HRP20100416T1 - Sumporni spojevi kao inhibitori serinske proteaze ns3 virusa hepatitisa c - Google Patents
Sumporni spojevi kao inhibitori serinske proteaze ns3 virusa hepatitisa c Download PDFInfo
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- HRP20100416T1 HRP20100416T1 HR20100416T HRP20100416T HRP20100416T1 HR P20100416 T1 HRP20100416 T1 HR P20100416T1 HR 20100416 T HR20100416 T HR 20100416T HR P20100416 T HRP20100416 T HR P20100416T HR P20100416 T1 HRP20100416 T1 HR P20100416T1
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- 102000012479 Serine Proteases Human genes 0.000 title 1
- 108010022999 Serine Proteases Proteins 0.000 title 1
- 108700012707 hepatitis C virus NS3 Proteins 0.000 title 1
- 239000003112 inhibitor Substances 0.000 title 1
- 150000003464 sulfur compounds Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract 100
- 125000000217 alkyl group Chemical group 0.000 claims abstract 22
- 125000003118 aryl group Chemical group 0.000 claims abstract 22
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract 19
- 150000003839 salts Chemical class 0.000 claims abstract 19
- 239000012453 solvate Substances 0.000 claims abstract 19
- 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 abstract 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract 18
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract 16
- 125000003342 alkenyl group Chemical group 0.000 claims abstract 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract 10
- 125000000304 alkynyl group Chemical group 0.000 claims abstract 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract 9
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract 9
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims abstract 7
- 125000001931 aliphatic group Chemical group 0.000 claims abstract 6
- 229910052760 oxygen Inorganic materials 0.000 claims abstract 5
- -1 carbalkoxy Chemical group 0.000 claims abstract 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims abstract 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract 4
- 125000004122 cyclic group Chemical group 0.000 claims abstract 4
- 229910052736 halogen Inorganic materials 0.000 claims abstract 4
- 150000002367 halogens Chemical class 0.000 claims abstract 4
- 125000004404 heteroalkyl group Chemical group 0.000 claims abstract 4
- 125000006413 ring segment Chemical group 0.000 claims abstract 4
- 125000003545 alkoxy group Chemical group 0.000 claims abstract 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract 3
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract 3
- 125000005281 alkyl ureido group Chemical group 0.000 claims abstract 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims abstract 3
- 125000005110 aryl thio group Chemical group 0.000 claims abstract 3
- 125000004104 aryloxy group Chemical group 0.000 claims abstract 3
- RGICCULPCWNRAB-UHFFFAOYSA-N 2-[2-(2-hexoxyethoxy)ethoxy]ethanol Chemical compound CCCCCCOCCOCCOCCO RGICCULPCWNRAB-UHFFFAOYSA-N 0.000 claims abstract 2
- 229930194542 Keto Natural products 0.000 claims abstract 2
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims abstract 2
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims abstract 2
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract 2
- 125000005422 alkyl sulfonamido group Chemical group 0.000 claims abstract 2
- 125000003368 amide group Chemical group 0.000 claims abstract 2
- 125000001769 aryl amino group Chemical group 0.000 claims abstract 2
- 125000005421 aryl sulfonamido group Chemical group 0.000 claims abstract 2
- 125000005518 carboxamido group Chemical group 0.000 claims abstract 2
- 125000000468 ketone group Chemical group 0.000 claims abstract 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims abstract 2
