WO2012109573A1 - Thiazoles substitués utilisés en tant qu'agents antiviraux - Google Patents

Thiazoles substitués utilisés en tant qu'agents antiviraux Download PDF

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WO2012109573A1
WO2012109573A1 PCT/US2012/024706 US2012024706W WO2012109573A1 WO 2012109573 A1 WO2012109573 A1 WO 2012109573A1 US 2012024706 W US2012024706 W US 2012024706W WO 2012109573 A1 WO2012109573 A1 WO 2012109573A1
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compound
virus
optionally substituted
derivatives
compounds
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PCT/US2012/024706
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English (en)
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Mark S. Cushman
Abdelrahman S. MAYHOUB
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Purdue Research Foundation
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    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the invention described herein pertains substituted thiazoles, their preparation and their use a antiviral agents.
  • Flavivirus is a genus of the positive-sense single- stranded RNA family
  • Flaviviridae which includes many clinically important species such as dengue, Japanese encephalitis and West Nile viruses. More than 50 million cases of dengue viral infections are reported per year in more than 80 countries in which the mosquito Aedes aegypti is endemic. 1 Of these cases, approximately 500,000 patients suffer the more severe and often lethal illnesses known as dengue hemorrhagic fever and dengue shock syndrome. (1. Munoz-Jordan, J. L.; Sanchez-Burgos, G. G; Laurent-Rolle, M..; Garcia-Sastre, A. Inhibition of Interferon Signaling by Dengue Virus. Proc. Natl. Acad. Sci.
  • Triphosphatase/Helicase Evidence for Activity on the Level of Substrate and/or Enzyme. Antimicrob. Agents Chemther. 2002, 46, 1231-1239; 4. Zhang, N.; H.-Ming Chen; Koch, V.; Schmitz, H.; Minczuk, M.; Stepien, P.; Fattom, A. I.; Naso, R. B.; Kalicharran, K.; Borowski, P.; Hosmane, R. S. Potent Inhibition of NTPase/Helicase of the West Nile Virus by Ring- Expanded ("Fat") Nucleoside Analogues. J. Med. Chem.
  • the flaviviral E-protein plays a crucial role at the first step in viral infection, since it contains a receptor-binding site and also plays a role in fusion. It undergoes substantial conformational and translational changes through the virus replication cycle, thereby causing the native homodimer to change into a fusogenic homotrimer.
  • the dengue virus type 2 E protein has been crystallized in the presence and the absence of «-octyl- ?-D-glucoside ( ⁇ -OG) (11. Modis, Y.; Ogata, S.; Clements, D.; Harrison, S.C. A Ligand-Binding Pocket in the Dengue Virus Envelope Glycoprotein. Proc. Natl. Acad. Sci.
  • R is CHO, carboxylic acid or derivative thereof, optionally substituted alkyl, or optionally substituted heteroaryl;
  • Z is CHO, a ketone, or a carboxylic acid, or a derivative of any of the foregoing; where Z is not C02Me; and
  • Ar is optionally substituted aryl or optionally substituted heteroaryl; and where the compound is not
  • X is adamantylmethoxy or 3,4-dichlorobenzylamino.
  • R is CHO, carboxylic acid or derivative thereof, optionally substituted alkyl, or optionally substituted heteroaryl;
  • Z is CHO or a derivative thereof, a ketone or derivative thereof, or a derivative of a carboxylic acid, or a derivative of any of the foregoing; where Z is not C02Me; and where
  • Z is not an ester or 3,4-dichlorobenzylamide when R is methyl
  • Ar is optionally substituted aryl or optionally substituted heteroaryl.
  • each of R 1 , R2 and R 3 are independently selected from hydrogen, halo, hydroxy, amino, thio, carboxylate or a derivative thereof, sulfinyl or a derivative thereof, sulfonyl or a derivative thereof, or alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted, wherein at least one of R 1 , R2 and R 3 is a sterically demanding or sterically hindered group, such as a branched alkyl, aryl, heteroaryl, arylalkyl, arylalkyl, or heteroarylalkyl acyl group, each of which is optionally substituted; and R 4 is an ester biois
  • A O, S, NH, CH 2 ;
  • B hydrogen or OH, or methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, or propargyl, each of which is optionally substituted;
  • G hydrogen or halo.
  • A-B does not include 0-0 or O-S.
  • compositions for treating a patient having a virus comprising one or more compounds of any one of the preceding embodiments is described.
  • a method for treating a patient having a virus comprising the step of administering to the patient a therapeutically effective amount of one or more compounds or compositions of any one of the preceding embodiments is described.
  • R is CHO, carboxylic acid or derivative thereof, optionally substituted alkyl, or optionally substituted heteroaryl;
  • Z is CHO, a ketone, or a carboxylic acid, or a derivative of any of the foregoing where Z is not C02Me;
  • Ar is optionally substituted aryl or optionally substituted heteroaryl; and where the compound is not
  • X is adamantylmethoxy or 3,4-dichlorobenzylamino.
