WO2007106450A2 - Acides diceto a squelettes nucleobase : inhibiteurs de replication anti-vih cibles au niveau de l'integrase du vih en therapie de combinaison - Google Patents

Acides diceto a squelettes nucleobase : inhibiteurs de replication anti-vih cibles au niveau de l'integrase du vih en therapie de combinaison Download PDF

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WO2007106450A2
WO2007106450A2 PCT/US2007/006245 US2007006245W WO2007106450A2 WO 2007106450 A2 WO2007106450 A2 WO 2007106450A2 US 2007006245 W US2007006245 W US 2007006245W WO 2007106450 A2 WO2007106450 A2 WO 2007106450A2
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azido
dideoxy
alkyl
methyl
independently
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PCT/US2007/006245
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WO2007106450A3 (fr
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Vasu Nair
Guochen Chi
Vinod R. Uchil
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University Of Georgia Research Foundation, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine

Definitions

  • the present invention relates to the field of antiviral therapy, in particular the treatment of HIV infections in humans, preferably in combination therapy.
  • HIV human immunodeficiency virus
  • the human immunodeficiency virus, HIV encodes three key viral enzymes through its pol gene and these enzymes are critical for the replication of this virus [Fauci, Science,
  • RT HIV reverse transcriptase
  • PR HIV protease
  • AIDS related complex (ARC) in HAART highly-active antiretroviral therapy
  • ARC AIDS related complex
  • HIV-I integrase is a protein of 32 kDa encoded at the
  • HIV DNA into the host cell chromosome. Because integrase has no human counterpart and because it plays the significant role of completing the invasion of the human cell cell by HIV, it is an attractive target for the discovery of inhibitors of therapeutic potential.
  • integrase Following assembly of viral DNA on integrase, the processing of viral DNA occurs where there is site specific endonuclease activity and two nucleotides are cleaved off from each 3 '-end of the double helical viral DNA to produce the tailored viral DNA recessed by two nucleotides and bearing a terminal CAOH-3'.
  • integrase apparently activates the phosphodiester bond towards cleavage.
  • the recessed viral DNA thus produced is joined in the next step to host cell DNA in the nucleus through a trans- esterification reaction. In this step, integrase positions the 3'-OH end of the viral DNA for nucleophilic attack on the phosphodiester bond in the host DNA.
  • a variety of compounds are inhibitors of HIV integrase but some of these compounds are non-specific inhibitors of the enzyme while evidence suggests that others may possess some specificity.
  • the various classes include nucleotides, oligonucleotides, dinucleotides, and miscellaneous small molecules including heterocyclic systems, natural products, diketo acids, sulfones and others [Nair, Rev. Med. Virol., 12, 179-193 (2002); Nair, Current Pharmaceutical Design, 9, 2553-2565 (2003); Chi and Nair, Bioorg. Med. Chem. Lett. 14, 4815-4817 (2004); Nair and coworkers, J. Am. Chem. Soc, 122, 5671-5677 (2000)].
  • the class of previously studied compounds that are most directly relevant to this patent are diketo acids with aryl or heteroaryl substitutions. Some of these compounds are inhibitors of HTV integrase, but most commonly of only the strand transfer step.
  • the integrase inhibition data have been reported in several scientific publications [Wai, et al., "4- Aryl-2,4-dioxobutanoic acid inhibitors of HIV-I integrase and viral replication in cells," J. Med. Chem. 43, 4923-4926 (2000); Pais, G. C. G., et al., "Structure activity of 3-aryl-l,3- diketo-containing compounds as HIV-I integrase inhibitors," J. Med.
  • integrase by diketo acids may be the result of interaction of the functional groups on these compounds with metal ions in the active site of integrase, resulting in a functional sequestration of these critical metal cofactors [Grobler, J. A., et al, Proc. Natl. Acad. Sci. U.S.A. 99, 6661-6666 (2002)].
  • Related patents to this application are: Selnick, H. G. et al., (Merck & Co. Inc.),
  • Angeletti SPA "Preparation of N- substituted hydroxypyrimidinone carboxamide inhibitors of HIV integrase," WO 2003035077; Belyk, et al., (Merck & Co. Inc., Institute Di Richerche Di Biologia Molecolare P.
  • Angeletti SPA "Preparation of N-(4-fluorobenzyl)-5-hydroxy-l-methyl-2-(l-methyl-l- ⁇ [(5-methyl-l,3,4-oxadiazol-2-yl)carbonyl]amino ⁇ ethyl)-6-oxo-l,6-dihydropyrimidine-4- carboxamide potassium salts as HIV integrase inhibitors," WO 2006060712; Sato, et al., (Japan Tobacco Inc.), “Preparation of quinolizinone compounds as HIV integrase inhibitors," WO 2006033422; Yoshida, H., et al., (Shionogi & Co.
  • nucleic acid base (nucleobase) scaffold which is a requirement for potent activity and which was not previously recognized.