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims abstract 2
- 230000000694 effects Effects 0.000 claims 17
- 229940122604 HCV protease inhibitor Drugs 0.000 claims 16
- 241000711549 Hepacivirus C Species 0.000 claims 10
- 239000000825 pharmaceutical preparation Substances 0.000 claims 9
- 229940079322 interferon Drugs 0.000 claims 7
- 102000014150 Interferons Human genes 0.000 claims 6
- 108010050904 Interferons Proteins 0.000 claims 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 6
- 208000035475 disorder Diseases 0.000 claims 6
- 239000003814 drug Substances 0.000 claims 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 4
- 108091005804 Peptidases Proteins 0.000 claims 4
- 239000004365 Protease Substances 0.000 claims 4
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims 4
- 239000003443 antiviral agent Substances 0.000 claims 4
- 238000004519 manufacturing process Methods 0.000 claims 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 3
- 125000002877 alkyl aryl group Chemical group 0.000 claims 3
- 229910052794 bromium Inorganic materials 0.000 claims 3
- 229910052801 chlorine Inorganic materials 0.000 claims 3
- 239000000460 chlorine Substances 0.000 claims 3
- 229940079593 drug Drugs 0.000 claims 3
- 229910052731 fluorine Inorganic materials 0.000 claims 3
- 239000001301 oxygen Substances 0.000 claims 3
- 229910052717 sulfur Inorganic materials 0.000 claims 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 2
- 102000006992 Interferon-alpha Human genes 0.000 claims 2
- 108010047761 Interferon-alpha Proteins 0.000 claims 2
- 229910003204 NH2 Inorganic materials 0.000 claims 2
- 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 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 2
- 125000005038 alkynylalkyl group Chemical group 0.000 claims 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- 238000000034 method Methods 0.000 claims 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 229960000329 ribavirin Drugs 0.000 claims 2
- 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 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 2
- 239000011593 sulfur Substances 0.000 claims 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- 101100240520 Caenorhabditis elegans nhr-14 gene Proteins 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 208000005176 Hepatitis C Diseases 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000004475 heteroaralkyl group Chemical group 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 230000000116 mitigating effect Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 238000007920 subcutaneous administration Methods 0.000 claims 1
- 239000000758 substrate Substances 0.000 claims 1
- 125000004434 sulfur atom Chemical group 0.000 claims 1
- 208000024891 symptom Diseases 0.000 claims 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D411/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
Spoj, ili enantiomeri, stereoizomeri, rotameri, tautomeri, te racemati navedenog spoja, ili farmaceutski prihvatljiva sol ili solvat navedenog spoja, gdje navedeni spoj ima opću strukturu prikazanu u Formuli I: naznačen time što: R1 je H, OR8, NR9R10 ili CHR9R10, gdje R8, R9 i R10 mogu biti isti ili različiti, gdje se svakog od njih neovisno bira iz skupine koju čine H, alkil-, alkenil-, alkinil-, aril-, heteroalkil-, cikloalkil-, heterociklil-, arilalkil-, te heteroarilalkil; A i M mogu biti isti ili različiti, gdje se svakog od njih neovisno bira između R, OR, NHR, NRR', SR, SO2R, te halogena; ili A i M su vezani zajedno, tako da ostatak: prikazan gore, u Formuli I, tvori bilo tro-, četvero-, šestero-, sedmero- ili osmeročlani cikloalkil, četvero- do osmeročlani