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WO2011071849A2 - Pyridinone hydroxycyclopentylcarboxamides : inhibiteurs de l'intégrase du vih ayant des applications thérapeutiques - Google Patents

Pyridinone hydroxycyclopentylcarboxamides : inhibiteurs de l'intégrase du vih ayant des applications thérapeutiques Download PDF

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Publication number
WO2011071849A2
WO2011071849A2 PCT/US2010/059183 US2010059183W WO2011071849A2 WO 2011071849 A2 WO2011071849 A2 WO 2011071849A2 US 2010059183 W US2010059183 W US 2010059183W WO 2011071849 A2 WO2011071849 A2 WO 2011071849A2
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Prior art keywords
deriv
azido
dideoxy
azt
acid
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PCT/US2010/059183
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English (en)
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WO2011071849A3 (fr
Inventor
Vasu Nair
Maurice O. Okello
Abdumalik A. Nishonov
Sanjaykumar Mishra
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University Of Georgia Research Foundation, Inc.
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Priority to EP10836497.7A priority Critical patent/EP2509949B1/fr
Priority to NZ600873A priority patent/NZ600873A/en
Priority to US13/513,448 priority patent/US8703801B2/en
Priority to PH1/2012/501095A priority patent/PH12012501095A1/en
Priority to AU2010328325A priority patent/AU2010328325B2/en
Priority to CN201080063257.1A priority patent/CN102753526B/zh
Priority to EA201270651A priority patent/EA201270651A1/ru
Priority to CA2783540A priority patent/CA2783540C/fr
Application filed by University Of Georgia Research Foundation, Inc. filed Critical University Of Georgia Research Foundation, Inc.
Priority to SG2012041331A priority patent/SG181524A1/en
Priority to MX2012006485A priority patent/MX2012006485A/es
Priority to JP2012543189A priority patent/JP2013512957A/ja
Publication of WO2011071849A2 publication Critical patent/WO2011071849A2/fr
Publication of WO2011071849A3 publication Critical patent/WO2011071849A3/fr
Priority to IL220113A priority patent/IL220113A0/en
Priority to ZA2012/04147A priority patent/ZA201204147B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom

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 The human immunodeficiency virus, HIV, encodes three key viral enzymes through its ol gene and these enzymes are critical for the replication of this virus [Katz & Skalka, Annu. Rev. Biochem., 63, 133-173 (1994); Frankcl. Annu. Rev. Biochem., 67, 1-25 (1998)].
  • Drug discovery involving two o these enzymes, HIV reverse transcriptase (RT) and HIV protease (PR) have led to clinically approved therapeutic agents for the treatment of acquired immunodeficiency syndrome (AIDS) and AIDS related complex (ARC) in HA ART (highly- active antiretro viral therapy) [Johnson & Gerbcr, in "Advances in internal Medicine," vol. 44. Mosby: St.
  • I I IV- 1 integrase is involved in the integration of HIV DNA into human chromosomal DNA. Because integrase has no human counterpart and because it is required for HIV replication, it is an attractive target for the discovery of anti-HIV agents.
  • a variety of compounds are inhibitors of HIV integrase including oligonucleotides, diiiucleotides, heterocycles, natural products, diketo acids, functionalized naphthyridines and pyrimidines and others [Nair, Rev. Med. Virol, 17, 277-295 (2007); Egbertson, Curr. Top. Med. Chem. 7, 1251-1272 (2007)].
  • Some diketo acids with aryl or heteroaryl substitutions are inhibitors of HIV integrase, but most commonly of only the strand transfer step [Wai, et al, "4-Aryl-2,4-dioxobutanoic acid inhibitors of HIV- 1 integrase and viral replication in cells," J. Med.
  • Inhibitors of HIV-l Integrase Ant i -HIV Data, SAR Analysis, Microsome Stability,
  • Patents of relevance to this invention disclosure are: Selnick, H. G. et al., (Merck & Co. Inc.), "Preparation of nitrogen -containing 4-licteroai yl-2.4-dioxobutyric acids useful as HIV integrase inhibitors," WO 9962513; Young, S. D., et al., (Merck & Co. Inc.), "Preparation of aromatic and heteroaromatic 4-aryl-2.4-dioxobutyrie acid derivatives useful as HIV integrase inhibitors," WO 9962897; Fujishita, T., et al., Yoshinaga, T., et al. (Shionogi & Co.
