SK7602002A3 - Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis - Google Patents

Info

Publication number

SK7602002A3

SK7602002A3 SK760-2002A SK7602002A SK7602002A3 SK 7602002 A3 SK7602002 A3 SK 7602002A3 SK 7602002 A SK7602002 A SK 7602002A SK 7602002 A3 SK7602002 A3 SK 7602002A3

Authority

SK

Slovakia

Prior art keywords

pharmaceutically acceptable

substituted

compound

heterocycloalkyl

group

Prior art date

1999-12-03

Links

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• Global Dossier
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• 150000001875 compounds Chemical class 0.000 title claims abstract description 293
• 239000000203 mixture Substances 0.000 title claims description 95
• 230000015572 biosynthetic process Effects 0.000 title description 15
• 239000000463 material Substances 0.000 title description 10
• 238000003786 synthesis reaction Methods 0.000 title description 9
• 108091005804 Peptidases Proteins 0.000 claims abstract description 27
• 239000004365 Protease Substances 0.000 claims abstract description 27
• 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims abstract description 26
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
• 241001144416 Picornavirales Species 0.000 claims abstract description 19
• -1 each R k is H Chemical group 0.000 claims description 198
• 125000000217 alkyl group Chemical group 0.000 claims description 196
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 147
• 229910052739 hydrogen Inorganic materials 0.000 claims description 117
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 106
• 125000003118 aryl group Chemical group 0.000 claims description 99
• 150000003839 salts Chemical class 0.000 claims description 99
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 95
• 125000001424 substituent group Chemical group 0.000 claims description 94
• 125000001072 heteroaryl group Chemical group 0.000 claims description 83
• 229940002612 prodrug Drugs 0.000 claims description 72
• 239000000651 prodrug Substances 0.000 claims description 72
• 239000012453 solvate Substances 0.000 claims description 71
• 239000002207 metabolite Substances 0.000 claims description 70
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 59
• 125000004429 atom Chemical group 0.000 claims description 44
• 125000006239 protecting group Chemical group 0.000 claims description 43
• 150000002367 halogens Chemical class 0.000 claims description 39
• 125000003545 alkoxy group Chemical group 0.000 claims description 38
• 229910052736 halogen Inorganic materials 0.000 claims description 38
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 36
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 34
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 33
• 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 31
• 229910052717 sulfur Inorganic materials 0.000 claims description 29
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 28
• 125000002252 acyl group Chemical group 0.000 claims description 25
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 25
• 230000000694 effects Effects 0.000 claims description 25
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 25
• 125000005129 aryl carbonyl group Chemical group 0.000 claims description 22
• 229930194542 Keto Natural products 0.000 claims description 21
• 125000004104 aryloxy group Chemical group 0.000 claims description 21
• 229910052731 fluorine Inorganic materials 0.000 claims description 21
• 125000000468 ketone group Chemical group 0.000 claims description 21
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 20
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 20
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 19
• 125000004414 alkyl thio group Chemical group 0.000 claims description 19
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 19
• 125000001183 hydrocarbyl group Chemical group 0.000 claims description 19
• 125000001188 haloalkyl group Chemical group 0.000 claims description 18
• 125000003441 thioacyl group Chemical group 0.000 claims description 18
• 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 17
• 230000002401 inhibitory effect Effects 0.000 claims description 17
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 16
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 16
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 16
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
• 125000003282 alkyl amino group Chemical group 0.000 claims description 15
• 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 14
• 229930195734 saturated hydrocarbon Natural products 0.000 claims description 13
• 125000005842 heteroatom Chemical group 0.000 claims description 12
• 238000003556 assay Methods 0.000 claims description 11
• 125000000623 heterocyclic group Chemical group 0.000 claims description 11
• 238000004519 manufacturing process Methods 0.000 claims description 11
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 10
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 10
• 125000005110 aryl thio group Chemical group 0.000 claims description 10
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 10
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 10
• 229910052760 oxygen Inorganic materials 0.000 claims description 10
• 125000003396 thiol group Chemical class [H]S* 0.000 claims description 10
• 125000001769 aryl amino group Chemical group 0.000 claims description 9
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 9
• 125000005226 heteroaryloxycarbonyl group Chemical group 0.000 claims description 9
• 239000000126 substance Substances 0.000 claims description 9
• 125000005323 thioketone group Chemical group 0.000 claims description 9
• 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 8
• 125000005530 alkylenedioxy group Chemical group 0.000 claims description 8
• 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 8
• 125000005170 cycloalkyloxycarbonyl group Chemical group 0.000 claims description 8
• 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 8
• 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 8
• 229930195735 unsaturated hydrocarbon Natural products 0.000 claims description 8
• 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 7
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• 125000005100 aryl amino carbonyl group Chemical group 0.000 claims description 7
• 125000004658 aryl carbonyl amino group Chemical group 0.000 claims description 7
• 125000004671 dialkylaminothiocarbonyl group Chemical group 0.000 claims description 7
• 125000005241 heteroarylamino group Chemical group 0.000 claims description 7
• 125000005222 heteroarylaminocarbonyl group Chemical group 0.000 claims description 7
• 229910052757 nitrogen Inorganic materials 0.000 claims description 7
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 7