heterociklil, šestero- do deseteročlani aril, ili petero- do deseteročlani heteroaril; E je C(H) ili C(R); L je C(H), C(R), CH2C(R) ili C(R)CH2;R, R', R2, te R3 mogu biti isti ili različiti, gdje se svakog od njih neovisno bira iz skupine koju čine H, alkil, alkenil, cikloalkil, heterociklil, aril, arilalkil, heteroaril, te heteroarilalkil, ili alternativno R i R' u NRR' su vezani zajedno, tako da NRR' tvori četvero- do osmeročlani heterociklil; ili R2 se bira iz skupine koju čine sljedeći ostaci: a Y se bira između sljedećih ostataka: gdje G je NH ili O; a R15, R16, R17 i R18 mogu biti isti ili različiti, gdje se svakog od njih neovisno bira iz skupine koju čine H, alkil, alkenil, alkinil, cikloalkil, heterociklil, aril, i heteroaril, ili alternativno, (i) R15 i R16 su vezani zajedno kako bi tvorili četvero- do osmeročlani ciklička struktura, i (ii) isto tako, neovisno R17 i R18 su vezani zajedno kako bi tvorili tro- do osmeročlani cikloalkil ili heterociklil; gdje svaki od navedenih alkila, arila, heteroarila, cikloalkila ili heterociklila može biti nesupstituiran ili izborno neovisno supstituiran s jednim ili više ostataka, koje se bira iz skupine koju čine: hidroksi, alkoksi, ariloksi, tio, alkiltio, ariltio, amino, amido, alkilamino, arilamino, alkilsulfonil, arilsulfonil, sulfonamido, alkilsulfonamido, arilsulfon-amido, alkil, aril, heteroaril, keto, karboksi, karbalkoksi, karboksamido, alkoksikarbonilamino, alkoksikarboniloksi, alkilureido, arilureido, halogen, cijano, te nitro, gdje: "alkil" znači alifatska ugljikovodična skupina koja može biti nerazgranata ili razgranata i sadrži 1 do 20 atoma ugljika u lancu; "alkenil" znači alifatska ugljikovodična skupina koja sadrži najmanje jednu dvostruku vezu ugljik-ugljik i može biti nerazgranata ili razgranata i sadrži 2 do 15 atoma ugljika u lancu; "alkinil" znači alifatska ugljikovodična skupina koja sadrži najmanje jednu trostruku vezu ugljik-ugljik i može biti nerazgranata ili razgranata i sadrži 2 do 15 atoma ugljika u lancu; "aril" znači aromatski monociklički ili policiklički prstenasti sustav s 6 do 14 atoma ugljika; "heteroaril" znači aromatski monociklički ili policiklički prstenasti sustav s 5 do 14 atoma u prstenu, u kojem
Claims (47)
1. Spoj, ili enantiomeri, stereoizomeri, rotameri, tautomeri, te racemati navedenog spoja, ili farmaceutski prihvatljiva sol ili solvat navedenog spoja, gdje navedeni spoj ima opću strukturu prikazanu u Formuli I:
[image]
naznačen time što:
R1 je H, OR8, NR9R10 ili CHR9R10, gdje R8, R9 i R10 mogu biti isti ili različiti, gdje se svakog od njih neovisno bira iz skupine koju čine H, alkil-, alkenil-, alkinil-, aril-, heteroalkil-, cikloalkil-, heterociklil-, arilalkil-, te heteroarilalkil;
A i M mogu biti isti ili različiti, gdje se svakog od njih neovisno bira između R, OR, NHR, NRR', SR, SO2R, te halogena;
ili A i M su vezani zajedno, tako da ostatak:
[image]
prikazan gore, u Formuli I, tvori bilo tro-, četvero-, šestero-, sedmero- ili osmeročlani cikloalkil, četvero- do osmeročlani heterociklil, šestero- do deseteročlani aril, ili petero- do deseteročlani heteroaril;
E je C(H) ili C(R);
L je C(H), C(R), CH2C(R) ili C(R)CH2;
R, R', R2, te R3 mogu biti isti ili različiti, gdje se svakog od njih neovisno bira iz skupine koju čine H, alkil, alkenil, cikloalkil, heterociklil, aril, arilalkil, heteroaril, te heteroarilalkil, ili alternativno R i R' u NRR' su vezani zajedno, tako da NRR' tvori četvero- do osmeročlani heterociklil;
ili R2 se bira iz skupine koju čine sljedeći ostaci:
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
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[image]
a Y se bira između sljedećih ostataka:
[image]
[image]
[image]
[image]
