WO2010028781A1 - 2'-désoxyguanosines 8- et 6,8-substituées et utilisations de celles-ci - Google Patents

2'-désoxyguanosines 8- et 6,8-substituées et utilisations de celles-ci Download PDF

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Publication number
WO2010028781A1
WO2010028781A1 PCT/EP2009/006423 EP2009006423W WO2010028781A1 WO 2010028781 A1 WO2010028781 A1 WO 2010028781A1 EP 2009006423 W EP2009006423 W EP 2009006423W WO 2010028781 A1 WO2010028781 A1 WO 2010028781A1
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Prior art keywords
deoxyguanosine
bis
butyldimethylsilyl
pyridyl
substituted
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PCT/EP2009/006423
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English (en)
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Nathan Luedtke
Anaëlle DUMAS
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Universität Zürich
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/173—Purine radicals with 2-deoxyribosyl as the saccharide radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to new 8-substituted and 6,8-disubstituted 2 -deoxyguano- sines and precursors for preparing these as well as methods for preparing said compounds and precursors. Moreover, the present invention is directed to the use of one or more of these compounds for preparing a medicament, preferably a medicament for the treatment and/or prevention of cancer, infections, autoimmune diseases, cardiovascular diseases, inherited genetic diseases, skin diseases and primary immunodeficiency diseases. In addition, the present invention concerns a pharmaceutical or diagnostic composition comprising the new 8-substituted and 6,8- disubstituted 2 -deoxyguanosines as well as diagnostic and medical methods involving these.
  • Nucleoside derivatives and analogues are a family of biologically active compounds that can be used to treat viral infections, bacterial infections, parasites and cancer. Nucleoside derivatives that closely mimic the natural metabolites can act as enzyme inhibitors and can disrupt the function of undesired RNA and DNA activities during cycles of viral, parasitic, bacterial and/or cancer cell replication and respiration. Nucleoside drugs used to treat hemic malignancies and solid tumours include cytosine arabinoside, fludarabine, cladribine and gemcitabine. Common nucleoside drugs used to treat viral infections include penciclovir, stavudine, acyclovir, ganciclovir and famciclovir.
  • Nucleoside analogues and their derivatives can also inhibit the enzymes involved in the biosynthesis of nucleotides and can activate the caspase cascade leading to cell death.
  • nucleoside synthesis and use are, for example, US Patent No. 5,726,174 (Nucleoside analogues), US Patent No. 6,306,899 (Inhibition and treatment of Hepatitis B virus and Flavivirus by Helioxanthin and its analogs), US Patent No. 7,405,204 (Nucleoside compounds for treating viral infections) as well as US Patent No. 6,436,945 (Substituted O6-benzyl-8-aza-guanines).
  • R1 denotes a linear or branched, substituted or non-substituted alkyl, alkenyl, alkynyl, alkylidene, aryl, heteroaryl, or carbocycle
  • R2 denotes independently of one another H, hydroxy I, thiol, seleno, azido, amino or a monovalent straight chain or cyclic radical ether (-OR1), thioether (-SR1), sulfate, phosphate, diphosphate, triphosphate, phosphate diester (-OPO 3 RI), phosphate triester (-OPO 3 (RI) 2 ) or cyclic derivatives thereof, and their diastereomers or enantiomers in the form of their acids, bases or salts of physiologically acceptable acids or bases.
  • R1 denotes a linear or branched, substituted or non-substituted alkyl, alkenyl, alkynyl, alkylidene, aryl, heteroaryl, or carbocycle
  • R2 denotes independently of one another H, hydroxy I, thiol, seleno, azido, amino or a monovalent straight chain or cyclic radical ether (-OR1), thioether (-SR1), sulfate, phosphate, diphosphate, triphosphate, phosphate diester (-OPO 3 RI), phosphate triester (-OPO 3 (RI) 2 ) or cyclic derivatives thereof
  • R3 denotes a linear or branched, substituted or non-substituted alkyl, alkenyl, alkynyl, alkylidene, aryl, heteroaryl, carbocycle, silyl (-Si(RI) 3 ) or alkylsilyl group, and their di
  • the present invention relates to precursors for preparing 8-substituted and 6,8-disubstituted 2 -deoxyguanosines containing at least a protecting group R3 at position 06 and an activating group R4 in the ⁇ -position.
