EP2061466A2 - Composés à base de quinoléine et de naphtyridine à substitution thio en position 4 - Google Patents

Composés à base de quinoléine et de naphtyridine à substitution thio en position 4

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Publication number
EP2061466A2
EP2061466A2 EP07837234A EP07837234A EP2061466A2 EP 2061466 A2 EP2061466 A2 EP 2061466A2 EP 07837234 A EP07837234 A EP 07837234A EP 07837234 A EP07837234 A EP 07837234A EP 2061466 A2 EP2061466 A2 EP 2061466A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
aryl
aralkyl
cycloalkyl
alkenyl
Prior art date
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.)
Withdrawn
Application number
EP07837234A
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German (de)
English (en)
Other versions
EP2061466A4 (fr
Inventor
Zhen Yang
Reza Fathi
Qiang Zhu
Hyun Joon Cho
Yixin Liu
Anthony Sandrasagra
Richard C. Wobbe
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
XTL Biopharmaceuticals Ltd
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XTL Biopharmaceuticals Ltd
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Publication date
Application filed by XTL Biopharmaceuticals Ltd filed Critical XTL Biopharmaceuticals Ltd
Publication of EP2061466A2 publication Critical patent/EP2061466A2/fr
Publication of EP2061466A4 publication Critical patent/EP2061466A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/36—Sulfur atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to 4-thio substituted quinoline and naphthyridine derivatives and processes for their preparation.
  • the invention also relates to methods for treating infection of Hepatitis C virus by administering a 4-thio substituted quinoline.or naphthyridine derivative.
  • the invention provides a synthetic process for the preparation of 4-thio substituted quinoline and naphthyridine derivatives using mild reaction conditions, which provides a high substituent tolerance and is appropriate for use in solid phase syntheses for producing a library of 4-thio substituted quinoline and naphthyridine derivatives for biological screening.
  • HCV Hepatitis C virus
  • HCV Replicon Assay developed in the laboratories of Bartenschlager (Lohman et al, Science 285, 110-113, 1999) and Rice (Blight et al, Science 290, 1972-1974, 2000).
  • the assay is performed using the Huh-Luc-Neo cell line (Lohman et al, Science 285, 110-113, 1999).
  • Huh-Luc-Neo cells are a human hepatoma cell line (Huh-7) stably expressing a bi-cistronic subgenomic replicon containing the HCV IRES in which the structural proteins of HCV have been deleted and replaced by a construct containing sequences coding for the firefly luciferase reporter gene, the neomycin selectable marker and the EMCV IRES to direct expression of a truncated HCV genome expressing the structural proteins NS3, NS4A, NS4B, NS5A, and NS5B.
  • HCV targets through which inhibitors could act to inhibit replication include the NS3 protease, the helicase/ATPase, NS5A, the NS5B- RNA dependent RNA polymerase, and the HCV IRES.
  • the present invention provides 4-thio substituted quinoline and naphthyridine derivatives having the formula I
  • a represents an optional double bond
  • X is selected from N, C-H and C-R 1 ; each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -(CH 2 )r-O-R n ,
  • A is a 5-, or 6-membered ring optionally comprising 0 to 3 heteroatoms; each R 2 is selected from the group consisting of alkyl, alkenyl, alkynyl, aralkyl, -(CH 2 )V-O-R 21 , -(CH 2 VN(R 22 XR 23 ), -(Oi 2 VN(R 21 MCH 2 VC(O)R 24 , -(CH 2 ) V -N(R 21 )SO 2 R 21 , -(CH 2 VSR 21 , -(CH 2 )v-C(O)R 24 , -(CH 2 VC(OMCH 2 VOR 21 , -(CH 2 )V-C(O)(CH 2 ) W -N(R 22 )(R 23 ), -(CH 2 VO-(CH 2 V-C(O)R 24 , -(CH 2 )v-OC(O)-(CH 2 V-N(R 22 )
  • R 3 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, a heterocyclic group, -(CH 2 ) ⁇ C(O)R 31 , -(CH 2 )*C(O)N(R 32 )(R 33 ), (CH 2 ) X C(O)OR 31 ,
  • R 31 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group
  • R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 32 and R 33 may be taken together with the nitrogen to which they are attached to form a 5- to 7- membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; x is 0 to 6; m is 0 or 1;
  • R 4 is selected from the group consisting of H, halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, a heterocyclic group, -(CH 2 VO-R 41 , -(CH 2 )y-N(R 42 )(R 43 ),
  • each R 41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
  • R 6 is selected from H, halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; or a pharmaceutically acceptable salt or hydrate thereof.
