CA2115737A1 - Condensed 5-membered heterocyclic compounds, processes for preparing them and pharmaceutical compositions containing these compounds - Google Patents

Info

Publication number

CA2115737A1

CA2115737A1 CA002115737A CA2115737A CA2115737A1 CA 2115737 A1 CA2115737 A1 CA 2115737A1 CA 002115737 A CA002115737 A CA 002115737A CA 2115737 A CA2115737 A CA 2115737A CA 2115737 A1 CA2115737 A1 CA 2115737A1

Authority

CA

Canada

Prior art keywords

group

denotes

groups

alkyl

formula

Prior art date

1993-02-16

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.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 150000001875 compounds Chemical class 0.000 title claims abstract description 124
• 238000000034 method Methods 0.000 title claims abstract description 28
• 230000008569 process Effects 0.000 title claims abstract description 8
• 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 5
• 150000000565 5-membered heterocyclic compounds Chemical class 0.000 title 1
• 150000003839 salts Chemical class 0.000 claims abstract description 36
• 230000002776 aggregation Effects 0.000 claims abstract description 8
• 238000004220 aggregation Methods 0.000 claims abstract description 8
• 150000007522 mineralic acids Chemical class 0.000 claims abstract description 3
• 150000007524 organic acids Chemical class 0.000 claims abstract description 3
• -1 4-carboxy-butyl Chemical group 0.000 claims description 170
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 93
• 229910052757 nitrogen Inorganic materials 0.000 claims description 89
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 77
• 239000000203 mixture Substances 0.000 claims description 62
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 50
• 125000000217 alkyl group Chemical group 0.000 claims description 48
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
• 125000003545 alkoxy group Chemical group 0.000 claims description 27
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 25
• 239000002253 acid Substances 0.000 claims description 25
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 25
• 229910052801 chlorine Inorganic materials 0.000 claims description 25
• 239000001257 hydrogen Substances 0.000 claims description 25
• 229910052739 hydrogen Inorganic materials 0.000 claims description 25
• 125000006239 protecting group Chemical group 0.000 claims description 24
• 125000003386 piperidinyl group Chemical group 0.000 claims description 22
• 239000000460 chlorine Substances 0.000 claims description 20
• 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 17
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 16
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 16
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 13
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 13
• KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 12
• 125000002947 alkylene group Chemical group 0.000 claims description 12
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 12
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
• 125000003282 alkyl amino group Chemical group 0.000 claims description 11
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 10
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 10
• 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 10
• 239000011541 reaction mixture Substances 0.000 claims description 10
• 229910052794 bromium Inorganic materials 0.000 claims description 9
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 9
• 150000001721 carbon Chemical group 0.000 claims description 9
• 229910052799 carbon Inorganic materials 0.000 claims description 9
• 125000004432 carbon atom Chemical group C* 0.000 claims description 9
• 229910052740 iodine Inorganic materials 0.000 claims description 9
• 125000001424 substituent group Chemical group 0.000 claims description 9
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 8
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
