WO2016038562A1 - Dérivés de thioguanine - Google Patents

Dérivés de thioguanine Download PDF

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Publication number
WO2016038562A1
WO2016038562A1 PCT/IB2015/056933 IB2015056933W WO2016038562A1 WO 2016038562 A1 WO2016038562 A1 WO 2016038562A1 IB 2015056933 W IB2015056933 W IB 2015056933W WO 2016038562 A1 WO2016038562 A1 WO 2016038562A1
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WIPO (PCT)
Prior art keywords
purin
alkyl
sulfanyl
amine
optionally substituted
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PCT/IB2015/056933
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English (en)
Inventor
Habibah A WAHAB
Maywan HARIONO
Mei Lan TAN
Ezatul Ezleen Binti KAMARULZAMAN
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Malaysian Institute Of Pharmaceuticals And Nutraceuticals
Universiti Sains Malaysia
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Publication of WO2016038562A1 publication Critical patent/WO2016038562A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/24—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one nitrogen and one sulfur atom

Definitions

  • This invention relates, inter alia, to the use of certain compounds in the treatment of dengue fever or West Nile virus.
  • Dengue virus is a mosquito-borne virus that causes significant disease worldwide. Endemic in more than 100 countries, DENV is estimated to cause 50 million infections each year. DENV infections can result in serious disease including dengue fever (DF), dengue hemorrhagic fever (DHF), dengue shock syndrome (DSS) and even death. Complicating matters further is the fact that DENV exists as four separate serotypes (DEN1V, DEN2V, DEN3V, and DEN4V) with infection by one serotype not providing protection from infections by the other serotypes.
  • DENV is considered to be the most important mosquito-borne viral disease in the world.
  • vaccines approved to prevent DENV infection and no approved antiviral drugs to treat the disease.
  • DENV is an enveloped, positive-strand RNA virus whose 1 1 kB genome is transcribed as a single polyprotein (See Tomlinson et al., 2009, Antiviral Res 82: 1 10-4) including the three structural (capsid, pre-m, and envelope) proteins at its 5' end followed by seven nonstructural proteins (Fields et al, 1996, Field's Virology, Third Edition, third ed. Lippincott Williams & Wilkins, Philadelphia).
  • the N-terminal 180 residues of the NS3 protein encode the viral protease (Chambers et al, 1993, J Virol 67:6797-807) and -40 residues from the central hydrophilic domain of the NS2B protein (Yusof et al., 2000, J Biol Chem 275:9963- 9) encode the protease cofactor (Leung et al, 2001 , J Biol Chem 276:45762-71 ).
  • NS2B-NS3 protease complex (NS2B-NS3pro) is responsible for cleavage of the viral polyprotein (Cahour 992, J Virol 66: 1535-1542) and has been shown to be required for viral replication (Falgout et al., 1991 , J Virol. 65:2467-2475).
  • NS2B-NS3 protease provides a strategic target for inhibition in the development of dengue fever antivirals (Tomlinson et al., 2009, Infect Disord Drug Targets 9:327-43).
  • Flavivirus is a genus of the family Flaviviridae. This genus includes the West Nile virus and dengue virus as well as several other viruses that may cause encephalitis. Due to the similarities between dengue viruses and West Nile viruses, NS2B-NS3 protease also provides a strategic target for inhibition in the development of West Nile virus treatments.
  • West Nile virus belongs to the family Flaviviridae that comprises more than 60 viruses, many of which are important human pathogens.
  • WN is a member of the Japanese encephalitis virus (JE) serocomplex of mosquito-borne flaviviruses that includes St. Louis encephalitis, JE, and Murray Valley encephalitis viruses (Calisher, CH. et al. 1989 J Gen Virol 70:27-43; Burke, D.S. & Monath, T . 2001 in: Fields Virology, eds. Knipe, D.M. & Howley, P.M. Lippincott Williams and Wilkins, Philadelphia, 4-th ed., pp. 1043-1 125).
  • JE Japanese encephalitis virus
  • WN is maintained in a natural cycle that involves mosquito vectors and birds, while humans and equines are usually incidental hosts.
  • WN has been recognized as one of the most widely distributed flaviviruses with a geographic range including Africa, Australia, Europe, the Middle East and West Asia (Burke, D.S. & Monath, T.P. 2001 in: Fields Virology, eds. Knipe, D.M. & Howley, P.M. Lippincott Williams and Wilkins, Philadelphia, 4-th ed., pp. 1043-1 125; Hayes, C.G. 1989 in: The Arboviruses: Epidemiology and Ecology, ed. Monath T.P. Boca Raton, FL CRC Press, Volume V, pp. 59-88).
