EP1796662A2 - Inhibition des virus a l'aide d'inhibiteurs de rnase h - Google Patents

Inhibition des virus a l'aide d'inhibiteurs de rnase h

Info

Publication number
EP1796662A2
EP1796662A2 EP05803872A EP05803872A EP1796662A2 EP 1796662 A2 EP1796662 A2 EP 1796662A2 EP 05803872 A EP05803872 A EP 05803872A EP 05803872 A EP05803872 A EP 05803872A EP 1796662 A2 EP1796662 A2 EP 1796662A2
Authority
EP
European Patent Office
Prior art keywords
group
substituted
heterogeneous
heteroaromatic
carbocyclic
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Withdrawn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
EP05803872A
Other languages
German (de)
English (en)
Inventor
John Beutler
Stuart F. J. Legrice
Scott R. Budihas
Anthony Wamiru
Roberta Gardella
Jennifer Wilson
Katya Goncharova
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.)
US Department of Health and Human Services
National Institutes of Health NIH
Original Assignee
US Department of Health and Human Services
National Institutes of Health NIH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by US Department of Health and Human Services, National Institutes of Health NIH filed Critical US Department of Health and Human Services
Publication of EP1796662A2 publication Critical patent/EP1796662A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present invention relates to the discovery of a class of compounds that inhibit HIV RNase H, to methods of using these compounds for the treatment of HIV infections, and to pharmaceutical compositions of these compounds.
  • Retroviral reverse transcription is a complex process carried out by the viral enzyme reverse transcriptase (RT).
  • RT reverse transcriptase
  • the complexity of reverse transcription requires RT to be multifunctional, with both RNA-dependent and DNA-dependent DNA polymerase activities and ribonuclease H (RNase H) activity, each of which is essential for HIV replication.
  • RNase H specifically hydrolyzes the RNA strand of an RNA/DNA hybrid. This enzyme activity is found in virtually all organisms, including retroviruses such as HIV-I, where it is present as a specific subdomain of the viral RT.
  • HIV-I RT-RNase H catalyzes a series of "sequence nonspecific" and "sequence-specific” cleavage reactions needed during reverse transcription.
  • Nonspecific cleavages by RT-RNase H hydrolyze the retroviral (+) strand genomic RNA once this RNA has been used as template for (-) strand DNA synthesis. These cleavages free the newly synthesized DNA strand to participate in strand transfer reactions and to be used as a template in the synthesis of the second DNA strand ((+) strand DNA) to complete viral DNA synthesis. Specific cleavages by RT- RNase H generate and subsequently remove the polypurine tract RNA primer needed to initiate (+) strand DNA synthesis.
  • RNase H activity may be inhibited by 3'-azido thymidylate 5 '-monophosphate (AZT-MP), a major intracellular metabolite of the NNRT inhibitor AZT, with an IC 50 in the 50 ⁇ M range (Tan et al., 1991, Biochemistry 30:4831-4835; Zhan et al., 1994, Biochemistry 33:1366-1372).
  • AZT-MP 3'-azido thymidylate 5 '-monophosphate
  • BBNH metal chelator N ⁇ (4-tert- butylbenzoyl)-2-hydroxy-lnaphthaldehyde hydrazone
  • BBNH has demonstrated potent RNase H inhibitory activity (IC 5 o-3.5 ⁇ M) and is effective against mutant reverse transcriptase enzymes that have a high-level of resistance to other NNRTIs (Borkow et al., 1997, Biochemistry 36:3179-3185).
  • BBNH also inhibits the DNA polymerase activity of reverse transcriptase, and thus may interact with more than one domain of reverse transcriptase.
  • Illimaquinone a natural product of marine origin, preferentially inhibits the RNase H activity of HIV-I reverse transcriptase.
  • Illimaquinone is not specific to HIV-I RNase and also inhibits the RNase H function of murine leukemia virus reverse transcriptase and E. coli Rnase H (Loya, 1993, J. Biol. Chan. 268:9323-9328; Loya et al., 1990, Antimicrob. Agents Chemother. 34(10):2009-2012).
  • the invention relates to the recognition of a class of compounds that are useful for the inhibition of viral RNase H and thus are useful for the treatment of viral disease.
  • the invention relates to a method of treating a subject having a retroid virus infection or at risk of having a retroid virus infection.
  • the method includes the step of administering a retroid virus RNase H inhibitor to the subject, in which the viral RNase H inhibitor includes a compound having the following structure (Formula I): T7US2005/030846
  • X is N(R') or oxygen
  • R 1 independently for each occurrence, is selected from the group consisting of a halogen atom, a hydroxyl group, a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group; y is O to 3;
  • R 2 is selected from the group consisting of -R 5 , — C(O)-N(R')- R 6 , and— C(O)-O-R 6 ;
  • R 5 is selected from the group consisting, of a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group;
  • R 6 is selected from the group consisting of hydrogen, a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group; or
  • R 1 and R 2 together with the atoms to which they are attached, may form a ring structure
  • R 3 is selected from the group consisting of hydrogen, a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group;
  • R 3 and R 4 together with the atoms to which they are attached, may form a ring structure
  • R' and R" are each, independently for each occurrence, hydrogen or lower alkyl
  • R 7 is selected from the group consisting of a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group; or or a pharmaceutically acceptable salt thereof.
  • the invention in another aspect relates to an anti-retroid virus composition
  • an anti-retroid virus composition comprising a pharmacologically acceptable excipient and a retroid virus RNase H inhibitor having Formula I above.
  • the invention relates to a method of treating a subject having a retroid virus infection or at risk of having a retroid virus infection.
  • the method includesthe step of administering a retroid virus RNase H inhibitor to the subject, wherein the RNase H inhibitor comprises a compound having the following structure: US2005/030846
  • R 2 is selected from the group consisting of— C— R 5 t, -C(O)-N-R 6 , -C(O)-O-R 6 ; wherein R 1 and R 5 are each independently selected from the group consisting of a halogen atom, a hydroxyl group, a hydrocarbon group, a substituted hydrocarbon group; a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group; wherein y is O to 3; wherein t is O to 3; wherein R 6 is selected from the group consisting of hydrogen, a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group,
  • the invention in another aspect relates to an anti-retroid virus composition