• 239000011737 fluorine Substances 0.000 claims description 8
• 229910052731 fluorine Inorganic materials 0.000 claims description 8
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 8
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
• 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 7
• 230000007062 hydrolysis Effects 0.000 claims description 7
• 238000006460 hydrolysis reaction Methods 0.000 claims description 7
• 125000001841 imino group Chemical group [H]N=* 0.000 claims description 7
• 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 7
• 206010027476 Metastases Diseases 0.000 claims description 6
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 6
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
• 238000007327 hydrogenolysis reaction Methods 0.000 claims description 6
• 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 6
• 239000001301 oxygen Substances 0.000 claims description 6
• 229910052760 oxygen Inorganic materials 0.000 claims description 6
• 125000003884 phenylalkyl group Chemical group 0.000 claims description 6
• 206010028980 Neoplasm Diseases 0.000 claims description 5
• 210000000988 bone and bone Anatomy 0.000 claims description 5
• 125000001246 bromo group Chemical group Br* 0.000 claims description 5
• 238000006731 degradation reaction Methods 0.000 claims description 5
• 230000000269 nucleophilic effect Effects 0.000 claims description 5
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 5
• 125000000355 1,3-benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
• 125000004955 1,4-cyclohexylene group Chemical group [H]C1([H])C([H])([H])C([H])([*:1])C([H])([H])C([H])([H])C1([H])[*:2] 0.000 claims description 4
• 208000007536 Thrombosis Diseases 0.000 claims description 4
• 230000015556 catabolic process Effects 0.000 claims description 4
• 125000004956 cyclohexylene group Chemical group 0.000 claims description 4
• 230000002140 halogenating effect Effects 0.000 claims description 4
• 125000000623 heterocyclic group Chemical group 0.000 claims description 4
• 125000002883 imidazolyl group Chemical group 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• 125000004076 pyridyl group Chemical group 0.000 claims description 4
• 238000001149 thermolysis Methods 0.000 claims description 4
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
• AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 3
• 150000001412 amines Chemical class 0.000 claims description 3
• 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 3
• 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 description 3
• KRRVQRQNHBWKGW-UHFFFAOYSA-N 3-[[1-methyl-2-(piperidin-4-ylcarbamoyl)benzimidazole-5-carbonyl]amino]propanoic acid Chemical compound N=1C2=CC(C(=O)NCCC(O)=O)=CC=C2N(C)C=1C(=O)NC1CCNCC1 KRRVQRQNHBWKGW-UHFFFAOYSA-N 0.000 claims description 2
• RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 2
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 2
• 125000004414 alkyl thio group Chemical group 0.000 claims description 2
• 125000004659 aryl alkyl thio group Chemical group 0.000 claims description 2
• 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 2
• 239000003153 chemical reaction reagent Substances 0.000 claims description 2
• 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 2
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
• 239000003814 drug Substances 0.000 claims description 2
• 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 2
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 2
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
• 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 2
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 6
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 5
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 5
• 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 5
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 3
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims 3