  • a first aspect relates to a compound of formula (I):
  • R 1 and R 4 each independently represent:
  • Ci-12 alkyl, C 2 .i 2 alkenyl, C 2 -i 2 alkynyl, C 3 -C 5 cycloalkyl, C 4 -C 5 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN, Ci-4 alkyl, C 2-4 alkenyl, C 2 _ 4 alkynyl, C 3-5 cycloalkyl (which latter four groups are optionally substituted by one or more substituents selected from OH, 0, halo, C 1-4 alkyl and C -4 alkoxy), phenyl, Het a (which latter two groups are optionally substituted by one or more substituents selected from OH, halo, N0 2 , C(0)OR 5a , Ci -4 alkyl and C 1-4 alkoxy), OR 5b , S(0) n R 5c , S(0) 2 N(R 5d )(R 5e ),
  • Hetb optionally substituted by one or more substituents selected from OH, halo, N0 2 , C(0)0R 5a , C 1-4 alkyl and C alkoxy; and
  • R 2 and R 3 each independently represent:
  • R 6a and R 6 independently represent, at each occurrence, phenyl or Het c , which two groups are optionally substituted by one or more substituents selected from OH, nitro, C(0)OR 5j , CN, , halo, Ci-4 alkyl and C 1-4 alkoxy;
  • R 5a to R 5J and R 5 ' each independently represent, at each occurrence, H or C 1-4 alkyl, which latter group is optionally substituted by one or more substituents selected from halo, OH and NH 2 ,
  • R 5k independently represents, at each occurrence, H or C ⁇ 5 alkyl, which latter group is optionally substituted by one or more substituents selected from halo, OH and NH 2 ,
  • R 7 represents phenyl which is optionally substituted by one or more substituents selected from OH, nitro, C(0)OR 51 , CN, halo, d_ 4 alkyl and C 1-4 alkoxy; each independently represents a bond or C 1-4 alkyl; each Hetg to Het d independently represents a 5- to 12-membered heterocyclic group containing from one to five heteroatoms selected from O, S and N; each n is independently, at each occurrence, 0, 1 or 2, or a pharmaceutically acceptable salt thereof, for use in the treatment of dengue fever or West Nile virus.
  • the first aspect of the invention is disclosed in Claim 1. Embodiments of this aspect are disclosed in Claims 2 to 7.
  • a second aspect relates to a compound, as defined herein, for use in the manufacture of a medicament for the treatment of dengue fever or West Nile virus.
  • the second aspect is disclosed in Claim 8.
  • a third aspect relates to a method of treating dengue fever comprising administration of a therapeutically effective amount of a compound, as defined herein, to a patient in need of such treatment.
  • the third aspect of the invention is disclosed in Claim 9.
  • Another aspect relates to a compound of formula (II)
  • R 1' represents H, ethyl, /-propyl, cyclopentyl or benzyl
  • R 4 independently represents:
  • R 2 represents H or benzyl
  • R 3' represents:
  • R 5k' independently represents, at each occurrence, Ci -4 alkyl
  • R 6a' represents a phenyl group optionally substituted by one or more substituents selected from C1- alkyl;
  • R 6b' represents a phenyl group optionally substituted by one or more substituents selected from OH, nitro, halo, Ci -4 alkyl and C1.4 alkoxy, or salts and solvates thereof;
  • R 7' independently represents phenyl which is optionally substituted by one or more substituents selected from OH, nitro, halo and C 1-4 alkoxy, provided that:
  • a fifth aspect of the invention relates to the use of the compounds of the fourth aspect of the invention for use in medicine.
  • a sixth aspect of the invention relates to a pharmaceutical formulation including a compound of the fourth aspect of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • Figure . illustrates inhibition assay plots a) to y) for example compounds (i) to (xxv).
  • Figure 2. illustrates the 3D structure of example compound (vi) solved by X-Ray crystallography.
  • Figure 3 illustrates the 3D structure of example compound (xi) solved by X-Ray crystallography.
  • references herein in any aspect or embodiment of the invention, to compounds of formula (I) and compounds of formula (II) includes references to such compounds per se, to tautomers of such compounds, as well as to pharmaceutically acceptable salts or solvates, or pharmaceutically functional derivatives of such compounds.