  • a new class of diketo acids constructed on nucleobase scaffolds, and designed as inhibitors of HIV replication through inhibition of HIV integrase, is described.
  • These compounds can be represented by the general formula I (and includes tautomers, regioisomers, geometric isomers and optical isomers thereof, as well as pharmaceutically acceptable salts thereof, where applicable), in which the moiety illustrated as a square is a molecular scaffold made up of a nucleic acid base (nucleobase) derivative.
  • These compounds have application in the prevention or treatment of infection by HIV and the treatment of AIDS and ARC, either as the compounds, or as their pharmaceutically acceptable salts, with pharmaceutically acceptable carriers, used alone or preferably, in combination with antivirals, immunomodulators, antibiotics, vaccines, and other therapeutic agents as otherwise disclosed herein. Methods of treating AIDS and ARC and methods of treating or preventing infection by HIV are also described.
  • the present invention further relates in preferred aspects to the use of at least one of the above compounds in combination with at least one additional compound, preferably an anti-HIV agent, as otherwise described herein.
  • compound refers to any specific chemical compound disclosed herein and includes tautomers, regioisomers, geometric isomers, and where applicable, optical isomers thereof, as well as pharmaceutically acceptable salts thereof,.
  • compound generally refers to a single compound, but also may include other compounds such as stereoisomers, regioisomers and/or optical isomers (including racemic mixtures) as well as specific enantiomers or enantiomerically enriched mixtures of disclosed compounds.
  • patient or “subject” is used throughout the specification within context to describe an animal, generally a mammal and preferably a human, to whom treatment, including prophylactic treatment, with the compositions according to the present invention is provided.
  • treatment including prophylactic treatment
  • patient refers to that specific animal.
  • the term "effective" is used herein y unless- otherwise indicated, to describe an amount of a compound or composition which, in context, is used to produce or effect an intended result, whether that result relates to the treatment of a viral, microbial or other disease state, disorder or condition associated with HIV, ARC or AIDS, including Kaposi's sarcoma, HBV infections and other microbial infection (tuberculosis and other infections often found in AIDS patients), or alternatively, is used to produce another compound, agent or composition or effect another intended result when the component is used within the context of its well-known use. This term subsumes all other effective amount or effective concentration terms which are otherwise described in the present application.
  • nucleoside scaffold is used throughout the specification to mean a nucleoside base selected from uracil, xanthine, hypoxanthine and purine which contain at least four substituents at four substitutable positions on the nucleoside base, one of which is a ketoacid as otherwise defined herein and the other three of which R 1 , R 2 andR 3 , are as defined herein.
  • heteroaryl shall mean a 5 or 6-membered heteroaromatic ring containing 1 to 2 heteroatoms selected from oxygen, nitrogen and sulfur, which heteroaromatic ring is optionally substituted with from 1 to 3 substituents such as halogen, hydroxyl, Qo alkyl, Ci -3 alkoxy and CF 3 .
  • heteroaryl and heteroaryomatic ring are used interchangeably herein.
  • human immunodeficieincy virus or "HIV” shall be used to describe human immunodeficiency viruses 1 and 2 (HIV-I and HIV-2).
  • ARC and "AIDS” refer to syndromes of the immune system caused by the human immunodeficiency virus, which are characterized by susceptibility to certain diseases and T cell counts which are depressed compared to normal counts. HIV progresses from Category 1 (Asymptomatic HIV Disease) to Category 2 (ARC), to Category 3 (AIDS), with the severity of the disease.
  • a Category 1 HIV infection is characterized by the patient or subject being HIV positive, asymptomatic (no symptoms) and having never had fewer than 500 CD4 cells. If the patient has had any of the AIDS-defining diseases listed for categories 2 (ARC) or 3 (AIDS), then the patient is not in this category. If the patient's t-cell count has ever dropped below 500, that patient is considered either Category 2 (ARC) or Category 3 (AIDS).
  • a Category 2 (ARC) infection is characterized by the following criteria: The patient's T-cells have dropped below 500 but never below 200, and that patient has never had any Category 3 diseases (as set forth below) but have had at least one of the following defining illnesses —
  • a Category 3 (AIDS) infection is characterized by the following criteria: your T-cells have dropped below 200 or you have had at least one of the following defining illnesses — '
  • kansasii disseminated or extrapulmonary o Mycobacterium tuberculosis, any site (pulmonary** or extrapulmonary) o Mycobacterium, other species or unidentified species, disseminated or extrapulmonary o Pneumocystis carinii pneumonia o Pneumonia, recurrent** o Progressive multifocal leukoencephalopathy o Salmonella septicemia, recurrent o Toxoplasmosis of brain o Wasting syndrome due to HIV
  • coadministration shall mean that at least two compounds or compositions are administered to the patient at the same time, such that effective amounts or concentrations of each of the two or more compounds may be found in the patient at a given point in time.
  • compounds according to the present invention may be co-administered to a patient at the same time, the term embraces both administration of two or more agents at the same time or at different times, provided that effective concentrations of all coadministered compounds or compositions are found in the subject at a given time.