gdje G je NH ili O; a R15, R16, R17 i R18 mogu biti isti ili različiti, gdje se svakog od njih neovisno bira iz skupine koju čine H, alkil, alkenil, alkinil, cikloalkil, heterociklil, aril, i heteroaril, ili alternativno, (i) R15 i R16 su vezani zajedno kako bi tvorili četvero- do osmeročlani ciklička struktura, i (ii) isto tako, neovisno R17 i R18 su vezani zajedno kako bi tvorili tro- do osmeročlani cikloalkil ili heterociklil; gdje svaki od navedenih alkila, arila, heteroarila, cikloalkila ili heterociklila može biti nesupstituiran ili izborno neovisno supstituiran s jednim ili više ostataka, koje se bira iz skupine koju čine: hidroksi, alkoksi, ariloksi, tio, alkiltio, ariltio, amino, amido, alkilamino, arilamino, alkilsulfonil, arilsulfonil, sulfonamido, alkilsulfonamido, arilsulfon-amido, alkil, aril, heteroaril, keto, karboksi, karbalkoksi, karboksamido, alkoksikarbonilamino, alkoksikarboniloksi, alkilureido, arilureido, halogen, cijano, te nitro,
gdje:
"alkil" znači alifatska ugljikovodična skupina koja može biti nerazgranata ili razgranata i sadrži 1 do 20 atoma ugljika u lancu;
"alkenil" znači alifatska ugljikovodična skupina koja sadrži najmanje jednu dvostruku vezu ugljik-ugljik i može biti nerazgranata ili razgranata i sadrži 2 do 15 atoma ugljika u lancu;
"alkinil" znači alifatska ugljikovodična skupina koja sadrži najmanje jednu trostruku vezu ugljik-ugljik i može biti nerazgranata ili razgranata i sadrži 2 do 15 atoma ugljika u lancu;
"aril" znači aromatski monociklički ili policiklički prstenasti sustav s 6 do 14 atoma ugljika;
"heteroaril" znači aromatski monociklički ili policiklički prstenasti sustav s 5 do 14 atoma u prstenu, u kojem jedan ili više atoma u prstenu je element koji nije ugljik;
"aralkil" ili "arilalkil" znači skupina aril-alkil-, u kojoj aril i alkil su kao što je opisano ranije, gdje veza na osnovni ostatak je preko alkila;
"alkilaril" znači skupina alkil-aril-, u kojoj alkil i aril su kao što je opisano ranije, gdje veza na osnovni ostatak je preko arila;
"cikloalkil" znači nearomatski mono- ili policiklički prstenasti sustav s 3 do 10 atoma ugljika;
"halogen" ili "halo" znači fluor, klor, brom ili jod;
"heterociklil" znači nearomatski zasićeni monociklički ili policiklički prstenasti sustav s 3 do 10 atoma u prstenu, u kojem jedan ili više atoma u prstenastom sustavu je element koji nije ugljik, kada u prstenastom sustavu nije prisutan izravno vezani atom kisika i/ili sumpora;
"alkinilalkil" znači skupina alkinil-alkil-, u kojoj alkinil i alkil su kao što je opisano ranije, gdje veza na osnovni ostatak je preko alkila;
"heteroaralkil" znači skupina heteroaril-alkil-, u kojoj heteroaril i alkil su kao što je opisano ranije, gdje veza na osnovni ostatak je preko alkila;
"alkoksi" znači skupina alkil-O-, u kojoj alkilna skupina je kao što je opisano ranije, gdje veza na osnovni ostatak je preko eterskog kisika;
"ariloksi" znači skupina aril-O-, u kojoj arilna skupina je kao što je opisano ranije, gdje veza na osnovni ostatak je preko eterskog kisika;
"alkiltio" znači skupina alkil-S-, u kojoj alkilna skupina je kao što je opisano ranije, gdje veza na osnovni ostatak je preko sumpora;
"ariltio" znači skupina aril-S-, u kojoj arilna skupina je kao što je opisano ranije, gdje veza na osnovni ostatak je preko sumpora;
"alkilsulfonil" znači skupina alkil-S(O2)-, gdje veza na osnovni ostatak je preko sulfonila; a
"arilsulfonil" znači skupina aril-S(O2)-, gdje veza na osnovni ostatak je preko sulfonila.
2. Spoj u skladu s patentnim zahtjevom 1, naznačen time što R1 je NR9R10, R9 je H, a R10 je H ili R14, gdje R14 je H, alkil, aril, heteroalkil, heteroaril, cikloalkil, alkil-aril, alkil-heteroaril, aril-alkil, alkenil, alkinil ili heteroaril-alkil.