  • salts include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula (I) or formula (II) with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of formula (I) or formula (II) in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • Examples of pharmaceutically acceptable salts include acid addition salts derived from mineral acids and organic acids, and salts derived from metals such as sodium, magnesium, or preferably, potassium and calcium.
  • acid addition salts include acid addition salts formed with acetic, 2,2- dichloroacetic, adipic, alginic, aryl sulfonic acids (e.g. benzenesulfonic, naphthalene-2- sulfonic, naphthalene-1 ,5-disulfonic and p-toluenesulfonic), ascorbic (e.g.
  • L-glutamic L-glutamic
  • ooxoglutaric glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic
  • lactic e.g. (+)-L-lactic and ( ⁇ )-DL-lactic
  • lactobionic maleic, malic (e.g.
  • salts are salts derived from mineral acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids; from organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, arylsulfonic acids; and from metals such as sodium, magnesium, or preferably, potassium and calcium.
  • mineral acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids
  • organic acids such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, arylsulfonic acids
  • metals such as sodium, magnesium, or preferably, potassium and calcium.
  • solvates are solvates formed by the incorporation into the solid state structure (e.g. crystal structure) of the compounds of the invention of molecules of a non-toxic pharmaceutically acceptable solvent (referred to below as the solvating solvent).
  • solvents include water, alcohols (such as ethanol, isopropanol and butanol) and dimethylsulfoxide.
  • Solvates can be prepared by recrystallising the compounds of the invention with a solvent or mixture of solvents containing the solvating solvent.
  • Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC) and X-ray crystallography.
  • TGE thermogravimetric analysis
  • DSC differential scanning calorimetry
  • X-ray crystallography X-ray crystallography
  • the solvates can be stoichiometric or non-stoichiometric solvates. Particularly preferred solvates are hydrates, and examples of hydrates include hemihydrates, monohydrates and dihydrates.
  • “Pharmaceutically functional derivatives” of compounds of formula (I) or formula (II) as defined herein includes ester derivatives and/or derivatives that have, or provide for, the same biological function and/or activity as any relevant compound of the invention.
  • the term also includes prodrugs of compounds of formula (I) or formula (II).
  • prodrug of a relevant compound of formula (I) or formula (II) includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)).
  • Prodrugs of compounds of formula (I) or formula (II) may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesizing the parent compound with a prodrug substituent.
  • Prodrugs include compounds of formula (I) or formula (II) wherein a hydroxyl, amino, sulfhydryl, carboxyl or carbonyl group in a compound of formula (I) or formula (II) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxyl or carbonyl group, respectively.
  • prodrugs include, but are not limited to, esters and carbamates of hydroxyl functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N- Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs” p. 1-92, Elsevier, New York-Oxford (1985).
  • Compounds of formula (I) or formula (II) may contain double bonds and may thus exist as E (entadel) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.
  • Compounds of formula (I) or formula (II) may contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crysiallisation.
  • the various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e.
  • a 'chiral pool' method by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.
  • treatment includes references to therapeutic or palliative treatment of patients in need of such treatment, as well as to the prophylactic treatment and/or diagnosis of patients which are susceptible to the relevant disease states.
  • patient' and “patients” include references to mammalian (e.g. human) patients.
  • the term "effective amount” refers to an amount of a compound, which confers a therapeutic effect on the treated patient (e.g. sufficient to treat or prevent the disease).
  • the effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).
  • halo when used herein, includes references to fluoro, chloro, bromo and iodo.
  • alkyl refers to a saturated straight chain or branched aliphatic group of 1-12 carbon atoms.
  • alkyl groups are Ci. C 7 alkyl, particularly Ci_C 4 alkyl.
  • alkyl include, but are not limited to, methyl, ethyl, D-propyl, isopropyl, r?-butyl, /-butyl, sec-butyl, f-butyl, n-pentyl, neopentyl, n-hexyl, n- hepty!, cyclopropyl, especially n-butyl.
  • alkoxy refers to a CMO alkyl or alkenyl linked to an oxygen atom. Alkoxy is preferably C 1-7 alkoxy, more preferably C 1-4 alkoxy. Examples of alkoxy groups include, but are not limited to, groups such as methoxy, ethoxy, n-butoxy, ferf-butoxy, and allyloxy.
