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WO2002032889A1 - Composes de thiazolyl thiouree aromatiques et heterocycliques et utilisation - Google Patents

Composes de thiazolyl thiouree aromatiques et heterocycliques et utilisation Download PDF

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WO2002032889A1
WO2002032889A1 PCT/US2000/041290 US0041290W WO0232889A1 WO 2002032889 A1 WO2002032889 A1 WO 2002032889A1 US 0041290 W US0041290 W US 0041290W WO 0232889 A1 WO0232889 A1 WO 0232889A1
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compound
hiv
substituted
compounds
subject
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PCT/US2000/041290
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Fatih M. Uckun
Taracad K. Venkatachalam
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Parker Hughes Institute
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Priority to EP00984552A priority Critical patent/EP1326852A1/fr
Priority to JP2002536271A priority patent/JP2004515476A/ja
Priority to AU2001221154A priority patent/AU2001221154A1/en
Priority to CA002426148A priority patent/CA2426148A1/fr
Priority to PCT/US2000/041290 priority patent/WO2002032889A1/fr
Publication of WO2002032889A1 publication Critical patent/WO2002032889A1/fr
Priority to US10/420,031 priority patent/US6960606B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • HIV including mutant strains of HIV, and effective in the treatment of NNl-resistant and multi-drug resistant HIV infection.
  • nucleoside analogs such as AZT
  • protease inhibitors such as nelfinavir
  • NRTI non- nucleoside reverse transcriptase inhibitors
  • Combination therapies may be a significant factor in the dramatic decrease in deaths from AIDS (a decrease in death rate as well as absolute number).
  • the most commonly used combinations include two nucleoside analogs with or without a protease inhibitor.
  • NNRTI compounds such as nevirapine have been used in combination with AZT and/or protease inhibitors for the treatment of HIV.
  • a new series of effective drug cocktails will most likely involve other NNRTIs in combination with nucleoside and protease inhibitors as a triple action treatment to combat the growing problem of drug resistance encountered in single drug treatment strategies.
  • mutants are resistant to the anti-viral agents previously administered to the patient.
  • Switching agents or using combination therapies may decrease or delay resistance, but because viral replication is not completely suppressed in single drug treatment or even with a two-drug combination, drug- resistant viral strains ultimately emerge.
  • Triple drug combinations employing one (or two) nucleoside analogs and two (or one) NNRTI targeting RT provide a very promising therapy to overcome the drug resistance problem. RT mutant strains resistant to such a triple action drug combination would most likely not be able to function.
  • mutant strains have been characterized as resistant to NNRTI compounds, including 1001, K103N, V106A, E138K, Y181C and Y188H.
  • the Y181C and K103N mutants may be the most difficult to treat, because they are resistant to most of the NNRTI compounds that have been examined.
  • Examples of NNRTI-resistant strains include Al7, with a Y181C mutation, and A17 variant, with Y181C plus K103N mutations.
  • Novel NNRTI designs able to reduce RT inhibition to subnanomolar concentrations with improved robustness against the most commonly observed mutants and preferably able to inhibit the most troublesome mutants are urgently needed.
  • New antiviral drugs will ideally have the following desired characteristics: (1) potent inhibition of RT; (2) minimum cytotoxicity; and (3) improved ability to inhibit known, drug-resistant strains of HIV. Currently, few anti-HIV agents possess all of these desired properties.
  • NNIs have been found to bind to a specific allosteric site of HIV- RT near the polymerase site and interfere with reverse transcription by altering either the conformation or mobility of RT, thereby leading to a noncompetitive inhibition of the enzyme (Kohlstaedt, L. A. et al., Science, 1992, 256, 1783-1790).
  • the present invention provides the synthesis and methods for using novel aromatic/heterocyclic thiazolyl thiourea compounds based on anti-HIV activity.
  • the invention provides novel thiazolyl-thiourea compounds as newly identified non-nucleoside inhibitors (NNRTI) of HIV reverse transcriptase.