  • the invention also provides a synthetic process for the preparation of compounds of the formula I.
  • the process uses mild reaction conditions, which provides a high substituent tolerance.
  • the process is applicable to the preparation of a wide variety of 4-thio substituted quinoline and naphthyridine derivatives with diverse substitution patterns.
  • the process is appropriate for use with combinatorial synthesis techniques.
  • the process provides a method for producing a library of 4-thio substituted quinoline and naphthyridine derivatives for biological screening.
  • the invention also provides compositions and methods for the treatment of HCV by administering a compound of the present invention in a therapeutically effective amount.
  • halo or halogen as used herein includes fluorine, chlorine, bromine and iodine.
  • alkyl as used herein contemplates substituted or unsubstituted, straight and branched chain alkyl radicals containing from one to fifteen carbon atoms.
  • lower alkyl as used herein contemplates both straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, is ⁇ propyl, butyl, isobutyl, tert- butyl, and the like.
  • the alkyl group may be optionally substituted with one or more substituents selected from halo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(R')(R"), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(0)N(R')(R") > -OC(O)R, -OC(O)N(R')(R"), SO 2 , -SOR, -SO 3 R, -SO 2 N(RO(R"), phosphate, phosphonate, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted cycloalkenyl, wherein the substituted cycloalkyl and the substituted cycloalkenyl may be substituted with one or more of halo, CN, CF 3 , CO 2 R, C(O)R, C(O)NR 2 , NR 2
  • alkenyl as used herein contemplates substituted or unsubstituted, straight and branched chain alkene radicals containing from two to 8 carbon atoms.
  • An alkenyl group may be optionally substituted with one or more substituents selected from halo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(R')(R"), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(0)N(R')(R"), -OC(O)R, -OC(O)N(R')(R"), SO 2 , -SOR, -SO 3 R, -SO 2 N(R')(R"), phosphate, phosphonate, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkenyl, substituted and unsubstituted aryl and
  • alkynyl as used herein contemplates substituted or unsubstituted, straight and branched carbon chain containing from two to 8 carbon atoms and having at least one carbon-carbon triple bond.
  • alkynyl includes, for example ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 3-methyl-l-butynyl, and the like.
  • An alkynyl group maybe optionally substituted with one or more substituents selected from halo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(R')(R"), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(R')(R"), -OC(O)R, -OC(O)N(R')(R"), SO 2 , -SOR, -SO 3 R, -SO 2 N(R')(R"), phosphate, phosphonate, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkenyl, substituted and unsubstituted aryl and substituted and a unsubstituted heterocyclic group, wherein the substituted cycloalkyl, substituted cycloalkenyl, substituted aryl and substituted heterocycl
  • cycloalkyl as used herein contemplates substituted or unsubstituted cyclic alkyl radicals containing form 3 to 7 carbon atoms and includes cyclopropyl, cyclopentyl, cyclohexyl, and the like.
  • a cycloalkyl group may be optionally substituted with one or more substituents selected from halo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(R')(R"), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(RO(R"), -OC(O)R, -OC(O)N(RO(R"), SO 2 , -SOR, -SO 3 R, -SO 2 N(R')(R"), phosphate, phosphonate, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkenyl, substituted and unsubstituted aryl and a substituted and unsubstituted heterocyclic group, wherein the substituted alkyl, substituted cycloalkenyl, substituted aryl and substituted heterocyclic group may be substituted with one
  • cycloalkenyl as used herein contemplates substituted or unsubstituted cyclic alkenyl radicals containing form 5 to 7 carbon atoms in which has a double bond between two of the ring carbons and includes cyclopentenyl, cyclohexenyl, and the like.
  • a cycloalkenyl group may be optionally substituted with one or more substituents selected from halo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(RO(R").
  • aralkyl as used herein contemplates a lower alkyl group which has as a substituent an aromatic group, which aromatic group may be substituted or unsubstituted.