  • cycloalkyi refers to a saturated or partially saturated (non-aromatic) ring comprising preferably 3 to 15 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the "cycloalkyi” groups preferably contain from 4 to 6 ring carbon atoms.
  • Het a , Het b , Het c and Het d refer to a heterocyclic group.
  • the heterocyclic group may contain up to 5 heteroatom ring members selected from O, N and S, and more particularly up to 4 heteroatom ring members.
  • the heterocyclic group may contain 1 , 2 or 3 heteroatom ring members.
  • Het a , Het b , Het c and Het d may each independently represent a monocyclic, bicyciic or tricyclic 5- to 14- or 3- to 10-membered heterocyclic group, respectively, containing 1 , 2, 3 or 4 heteroatom ring members selected from O, N and S.
  • Het a , Het , Het c or Het d may be selected, for example, from (i) monocyclic heterocyclic groups of 5 to 7 ring members containing 1 , 2, 3 or 4 heteroatom ring members selected from O, N and S; (ii) 6.5 fused bicyciic heterocyclic groups of 9 ring members containing 1 , 2, 3 or 4 heteroatom ring members selected from O, N and S; (iii) 6.6 fused bicyciic heterocyclic groups of 9 ring members containing 1 , 2, 3 or 4 heteroatom ring members selected from O, N and S; (iv) 6.5.6 fused tricyclic heterocyclic groups of 13 ring members containing 1 , 2, 3 or 4 heteroatom ring members selected from O, N and S; (v) 6.6.6 fused tricyclic heterocyclic groups of 14 ring members containing 1 , 2, 3 or 4 heteroatom ring members selected from O, N and S; and (vi) bridged
  • bridged ring systems is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 131- 33, 1992.
  • each of Het a , Het b , Het c and Het d may be selected from the group comprising of azepinyl, diazepinyl, dihydrofuranyl (e.g. 2,3-dihydrofuranyl, 2,5-dyhdrofuranyl), 4,5- dihydro-1 A7-maleimido, dioxolanyl, furanyl, furazanyl, hydantoinyl, imidazolyl, isothiaziolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, 1 ,2- or 1 ,3-oxazinanyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolidinonyl, pyr
  • Compounds of formula (I) or formula (II) may be administered by any suitable route, but may particularly be administered orally, intravenously, intramuscularly, cutaneously, subcutaneously, transmucosally (e.g. sublingually or buccally), rectally, transdermal ⁇ , nasally, pulmonarily (e.g. tracheally or bronchially), topically, by any other parenteral route, in the form of a pharmaceutical preparation comprising the compound in a pharmaceutically acceptable dosage form.
  • Particular modes of administration that may be mentioned include oral, intravenous, cutaneous, subcutaneous, nasal, intramuscular or intraperitoneal administration.
  • Compounds of formula (I) or formula (II) will generally be administered as a pharmaceutical formulation in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which may be selected with due regard to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutically acceptable adjuvant diluent or carrier
  • Such pharmaceutically acceptable carriers may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use.
  • Suitable pharmaceutical formulations may be found in, for example, Remington, The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995).
  • a parenterally acceptable aqueous solution may be employed, which is pyrogen free and has requisite pH, isotonicity, and stability. Suitable solutions will be well known to the skilled person, with numerous methods being described in the literature. A brief review of methods of drug delivery may also be found in e.g. Langer, Science (1990) 249, 1527.
  • any pharmaceutical formulation used in accordance with the present invention will depend on various factors, such as the severity of the condition to be treated, the particular patient to be treated, as well as the compound(s) which is/are employed. In any event, the amount of compound of formula I in the formulation may be determined routinely by the skilled person.
  • a solid oral composition such as a tablet or capsule may contain from 0.0 to 99.99 % (w/w) active ingredient; from 0 to 99% (w/w) diluent or filler; from 0 to 20% (w/w) of a disintegrant; from 0 to 5% (w/w) of a lubricant; from 0 to 5% (w/w) of a flow aid; from 0 to 50% (w/w) of a granulating agent or binder; from 0 to 5% (w/w) of an antioxidant; and from 0 to 5% (w/w) of a pigment.
  • a controlled release tablet may in addition contain from 0 to 90 % (w/w) of a release-controlling polymer.
  • a parenteral formulation (such as a solution or suspension for injection or a solution for infusion) may contain from 0.0 to 50 % (w/w) active ingredient; and from 50% (w/w) to 99% (w/w) of a liquid or semisolid carrier or vehicle (e.g. a solvent such as water); and 0-20% (w/w) of one or more other excipients such as buffering agents, antioxidants, suspension stabilisers, tonicity adjusting agents and preservatives.
