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WO2002032873A1 - Composes a base de phenoxyethyl-thio-uree-pyridine et leur utilisation dans le traitement d'infections au vih - Google Patents

Composes a base de phenoxyethyl-thio-uree-pyridine et leur utilisation dans le traitement d'infections au vih Download PDF

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Publication number
WO2002032873A1
WO2002032873A1 PCT/US2000/041209 US0041209W WO0232873A1 WO 2002032873 A1 WO2002032873 A1 WO 2002032873A1 US 0041209 W US0041209 W US 0041209W WO 0232873 A1 WO0232873 A1 WO 0232873A1
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Prior art keywords
compound
hiv
acceptable carrier
compounds
pharmaceutically acceptable
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PCT/US2000/041209
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English (en)
Inventor
Fatih M. Uckun
Taracad K. Venkatachalam
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Parker Hughes Institute
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Parker Hughes Institute filed Critical Parker Hughes Institute
Priority to PCT/US2000/041209 priority Critical patent/WO2002032873A1/fr
Priority to AU2001219672A priority patent/AU2001219672A1/en
Publication of WO2002032873A1 publication Critical patent/WO2002032873A1/fr
Priority to US10/420,032 priority patent/US6727265B2/en

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Classifications

    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the invention relates to compounds as non-nucleoside inhibitors of reverse 5 transcriptase that are effective against HIV, including mutant strains of HIV, and effective in the treatment of multi-drug resistant HIV infection.
  • nucleoside analogs such as AZT
  • protease inhibitors such as nelfmavir
  • NNI 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.
  • Nevirapine is currently the only NNI compound which has been used in 20 combination with AZT and/or protease inhibitors for the treatment of HIV.
  • a new series of effective drug cocktails will most likely involve other NTMIs 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.
  • the high replication rate of the virus unfortunately leads to genetic variants 25 (mutants), especially when selective pressure is introduced in the form of drug treatment. These 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- 30 resistant viral strains ultimately emerge.
  • Triple drug combinations employing one (or two) nucleoside analogs and two (or one) NNI 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 NNI compounds, including L 1001 , K.103N, V106A, E138 , Y181C and Y188H.
  • the Y181C and K103N mutants may be the most difficult to treat, ecause they are resistant to most of the NNI compounds that have been examined.
  • Novel NNI 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.
  • Two non-nucleoside inhibitors (NNI) of HIV RT that have been approved by the U.S.
  • NNIs non-nucleoside inhibitors
  • DABO dihydroalkoxybenzyloxopyrimidine
  • HEPT hydroxyethoxymethyl]-6-(phenylthio)thymine
  • TIBO tetrahydrobenzondiazepine
  • TSAO 2',5'-Bis-0-(tert-butyldimethylsilyl)-3'-spiro- 5"-(4"-amino-l",2"- oxathiole-2",2'-dioxide)pyrimidine
  • TSAO oxathiin carboxanilide derivatives
  • quinoxaline derivatives thiadiazole derivative
  • 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 invention provides substituted and unsubstituted phenoxyethyl-thiourea- pyridine compounds which inhibit reverse transcriptase (RT) and which inhibit replication of a retrovirus, such as human immunodeficiency virus-1 (HIV-l ).
  • RT reverse transcriptase
  • HIV-l human immunodeficiency virus-1
  • the invention additionally provides a method for inhibiting reverse transcriptase activity of a retrovirus, such as HIV-l, comprising contacting the retrovirus with a compound of the invention.
  • the invention additionally provides a method for inhibiting replication of a retrovirus, such as HIV-l , comprising contacting the retrovirus with a compound of the invention.
  • the invention also provides a method for treating a retroviral infection in a subject, such as an HIV-l infection, comprising administering a compound of the invention to the subject.
  • the invention also provides compositions comprising a compound or inhibitor of the invention, and optionally, an acceptable carrier. In one embodiment, the composition is a pharmaceutical composition.
  • a retrovirus includes any virus that expresses reverse transcriptase.
  • retrovirus examples include, but are not limited to, HIV-l , HIV- 2, HTLV-I, HTLV-II, FeLV, FIV, SIV, AMV, MMTV, and MoMuLV.
  • reverse transcriptase (RT) refers to an enzyme having a non-nucleoside inhibitor (NNI) binding site similar to that of HIV-l RT and to which ligands which bind the composite binding pocket of the invention bind.
  • NNI non-nucleoside inhibitor
  • RT activity means the ability to effect reverse transcription of retroviral RNA to proviral DNA.
  • RT activity is by measuring viral replication.