  • An aralkyl group may be optionally substituted with one or more substituents selected from halo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(R')(R"), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(R')(R"), -OC(O)R, -OC(O)N(R * )(R"), SO 2 , -SOR, -SO 3 R, -SO 2 N(R')(R"), phosphate, phosphonate, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted cycloalky
  • phosphate and phosphonate refer to the moieties having the following structures, respectively:
  • heterocyclic group or "heterocyclic ring” as used herein contemplates substituted or unsubstituted aromatic and non-aromatic cyclic radicals having at least one heteroatom as a ring member.
  • Preferred heterocyclic groups are those containing 5 or 6 ring atoms which includes at least one hetero atom, and includes cyclic amines such as morpholino, piperidino, pyrrolidino, and the like, and cyclic ethers, such as tetrahydrofuran, tetrahydropyran, and the like.
  • Aromatic heterocyclic groups also termed "heteroaryl” groups contemplates single-ring hetero-aromatic groups that may include from one to three heteroatoms, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.
  • heteroaryl also includes polycyclic hetero- aromatic systems having two or more rings in which two atoms are common to two adjoining rings (the rings are "fused") wherein at least one of the rings is a heteroaryl, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls.
  • polycyclic heteroaromatic systems include quinoline, isoquinoline, tetrahydroisoquinoline, quinoxaline, quinaxoline, benzimidazole, benzofuran, purine, imidazopyridine, benzotriazole, and the like.
  • a heterocyclic group may be optionally substituted with one or more substituents selected from halo, alkyl, CN, NO 2 , CO 2 R, C(O)R, -O R, -N(R')(R"), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(R')(R"), -OC(O)R, -OC(O)N(R')(R"), SO 2 , -SOR, -SO 3 R, -SO 2 N(RO(R"), phosphate, phosphonate, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkenyl, substituted and unsubstituted aryl and a substituted and unsubstituted heterocyclic group, wherein the substituted
  • aryl as used herein contemplates substituted or unsubstituted single-ring aromatic groups (for example, phenyl, pyridyl, pyrazole, etc.) and polycyclic ring systems (naphthyl, quinoline, etc.).
  • the polycyclic rings may have two or more rings in which two atoms are common to two adjoining rings (the rings are "fused") wherein at least one of the rings is aromatic, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls.
  • the aryl group may be optionally substituted with one or more substituents selected from halo, alkyl, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(RO(R"), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(RO(R"), -OC(O)R, -OC(O)N(RO(R"), SO 2 , -SOR, -SO 3 R, -SO 2 N(RO(R"), phosphate, phosphonate, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkenyl, substituted and unsubstituted aryl and a substituted and unsubstituted heterocyclic group, wherein the substituted alkyl, substitute
  • each R is independently selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkenyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aralkyl, substituted and unsubstituted aryl and a substituted and unsubstituted heterocyclic group.
  • Each R' and R" are independently selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkenyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aralkyl, substituted and unsubstituted aryl and substituted and unsubstituted heterocyclic group; or R 1 and R" may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom.
  • the substituted alkyl, substituted cycloalkyl, substituted cycloalkenyl, substituted alkenyl, substituted alkynyl, substituted aralkyl, substituted aryl and substituted heterocyclic group may be substituted with one or more of halo, CN, CF 3 , OH, CO 2 H, NO 2 , and -N(C, - 6 alkyl) 2 .
  • heteroatom particularly as a ring heteroatom, refers to N, O, and S.