  • an anti-retroid virus composition comprising a pharmacologically acceptable excipient and a retroid virus RNase H inhibitor having Formula II above.
  • Figure 1 depicts a comparison of the inhibitory effects of NSC 727447 on RNase H proteins derived from the following organisms: HIV-I, HIV-2, E. coli, moloney murine leukemia virus (MMLV) and humans. '
  • Figure 2 depicts a comparison of the inhibitory effects of NSC 727448 on RNase H proteins derived from the following organisms: HIV-I, HIV-2, E. coli, moloney murine leukemia virus (MMLV) and humans.
  • Figure 3 is a graph showing the effects of varying concentrations of NSC 727447 (Panel A) or NSC 727448 (Panel B) on HIV-I infection of the C ⁇ M T4 lymphocyte cell line and on cell viability.
  • Cell viability in both the infected and uninfected samples is measured by assaying the ability of the cells to convert a colorless tetrazolium salt (XTT) to a highly colored soluble formazan. Results are measured in a spectrophotometer and presented as a percentage of control values.
  • XTT colorless tetrazolium salt
  • Figure 4 is a graph showing the effects of varying concentrations of NSC 727447 on HIV-I infection of the C ⁇ M T4 lymphocyte cell line and on cell viability.
  • Cell viability in both the infected and uninfected samples is measured by assaying the ability of the cells to convert a colorless tetrazolium salt (XTT) to a highly colored soluble formazan. Results are measured in a spectrophotometer and presented as a percentage of control values.
  • XTT colorless tetrazolium salt
  • Figure 5 is a graph showing the effects of varying concentrations of NSC 731246 (Panel A) or NSC 731247 (Panel B) on HIV-I infection of the CEM T4 lymphocyte cell line and on cell viability.
  • Cell viability in both the infected and uninfected samples is measured by assaying the ability of the cells to convert a colorless tetrazolium salt (XTT) to a highly colored soluble formazan. Results are measured in a spectrophotometer and presented as a percentage of control values.
  • XTT colorless tetrazolium salt
  • Figure 6 is a graph showing the effects of varying concentrations of NSC 732532 (Panel A) or NSC 732533 (Panel B) on HIV-I infection of the CEM T4 lymphocyte cell line and on cell viability.
  • Cell viability in both the infected and uninfected samples is measured by assaying the ability of the cells to convert a colorless tetrazolium salt (XTT) to a highly colored soluble formazan. Results are measured in a spectrophotometer and presented as a percentage of control values.
  • XTT colorless tetrazolium salt
  • Figure 7 is a graph showing the effects of varying concentrations of NSC 732526 (Panel A) or NSC 732527 (Panel B) on HIV-I infection of the CEM T4 lymphocyte cell line and on cell viability.
  • Cell viability in both the infected and uninfected samples is measured by assaying the ability of the cells to convert a colorless tetrazolium salt (XTT) to a highly colored soluble formazan. Results are measured in a spectrophotometer and presented as a percentage of control values.
  • XTT colorless tetrazolium salt
  • Figure 8 is a graph showing the effects of varying concentrations of NSC 732520 (Panel A) or NSC 732521 (Panel B) on HIV-I infection of the CEM T4 lymphocyte cell line and on cell viability.
  • Cell viability in both the infected and uninfected samples is measured by assaying the ability of the cells to convert a colorless tetrazolium salt (XTT) to a highly colored soluble formazan. Results are measured in a spectrophotometer and presented as a percentage of control values.
  • XTT colorless tetrazolium salt
  • the invention relates to the activity of a certain class of compounds that are effective in inhibiting RNase H activity of HIV-I and HIV-2, and that have been 5 030846
  • the invention relates to the uses of a class of compounds that are useful for the treatment of human immunodeficiency virus infections, particularly HIV-I and HIV-2, and other retroid virus and retrovirus infections in humans and in non-human mammals and birds.
  • preferred compounds of the invention have the following structure (Formula I):
  • X is N(R') or oxygen
  • R 1 is selected from the group consisting of a halogen atom, a hydroxyl group, a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group; y is 0 to 3;
  • R 2 is selected from the group consisting Of-R 5 , — C(O)-N(R')- R 6 , and— C(O)-O-R 6
  • R 5 is selected from the group consisting of a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted T/US2005/030846
  • heterocyclic group an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group
  • R 6 is selected from the group consisting of hydrogen, a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group; or
  • R 1 and R 2 together with the atoms to which they are attached, may form a ring structure
  • R 3 is selected from the group consisting of hydrogen, a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group;
  • R' and R" are each, independently for each occurrence, hydrogen or lower alkyl
  • R 7 is selected from the group consisting of a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group; or or a pharmaceutically acceptable salt thereof.
  • y is equal to 0 or 1
  • R 1 together with R 2 forms a ring structure, preferably a carbocyclic ring comprising 5-8 ring atoms, more preferably 6, 7, or 8 carbon ring atoms.
  • R 2 taken together with R 1 and the atoms to which they are attached, forms a ring structure.
  • R 2 is methyl, phenyl, -C(0)-N(R')-R.6, Or-C(O)-O-R 6 ; in which R' is H and R 6 is alkyl or optionally substituted aromatic.
  • R 4 is selected from the group consisting of NH 2 and -N-C(O)-R 7 , wherein R 4 and R 3 are not cyclized in a ring structure.
  • R 4 is NH 2 .
  • R 4 is — N-C(O)-R 7
  • R 7 is an aromatic or heteroaromatic group or -CH 2 -aromatic group or - CH 2 -heteroaromatic group; in each case, the aromatic or heteroaromatic group may be substituted or unsubstituted.
  • an aromatic group is a phenyl group.
  • a heteroaroamtic group is a furanyl group, more preferably a furan-2-yl group.
  • the ring structure when R 3 and R 4 , together with the atoms to which they are attached, form a ring structure, the ring structure has from 5 to 8 atoms in ⁇ the ring, including 1-2 heteroatoms. ' '
  • the invention in another aspect, relates to a method of treating a subject having a retroid virus infection or at risk of having a retroid virus infection.
  • the method includes administering a retroid virus RNase H inhibitor to the subject, wherein the RNase H inhibitor comprises a compound having the following structure (Formula II):
  • X is nitrogen or oxygen; wherein R 2 is selected from the group consisting of— C— Rs t , -C(O)-N-R 6 ,