  • precursors of the invention may comprise additional protecting groups in the R5 and R6 position shown below.
  • the precursors are compounds of formula (III)
  • R3 denotes a protecting group, preferably a linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkylidene, aryl, heteroaryl, carbocycle, silyl (- Si(RI) 3 ) or alkylsilyl group
  • R4 denotes an activating group, preferably a halogen, ethynyl, boronic acid, boronic acid ester (-B(ORI) 2 ), stannane (-Sn(RI) 3 ), triflate, sulfonate (-OSO 2 RI) or phosphate triester (-OPO 3 (RI) 2 )
  • R5 denotes an amine or a protecting group, preferably an amide (-NHC(O)-RI), carbamate (-NHC(O)-ORI), thiocarbamate (-NHC(O)-SRI), urea (-NHC(O)
  • Precursor compounds of formula (III) can be chemically transformed into preferred precursor compounds of formula (IV):
  • R1 denotes a linear or branched, substituted or non-substituted alkyl, alkenyl, alkynyl, alkylidene, aryl, heteroaryl, or carbocycle.
  • R3 denotes a protecting group, preferably a linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkylidene, aryl, heteroaryl, carbocycle, silyl (-Si(RI) 3 ) or alkylsilyl group
  • R5 denotes an amine or a protecting group, preferably an amide (-NHC(O)-RI), cabamate (-NHC(O)- 0R1), thiocarbamate (-NHC(O)-SRI), urea (-NHC(O)-NHRI), thiourea (-NHC(S)-NHRI) or sulphonamide (-NHS(O 2 )-
  • each R1 group is selected independently of one another from the above definitions.
  • the compound according to the invention is selected from the group consisting of 8-bromo-3 l ,5'-O-bis(te/t-butyldimethylsilyl)-2'-deoxy- guanosine (3), 8-bromo-3',5'-O-bis(terf-butyldimethylsilyl)-O 6 -benzyl-2'-deoxyguanosine (4), 8-(2-pyridyl)-3',5 I -O-bis(fert-butyldimethylsilyl)-O 6 -benzyl-2 1 -deoxyguanosine (5), 8- (3-pyridyl)-3',5'-O-bis(te/t-butyldimethylsilyl)-O 6 -benzyl-2 1 -deoxyguanosine (6), 8-(4- pyridyl)-3',5 l -O-bis(teAt-butyl)
  • linear or branched, substituted or non-substituted indicate that each one of the subsequent terms is to be interpreted as being modified by said antecedent term.
  • linear or branched, substituted or non-substituted alkyl, alkenyl, alkynyl, alkylidene, carbocycle encompasses linear or branched, substituted or non-substituted alkyl; linear or branched, substituted or non-substituted alkenyl; linear or branched, substituted or non-substituted alkynyl; linear or branched, substituted or non- substituted alkylidene; and linear or branched, substituted or non-substituted carbocycle.
  • C 2 -C 12 alkenyl, alkynyl or alkylidene indicates the group of compounds having 2 to 12 carbons and alkenyl, alkynyl or alkylidene functionality.
  • heteroatom shall be understood to mean atoms other than carbon and hydrogen such as and preferably O, N, S and P.
  • alkyl, alkenyl, alkynyl, alkylidene, etc. shall be understood as encompassing linear as well as branched forms of carbon-containing chains where structurally possible.
  • one or more carbon atoms can be optionally replaced by heteroatoms, preferably by O 1 S or N. If N is not substituted it is NH.
  • the heteroatoms may replace either terminal or internal carbon atoms within a linear or branched carbon chain.
