JP2004504404A5 - - Google Patents

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Publication number

JP2004504404A5

JP2004504404A5 JP2002514149A JP2002514149A JP2004504404A5 JP 2004504404 A5 JP2004504404 A5 JP 2004504404A5 JP 2002514149 A JP2002514149 A JP 2002514149A JP 2002514149 A JP2002514149 A JP 2002514149A JP 2004504404 A5 JP2004504404 A5 JP 2004504404A5

Authority

JP

Japan

Prior art keywords

compound

alkyl

prodrug

conhch

embedded image

Prior art date

2001-07-19

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.)

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• 150000001875 compounds Chemical class 0.000 claims description 249
• 239000000651 prodrug Substances 0.000 claims description 65
• 229940002612 prodrug Drugs 0.000 claims description 65
• 241000711549 Hepacivirus C Species 0.000 claims description 52
• 239000008194 pharmaceutical composition Substances 0.000 claims description 51
• 229940079322 interferon Drugs 0.000 claims description 35
• 108091005804 Peptidases Proteins 0.000 claims description 32
• 239000004365 Protease Substances 0.000 claims description 32
• 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims description 32
• 150000003839 salts Chemical class 0.000 claims description 32
• 239000012453 solvate Substances 0.000 claims description 32
• -1 aryl-heteroaryl Chemical group 0.000 claims description 30
• 125000000217 alkyl group Chemical group 0.000 claims description 29
• 102000014150 Interferons Human genes 0.000 claims description 28
• 108010050904 Interferons Proteins 0.000 claims description 28
• 229910005965 SO 2 Inorganic materials 0.000 claims description 26
• 238000000034 method Methods 0.000 claims description 23
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
• 230000001747 exhibiting effect Effects 0.000 claims description 22
• 230000002401 inhibitory effect Effects 0.000 claims description 22
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 20
• 125000003118 aryl group Chemical group 0.000 claims description 19
• 125000001072 heteroaryl group Chemical group 0.000 claims description 16
• 239000003443 antiviral agent Substances 0.000 claims description 15
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
• 229910052760 oxygen Inorganic materials 0.000 claims description 14
• 229910052717 sulfur Inorganic materials 0.000 claims description 13
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 12
• 125000003545 alkoxy group Chemical group 0.000 claims description 10
• 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 10
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 10
• 229910052757 nitrogen Inorganic materials 0.000 claims description 10
• 239000000126 substance Substances 0.000 claims description 10
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 9
• 239000004480 active ingredient Substances 0.000 claims description 8
• 125000003342 alkenyl group Chemical group 0.000 claims description 8
• 125000004104 aryloxy group Chemical group 0.000 claims description 8
• 229910052799 carbon Inorganic materials 0.000 claims description 8
• 125000004122 cyclic group Chemical group 0.000 claims description 8
• IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical group N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 7
• 125000001769 aryl amino group Chemical group 0.000 claims description 7
• 229960000329 ribavirin Drugs 0.000 claims description 7
• HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 7
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 6