  • A O, S, NH, CH 2 ;
  • B hydrogen or OH, or methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, propargyl, each of which is optionally substituted;
  • G hydrogen or halo, wherein A-B does not include 0-0 or O-S.
  • composition for treating a patient having a virus, the composition comprising one or more compounds of any one of the preceding clauses.
  • composition of clause 32 further comprising one or more carriers, diluents, or excipients, or a combination thereof.
  • a method for treating a patient having a virus comprising the step of administering to the patient a therapeutically effective amount of one or more compounds or compositions of any one of the preceding clauses.
  • composition further comprises one or more carriers, diluents, or excipients, or a combination thereof.
  • treating includes, but is not limited to, alleviating and/or preventing viral infections, including their signs and symptoms, and primary and secondary complications.
  • the formulae include and represent not only all pharmaceutically acceptable salts of the compounds, but also include any and all hydrates and/or solvates of the compound formulae. It is appreciated that certain functional groups, such as the hydroxy, amino, and like groups form complexes and/or coordination compounds with water and/or various solvents, in the various physical forms of the compounds. Accordingly, the above formulae are to be understood to include and represent those various hydrates and/or solvates. In each of the foregoing and following embodiments, it is also to be understood that the formulae include and represent each possible isomer, such as stereoisomers and geometric isomers, both individually and in any and all possible mixtures. In each of the foregoing and following embodiments, it is also to be understood that the formulae include and represent any and all crystalline forms, partially crystalline forms, and non crystalline and/or amorphous forms of the compounds.
  • the compounds described herein may contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. It is to be understood that in one embodiment, the invention described herein is not limited to any particular sterochemical requirement, and that the compounds, and compositions, methods, uses, and medicaments that include them may be optically pure, or may be any of a variety of stereoisomeric mixtures, including racemic and other mixtures of enantiomers, other mixtures of diastereomers, and the like. It is also to be understood that such mixtures of stereoisomers may include a single stereochemical configuration at one or more chiral centers, while including mixtures of stereochemical configuration at one or more other chiral centers.
  • the compounds described herein may be include geometric centers, such as cis, trans, E, and Z double bonds. It is to be understood that in another embodiment, the invention described herein is not limited to any particular geometric isomer requirement, and that the compounds, and compositions, methods, uses, and medicaments that include them may be pure, or may be any of a variety of geometric isomer mixtures. It is also to be understood that such mixtures of geometric isomers may include a single configuration at one or more double bonds, while including mixtures of geometry at one or more other double bonds.
  • alkyl includes a chain of carbon atoms, which is optionally branched.
  • alkenyl and alkynyl includes a chain of carbon atoms, which is optionally branched, and includes at least one double bond or triple bond, respectively. It is to be understood that alkynyl may also include one or more double bonds. It is to be further understood that in certain embodiments, alkyl is advantageously of limited length, including Ci-C 24 , CrC 12 , Ci-Cg, Ci-Ce, and CrC 4 .
  • alkenyl and/or alkynyl may each be advantageously of limited length, including C 2 -C 24 , C 2 -C 12 , C 2 -Cg, C 2 -C 6 , and C 2 -C 4 . It is appreciated herein that shorter alkyl, alkenyl, and/or alkynyl groups may add less lipophilicity to the compound and accordingly will have different pharmacokinetic behavior.
  • Illustrative alkyl groups are, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2- pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl and the like.
  • cycloalkyl includes a chain of carbon atoms, which is optionally branched, where at least a portion of the chain in cyclic. It is to be understood that cycloalkylalkyl is a subset of cycloalkyl. It is to be understood that cycloalkyl may be polycyclic. Illustrative cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, 2-methylcyclopropyl, cyclopentyleth-2-yl, adamantyl, and the like.
  • cycloalkenyl includes a chain of carbon atoms, which is optionally branched, and includes at least one double bond, where at least a portion of the chain in cyclic. It is to be understood that the one or more double bonds may be in the cyclic portion of cycloalkenyl and/or the non-cyclic portion of cycloalkenyl. It is to be understood that cycloalkenylalkyl and cycloalkylalkenyl are each subsets of cycloalkenyl. It is to be understood that cycloalkyl may be polycyclic.
  • Illustrative cycloalkenyl include, but are not limited to, cyclopentenyl, cyclohexylethen-2-yl, cycloheptenylpropenyl, and the like. It is to be further understood that chain forming cycloalkyl and/or cycloalkenyl is advantageously of limited length, including C 3 -C 24 , C 3 -C 12 , C 3 -C8, C 3 -C 6 , and C5-C 6 . It is appreciated herein that shorter alkyl and/or alkenyl chains forming cycloalkyl and/or cycloalkenyl, respectively, may add less lipophilicity to the compound and accordingly will have different pharmacokinetic behavior.