3. Spoj u skladu s patentnim zahtjevom 2, naznačen time što R14 se bira iz skupine koju čine:
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4. Spoj u skladu s patentnim zahtjevom 1, naznačen time što R2 se bira iz skupine koju čine sljedeći ostaci:
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5. Spoj u skladu s patentnim zahtjevom 1, naznačen time što R3 se bira iz skupine koju čine:
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gdje R31 je OH ili O-alkil; a
R32 je H, C(O)CH3, C(O)OtBu ili C(O)N(H)tBu.
6. Spoj u skladu s patentnim zahtjevom 5, naznačen time što R3 se bira iz skupine koju čine sljedeći ostaci:
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7. Spoj u skladu s patentnim zahtjevom 1, naznačen time što Y se bira između sljedećih ostataka:
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gdje R15, R16, R17 i R18 mogu biti isti ili različiti, gdje se svakog od njih neovisno bira iz skupine koju čine H, alkil, heteroalkil, alkenil, heteroalkenil, alkinil, heteroalkinil, cikloalkil, heterociklil, aril, arilalkil, heteroaril, te heteroarilalkil, ili alternativno, R15 i R16 su vezani zajedno kako bi tvorili četvero- do osmeročlanu cikloalkilnu ili heterocikličku strukturu; R17 i R18 su vezani zajedno kako bi tvorili tro- do osmeročlani cikloalkil ili heterociklil, gdje svaki od navedenih arila, heteroarila, cikloalkila ili heterociklila može biti nesupstituiran ili izborno neovisno supstituiran s jednim ili više ostataka, koje se bira iz skupine koju čine: hidroksi, alkoksi, ariloksi, tio, alkiltio, ariltio, amino, amido, alkilamino, arilamino, alkilsulfonil, arilsulfonil, sulfonamido, alkilsulfonamido, arilsulfonamido, alkil, aril, heteroaril, karboksi, karbalkoksi, karboksamido, alkoksikarbonilamino, alkoksikarboniloksi, alkilureido, arilureido, halogen, cijano, te nitro.
8. Spoj u skladu s patentnim zahtjevom 7, naznačen time što Y se bira iz skupine koju čine:
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gdje Y31 se bira iz skupine koju čine:
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Y32 se bira iz skupine koju čine:
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a Y12 se bira iz skupine koju čine H, CO2H, CO2Me, OMe, F, Cl, Br, NH2, N(H)S(O2)CH3, N(H)C(O)CH3, NO2, S(O2)NH2, CF3, Me, OH, OCF3, te C(O)NH2.
9. Spoj u skladu s patentnim zahtjevom 1, naznačen time što ostatak:
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se bira između sljedećih struktura:
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10. Spoj u skladu s patentnim zahtjevom 9, naznačen time što ostatak
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se bira između sljedećih struktura
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11. Spoj u skladu s patentnim zahtjevom 10, naznačen time što ostatak:
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se bira između sljedećih struktura:
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12. Spoj u skladu s patentnim zahtjevom 1, naznačen time što:
R1 je NHR14, gdje R14 se bira iz skupine koju čine:
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R2 se bira iz skupine koju čine sljedeći ostaci:
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R3 se bira iz skupine koju čine sljedeći ostaci:
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Y se bira iz skupine koju čine:
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gdje Y31 se bira iz skupine koju čine:
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i
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Y32 se bira iz skupine koju čine:
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Y12 se bira iz skupine koju čine H, CO2H, CO2Me, OMe, F, Cl, Br, NH2, N(H)S(O2)CH3, N(H)C(O)CH3, NO2, S(O2)NH2, CF3, Me, OH, OCF3, te C(O)NH2; a ostatak:
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je:
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13. Farmaceutski pripravak, naznačen time što kao aktivni sastojak sadrži najmanje jedan spoj u skladu s patentnim zahtjevom 1.