  • NRTI non-nucleoside inhibitors
  • the novel thiazolyl-thiourea compounds, compositions, and methods of the invention are useful in the treatment of HIV infection, with particular efficacy against multiple strains of HIV, including NNRTI-resistant and multi-drug resistant mutant strains.
  • the thiazolyl-thiourea compounds, compositions, and methods of the invention are useful for inhibiting reverse transcriptase activity and inhibiting replication of multiple strains of HIV, including NNRTI-resistant and multi-drug resistant strains.
  • the thiazolyl-thiourea compounds of the invention are useful for treating retroviral infection in a subject, such as an HTV-1 infection, by administration of the thiazolyl-thiourea compounds of the invention, for example, in a pharmaceutical composition.
  • the compounds of the invention may be combined with carriers and/or agents to enhance delivery to sites of viral infection, such as targeting antibodies, cytokines, or ligands.
  • the compounds may include chemical modifications to enhance entry into cells, or may be encapsulated in various known delivery systems.
  • the thiazolyl-thiourea compound has a structure shown in Formula I.
  • R 1 is an aryl, heteroaryl, cycloalkyl or aryloxy moiety which may be substituted or unsubstituted.
  • compounds Formula I may be in the form of a pharmaceutically acceptable salt.
  • the thiazolyl-thiourea compound has a structure shown in Formula II.
  • R 2 is hydrogen, halogen, alkyl or arylalkyl and n is 0 or 2.
  • R * is a substituted or unsubstituted, saturated or unsaturated, 5 or 6 member organic monocyclic ring having 0 to 3 heteroatoms selected from O, S, and N; or a substituted or unsubstituted, saturated or unsaturated, 7- to 10- member organic bicyclic or tricyclic ring having 0 to 3 heteroatoms selected from O, S, and N; or a pharmaceutically acceptable salt thereof.
  • the thiazolyl-thiourea compounds and compositions useful in the invention exhibit very low cytotoxicity and very high potency against HIV including both wild-type and NNRTI-resistant HIV.
  • Figures 1A, IB, IC and ID are schematic diagrams of X-ray crystal structures of Compound 2: N-[2-(l-Cyclohexenylethyl)]-N'-[2-(thiazolyl)]thiourea ( Figure 1A), Compound 6: N-[l-(l-Furoylmethyl)]-N'-[2-(thiazolyl)]thiourea ( Figure IB), Compound 7: N-[3-(2-Imidazole)propyl]-N'-[2-(thiazolyl)]thiourea ( Figure IC), and Compound 8: N-[2-(2-Indole)ethyl]-N'-[2-(thiazolyl)]thiourea ( Figure ID). Detailed Description of the Invention Definitions
  • Retrovirus includes any virus that expresses reverse transcriptase.
  • retrovirus include, but are not limited to, HIV-1, HIV-2, HT N-I, HTLN-II, FeLV, FIV, SIV, AMV, MMTV, and MoMuLV.
  • Reverse transcriptase (RT) refers to an enzyme having reverse transcriptase activity and an ⁇ I binding site similar to that of HIV-1 RT and to which ligands that bind the composite binding pocket of the invention bind.
  • Reverse transcriptase (RT) activity means the ability to effect reverse transcription of retroviral R ⁇ A to proviral D ⁇ A.
  • One means by which RT activity can be determined is by measuring viral replication.
  • One measure of HIV-1 viral replication is the p24 core antigen enzyme immunoassay, for example, using the assay commercially available from Coulter Corporation/Immunotech, Inc. (Westbrooke, MI).
  • RT activity is analyzed is by assay of recombinant HIV-1 reverse transcriptase (rRT) activity, for example, using the Quan-T-RT assay system commercially available from Amersham (Arlington Heights, IL) and described in Bosworth, et al., Nature 1989, 341 :167-168.
  • rRT recombinant HIV-1 reverse transcriptase
  • ⁇ RTI means non-nucleoside reverse transcriptase inhibitor.
  • non-nucleoside inhibitors of HIV reverse transcriptase (RT) are defined.
