ME01318B - Makrociklički inhibitori virusa hepatitisa C - Google Patents
Makrociklički inhibitori virusa hepatitisa CInfo
- Publication number
- ME01318B ME01318B MEP-2011-194A MEP19411A ME01318B ME 01318 B ME01318 B ME 01318B ME P19411 A MEP19411 A ME P19411A ME 01318 B ME01318 B ME 01318B
- Authority
- ME
- Montenegro
- Prior art keywords
- formula
- het
- 6alkyl
- substituted
- compound
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title claims 2
- 241000711549 Hepacivirus C Species 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 26
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 15
- 125000003118 aryl group Chemical group 0.000 claims 15
- 125000000217 alkyl group Chemical group 0.000 claims 13
- 229910052739 hydrogen Inorganic materials 0.000 claims 12
- 239000001257 hydrogen Substances 0.000 claims 12
- 125000001475 halogen functional group Chemical group 0.000 claims 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 9
- 125000003545 alkoxy group Chemical group 0.000 claims 9
- 150000002431 hydrogen Chemical class 0.000 claims 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 9
- 125000001424 substituent group Chemical group 0.000 claims 9
- 125000002757 morpholinyl group Chemical group 0.000 claims 8
- 125000003386 piperidinyl group Chemical group 0.000 claims 8
- -1 polyhalo- C1-6alkyl Chemical group 0.000 claims 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 7
- 229910052757 nitrogen Inorganic materials 0.000 claims 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 6
- 238000006243 chemical reaction Methods 0.000 claims 5
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 5
- 125000004193 piperazinyl group Chemical group 0.000 claims 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 5
- 150000003839 salts Chemical class 0.000 claims 5
- 125000003282 alkyl amino group Chemical group 0.000 claims 4
- 230000015572 biosynthetic process Effects 0.000 claims 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims 4
- 125000000623 heterocyclic group Chemical group 0.000 claims 4
- 238000000034 method Methods 0.000 claims 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims 4
- 125000004076 pyridyl group Chemical group 0.000 claims 4
- 125000000335 thiazolyl group Chemical group 0.000 claims 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 3
- 125000005842 heteroatom Chemical group 0.000 claims 3
- 229910052760 oxygen Inorganic materials 0.000 claims 3
- 239000001301 oxygen Substances 0.000 claims 3
- 229920006395 saturated elastomer Polymers 0.000 claims 3
- 229910052717 sulfur Inorganic materials 0.000 claims 3
- 239000011593 sulfur Substances 0.000 claims 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 2
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- 150000001204 N-oxides Chemical class 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 2
- 125000004122 cyclic group Chemical group 0.000 claims 2
- 150000002678 macrocyclic compounds Chemical class 0.000 claims 2
- 125000002950 monocyclic group Chemical group 0.000 claims 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims 1
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 238000006751 Mitsunobu reaction Methods 0.000 claims 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 238000005865 alkene metathesis reaction Methods 0.000 claims 1
- 230000000840 anti-viral effect Effects 0.000 claims 1
- 238000006254 arylation reaction Methods 0.000 claims 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 150000002170 ethers Chemical class 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 125000000524 functional group Chemical group 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims 1
- 125000004254 isoquinolin-1-yl group Chemical group [H]C1=C([H])C2=C([H])C([H])=C([H])C([H])=C2C(*)=N1 0.000 claims 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 125000001624 naphthyl group Chemical group 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- 125000004043 oxo group Chemical group O=* 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims 1