  • R 1 and R 5 are each independently selected from the group consisting of a halogen atom, a hydroxyl group, a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group; wherein y is 0 to 3; wherein t is 0 to 3; wherein R 6 is selected from the group consisting of hydrogen, a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic
  • y is equal to 0 or 1
  • R 1 cyclizes with R 2 to form a ring structure, preferably a carbocyclic ring comprising 6, 7, or 8 carbon ring atoms. 2005/030846
  • R 4 is selected from the group consisting of NH 2 , -N-C(O)-R 7 , wherein R 4 and R 3 are not cyclized in a ring structure.
  • R 3 and R 4 are not cyclized in a ring structure.
  • the invention in another aspect relates to an anti-retroid virus composition including a pharmacologically acceptable excipient and a retroid virus RNase H inhibitor having Formula II above.
  • R 1 and R 2 when R 1 and R 2 are cyclized in a ring structure, R 3 and R 4 are not cyclized in a ring structure.
  • hydrocarbon group means a chain of 1 to 25 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 10 carbon atoms, and most preferably
  • Hydrocarbon groups may have a linear or branched chain structure.
  • Preferred hydrocarbon groups have one or two branches, preferably 1 branch.
  • Preferred hydrocarbon groups are saturated (i.e., alkyl groups), more preferably lower alkyl groups.
  • Unsaturated hydrocarbon groups (including alkenyl and alkynyl groups) have one or more double bonds, one or more triple bonds, or combinations thereof. Preferred unsaturated hydrocarbon groups have one or two double bonds or one triple bond; more preferred unsaturated hydrocarbon groups have one double bond.
  • heterogeneous group means a saturated or unsaturated chain of non-hydrogen member atoms comprising carbon atoms and at least one heteroatom. Heterogeneous groups typically have 1 to 25 member atoms. Preferably, the chain contains 2005/030846
  • the chain may be linear or branched.
  • Preferred branched heterogeneous groups have one or two branches, preferably one branch.
  • Preferred heterogeneous groups are saturated. Unsaturated heterogeneous groups have one or more double bonds, one or more triple bonds, or both.
  • Preferred unsaturated heterogeneous groups have one or two double bonds or one triple bond. More preferably, the unsaturated heterogeneous group has one double bond.
  • aromatic group means an aromatic group having a monocyclic or polycyclic ring structure.
  • Monocyclic aromatic groups contain 4 to 10 carbon atoms, preferably 4 to 7 carbon atoms, and more preferably 4 to 6 carbon atoms in the ring.
  • Preferred polycyclic ring structures have two or three rings.
  • Polycyclic structures having two rings typically have 8 to 12 carbon atoms, preferably 8 to 10 carbon atoms in the rings.
  • Polycyclic aromatic groups include groups wherein at least one, but not all, of the rings are aromatic. • , ; • ,
  • heteromatic group means an aromatic group containing carbon atoms and 1 to 4 heteroatoms in the ring.
  • Monocyclic heteroaromatic groups contain 4 to 10 member atoms, preferably 4 to 7 member atoms, and more preferably 4 to 6 member atoms in the ring.
  • Preferred polycyclic ring structures have two or three rings.
  • Polycyclic structures having two rings typically have 8 to 12 member atoms, preferably 8 to 10 member atoms in the rings.
  • Polycyclic heteroaromatic groups include groups wherein at least one, but not all, of the rings are heteroaromatic.
  • Carbocyclic group means a saturated or unsaturated carbocyclic hydrocarbon ring. Carbocyclic groups are not aromatic. Carbocyclic groups are monocyclic or polycyclic. Polycyclic carbocyclic groups can be fused, spiro, or bridged ring systems. Monocyclic carbocyclic groups contain 4 to 10 carbon atoms, preferably 4 to 7 carbon atoms, and more preferably 5 to 6 carbon atoms in the ring. Bicyclic carbocyclic groups preferably contain 8 to 12 carbon atoms, preferably 9 to 10 carbon atoms in the rings.
  • heterocyclic group means a saturated or unsaturated ring structure containing carbon atoms and 1 or more heteroatoms in the ring.
  • Heterocyclic groups are not aromatic.
  • Heterocyclic groups are monocyclic or polycyclic.
  • Polycyclic heteroaromatic groups can be fused, spiro, or bridged ring systems.
  • Monocyclic heterocyclic groups contain 4 to 10 member atoms (i.e., including both carbon atoms and at least 1 heteroatom), preferably 4 to 7, and more preferably 5 to 6 in the ring.
  • Bicyclic heterocyclic groups preferably contain 8 to 18 member atoms, preferably 9 or 10 in the rings.
  • heteroatom means an atom other than carbon or hydrogen, e.g., in the ring of a heterocyclic group or the chain of a heterogeneous group.
  • heteroatoms are selected from the group consisting of sulfur, phosphorous, nitrogen and oxygen atoms. Groups containing more than one heteroatom may contain different heteroatoms.
  • substituted hydrocarbon group means a hydrocarbon group wherein 1 or more of the hydrogen atoms bonded to carbon atoms in the chain have been replaced with other substituents.
  • substituents include halogen atoms (e.g., fluorine, chlorine, bromine, iodine), monovalent aromatic groups, monovalent substituted aromatic groups, monovalent hydrocarbon groups including alkyl groups (e.g. methyl groups), monovalent substituted hydrocarbon groups such as benzyl, and monovalent heterogeneous groups including alkoxy groups (e.g. methoxy). Additional preferred substituents include hydroxy, nitro, cyano, and trifluoromethyl.
  • substituted heterogeneous group means a heterogeneous group, wherein 1 or more of the hydrogen atoms bonded to carbon atoms in the chain have been replaced with other substituents.
  • Preferred substituents include monovalent hydrocarbon groups including alkyl groups (e.g. methyl groups) and monovalent heterogeneous groups including alkoxy groups (e.g. methoxy groups). Additional preferred substituents include hydroxy, nitro, cyano, and trifluoromethyl groups.
  • substituted aromatic group means an aromatic group wherein 1 or more of the hydrogen atoms bonded to carbon atoms in the ring have been replaced with other substituents.
  • Preferred substituents include halogen atoms, nitro groups, hydrocarbon groups (e.g. methyl groups) and heterogeneous groups including alkoxy groups (e.g. methoxy groups). Additional preferred substituents include hydroxy, cyano, and trifluoromethyl groups. The substituents maybe substituted at the ortho, meta, or para position on the ring, or any combination thereof.
  • substituted heteroaromatic group means a heteroaromatic group wherein 1 or more hydrogen atoms bonded to carbon atoms in the ring have been replaced with other substituents.