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 2
• 125000006590 (C2-C6) alkenylene group Chemical group 0.000 claims 2
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 2
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 2
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 1
• 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims 1
• 125000006557 (C2-C5) alkylene group Chemical group 0.000 claims 1
• YSVQWIIAHWOJLE-UHFFFAOYSA-N 3-[[1-methyl-2-(2-piperidin-4-ylethyl)benzimidazole-5-carbonyl]amino]propanoic acid Chemical compound N=1C2=CC(C(=O)NCCC(O)=O)=CC=C2N(C)C=1CCC1CCNCC1 YSVQWIIAHWOJLE-UHFFFAOYSA-N 0.000 claims 1
• LKUQQCSMRJHREU-UHFFFAOYSA-N 5-[1-methyl-2-(2-piperidin-4-ylethyl)benzimidazol-5-yl]-5-oxopentanoic acid Chemical compound N=1C2=CC(C(=O)CCCC(O)=O)=CC=C2N(C)C=1CCC1CCNCC1 LKUQQCSMRJHREU-UHFFFAOYSA-N 0.000 claims 1
• ZQMCKYXUJWLVEQ-UHFFFAOYSA-N 5-[3,9-dimethyl-2,6-dioxo-8-(2-piperidin-4-ylethyl)purin-1-yl]pentanoic acid Chemical compound N=1C(C(N(CCCCC(O)=O)C(=O)N2C)=O)=C2N(C)C=1CCC1CCNCC1 ZQMCKYXUJWLVEQ-UHFFFAOYSA-N 0.000 claims 1
• MLIPPKYLDKUXRF-UHFFFAOYSA-N 5-[3-methyl-2,6-dioxo-8-(2-piperidin-4-ylethyl)-7h-purin-1-yl]pentanoic acid Chemical compound N1C=2C(=O)N(CCCCC(O)=O)C(=O)N(C)C=2N=C1CCC1CCNCC1 MLIPPKYLDKUXRF-UHFFFAOYSA-N 0.000 claims 1
• HMMVMYLUPGOJKF-UHFFFAOYSA-N C1=CC(C(=N)N)=CC=C1C1=NC(C(N(CCCCC(O)=O)C2=O)=O)=C3N2CCCN13 Chemical compound C1=CC(C(=N)N)=CC=C1C1=NC(C(N(CCCCC(O)=O)C2=O)=O)=C3N2CCCN13 HMMVMYLUPGOJKF-UHFFFAOYSA-N 0.000 claims 1
• ALVCRNYQLWLLCO-UHFFFAOYSA-N methyl 3-[[1-methyl-2-(2-piperidin-4-ylethyl)benzimidazole-5-carbonyl]amino]propanoate Chemical compound N=1C2=CC(C(=O)NCCC(=O)OC)=CC=C2N(C)C=1CCC1CCNCC1 ALVCRNYQLWLLCO-UHFFFAOYSA-N 0.000 claims 1
• 150000002391 heterocyclic compounds Chemical class 0.000 abstract description 5
• 230000002401 inhibitory effect Effects 0.000 abstract description 5
• 230000000144 pharmacologic effect Effects 0.000 abstract description 3
• 235000005985 organic acids Nutrition 0.000 abstract description 2
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 318
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 178
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 157
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 129
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 113
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 72
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 69
• 239000000741 silica gel Substances 0.000 description 63
• 229910002027 silica gel Inorganic materials 0.000 description 63
• 229940073584 methylene chloride Drugs 0.000 description 59
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 58
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
• 239000000243 solution Substances 0.000 description 54
• 229960000583 acetic acid Drugs 0.000 description 53
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 52
• 238000002844 melting Methods 0.000 description 49
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 47
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
• 239000012362 glacial acetic acid Substances 0.000 description 46
• 230000008018 melting Effects 0.000 description 46
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
• 239000002904 solvent Substances 0.000 description 40
• 239000012071 phase Substances 0.000 description 33
• 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 30
• 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 30
• 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 30
• 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 30
• 239000011780 sodium chloride Substances 0.000 description 29
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 28
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 28
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 26
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 26
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 23