  • One measure of viral replication is the p24 assay described herein.
  • a compound that "inhibits replication of human immunodeficiency virus (HIV)" means a compound that, when contacted with HIV- 1, for example, via HIV-infected cells, effects a reduction in the amount of HIV-l as compared with untreated control. Inhibition of replication of HIV-l can be measured by various means known in the art, for example, the p24 assay disclosed herein.
  • NNI nonnucleoside inhibitor of HIV reverse- transcriptase
  • nonnucleoside inhibitors of HIV-RT include, but are not limited to, tetrahydroimidazobenzodiazepinthiones (TIBO), 1 ⁇ [(2-hydroxyethoxy)methyl]- ⁇ - (phenylthio)thymines (HEPT), bis(heteroaryl)piperazines (BHAP), 2' ⁇ 5'-bis- ⁇ 3- (tertbutyldimethylsilyl)-3 , ⁇ spiro-5"-(4"-amino-r, 2"-oxathiole-2", 2"-dioxide) pyrimidines (TSAO), dihydroalkoxybenzyloxopyrimidine (DABO) and phenethylthiazolylthiourea (PETT) analogs.
  • the nonnucleoside inhibitor of HIV- RT of this invention are substituted and unsubstituted phenoxyethyl-thiourea- pyridine compounds
  • derivative means a chemical substance derivable from a parent substance by addition or substitution of components and which maintains the activity of the parent substance.
  • halogen includes fluoro, chloro, bromo and iodo.
  • salts refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects.
  • examples of such salts include, but are not limited to, (a) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; and salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, furmaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfomc acids, naphthalenedisulfomc acids, polygalacturonic acid; (b) salts with polyvalent metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum,
  • pharmaceutically acceptable carrier includes any material which, when combined with a compound of the invention, allows the compound to retain biological activity, such as the ability to inhibit RT activity, and is non- reactive with the subject's immune system.
  • examples include, but are not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solution, water, emulsions such as oil/water emulsion, and various types of wetting agents.
  • Preferred diluents for aerosol or parenteral administration are phosphate buffered saline or normal (0.9%) saline.
  • Compositions comprising such carriers are formulated by well known conventional methods (see, for example, Remington's Pharmaceutical Sciences, Chapter 43, 14th Ed., Mack Publishing Col, Easton PA 18042, USA).
  • Compounds of the invention are phenoxyethyl-thiourea-pyridine compounds that are useful as non-nucleoside inhibitors of reverse transcriptase.
  • the compounds were designed as inhibitors of HIV-l RT, based on a composite binding pocket computer model constructed from nine (9) individual crystal structures of RT-NNI complexes [51, 52].
  • Modeling studies for rational drug design included the construction of a composite NNI binding pocket for nine RT-NNI crystal structures, the analyses of surface complementarity between NNIs and RT, and application of inhibitory constants (K. values) combined with a docking procedure involving the novel thiourea compounds [51 , 52].
  • the compounds of the invention are phenoxyethyl-thiourea-pyridine compounds useful as non-nucleoside inhibitors of reverse transcriptase having the formula I:
  • the pyridine may be unsubstituted or substituted.
  • R 1 can be hydrogen, hydroxyl or halo.
  • Preferred compounds of the invention include N-[2-(Phenoxy)ethyl]- V' -[2-
  • the compounds of the invention have the ability to inhibit replication of a retrovirus, such as human immunodeficiency virus (HIV).
  • HIV human immunodeficiency virus
  • the compound inhibits replication of HIV with an IC 50 of less than 50 ⁇ M, as determined by p24 enzyme immunoassay.
  • the compound inhibits replication of HIV with an IC 50 of less than 5 ⁇ M.
  • the compound inhibits replication of HIV with an IC 50 of less than 1 ⁇ M.
  • the compound inhibits replication of HIV with an IC 50 of less than 5 nM.
  • the compound inhibits replication of HIV with an IC 50 of less than 1 nM.
  • compositions of the invention are useful for prevention and treatment of retroviral infection, such as HIV infection.
  • 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 / ' // 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-l . 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, and include treating a retroviral infection in a subject, such as an HIV-l infection, by administering an effective inhibitory amount of a compound or a pharmaceutically acceptable acid addition salt of a compound of the Formula I.
  • the compound or inhibitor of Formula I 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 can be administered orally, parentally (including subcutaneous injection, intravenous, intramuscular, intrasternal or infusion techniques), by inhalation spray, topically, by absorption through a mucous membrane, or rectally, in dosage unit formulations containing conventional non- toxic pharmaceutically acceptable carriers, adjuvants or vehicles.