  • a represents an optional double bond
  • X is selected from N, C-H and C-R 1 ; each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -(CH 2 VO-R 11 ,
  • A is a 5-, or 6-membered ring optionally comprising O to 3 heteroatoms; each R 2 is selected from the group consisting of alkyl, alkenyl, alkynyl, aralkyl, -(CH 2 ) V -O-R 21 , -(CH 2 ) V -N(R 22 )(R 23 ), -(CH 2 )V-N(R 21 MCH 2 VC(O)R 24 , -(CH 2 ) V -N(R 21 )SO 2 R 21 , -(CH 2 ) V -SR 21 , -(CH 2 )V-C(O)R 24 , -(CH 2 ) ⁇ ,-C(O)-(CH 2 ) w OR 21 , -(CH 2 ) v -C(O)(CH 2 ) w -N(R 22 )(R 23 ), -(CH 2 ) v -O-(CH 2 ) w
  • R 3 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, a heterocyclic group, -(CH 2 ) ⁇ C(O)R 31 , -(CH 2 ),C(O)N(R 32 )(R 33 ), (CH 2 ) ⁇ C(O)OR 31 ,
  • R 31 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
  • R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 32 and R 33 may be taken together with the nitrogen to which they are attached to form a 5- to 7- membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; x is 0 to 6; m is 0 or 1 ;
  • R 4 is selected from the group consisting of H, halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, a heterocyclic group, -(CH 2 VO-R 41 , -(CH 2 )yN(R 42 )(R 43 ),
  • each R 41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
  • R 6 is selected from H, halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; or a pharmaceutically acceptable salt or hydrate thereof.
  • ring A is selected from an aryl group. In particularly preferred embodiments, ring A is phenyl.
  • R 6 is H.
  • X is selected from N, C-H and C-R 1 ; each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -(CHzVO-R 11 ,
  • A is a 5-, or 6-membered ring optionally comprising 0 to 3 heteroatoms; each R 2 is selected from the group consisting of alkyl, alkenyl, alkynyl, aralkyl, -(CH 2 ) V -O-R 21 , -(CH 2 VN(R 22 XR 23 ), -(CH 2 ) V -N(R 21 )-(CH 2 ) W -C(O)R 24 , -(CH 2 ) V -SR 21 , -(CH 2 ) V -C(O)R 24 , -(CH 2 ) V -C(O)-(CH 2 ) H ,OR 21 , -(CH 2 ) V -C(O)(CH 2 ) W -N(R 22 )(R 23 ), -(CH 2 )V-O-(CH 2 )H 1 -C(O)R 24 , -(CH 2 ) V -OC(
  • R 3 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, a heterocyclic group, -(CH 2 ) ⁇ C(O)R 31 , -(CH 2 ) X C(O)N(R 32 )(R 33 ), (CH 2 ) X C(O)OR 31 , R 31 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
  • R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 32 and R 33 may be taken together with the nitrogen to which they are attached to form a 5- to 7- membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; and x is 0 to 6; or a pharmaceutically acceptable salt or hydrate thereof.
  • R 6 is H
  • m is 1
  • ring A is phenyl to give a compound of the formula IH:
  • X is selected from N, C-H and C-R 1 ; each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -(CH 2 V-O-R 11 ,
  • each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alky
  • R 3 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, a heterocyclic group, -(CH 2 ) ⁇ C(O)R 31 , -(CH 2 ) ⁇ C(O)N(R 32 XR 33 ), (CH 2 ),C(O)OR 31 ,
  • R 31 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
  • R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 32 and R 33 may be taken together with the nitrogen to which they are attached to form a 5- to 7- membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; and x is 0 to 6; or a pharmaceutically acceptable salt or hydrate thereof.
  • the invention provides a compound of the formula III a ::
  • R la and R lb are independently selected from H, alkyl, alkenyl, alkynyl, aralkyl, -(CH 2 ) ⁇ O-R 11 , -(CH 2 yN(R 12 )(R 13 ), -(CH 2 ) ⁇ N(R l l )-(CH 2 ),C(O)R 14 , -(CH 2 VN(R 11 JSO 2 R 11 , -(CH 2 VSR 11 , -(CH 2 VC(O)R 14 , -(CH 2 VC(OMCH 2 ) ⁇ OR 11 , -(CH 2 VC(O)-(CH 2 ) 5 N(R 12 )(R 13 ), -(CH 2 ) ⁇ O-(CH 2 VC(O)R 14 , -(CH 2 ) r OC(O)-(CH 2 ),N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 ,
  • each R 24 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl,
  • R la and R 2a are independently selected from H, -NH 2 , halo, alkyl, and -O-alkyl, and R 23 is selected from H and halo.