  • the class of compounds described in this invention disclosure are chiral and achiral oxy- substituted cyclopentyl pyridinone diketocarboxamides and their derivatives.
  • the compounds have been designed as inhibitors of H IV- 1 integrase and have been discovered to possess significant in vitro anti-HIV activity. Two examples are shown below ( Figure la and b).
  • the chiral compound S,S- isomer.
  • Figure l a) exhibits anti-HIV activity in cell culture with an EC50 of 25 nM (TI >1 ,500).
  • the achiral compound ( Figure lb) is more active and has an EC 50 of 10 nM (TI > 10,000).
  • Chiral and achiral oxy-substituted cyclopentyl pyridinone d ik etocarbox am ides and their derivatives and methods for their preparations are disclosed.
  • the compounds are represented by formula I and include chiral and achiral compounds, tautomers, regioisomers, geometric isomers, wherein the modified nucleobase scaffold and R, X and Z groups are as otherwise defined in the specification.
  • These complex carboxamides are designed as inhibitors of HIV replication through inhibition of HIV integrase.
  • the compounds are useful in the prevention, inhibition or treatment of infection by HIV and in the treatment of AIDS and ARC, either as the compounds, or as pharmaceutically acceptable salts, with pharmaceutically acceptable carriers, used alone or in combination with antivirals, immunomodulators, antibiotics, vaccines, and other therapeutic agents, especially other anti-HIV compounds (including other anti-H IV integrase agents), which can be used to create combination anti-HIV cocktails.
  • pharmaceutically acceptable carriers used alone or in combination with antivirals, immunomodulators, antibiotics, vaccines, and other therapeutic agents, especially other anti-HIV compounds (including other anti-H IV integrase agents), which can be used to create combination anti-HIV cocktails.
  • Compounds according to the present invention exhibit one or more of the following characteristics desired in anti-HIV compounds: increased anti-HIV activity, enhanced bioavailability, enhanced therapeutic index, enhanced stability to metabolic degradation and little drug-to-drug interaction in comparison with prior art compounds of similar (anti-H IV ) activity.
  • the present compounds represent a material advance in the treatment and/or prevention of HIV and related secondary conditions and/or disease states.
  • compositions which include one or more compounds according to the present invention in combination with a pharmaceutically acceptable carrier, additive or excipient, optionally in combination with at least one additional agent as otherwise described herein represent an additional aspect of the invention.
  • a kit comprising a pharmaceutical composition according to the present invention and instructions on how to administer the composition to a patient in need represent a further aspect of the invention.
  • compound refers to any specific chemical compound disclosed herein and includes tautomers, regioisomers, geometric isomers, and where applicable, optical isomers thereof, as well as
  • the term 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.
  • the breadth of the term "compound” shall be construed within the context of the use of the term. It is noted that in the present invention, where relevant, chiral atoms are represented by an asterisk (*) next to the carbon atom. The symbol is used to signify a single or double bond according to the context in which the bond is used.
  • scaffold is used to mean a pyridinone chemical structure containing at least three substituents on this scaffold, one of which is the diketocarboxamide moiety as otherwise defined herein, and the other two are benzyl groups of which R ] , R 2 , R 3 and R 4 are as defined herein.
  • prevention is used within context to mean “reducing the likelihood” of a condition or disease state from occurring as a consequence of administration or concurrent administration of one or more compounds or compositions according to the present invention, alone or in combination with another agent.
  • prevention is used within the context of a qualitative measure and it is understood that the use of a compound according to the present invention to reduce the likelihood of an occurrence of a condition or disease state as otherwise described herein will not be absolute, but will reflect the ability of the compound to reduce the likelihood of the occurrence within a population of patients or subjects in need of such prevention.
  • human immunodeficiency virus or "HIV” shall be used to describe human immunodeficiency viruses 1 and 2 (HIV-1 and I IlV-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 di sease.
  • 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.