  • Wild HIV means a strain of HIV having one or more mutated or altered amino acids as compared with wild type.
  • wild-type means the phenotype that is characteristic of most of the members of a species occurring naturally and contrasting wit the phenotype of a mutant.
  • Multi-Drug Resistant HIV means one or more HIV strain that is resistant to treatment with one or more chemotherapeutic agent.
  • “Therapeutically effective amount” is a dose that provides some therapeutic benefit on administration, including, in the context of the invention, reduced viral activity or viral load in a patient, and also including inhibition of viral RT activity and/or replication of virus.
  • "Docking" a compound in a binding pocket means positioning a model of a compound in a model of the binding pocket. In one embodiment, the docking is performed with the use of computer software, such as the Affinity program within Insightll (Molecular Simulations Inc., 1996, San Diego, California). Docking pennits the identification of positions of the compound within the binding pocket that are favored, for example, due to minimization of energy.
  • Conjugate means a complex formed with two or more compounds.
  • Targeting moiety means a compound that serves to deliver the compound of the invention to a specific site for the desired activity.
  • Targeting moieties include, for example, molecules that specifically bind molecules present on a cell surface.
  • Such targeting moieties useful in the invention include anti-cell surface antigen antibodies.
  • Cytokines, including interleukins, factors such as epidermal growth factor (EGF), and the like, are also specific targeting moieties known to bind cells expressing high levels of their receptors.
  • Alkyl refers to straight or branched hydrocarbon radicals, such as methyl, ethyl, propyl, butyl, octyl, isopropyl, tert-butyl, sec-pentyl, and the like.
  • Alkyl groups can either be unsubstituted or substituted with one or more substituents, such as, for example, halogen, hydroxy, alkoxy, aryl, arylalkyl, aralkoxy, oxo and the like.
  • substituents such as, for example, halogen, hydroxy, alkoxy, aryl, arylalkyl, aralkoxy, oxo and the like.
  • alkyl groups include 1 to 8 carbon atoms, preferably 1 to 6, more preferably 1-4, and most preferably 1 to 3 carbon atoms.
  • Cycloalkyl refers to a 3- to 8-member hydrocarbon ring containing 0 to 3 heteroatoms selected from O, N, and S; or a bicyclic or tricyclic 4- to 12-member hydrocarbon ring system containing 0 to 3 heteroatoms selected from 0, N, and S. Cycloalkyl groups can either be unsubstituted or substituted with one or more substituents, such as, for example, halogen, hydroxyl, alkoxy, aryl, arylalkyl, aralkoxy, oxo and the like.
  • Aryl refers to monovalent unsaturated aromatic carbocyclic radicals having a single ring, such as phenyl, or multiple condensed rings, SUGII as naphthyl or anthryl, which can be optionally substituted by substituents such as, for example, halogen, alkyl, alkoxy, hydroxy, and the like.
  • Heteroaryl refers to a heteroaromatic ring containing 1 to 3 heteroatoms selected from O, N, and S; a bicyclic 9- or 10-member heteroaromatic ring system containing 1 to 3 heteroatoms selected from O, N, and S; or a tricyclic 13- or 14- member heteroaromatic ring system containing 1 to 3 heteroatoms selected from O, N, and S; each of which rings can be optionally substituted by substituents such as halogen, alkyl, alkoxy, hydroxy, and the like.
  • Aryloxy refers to an oxygen atom substituted with an aryl radical as defined above. Typical aryloxy groups include phenoxy, naphthoxy and the like. Preferable aryloxy groups include phenoxy.
  • Alkoxy refers to an oxygen atom substituted with an alkyl radical as defined above. Typical alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and the like. Preferable alkoxy groups include methoxy and ethoxy.
  • Arylalkyl refers to an alkyl radical defined as above substituted with an aryl radical as defined above. Typical arylalkyl groups include phenethyl, benzyl, and naphthethyl.
  • Alkoxy refers to an alkoxy group as defined above where the alkyl group is substituted with an aryl radical as defined above.