  • one or more of the diketo acid compounds described above are coadministered in combination with at least one additional anti-HIV agent as otherwise described herein in a cocktail for the treatment of HIV infections.
  • the co-administration of compounds results in synergistic anti-HIV activity of the therapy.
  • the present invention is directed to compounds of the general molecular formula I, combinations thereof, or pharmaceutically acceptable salts thereof, in the inhibition of HFV integrase, the prevention or treatment of HIV infections and in the treatment of AIDS and ARC.
  • Compounds of formula I are defined as follows:
  • nucleobase scaffold and R groups are defined as:
  • keto acids with uracil nucleobase scaffold (i) keto acids with uracil nucleobase scaffold
  • R 1 and R 2 are independently: a) H, b) C 1-6 alkyl. c) C i-6 fluoroalkyl, d) Ci- 6 alkyl S(O) n R, wherein n selected from 0-2, R is selected from alkyl, phenyl and substituted phenyl with substituents selected from:
  • each R b is 5 or 6 membered heteroaromatic ring containing 1 to 2 heteroatoms selected from oxygen, nitrogen and sulfiir, the ring could be substituted or not on carbon or nitrogen with 1 to 3 substituents selected from: 1) halogen,
  • R 3 is selected from: a) H, b) C 1-6 alkyl, c) Halogen, d) Hydroxyl, e) Phenylthio, f) Substituted phenylthio with 1 to 3 substituents selected from:
  • R 4 is selected from: a) CO 2 R C , wherein R c is selected from:
  • keto acids with xanthine nucleobase scaffold (ii) keto acids with xanthine nucleobase scaffold
  • R , R 2 and R 3 are independently: a) H, b) C 1-6 alky], c) Ci- ⁇ fluoroalkyl, d) Ci ⁇ alkyl S(O) n R, wherein n selected from 0-2, R selected from C 1 - 3 alkyl, phenyl and substituted phenyl with substituents selected from:
  • each R b is 5 or 6 membered heteroaromatic ring containing 1 to 2 heteroatoms selected from oxygen, nitrogen and sulfur, the ring could be substituted or not on carbon or nitrogen with 1 to 3 substituents selected from: 1) halogen,
  • R is selected from: a) C ⁇ 2 R c , wherein R c is selected from:
  • keto acids with hypoxanthine nucleobase scaffold keto acids with hypoxanthine nucleobase scaffold
  • R 1 , R 2 and R 3 are independently: a) H, b) C 1.6 alkyl, c) Ci- ⁇ fluoroalkyl, d) C i- 6 alkyl S(O) n R, wherein n selected from 0-2, R selected from Cu alkyl, phenyl and substituted phenyl with substituents selected from:
  • each R b is 5 or 6 membered heteroaromatic ring containing 1 to 2 heteroatoms selected from oxygen, nitrogen and sulfur, the ring could be substituted or not on carbon or nitrogen with 1 to 3 substituents selected from: 1) halogen,
  • R 4 is selected from: a) C ⁇ 2R c , wherein R c is selected from:
  • R 1 , R 2 and 1 R 3 are independently: a) H, b) C ⁇ _6 alkyl, c) C i- 6 fluoroalkyl,
  • Ci-6 alkyl S(O) n R wherein n selected from 0-2, R selected from C1-3 alkyl, phenyl and substituted phenyl with substituents selected from:
  • Ci- 6 alkyl CO n R 8 wherein n selected from 1 and 2, R a selected from: l) C,- 6 alkyl, 2) H, h) Phenyl, 5 i) Substituted phenyl with 1 to 3 substituents selected from:
  • each R b is 5 or 6 membered heteroaromatic ring containing 1 to 2 heteroatoms selected from oxygen, nitrogen and sulfur, the ring could be substituted or 30 not on carbon or nitrogen with 1 to 3 substituents selected from:
  • R 4 is selected from: a) C ⁇ 2 R c , wherein R c is selected from:
  • compositions useful for inhibiting HIV integrase comprising of an effective amount of a compound of this invention, optionally another anti-HFV agent (as discussed below) and a pharmaceutically acceptable carrier.
  • Pharmaceutical compositions useful for treating infection by HIV or for treating AIDS or ARC are also included by the present invention.
  • the present invention also includes methods for inhibiting the viral enzyme, HIV integrase, and a method of inhibiting HIV growth or replication, or treating an HIV infection or for treating AIDS or ARC.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising, in combination, a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of an agent for the treatment of AIDS selected from (i) an AIDS or HIV antiviral agent, (ii) an anti-infective agent, (iii) an immunomodulator, (iv) other useful therapeutic agents including antibiotics and other antiviral agents.
  • the compounds of the present invention may have regioisomers with respect to R 1 , R 2 and R 3 and these regioisomeric forms are included in the present invention.
  • the compounds of the present invention may have asymmetric centers and may occur as optical isomers and all of these isomeric forms are included in the present patent invention.