• 125000004414 alkyl thio group Chemical group 0.000 claims description 6
• 125000000304 alkynyl group Chemical group 0.000 claims description 6
• 125000005110 aryl thio group Chemical group 0.000 claims description 6
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 6
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• 229910052736 halogen Inorganic materials 0.000 claims description 6
• 150000002367 halogens Chemical class 0.000 claims description 6
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 6
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
• 229920001184 polypeptide Polymers 0.000 claims description 6
• 102000004196 processed proteins & peptides Human genes 0.000 claims description 6
• 108090000765 processed proteins & peptides Proteins 0.000 claims description 6
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
• 238000007920 subcutaneous administration Methods 0.000 claims description 5
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 4
• 125000003282 alkyl amino group Chemical group 0.000 claims description 4
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 4
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
• 239000004202 carbamide Substances 0.000 claims description 4
• 125000004432 carbon atom Chemical group C* 0.000 claims description 4
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
• 150000002148 esters Chemical class 0.000 claims description 4
• 229910052731 fluorine Inorganic materials 0.000 claims description 4
• 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 4
• 125000004475 heteroaralkyl group Chemical group 0.000 claims description 4
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 4
• 125000000623 heterocyclic group Chemical group 0.000 claims description 4
• 229910052739 hydrogen Inorganic materials 0.000 claims description 4
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
• 150000002576 ketones Chemical class 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 3
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 3
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
• 239000003814 drug Substances 0.000 claims description 3
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
• 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 claims description 2
• RGICCULPCWNRAB-UHFFFAOYSA-N 2-[2-(2-hexoxyethoxy)ethoxy]ethanol Chemical compound CCCCCCOCCOCCOCCO RGICCULPCWNRAB-UHFFFAOYSA-N 0.000 claims description 2
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
• 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 2
• 208000005176 Hepatitis C Diseases 0.000 claims description 2
• SOWBFZRMHSNYGE-UHFFFAOYSA-N Monoamide-Oxalic acid Natural products NC(=O)C(O)=O SOWBFZRMHSNYGE-UHFFFAOYSA-N 0.000 claims description 2
• 229940100389 Sulfonylurea Drugs 0.000 claims description 2
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
• 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
• 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 2
• 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 2
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 2
• 125000004947 alkyl aryl amino group Chemical group 0.000 claims description 2
• 125000005248 alkyl aryloxy group Chemical group 0.000 claims description 2
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
• 125000004422 alkyl sulphonamide group Chemical group 0.000 claims description 2
• 125000005281 alkyl ureido group Chemical group 0.000 claims description 2
• 150000001408 amides Chemical class 0.000 claims description 2