  • Pharmaceutical compositions of the invention can be in the form of suspensions or tablets suitable for oral administration, nasal sprays, creams, sterile injectable preparations, such as sterile injectable aqueous or oleagenous suspensions or suppositories.
  • the TET compounds of the invention can be applied intravaginally and/or topically, for example in gel form, for prevention of heterosexual transmission of HIV.
  • compositions can be prepared according to techniques well-known in the art of pharmaceutical formulation.
  • the compositions can contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose 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 the art.
  • 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 bioavailability, fluorocarbons or other solubilizing or dispersing agents known in the art.
  • the 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.
  • 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 AIDS-related complex (ARC), with oral doses 2 to 5 times higher.
  • retroviral infection such as HIV infection, AIDS or AIDS-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 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.
  • conjugate means a complex formed with two or more compounds.
  • targeting moiety means a compound which serves to deliver the compound of the invention to a specific site for the desired activity.
  • Targeting moieties include, for example, molecules which specifically bind molecules present on a cell surface.
  • 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.
  • 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. Methods of Making the Compounds of the Invention
  • the compounds of the invention are prepared as follows. First an amine substituted pyridine is reacted with thiocarbonyldiimidazole in acetonitrile at room temperature. The reaction precipitate is then filtered to yield the thiocarbonyl intermediate. Dimethyl fomiamide was then added to the thiocarbony! intermediate to create a solution. An appropriate amine was then added to the thiocarbonyl intermediate solution, and the resulting solution was heated. The solution was cooled, precipitated, filtered, and the solvent evaporated to yield the desired thiourea compound. The compounds were further purified by column chromatography. The compounds of the invention are prepared as depicted in Scheme 1 below:
  • Elemental analysis was performed by Atlantic Microlabs (Norcross, GA). Column chromatography was performed using silica gel obtained from the Baker Company. The solvents used for elution varied depending on the compound and included one of the following: ethyl acetate, methanol, chloroform, hexane, methylene chloride and ether. Characterization data for the synthesized compounds is shown below:
  • the synthesized compounds were tested for RT inhibitory activity (IC 50 [rRT]) against purified recombinant HIV RT using the cell-free Quan-T-RT system (Amersham, Arlington Heights, IL), which utilizes the scintillation proximity assay principle as described in Bosworth, et al., 1989, Nature 341 : 167-168.
  • a DNA/RNA template is bound to SPA beads via a biotin/strepavidin linkage.
  • the primer DNA is a 16-mer oligo(T) which has been annealed to a poly(A) template.
  • the primer/template is bound to a strepavidin-coated SPA bead.
  • 3 H-TTP is incorporated into the primer by reverse transcription.
  • 3 H- TTP at a final concentration of 0.5 ⁇ Ci/sample, was diluted in RT assay buffer (49.5 mM Tris-Cl, pH 8.0, 80 mM KC1, 10 Mm MgCi, 10 mM DTT, 2.5 mMEGTA, 0.05% Nonidet-P-40), and added to annealed DNA/RNA bound to SPA beads.
  • the compound being tested was added to the reaction mixture at 0.001 ⁇ M-100 ⁇ M concentrations.
  • Addition of 10 mU of recombinant HIV RT and incubation at 37°C for 1 hour resulted in the extension of the primer by incorporation of "H-TTP.
  • the reaction was stopped by addition of 0.2 ml of 120 mM EDTA.
  • the samples were counted in an open window using a Beckman LS 7600 instrument and IC 50 values were calculated by comparing the measurements to untreated samples
  • the anti-HIV activity of the compounds was measured by determining their ability to inhibit the replication of the HIV-l strain HTLVIIIB in peripheral blood mononuclear cells (PBMC) from healthy volunteer donors, using the method described in Uckun et.al., 1998, Antimicrobial Agents and Chemotherapy 42:383.
  • PBMC peripheral blood mononuclear cells
  • the HIV strain HTLVIIIB was kindly provided by Dr. Neal T.Wetherall, VIROMED Laboratories, Inc., and was propagated in CCR CEM cells.
  • Table IB HIV-RT inhibitory activity of phenethyl thiourea pyridine compounds.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Tropical Medicine & Parasitology (AREA)
  • Communicable Diseases (AREA)
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  • AIDS & HIV (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