  • heteroalkyl includes a chain of atoms that includes both carbon and at least one heteroatom, and is optionally branched.
  • Illustrative heteroatoms include nitrogen, oxygen, and sulfur. In certain variations, illustrative heteroatoms also include phosphorus, and selenium.
  • cycloheteroalkyl including heterocyclyl and heterocycle, includes a chain of atoms that includes both carbon and at least one heteroatom, such as heteroalkyl, and is optionally branched, where at least a portion of the chain is cyclic.
  • Illustrative heteroatoms include nitrogen, oxygen, and sulfur. In certain variations, illustrative heteroatoms also include phosphorus, and selenium.
  • Illustrative cycloheteroalkyl include, but are not limited to, tetrahydrofuryl, pyrrolidinyl,
  • aryl includes monocyclic and polycyclic aromatic carbocyclic groups, each of which may be optionally substituted.
  • Illustrative aromatic carbocyclic groups described herein include, but are not limited to, phenyl, naphthyl, and the like.
  • heteroaryl includes aromatic heterocyclic groups, each of which may be optionally substituted.
  • Illustrative aromatic heterocyclic groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl,
  • amino includes the group NH 2 , alkylamino, and dialkylamino, where the two alkyl groups in dialkylamino may be the same or different, i.e. alkylalkylamino.
  • amino includes methylamino, ethylamino, dimethylamino, methylethylamino, and the like.
  • amino modifies or is modified by another term, such as aminoalkyl, or acylamino the above variations of the term amino are included therein.
  • aminoalkyl includes H 2 N-alkyl, methylaminoalkyl, ethylaminoalkyl, dimethylaminoalkyl, methylethylaminoalkyl, and the like.
  • acylamino includes acylmethylamino, acylethylamino, and the like.
  • amino and derivatives thereof includes amino as described herein, and alkylamino, alkenylamino, alkynylamino, heteroalkylamino,
  • heteroalkenylamino heteroalkynylamino, cycloalkylamino, cycloalkenylamino,
  • cycloheteroalkylamino cycloheteroalkenylamino, arylamino, arylalkylamino
  • amino derivative also includes urea, carbamate, and the like.
  • hydroxy and derivatives thereof includes OH, and alkyloxy, alkenyloxy, alkynyloxy, heteroalkyloxy, heteroalkenyloxy, heteroalkynyloxy, cycloalkyloxy, cycloalkenyloxy, cycloheteroalkyloxy, cycloheteroalkenyloxy, aryloxy, arylalkyloxy, arylalkenyloxy, arylalkynyloxy, heteroaryloxy, heteroarylalkyloxy,
  • heteroarylalkenyloxy heteroarylalkynyloxy, acyloxy, and the like, each of which is optionally substituted.
  • hydroxy derivative also includes carbamate, and the like.
  • thio and derivatives thereof includes SH, and alkylthio, alkenylthio, alkynylthio, heteroalkylthio, heteroalkenylthio, heteroalkynylthio, cycloalkylthio, cycloalkenylthio, cycloheteroalkylthio, cycloheteroalkenylthio, arylthio, arylalkylthio, arylalkenylthio, arylalkynylthio, heteroarylthio, heteroarylalkylthio,
  • thio derivative also includes thiocarbamate, and the like.
  • acyl includes formyl, and alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, heteroalkylcarbonyl, heteroalkenylcarbonyl,
  • heteroalkynylcarbonyl cycloalkylcarbonyl, cycloalkenylcarbonyl, cycloheteroalkylcarbonyl, cycloheteroalkenylcarbonyl, arylcarbonyl, arylalkylcarbonyl, arylalkenylcarbonyl,
  • arylalkynylcarbonyl heteroarylcarbonyl, heteroarylalkylcarbonyl, heteroarylalkenylcarbonyl, heteroarylalkynylcarbonyl, acylcarbonyl, and the like, each of which is optionally substituted.
  • carbonyl and derivatives thereof includes the group C(O), C(S), C(NH) and substituted amino derivatives thereof.
  • carboxylate and derivatives thereof includes the group C0 2 H and salts thereof, and esters and amides thereof, and CN.
  • sulfinyl or a derivative thereof includes S0 2 H and salts thereof, and esters and amides thereof.
  • sulfonyl or a derivative thereof includes SO 3 H and salts thereof, and esters and amides thereof.
  • phosphinyl or a derivative thereof includes P(R)0 2 H and salts thereof, and esters and amides thereof, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted.
  • phosphonyl or a derivative thereof includes P0 3 H 2 and salts thereof, and esters and amides thereof.
  • hydroxylamino and derivatives thereof includes NHOH, and alkyloxylNH alkenyloxylNH alkynyloxylNH heteroalkyloxylNH
  • heteroarylalkenyloxylNH heteroarylalkynyloxylNH acyloxy and the like, each of which is optionally substituted.