  • 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— o Bacillary angiomatosis
  • Herpes zoster shingles
  • shingles involving at least two distinct episodes or more than one dermatome
  • a Category 3 (AIDS) infection is characterized by the following criteria:
  • Herpes simplex chronic ulcer(s) (greater than 1 month's duration); or bronchitis, pneumonitis, or esophagitis
  • o Lymphoma primary, of brain
  • Mycobacterium tuberculosis any site (pulmonary** or extrapulmonary ) o Mycobacterium, other species or unidentified species, disseminated or
  • 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 preferably that effective concentrations of coadministered compounds or compositions are found in the subject at a given time.
  • coadministration also encompasses, in certain instances, the serial administration of agents which are administered serially in a patient to produce an intended effect, regardless of the time of administration and concentration of agent found in the subject.
  • the term "independently” is used herein to indicate that a variable, which is independently applied, varies independently from application to application.
  • the present invention is directed to compounds of the general molecular formula I, combinations thereof, or pharmaceutically acceptable salts thereof, in the inhibition of HIV integrase, the inhibition, prevention which reduces the likelihood of or treatment of HIV infections and in the treatment of AIDS and ARC.
  • Compounds of formula I are defined as follows:
  • R , . R 2 , R 3 and R4 are each independently H or a halogen (F, CI, Br or I, preferably
  • X and Z are each independently represented by the following:
  • Ri, R 2 , R 3 and R4 are as
  • Ri o-F
  • R 2 H
  • R p-F
  • R 4 o-F (by way of convention, for example, o-F represents an ortho substituted fluorine, p-F represents a para substituted fluorine)
  • Ri o-F
  • R 2 o-F
  • R 3 o-F
  • R4 H
  • R, o-F
  • R 2 p-F
  • R 3 p-F
  • R o-F
  • R T o-F
  • R 2 o-F
  • R 3 o-F
  • compositions useful for inhibiting HIV integrase comprising an effective amount of a compound of this invention as described herein, and a pharmaceutically acceptable earner, additive or excipient.
  • 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 and/or replication, or treating an HIV infection or for treating AIDS or ARC in a patient in need thereof.
  • the present invention is directed to 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 o f 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 also embrace regioisomers with respect to the pyridinone scaffold and Ri , R 2 , R 3 and R 4 and these regioisomeric forms are included in the present invention.
  • the compounds also embrace geometric isomers and these forms are also included in the present invention.
  • Tautomeric forms may also exist with compounds of the present invention.
  • the termmology "and tautomers thereof is used in describing tautomeric forms of compounds of formula I such as la and lb (shown below).
  • compounds as being represented by the general formula I and tautomers thereof, it is understood that for the purposes of the present invention that tautomers la and lb are also included.
  • compound (la) it is understood for the purposes of the present application that tautomers (I) and (lb) are also intended to be included. The same holds true for references to tautomer (lb).
  • the compounds of the present invention have both chiral (asymmetric) and achiral (symmetric) centers.
  • opt ical isomers resulting from the presence of asymmetric centers represent a further aspect of the present invention. Examples of both chiral and achiral compounds are shown below in Figure 2.
  • Particular compounds of structural formula I include:
  • the compounds of the present invention are useful in the inhibition of HIV integrase, the prevention, the likelihood of reduction of and/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, such patients or subjects being considered at risk for HIV infection).
  • 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 o 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 inliibiting 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.
  • pharmaceutically acceptable such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bi sulfate, 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
  • 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, d i el hanol amine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide, among numerous others.
  • bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N, N'- dibenzylethylenediamine, chloroprocaine, d i el hanol amine, procaine, N- benzylphenethylamine
  • esters may be employed, e.g., acetate, maleate, pivaloyloxymethyl and others, more preferably C - C 20 esters (preferably C 2 to Ci? esters) and those esters known in the art for improving solubility or hydrolysis characteristics for use as sustained release or pro-drug formulations.
  • Therapeutically effective amounts of the compounds of the present invention may be administered to patients orally, parenterally, by inhalation spray, topically, or rectally, in dosage unit formulations containing pharmaceulically-acccptable carriers, adjuvants and vehicles including nanoparticlc drug delivery approaches.