  • the compounds may have geometric isomers and these forms are included in the present invention.
  • Tautomeric forms may also exist with compounds of the present invention.
  • the terminology "and tautomers thereof is used in describing tautomeric forms of compounds of formula I such as Ia and Ib (shown below).
  • the compounds of the present invention are useful in the inhibition of HIV integrase, the prevention or treatment of infection by HIV and in the treatment of the disease known as AIDS. Treating AIDS or preventing or treating infection by HIV is defined as including the treatment of a wide range .of states of HIV infection: AIDS, ARC and actual or potential exposure to HIV (e.g., through blood transfusion, exchange of body fluids, bites, needle punctures, exposure to infected patient blood during medical or dental procedures, and other means). Other applications are also part of this invention.
  • the compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds including in the isolation of viral enzyme mutants and in further understanding of the enzyme, HIV integrase.
  • the present invention also provides for the use of a compound of structural formula (I) to make a pharmaceutical composition useful for inhibiting HIV integrase and in the treatment of AIDS or ARC.
  • the compounds of the present invention may be administered in the form of "well- known pharmaceutically acceptable” salts.
  • the latter is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate, estolate, palmitate, esylate, fumarate, phosphate, diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glyco
  • the pharmaceutically acceptable salts of this invention include those with counterions such as sodium, potassium, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.
  • bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane
  • esters can be employed, e.g., acetate, maleate, pivaloyloxymethyl and others, more preferably C 1 -C2 0 esters and those esters known in the art for improving solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • Pharmaceutically acceptable esters can also be employed in the case where a phosphonic acid group [-PO(OH ⁇ ] is present. Diketo phosphonic acids attached to nucleobase scaffolds are also part of this invention.
  • Therapeutically effective amounts of the compounds of the present invention may be administered to patients orally, parenterally, by inhalation spray, or rectally, in dosage unit formulations containing pharmaceutically-acceptable carriers, adjuvants and vehicles including nanoparticle drug delivery approaches.
  • pharmaceutically acceptable is meant to infer that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the patient or recipient.
  • Pharmaceutical compositions may be in the form of orally-administrable suspensions or tablets, nasal sprays and injectible preparations (rnjectible aqueous or oleagenous suspensions or suppositories). This method of treatment is part of the invention.
  • the administration approaches used orally as solution or suspension, immediate release tablets, nasal aerosol or inhalation, injectible solutions or suspensions or rectally administered in the form of suppositories) involve techniques that are well-known in the art of pharmaceutical formulation.
  • the compounds of this invention can be administered orally to humans in a preferred form (such as tablets) and in a preferred dosage range of about 0.1 to 200 mg/kg body weight in divided doses.
  • a preferred form such as tablets
  • a preferred dosage range of about 0.1 to 200 mg/kg body weight in divided doses.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including compound activity, compound metabolism and duration of action, patient age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the condition of the patient undergoing therapy.
  • the present invention also includes therapeutically effective combinations of the HIV integrase inhibitor compounds of formula I with one or more other therapeutic agents such as AIDS antivirals, other antiviral agents, immunomodulators, antiinfectives, antibiotics, vaccines or other therapeutic agents. Some examples are given hereinbelow.
  • Abacavir (1592U89) Glaxo Wellcome HIV infection, AIDS, GW 1592 ARC (RT inhibitor)
  • Cidofovir Gilead Science CMV retinitis, herpes, papillomavirus
  • Efavirenz DMP-266
  • AIDS ARC
  • ELlO Elan Corp PLC HIV infection (Gainesville, GA)
  • Famciclovir Smith Kline Herpes zoster, herpes simplex
  • HBY097 Hoechst Marion Roussel HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase inhibitor)
  • ISIS-2922 ISIS Pharmaceuticals CMV retinitis KNI-272 Natl. Cancer Institute HFV-associated diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor); also with AZT
  • PNU- 140690 Pharmacia Upjohn HIV infection, AIDS, ARC (protease inhibitor)
  • Valaciclovir Glaxo Wellcome Genital HSV & CMV infections Virazole Ribavirin Viratek/ICN (Costa Asymptomatic HIV Mesa, CA) positive, LAS, ARC VX-478 Vertex HTV infection, AIDS, ARC Zalcitabine Hoffinann-LaRoche HF/ infection, AIDS, ARC with AZT Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC, Kaposi's sarcoma, in combination with other therapies
  • Abacavir succinate or GSK HIV infection, AIDS, Ziagen ® ) (reverse transcriptase inhibitor)
  • Fuzeon ® or T-20
  • Roche/Trimeris HIV infection AIDS, viral Fusion inhibitor
  • Methionine-Enkephalin TNI Pharmaceutical AIDS, ARC (Chicago, IL)
  • Tumor Necrosis Factor Genentech ARC in combination (TNF) w/gamma Interferon ANTI-INFECTIVES
  • Pentamidine LyphoMed (Rosemont, PCP treatment Isethionate (IM & IV) IL)
  • Megestrol Acetate Bristol-Myers Squibb Treatment of anorexia associated w/AIDS Testosterone Alza, Smith Kline AIDS-related wasting Total Enteral Nutrition Norwich Eaton Diarrhea and
  • AIDS antivirals as described above and as otherwise set forth and described hereinbelow, other antivirals, immunomodulators, anti-infectives, antibiotics, vaccines, other therapeutic agents are not limited to the list in the above Table, but includes, in principle, any combination with any pharmaceutical composition useful for the treatment against infection by HIV or for treating AIDS or ARC.