  • Preferred substituents include monovalent hydrocarbon groups including alkyl groups (e.g. methyl groups) such as methyl groups and monovalent • •: : ⁇ heterogeneous groups including alkoxy groups (e.g. methoxy groups). Additional preferred substituents include halogen atoms, hydroxy, nitro, cyano, and trifluoromethyl groups:- The substituents may be substituted at the ortho, meta, or para position on the ring, or any*" ⁇ combination thereof.
  • substituted carbocyclic group means a carbocyclic group wherein 1 or more hydrogen atoms bonded to carbon atoms in the ring have been replaced with other substituents.
  • Preferred substituents include hydrocarbon groups such as alkyl groups (e.g., methyl groups) and heterogeneous groups such as alkoxy groups (e.g., methoxy groups). Additional preferred substituents include halogen atoms, hydroxy, nitro, cyano, and trifluoromethyl groups.
  • substituted heterocyclic group means a heterocyclic group wherein 1 or more hydrogen atoms bonded to carbon atoms in the ring have been replaced with other substituents.
  • Preferred substituents include monovalent hydrocarbon groups including alkyl groups such as methyl groups and monovalent heterogeneous groups including alkoxy groups such as methoxy groups. Additional preferred substituents include halogen atoms, hydroxy, nitro, cyano, and trifluoromethyl groups. Substituted heterocyclic groups are not aromatic.
  • the invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the clathrates, hydrates and solvates of compounds of Formula I.
  • solvates of the compounds is taken to mean adductions of inert solvent molecules onto the compounds which form owing to their mutual attractive force. Solvates are, for example, monohydrates or dihydrates or alkoxides.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds).
  • the compounds delineated herein are commercially available or readily synthesized by one of ordinary skill in the art using methodology known in the art.
  • the term "pharmaceutically acceptable salt,” is a salt formed from, for example, an acid and a basic group of a compound of any one of the formulae disclosed herein.
  • Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, besylate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate, and pamoate ⁇ i
  • Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-
  • pharmaceutically acceptable salt also refers to a salt prepared from a compound of any one of the formulae disclosed herein having a basic functional group, such as an amino functional group, and a pharmaceutically acceptable inorganic or organic acid.
  • suitable acids include hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid.(HCl), hydrogen bromide (HBr), hydrogen iodide (HI), nitric acid, phosphoric acid, lactic acid, salicylic acid, tartaric acid, bitartratic acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and/>-toluenesulfonic acid.
  • Preferred compounds of the invention show a greater than 10%, preferably greater than 20%, more preferably greater than 30% and most preferably greater than 40% inhibition of HIV-I RT associated RNaseH at a concentration of 10 ⁇ M. Inhibition of HIV- 1 RT associated RNase H can be assessed, for example, using the fluorescence resonance energy transfer (FRET) quenching assay described in Example 1 herein. Preferred compounds of the invention show inhibition of the cytopathic effect of an HIV virus at concentrations that do not significantly inhibit cell growth. For example, preferred compounds of the invention are NSC 727447, NSC 731247, NSC 732520, NSC 732526, and NSC 732533, as shown in the Tables, supra.
  • FRET fluorescence resonance energy transfer
  • Cytopathic effect may be measured, for example, using an isolated HW strain and the CD4+ lymphoblast cell line, CEM (ATCC Number: CCL-119), and using the procedures described by Weislow et al. (1989, J. Natl. Cancer Inst. 81:577-586).
  • the EC 50 represents the concentration of agent which reduces an HIV cytopathic effects 50% relative to untreated control.
  • the TC 5 0 represents the concentration of the agent which inhibits 50% of the viability of uninfected cells.
  • the EC 50 is less than about 75% of the TC 50 , more preferably less than about 50% of the TC 5O , and most preferably less than about 25% of the TC 50 .
  • Retroid virus infections via decreasing or inhibiting the proliferation or replication of a retroid virus, particularly retrovirus infections, particularly lentivirus infections, most preferably human immunodeficiency virus infections in humans or non- human mammals.
  • retroid viruses include, but are not limited to, Hepadnaviruses (e.g., Arctic ground squirrel hepatitis B virus, Duck hepatitis B virus, Ground squirrel hepatitis virus, Hepatitis B virus, Heron hepatitis B virus, Orangutan hepadnavirus, Stork hepatitis B virus, Woodchuck hepatitis B virus, Woolly monkey hepatitis B Virus) and retroviruses (e.g., Abelson murine leukemia virus, Avian leukosis virus, Avian myelocytomatosis virus, Avian sarcoma virus, Avian sarcoma virus Y73, Bovine foamy virus, Bovine immunodeficiency virus, Bovine leukemia virus, Caprine arthritis-encephalitis virus, Caprine nasal tumor virus, Equine foamy virus, Equine infectious anemia virus, Feline foamy virus, Feline immunodeficiency virus, Feline leukemia virus, Friend murine
  • the present invention provides a method of preventing or treating a retroid virus infection by administering to a subject having or at risk of having a retroid virus infection an effective amount of an inhibitory agent of Formula I or II or pharmaceutical composition containing an inhibitory agent of Formula I or II.
  • an effective amount of an inhibitory agent of Formula I or II is an amount which inhibits, reduces, or stabilizes at least one sign or symptom associated with a retroid virus infection.
  • Signs or symptoms which may be evaluated to determine the effectiveness of a compound or composition of the invention include, but are not limited to, viral load as determined by well-known methods such as quantitative RT-PCR, northern blot analysis, determining RNase H activity, measuring cell-associated viral capsid protein, and the like.
  • CD4 + T cell responses are generally related to the degree of viral load/viral load suppression, and these responses may also be measured. Individuals who have benefited from a compound or composition of the present invention may exhibit a low baseline viremia, a high baseline CD4+ T cell count, or a rapid decline of viremia.
  • Compounds of the invention may be administered therapeutically, so as to lessen the severity of an existing infection, or they may be administered prophylactically to prevent or lessen the likelihood of a future infection.