  • compositions are in pharmaceutical dosage form and may be administered in the form of orally-administrable suspensions or tablets, nasal sprays and injectible preparations (injectible aqueous or oleagenous suspensions or suppositories). This method of treatment is part of the invention.
  • the administration approaches used e.g., orally as solution or suspension, immediate release tablets, nasal aerosol or inhalation, injectible solutions or suspensions or rectally administered in the form of suppositories
  • the compounds of this invention can be administered orally to humans in a preferred form (such as tablets) and in an effective amount within a preferred dosage range of about 0.05 to 200 mg/kg, more preferably about 0.1 to about 25 mg/kg body weight in divided doses.
  • a preferred dosage range of about 0.05 to 200 mg/kg, more preferably about 0.1 to about 25 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 1 with one or more other therapeutic agents such as AIDS antiviral s, other antiviral agents, i mm u nomodu 1 ators, antiin cctivcs, antibiotics, vaccines or other therapeutic agents. Some examples are given below.
  • Abacavir (1592U89) Glaxo Wellcome HIV infection, AIDS,
  • AL-721 Ethigen (Los Angeles, ARC, PGL H IV positive.
  • Cidofovir Gilead Science CMV retinitis, herpes, papillomavirus
  • DMP-450 AVID (Camden. NJ) HIV infection, AIDS,
  • ARC non-nucleoside RT inhibitor
  • Famciclovir Smith Kline Herpes zoster, herpes simplex
  • ARC non-nucleoside reverse transcriptase inhibitor
  • Isentress (Raltegravir) Merck HIV infection, AIDS,
  • ARC reverse transcriptase inhibitor
  • PNU- 140690 Pharmacia Upjohn HIV infection, AIDS.
  • VX-478 Vertex HIV infection, AIDS,
  • Abacavir succinate or GSK H IV infection, AIDS
  • Fuzeon 8 (or T-20) Roche/Trimeris H IV infection, AIDS, viral Fusion inhibitor
  • IMREG- 1 Imreg New Orleans, LA
  • Kaposi's sarcoma Kaposi's sarcoma
  • IMREG-2 Imreg New Orleans, LA AIDS. Kaposi's sarcoma
  • Methionine-Enkephalin TNI Pharmaceutical AIDS, ARC
  • Tumor Necrosis Factor Genentech ARC in combination (TNF) w/gamma Interferon
  • AK602 Kumam HIV infection (entry and oto fusion inhibitor)
  • Atazanavir (Reyataz) Bristol -Myers Squibb H IV infection (protease inhibitor) AVX754 (apricitabine) Ave a Ltd. HIV infection
  • Fosamprenavir (Lexiva) GlaxoSmithKline HIV infection (protease inhibitor)
  • GW640385 GlaxoSmithKline H I V infection (protease inhibitor)
  • VGX410 Viral Genomix HIV infection (gene RU486) therapy,interferes with vpr
  • PA-457 Panacos Phamiaceuticals, Treatment of HIV
  • PRO 140 Progenies HIV infection (entry and
  • PRO 542 Progenies HIV infection (entry and
  • TA -652 Takeda HIV infection (entry and fusion inhibitor) Tipranavir (Aptivus) Boehringer Ingelheim HIV infection (protease Pharmaceuticals inhibitor)
  • TMC125 etravirine Tibotec HIV infection (non- nucleoside RT inhibitor)
  • Amphotericin B (Abelecet, Pfizer, Bristol - Myers Antifungal
  • Epoetin alfa (Epogen, Ortho Biotech Anemia
  • Megestrol (Megace, Bristol - Myers Squibb Anticachectic
  • Testosterone (Androderm, Pfizer Inc, Unimed Androg
  • AIDS antivirals including anti-HIV integrase-based antivirals
  • other antivirals including anti-HIV integrase-based antivirals
  • immunomodulators including anti-infectives, antibiotics, vaccines, other therapeutic agents
  • antibiotics including antibiotics, vaccines, other therapeutic agents
  • 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 H I V 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 and 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 and 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 (coadministered).
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • Sorivudine SQ-32756; Bravavir; Brovavir; Usevir; YN-72; Bromovinyl araU; BVAU
  • Adefovir PMEA; GS-0393
  • Adefovir dipivoxil BisPom PMEA; GS-840; Preveon®
  • E-EPSeU HEPT deriv.