  • hydrozino and derivatives thereof includes alkylNHNH, alkenylNHNH, alkynylNHNH, heteroalkylNHNH, heteroalkenylNHNH, heteroalkynylNHNH, cycloalkylNHNH, cycloalkenylNHNH, cycloheteroalkylNHNH, cycloheteroalkenylNHNH, arylNHNH, arylalkylNHNH, arylalkenylNHNH,
  • arylalkynylNHNH heteroarylNHNH, heteroarylalkylNHNH, heteroarylalkenylNHNH, heteroarylalkynylNHNH, acylNHNH, and the like, each of which is optionally substituted.
  • optionally substituted includes the replacement of hydrogen atoms with other functional groups on the radical that is optionally substituted.
  • Such other functional groups illustratively include, but are not limited to, amino, hydroxyl, halo, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids and derivatives thereof, carboxylic acids and derivatives thereof, and the like.
  • any of amino, hydroxyl, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and/or sulfonic acid is optionally substituted.
  • the terms "optionally substituted aryl” and “optionally substituted heteroaryl” include the replacement of hydrogen atoms with other functional groups on the aryl or heteroaryl that is optionally substituted.
  • Such other functional groups illustratively include, but are not limited to, amino, hydroxy, halo, thio, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids and derivatives thereof, carboxylic acids and derivatives thereof, and the like.
  • any of amino, hydroxy, thio, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and/or sulfonic acid is optionally substituted.
  • Illustrative substituents include, but are not limited to, a radical -(CH 2 ) x Z , where x is an integer from 0-6 and Z is selected from halogen, hydroxy, alkanoyloxy, including C -C alkanoyloxy, optionally substituted aroyloxy, alkyl, including C -C alkyl, alkoxy, including C -C alkoxy, cycloalkyl, including C 3 -C 8 cycloalkyl, cycloalkoxy, including C 3 -C 8 cycloalkoxy, alkenyl, including C 2 -C 6 alkenyl, alkynyl, including C 2 -C 6 alkynyl, haloalkyl, including CrC 6 haloalkyl, haloalkoxy, including CrC 6 haloalkoxy, halocycloalkyl, including C 3 -C 8 halocycloalkyl, halocycloalkoxy
  • alkyl alkylcarbonylamino, aminoalkyl, CrC 6 alkylaminoalkyl, (CrC 6 alkyl)(Ci-C 6
  • Z x is selected from -C0 2 R 4 and -CONR 5 R 6 , where R 4 , R 5 , and R 6 are each independently selected in each occurrence from hydrogen, C -C alkyl, aryl-Ci-C 6 alkyl, and heteroaryl-Ci-C6 alkyl.
  • therapeutically effective amount refers to that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • the therapeutically effective amount is that which may treat or alleviate the disease or symptoms of the disease at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the total daily usage of the compounds and compositions described herein may be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender and diet of the patient: the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidentally with the specific compound employed; and like factors well known to the researcher, veterinarian, medical doctor or other clinician of ordinary skill.
  • composition generally refers to any product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. It is to be understood that the compositions described herein may be prepared from isolated compounds described herein or from salts, solutions, hydrates, solvates, and other forms of the compounds described herein. It is also to be understood that the compositions may be prepared from various amorphous, non-amorphous, partially crystalline, crystalline, and/or other morphological forms of the compounds described herein. It is also to be understood that the compositions may be prepared from various hydrates and/or solvates of the compounds described herein.
  • compositions that recite compounds described herein are to be understood to include each of, or any combination of, the various morphological forms and/or solvate or hydrate forms of the compounds described herein.
  • compositions may include one or more carriers, diluents, and/or excipients.
  • the compounds described herein, or compositions containing them, may be formulated in a therapeutically effective amount in any conventional dosage forms appropriate for the methods described herein.
  • compositions containing them may be administered by a wide variety of conventional routes for the methods described herein, and in a wide variety of dosage formats, utilizing known procedures (see generally, Remington: The Science and Practice of Pharmacy, (21 st ed., 2005)).
  • administering includes all means of introducing the compounds and compositions described herein to the patient, including, but are not limited to, oral (po), parenteral, intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, and the like.
  • the compounds and compositions described herein may be administered in unit dosage forms and/or formulations containing conventional nontoxic pharmaceutically-acceptable carriers, adjuvants, and vehicles.
  • a therapeutically effective amount of one or more compounds in any of the various forms described herein may be mixed with one or more excipients, diluted by one or more excipients, or enclosed within such a carrier which can be in the form of a capsule, sachet, paper, or other container.
  • Excipients may serve as a diluent, and can be solid, semi-solid, or liquid materials, which act as a vehicle, carrier or medium for the active ingredient.