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 1
- 125000004546 quinazolin-4-yl group Chemical group N1=CN=C(C2=CC=CC=C12)* 0.000 claims 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims 1
- 125000004549 quinolin-4-yl group Chemical group N1=CC=C(C2=CC=CC=C12)* 0.000 claims 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims 1
- 230000010076 replication Effects 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 claims 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 claims 1
- 229960000311 ritonavir Drugs 0.000 claims 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims 1
- 229940124530 sulfonamide Drugs 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 230000009466 transformation Effects 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
- C07D245/04—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Claims (16)
1. Jedinjenje, naznačeno time, da je predstavljeno sledećom formulom i njegovi N-oksidi, soli i stereoizomeri, gde svaka isprekidana linija (predstavljena sa - - - - -) predstavlja neku opcionalnu dvostruku vezu; X je N, CH, a kada X sadrži dvostruku vezu, tada je C; Rla i Rlb su, nezavisno, vodonik, C3-7cikloalkil, aril, Het, C1-6alkoksi, C1-6alkil ponekad supstituisan sa halo, C1-6alkoksi, cijano, polihaloC1-6alkoksi, C3-7cikloalkil, aril ili sa Het; ili R1a i R1b zajedno sa azotom na kojeg su spojeni formiraju od 4 do 6-člani zasićeni, delomično ne-zasićeni ili potpuno ne-zasićeni heterociklički prsten koji ponekad sadrži dodatna 1 do 3 heteroatoma od koji je svaki nezavisno izabran iz azota, kiseonika i sumpora i gde pomenuti heterociklički prsten može da ponekad bude supstituisan sa jednim ili dva supstituenta od kojih je svaki nezavisno izabran iz grupe koja obuhvata halo, C1-6alkil, polihaloC1-6alkil, hidroksi, C1-6alkoksi, polihaloC1-6alkoksi, C1-6alkoksiC1-6alkil, karboksil, C1-6alkilkarbonil, cijano, mono- i diC1-6alkilamino, aril i arilC1-6alkil; L je direktna veza, -O-, -O-C1-4alkandiil-, -O-CO-, -O-C(=O)-NR5a- ili -O-C(=O)-NR5a- C1-4alkandiil-; R2 je vodonik, a kada X je C ili CH, R2 može takođe da bude i C1-6alkil; R3 je vodonik, C1-6alkil, C1-6alkoksiC1-6alkil, C3-7cikloalkil, amino, mono- ili diC1-6alkilamino; R4 je aril ili zasićeni, delomično ne-zasićeni ili kompletno ne-zasićeni 5 ili 6-člani monociklički ili 9 do 12-člani biciklički heterociklički prstenski sistem gde pomenuti prstenski sistem sadrži jedan azot, a ponekad i jedan do tri dodatna heteroatoma koja su izabrana iz grupe koja sadrži kiseonik, sumpor i azot i gde preostali članovi prstena su atomi ugljenika; gde pomenuti prstenski sistem može ponekad da bude supstituisan sa bilo kojim ugljenikovim ili azotnim prstenskim atomom sa jedan, dva, tri ili četiri supstituenata od kojih je svaki nezavisno izabran iz C3-1cikloalkila, arila, Het, - C(=O)NR5aR5b, -C(=O)R7, -C(=O)0R6a i C1-6alkila koji je ponekad supstituisan sa C3-7cikloalkilom, arilom, Het, -C(=O)NR5aR5b, -NR5aR5b, -C(=O)R7, -NR5aC(=O)R7, - NR5aSOpR8, -SOpR8, -SOpNR5aR5b, -C(=O)OR6 ili -NR5aC(=OR6a; i gde pomenuti supstituenti ili bilo koji ugljenikov atom iz heterocikličkog prstena mogu takođe da budu izabrani iz C1-6alkoksi, hidroksi, halo, polihalo- C1-6alkila, C1-6alkiltio, okso, cijano, nitro, azido, -NR5aR5b, -NR5aC(=O)R7, -NR5aSOpR8, -SOpR8, -SOpNR5aR5b, - C(=O)OH i -NR53C(=O)OR6a; n je 3, 4, 5 ili 6; p je 1 ili 2; svaki od R5a i R5b je, nezavisno, vodonik, C3-7cikloalkil, aril, Het, C1-6alkil koji je ponekad supstituisan sa halo, C1-6alkoksi, cijano, polihaloC1-6alkoksi, C3-7cikloalkilom, arilom ili sa Het; R6 je vodonik, C2-6alkenil, C3-7cikloalkil, Het ili C1-6alkil koji je ponekad supstituisan sa C3-7cikloalkilom, arilom ili Het; R6a je C2-6alkenil, C3-7cikloalkil, Het ili C1-6alkil koji je ponekad supstituisan sa C3-7cikloalkilom, arilom