NO (1) | NO20022932L (ja) |
NZ (1) | NZ519219A (ja) |
PL (1) | PL356525A1 (ja) |
RU (2) | RU2273642C2 (ja) |
SK (1) | SK8892002A3 (ja) |
WO (1) | WO2001047935A2 (ja) |
ZA (1) | ZA200204399B (ja) |
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2000
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- 2000-12-22 SK SK889-2002A patent/SK8892002A3/sk not_active Application Discontinuation
- 2000-12-22 AU AU52447/01A patent/AU784370B2/en not_active Ceased
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2003
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KR100875335B1 (ko) | 2008-12-22 |
US6965033B2 (en) | 2005-11-15 |
WO2001047935A3 (en) | 2002-03-21 |
RU2002119708A (ru) | 2004-03-20 |
PL356525A1 (en) | 2004-06-28 |
CZ301401B6 (cs) | 2010-02-17 |
JP2003519154A (ja) | 2003-06-17 |
NO20022932D0 (no) | 2002-06-18 |
AU5244701A (en) | 2001-07-09 |
AU784370B2 (en) | 2006-03-23 |
MXPA02006156A (es) | 2003-09-22 |
CA2396713A1 (en) | 2001-07-05 |
RU2005138719A (ru) | 2007-06-20 |
US20020173490A1 (en) | 2002-11-21 |
BR0017048A (pt) | 2002-11-05 |
HK1049841A1 (zh) | 2003-05-30 |
HUP0204092A3 (en) | 2005-02-28 |
ZA200204399B (en) | 2003-11-26 |
RU2273642C2 (ru) | 2006-04-10 |
CN1434828A (zh) | 2003-08-06 |
IL149887A0 (en) | 2002-11-10 |
NO20022932L (no) | 2002-08-22 |
EP1240174A2 (en) | 2002-09-18 |
CN1740182A (zh) | 2006-03-01 |
CN100595204C (zh) | 2010-03-24 |
WO2001047935A2 (en) | 2001-07-05 |
KR20020063248A (ko) | 2002-08-01 |
NZ519219A (en) | 2004-03-26 |
US20050004077A1 (en) | 2005-01-06 |
HUP0204092A2 (hu) | 2003-03-28 |
US20090192121A1 (en) | 2009-07-30 |
CZ20022172A3 (cs) | 2003-01-15 |
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