  • the formulation compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the compositions may contain anywhere from about 0.1% to about 99.9% active ingredients, depending upon the selected dose and dosage form.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents;
  • compositions can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. It is appreciated that the carriers, diluents, and excipients used to prepare the compositions described herein are advantageously GRAS (generally regarded as safe) compounds.
  • emulsifying agents are naturally occurring gums (e.g., gum acacia or gum tragacanth) and naturally occurring phosphatides (e.g., soybean lecithin and sorbitan monooleate derivatives).
  • antioxidants are butylated hydroxy anisole (BHA), ascorbic acid and derivatives thereof, tocopherol and derivatives thereof, butylated hydroxy anisole, and cysteine.
  • preservatives are parabens, such as methyl or propyl p- hydroxybenzoate, and benzalkonium chloride.
  • humectants are glycerin, propylene glycol, sorbitol, and urea.
  • Examples of penetration enhancers are propylene glycol, DMSO, triethanolamine, N,N-dimethylacetamide, ⁇ , ⁇ -dimethylformamide, 2-pyrrolidone and derivatives thereof, tetrahydrofurfuryl alcohol, and AZONE.
  • Examples of chelating agents are sodium EDTA, citric acid, and phosphoric acid.
  • Examples of gel forming agents are
  • CARBOPOL cellulose derivatives, bentonite, alginates, gelatin and polyvinylpyrrolidone.
  • ointment bases are beeswax, paraffin, cetyl palmitate, vegetable oils, sorbitan esters of fatty acids (Span), polyethylene glycols, and condensation products between sorbitan esters of fatty acids and ethylene oxide (e.g., polyoxyethylene sorbitan monooleate (TWEEN)).
  • Span sorbitan esters of fatty acids
  • TWEEN polyoxyethylene sorbitan monooleate
  • C4 and/or C5 substitution references to positions C4 and C5 refer to the 4- and 5- position of the thiazole ring, unless otherwise indicated, on the antiviral activity.
  • Described herein are compounds in which the dibromomethyl and methyl ester moieties are replaced by a variety of substituents. Without being bound by theory, it is believet herein that the methyl ester moiety may be metabolically labile to non-specific esterases in blood plasma and the corresponding free acid analogue has already been established in many cases to be a substantially less active compound. Also described herein are compounds in which the methyl ester at C5 has been replaced by bioisosteres, including but not limited to amides, thioesters, ketones and more sterically bulky or demanding esters, which without being bound by theory are believed herein to be more metabolically stable.
  • Described herein are compounds where Z is a methyl ketone or methyl and ethyl thioester analogues (structures 20, 16, and 15). Both ketone 20 (EC 50 1.3 ⁇ ) and ethyl thioester 15 (EC 50 1.6 ⁇ ) derivatives display approximately double the antiviral potency compared with analogous methyl esters.
  • the methyl thioester 16 (EC 50 1.4 ⁇ , GI 5 o 368.7 ⁇ ) displays high antiviral potency and low cytotoxicity in uninfected cells compared with analogous methyl esters, resulting in a high therapeutic index (TI) for 16 of 263.
  • Flavivirus Envelope Glycoprotein in Its Low-/?H-Induced Membrane Fusion Conformation. EMBO J. 2004, 23, 728-738.
  • the envelope proteins are predicted to be very similar in their overall fold and domain arrangement, including the hinge region, which is highly conserved.
  • One docking pose of is substantially parallel to a docked structure of ⁇ -OG in the dengue viral 2 E protein ⁇ -OG binding pocket.
  • the other pose is substantially anti-parallel to the docked structure of ⁇ -OG.
  • compounds are described herein that are capable of interacting with predetermined residues of viruses.
  • compounds are described herein that are capable of interacting with one or more residues of Dengue viral 2 E protein, including but not limited to Ser274, Gln271, and Gln200.
  • Such interaction may be determined and assessed using a variety of computational methods, including molecular modeling and molecular docking, as well as empirical methods, including X-ray crystallography.
  • the terminal hydroxy group of the dihydroxypropyl moiety of 23 is calculated to have a binding pose that is close to that of the sugar moiety of ⁇ -OG.
  • monobromo derivative 38 showed an improved EC 50 value of 1.6 ⁇ compared with analogous methyl esters.
  • the cytotoxicity of compound 38 was in an acceptable range (GI 50 > 40 ⁇ ).
  • BHK baby hamster kidney cells
  • ⁇ -OG «-octyl- ?-D-glucoside
  • EMCV encephalomyocarditis virus
  • E-protein Envelop-protein
  • FBS fetal bovine serum
  • Luc luciferase
  • MEM minimal essential medium
  • NBS N- bromosuccinimide
  • NCS N-chlorosuccinimide
  • PCR polymerase chain reaction
  • SARs structure-activity relationships
  • TI therapeutic index
  • YFV yellow fever virus
  • IRES internal ribosome entry site.