  • R 6 is H, and m is 0 to give a compound of the formula IV:
  • X is selected from N, C-H and C-R 1 ; each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -(CH 2 V-O-R 11 ,
  • A is a 5-, or 6-membered ring optionally comprising 0 to 3 heteroatoms; each R 2 is selected from the group consisting of alkyl, alkenyl, alkynyl, aralkyl, -(CH 2 )V-O-R 21 , -(CH 2 ) V -N(R 22 )(R 23 ), -(CH 2 ) V -N(R 21 MCH 2 VC(O)R 24 , -(CH 2 ) V -N(R 21 )SO 2 R 21 , -(CH 2 ) V -SR 21 , -(CH 2 )v-C(O)R 24 , -(CH 2 VC(O)-(CH 2 ) ⁇ OR 21 , -(CH 2 )v-C(O)(CH 2 ) w -N(R 22 )(R 23 ), -(CH 2 )v-O-(CH 2 ) w -C(O)R 24 ,
  • R 4 is selected from the group consisting of H, halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, a heterocyclic group, -(CH 2 VO-R 41 , -(CH 2 VN(R 42 XR 43 ),
  • each R 41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
  • R 42 and R 43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 42 and R 43 may be taken together with the nitrogen to which they are attached to form a 5- to 7- membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; y is O to 6; and z is O to 6; or a pharmaceutically acceptable salt or hydrate thereof.
  • R 7 is selected to be an aryl group.
  • R 6 is H, m is 0, and ring A is phenyl to give a compound of the formula V:
  • X is selected from N, C-H and C-R 1 ; each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -(CH 2 VO-R 11 ,
  • R 4 is selected from the group consisting of H, halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, a heterocyclic group, -(CH 2 VO-R 41 , -(CH 2 )y-N(R 42 )(R 43 ),
  • each R 41 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
  • R 42 and R 43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
  • R 42 and R 43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
  • R 42 and R 43 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a
  • the substances according to the invention may also be present as salts.
  • “Pharmaceutically acceptable salts” refers to an acid addition salt or a basic addition salt of a compound of the invention in which the resulting counter ion is understood in the art to be generally acceptable for pharmaceutical uses.
  • Pharmaceutically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids.
  • salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid
  • organic carboxylic or sulfonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.
  • Pharmaceutically acceptable salts can also be metal or ammonium salts of the compounds according to the invention.
  • ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
  • ammonia or organic amines such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
  • each R 1 group may be selected independently.
  • the R 1 groups may be selected from any of the stated groups so as to be the same or different. This also holds true for any other group or substituent which may be selected independently from among various groups or values.
  • Aj may be treated with a thiol (HS-A-R 2 ) in the presence of an appropriate base.
  • LG represents a leaving group, such as halo, aryl sulfones (tosyl, etc.), triflate or other appropriate leaving group as would be recognized by the ordinarily skilled practitioner.
  • a preferred leaving group is halo, particularly Cl.
  • the base may be selected from amine bases, hydroxide salts (non-limiting examples include sodium hydroxide and tetraalkylamonium hydroxides), carbonate salts, hydrides, alkoxide salts (non-limiting examples include sodium methoxide and potassium f-butoxide) and the like. Hydrides, such as sodium hydride, are preferred bases.
  • An optionally substituted 2,4-quinolinediol A2 can be converted to the corresponding 2,4-dichloroquinoline B2 y for example by treatment with POCI 3 , either neat or in a solvent.
  • the solvent may be a polar aprotic solvent.
  • the 2,4-dichloroquinoline B2 may be treated with a thiol (HS-A-R 2 ) in the presence of an appropriate base.
  • the base may be selected from amine bases, hydroxide salts (non-limiting examples include sodium hydroxide and tetraalkylamonium hydroxides), carbonate salts, hydrides, alkoxide salts (non-limiting examples include sodium methoxide and potassium f-butoxide) and the like.
  • the 2-chloro-4-thioquinoline C2 may be converted to D2, for example by treatment with HCl in TFA.
  • An optionally substituted 4-hydroxy-2-quinolone A3 can be converted to the corresponding 4-chloro-2-quinolone B3, for example by treatment with POCI 3 , either neat or in a solvent.
  • the solvent may be a polar aprotic solvent.
  • the 4-chloro-2-quinolone B3 may be treated with a thiol (HS-A-R 2 ) in the presence of an appropriate base.