  • MKC-442 deriv.
  • 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 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 ( at the following website):
  • Abacavir/Lamivudine Abelecet; Acyclovir; Adefovir dipivoxil; Adriamycin; Agenerase;
  • Amphotericin B Ampligen; Amprenavir; Androderm; Androgel; Apricitabine; Aptivus; Atazanavir; Atripla; Azithromycin; BMS-378806; BMS-488043; Bactrim; Baraclude;
  • DAPD DAPD
  • DLV DLV
  • DS Daranavir
  • Delavirdine Depo-Testosterone
  • Dextran sulfate Didanosine; Diflucan
  • Doxil Doxorubicin (liposomal); Dronabinol
  • EFV Efavirenz
  • Elvucitabine
  • Emtricitabine 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
  • 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; Isentress; Isoniazid; Itraconazole; KP-1461 ;
  • Lamivudine/Zidovudine Lamivudine/Zidovudine; Lexiva; Lopinavir/Ritonavir; MK-0518; ebupent: Nelfinavir;
  • Somatropin Stavudinie; Sulfamethoxazole / Trimethoprim; Sustanon; Sustiva; TNX-355;
  • Taxol Tenofovir; Tenofovir disoproxil fumarate; Testosterone; Tipranavir; Toposar;
  • Trimetrexate Trizivir; Truvada (Emtriva and Viread combination); U-90152S (Delaviridine);
  • Step 1 Preparation of (2,4-difluorophenyl)(6-methoxypyridin-3-yl)methanol (2).
  • Step 2 Preparation of 5-(2,4-difluoiObenzyl)pyridin-2(lZ/)-one (3).
  • Step 3 Preparation of 5-(2,4-difluorobenzyl)-3-iodopyridiii-2(lH)-one (4).
  • Step 5 Preparation of 3-acetyl-5-(2,4-difluorobenzyl)-l-(2-fluorobenzy])pyridin-2(lH)-one (6).
  • Step 6 Preparation of methyl 4-(5-(2,4-difluorobenzyl)-l -(2-fluorobenzyl)-2- dihydropyndin-3-yl)-2-hydroxy-4-oxobut-2-enoate (7).
  • Step 7 Preparation of 4-(5-(2,4-difJuorobenzyl)-l -(2-fluorobenzyl)-2-oxo-l ,2- dihydropyridm-3-yl)-2-hydroxy-4-oxobut-2-enoic acid (8).
  • the titled compound was synthesized using the procedure described above using compound 8.
  • the coupling compound, (lR, 2R)-2-aminocyclopentanol hydrochloride, was synthesized by modification of the following procedure: Overman L.E.; Sugai, S.,J. Org. Chem.50,
  • Target compound 12 was prepared from 11 using the procedure described above for 9 to give 12 as a yellow solid, mp 67- 69 °C, [ 20 D ] -28.3, (c 0.12, MeOH), UV (MeOH) 395 nm ( ⁇
  • Target compound 13 was prepared from 11 using the procedure described above for 9 to give 13 as a yellow solid, mp 79-80 °C, [a] 20 D +33.0 (c 0.25, MeOH), UV (MeOH) 395 nm ( ⁇
  • the precursor compound 14 was synthesized as described above for precursor 8 to give 14 as a yellow solid, mp 197-198°C, UV (MeOH) 396 nm ( ⁇ 14070), 319 urn ( ⁇ 6226). 1 H NMR
  • Target compound 15 was prepared from 14 using the procedure described above for 9 to give 15 as a yellow solid, mp 88-90 °C, [a] 20 D +28.8 (c 0.27, MeOH), UV (MeOH) 399 nm ( ⁇ 1 1,600), 318 nm ( ⁇ 6516). ⁇ NMR (CDC1 3 , 500 MHz): 6 8.1 6 (s, I H ), 8.09 (s, H I).
  • Target compound 16 was prepared from 14 using the procedure described above for 9 to give 16 as a yellow solid, mp 85-86 °C, [a] 20 D -28.9 (c 0.19, MeOH), UV (MeOH) 398nm, ( ⁇ 12,800), 321 nm ( ⁇ 6459).