14. Farmaceutski pripravak u skladu s patentnim zahtjevom 13, naznačen time što je namijenjen upotrebi u liječenju poremećaja povezanih s HCV-om.
15. Farmaceutski pripravak u skladu s patentnim zahtjevom 13, naznačen time što dodatno sadrži najmanje jedan farmaceutski prihvatljiva podloga.
16. Farmaceutski pripravak u skladu s patentnim zahtjevom 15, naznačen time što dodatno sadrži najmanje jedno protuvirusno sredstvo.
17. Farmaceutski pripravak u skladu s patentnim zahtjevom 16, naznačen time što dodatno sadrži još najmanje jedan interferon.
18. Farmaceutski pripravak u skladu s patentnim zahtjevom 17, naznačen time što navedeno najmanje jedno protuvirusno sredstvo je ribavirin, a navedeni najmanje jedan interferon je α-interferon ili pegilirani interferon.
19. Upotreba najmanje jednog spoja u skladu s patentnim zahtjevom 1, naznačena time što jedan ili više navedenih spojeva su namijenjeni proizvodnji medikamenta za liječenje poremećaja povezanih s HCV.
20. Upotreba u skladu s patentnim zahtjevom 19, naznačena time što se navedeno liječenje sastoji u oralnoj ili supkutanoj primjeni medikamenta.
21. Postupak priprave farmaceutskog pripravka za liječenje poremećaja povezanih s HCV-om, naznačene time što se navedeni postupak sastoji u dovođenju u blizak kontakt najmanje jednog spoja u skladu s patentnim zahtjevom 1 s najmanje jednom farmaceutski prihvatljivom podlogom.
22. Spoj u skladu s patentnim zahtjevom 1 koji pokazuje aktivnost inhibitora HCV proteaze, ili enantiomeri, stereoizomeri, rotameri, tautomeri, te racemati navedenog spoja, ili farmaceutski prihvatljiva sol ili solvat navedenog spoja, naznačen time što se navedeni spoj bira između spojeva čije su strukture prikazane niže:
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23. Farmaceutski pripravak za liječenje poremećaja povezanih s HCV-om, naznačen time što navedeni pripravak sadrži terapijski djelotvornu količinu jednog ili više spojeva u skladu s patentnim zahtjevom 22 i farmaceutski prihvatljivu podlogu.
24. Farmaceutski pripravak u skladu s patentnim zahtjevom 23, naznačen time što dodatno sadrži najmanje jedno protuvirusno sredstvo.
25. Farmaceutski pripravak u skladu s patentnim zahtjevom 24, naznačen time što dodatno sadrži još najmanje jedan interferon ili konjugat PEG-interferona α.
26. Farmaceutski pripravak u skladu s patentnim zahtjevom 25, naznačen time što navedeno najmanje jedno protuvirusno sredstvo je ribavirin, a navedeni najmanje jedan interferon je α-interferon ili pegilirani interferon.
27. Upotreba jednog ili više spojeva u skladu s patentnim zahtjevom 22, naznačena time što jedan ili više navedenih spojeva su namijenjeni proizvodnji medikamenta za liječenje poremećaja povezanog s virusom hepatitisa C.
28. Upotreba jednog ili više spojeva u skladu s patentnim zahtjevom 22, naznačena time što jedan ili više navedenih spojeva su namijenjeni proizvodnji medikamenta za liječenje, sprječavanje ili ublažavanje jednog ili više simptoma hepatitisa C.
29. Upotreba u skladu s patentnim zahtjevom 28, naznačena time što jedan ili više spojeva moduliraju aktivnost proteaze iz virusa hepatitisa C (HCV).