  • Halo refers to fluoride, chloride, bromide, and iodide radicals.
  • Compounds of the present invention are thiazolyl-thiourea compounds useful as non-nucleoside inhibitors of RT having formula I.
  • R 1 moiety in compounds of formula I is typically substituted or unsubstituted aryl, heteroaryl, cycloalkyl, or aryloxy.
  • R 1 may be substituted or unsubstituted phenyl, phenoxy, indolyl, pyridyl, piperidinyl, and the like.
  • R 1 may be substituted at one or more positions with, for example, halo, (C, - C 4 ) alkyl, hydroxyl, and the like.
  • R 1 is substituted with methyl or hydroxyl.
  • Exemplary compounds of the invention are N-[2-(phenoxyethyl)]-N'-[2- (thiazolyl)Jthiourea where R 1 is an unsubstituted phenoxy, N-[2-(2-indole)ethyl]-N'- [2-(thiazolyl)]thiourea where R 1 is an unsubstituted indolyl, N-[2-(2- piperdine)ethyl]-N'-[2-(thiazolyl)]thiourea where R 1 is an unsubstituted piperidinyl, and N-[2-pyridylethyl]-N'-[2-(thiazolyl)]thiourea where R 1 is an unsubstituted pyridyl.
  • R 1 is phenyl, optionally substituted with one or more substituents, for example, with halo, (C, - C 4 ) alkyl or hydroxy where the phenyl group is not monosubstituted with methyl or hydroxy at an ortho position.
  • Exemplary compounds of the invention are N-[2-(4-methylphenyl)ethyl]-N'-[2- (thiazolyl)]thiourea (Compound 4) where R 1 is a phenyl substituted with methyl in the para position and N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(thiazolyl)]thiourea (Compound 10) where R 1 is a phenyl substituted with hydroxy in the para position.
  • the thiazolyl-thiourea compound has a structure shown in Formula II.
  • n in compounds of formula II include 0, 1, 2, 3, and 4.
  • n is 0, 1, or 2.
  • n is 0 or 2.
  • R 2 moiety in compounds of formula II is typically hydrogen, halogen, alkyl or arylalkyl.
  • R 2 is hydrogen, C,-C 6 alkyl or halogen.
  • R 2 is methyl or ethyl.
  • R 3 moiety in compounds of formula II is typically a substituted or unsubstituted, saturated or unsaturated, 5 or 6 member organic monocyclic ring having 0 to 3 heteroatoms selected from O, S, and N. Additionally, R 3 includes substituted or unsubstituted, saturated or unsaturated, 7- to 10- member organic bicyclic or tricyclic rings having 0 to 3 heteroatoms selected from O, S, and N. Substituents on R 3 include, for example, halogen, alkyl, and hydroxyl.
  • R 3 is, for example, substituted or unsubstituted adamantyl, phenyl, furoyl, thiazolyl, cyclohexenyl, imidazolyl, indolyl, piperidinyl, pyridinyl, or 2-pyrrolidinonyl.
  • n is 0, R 2 is hydrogen or alkyl and R 3 is furoyl, adamantyl or phenyl.
  • Exemplary compounds of the invention are N-[l-(l-adamantyl)methyl]-N'-[2-(thiazolyl)]thiourea (Compound 5) where R 3 is unsubstituted adamantyl and R 2 is hydrogen, N-[l-(l-furoylmethyl)]- N'-[2-(thiazolyl)]thiourea where R 3 is unsubstituted furoyl and R 2 is hydrogen, and N-[ ⁇ -ethylbenzyl]-N'-[2-(thiazolyl)]thiourea (Compound 13) where R 3 is phenyl and R 2 is ethyl.
  • n is 2
  • R 2 is hydrogen and R 3 is imidazolyl, indolyl, piperidinyl or 2-pyrrolidinonyl.
  • exemplary compounds of the invention are N-[3-(2-imidazole)propyl]-N'-[2- (thiazolyl)]thiourea (Compound 7) where R 3 is unsubstituted imidazole, and N-[3- (pyrrolidinone)propyl]-N'-[2-(thiazolyl)]thiourea (Compound 12) where R 3 is unsubstituted imidazole.