  • Preferred combinations are simultaneous or alternating treatments of a compound of the present invention and a protease inhibitor (e.g., indinavir, nelfinavir, ritonavir, saquinavir among others), a reverse transcriptase inhibitor [nucleoside (e.g., AZT, 3TC, ddC, ddl, d4T, abacavir and others, and/or non-nucleoside (e.g., efavirenz, nevirapine, and others), or some combination of two or more of these inhibitors (see Table above).
  • a protease inhibitor e.g., indinavir, nelfinavir, ritonavir, saquinavir among others
  • a reverse transcriptase inhibitor e.g., AZT, 3TC, ddC, ddl, d4T, abacavir and others
  • non-nucleoside
  • the compound of the present invention and other active agents may be separately administered or concurrently administered in effective amount.
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • drugs or bioactive agents effective against HIV or having benefits when used in the treatment of HIV or secondary indications/conditions of HIV including AIDS/ARC and secondary conditions or disease states such as Kaposi's sarcoma, hepatitis B virus infections, etc., which may be combined with compounds according to the present invention in providing pharmaceutical compositions and methods of treating HIV infections or their secondary conditions or disease states.
  • these drugs or bioactive agents are included in effective amounts to resolve the condition or disease state for which the compounds have been administered.
  • HEPT-M • l-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine
  • HEPT-S
  • Adefovir dipivoxil BisPom PMEA; GS-840; Preveon®
  • Foscarnet Phosphonoformic acid
  • Foscavir Phosphonoformic acid
  • drugs and/or bioactive agents useful in the treatment of HIV infections, or conditions or disease states which are secondary to HIV infections is set forth hereinbelow.
  • One or more of these agents may be used in combination (coadminstered) with at least one diketo acid anti-HIV agent as otherwise disclosed herein to treat HIV or one of its secondary conditions or disease states, including AIDS/ARC, Kaposi's sarcoma, hepatitis B virus infections, other microbial infections (such as tuberculosis) etc.
  • these compounds are also included in effective amounts. These include: ACV; AK602; AMD070; APV; ATV; ATZ; AVX754 (apricitabine);
  • Abacavir Abacavir / Lamivudine / Zidovudine
  • Abacavir sulfate Abacavir sulfate/Lamivudine
  • Abacavir/Lamivudine Abelecet; Acyclovir; Adefovir dipivoxil;
  • Adriamycin Adriamycin; Agenerase; Aldesleukin; Alovudine; Aluvia; AmBisome; Amdoxovir; 5 Amphocin; Amphotec; Amphotericin B; Ampligen; Amprenavir; Androderm; Androgel;
  • Apricitabine Aptivus; Atazanavir; Atripla; Azithromycin; BMS-378806; BMS-488043;
  • Elvucitabine Emtricitabine; Tenofovir disoproxil fumarate; Emtriva; Enfufirtide; Entecavir;
  • Epoetin alfa Epogen; Epzicom; Etopophos (phosphate salt); Etoposide; Etravirine;
  • FTC Fluconazole; Fortovase; Fosamprenavir; Foxivudine tidoxil; Fungizone; Fuzeon; GS 15 9137; GSK-873,140 (aplaviroc); GW433908; GW640385 (brecanavir); Ganciclovir;
  • INH Immune Globulin Intravenous (Human); Indinavir; Interferon alfa-2; Interleukin-2, recombinant human; Intron A (2b); Invirase; Isoniazid; Itraconazole; KP- 1461;
  • Lamivudine/Zidovudine Lexiva; Lopinavir/Ritonavir; MK-0518; Nebupent; Nelfinavir; 20 Neutrexin; Nevirapine; Norvir; Nydrazid; Peptide T; PMPA Prodrug (Viread)' Prezista
  • Trimetrexate Trizivir; Truvada (Emtriva and Viread combination); U-90152S (Delaviridine);
  • ⁇ - hereinbelow.
  • these agents may be used in combination (coadminstered) with at least one diketo acid anti-HIV agent as otherwise disclosed herein to treat HIV or one of its secondary conditions or disease states, including AIDS/ARC, Kaposi's sarcoma, hepatitis B virus infections, other microbial infections (such as tuberculosis) etc. When used, these compounds are also included in effective amounts.