  • Such groups can be substituted as herein described by groups such as oxo to result in definitions such as but not limited to alkoxycarbonyl, aery I, amido and thioxo.
  • Carbocycle shall be understood to mean an aliphatic hydrocarbon radical containing from 3 to 20, preferably 3 to 12 carbon atoms, more preferably 5 or 6 carbon atoms.
  • Carbocylces include hydrocarbon rings containing from 3 to 20, preferably 3 to 10 carbon atoms.
  • These carbocycles may be either aromatic or non-aromatic systems.
  • the non-aromatic ring systems may be mono- or polyunsaturated.
  • Preferred carbocycles include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, decahydronaphthyl, benzocycloheptanyl, and benzocycloheptenyl. Certain terms for cycloalkyl such as cyclobutanyl and cyclobutyl shall be used interchangeably.
  • cycloalkyl shall be understood to mean aliphatic hydrocarbon-containing rings having from 3 to 20, preferably 3 to 12 carbon atoms. These non-aromatic ring systems may be mono- or polyunsaturated, i.e. the term encompasses cycloalkenyl and cycloalkynyl.
  • the cycloalkyl may comprise heteroatoms, preferably O, S or N, and be substituted or non-substituted.
  • cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, benzocyclobutanyl, benzocycloheptanyl und benzocycloheptenyl.
  • heterocyclic refers to a stable non-aromatic, preferably 3 to 20-membered, more preferably 3 to 12-membered, most preferably 5 or 6-membered, monocyclic or multicyclic, preferably 8 to 12-membered bicyclic, heteroatom-containing cyclic radical, that may be either saturated or unsaturated.
  • Each heterocycle consists of carbon atoms and one or more, preferably 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulphur.
  • the heterocyclic residue may be bound to the remaining structure of the complete molecule by any atom of the cycle, which results in a stable structure.
  • heterocycles include, but are not limited to, pyrrolidinyl, pyrrolinyl, morpho- linyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, dioxalanyl, piperidinyl, piperazinyl, tetrahydrofuranyl, 1-oxo- ⁇ 4-thiomorpholinyl, 13-oxa-11-aza- tricyclo[7.3.1.0-2,7]tridecy-2,4,6-triene, tetrahydropyranyl, 2-oxo-2H-pyranyl, tetrahydrofuranyl, 1 ,3-dioxolanone, 1 ,3-dioxanone, 1 ,4-dioxanyl, 8-oxa-3-aza-bicyclo[3.2.1]octanyl, 2-oxa-5-aza-bicyclo[2.2.1]h
  • aryl as used herein shall be understood to mean an aromatic carbocycle or heteroaryl as defined herein.
  • Each aryl or heteroaryl unless otherwise specified includes its partially or fully hydrogenated derivative.
  • quinolinyl may include decahydroquinolinyl and tetrahydroquinolinyl; naphthyl may include its hydrogenated derivatives such as tetrahydronaphthyl.
  • Other partially or fully hydrogenated derivatives of the aryl and heteroaryl compounds described herein will be apparent to one of ordinary skill in the art.
  • the term encompasses aralkyl and alkylaryl, both of which are preferred embodiments for practicing the compounds of the present invention.
  • aryl encompasses phenyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl and decahydronaphthyl.
  • heteroaryl shall be understood to mean an aromatic C 3 -C 2O , preferably 5 to 8- membered monoxyclic or preferably 8 to 12-membered bicyclic ring containing 1 to 4 heteroatoms such as N, O and S.
  • heteroaryls comprise aziridinyl, thienyl, furanyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, quinolinyl, quinazolinyl, naphthyridinyl, indazolyl, triazolyl, pyrazolo[3,4-b]pyrimidinyl, purinyl, pyrrolo[2,3- bjpyridinyl, pyrazole[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5
  • nitrogen and sulphur include any oxidized form of nitrogen and sulphur and the quaternized form of any basic nitrogen as long as the resulting compound is chemically stable.