  • the compounds of the invention preferably bind to a specific allosteric site of HIV- RT near the polymerase site and interfere with reverse transcription, for example, by altering either the conformation or mobility of RT.
  • the compounds of the invention may also be in the form of pharmaceutically acceptable acid addition salts.
  • Pharmaceutically acceptable acid addition salts are formed with organic and inorganic acids.
  • acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, gluconic, fumaric, succinic, asorbic, maleic, methanesulfonic, tetrafluoroboric, methanesulfonic, trifluoromethanesulfonic, and the like.
  • the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce either a mono or di, etc. salt in the conventional manner.
  • the free base forms may be regenerated by treating the salt form with a base. For example, dilute solutions of aqueous base may be utilized.
  • Dilute aqueous sodium hydroxide, potassium carbonate, ammonia, and sodium bicarbonate solutions are suitable for this purpose.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties SUGI as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention.
  • the compounds of the invention are useful in methods for inhibiting reverse transcriptase activity of a retrovirus.
  • Retroviral reverse transcriptase is inhibited by contacting RT in vitro or in vivo, with an effective inhibitory amount of a compound of the invention.
  • the compounds of the invention also inhibit replication of retrovirus, particularly of HIV, such as HIV-1. Viral replication is inhibited, for example, by contacting the virus with an effective inhibitory amount of a compound of the invention.
  • the methods of the invention are useful for inhibiting reverse transcriptase and/or replication of multiple strains of HIV, including mutant strains such as multi- drug-resistant and NNRTI-resistant strains, and include treating a retroviral infection in a subject, such as an HIV-1 infection, by administering an effective inhibitory amount of a compound or a pharmaceutically acceptable acid addition salt of a compound of Formula I or II.
  • the compound of Formula I or II is preferably administered in combination with a pharmaceutically acceptable carrier, and may be combined with specific delivery agents, including targeting antibodies and/or cytokines.
  • the compound or inhibitor of the invention may be administered in combination with other antiviral agents, immunomodulators, antibiotics or vaccines.
  • the compounds of Formula I or II can be administered orally, parentally
  • compositions of the invention can be in the form of suspensions or tablets suitable for oral administration, nasal sprays, creams, and sterile injectable preparations, such as sterile injectable aqueous or oleagenous suspensions or suppositories.
  • thiazolyl-thiourea compounds of the invention can be applied intravaginally and/or topically, for example in gel form, for prevention of heterosexual transmission of HIV.
  • the compositions can be prepared according to techniques well known in the art of pharmaceutical fonriulation.
  • the compositions can contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, me hylcellulose as a viscosity enhancer, and sweeteners or flavoring agents.
  • the compositions can contain microcrystalline cellulose, starch, magnesium stearate and lactose or other excipients, binders, extenders, disintegrants, diluents and lubricants known in
  • compositions can be prepared according to techniques well known in the art of pharmaceutical formulation.
  • the compositions can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavai lability, fluorocarbons or other solubilizing or dispersing agents known in the art.
  • compositions can be formulated according to techniques well-known in the art, using suitable dispersing or wetting and suspending agents, such as sterile oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • suitable dispersing or wetting and suspending agents such as sterile oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • the compositions can be prepared by mixing with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ambient temperatures, but liquefy 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 ambient temperatures, but liquefy or dissolve in the rectal cavity to release the drug.
  • Dosage levels of approximately 0.02 to approximately 10.0 grams of a compound of the invention per day are useful in the treatment or prevention of retroviral infection, such as HIV infection, AIDS or AlDS-related complex (ARC), with oral doses 2 to 5 times higher.
  • retroviral infection such as HIV infection, AIDS or AlDS-related complex (ARC)
  • HIV infection can be treated by administration of from about 0.1 to about 100 milligrams of compound per kilogram of body weight from one to four times per day.