  • An effective amount of one or more of the RNase H inhibitors of the present invention maybe determined by one of ordinary skill in the art, and includes exemplary dosage amounts for a human of from about 0.05 to about 200 mg/kg/day. This dosage is typically administered in a single dose, but can be given in multiple doses.
  • the compound(s) may be administered in a frequent regimen, e.g., daily, every two days for five doses, etc. or intermittently, e.g., every four days for three doses or every eight days for three doses.
  • the specific dose level and frequency of administration for a given subject may be varied and will depend upon a variety of factors including, for example, the subject's age, body weight, general health, sex, diet and the like, and the mode of administration, the stage and type of disease associated with HIV infection, and the other types of anti-HIV compounds that are being simultaneously administered.
  • the RNase inhibitor compounds are administered in pharmaceutical compositions containing an amount thereof effective for anti-HIV therapy, and a pharmaceutically acceptable carrier.
  • Such compositions may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation and/or called for by accepted pharmaceutical practice.
  • the RNase inhibitor compounds may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, intracissternal, or intrathecal injection or infusion techniques (e.g., as sterile injectable aqueous or non ⁇ aqueous solutions or suspensions); nasally, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents.
  • the subject compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the 46
  • compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.
  • the subject compounds may also be administered liposomally.
  • Suitable dosage forms for the RNase H inhibitor compounds include, without intended limitation, an orally effective composition such as a tablet, capsule, solution or suspension containing about 0.1 to about 500 mg per unit dosage of a compound of the invention. They may be compounded in a conventional manner with a physiologically acceptable vehicle or carrier, excipient, binder, preservative, stabilizer, flavor, etc.
  • the RNase H inhibitor compounds can also be formulated in compositions such as sterile solutions or suspensions for parenteral administration. About 0.1 mg to about 500 mg of a compound of the invention may be compounded with a physiologically acceptable vehicle, carrier, excipient, binder preservative, stabilizer, etc., in a unit dosage form as called for by accepted pharmaceutical practice.
  • the amount of active substance in these compositions or preparations is preferably such that a suitable dosage in the range indicated is obtained.
  • compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. Molded tablets, compressed tablets or freeze- dried tablets are exemplary forms that may be used.
  • compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (Avicel) or polyethylene glycols (PEG). Such formulations may also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g. Gantrez), and agents to control release such as polyacrylic acid copolymer (e.g. Carbopol 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
  • fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins
  • compositions for nasal aerosol or inhalation administration include solutions in saline, which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
  • compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parentally acceptable diluents or solvents, such as Cremophor (polyoxyethylated caster oil surfactant), mannitol, 1,3-butanediol, water, Ringer's solution, Lactated Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • suitable non-toxic, parentally acceptable diluents or solvents such as Cremophor (polyoxyethylated caster oil surfactant), mannitol, 1,3-butanediol, water, Ringer's solution, Lactated Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids
  • compositions for rectal administration include suppositories, which may contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperature, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperature, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • the RNase H inhibitors may be administered either alone or in combination with other anti-HIV drugs.
  • the RNase inhibitors will be administered in combination with other anti-HIV drugs.
  • anti-HIV drugs may include (but are not limited to), for example, the following: nonnucleoside reverse transcriptase inhibitors, nucleoside analog reverse transcriptase inhibitors, nucleotide reverse transcriptase inhibitor, protease inhibitors, and fusion inhibitors.
  • Nonnucleoside reverse transcriptase inhibitors include, for example, Delaviridine, Efavirenz, and Nevirapine.
  • Nucleoside reverse transcriptase inhibitors include, for example, Abacavir, Lamivudine, Zidovudine, Didanosine, Emtricitabine, Stavudine, Tenofovir DF, and Zalcitabine.
  • Nucleotide reverse transcriptase inhibitors include tenofovir disoproxil fumarate (sold under the trade name Viread)
  • Protease inhibitors include, for example, Amprenavir, Atazanavir, Fosamprenavir, 46
  • Enfuvirtide maybe used as a fusion inhibitor.
  • the RNase H inhibitors are administered prophylactically to prevent or lessen the likelihood of the transfer of an HIV virus from an infected individual, or a potentially infected individual, to second individual.
  • the RNase H inhibitors may be administered as a composition (e.g. a foam or gel) that is applied, for example, vaginally, rectally, or to the penis prior to sexual contact.
  • Compositions of the invention may also be formulated or packaged with condoms or gloves, or other physical barrier devices, for prophylactic use.
  • FRET fluorescence resonance energy transfer
  • the oligonucleotides 5'-GAU CUG AGC CUG GGA GCU-fluorescein-3' (SEQ ID NO:1) and 5'-Dabcyl-AGC TCC CAG GCT CAG ATC-3' (SEQ ID NO:2) are synthesized and provided as the annealed RNA/DNA hybrid by TriLink Biotechnologies (San Diego, CA). Recombinant wild-type p66/p51 HIV-I RT is over-expressed and purified as described in Miller et al., 2001, Methods MoI. Biol. 160:335-354. The oligonucleotides and the purified HIV RT is used in a high-throughput screen of a non ⁇ exclusive library purchased from ChemBridge Corporation (San Diego, California).
  • RNA/DNA hybrid substrate is stored frozen at -2O 0 C as a 0.1 mM stock solution. After thawing, 400 ⁇ l is added to 100 ml of assay buffer immediately prior to assay. Then 22 ⁇ l of duplex in assay buffer is added to individual wells of the microplate (Cliniplate 384 black, round-well, low profile plates; Thermo Labsystems, Boston, MA; total volume 56 ⁇ l) using a 96-channel robotic liquid handler (Biomek FX; Beckman Coulter, Fullerton, CA). HIV-I RT is stored at -2O 0 C as a stock solution at 2.7 mg/rnl in 50% glycerol.