  • -S-C 1-6 alkyl radical shall be understood to include -S(O)-Ci -6 alkyl and -S(O) 2 -Ci -6 alkyl.
  • the compounds of the invention are only those which are contemplated to be 'chemically stable' as will be appreciated by those skilled in the art.
  • compounds having a 'dangling valency' or a 'carbanion' are not compounds contemplated by the inventive concept disclosed herein.
  • R1 is a linear or branched, substituted or non-substituted, alkyl, aryl, alkenyl, alkynyl, arylalkyl, arylalkenyl or arylalkynyl group of preferably 1 to 20, more preferably 1 to 10 carbons, most preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, phenyl, pyridyl, naphthyl, biphenyl, furanyl, pyrrolyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, indolyl, aryl groups substituted with one
  • R3 is a linear or branched, substituted or non- substituted alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, aryl or heteroaryl group, silyl (-Si(RI) 3 ) or alkylsilyl group of preferably 1 to 20, more preferably 1 to 10 carbons.
  • the compounds and precursor compounds of the present invention can be prepared without any undue burden or inventive skill by any appropriate conventional synthetic strategy known to those of skill in organic chemistry and as demonstrated below and in the examples in combination with Figures 1 to 5.
  • the compounds of formula I and Il contain substitutions at the 8-position (R1) of guanosine alone (I) or in combination with variable groups at the 6 position (R3) (II).
  • the present invention relates to methods for preparing compounds of formula I, Il and IV.
  • the two key features of this method are the addition of a protecting group (R3) to the 06-position of 2'-deoxyguanosine (dG) and the activation of the 8- position, e.g. by the addition of a halogen, boron, triflate, tin or the like to the 8-position of dG (R4).
  • R3 protecting group
  • dG 2'-deoxyguanosine
  • R4 the activation of the 8- position, e.g. by the addition of a halogen, boron, triflate, tin or the like to the 8-position of dG (R4).
  • the resulting 8-activated, 06-protected 2'-deoxyguanosines are useful as precursors for highly efficient metal-catalysed carbon-carbon bond forming reactions to install new groups at the 8-position of dG.
  • the method of the invention comprises the preparation of precursors by adding a protecting group to the 06-position and an activating group to the 8-position of 2'-deoxyguanosine (dG). More preferably, said method further comprises the use of said precursors in metal-catalyzed cross-coupling reactions to modify the 8-position of dG through carbon-carbon bond formation. Most preferably, said method comprises the (optionally selective) deprotection to furnish compounds either lacking (compounds of formula (I)) or still containing a group at the 06-position (compounds of formula (II) to provide 8-substituted and 6,8-disubstituted 2'-deoxyguanosines, respectively.
  • the term precursor as used herein is meant to refer to modified 2 -deoxyguanosines comprising both a protecting group R3 at 06 and an activating group R4 at the 8- position.
  • An "activating group” refers to functional groups for use in carbon-carbon forming reactions including, but not limited to, halogens (e.g. Cl, Br, I), triflate (- OSO 2 CF 3 ), boronic acids (-B(OH) 2 ), boronic acid esters (-B(ORI) 2 ), stannanes (- Sn(RI) 3 ) and the like.
  • a “protecting group” refers to functional groups that do not participate directly in carbon-carbon forming reactions, but facilitate this reaction by preventing side reactions. The protecting groups may or may not be removed after the carbon-carbon forming reactions.