  • Acid chloride 4 served as a key intermediate for the replacement of the metabolically labile ester with more stable bioisosteres. As shown in Scheme 1, two pathways were used to synthesize it. Hydrolysis of ester 1 gave a low yield of the corresponding free acid because, under the reaction conditions, the carboxylate salt formed in situ underwent SN2 reaction with the adjacent alkyl bromide, forming a cyclic lactone by-product. Bromination of the acid chloride 3, utilizing NBS and UV light as a free radical initiator, gave the dibromo acid chloride derivative 4 in a good yield with no detectable mono or tribromo by-products.
  • the methyl ketone 19 was prepared by utilizing thioamide 18 and the appropriate diketo derivative 17 (Scheme 2). It was discovered that efficient dibromination of the C4 methyl group without detectable bromination of the methyl of the C5 acetyl group required careful control of the amount of NBS used (two equivalents), the solvent (CC1 4 ), and free radical initiation (UV irradiation). Using other chemical-free radical initiators afforded mixtures of different brominated compounds. The site of bromination was assigned to be the C5-methyl , and not the acetyl methyl, based on spectral data.
  • the C5-methyl carbon signal of 19 at 18.34 ppm was not present in the 13 C NMR spectrum of the product 20, which revealed only two signals corresponding to dibromomethyl and acylmethyl groups at 32.00 and 31.28 ppm in the aliphatic region.
  • the mass spectrum showed a base peak at m/z 395, which is believed to correspond to the acylium cation (M + - CH 3 ).
  • Amide derivatives with hydroxyalkyl or carbohydrate moieties were prepared by treatment of acid chloride 4 with the appropriate amines in DMF (Scheme 3).
  • chlorination of the commercially available dicarbonyl compounds 26a-c was performed using sulfuryl chloride to afford the corresponding a-chloro derivatives 27a-d in high yields (Scheme 4).
  • the 1H NMR spectra of these compounds exhibited singlets at approximately ⁇ 5 ppm believed to be due to the methine proton.
  • Aldehyde derivative 35 was treated with acetyl chloride and a catalytic amount of A1C1 3 to afford the dichloromethyl derivative 37, which could not be obtained by treatment of 2 with NCS (Scheme 6).
  • the nitrile derivative 36 was obtained from the reaction of the corresponding aldehyde 35 and ammonia solution. Oxidation of the imine intermediate in situ by elemental iodine provided the required nitrile in quantitative yield (Scheme 6).
  • the sulfone derivative 39 was obtained from the corresponding monobromo derivative 38 (Scheme 7).
  • the thiazole derivatives are evaluated in a yellow fever virus luciferase cellular assay. Without being bound by theory, it is believed herein that modification of R 4 at thiazole- C5 may contribute to both the increase in metabolic stability and potency compared to analogous methyl esters. Described herein is the replacement of the ester group by groups that could be more metabolically stable such as, but not limited to, amides, thioesters, or ketones. Described herein are amides (Scheme 2), the unsubstituted amide 6 and the methyl amide derivative 8 revealed better EC 50 values compared with analogous methyl esters (Table 1).
  • esters 1, 13, and 14 are consistent with a correlation of decreased antiviral activity with an increase in hydrophobicity. It is believed that these observations are consistent with a hydrophobic ally and sterically unfavorable region of the envelope protein surrounding the C-5 substituent of the ligand.
  • the yellowish- white precipitate was purified by silica gel chromatography (ethyl acetate -hexanes 1: 1) to provide the compound as a white solid (3.55 g, 63.7%).
  • Method B NaOH (80 mg, 2 mmol) was added to a solution of methyl ester 1 (423 mg, 1 mmol) in methanol (20 mL) and water (5 mL). The reaction mixture was heated at reflux for 6 h and then allowed to cool to room temperature. The reaction mixture was filtered and the pH of the liquid phase was adjusted to 2 with hydrochloride acid.
  • the solid was filtered and dried and purified by silica gel chromatography (hexanes-ethyl acetate- glacial acetic acid 50:49: 1) to provide the carboxylic acid.
  • the free acid (411 mg, 1 mmol) was heated at reflux with thionyl chloride (7 mL) for 2 h. The solvent was evaporated under pressure. The pale yellow residue was collected and recrystallized from chloroform to yield a white solid product (231.7 mg, 53%): mp 131-132°C.
  • the white flocculant solid was collected by filtration and washed with HC1 (0.1 M, 5 mL) and then water (3 x 10 mL). The white solid was further purified by crystallization from EtOAc to yield a white solid (339.4 mg, 91%): mp 113-114°C.
  • reaction mixture was charged with aqueous Na 2 S 2 0 3 (5% solution), followed by extraction with ethyl acetate (2 x 5 mL) to give the crude nitrile 36, which was purified by column chromatography on silica gel using a mixture of hexane-ethyl acetate (7:3) to yield a white solid (18.5 mg, 99%): mp 142- 143°C.