  • the RNase H inhibiting activity of the twenty-seven compounds identified in Example 1 above is confirmed using capillary-electrophoresis (CE)-based assay that allows for quantitative and qualitative analyses in a moderate through-put format (Chan et al., 2004, A capillary electrophoresis assay for ribonuclease activity, Anal. Biochem. 331(2): 296-302).
  • CE assay is an extension of the FRET assay described in Example 1 above, wherein the substrate lacks a dabcyl quencher and its cleavage product is separated by CE.
  • the CE assay allows for the separation of fluorescent or fluorescence quenching sample compounds from the assay components, thereby yielding a more reliable measurement of enzyme inhibition.
  • oligonucleotides 5'-GAU CUG AGC CUG GGA GCU-fluorescein-3' (SEQ ID NO: 1) and 5'-AGC TCC CAG GCT CAG ATC-3' (SEQ ID NO:2) are synthesized and provided as the annealed RNA/DNA hybrid by TriLink Biotechnologies (San Diego, CA). Recombinant wild-type p66/p51 HIV-I RT is expressed and purified as described in Miller et al., 2001, Methods MoI. Biol. 160:335-354.
  • Samples for assay are prepared in 96-well black polystyrene plates in a total volume of 100 ⁇ l. Stock solutions of the substrate and HIV-I RT are diluted to the appropriate concentration immediately before use, since extended dilution reduced enzymatic activity. Fifty microliters of a 0.4 ⁇ M solution of RNA/DNA hybrid in 5OmM Tris, pH 8.0, containing 6OmM KCl and 1OmM MgCl 2 is added to individual wells of the microplate using a Beckman BioMek FX.
  • Reactions are initiated by addition of 50 ⁇ l of 13.6 nM HIV- 1 RT in 5OmM Tris, pH 8.0, containing 6OmM KCl and 1OmM MgCl 2 and allowed to proceed at room temperature for 30 minutes. Reactions are quenched by the addition of 10 ⁇ l of 0.5M EDTA, pH 8.0. To assess the effect of inhibitors, 6 ⁇ l of inhibitor in dimethyl sulfoxide was added to the microplate well after addition of substrate but prior to RT addition. Completed assay plates are stored frozen at -20 0 C before CE analysis.
  • a Beckman MDQ CE system equipped with a 488 nm laser-induced fluorescence module is used to analyze the samples. Separations are performed with either a 30- or 50- ⁇ m i.d.x30-cm capillary (Polymicro) at 20 °C. A new capillary was treated by washing it with IN sodium hydroxide overnight. The capillary was rinsed with IN NaOH and running buffer for lmin each between runs. All samples were diluted fivefold with distilled water before injection. Samples were injected by vacuum (0.5 psi at 5 s) or voltage (5 kV at 5 s) and typically separated by applying a voltage of 15 kV.
  • MALDI-TOF mass spectroscopy was performed on an Axima-CFR MALDI mass spectrometer (Shimadzu) in reflectron mode. Substrate and product spectra were obtained by drying the reaction mixtures described above after incubation with or without enzyme. The enzyme concentration is doubled to increase the extent of substrate cleavage. The resulting samples are processed through C-18 ZipTips (Millipore) according to the manufacturer's specifications, and their spectra are obtained, without additional purification, using 3- hydroxypicolinic acid (Fluka) or 6-aza-2-thiothymine (Aldrich) as a matrix.
  • the twenty-seven identified RNase H inhibitors are assessed for their selectivity in inhibiting HIV RNase H versus E. coli, moloney murine leukemia virus, or human RNase H. Selectivity is assessed using the FRET assay described in Example 1 on a smaller scale and in a dose response format.
  • HIV 1 and HIV-2 RT are prepared as described in Miller et al., 2001, Methods MoI. Biol. 160:335-354.
  • E. coli RNase HI is prepared as described in Ma et al., 1994, Bioorg. Med. Chem. 2:169-179.
  • Human RNase Hl is prepared as described in Pileur et al., 2003, Nucleic Acids Res. 31 -.5776-5788.
  • Enzyme levels were adjusted to give equivalent levels of cleavage using the FRET quenching assay. All of the identified twenty seven HW-I RNase H inhibitors showed selectivity for inhibiting HIV-I and HIV-2 RNase H versus human, moloney murine leukemia virus, or E. coli RNase H. For two of the compounds, NSC 727447 and NSC 727448, results from the selectivity analysis are shown in Figure 1 and Figure 2, respectively. 05/030846
  • Compounds identified as inhibitors of isolated HIV RNase H are assessed for activity in inhibiting the cytopathicity HIV-I .
  • compounds are assessed for activity in inhibiting the cytopathicity of HIV-I (RF strain) in the CEM cell line of CD4 + lymphoblast cells (ATCC Number: CCL-119). Briefly, samples containing lymphoblast cells, the HIV-I virus, and appropriate dilutions of the test compounds are incubated at 37 0 C for six days.
  • Cell viability is measured by the ability of cells to convert a colorless tetrazolium salt (XTT) to a highly colored soluble formazan, and the intensity of the color is read using a spectrophotometer using an automated system. Samples are also examined microscopically to confirm the protective activity of the compounds.
  • the EC 50 represents the concentration of agent which reduces HIV-I cytopathic effects 50% relative to untreated control. Cellular toxicity of the agents is estimated from the TG 50 , which represents the concentration of the agent which inhibits 50% of the viability of uninfected cells. Results from the cytopathicity inhibition assays are presented in Table 3 and Table 4 below.
  • Table 3 shows a summary of the results of the cytopathicity inhibition assays for twenty-seven compounds that were identified as specific RNase H inhibitors in the assays described in Examples 1 and 2 above.
  • Table 4 shows the specific results for certain of these compounds, and the results presented in Table 4 are also shown in graphs in Figures 3 through 8. This data shows that five compounds out of the twenty-seven identified RNase H inhibitors were able to block the cytopathic effect of the HIV-I virus at concentrations which did not inhibit cell growth.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Virology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Méthodes et compositions pour le traitement d'infections virales utilisant des inhibiteurs de RNase H.
EP05803872A 2004-08-30 2005-08-30 Inhibition des virus a l'aide d'inhibiteurs de rnase h Withdrawn EP1796662A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US60516504P 2004-08-30 2004-08-30
PCT/US2005/030846 WO2006026619A2 (fr) 2004-08-30 2005-08-30 Methodes et compositions ayant trait a l'inhibition de virus utilisant des inhibiteurs de rnase h