30. Upotreba u skladu s patentnim zahtjevom 29, naznačen time što HCV proteaza je proteaza NS3/NS4a.
31. Upotreba u skladu s patentnim zahtjevom 30, naznačena time što spoj ili spojevi inhibiraju HCV proteazu NS3/NS4a.
32. Upotreba najmanje jednog spoja, ili enantiomera, stereoizomera, rotamera, tautomera, te racemata navedenog spoja, ili farmaceutski prihvatljive soli ili solvata navedenog spoja, naznačena time što je navedeni spoj namijenjen proizvodnji medikamenta za liječenje poremećaja povezanih s HCV-om, gdje se navedeni spoj bira između sljedećih:
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33. Spoj u skladu s patentnim zahtjevom 1 koji pokazuje aktivnost inhibitora HCV proteaze, ili enantiomeri, stereoizomeri, rotameri, tautomeri, te racemati navedenog spoja, ili farmaceutski prihvatljiva sol ili solvat navedenog spoja, naznačen time što navedeni spoj ima strukturu:
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34. Spoj u skladu s patentnim zahtjevom 1 koji pokazuje aktivnost inhibitora HCV proteaze, ili enantiomeri, stereoizomeri, rotameri, tautomeri, te racemati navedenog spoja, ili farmaceutski prihvatljiva sol ili solvat navedenog spoja, naznačen time što navedeni spoj ima strukturu:
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35. Spoj u skladu s patentnim zahtjevom 1 koji pokazuje aktivnost inhibitora HCV proteaze, ili enantiomeri, stereoizomeri, rotameri, tautomeri, te racemati navedenog spoja, ili farmaceutski prihvatljiva sol ili solvat navedenog spoja, naznačen time što navedeni spoj ima strukturu:
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36. Spoj u skladu s patentnim zahtjevom 1 koji pokazuje aktivnost inhibitora HCV proteaze, ili enantiomeri, stereoizomeri, rotameri, tautomeri, te racemati navedenog spoja, ili farmaceutski prihvatljiva sol ili solvat navedenog spoja, naznačen time što navedeni spoj ima strukturu:
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37. Spoj u skladu s patentnim zahtjevom 1 koji pokazuje aktivnost inhibitora HCV proteaze, ili enantiomeri, stereoizomeri, rotameri, tautomeri, te racemati navedenog spoja, ili farmaceutski prihvatljiva sol ili solvat navedenog spoja, naznačen time što navedeni spoj ima strukturu:
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38. Spoj u skladu s patentnim zahtjevom 1 koji pokazuje aktivnost inhibitora HCV proteaze, ili enantiomeri, stereoizomeri, rotameri, tautomeri, te racemati navedenog spoja, ili farmaceutski prihvatljiva sol ili solvat navedenog spoja, naznačen time što navedeni spoj ima strukturu:
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39. Spoj u skladu s patentnim zahtjevom 1 koji pokazuje aktivnost inhibitora HCV proteaze, ili enantiomeri, stereoizomeri, rotameri, tautomeri, te racemati navedenog spoja, ili farmaceutski prihvatljiva sol ili solvat navedenog spoja, naznačen time što navedeni spoj ima strukturu:
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40. Spoj u skladu s patentnim zahtjevom 1 koji pokazuje aktivnost inhibitora HCV proteaze, ili enantiomeri, stereoizomeri, rotameri, tautomeri, te racemati navedenog spoja, ili farmaceutski prihvatljiva sol ili solvat navedenog spoja, naznačen time što navedeni spoj ima strukturu:
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41. Spoj u skladu s patentnim zahtjevom 1 koji pokazuje aktivnost inhibitora HCV proteaze, ili enantiomeri, stereoizomeri, rotameri, tautomeri, te racemati navedenog spoja, ili farmaceutski prihvatljiva sol ili solvat navedenog spoja, naznačen time što navedeni spoj ima strukturu:
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42. Spoj u skladu s patentnim zahtjevom 1 koji pokazuje aktivnost inhibitora HCV proteaze, ili enantiomeri, stereoizomeri, rotameri, tautomeri, te racemati navedenog spoja, ili farmaceutski prihvatljiva sol ili solvat navedenog spoja, naznačen time što navedeni spoj ima strukturu:
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43. Spoj u skladu s patentnim zahtjevom 1 koji pokazuje aktivnost inhibitora HCV proteaze, ili enantiomeri, stereoizomeri, rotameri, tautomeri, te racemati navedenog spoja, ili farmaceutski prihvatljiva sol ili solvat navedenog spoja, naznačen time što navedeni spoj ima strukturu:
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44. Spoj u skladu s patentnim zahtjevom 1 koji pokazuje aktivnost inhibitora HCV proteaze, ili enantiomeri, stereoizomeri, rotameri, tautomeri, te racemati navedenog spoja, ili farmaceutski prihvatljiva sol ili solvat navedenog spoja, naznačen time što navedeni spoj ima strukturu:
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45. Spoj u skladu s patentnim zahtjevom 1 koji pokazuje aktivnost inhibitora HCV proteaze, ili enantiomeri, stereoizomeri, rotameri, tautomeri, te racemati navedenog spoja, ili farmaceutski prihvatljiva sol ili solvat navedenog spoja, naznačen time što navedeni spoj ima strukturu:
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46. Spoj u skladu s patentnim zahtjevom 1 koji pokazuje aktivnost inhibitora HCV proteaze, ili enantiomeri, stereoizomeri, rotameri, tautomeri, te racemati navedenog spoja, ili farmaceutski prihvatljiva sol ili solvat navedenog spoja, naznačen time što navedeni spoj ima strukturu:
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47. Spoj u skladu s patentnim zahtjevom 1 koji pokazuje aktivnost inhibitora HCV proteaze, ili enantiomeri, stereoizomeri, rotameri, tautomeri, te racemati navedenog spoja, ili farmaceutski prihvatljiva sol ili solvat navedenog spoja, naznačen time što navedeni spoj ima strukturu:
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| US54867004P | 2004-02-27 | 2004-02-27 | |
| PCT/US2005/005795 WO2005087731A1 (en) | 2004-02-27 | 2005-02-24 | Sulfur compounds as inhibitors of hepatitis c virus ns3 serine protease |
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| HU227742B1 (en) | 1996-10-18 | 2012-02-28 | Vertex Pharma | Inhibitors of serine proteases, particularly hepatitis c virus ns3 protease |
| US7816326B2 (en) * | 2004-02-27 | 2010-10-19 | Schering Corporation | Sulfur compounds as inhibitors of hepatitis C virus NS3 serine protease |
| PT1730110E (pt) * | 2004-02-27 | 2010-09-14 | Schering Corp | Compostos de enxofre como inibidores de serina-protease ns3 do vírus da hepatite c |
| GB0426661D0 (en) * | 2004-12-06 | 2005-01-05 | Isis Innovation | Pyrrolidine compounds |
| WO2006130666A2 (en) * | 2005-06-02 | 2006-12-07 | Schering Corporation | Medicaments and methods combining a hcv protease inhibitor and an akr competitor |
| WO2006130686A2 (en) | 2005-06-02 | 2006-12-07 | Schering Corporation | Hcv protease inhibitors in combination with food |
| BRPI0610737A2 (pt) * | 2005-06-02 | 2010-07-20 | Schering Corp | formulações farmacêuticas e métodos de tratamento usando as mesmas |
| US20060276407A1 (en) * | 2005-06-02 | 2006-12-07 | Schering Corporation | Methods of treating hepatitis C virus |
| US20070237818A1 (en) * | 2005-06-02 | 2007-10-11 | Malcolm Bruce A | Controlled-release formulation of HCV protease inhibitor and methods using the same |
| CA2611145A1 (en) * | 2005-06-02 | 2006-12-07 | Schering Corporation | Controlled-release formulation useful for treating disorders associated with hepatitis c virus |
| US20060275366A1 (en) * | 2005-06-02 | 2006-12-07 | Schering Corporation | Controlled-release formulation |
| WO2006130626A2 (en) * | 2005-06-02 | 2006-12-07 | Schering Corporation | Method for modulating activity of hcv protease through use of a novel hcv protease inhibitor to reduce duration of treatment period |
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