  • Methyl ester 2 (1.045 g, 3.9 mmol), NBS (767 mg, 4.3 mmol) and benzoylperoxide (10 mg) were added to CC1 4 (25 mL). The reaction mixture was heated at reflux for 24 h. After removal of solvent under reduced pressure, the residual NBS was removed by adding saturated aq NaOH (20 mL), filtering and washing with distilled water. The collected yellowish- white precipitate was purified by silica gel chromatography (ethyl acetate-hexanes 1:4) to provide the compound as a white solid (676 mg, 50%): mp 151-152°C.
  • BHK cells BHK-15 cells obtained from the American Type Culture Collection (ATCC, Rockville, MD) were maintained in MEM (Invitrogen, Carlsbad, CA) containing 10% FBS. Cells were grown in incubators at 37 °C in the presence of 5% C0 2 .
  • YFV-IRES-Luc A fire-fly luciferase reporter gene was inserted into pYF23, a derivative of pACNR which is the full-length cDNA clone of YFV 17D, to construct YFV- IRES-Luc, a luciferase-reporting full-length virus.
  • an Nsil restriction site was introduced at the beginning of the 3'NTR immediately following the UGA termination codon of NS5 in pYF23 using standard overlapping PCR mutagenesis.
  • YFV-IRES-Luc an IRES-FF.Luc (EMCV IRES-fire fly luciferase) cassette was amplified by PCR from YFRP-IRES-Luc, a YFV replicon, and inserted into the Nsil restriction site.
  • IRES-FF.Luc EMCV IRES-fire fly luciferase
  • YFV-IRES-Luc Virus In vitro transcribed YFV-IRES-Luc RNA was transfected into BHK-15 cells using Lipofectamine (Invitrogen, Carlsbad,CA).
  • the resulting YFV-IRES-Luc virus was harvested and the titer of the virus determined by a standard plaque assay.
  • the infectivity of the virus could be assayed directly as a measure of the luciferase amounts produced in infected cells over a period of time.
  • BHK cells were plated in a 96-well plate and grown at 37°C. At confluency, cells were infected with YF-IRES-Luc virus at a multiplicity of infection (MOI) of 0.1. A low MOI was utilized to ensure that fewer cells were infected so that the spread of released virus could be monitored. Cells were then overlaid with culture media containing serial dilutions of compounds at concentrations below the GI 50 values. Controls included uninfected cells, infected cells, and DMSO-treated infected cells.
  • MOI multiplicity of infection
  • Luciferase activity was determined from the luminescence generated with fire-fly luciferase substrate (Promega Inc., Madison, WI). Luminescense was measured in a 96-well-plate luminometer, LMax II (Molecular Devices, Sunnyvale, CA). A reduction in luciferase activity indicates inhibition of YFV-IRES-Luc virus growth. The luciferase luminescence as a function of compound concentration was analyzed by non-linear regression analysis using
  • the IC 50 was defined as the concentration of the compound to cause 50% reduction of luciferase activity in infected cells as compared to the DMSO-treated cells.
  • BHK cells were plated in a 96-well plate and grown at 37°C. At confluency, cells were overlaid with culture media containing serial dilutions of compounds (compound stocks were generated by dissolving compounds in DMSO). Untreated and DMSO-treated cells served as positive controls. Cells were then incubated at 37°C, 5% C0 2 for -36 h. At -36 h post-treatment, media on cells was replaced with fresh media to remove the compounds. Then 10 ⁇ ⁇ of XTT-substrate from the Quick Cell Proliferation Kit (Biovision Inc., CA) was added to each well. Cells were incubated at 37 °C for a further 2 h.
  • the conformers located at the starting point at the each round of simulation were selected for the further energy refinement using the same parameter set as the ones in molecular construction.
  • the minimized conformer with the lowest energy was selected as the optimized conformation of the molecule which was docked into the ⁇ -OG binding pocket of the yellow fever virus E-protein (PDB ID: 10KE).
  • the parameters were set as the default values for GOLD.
  • the maximum distance between hydrogen bond donors and acceptors for hydrogen bonding was set to 3.5 A.
  • the first pose conformation of compounds 1, 23-25, and 39 were merged into the ligand-free protein.
  • the new ligand-protein complex was subsequently subjected to energy minimization using the Amber force field with Amber charges. During the energy
  • the plasma solution was incubated again at 37 °C for an additional 5 min.
  • An aliquot of the compounds 1 and 16 in DMSO (100 ⁇ ) were added to the rat plasma (0.75 mL) and the mixture was incubated at 37 °C throughout the course of the experiment.
  • Aliquots (10 ⁇ ) of the compound- plasma mixture were collected at various time intervals and diluted with methanol (90 ⁇ ) to precipitate any proteins present.