  • Abacavir Abacavir / Lamivudine / Zidovudine
  • Abacavir sulfate Abacavir sulfate/Lamivudine
  • Abacavir/Lamivudine Abelecet; Acyclovir; Adefovir dipivoxil;
  • Adriamycin Adriamycin; Agenerase; Aldesleukin; Alovudine; Aluvia; AmBisome; Amdoxovir; Amphocin; Amphotec; Amphotericin B; Ampligen; Amprenavir; Androderm; Androgel;
  • Apricitabine Aptivus; Atazanavir; Atripla; Azithromycin; BMS-378806; BMS-488043;
  • Elvucitabine Emtricitabine; Emtricitabine;Tenofovir disoproxil fumarate; Emtriva;
  • Etoposide Etravirine; FTC; Fluconazole; Fortovase; Fosamprenavir; Foxivudine tidoxil; Fungizone; Fuzeon; GS 9137; GSK-873,140 (aplaviroc); GW433908; GW640385
  • brecanavir Ganciclovir
  • Globulin Immune
  • Growth hormone ⁇ human
  • Hepsera Hivid
  • Interferon alfa-2 Interleukin-2, recombinant human; Intron A (2b); Invirase; Isoniazid;
  • VePesid VePesid; Vicriviroc; Videx; Viracept (Tennofovir DF); Viramune; Virazole; Viread;
  • the following representative examples are provided to illustrate details for the preparation of the compounds of the present invention. The examples are not intended to be limitations on the scope of the present invention and they should not be so construed. Furthermore, the compounds described in the following examples are not to be viewed as forming the only set of compounds that is considered as the invention, and any combination of components of the compounds or their moieties may itself form a set. This has been addressed previously in this patent document. Those skilled in the art will readily comprehend that known variations of reaction conditions and synthetic conversions described in the following preparative procedures can be used to prepare these other compounds.
  • Stepl preparation of 5-acetyl-l,3-dibenzyluracil (2a).
  • Step 2 preparation of methyl 4-(l,3-dibenzyl-l,2,3,4-tetrahydro-2,4-dioxopyrimidin- 5-yl)-2-hydroxy-4-oxobut-2-enoate (3a) .
  • Step 1 preparation of l,3-bis(2-fluorobenzyl)-5-acetyluracil (2b)
  • Step 2 preparation of methyl 4-[l,3-bis(2-fluorobenzyl)-l,2,3,4-tetrahydro-2,4- dioxopyrimidin-5 -yl]-2-hydroxy-4-oxobut-2-enoate (3b).
  • the title compound for this step was synthesized using a similar procedure to that described in the Example 1, step 2, except that 5-acetyl-l,3.-dibenzyluracil was replaced with l,3-bis(2-fluorobenzyl)-5-acetyluracil.
  • the title compound was crystallized from the mixture of hexane and ethyl acetate (3 : 1) and obtained in 21.1% yield. Mp. 158-160 0 C.
  • the title compound was synthesized using a similar procedure to that described in Example 2, except that methyl 4-(l,3-dibenzyl-l,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl)- 2-hydroxy-4-oxobut-2-enoate was replaced with methyl 4-[l,3-bis(2-fluorobenzyl)-l,2,3,4- tetrahydro-2,4-dioxopyrimidin-5-yl]-2-hydroxy-4-oxobut-2-enoate (3b).
  • the title compound was crystallized from hexane and ethyl acetate (2 : 1) to give an off-white solid. The yield was 56.5%. Mp.
  • Step 2 preparation of methyl 4-[ l,3-bis(4-fluorobenzyl)- 1,2,3 ,4-tetrahydro-2,4- dioxopyrimidin-5-yl]-2-hydroxy-4-oxobut-2-enoate (3c).
  • Example 2 except that methyl 4-(l,3-dibenzyl- 1,2,3 ,4-tetrahydro-2,4-dioxopyrimidin-5-yl)- 2-hydroxy-4-oxobut-2-enoate was replaced with methyl 4-[l,3-bis(4-fluorobenzyl)-l,2,3,4- tetrahydro-2,4-dioxopyrimidin-5-yl]-2-hydroxy-4-oxobut-2-enoate (3c).
  • the title compound was crystalized from hexane and ethyl acetate (3 : 1). The yield was 49.7%. Mp. 186-188 0 C.
  • Step 1 preparation of 1 ,3-bis(4-(trifiuoromethyl)benzy l)-5-acetyluracil (2d).
  • Step 2 preparation of methyl 4-[l,3-bis(4-(trifluoromethyl)benzyl)-l,2,3,4- tetrahydro-2,4-dioxopyrimidin-5-yl]-2-hydroxy-4-oxobut-2-enoate (3d).
  • Example 2 except that methyl 4-(l,3-dibenzyl-l ,2,3,4-tetrahydro-2,4-dioxo ⁇ yrimidin-5-yl)- 2-hydroxy-4-oxobut-2-enoate was replaced with methyl 4-[l,3-bis(4- (trifluoromethyl)benzyl)-l,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl]-2-hydroxy-4-oxobut-2- enoate (3d).