• 241000124008 Mammalia Species 0.000 claims description 6
• 125000004670 alkyl amino thio carbonyl group Chemical group 0.000 claims description 6
• 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 6
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
• 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 6
• 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims description 6
• 238000004113 cell culture Methods 0.000 claims description 6
• 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 6
• 125000005167 cycloalkylaminocarbonyl group Chemical group 0.000 claims description 6
• 125000005169 cycloalkylcarbonylamino group Chemical group 0.000 claims description 6
• 125000005224 heteroarylcarbonylamino group Chemical group 0.000 claims description 6
• 239000003795 chemical substances by application Substances 0.000 claims description 5
• 239000003085 diluting agent Substances 0.000 claims description 5
• 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 5
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
• 239000003981 vehicle Substances 0.000 claims description 4
• 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 claims description 3
• 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 3
• 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 claims description 3
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 125000005843 halogen group Chemical group 0.000 claims description 3
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
• 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 claims description 2
• 125000002877 alkyl aryl group Chemical group 0.000 claims 1
• 125000005204 heteroarylcarbonyloxy group Chemical group 0.000 claims 1
• 239000000543 intermediate Substances 0.000 abstract description 341
• 108010091324 3C proteases Proteins 0.000 abstract description 9
• 230000004071 biological effect Effects 0.000 abstract description 4
• 238000010189 synthetic method Methods 0.000 abstract description 3
• 241000709664 Picornaviridae Species 0.000 abstract description 2
• 238000002360 preparation method Methods 0.000 description 204
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 131
• 238000000034 method Methods 0.000 description 104
• 229910052799 carbon Inorganic materials 0.000 description 84
• 238000006243 chemical reaction Methods 0.000 description 81
• 241000710122 Rhinovirus B14 Species 0.000 description 72
• 239000000047 product Substances 0.000 description 69
• 239000000460 chlorine Substances 0.000 description 67
• 239000000243 solution Substances 0.000 description 65
• 235000019439 ethyl acetate Nutrition 0.000 description 60
• 239000011541 reaction mixture Substances 0.000 description 59
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 57
• 239000012267 brine Substances 0.000 description 56
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 56
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
• QMMOXUPEWRXHJS-UHFFFAOYSA-N pent-2-ene Chemical compound CCC=CC QMMOXUPEWRXHJS-UHFFFAOYSA-N 0.000 description 53
• 150000001412 amines Chemical class 0.000 description 48
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
• 239000011734 sodium Substances 0.000 description 38
• 150000001408 amides Chemical class 0.000 description 36
• 238000003818 flash chromatography Methods 0.000 description 36
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
• 238000000746 purification Methods 0.000 description 34
• 239000007787 solid Substances 0.000 description 31
• 150000003254 radicals Chemical class 0.000 description 30
• 238000007429 general method Methods 0.000 description 29
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 28
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 27
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
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• 241000700605 Viruses Species 0.000 description 24
• UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 24
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
• 125000004494 ethyl ester group Chemical group 0.000 description 23
• 241000710130 Human rhinovirus 1A Species 0.000 description 22
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• 231100001274 therapeutic index Toxicity 0.000 description 21
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• 238000010992 reflux Methods 0.000 description 20
• 238000003756 stirring Methods 0.000 description 20
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 20
• XWHHYOYVRVGJJY-QMMMGPOBSA-N 4-fluoro-L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(F)C=C1 XWHHYOYVRVGJJY-QMMMGPOBSA-N 0.000 description 19
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
• 239000012044 organic layer Substances 0.000 description 19
• 229920006395 saturated elastomer Polymers 0.000 description 17
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
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• 239000000706 filtrate Substances 0.000 description 12
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
• 238000010828 elution Methods 0.000 description 11
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• 238000012360 testing method Methods 0.000 description 10
• WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 10
• 241000282414 Homo sapiens Species 0.000 description 9
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• 238000005755 formation reaction Methods 0.000 description 9
• VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 9
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
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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 9
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• 239000002904 solvent Substances 0.000 description 8
• YZDVNWXOYGTHJO-MRVPVSSYSA-N (2r)-3-(4-fluorophenyl)-2-hydroxypropanoic acid Chemical compound OC(=O)[C@H](O)CC1=CC=C(F)C=C1 YZDVNWXOYGTHJO-MRVPVSSYSA-N 0.000 description 7
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• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
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• 235000001014 amino acid Nutrition 0.000 description 6
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• 150000001413 amino acids Chemical class 0.000 description 6
• 125000004432 carbon atom Chemical group C* 0.000 description 6
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• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
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• 230000008569 process Effects 0.000 description 6
• 238000010926 purge Methods 0.000 description 6
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
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• 238000010898 silica gel chromatography Methods 0.000 description 6
• 159000000000 sodium salts Chemical class 0.000 description 6
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