  • Target compound 18 was prepared from the corresponding trifluoro diketo acid using the procedure described above for 17 to give 18 as a yellow solid, mp 175-176°C (amorphous powder), UV (methanol), ⁇ ⁇ 401 nm ( ⁇ 9139), ⁇ ⁇ 3 ⁇ 318 nni ( ⁇ 6225). ⁇ -NMR (CDCh. 500MHz), ⁇ 8.88 (s, I II ). 8.24 (s, 1H), 8.01 (s, I I I ).
  • Target compound 19 was prepared from 14 using the procedure described above for 17 to give 19 as a yellow solid, mp 87-88 °C, UV (MeOH) 400 nm ( ⁇ 8500), 320 nm ( ⁇ 6472).
  • Target compound 20 was prepared from the corresponding tetrafluoro diketo acid using the procedure described above for 17 to give 20 as a yellow solid, nip 82-83 °C, UV (MeOH) 400 urn ( ⁇ 7500), 322 inn ( ⁇ 5400).

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Abstract

La présente invention a pour objet de nouveaux cyclopentylpyridinone dicétocarboxamides oxy-substitués chiraux et achiraux et leurs dérivés et leurs procédés de préparation. Les composés comprennent les tautomères, les régioisomères et les isomères géométriques. Ces carboxamides complexes sont conçus en tant qu'inhibiteurs de la réplication du VIH par l'inhibition de l'intégrase du VIH. Les composés sont utiles dans la prévention ou le traitement d'une infection par le VIH et dans le traitement du SIDA et du para-SIDA, soit en tant que composés, soit en tant que sels pharmaceutiquement acceptables, avec des véhicules pharmaceutiquement acceptables, utilisés seuls ou en association avec des antiviraux, des immunomodulateurs, des antibiotiques, des vaccins, et d'autres agents thérapeutiques, spécialement d'autres composés anti-VIH (y compris d'autres agents anti-intégrase du VIH), qui peuvent être utilisés pour créer des cocktails d'anti-VIH en association. La présente invention concerne également des méthodes de traitement du SIDA et du para-SIDA et des méthodes de traitement ou de prévention d'une infection par le VIH.
PCT/US2010/059183 2009-12-07 2010-12-07 Pyridinone hydroxycyclopentylcarboxamides : inhibiteurs de l'intégrase du vih ayant des applications thérapeutiques WO2011071849A2 (fr)

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EA201270651A EA201270651A1 (ru) 2009-12-07 2010-12-07 Карбоксамиды пиридинон гидроксициклопентила: ингибиторы вич интегразы и области терапевтического применения
US13/513,448 US8703801B2 (en) 2009-12-07 2010-12-07 Pyridinone hydroxycyclopentyl carboxamides: HIV integrase inhibitors with therapeutic applications
PH1/2012/501095A PH12012501095A1 (en) 2009-12-07 2010-12-07 Pyridinone hydroxycyclopentyl carboxamides: hiv integrase inhibitors with therapeutic applications
AU2010328325A AU2010328325B2 (en) 2009-12-07 2010-12-07 Pyridinone hydroxycyclopentyl carboxamides: HIV integrase inhibitors with therapeutic applications
CN201080063257.1A CN102753526B (zh) 2009-12-07 2010-12-07 吡啶酮羟基环戊基羧酰胺：具有治疗用途的hiv 整合酶抑制剂
CA2783540A CA2783540C (fr) 2009-12-07 2010-12-07 Pyridinone hydroxycyclopentylcarboxamides : inhibiteurs de l'integrase du vih ayant des applications therapeutiques
SG2012041331A SG181524A1 (en) 2009-12-07 2010-12-07 Pyridinone hydroxycyclopentyl carboxamides: hiv integrase inhibitors with therapeutic applications
EP10836497.7A EP2509949B1 (fr) 2009-12-07 2010-12-07 Pyridinone hydroxycyclopentylcarboxamides : inhibiteurs de l'intégrase du vih ayant des applications thérapeutiques
NZ600873A NZ600873A (en) 2009-12-07 2010-12-07 Pyridinone hydroxycyclopentyl carboxamides: hiv integrase inhibitors with therapeutic applications
MX2012006485A MX2012006485A (es) 2009-12-07 2010-12-07 Piridinon hidroxiclicopentil carboxamidas: inhibidores de la integrasa del vih con aplicaciones terapeuticas.