  • the base may be selected from amine bases, hydroxide salts (non-limiting examples include sodium hydroxide and tetraalkylamonium hydroxides), carbonate salts, hydrides, alkoxide salts (non-limiting examples include sodium methoxide and potassium f-butoxide) and the like.
  • An optionally substituted l-benzyl-4-hydroxy-naphthyridin-2-one A4 may be treated with POCI 3 , either neat or in a solvent to give the corresponding l-benzyl-4-chloro- naphthyridin-2-one B4 and the corresponding 2,4-dichloronaphthyridine.
  • the solvent may be a polar aprotic solvent.
  • the 2,4-dichloronaphthyridine A5 may be converted to B5, for example by treatment with HCl in a polar aprotic solvent with heating, typically under reflux.
  • B5 is treated with an appropriate base and methyl iodide in a polar aprotic solvent to give C5.
  • the base may be selected from hydroxide salts (non-iimiting examples include sodium hydroxide and tetraalkylamonium hydroxides), carbonate salts, hydrides, alkoxide salts (non-limiting examples include sodium methoxide and potassium r-butoxide) and the like.
  • C5 may be treated with a thiol (HS-A-R 2 ) in the presence of an appropriate base.
  • the base may be selected from amine bases, hydroxide salts (non-limiting examples include sodium hydroxide and tetraalkylamonium hydroxides), carbonate salts, hydrides, alkoxide salts (non-limiting examples include sodium methoxide and potassium f-butoxide) and the like.
  • A6 may be treated with a thiol (HS-A-R ) in the presence of an appropriate base.
  • the base may be selected from amine bases, hydroxide salts (non-limiting examples include sodium hydroxide and tetraalkylamonium hydroxides), carbonate salts, hydrides, alkoxide salts (non-limiting examples include sodium methoxide and potassium f-butoxide) and the like.
  • protecting group means temporary modifications of a potentially reactive functional group which protect it from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2 nd ed.; Wiley: New York, 1991).
  • the compounds and processes disclosed herein are useful in the production of a library of 4-thio substituted quinoline and naphthyridine derivatives for biological screening.
  • Derivatives of quinoline and naphthyridine posses a range of biological activities.
  • Quinoline- based compounds have shown efficacy, for example, as antivirals.
  • the compounds of the present invention may be used to prevent or treat infection with HCV.
  • the HCV Replicon Assay may be used to predict compound efficacy in treatment and/or prevention of HCV infection as well as inhibition of HCV replication and/or proliferation.
  • the HCV Replicon encompasses a multiplicity of viral and host targets through which an inhibitor could work to inhibit HCV Replication.
  • Viral targets expressed in the HCV Replicon include the HCV IRES (for translation), NS3 Protease, the HCV Helicase/ATPase, NS5A phosphorylation, and the NS5B polymerase.
  • HCV IRES for translation
  • NS3 Protease for translation
  • the HCV Helicase/ATPase HCV Helicase/ATPase
  • NS5A phosphorylation NS5B polymerase
  • the compounds of the present invention inhibit HCV replication.
  • the compounds of the invention may inhibit replication as by acting on the IRES, NS3 protease, NS5B polymerase, Helicase/ATPase, or NS 5 A phosphorylation.
  • HCV IRES driven luciferase reporter activity and HCV RNA are measured to obtain indirect and direct measures of replication of HCV RNA respectively.
  • Inhibitors of HCV replication and/or proliferation are determined by initially identifying molecules that inhibit expression of the HCV IRES driven luciferase reporter in this HCV Replicon Luciferase Assay. Cell viability assays and control cell based luciferase assays are then run on hits identified in the HCV Replicon Luciferase Assay to eliminate cytoxic compounds and non-specific compounds which act by inhibiting the luciferase enzyme.
  • HCV Replicon Luciferase hits that are specific and non-cytoxic and demonstrating that these compounds inhibit expression of HCV RNA using a quantitative PCR based approach (Taqman) using primers and probes specific for HCV RNA (HCV Replicon RNA Assay).
  • the present invention provides pharmaceutical compositions comprising an anti-HCV effective amount of a compound of formula I, or a pharmaceutically acceptable salt or hydrate thereof, in combination with a pharmaceutically acceptable carrier or auxiliary agent.