• 125000005129 aryl carbonyl group Chemical group 0.000 claims description 2
• 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 2
• 125000004421 aryl sulphonamide group Chemical group 0.000 claims description 2
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
• 150000001540 azides Chemical class 0.000 claims description 2
• 125000002619 bicyclic group Chemical group 0.000 claims description 2
• 229910052794 bromium Inorganic materials 0.000 claims description 2
• 150000001721 carbon Chemical group 0.000 claims description 2
• 229910052801 chlorine Inorganic materials 0.000 claims description 2
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 2
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 2
• 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 2
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
• 230000000694 effects Effects 0.000 claims description 2
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
• 125000005241 heteroarylamino group Chemical group 0.000 claims description 2
• 125000005222 heteroarylaminocarbonyl group Chemical group 0.000 claims description 2
• 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 2
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 2
• 125000005226 heteroaryloxycarbonyl group Chemical group 0.000 claims description 2
• 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 2
• 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 2
• 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 claims description 2
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
• 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 2
• 239000000203 mixture Substances 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
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
• ZEJHEROGFWIRLO-UHFFFAOYSA-N nitrosulfonylformonitrile Chemical compound [O-][N+](=O)S(=O)(=O)C#N ZEJHEROGFWIRLO-UHFFFAOYSA-N 0.000 claims description 2
• 239000001301 oxygen Substances 0.000 claims description 2
• 125000004437 phosphorous atom Chemical group 0.000 claims description 2
• 229910052698 phosphorus Inorganic materials 0.000 claims description 2
• 125000005936 piperidyl group Chemical class 0.000 claims description 2
• 125000004076 pyridyl group Chemical class 0.000 claims description 2
• 238000006467 substitution reaction Methods 0.000 claims description 2
• 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 2
• 150000003457 sulfones Chemical class 0.000 claims description 2
• 150000003462 sulfoxides Chemical class 0.000 claims description 2
• 239000011593 sulfur Substances 0.000 claims description 2
• 208000024891 symptom Diseases 0.000 claims description 2
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
• 125000001544 thienyl group Chemical class 0.000 claims description 2
• 125000003368 amide group Chemical group 0.000 claims 1
• 0 FC(C(C(CC1)CCC1C1*C1)C(F)(F)F)(F)F Chemical compound FC(C(C(CC1)CCC1C1*C1)C(F)(F)F)(F)F 0.000 description 13
• 102000006992 Interferon-alpha Human genes 0.000 description 8
• 108010047761 Interferon-alpha Proteins 0.000 description 8
• JMEPTQIVALKSSB-UHFFFAOYSA-N CC(CC1)CCS1=O Chemical compound CC(CC1)CCS1=O JMEPTQIVALKSSB-UHFFFAOYSA-N 0.000 description 2
• BPEOLNQALWEEAO-UHFFFAOYSA-N CC(C(N(C1)C(C)=O)=CC11SCCS1)=O Chemical compound CC(C(N(C1)C(C)=O)=CC11SCCS1)=O BPEOLNQALWEEAO-UHFFFAOYSA-N 0.000 description 1
• KPXKHIURAUYKDK-JSGCZJAVSA-N CC(C)(C)OC(N[C@@H](C1CCCCC1)C(N(C[C@@H]1OC(C)(C)C[C@@H]11)[C@@H]1C(N[C@@H](CC1CC1)C(C(NCC(N[C@H](C(N(C)C)=O)c1ccc[s]1)=O)=O)=O)=O)=O)=O Chemical compound CC(C)(C)OC(N[C@@H](C1CCCCC1)C(N(C[C@@H]1OC(C)(C)C[C@@H]11)[C@@H]1C(N[C@@H](CC1CC1)C(C(NCC(N[C@H](C(N(C)C)=O)c1ccc[s]1)=O)=O)=O)=O)=O)=O KPXKHIURAUYKDK-JSGCZJAVSA-N 0.000 description 1