JP2012543189A JP2013512957A (ja) 2009-12-07 2010-12-07 ピリジノンヒドロキシシクロペンチルカルボキサミド類：治療用途を備えたｈｉｖインテグラーゼ阻害剤
IL220113A IL220113A0 (en) 2009-12-07 2012-06-03 Pyridinone hydroxycyclopentyl carboxamides: hiv integrase inhibitors with therapeutic applications
ZA2012/04147A ZA201204147B (en) 2009-12-07 2012-06-06 Pyridinone hydroxycyclopentyl carboxamides:hiv integrase inhibitors with therapeutic applications

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US8703801B2 (en) 2009-12-07 2014-04-22 University Of Georgia Research Foundation, Inc. Pyridinone hydroxycyclopentyl carboxamides: HIV integrase inhibitors with therapeutic applications
US20140371311A1 (en) * 2011-10-19 2014-12-18 Korea Research Institute Of Bioscience And Biotechnology Ingenane-type diterpene compound, and pharmaceutical composition for treating or preventing viral infectious diseases containing same
US9593137B2 (en) 2011-12-22 2017-03-14 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US10758556B2 (en) 2017-08-07 2020-09-01 Nbe-Therapeutics Ag Anthracycline-based antibody drug conjugates having high in vivo tolerability

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US8703801B2 (en) 2009-12-07 2014-04-22 University Of Georgia Research Foundation, Inc. Pyridinone hydroxycyclopentyl carboxamides: HIV integrase inhibitors with therapeutic applications
US20140371311A1 (en) * 2011-10-19 2014-12-18 Korea Research Institute Of Bioscience And Biotechnology Ingenane-type diterpene compound, and pharmaceutical composition for treating or preventing viral infectious diseases containing same
US9481630B2 (en) * 2011-10-19 2016-11-01 Korea Research Institute Of Bioscience And Biotechnology Ingenane-type diterpene compound, and pharmaceutical composition for treating or preventing viral infectious diseases containing same
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
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WO2013148174A1 (fr) 2012-03-31 2013-10-03 University Of Georgia Research Foundation, Inc. Nouveaux médicaments anti-mycobactériens contre la tuberculose
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CN104254526B (zh) * 2012-03-31 2017-06-20 乔治亚大学研究基金公司 针对结核病的新的抗分枝杆菌药物
CN103524396A (zh) * 2012-09-29 2014-01-22 中国医学科学院医药生物技术研究所 含吲哚环的二脒类衍生物及其制备方法和应用
CN103524396B (zh) * 2012-09-29 2018-05-25 中国医学科学院医药生物技术研究所 含吲哚环的二脒类衍生物及其制备方法和应用
US10758556B2 (en) 2017-08-07 2020-09-01 Nbe-Therapeutics Ag Anthracycline-based antibody drug conjugates having high in vivo tolerability
US12121527B2 (en) 2017-08-07 2024-10-22 Nbe-Therapeutics Ag Anthracycline-based antibody drug conjugates having high in vivo tolerability

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PH12012501095A1 (en) 2015-04-22
AU2010328325A1 (en) 2012-06-21
CN102753526B (zh) 2014-11-26
IL220113A0 (en) 2012-07-31
EA201270651A1 (ru) 2013-01-30
NZ600873A (en) 2014-08-29
US8703801B2 (en) 2014-04-22
EP2509949A2 (fr) 2012-10-17
AU2010328325B2 (en) 2015-02-05
JP2013512957A (ja) 2013-04-18
KR20120094098A (ko) 2012-08-23
MX2012006485A (es) 2012-08-23
EP2509949B1 (fr) 2014-04-23
CA2783540A1 (fr) 2011-06-16
ZA201204147B (en) 2013-02-27
CN102753526A (zh) 2012-10-24
MY172005A (en) 2019-11-11
US20120282218A1 (en) 2012-11-08

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