  • a liquid or semisolid carrier or vehicle e.g. a solvent such as water
  • one or more other excipients such as buffering agents, antioxidants, suspension stabilisers, tonicity adjusting agents and preservatives.
  • compounds of formula (I) or formula (II) may be administered at varying therapeutically effective doses to a patient in need thereof.
  • the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe.
  • the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease.
  • Administration may be continuous or intermittent (e.g. by bolus injection).
  • the dosage may also be determined by the timing and frequency of administration.
  • the dosage can vary from about 0.01 mg to about 1000 mg per day of a compound of formula (I) or formula (II).
  • the dengue protease activity assay was conducted by modifying the method of Yusof and co-workers (Yusof, R., Clum, S., Wetzel, M., Murthy, H. M. K. and Padmanabhan, R. (2000).
  • Purified NS2B/NS3 serine protease of dengue virus type 2 exhibits cofactor NS2B dependence of cleavage of substrate with dibasic amino acids in vitro. J. Biol. Chem., 275, 9963-9969) and comprised using 200 mM Tris-HCI pH 8.5 as the assay buffer, DENV2 NS2B-NS3pro as the protease and Boc-GRR-MCA as the substrate.
  • the protease optimisation assay was executed to ascertain the maximum protease activity at a constant 5 ⁇ substrate concentration.
  • the protease concentrations were varied within the range of 0-10 ⁇ .
  • the next process including pre-incubation as well as fluorescence intensity measurements was done by using the above mentioned Yusof procedure.
  • the substrate optimisation assay was determined using a constant 3 ⁇ protease at varied substrate concentration (0-50 ⁇ ).
  • the 200 pL reaction assays contained assay buffer, and constant 3 ⁇ protease. The same procedure of pre-incubation was applied. Subsequently, the 7-amino-4-methylcoumarin (AMC) produced were measured as fluorescence intensity at ⁇ excitation 340 nm and ⁇ emission 440 nm by using enzyme-linked immunosorbent assay (ELISA) modulus micro plate reader.
  • AMC 7-amino-4-methylcoumarin
  • Dengue Protease Inhibition Assay was carried out by preparing the reaction mixture containing assay buffer, test samples (a varied concentration of from 0 to 800 pg/mL), and constant 3 ⁇ proteases were pre-incubated at 37°C for 10 minutes with centrifugation at 200 rpm. Then after the addition of 25 ⁇ substrate, the reaction assays were incubated at 37°C for 60 minutes with centrifugation at 200 rpm. The assays were quadruplicated. The fluorescence intensities of 7-amino-4-methylcoumarin (AMC) product were measured by Modulus Microplate Reader with UV optical kit. Examples
  • Compounds of formula (I) may be known and/or may be commercially available. Other compounds of formula (I) (e.g. that are not commercially available) may be prepared in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter.
  • 6-thiouguanine 0.598 mmol
  • Cs 2 C0 3 caesium carbonate
  • DMF dimethylformamide
  • the first mixture was added into the second mixture and the stirring was continued at room temperature for six hours.
  • the reaction progress was monitored by TLC using solvent system of /?-hexane:ethyl acetate (EtOAc) (1 :3).
  • EtOAc solvent system of /?-hexane:ethyl acetate
  • the reaction mixture was diluted with 70 mL of water and then extracted using 3 x 70 mL of EtOAc.
  • the organic phase was collected, washed with 3 x 70 mL of water and then dried over anhydrous magnesium sulfate.
  • the resultant organic phase was then evaporated in vacuo and then purified using PLC with the same solvent system used in the monitoring of the reaction progress.
  • Example compound (vii) 9-cyclopentyl-6-cyclopentylsulfanyl-purin-2-amine.
  • Example compound (ix) 6-(2-pyridylmethylsulfanyl)-9H-purin-2-amine.
  • Example compound (x) N,9-dibenzyl-6-benzylsulfanyl-purin-2-amine.
  • Example compound (xii) N,9-dibenzyl-6-benzylsulfanyl-purin-2-amine.
  • Example compound (xiii) N,N,9-tribenzyl-6-benzylsulfanyl-purin-2-amine.
  • 6-thioguanine (0.598 mmol) was mixed with one molar equivalent of the corresponding aromatic aldehyde and stirred for up to 15 minutes.