  • the present invention is directed to a method for preparing compound IV as defined above, comprising the step of reacting compound III as defined above with an activated compound of the general structure R1-R4 in the presence of a suitable metal catalyst (cat.) to substitute the R4-group of said activated compound III for an R1 group, wherein R1 , R3, R4, R5 and R6 are as defined above, according to the following reaction:
  • Preferred metal catalysts for the above reaction are selected from the group consisting of phosphine palladium catalysts, preferably tetrakis(triphenylphosphine)palladium(0) (Pd(PPh 3 ) 4 ), dichlorobis(triphenylphosphine)palladium(ll) (Pd(PPh 3 ) 2 CI 2 ), dichlorobis- (tricyclohexylphosphine)palladium(ll) (Pd(PcHex 3 ) 2 CI 2 ), dichloro-(1 ,2-bis(diphenyl- phosphino)ethane)palladium(ll) (Pd(dppe)CI 2 ), dichloro-(1 ,2-bis(diphenylphosphino)- ferrocenyl)palladium(ll) (Pd(dppf)CI 2 ); palladium(O) precursors such as Pd(OAc) 2 used in combination with phosphine
  • the present invention is directed to a method for preparing compound I as defined above, comprising the step of removing R3, substituting R5 by NH 2 and substituting R6 by R2 of compound IV, wherein R1 to R3 and R5 and R6 are as defined above, according to the following reaction:
  • this deprotection can also be performed selectively, i.e. by deprotecting R5 and R6 only and leaving R3 in the 06 position in order to arrive at compounds of formula (II).
  • the present invention concerns a method for preparing compound Il of the invention, comprising the step of selectively substituting R5 by NH 2 and substituting R6 by R2 of compound IV as defined above, wherein R1 to R3 and R5 and R6 are as defined above, according to the following reaction:
  • the method for preparing compound I comprises preparing compound (IV) from compound (III) and then preparing compound I from compound (IV) as illustrated above.
  • the method for preparing compound Il comprises preparing compound (IV) from compound (III) and then preparing compound Il from compound (IV) as illustrated above.
  • the invention includes pharmaceutically acceptable derivatives of compounds of formula (I) and (II).
  • a "pharmaceutically acceptable derivative” refers to any pharmaceutically acceptable salt or ester or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound of the invention, or a pharmacologically active metabolite or pharmacologically active residue thereof.
  • a pharmacologically active metabolite shall be understood to mean any compound of the invention capable of being metabolized enzymatically or chemically. This includes, for example, hydroxylated or oxidized derivative compounds of the formula (I) or (II).
  • Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • acids examples include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric and benzenesulfonic acids.
  • Other acids such as oxalic acid, while not themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds and their pharmaceutically acceptable acid addition salts.
  • Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g. magnesium), ammonium and N-(C 1 -C 4 BIkYl) 4 + salts.
  • prodrugs of compounds of formula (I) and (II) include those compounds that, upon simple chemical transformation, are modified to produce compounds of the invention. Simple chemical transformations include hydrolysis, oxidation and reduction. Specifically, when a prodrug is administered to a patient, the prodrug may be transformed into a compound disclosed hereinabove, thereby imparting the desired pharmacological effect.
  • another aspect of the present invention relates to the use of one or more compounds of the invention for preparing a medicament.
  • one or more compounds of the present invention are used for preparing a medicament for the treatment and/or prevention of a disease or medical condition selected from the group consisting of cancer, preferably hemic malignancies and solid tumours, infections, preferably viral, bacterial and parasitic infections, autoimmune diseases, preferably rheumatoid arthritis and multiple sclerosis, cardiovascular diseases, preferably atherosclerosis, inherited genetic diseases, preferably cystic fibrosis, skin diseases, preferably psoriasis, and primary immunodeficiency diseases, preferably Boder-Sedgwick syndrome.
  • cancer preferably hemic malignancies and solid tumours
  • infections preferably viral, bacterial and parasitic infections
  • autoimmune diseases preferably rheumatoid arthritis and multiple sclerosis
  • cardiovascular diseases preferably atherosclerosis
  • inherited genetic diseases preferably cystic fibrosis
  • skin diseases preferably psoriasis
  • primary immunodeficiency diseases preferably Boder-Sedgwick syndrome.
  • the present invention also relates to a pharmaceutical composition, comprising as active substance one or more compounds according to the invention or pharmaceutically acceptable derivatives or prodrugs thereof, optionally combined with conventional excipients and/or carriers.
  • the present invention relates to a method for the treatment and/or prevention of a disease or medical condition comprising the step of administering a pharmaceutical composition according to the invention to a patient in need thereof.