  • pharmaceutically acceptable salts and “hydrates” refer to those salts and hydrated forms of the compound that would favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, absorption, distribution, metabolism and excretion.
  • Other factors, more practical in nature, which those skilled in the art may take into account in the selection include the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug.
  • the invention also provides a method of treating HCV infection in a mammal, preferable a human, by administering to the mammal an effective amount of a compound of the present invention, a pharmaceutically acceptable salt or hydrate thereof, or a composition as described above.
  • the compounds of the invention may be administered alone or may be administered in combination with other approved therapeutics, such as: an interferon (pegylated or not), preferably ⁇ -interferon, ribavirin, or interferon and ribavirin, or one or more other anti-HCV agent, such as an HCV protease inhibitor, HCV polymerase inhibitor, HCV IRES inhibitor, HCV Helicase and/or ATPase inhibitor, NS5 A phosphorylation inhibitor, HCV NS2 inhibitor, or other HCV life cycle inhibitor.
  • Combination therapies with may include a compound of the invention with multiple different inhibitors of HCV life cycle (immunomodulatory agents, Toll Like Receptor modulators, antisense therapeutics etc.).
  • the agents that comprise a combination therapy may be administered together or separately, e.g., prior to, concurrently with or following the administration of the compound of the invention or pharmaceutically acceptable salt thereof.
  • additional agents may be combined with the compounds of this invention to create a single pharmaceutical dosage form.
  • these additional agents may be separately administered to the patient as part of a multiple dosage form, for example, using a kit.
  • Such additional agents may be administered to the patient prior to, concurrently with, or following the administration of a compound of formula (J), or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention may be employed in solid or liquid form including, for example, amorphous powder or crystalline form, in solution or in suspension. They may be administered in numerous different ways, such as orally, parenterally, topically, transdermally or by inhalation. Oral administration or administration by injection is preferred.
  • the choice of carrier and the content of active compound in the carrier are generally determined in accordance with the solubility and chemical properties of the desired product, the particular mode of administration and well established pharmaceutical practice.
  • the pharmaceutical composition of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, and intralesional injection or infusion techniques.
  • liquid carriers examples include syrups, peanut oil, olive oil, water, saline and the like.
  • emulsions, suspensions or solutions of the compounds according to the invention in vegetable oil for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, may be used.
  • Injectable forms must be fluid to the extent they can be easily syringed, and proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of the injectable compositions can be brought about by use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • the pharmaceutical composition may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may ' be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example Tween 80) and suspending agents.
  • the pharmaceutical composition of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions.
  • Compounds of the invention may be enclosed in hard or soft shell gelatin capsules, or compressed into tablets.
  • oral liquid dosage forms include solutions, suspensions, syrups, emulsions, soft gelatin capsules and the like.
  • Carriers for oral use may include time delay materials known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • lactose and a liquid carrier such as high molecular weight polyethylene glycols.
  • compositions and dosage forms prepared in accordance with the present invention optionally may contain lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silica gels combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for preparing tablets, capsules and the like.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, and capsules may be coated with shellac, sugar or both. When aqueous suspensions are used they may contain emulsifying agents or agents which facilitate suspension.
  • Diluents such as sucrose, ethanol, polyols such as polyethylene glycol, propylene glycol and glycerol, and mixtures thereof also may be used.
  • the active compound may be incorporated into sustained-release preparations and formulations. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
  • suitable vehicles or carriers for the above noted formulations and compositions can be found in standard pharmaceutical texts, e.g. in "Remington's Pharmaceutical Sciences", The Science and Practice of Pharmacy, 19.sup.th Ed. Mack Publishing Company, Easton, Pa., (1995).
  • the resulting composition may be administered in vivo to mammals, such as man, to treat or prevent HCV virus infection.
  • mammals such as man
  • Such treatment may also be achieved using a compound of this invention in combination with other anti- viral agents which include, but are not limited to a-interferon and ribavirin.
  • the additional agents may be combined with compounds of this invention to create a single dosage form. Alternatively these additional agents may be separately administered to a mammal as part of a multiple dosage form.