  • a liquid mixture of ethanol-NaOH 10% (1.5 mL (1 :1 )) was added to the first mixture and stirred until a yellowish precipitate formed.
  • a second volume of ethanol-NaOH 10% was then added and the stirring was continued until the product was completely formed (monitored by TLC with CHCI 3 - Methanol (2:2) as a solvent).
  • the mixture was neutralized using 6M HCI and the solid product was collected by filtration.
  • the product was then washed with water, ethyl acetate and then recrystallized from a hot methanol to afford the pure product.
  • 6-thioguanine (0.598 mmol) was dissolved in 5 mL of NaOH 10% whilst cooling using an ice bath.
  • a corresponding benzenesulfonyl chloride (0.718 mmol) was carefully added dropwise and the mixture was stirred at room temperature while monitoring the reaction progress using TLC (n-hexane-ethyl acetate (2:2)).
  • 6M HCI was added until the pH of the mixture became neutral.
  • the solid product was collected by filtration, washed with water, followed by washing with cold methanol before drying at 50°C to afford the crude product. The pure product was then afforded by recrystallizing the crude product from hot ethanol.
  • Example compound (xx) 3-methyl-N-[6-(m-tolylsulfonylsulfanyl)-9H-purin- 2yl]benzenesulfonamide.
  • example compound (xxiii) was modified from the procedures found in Hu, Y. L, Liu, X., Lu, M., Ge, Q. and Liu, X. B. (2010). Synthesis of some biologically actives halogenopurines. J. Kor. Chem. Soc, 54, 429-43.6
  • 6-thioguanine (0.598 mmol) was mixed with anhydride acetic acid (Ac 2 0) (1.2 mL) in 1.2 mL of glacial acetic acid (GAA). The mixture was then refluxed at 135°C for 7.5 hours and the reaction progress was monitored by TLC using chloroform (CHCI 3 ) : acetone (AcO) (2:2) as the solvent system. After the product formed, the reaction mixture was diluted with 70 mL of ice water and then extracted using 3 x 70 mL of EtOAc. The organic phase was then collected, washed with 3 x 70 mL of water and then dried over anhydrous magnesium sulfate. The organic phase was then evaporated in vacuo to afford the product as off-white powder.
  • Ac 2 0 anhydride acetic acid
  • GAA glacial acetic acid
  • example compound (xxiv) was modified from the procedures found in Salvatore, R. N., Nagle, A. S. and Jung, K. W. . (2002). Cesium effect: high chemoselectivity in direct N-alkylation of amines. J. Org. Chem., 67, 674-683.
  • example compound (xxv) was modified from the procedures found in Saqib, A., Karigar, C. S., Pasha, M. A. and Harish, M. S. R. (2012). Synthesis, characterization and pharmacological evaluation of palmitic acid derivatives of salicylic acid and anthranilic acid. JPRO, 4, 35-38.
  • 6-thioguanine (0.598 mmol) was mixed with palmitoyi chloride and before the addition of pyridine. The mixture was stirred for 1 hour at a room temperature followed by neutralization using cold 6M HCI. The solid product was then collected by filtration, washed with water, cold methanol and then evaporated to dryness under reduced pressure.
  • Example compounds (i) to (xxv) were found to possess activity in the biological test described above. Biological activity determined by the above mentioned biological test includes IC 50 and % inhibition values for NS2B-NS3 protease. Example compounds (i) to (xxv) were found to have IC 50 values as illustrated in the table below:
  • n-, s-, /- tert- have their usual meanings: normal, secondary, iso and tertiary.

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Abstract

Cette invention concerne l'utilisation de dérivés de thioguanine et leur utilisation pour traiter la dengue ou lutter contre le virus du Nil occidental.
PCT/IB2015/056933 2014-09-11 2015-09-10 Dérivés de thioguanine WO2016038562A1 (fr)

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MYPI2014002618A MY171137A (en) 2014-09-11 2014-09-11 Thioguanine derivatives
MYPI2014002618 2014-09-11

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WO2016038562A1 true WO2016038562A1 (fr) 2016-03-17

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114716439A (zh) * 2022-04-26 2022-07-08 陕西师范大学 一种铜催化合成6-硫代嘌呤衍生物的方法
CN114716439B (zh) * 2022-04-26 2023-08-15 陕西师范大学 一种铜催化合成6-硫代嘌呤衍生物的方法

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