  • the aliquots were mixed and centrifuged at 10,000 rpm for 5- 10 min to pellet the precipitated proteins. After centrifugation, the supernatants (20 ⁇ ) of the aliquots were analyzed by HPLC to determine the residual amount of tested compounds present in the sample.
  • the aliquot supernatants were analyzed using a Waters binary HPLC system (Model 1525, 10 ⁇ ⁇ injection loop) and a Waters dual wavelength absorbance UV detector (Model 2487) set for 254 nM. Data were collected and processed using the Breeze software (version 3.3) on a Dell Optiplex GX280 personal computer.
  • the mobile phase consisted of 85: 15 (v/v) methanol/water and the Sunrise ® HPLC column (4.6 mm x 150 mm) was packed with C18 Silica from Waters. The column was maintained at room temperature during the analyses. The half-life of 1 and 16 were calculated from regression curves fitted to plots of the compound concentration versus time.
  • aReagents and conditions (a, a') NBS, UV irradiation, heat to reflux for 24 h, CCI 4 , 87% for a and 63% for a'; (b, b') i, 80% methanol, NaOH, heat to reflux for 2 h, ii, SOCI 2 , heat to reflux for 2 h, 95% for b and 53% for b'.
  • 20 21 aReagents and conditions: (a) absolute ethanol, heat to reflux for 24 h, 73%; (b) NBS, UV irradiation, heat to reflux for 12 h, CCI 4 , 50%; (c) DMF-DMA, dry toluene, heat to reflux to 24 h, 66%.
  • aReagents and conditions (a) DMF, 23 °C, 0.5-1 h, 12-86%.
  • aReagents and conditions (a) CH 2 CI 2 , S0 2 CI 2 , 23 °C, 2 h, 90-96%; (b) absolute ethanol, heat to reflux for 24 h, 63-96%.
  • the GI 50 is the concentration of the compound causing a 50% growth inhibition of uninfected BHK cells.
  • the EC 50 is the concentration of the compound resulting in a 50% inhibition in virus production.
  • NA indicates that the value was not determined.

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Abstract

L'invention concerne des thiazoles substitués. L'invention concerne également des préparations de thiazoles substitués ainsi que l'utilisation de ces thiazoles substitués comme agents antiviraux.
PCT/US2012/024706 2011-02-11 2012-02-10 Thiazoles substitués utilisés en tant qu'agents antiviraux WO2012109573A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4080457A (en) * 1971-05-05 1978-03-21 Harrison William A Thiazoles and their use in controlling insects and pests
US5614520A (en) * 1990-11-30 1997-03-25 Teijin Limited 2-arylthiazole derivatives and pharmaceutical composition thereof
US7138403B2 (en) * 2001-08-13 2006-11-21 Janssen Pharmaceutica N.V. 2,4,5-trisubstituted thiazolyl derivatives and their antiinflammatory activity
US20090233919A1 (en) * 2004-12-17 2009-09-17 Albert Kudzovi Amegadzie Thiazolopyridinone derivates as mch receptor antagonists
WO2010128163A2 (fr) * 2009-05-08 2010-11-11 Pike Pharma Gmbh Inhibiteurs à petite molécule du virus de la grippe a et b et de la réplication du virus respiratoire syncytial
WO2010129497A1 (fr) * 2009-05-05 2010-11-11 Dow Agrosciences Llc Compositions pesticides

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4080457A (en) * 1971-05-05 1978-03-21 Harrison William A Thiazoles and their use in controlling insects and pests
US5614520A (en) * 1990-11-30 1997-03-25 Teijin Limited 2-arylthiazole derivatives and pharmaceutical composition thereof
US7138403B2 (en) * 2001-08-13 2006-11-21 Janssen Pharmaceutica N.V. 2,4,5-trisubstituted thiazolyl derivatives and their antiinflammatory activity
US20090233919A1 (en) * 2004-12-17 2009-09-17 Albert Kudzovi Amegadzie Thiazolopyridinone derivates as mch receptor antagonists
WO2010129497A1 (fr) * 2009-05-05 2010-11-11 Dow Agrosciences Llc Compositions pesticides
WO2010128163A2 (fr) * 2009-05-08 2010-11-11 Pike Pharma Gmbh Inhibiteurs à petite molécule du virus de la grippe a et b et de la réplication du virus respiratoire syncytial

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LI ET AL.: "Design, Synthesis, and Biological Evaluation of Antiviral Agents Targeting Flavivirus Envelope Proteins", J. MED. CHEM., vol. 51, no. 15, 14 August 2008 (2008-08-14), pages 1 - 32 *
MAYHOUB ET AL.: "An Oxidation of Benzyl Methyl Ethers with NBS that Selectively Affords Either Aromatic Aldehydes or Aromatic Methyl Esters", J. ORG. CHEM., vol. 75, no. 10, 21 May 2010 (2010-05-21), pages 1 - 22 *

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