ili Het; R7 je vodonik, C1-6alkil, C3-1cikloalkil ili aril; R8 je vodonik, polihaloC1-6alkil, C3-7cikloalkil, aril, Het ili C1-6alkil koji je ponekad supstituisan sa C3-7cikloalkilom, arilom ili Het; aril kao grupa ili deo grupe je fenil, naftil, indanil ili 1, 2, 3, 4-tetra-hidronaftil, a svaki od njih može da ponekad bude supstituisan sa jednim, dva ili tri supstituenata koja su izabrana iz halo, C1-6alkila, polihaloC1-6alkila, hidroksi, C1-6alkoksi, polihaloC1-6alkoksi, C1-6alkoksiC1-6alkila, karboksila, C1-6alkilkarbonila, C1-6alkoksi-karbonila, cijano, nitro, amino, mono- ili diC1-6alkilamino, aminokarbonila, mono- ili diC1-6alkilaminokarbonila, azido, merkapto, C3-7cikloalkila, fenila, piridila, tiazolila, pirazolila, pirolidinila, piperidinila, piperazinila, 4-C1-6alkilpiperazinila, 4-C1-6alkilkarbonil-piperazinila i morfolinila; gde pomenute morfolinilne i piperidinilne grupe mogu da ponekad budu supstituisane sa jednim ili dva C1-6alkil radikala; a pomenute fenilne, piridilne, tiazolilne, pirazolilne grupe mogu ponekad da budu supstituisane sa 1, 2 ili 3 supstituenta od kojih je svaki nezavisno izabran iz C1-6alkila, C1-6alkoksi, halo, amino, mono- ili diC1-6alkilamino; Het, kao grupa ili deo grupe, je 5 ili 6-člani zasićeni, delomično ne-zasićeni ili kompletno ne-zasićeni heterociklički prsten koji sadrži 1 do 4 heteroatoma od kojih je svaki nezavisno izabran iz azota, kiseonika i sumpora i koji je ponekad kondenzovan sa nekim benzenskim prstenom, a gde pomenuta grupa Het kao celo može ponekad da bude supstituisana sa jednim, dva ili tri supstituenta od kojih je svaki nezavisno izabran iz grupe koja obuhvata halo, C1-6alkil, polihaloC1-6alkil, hidroksi, C1-6alkoksi, polihaloC1-6alkoksi, C1-6alkoksiC1-6alkil, karboksil, C1-6alkilkarbonil, C1-6 alkoksikarbonil, cijano, nitro, amino, mono- ili diC1-6alkilamino, amino- karbonil, mono- ili diC1-6alkilaminokarboni 1, C3-7cikloalkil, fenil, piridil, tiazolil, pirazolil, pirolidinil, piperidinil, piperazinil, 4-C1-6alkilpiperazinil, 4-C1-6alkilkarbonil-piperazinil i morfolinil; gde pomenute morfolinilne i piperidinilne grupe mogu ponekad da budu supstituisane sa jednim ili dva C1-6alkil radikala; a pomenute fenilne, piridilne, tiazolilne, pirazolilne grupe mogu ponekad da budu supstituisane sa 1, 2 ili 3 supstituenata od kojih je svaki nezavisno izabran iz C1-6alkila, C1-6alkoksi, halo, amino, mono- ili diC1-6alkilamino.
2.Jedinjenje u skladu sa zahtevom 1, naznačeno time, da pomenuto jedinjenje ima formulu (I -c), (I-d) ili (I-e):
3. Jedinjenje u skladu sa bilo kojem od zahteva od 1-2, naznačeno time, da (a)svaki od Rla i Rlb je, nezavisno, vodonik ili metil, etil ili tert-butil; ili (b)jedan od Rla i Rlb je ciklopropil ili fenil; ili (c)Rla i Rlb zajedno sa atomom azota na kojeg su spojeni formiraju pirolidinil, piperidinil, piperazinil, 4-C1-6alkilpiperazini1, 4-C1-6alkil-karbonilpiperazinil ili morfolinil; ili (d)jedan od R1a i R1b je neka Het grupa koja je izabrana od
4. Jedinjenje u skladu sa zahtevom 1, naznačeno time, da L je -O-, -O-CO- ili direktna veza.
5. Jedinjenje u skladu sa bilo kojim od zahteva od 1-4, naznačeno time, da Lje -O-, R4 je kinolinil (a posebno kinolin-4-il), izokinolinil (a posebno izokinolin-l-il), kinazolinil (a posebno kinazolin-4-il) ili pirimidinil (a posebno pirimidin-4-il), od koji je svaki, nezavisno, ponekad mono, di ili tri supstituisani sa C1-6alkilom, C1-6alkoksi, nitro, hidroksi, halo, trifluorometilom, -NR5aR5b, -C(=O)NR5aR5b, C3-7cikloalkilom, arilom, Het, -C(=O)OH ili -C(=O)OR6a; a gde aril ili Het su svaki nezavisno, ponekad supstituisani sa halo, C1-6alkilom, C1-6alkoksi, amino, mono- ili diC1-6alkilamino, pirolidinilom, piperidinilom, piperazinilom, 4C1-6alkilpiperazinilom (na primer, 4- metilpiperazinil) ili morfolinilom; a gde pomenute morfolinilne i piperidinilne grupe mogu ponekad da budu supstituisane sa jednim ili dva C1-6alkil radikala.