  • the compounds of the invention may be administered in any conventional dosage form in any conventional manner.
  • Routes of administration include, but are not limited to, intravenously, intramuscularly, subcutaneously, intra- synovially, by infusion, sublingually, transdermally, orally, topically, or by inhalation.
  • the preferred modes of administration are oral and intravenous.
  • the compounds may be administered alone or in combination with adjuvants that enhance stability of the compounds, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase cytotoxic activity, provide adjunct therapy, and the like, including other active ingredients.
  • Advantageously such combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies.
  • the above described compounds may be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition.
  • Reference is this regard may be made to Cappola et al.: U.S. patent application no. 09/902,822, PCT/US 01/21860 und US provisional application no. 60/313,527, each incorporated by reference herein in their entirety.
  • the compounds may then be administered together in a single dosage form.
  • the pharmaceutical compositions comprising such combinations of compounds contain at least about 5 %, but more preferably at least about 20 %, of a compound of formula (I) or (II) (w/w) or a combination thereof.
  • w/w percentage of a compound of the invention
  • the compounds may be administered separately (either serially or in parallel). Separate dosing allows for greater flexibility in the dosing regime.
  • dosage forms of the compounds described herein include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art.
  • carriers and adjuvants include, for example, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes and cellulose-based substances.
  • Preferred dosage forms include, tablet, capsule, caplet, liquid, solution, suspension, emulsion, lozenges, syrup, reconstitutable powder, granule, suppository and transdermal patch. Controlled release dosage forms with or without immediate release portions are also envisaged. Methods for preparing such dosage forms are known (see, for example, H. C. Ansel and N. G.
  • Dosage levels and requirements are well-recognized in the art and may be selected by those of ordinary skill in the art from available methods and techniques suitable for a particular patient. In some embodiments, dosage levels range from about 1 - 100 mg/dose for a 70 kg patient. Although one dose per day may be sufficient, up to 5 doses per day may be given. For oral doses, up to 2000 mg/day may be required. Reference in this regard may also be made to US provisional application no. 60/339,249. As the skilled artisan will appreciate, lower or higher doses may be required depending on particular factors.
  • the compounds of the present invention can be administered the same way as other cytotoxic nucleoside compounds.
  • they are administered orally, preferably as hydrochloride salts.
  • Each capsule may contain 10 to 500, preferably 150 to 300, more preferably 200 to 250 mg of a compound of the invention.
  • non-medicinal ingredients in capsules for the compounds of the present invention are - capsule shell: D&C yellow No. 10, FD&C blue No. 1 , FD&C red No. 3, FD&C yellow No. 6, gelatin and titanium dioxide. Bottles of 100. (see also Martindale: the complete drug reference, 34 th Edition, 2005, Pharmaceutical Press, p 612.)
  • the compounds (I) and (II) of the invention exhibit substantial fluorescent properties that make them useful for preparing a fluorescent diagnostic substance or composition, preferably a diagnostic fluorescent probe for in vitro and/or in vivo use.
  • the compounds of the invention can be combined with specific marker substances, e.g. antibodies, diabodies, etc. that bind specifically to biological structures that are indicative of a healthy or diseased biology in a mammal, mammalian tissue or mammalian cell.
  • specific marker substances e.g. antibodies, diabodies, etc. that bind specifically to biological structures that are indicative of a healthy or diseased biology in a mammal, mammalian tissue or mammalian cell.
  • the fluorescent action of the compounds will allow for specifically detecting, locating and quantifying target structures in a compound-bound or unbound state.
  • a diagnostic composition comprising as active substance one or more compounds of the invention or pharmaceutically acceptable derivatives or prodrugs thereof, optionally combined with conventional excipients and/or carriers, is used in a method for the diagnosis of a disease or medical condition comprising the step of adding or administering a diagnostic composition of the invention to a diagnostic sample or a patient in need thereof.