L'invention concerne des composés correspondant à la formule (I) dans laquelle R1 représente H ou un groupe attracteur d'électrons, n représente un nombre entier compris entre 0 et 5, et R représente hydrogène, alkyle C¿1?-C6, alcoxy, hydroxy, amino ou halo. Ces composés inhibent les transcriptases inverses et inhibent la réplication d'un rétrovirus, tel que le virus 1 du syndrome immunodéficitaire acquis (VIH-1). Les composés de l'invention sont des phénoxyéthyl-thio-urée-pyridines. En outre, l'invention concerne un procédé d'inhibition de l'activité des transcriptases inverses d'un rétrovirus, tel que le VIH-1, consistant à mettre ce rétrovirus en contact avec un composé de l'invention. L'invention concerne encore un procédé d'inhibition de la réplication d'un rétrovirus, tel que le VIH-1, consistant à mettre ce rétrovirus en contact avec un composé de l'invention.
PCT/US2000/041209 2000-10-18 2000-10-18 Composes a base de phenoxyethyl-thio-uree-pyridine et leur utilisation dans le traitement d'infections au vih WO2002032873A1 (fr)

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Application Number Priority Date Filing Date Title
PCT/US2000/041209 WO2002032873A1 (fr) 2000-10-18 2000-10-18 Composes a base de phenoxyethyl-thio-uree-pyridine et leur utilisation dans le traitement d'infections au vih
AU2001219672A AU2001219672A1 (en) 2000-10-18 2000-10-18 Phenoxyethyl-thiourea-pyridine compounds and their use for the treatment of hiv-infections
US10/420,032 US6727265B2 (en) 2000-10-18 2003-04-15 Phenoxyethyl-thiourea-pyridine compounds and their use for treatment of HIV-infections

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PCT/US2000/041209 WO2002032873A1 (fr) 2000-10-18 2000-10-18 Composes a base de phenoxyethyl-thio-uree-pyridine et leur utilisation dans le traitement d'infections au vih

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5593993A (en) * 1991-08-02 1997-01-14 Medivir Ab Method for inhibition of HIV related viruses
US6124324A (en) * 1999-06-23 2000-09-26 Hughes Institute Thiophene-ethyl thiourea compounds and use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5593993A (en) * 1991-08-02 1997-01-14 Medivir Ab Method for inhibition of HIV related viruses
US6124324A (en) * 1999-06-23 2000-09-26 Hughes Institute Thiophene-ethyl thiourea compounds and use

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ANTIVIRAL CHEM. CHEMOTHER. (2000), 11(5), 329-336 *
BELL ET AL: "Phenethylthiazolethiourea (PETT) Compounds, a New Class of HIV-1 Reverse Transcriptase Inhibitors. 1. Synthesis and Basic Structure-Activity Relationship Studies of PETT Analogs", JOURNAL OF MEDICINAL CHEMISTRY,US,AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 38, no. 25, 1996, pages 4261 - 4274, XP002108200, ISSN: 0022-2623 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; VENKATACHALAM, T. K. ET AL: "Piperidinylethyl, phenoxyethyl and fluoroethyl bromopyridyl thiourea compounds with potent anti- HIV activity", XP002167696, retrieved from STN Database accession no. 134:202425 *
F W BELL: "Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse transcriptase inhibitors. Synthesis and basic structure-activity relationship studies of PETT analogs", JOURNAL OF MEDICINAL CHEMISTRY,US,AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 38, no. 25, 1995, pages 4929 - 4936, XP002108199, ISSN: 0022-2623 *

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