Publications (1)

Publication Number Publication Date
EP1796662A2 true EP1796662A2 (fr) 2007-06-20

Family

ID=35744862

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05803872A Withdrawn EP1796662A2 (fr) 2004-08-30 2005-08-30 Inhibition des virus a l'aide d'inhibiteurs de rnase h

Country Status (4)

Country Link
EP (1) EP1796662A2 (fr)
AU (1) AU2005279845A1 (fr)
CA (1) CA2579089A1 (fr)
WO (1) WO2006026619A2 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011136269A1 (fr) 2010-04-28 2011-11-03 アステラス製薬株式会社 Composé de tétrahydrobenzothiophène
EP2715345A1 (fr) 2011-06-02 2014-04-09 Massachusetts Institute of Technology Forme intermédiaire de réplication du génome hybride arndb/adn des cellules souches métacaryotes
CA2853688C (fr) 2011-10-27 2018-06-12 Astellas Pharma Inc. Derive de n-thienyl benzamide substitue avec un aminoalkyle
US9351494B2 (en) 2013-05-03 2016-05-31 Inscent, Inc. Honeybee repellents and uses thereof
WO2014179785A1 (fr) * 2013-05-03 2014-11-06 Inscent, Inc. Répulsifs améliorés contre les abeilles domestiques et leurs utilisations
ES2922932T3 (es) * 2016-12-29 2022-09-21 Enyo Pharma Derivados de tiofeno como agentes antivirales
US11358947B2 (en) * 2017-04-17 2022-06-14 The Regents Of The University Of California Substituted 2-acylamino-cycloalkylthiophene-3-carboxylic acid arylamides as inhibitors of calcium-activated chloride channel TMEM16A
WO2020102889A1 (fr) * 2018-11-19 2020-05-28 Fouda Ahmed Modulateurs de 4,5,6,7-tétrahydro-l-benzothiophène de récepteurs nucléaires orphelins (ror) liés au récepteur de l'acide rétinoïque (rar)