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 22
• 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 description 20
• 229940075420 xanthine Drugs 0.000 description 20
• 238000006243 chemical reaction Methods 0.000 description 19
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 18
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
• 235000011121 sodium hydroxide Nutrition 0.000 description 18
• 239000002585 base Substances 0.000 description 17
• 229940083608 sodium hydroxide Drugs 0.000 description 17
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 16
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 15
• 239000013543 active substance Substances 0.000 description 15
• 239000001117 sulphuric acid Substances 0.000 description 15
• 235000011149 sulphuric acid Nutrition 0.000 description 15
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
• 229910021529 ammonia Inorganic materials 0.000 description 13
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
• 238000009835 boiling Methods 0.000 description 11
• 239000003054 catalyst Substances 0.000 description 11
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
• 125000003277 amino group Chemical group 0.000 description 10
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 10
• 238000005245 sintering Methods 0.000 description 9
• 239000012265 solid product Substances 0.000 description 9
• 239000000126 substance Substances 0.000 description 9
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
• 229910000147 aluminium phosphate Inorganic materials 0.000 description 8
• 239000003208 petroleum Substances 0.000 description 8
• 238000002360 preparation method Methods 0.000 description 8
• 230000002829 reductive effect Effects 0.000 description 8
• CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 8
• KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 7
• 239000002775 capsule Substances 0.000 description 7
• 239000003795 chemical substances by application Substances 0.000 description 7
• 229910000027 potassium carbonate Inorganic materials 0.000 description 7
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
• MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
• LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
• 238000004587 chromatography analysis Methods 0.000 description 6
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
• 238000005984 hydrogenation reaction Methods 0.000 description 6
• NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
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• 229960004873 levomenthol Drugs 0.000 description 1
• 230000000670 limiting effect Effects 0.000 description 1
• 210000004072 lung Anatomy 0.000 description 1
• VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
• 239000011976 maleic acid Substances 0.000 description 1
• 239000001630 malic acid Substances 0.000 description 1
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• 229960002510 mandelic acid Drugs 0.000 description 1
• 239000000463 material Substances 0.000 description 1
• 229910052751 metal Inorganic materials 0.000 description 1
• 239000002184 metal Substances 0.000 description 1
• 229910052987 metal hydride Inorganic materials 0.000 description 1
• 150000004681 metal hydrides Chemical class 0.000 description 1
• 150000002739 metals Chemical class 0.000 description 1
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
• OGBINJLTBZWRRB-UHFFFAOYSA-N methyl 2,2,2-trichloroethanimidate Chemical compound COC(=N)C(Cl)(Cl)Cl OGBINJLTBZWRRB-UHFFFAOYSA-N 0.000 description 1
• RKTZGHIVCMOBFD-UHFFFAOYSA-N methyl 3-[1-methyl-2-(4-piperazin-1-ylphenyl)benzimidazol-5-yl]propanoate Chemical compound N=1C2=CC(CCC(=O)OC)=CC=C2N(C)C=1C(C=C1)=CC=C1N1CCNCC1 RKTZGHIVCMOBFD-UHFFFAOYSA-N 0.000 description 1
• KVPGFVDWDWEYHY-UHFFFAOYSA-N methyl 3-[1-methyl-2-(4-piperidin-4-ylphenyl)benzimidazol-5-yl]prop-2-enoate Chemical compound N=1C2=CC(C=CC(=O)OC)=CC=C2N(C)C=1C(C=C1)=CC=C1C1CCNCC1 KVPGFVDWDWEYHY-UHFFFAOYSA-N 0.000 description 1