  • dosages of about 100 to about 400 milligrams of compound are administered orally every six hours to a subject.
  • the specific dosage level and frequency for any particular subject will be varied and will depend upon a variety of factors, including the activity of the specific compound the metabolic stability and length of action of that compound, the age, body weight, general health, sex, and diet of the subject, mode of administration, rate of excretion, drug combination, and severity of the particular condition.
  • the compounds of formula I or 11 can be administered in combination with other agents useful in the treatment of HIV infection, AIDS or ARC.
  • the compound of the invention can be administered in combination with effective amounts of an antiviral, immunomodulator, anti-infective, or vaccine.
  • the compound of the invention can be administered prior to, during, or after a period of actual or potential exposure to retrovirus, such as HIV.
  • the compound of the invention can be targeted for specific delivery to the cells to be treated by conjugation of the compounds to a targeting moiety.
  • Targeting moiety useful for conjugation to the compounds of the invention include antibodies, cytokines, and receptor ligands expressed on the cells to be treated.
  • Particularly useful targeting moieties for targeting the compounds of the invention to cells for therapeutic activity include those ligands that bind antigens or receptors present on virus-infected cells to be treated.
  • antigens present on T-cells such as CD48
  • Antibody fragments including single chain fragments, can also be used.
  • Other such ligand-receptor binding pairs are known in the scientific literature for targeting anti-viral treatments to target cells. Methods for producing conjugates of the compounds of the invention and the targeting moieties are known.
  • the compounds of the invention may be prepared as shown in Scheme 1.
  • a 2-aminothiazole (A) is contacted with a thiocarbonyldimidazole in an appropriate organic solvent such as, for example, acetonitrile or dimethylformamide under an inert atmosphere at ambient temperatures to form a thiazolethiocarbonylimidazole product (B).
  • the resulting product (B) is then isolated using methods known to those of skill in the art.
  • the product (B) is then further contacted with an appropriate amine in an appropriate organic solvent such as, for example, acetonitrile or dimethylformamide under an inert atmosphere.
  • the resulting product (C) is then isolated using methods known to those of skill in the art.
  • Compound (C) is further purified using silica gel column chromatography. The physicochemical properties of the compounds are determined using standard analytical methods.
  • thiazolyl thiourea compounds of the invention can be synthesized as described above, or by other known synthetic methods.
  • PBMNC normal human peripheral blood mononuclear cells from HIV- negative donors were cultured 72 hours in RPM1 1640 supplemented with 20% (v/v) heat-inactivated fetal bovine serum (FBS), 3% interleukin-2, 2 mM L-glutamine, 25 mM HEPES, 2 g/L NaHCO-,, 50 ⁇ g/mL gentamicin, and 4 ⁇ g/mL phytohemagglutinin prior to exposure to the HIV-1 strain HTLV [1IB .
  • the cells were then infected with virus at a multiplicity of infection (MOI) of 0.1 during a 1-hour adsorption period at 37 ° C in a humidified 5% CO 2 atm.
  • MOI multiplicity of infection
  • EIA enzyme immunoassay
  • Percent viral inhibition was calculated by comparing the p24 values from the test substance-treated infected cells with p24 values from untreated infected cells (i.e., virus controls). The effects of various treatments on cell viability were also examined and the results were expressed as the cytotoxic concentration (CC) 50 values.
  • These six lead compounds are minimally toxic to PBMC with CC 50 values ranging from 28 ⁇ M to >100 ⁇ M and their selectivity indices are remarkably high ranging from 28,000 to > 100,000.
  • the 6 lead compounds are between 9 and 34 times more potent than the standard NNRTI nevirapine and delavirdine and between 7 and 30 times more potent than the previously reported NNRTI HI-443 and HI-244.