  • the title compound was recrystalized from hexane and ethyl acetate (3 : 1). The yield was 68.2%. Mp. 176-178 0 C.
  • Step 1 preparation of 5-acetyl-l-benzyluracil (2e).
  • Step 2 preparation of methyl 4-( 1 -benzyl- 1,2,3 ,4-tetrahydro-2,4-dioxopyrimidin-5- yl)-2-hydroxy-4-oxobut-2-enoate (3e).
  • Example 2 replacing methyl 4-(l,3-dibenzyl-l,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl)-2- hydroxy-4-oxobut-2-enoate with methyl 4-(l-benzyl-l,2,3,4-tetrahydro-2,4-dioxopyrimidin- 5-yl)-2-hydroxy-4-oxobut-2-enoate (3e).
  • the title compound was crystallized from mixture of tetrahydofuran and chloroform (2 : 3). The yield was 79.7%. Mp. 195-197 0 C. 1 HNMR
  • Step 1 preparation of 3-(4-fluorobenzyl)-5-acetyl-l-ben2yluracil (2f).
  • Step 2 preparation of methyl 4-[3-(4-fluorobenzyl)-l -benzyl- l,2,3,4-tetrahydro-2,4- dioxopyrimidin-5-yl]-2-hydroxy-4-oxobut-2-enoate (3f).
  • Example 1 step 2 replacing 5-acetyl-l,3-dibenzyluracil with 3-(4-fluorobenzyl)-5-acetyl-l- benzyluracil.
  • the title compound was crystallized from ethanol and obtained in 30.5% yield. Mp. 165-167 0 C.
  • 1 HNMR (CDCl 3 ): 15.04 (br, s, IH), 8.36 (s, IH), 7.72 (s, IH), 7.28-7.52 (m, 7H), 7.01 (t, 2H, J 8.5 Hz), 5.15 (s, 2H), 5.06 (s, 2H), 3.93 (s, 3H).
  • Step 3 9-Benzyl-6-( ⁇ -ethoxyvinyl)purine (8).
  • Step 5 Methyl 4-(9-benzyl-9H-purin-6-yl)-2-hydroxy-4-oxo-but-2-enoate (10).
  • Step 1 Described in step 1 of Example 13.
  • Step 2 Synthesis of 9-benzylpurine (12)
  • N-bromosuccinamide (45.20 g, 253.9 mmol) and the reaction mixture stirred under an atmosphere of nitrogen and at reflux temperature for 5 h.
  • the reaction mixture was transferred to a separatory funnel and washed with saturated sodium sulfite solution (2 x 250 mL) followed by brine solution (2 x 250 mL).
  • the chloroform fraction was dried over anhydrous sodium sulfate and concentrated and the reddish oil was purified by flash chromatography on silica gel using EtOAc/hexane (4:6) for elution. Yield 6.05 g. (41.2 %).
  • Step 6 Methyl 4-(9-benzyl-9H-purine-8-yl)-2-hydroxy-4-oxo-but-3-enoate (16).
  • Methyl-4-(9-benzyl-9H-purin-6-yl)-4-ethoxy-2-oxo-but-3-enoate (210 mg, 0.50 mmole ) obtained in above step was stirred at room temperature in CH 2 Cl 2 (60 mL) and treated with FeCl 3 -OH 2 O ( 0.262 g, 0.9 mmole). The reaction mixture stirred at 40 0 C for 6 h and concentrated and the residue obtained was treated with 1 N HCl (50 mL) for 5 min and extracted with EtOAc (4 x 20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give a yellowish residue which was purified by ion exchange chromatography.
  • Step 7 Synthesis of 4-(9-benzyl-9H-purine-8-yl)-2-hydroxy-4-oxo-but-3-enoic acid (17).
  • reaction mixture allowed to stir at 0 0 C for 30 min and then at ambient temperature for 30 min.
  • the reaction mixture was neutralized with 1 N HCl and the precipitated solid was filtered dried and triturated with chloroform to give yellow solid.
  • Step 1 Described in step 1 of example 13.
  • Step 2 Synthesis of 9-benzyl-8-bromoadenine (18).
  • Step 4 l,9-Dibenzyl-6,9-dihydro-6-oxo-8-bromopurine (20).
  • Step 5 Synthesis of l,9-dibenzyl-6,9-dihydro-6-oxo-8-( ⁇ -ethoxyvinyl)purine (21)
  • Step 7 Methyl 4-(l ,9-benzyl-6,9-dihydro-6-oxo-lH-purin-8-yl)-2-hydroxy-4-oxo- but-3-enoate (23).
  • Step 8 Synthesis of 4-(l,9-benzyl-6,9-dihydro-6-oxo-lH-purin-8-yl)-4-hydroxy-2- oxo-but-3-enoic acid (24).