• IDKAJTIEEAKXAB-VIFPVBQESA-N CC(C)(C[C@H]1C(C)=O)CN1C(C)=O Chemical compound CC(C)(C[C@H]1C(C)=O)CN1C(C)=O IDKAJTIEEAKXAB-VIFPVBQESA-N 0.000 description 1
• ZHLRZLIMBBVZBH-JSTQBOTJSA-N CC(C)C(C(C(N[C@H](CC1CCC1)C(C(N)=O)=O)=O)N(CC1)C([C@H](C(C)(C)C)NC(NC2(CC(C3)C4)CC4CC3C2)=O)=O)C1=C=C Chemical compound CC(C)C(C(C(N[C@H](CC1CCC1)C(C(N)=O)=O)=O)N(CC1)C([C@H](C(C)(C)C)NC(NC2(CC(C3)C4)CC4CC3C2)=O)=O)C1=C=C ZHLRZLIMBBVZBH-JSTQBOTJSA-N 0.000 description 1
• ZHEXBRXKIXWCCR-UHFFFAOYSA-N CC(C)CC(C(C)c1ccccc1)=O Chemical compound CC(C)CC(C(C)c1ccccc1)=O ZHEXBRXKIXWCCR-UHFFFAOYSA-N 0.000 description 1
• OYWXBXGRCATCMZ-GLVFCQMZSA-N CC(C)C[C@@H](C(C(/C=C/CC(C(CC(C(C=C(C)C)=O)c1ccccc1)=C)=O)=O)=O)NC([C@H](C1C(C)(C)C1C1)/C1=C/C(C(C(C)(C)C)/C=C/C(OCC(C)C)=O)=O)=O Chemical compound CC(C)C[C@@H](C(C(/C=C/CC(C(CC(C(C=C(C)C)=O)c1ccccc1)=C)=O)=O)=O)NC([C@H](C1C(C)(C)C1C1)/C1=C/C(C(C(C)(C)C)/C=C/C(OCC(C)C)=O)=O)=O OYWXBXGRCATCMZ-GLVFCQMZSA-N 0.000 description 1
• GIMBKDZNMKTZMG-UHFFFAOYSA-N CC(C)c1nccnc1 Chemical compound CC(C)c1nccnc1 GIMBKDZNMKTZMG-UHFFFAOYSA-N 0.000 description 1
• XCWKPRLRTXTBIT-UHFFFAOYSA-N CC(C1(C)CCCCC1)C(C)=O Chemical compound CC(C1(C)CCCCC1)C(C)=O XCWKPRLRTXTBIT-UHFFFAOYSA-N 0.000 description 1
• VBZMYSMYHXKMKD-ZFWWWQNUSA-N CC([C@H](C[C@@H](CNC(c1ccccc1)=O)C1)N1C(C)=O)=O Chemical compound CC([C@H](C[C@@H](CNC(c1ccccc1)=O)C1)N1C(C)=O)=O VBZMYSMYHXKMKD-ZFWWWQNUSA-N 0.000 description 1
• LTFLSYOLFGUVRM-OCCSQVGLSA-N CC([C@H](C[C@H](C1)NS(c2ccccc2)(=O)=O)N1C(C)=O)=O Chemical compound CC([C@H](C[C@H](C1)NS(c2ccccc2)(=O)=O)N1C(C)=O)=O LTFLSYOLFGUVRM-OCCSQVGLSA-N 0.000 description 1
• UIWORXHEVNIOJG-UHFFFAOYSA-N CC1CCC(C)(C)CC1 Chemical compound CC1CCC(C)(C)CC1 UIWORXHEVNIOJG-UHFFFAOYSA-N 0.000 description 1
• CYISMTMRBPPERU-UHFFFAOYSA-N CCC1CCC(C)CC1 Chemical compound CCC1CCC(C)CC1 CYISMTMRBPPERU-UHFFFAOYSA-N 0.000 description 1
• JXOKDXRVGZDJJN-YRMYZHMDSA-N CCCC(C(C(NCC(NCC(N)O)Oc1ccccc1)=O)=O)NC(C(CC(CNC(c1cc(Oc2ccccc2)ccc1)=O)C1)N1C([C@H](C1CCCCC1)NC(c(cccc1)c1C(C)=O)=O)=O)=O Chemical compound CCCC(C(C(NCC(NCC(N)O)Oc1ccccc1)=O)=O)NC(C(CC(CNC(c1cc(Oc2ccccc2)ccc1)=O)C1)N1C([C@H](C1CCCCC1)NC(c(cccc1)c1C(C)=O)=O)=O)=O JXOKDXRVGZDJJN-YRMYZHMDSA-N 0.000 description 1
• KAYQMXDHDUNLOW-MVISEALSSA-N CCCC(C(C(NCC(N[C@H](C(N)=O)c1ccccc1)=O)=O)=O)NC(C(CC(C1)NS(c2ccccc2)(=O)=O)N1C([C@H](C1CCCCC1)NC(OCC(C)C)=O)=O)=C Chemical compound CCCC(C(C(NCC(N[C@H](C(N)=O)c1ccccc1)=O)=O)=O)NC(C(CC(C1)NS(c2ccccc2)(=O)=O)N1C([C@H](C1CCCCC1)NC(OCC(C)C)=O)=O)=C KAYQMXDHDUNLOW-MVISEALSSA-N 0.000 description 1
• VZBCRTXBQMZMEO-UHFFFAOYSA-N CCOC(N(CC1)CCN1c1ccc(C)cn1)=O Chemical compound CCOC(N(CC1)CCN1c1ccc(C)cn1)=O VZBCRTXBQMZMEO-UHFFFAOYSA-N 0.000 description 1
• GITXOBUSWMVQGO-JTQLQIEISA-N CCON(C)C([C@@H](C)c1ccccc1)=O Chemical compound CCON(C)C([C@@H](C)c1ccccc1)=O GITXOBUSWMVQGO-JTQLQIEISA-N 0.000 description 1
• NCCHARWOCKOHIH-UHFFFAOYSA-N CNC(c1ccccc1)=O Chemical compound CNC(c1ccccc1)=O NCCHARWOCKOHIH-UHFFFAOYSA-N 0.000 description 1
• ZWDCLCKNBAZGBO-RCOVLWMOSA-N C[C@@H](CC[C@H]1C(C)=O)N1C(C)=O Chemical compound C[C@@H](CC[C@H]1C(C)=O)N1C(C)=O ZWDCLCKNBAZGBO-RCOVLWMOSA-N 0.000 description 1
• WSMQKESQZFQMFW-UHFFFAOYSA-N Cc1n[nH]c(C(O)=O)c1 Chemical compound Cc1n[nH]c(C(O)=O)c1 WSMQKESQZFQMFW-UHFFFAOYSA-N 0.000 description 1
• 125000005100 aryl amino carbonyl group Chemical group 0.000 description 1
• 230000002265 prevention Effects 0.000 description 1