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997027200A1 (fr) * 1996-01-26 1997-07-31 Smithkline Beecham Plc Derives de la thienoxazinone utiles comme agents antiviraux
US6083706A (en) * 1997-02-26 2000-07-04 Ciblex Corporation Inhibitors of leaderless protein export
WO1998045298A1 (fr) * 1997-04-10 1998-10-15 Smithkline Beecham Plc Agents antiviraux
US6414013B1 (en) * 2000-06-19 2002-07-02 Pharmacia & Upjohn S.P.A. Thiophene compounds, process for preparing the same, and pharmaceutical compositions containing the same background of the invention
UA82827C2 (en) * 2000-12-18 2008-05-26 Inhibitors against the production and release of inflammatory cytokines
EP1506172B1 (fr) * 2002-05-20 2011-03-30 Bristol-Myers Squibb Company Inhibiteurs du virus de l'hepatite c
MXPA05000381A (es) * 2002-07-19 2005-03-31 Pharmacia Corp Compuestos de carboxamida tiofeno sustituido para el tratamiento de inflamacion.
ATE453386T1 (de) * 2003-04-02 2010-01-15 Taigen Biotechnology Co Ltd Polyamin-verbindungen zur behandlung von chemokin-rezeptor-vermittelten krankheiten
SI1663185T1 (sl) * 2003-09-22 2009-04-30 Onepharm Res & Dev Gmbh Preprečevanje in zdravljenje z vnetjem inducirane in/ali imunsko posredovane izgube kosti
US20050250794A1 (en) * 2003-12-19 2005-11-10 Andrew Napper Methods of treating a disorder
EP1715855A4 (fr) * 2004-01-29 2010-06-16 Elixir Pharmaceuticals Inc Medicaments antiviraux

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006026619A2 *

Also Published As

Publication number Publication date
WO2006026619A2 (fr) 2006-03-09
AU2005279845A1 (en) 2006-03-09
CA2579089A1 (fr) 2006-03-09
WO2006026619A3 (fr) 2006-05-04

Similar Documents

Publication Publication Date Title
CA2872424C (fr) Derives de bisfurane utiles dans la prevention de l'emergence de souches de vih multiresistantes aux medicaments et le traitement du vih
WO2006026619A2 (fr) Methodes et compositions ayant trait a l'inhibition de virus utilisant des inhibiteurs de rnase h
WO2021207409A2 (fr) Inhibiteurs à petites molécules de la replication virale du sars-cov-2 et leurs utilisations
JP2007519704A (ja) 治療剤の組み合わせ
WO2021175295A1 (fr) Application d'un composé de myricétine dans la préparation de médicaments pour la prévention et le traitement de la pneumonie à nouveau coronavirus
CN113289018A (zh) 金诺芬等老药及其组合物在抗单正链rna病毒中的应用
JP2016508145A (ja) ピリドン誘導体及びウイルス性疾患の治療、改善又は予防におけるそれらの使用
WO2022262820A1 (fr) Groupe de composés de série imb-c5 ayant une activité anti-coronavirus et leur application
US9833492B2 (en) Combinations of a caspase inhibitor and an antiviral agent
WO1999048371A1 (fr) Nouveaux inhibiteurs de vih integrase et traitement du vih fonde sur des combinaisons de medicaments contenant des inhibiteurs d'integrase
JP2017520610A (ja) Ｈｉｖ関連障害を治療するための方法及び組成物
JP2009242247A (ja) ヒト免疫不全ウイルス感染阻害剤およびエイズの治療薬または予防薬
KR102063286B1 (ko) Hdac 억제제로서 신규한 퀴나졸린-4(3h)-원 기반 하이드록삼산 및 이를 유효성분으로 포함하는 항암제 조성물
US20160002226A1 (en) Pyridopyrazine compounds and their use in the treatment, amelioration or prevention of influenza
EP1802297A2 (fr) Compositions et procedes de traitement de maladies causees par l'infection yersinia spp
Lee et al. Styrylquinazoline Derivatives as HIV‐1 Integrase Inhibitors
JP2014532636A (ja) ウイルス感染の処置のためのヌクレオシドアナログおよび該処置に対する感受性を評価するための方法
CN114699419A (zh) PLpro蛋白抑制剂在治疗或预防新型冠状病毒感染的药物中的应用
US20050049242A1 (en) Novel HIV integrase inhibitors and HIV therapy based on drug combinations including integrase inhibitors
RU2515413C2 (ru) Производные 1,2,5-оксадиазолов, обладающие анти-вич активностью, фармацевтическая композиция, способ ингибирования интегразы вич-1
AU2004200629B2 (en) Method of treating HIV infection
JP2024504982A (ja) マラリアを治療するための化合物および方法
WO2022122968A1 (fr) Composés destinés à être utilisés pour le traitement de la covid-19
GÜNEŞ HIV Integrase Inhibitors
US10301258B2 (en) Benzende sulfonamide derivatives as HIV integrase inhibitors

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20070222

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20100108

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20110301