  • Step 2 preparation of ethyl 3-(l,3-dibenzyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl)-3,3- ethylenedioxy-propionate (28)
  • Step 4 preparation of dimethyl 3-(l,3-dibenzyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl)- 1 -hydroxy-3-oxopropylphosphonate (31)
  • Step 5 preparation of sodium methyl 3-(l,3-dibenzyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidin- 5-yl)- 1 -hydroxy-3-oxoprop- 1 -enylphosphonate (33)
  • Step 6 preparation of 3-(l,3-dibenzyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl)-l- hydroxy-3-oxoprop-l-enylphosphonic acid as its monosodium salt (35)

Abstract

La présente invention concerne une nouvelle classe d'acides dicéto construite sur des squelettes de nucléobase, conçus comme inhibiteurs de réplication VIH par l'inhibition de l'intégrase du VIH. Ces composés sont utiles dans la prévention ou le traitement d'une infection par HFV et dans le traitement du SIDA et du para-sida (ARC), soit en tant que composés ou sels pharmaceutiquement acceptables, avec des supports pharmaceutiquement acceptables, en combinaison avec des agents antiviraux, immunomodulateurs, antibiotiques, vaccins et autres agents thérapeutiques, particulièrement d'autres composés anti-VIH (y compris d'autres agents de l'intégrase anti-VIH) qui peuvent être utilisés pour créer des cocktails de combinaison anti-VIH comme indiqué ici. Des procédés de traitement du SIDA et de l'ARC et des procédés de traitement ou de prévention d'une infection par le VIH sont également décrits. Citons parmi les composés de la présente application, ceux de formule I et des tautomères, régioisomères, isomères géométriques et, le cas échéant, des isomères optiques dérivés et des sels pharmaceutiquement acceptables, sachant que le squelette de nucléobase et les groupes R sont tels qu'autrement définis dans la spécification. Ils sont combinés avec tout un ensemble d'autres agents anti-VIH typiques afin de fournir une modalité de traitement efficace des infections HIV, y compris le SIDA et le para-sida.
PCT/US2007/006245 2006-03-10 2007-03-09 Acides diceto a squelettes nucleobase : inhibiteurs de replication anti-vih cibles au niveau de l'integrase du vih en therapie de combinaison WO2007106450A2 (fr)

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US8106064B2 (en) 2006-07-24 2012-01-31 Korea Research Institute Of Chemical Technology Pyrimidine-2,4-dione HIV reverse transcriptase inhibitors
US8119800B2 (en) 2007-12-21 2012-02-21 Korea Research Institute Of Chemical Technology Processes for preparing HIV reverse transcriptase inhibitors
US8334295B2 (en) 2007-06-29 2012-12-18 Korea Research Institute Of Chemical Technology Pyrimidine derivatives as HIV reverse transcriptase inhibitors
US8354421B2 (en) 2007-06-29 2013-01-15 Korea Research Insitute Of Chemical Technology HIV reverse transcriptase inhibitors
US8703801B2 (en) 2009-12-07 2014-04-22 University Of Georgia Research Foundation, Inc. Pyridinone hydroxycyclopentyl carboxamides: HIV integrase inhibitors with therapeutic applications
US9593137B2 (en) 2011-12-22 2017-03-14 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
JP2017057200A (ja) * 2015-09-18 2017-03-23 ヤマサ醤油株式会社 抗ｄｎａウィルス活性などの生理活性を有するヌクレオシド誘導体
CN111269264A (zh) * 2014-08-25 2020-06-12 美迪维尔公司 用于治疗癌症的尿苷的二氧戊环类似物

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8106064B2 (en) 2006-07-24 2012-01-31 Korea Research Institute Of Chemical Technology Pyrimidine-2,4-dione HIV reverse transcriptase inhibitors
US8334295B2 (en) 2007-06-29 2012-12-18 Korea Research Institute Of Chemical Technology Pyrimidine derivatives as HIV reverse transcriptase inhibitors
US8354421B2 (en) 2007-06-29 2013-01-15 Korea Research Insitute Of Chemical Technology HIV reverse transcriptase inhibitors
US8119800B2 (en) 2007-12-21 2012-02-21 Korea Research Institute Of Chemical Technology Processes for preparing HIV reverse transcriptase inhibitors
US8703801B2 (en) 2009-12-07 2014-04-22 University Of Georgia Research Foundation, Inc. Pyridinone hydroxycyclopentyl carboxamides: HIV integrase inhibitors with therapeutic applications
US9593137B2 (en) 2011-12-22 2017-03-14 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US10035814B2 (en) 2011-12-22 2018-07-31 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US10562926B2 (en) 2011-12-22 2020-02-18 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US11279720B2 (en) 2011-12-22 2022-03-22 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
CN111269264A (zh) * 2014-08-25 2020-06-12 美迪维尔公司 用于治疗癌症的尿苷的二氧戊环类似物
JP2017057200A (ja) * 2015-09-18 2017-03-23 ヤマサ醤油株式会社 抗ｄｎａウィルス活性などの生理活性を有するヌクレオシド誘導体

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