6. Jedinjenje u skladu sa bilo kojim od zahteva od 1-4, naznačeno time, da L je -O-, a R4 je (d-1) radikal sa formulom (d-2) radikal sa formulom (d-3) radikal sa formulom (d-4) radikal sa formulom ili posebno, (d-4-a) radikal sa formulom (d-5) radikal sa formulom gde u radikalima (d-l)-(d-5), kao i u (d-4-a) i (d-5-a): svaki Rla, Rlb, Rlb, Rld, Rld, Rle, R11 je nezavisno bilo koji od supstituenata koji su izabrani iz onih koji su pomenuti kao mogući supstituenti na monocikličkom ili bicikličkom prstenskom sistemu iz R1, kao šta je već specifikovano u zahtevu 1.
7. Jedinjenje u skladu sa zahtevom 6, naznačeno time, da L je -O-, a R4 je neki radikal sa formulom gde R1f je vodonik, C1-6alkil, amino, mono- ili diC1-6alkilamino, pirolidinil, piperidinil, piperazinil, 4-C1-6alkilpiperazinil (a posebno 4-metilpiperazinil) ili morfolinil.
8.Jedinjenje u skladu sa bilo kojim od zahteva od 1-4, naznačeno time, da R3 je (a)R3 je vodonik; ili (b)R3 je C1-6alkil; ili (c)R3 je amino ili mono- ili diC1-6alkilamino.
9.Jedinjenje u skladu sa bilo kojim od zahteva od 1-6, naznačeno time, da nje 4 ili 5.
10.Jedinjenje u skladu sa bilo kojim od zahteva od 1-6, naznačeno time, da R2 je vodonik.
11. Jedinjenje u skladu sa bilo kojim od zahteva od 1-10, naznačeno time, da je različito od N-oksida ili soli.
12. Kombinacija, naznačena time, da obuhvata (a)neko jedinjenje kao šta je definisano u bilo koje od zahteva od 1 do 11 ili neku njegovu farmaceutski prihvatljivu so; i (b)ritonavir ili neku njegovu farmaceutski prihvatljivu so.
13. Farmaceutska kompozicija, naznačena time, da obuhvata neki kerijer i kao aktivni sastojak neku anti-viralno efektivnu količinu nekog jedinjenja kao šta se zahteva u bilo kojem od zahteva od 1-11 ili u kombinaciji u skladu sa zahtevom 12.
14. Jedinjenje u skladu sa bilo kojem od zahteva od 1-11 ili kombinacija u skladu sa zahtevom 12, naznačeni time, da se koriste kao lek.
15. Jedinjenje u skladu sa bilo kojim od zahteva od 1-11 ili kombinacija u skladu sa zahtevom 12, naznačeni time, da se koriste kao inhibitori HCV replikacije.