  • Compounds 2-6, 8, and 13 inhibit A17 at nanomolar concentrations with 1C 50 values ranging from 0.6 ⁇ M to 4.4 ⁇ M, which are approximately 1-log better than the IC 50 values of HI-443 or HI-244 and 1-2 logs better than the IC 50 values of nevirapine or delavirdine against the same NNRTI-resistant HIV-1 strain. Additionally, compounds 5, 6, 8, and 13 are very effective against A17 variant with IC 50 values ranging from 0.6 ⁇ M to 3.7 ⁇ M, which are similar to the IC 50 value of HI-443 and almost 2-logs better than the IC 50 values of nevirapine, delavirdine, or compound HI-244 against the same NNRTI-resistant HIN-1 strain.
  • Compounds 5, 6, 8, and 13 were effective against both ⁇ RTI-resistant HIV-1 isolates at nanomolar to low micro molar concentrations and exhibit much greater potency against both wild-type as well as ⁇ RTI-resistant HIV-1 than nevirapine, delavirdine, HI-443, and HI-244.
  • Compound 6 is particularly promising because it was minimally toxic to PBMC and had a selectivity index of >100,000.
  • the structures of compounds 2 and 6-8 were resolved by X-ray crystallography and are diagramatically shown in Figures 1 A - ID.
  • the X-ray structures confirmed that the essential binding components for the ⁇ RTI binding pocket are present in these new compounds.
  • the crystal structures of compounds 2 and 6-8 show that each molecule contains an intramolecular hydrogen bond between a thiourea ⁇ H and a nitrogen atom on the thiazolyl ring.
  • the more compact molecular conformation resulting from this hydrogen bond allows the molecule to more easily fit into the nonucleoside-binding site of HIV RT and is consistent with molecular modeling studies evaluating how NNRTI compounds can bind to HIV RT.

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Abstract

La présente invention concerne de nouveaux composés de thiazolyl thiourée aromatiques et hétérocycliques, de la formule I et II et des compositions pharmaceutiques les contenant, ainsi que des méthodes d'utilisation desdits composés. Lesdits composés sont des agents efficaces pour le traitement des infections à VIH, notamment des souches de VIH résistantes aux inhibiteurs non nucléotidiques et à l'action de plusieurs médiacaments.
PCT/US2000/041290 2000-10-19 2000-10-19 Composes de thiazolyl thiouree aromatiques et heterocycliques et utilisation WO2002032889A1 (fr)

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EP00984552A EP1326852A1 (fr) 2000-10-19 2000-10-19 Composes de thiazolyl thiouree aromatiques et heterocycliques et utilisation
JP2002536271A JP2004515476A (ja) 2000-10-19 2000-10-19 芳香族およびヘテロサイクリックチアゾール尿素化合物およびその使用
AU2001221154A AU2001221154A1 (en) 2000-10-19 2000-10-19 Aromatic and heterocyclic thiazolyl thiourea compounds and use
CA002426148A CA2426148A1 (fr) 2000-10-19 2000-10-19 Composes de thiazolyl thiouree aromatiques et heterocycliques et utilisation
PCT/US2000/041290 WO2002032889A1 (fr) 2000-10-19 2000-10-19 Composes de thiazolyl thiouree aromatiques et heterocycliques et utilisation
US10/420,031 US6960606B2 (en) 2000-10-19 2003-04-15 Adamantyl Thiazole Thioureas

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PCT/US2000/041290 WO2002032889A1 (fr) 2000-10-19 2000-10-19 Composes de thiazolyl thiouree aromatiques et heterocycliques et utilisation

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WO2004050643A3 (fr) * 2002-12-04 2004-09-10 Boehringer Ingelheim Int Inhibiteurs de la transcriptase inverse exempts de nucleosides

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004050643A3 (fr) * 2002-12-04 2004-09-10 Boehringer Ingelheim Int Inhibiteurs de la transcriptase inverse exempts de nucleosides
US7642277B2 (en) 2002-12-04 2010-01-05 Boehringer Ingelheim International Gmbh Non-nucleoside reverse transcriptase inhibitors

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JP2004515476A (ja) 2004-05-27
CA2426148A1 (fr) 2002-04-25
AU2001221154A1 (en) 2002-04-29
EP1326852A1 (fr) 2003-07-16

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