• ZNJUYUCIQPRDQL-UHFFFAOYSA-N methyl 3-[3-amino-4-(methylamino)phenyl]prop-2-enoate Chemical compound CNC1=CC=C(C=CC(=O)OC)C=C1N ZNJUYUCIQPRDQL-UHFFFAOYSA-N 0.000 description 1
• IJWGQQYFYDBASI-UHFFFAOYSA-N methyl 3-[[1-butyl-2-(2-piperidin-4-ylethyl)benzimidazole-5-carbonyl]amino]propanoate Chemical compound N=1C2=CC(C(=O)NCCC(=O)OC)=CC=C2N(CCCC)C=1CCC1CCNCC1 IJWGQQYFYDBASI-UHFFFAOYSA-N 0.000 description 1
• ASMBHKMBBYLJMT-UHFFFAOYSA-N methyl 3-[[1-methyl-2-(2-piperidin-4-ylethyl)benzimidazol-5-yl]sulfonylamino]propanoate Chemical compound N=1C2=CC(S(=O)(=O)NCCC(=O)OC)=CC=C2N(C)C=1CCC1CCNCC1 ASMBHKMBBYLJMT-UHFFFAOYSA-N 0.000 description 1
• GZRNFNHSRBSRIW-UHFFFAOYSA-N methyl 3-[[1-methyl-2-(2-pyridin-4-ylethyl)benzimidazole-5-carbonyl]amino]propanoate Chemical compound N=1C2=CC(C(=O)NCCC(=O)OC)=CC=C2N(C)C=1CCC1=CC=NC=C1 GZRNFNHSRBSRIW-UHFFFAOYSA-N 0.000 description 1
• BITQACGETHBLOV-UHFFFAOYSA-N methyl 3-[[1-methyl-2-(piperidin-4-yloxymethyl)benzimidazole-5-carbonyl]amino]propanoate Chemical compound N=1C2=CC(C(=O)NCCC(=O)OC)=CC=C2N(C)C=1COC1CCNCC1 BITQACGETHBLOV-UHFFFAOYSA-N 0.000 description 1
• VWFJYEBFUKPDSW-UHFFFAOYSA-N methyl 3-[[1-methyl-2-[2-(1-methylpiperidin-4-yl)ethyl]benzimidazole-5-carbonyl]amino]propanoate Chemical compound N=1C2=CC(C(=O)NCCC(=O)OC)=CC=C2N(C)C=1CCC1CCN(C)CC1 VWFJYEBFUKPDSW-UHFFFAOYSA-N 0.000 description 1
• BXAQQCILTBPJLH-UHFFFAOYSA-N methyl 3-[[2-(3-imidazol-1-ylpropyl)-1-methylbenzimidazole-5-carbonyl]amino]propanoate Chemical compound N=1C2=CC(C(=O)NCCC(=O)OC)=CC=C2N(C)C=1CCCN1C=CN=C1 BXAQQCILTBPJLH-UHFFFAOYSA-N 0.000 description 1
• XAGVORQFDUFBNK-UHFFFAOYSA-N methyl 3-[[3-amino-4-(methylamino)benzoyl]amino]propanoate Chemical compound CNC1=CC=C(C(=O)NCCC(=O)OC)C=C1N XAGVORQFDUFBNK-UHFFFAOYSA-N 0.000 description 1
• QAAWNGPOMVVPJD-UHFFFAOYSA-N methyl 3-[[4-(methylamino)-3-nitrobenzoyl]amino]propanoate Chemical compound COC(=O)CCNC(C1=CC(=C(C=C1)NC)[N+](=O)[O-])=O QAAWNGPOMVVPJD-UHFFFAOYSA-N 0.000 description 1
• CPXJNZYKHUKKQQ-UHFFFAOYSA-N methyl 4-[3-methyl-2-(2-piperidin-4-ylethyl)benzimidazol-5-yl]sulfanylbutanoate Chemical compound CN1C2=CC(SCCCC(=O)OC)=CC=C2N=C1CCC1CCNCC1 CPXJNZYKHUKKQQ-UHFFFAOYSA-N 0.000 description 1
• NEZYHONHWVUFPF-UHFFFAOYSA-N methyl 4-[[1-methyl-2-(2-piperidin-4-ylethyl)benzimidazole-5-carbonyl]amino]butanoate Chemical compound N=1C2=CC(C(=O)NCCCC(=O)OC)=CC=C2N(C)C=1CCC1CCNCC1 NEZYHONHWVUFPF-UHFFFAOYSA-N 0.000 description 1
• HYJBTRWZGTUXJJ-UHFFFAOYSA-N methyl 5-[1-methyl-2-(2-piperidin-4-ylethyl)benzimidazol-5-yl]pentanoate Chemical compound N=1C2=CC(CCCCC(=O)OC)=CC=C2N(C)C=1CCC1CCNCC1 HYJBTRWZGTUXJJ-UHFFFAOYSA-N 0.000 description 1
• NHCYCOAQYSWGRJ-UHFFFAOYSA-N methyl 5-[2-(4-carbamimidoylphenyl)-5,7-dioxo-1,3,6,8-tetrazatricyclo[6.3.1.04,12]dodeca-2,4(12)-dien-6-yl]pentanoate Chemical compound N=1C(=C23)C(=O)N(CCCCC(=O)OC)C(=O)N2CCCN3C=1C1=CC=C(C(N)=N)C=C1 NHCYCOAQYSWGRJ-UHFFFAOYSA-N 0.000 description 1
• ZHUGLWYSMKXQRQ-UHFFFAOYSA-N methyl 5-[3-(2-amino-2-oxoethyl)-9-methyl-2,6-dioxo-8-(2-piperidin-4-ylethyl)purin-1-yl]pentanoate Chemical compound N=1C=2C(=O)N(CCCCC(=O)OC)C(=O)N(CC(N)=O)C=2N(C)C=1CCC1CCNCC1 ZHUGLWYSMKXQRQ-UHFFFAOYSA-N 0.000 description 1
• YMYANLADGILJBQ-UHFFFAOYSA-N methyl 5-[3-benzyl-8-(4-carbamimidoylphenyl)-9-methyl-2,6-dioxopurin-1-yl]pentanoate Chemical compound C1=2N(C)C(C=3C=CC(=CC=3)C(N)=N)=NC=2C(=O)N(CCCCC(=O)OC)C(=O)N1CC1=CC=CC=C1 YMYANLADGILJBQ-UHFFFAOYSA-N 0.000 description 1
• KXJYTEWOKLLDBK-UHFFFAOYSA-N methyl 5-[3-butyl-8-(4-carbamimidoylphenyl)-9-methyl-2,6-dioxopurin-1-yl]pentanoate Chemical compound N=1C=2C(=O)N(CCCCC(=O)OC)C(=O)N(CCCC)C=2N(C)C=1C1=CC=C(C(N)=N)C=C1 KXJYTEWOKLLDBK-UHFFFAOYSA-N 0.000 description 1
• LHXUNZWKKKEIAN-UHFFFAOYSA-N methyl 5-[8-(4-carbamimidoylphenyl)-2,6-dioxo-9-propan-2-yl-3h-purin-1-yl]pentanoate Chemical compound N=1C=2C(=O)N(CCCCC(=O)OC)C(=O)NC=2N(C(C)C)C=1C1=CC=C(C(N)=N)C=C1 LHXUNZWKKKEIAN-UHFFFAOYSA-N 0.000 description 1