16. Proces za pripremu jedinjenja kao šta se zahteva u bilo kojem od zahteva od 1-11, naznačen time, da pomenuti proces obuhvata: (a) preparaciju jedinjenja sa formulom (I) gde veza između C7 i C8 je dvostruka veza, šta predstavlja jedinjenje sa formulom (I-i), uz pomoć formiranja dvostruke veze među C7 i C8, a posebno preko neke olefin metatezne reakcije, uz prateću ciklizaciju na makrociklu kao šta je navedeno u sledećoj reakcionoj šemi: gde u gornjim i u idućim strukturnim formulama, grupa je predstavljena sa -R1; (b) konvertovanje jedinjenje sa formulom (I-i) ujedinjenje sa formulom (I) gde spoj među C7 i C8 u makrociklu je jednostruka veza, tj. ujedinjenje sa formulom (I- j): uz pomoć redukovanja C7-C8 dvostruke veze u pomenutom jedinjenju sa formulom (I-j); (c)formiranje amidne veze među intermedijara (2a) i sulfonilamida (2b), kao šta je navedeno u sledećoj šemi gde G predstavlja neku grupu: (d)preparaciju jedinjenja sa formulom (I) gde R3 je vodonik, a pomenuto jedinjenje je predstavljeno sa (I-L), iz odgovarajućeg azot-zaštićenog intermedijara (3a), gde PG predstavlja neku azot-zaštitnu grupu: (e)reagovanje intermedijara (4a) sa intermedijarom (4b), (4c), (4d), (4e) ili (4f) kao šta je navedeno u sledećoj reakcionoj šemi: gde Y u (4a) predstavlja hidroksi ili neku izlaznu grupu; a koja reakcija posebno predstavlja neku O-arilacionu reakciju gde Y je neka izlazna grupa ili neku Mitsunobu-ovu reakciju gde Y je hidroksi; i gde (4a) i (4c) ili (4d) su reagovani u prisutnosti nekog agensa koji uvodi karbonil sa ciljem da se formira L koji je neka uretanska grupa (L je -O-C(=O)- NR5a-); i gde (4a) i (4e) su reagovani u proceduri koja dovodi do nastanka nekog estera; i gde (4a) i (4f) su reagovani u proceduri koja dovodi do nastanka etara; (f)konvertovanje jedinjenja sa formulom (I) jedno u drugo uz pomoć reakcije transformacije funkcionalnih grupa; ili (g)preparaciju neke solne forme uz pomoć reagovanja slobodne forme nekog jedinjenja sa formulom (I) sa nekom kiselinom ili nekom bazom.
Applications Claiming Priority (4)
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| EP05107416 | 2005-08-11 | ||
| PCT/EP2006/064819 WO2007014925A1 (en) | 2005-07-29 | 2006-07-28 | Macrocylic inhibitors of hepatitis c virus |
| EP06764267A EP1912997B1 (en) | 2005-07-29 | 2006-07-28 | Macrocyclic inhibitors of hepatitis c virus |
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| SI (1) | SI1912997T1 (me) |
| TW (1) | TW200745061A (me) |
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- 2006-07-28 AR ARP060103311A patent/AR055361A1/es unknown
- 2006-07-28 BR BRPI0614637-6A patent/BRPI0614637A2/pt not_active Application Discontinuation
- 2006-07-28 WO PCT/EP2006/064819 patent/WO2007014925A1/en not_active Ceased
- 2006-07-28 PL PL06764267T patent/PL1912997T3/pl unknown
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- 2006-07-28 AT AT06764267T patent/ATE524475T1/de active
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- 2006-07-28 JP JP2008523381A patent/JP5230417B2/ja not_active Expired - Fee Related
- 2006-07-28 EP EP06764267A patent/EP1912997B1/en active Active
- 2006-07-28 RS RS20110542A patent/RS52058B/sr unknown
- 2006-07-28 TW TW095127591A patent/TW200745061A/zh unknown
-
2008
- 2008-01-16 US US11/995,835 patent/US8227407B2/en not_active Expired - Fee Related
-
2011
- 2011-12-14 CY CY20111101239T patent/CY1112147T1/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ES2373685T3 (es) | 2012-02-07 |
| JP2009502888A (ja) | 2009-01-29 |
| HRP20110885T1 (hr) | 2011-12-31 |
| WO2007014925A1 (en) | 2007-02-08 |
| JP5230417B2 (ja) | 2013-07-10 |
| US8227407B2 (en) | 2012-07-24 |
| PT1912997E (pt) | 2011-12-19 |
| EP1912997B1 (en) | 2011-09-14 |
| MY139923A (en) | 2009-11-30 |
| CY1112147T1 (el) | 2015-11-04 |
| PL1912997T3 (pl) | 2012-02-29 |
| EP1912997A1 (en) | 2008-04-23 |
| TW200745061A (en) | 2007-12-16 |
| AR055361A1 (es) | 2007-08-22 |
| RU2008107768A (ru) | 2009-09-10 |
| RS52058B (sr) | 2012-04-30 |
| US20090062311A1 (en) | 2009-03-05 |
| CN101282978B (zh) | 2012-07-11 |
| ATE524475T1 (de) | 2011-09-15 |
| SI1912997T1 (sl) | 2012-02-29 |
| DK1912997T3 (da) | 2012-01-02 |
| BRPI0614637A2 (pt) | 2011-04-12 |
| CN101282978A (zh) | 2008-10-08 |
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