  • reaction solvents were commercially purchased from Acros and Aldrich without further purification and reagents were used as received. Reactions for the synthesis of the starting material were monitored by thin-layer chromatography (TLC) on 0.25 mm precoated Merck Silica Gel 60 F 254 , visualizing with ultraviolet light or phosphomolybdic acid stain. Flash column chromatography was performed on Merck Silica Gel 60 (230-400 mesh) using reagent grade hexanes, dichloromethane, methanol and ethyl acetate.
  • Reaction reagents were commercially purchased from Alrich and used as received. 1 H and 13 C NMR spectra were recorded on a Varian 500 MHz spectrometer and are referenced to residual solvent peaks or to' an internal reference of tetramethylsilane in CDCI 3 .
  • LC-MS were obtained on a Micromass ZQ mass spectrometer in ES+ mode with a Water 2790 HPLC system. HPLC condition: C18 column (3.5 ⁇ m, 2.1 X 50 mm, W93491F 26) using a flow rate of 0.4 mL/min in a gradient of 15-100% CH 3 CN in H2O in 9 min with 1 min wash.
  • Huh-Luc-Neo Cells are seeded at 25,000/well in an opaque-walled 96 plate with Growth Medium (DMEM phenol red free + PS + 2mM glutamine; 100 ⁇ l/well). The compounds to be tested are added to the experimental wells (10 ⁇ l/well at 1OX assay concentration) and the cells are then incubated (5% CO 2 , 37 0 C) for 48h.
  • Growth Medium DMEM phenol red free + PS + 2mM glutamine
  • Bright-Glo Luciferase Assay reagent Bright-Glo Luciferase Assay Buffer + Bright-Glo Luciferase Assay. Substrate Mixture
  • the well contents are mixed for 5 min. on an orbital shaker at room temperature to induce cell lysis and the luminescence is then measured using a luminometer.
  • the data is analyzed and IC50s are determined using GraphPad Prism 4 software.
  • Hits validated in the Replico ⁇ Luciferase assay have IC50s ⁇ 8.0 ⁇ M and show ⁇ 30% inhibition of Cell Viability at a compound concentration of 100 ⁇ M (Cell Titer Glow Assay, cell viability assay conditions identical to HCV Replicon Luciferase Assay conditions).
  • Huh-Luc-Neo Cells are seeded at 25,000/well in an opaque-walled 96 plate with Growth Medium (DMEM phenol red free + PS + 2mM glutamine; 100 ⁇ l/well).
  • the compounds to be tested are added to the experimental wells (10 ⁇ l/well at 1OX assay concentration) and the cells are then incubated (5% CO2, 37°C).
  • RNA Isolation and cDNA Synthesis The cells are washed with IX Phosphate Buffered Saline (PBS) once. Cells are then lysed and RNA is isolated in 96 well format, using a vacuum manifold and the RNAeasy 96 kit (Qiagen) according to the manufacturer's suggested protocol. cDNA is then synthesized from RNA isolated from each well using the Taqman Reverse Transcription Reagents kit (Applied Biosystems) according to manufacturer's suggested protocol.
  • PBS IX Phosphate Buffered Saline
  • Huh-Luc-Neo Cells are seeded at 25,000/well in an opaque-walled 96 plate with Growth Medium (DMEM phenol red free + PS + 2mM glutamine; lOOul/well).
  • the compounds to be tested for inhibition of cell viability are added to the experimental wells (10 ⁇ l/well at 1OX assay concentration) and the cells are then incubated (5% CO 2 , 37 0 C) for 48h.

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Abstract

La présente invention concerne des derivés de quinoléine et de naphtyridine à substitution thio en position 4 et leurs procédés de préparation. L'invention concerne également des procédés de traitement d'infection du virus de l'hépatite C par l'administration de dérivé de quinoléine et de naphtyridine à substitution thio en position 4.
EP07837234A 2006-08-23 2007-08-22 Composés à base de quinoléine et de naphtyridine à substitution thio en position 4 Withdrawn EP2061466A4 (fr)

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US83992206P 2006-08-23 2006-08-23
PCT/US2007/018607 WO2008024423A2 (fr) 2006-08-23 2007-08-22 Composés à base de quinoléine et de naphtyridine à substitution thio en position 4

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EP2061466A2 true EP2061466A2 (fr) 2009-05-27
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CA2677001A1 (fr) 2008-02-28
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