• OCZGPHIEDIJLAF-UHFFFAOYSA-N methyl 5-[8-(4-carbamimidoylphenyl)-3,7-dimethyl-2,6-dioxopurin-1-yl]pentanoate Chemical compound CN1C=2C(=O)N(CCCCC(=O)OC)C(=O)N(C)C=2N=C1C1=CC=C(C(N)=N)C=C1 OCZGPHIEDIJLAF-UHFFFAOYSA-N 0.000 description 1
• YOZHDZXNZRPRQZ-UHFFFAOYSA-N methyl 5-[8-(4-carbamimidoylphenyl)-3,9-dimethyl-2,6-dioxopurin-1-yl]-2-methylpentanoate Chemical compound N=1C=2C(=O)N(CCCC(C)C(=O)OC)C(=O)N(C)C=2N(C)C=1C1=CC=C(C(N)=N)C=C1 YOZHDZXNZRPRQZ-UHFFFAOYSA-N 0.000 description 1
• DOZVZRNBNVPUCT-UHFFFAOYSA-N methyl 5-[8-(4-carbamimidoylphenyl)-3,9-dimethyl-2,6-dioxopurin-1-yl]pentanoate Chemical compound N=1C=2C(=O)N(CCCCC(=O)OC)C(=O)N(C)C=2N(C)C=1C1=CC=C(C(N)=N)C=C1 DOZVZRNBNVPUCT-UHFFFAOYSA-N 0.000 description 1
• LOPAHYNQMNTDCV-UHFFFAOYSA-N methyl 5-[8-(4-carbamimidoylphenyl)-3-methyl-2,6-dioxo-9-(3-phenylpropyl)purin-1-yl]pentanoate Chemical compound C=1C=C(C(N)=N)C=CC=1C1=NC=2C(=O)N(CCCCC(=O)OC)C(=O)N(C)C=2N1CCCC1=CC=CC=C1 LOPAHYNQMNTDCV-UHFFFAOYSA-N 0.000 description 1
• ZLPPQFNZTFQFNR-UHFFFAOYSA-N methyl 5-[8-(4-carbamimidoylphenyl)-9-methyl-2,6-dioxo-3-(3-phenylpropyl)purin-1-yl]pentanoate Chemical compound C1=2N(C)C(C=3C=CC(=CC=3)C(N)=N)=NC=2C(=O)N(CCCCC(=O)OC)C(=O)N1CCCC1=CC=CC=C1 ZLPPQFNZTFQFNR-UHFFFAOYSA-N 0.000 description 1
• ZJDMDNCRWQBCCV-UHFFFAOYSA-N methyl 5-[8-(4-carbamimidoylphenyl)-9-methyl-2,6-dioxo-3h-purin-1-yl]pentanoate Chemical compound N=1C=2C(=O)N(CCCCC(=O)OC)C(=O)NC=2N(C)C=1C1=CC=C(C(N)=N)C=C1 ZJDMDNCRWQBCCV-UHFFFAOYSA-N 0.000 description 1
• XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
• 230000011987 methylation Effects 0.000 description 1
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• GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
• PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
• WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
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• 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
• UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
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• RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
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• NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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• CMXPERZAMAQXSF-UHFFFAOYSA-M sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate;1,8-dihydroxyanthracene-9,10-dione Chemical compound [Na+].O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O.CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC CMXPERZAMAQXSF-UHFFFAOYSA-M 0.000 description 1
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• HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
• 239000000829 suppository Substances 0.000 description 1
• 238000003786 synthesis reaction Methods 0.000 description 1
• IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
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• ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 1
• 238000002560 therapeutic procedure Methods 0.000 description 1
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• 230000002537 thrombolytic effect Effects 0.000 description 1
• RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
• 229910052718 tin Inorganic materials 0.000 description 1
• 239000011135 tin Substances 0.000 description 1
• AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
• 238000005809 transesterification reaction Methods 0.000 description 1
• 238000002834 transmittance Methods 0.000 description 1
• BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
• HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
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• 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
• 229960005356 urokinase Drugs 0.000 description 1
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• 239000011701 zinc Substances 0.000 description 1
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