  • a further aspect of the invention relates to the use of the inventive compounds as optical sensors.
  • inventive compounds can be used as metal ion sensors, preferably for detecting and/or quantifying Cd (II), Cu(II), Ni(II), Pd(II), Pt(II), Hg(II) and Zn (II), preferably in diagnostic kits as well as in other diagnostic equipment.
  • Cd (II) Cu(II), Ni(II), Pd(II), Pt(II), Hg(II) and Zn (II)
  • diagnostic kits as well as in other diagnostic equipment.
  • evidence for the suitability of the inventive compounds for said purpose is provided in example 6 below.
  • Fig. 1 Synthesis and use of precursor 8-bromo-3',5'-O-bis(teff-butyldimethylsilyl)-O 6 - benzyl-2'-deoxyguanosine (4) in carbon-carbon bond forming reactions for preparing compounds (5 - 7). Removal of the TBDMS protecting group generates the corresponding 6,8-disubstituted 2'-deoxyguanosines (8 - 10).
  • Fig. 2 Synthesis and use of precursor 8-bromo-3',5'-O-bis(te/t-butyldimethylsilyl)-O 6 - (trimethylsilyl-ethylether)-2'-deoxyguanosine (11) in carbon-carbon bond forming reactions,
  • Fig. 6 lists the photophysical properties of selected 8-aryl-2'-deoxyguanosines.
  • ⁇ AbS max indicates the wavelength of maximal absorbance
  • ⁇ Em max indicates the wavelength of maximal fluorescence emission
  • ⁇ indicates the molar extinction coefficient (cm 1 M "1 ) at the indicated ⁇ Abs max
  • ⁇ (H 2 O) indicates the quantum yield in water
  • ⁇ (CH 3 CN) indicates the quantum yield in acetonitrile.
  • Fig. 7 lists the cytotoxic activities of selected 8-aryl-2'-deoxyguanosines.
  • a standard viability assay was used to quantify metabolic activity of cancer cells (skMel28, MCF7, Mac, or B16-F10 cells) exposed to variable concentrations of 8-aryl-2'-deoxyguanosines for 24 hours.
  • Example 1 General synthetic route with reference to Fig. 1
  • the 0(6) position of 2'-deoxyguanosine was protected with a benzyl group (R3) to furnish the precursor compound 8-bromo-3',5'-O-bis(te/f-butyldimethyl- silyl)-O 6 -benzyl-2'-deoxyguanosine (4) (Fig.
  • compound (24) was deprotected by action of tetrabutylammonium fluoride trihydrate (TBAF) to furnish the corresponding 8-substituted 2'-deoxyguanosine: 8-(6-indolyl)-2'- deoxyguanosine (25) (Fig. 3).
  • TBAF tetrabutylammonium fluoride trihydrate
  • Example 4 General synthetic route with reference to Fig. 4
  • 8-bromo-3 1 ,5 I -O-bis(tert-butyldimethylsilyl)-O 6 -(trimethylsilyl- ethylether)-2'-deoxyguanosine (11) was converted into precursor 8-(alkynyl)-3',5'-O- bis(fert-butyldimethylsilyl)-O 6 -(trimethylsilyl-ethylether)-2'-deoxyguanosine (26) using a metal-catalyzed cross-coupling reaction with trimethylsilyl (TMS) acetylene followed by deprotection of TMS under basic conditions (Fig. 4).
  • TMS trimethylsilyl
  • compound (28) was deprotected by action of tetrabutylammonium fluoride trihydrate (TBAF) to furnish the corresponding 8-substituted 2'-deoxyguanosine: 8-(1- methyl-4-trizyl)-2'-deoxyguanosine (29) (Fig. 4).
  • TBAF tetrabutylammonium fluoride trihydrate
  • compound (31) was deprotected by action of tetrabutylammonium fluoride trihydrate (TBAF) to furnish the corresponding 8-substituted 2'-deoxyguanosine: 8-(3-thiophyl)-2'-deoxyguanosine (29) (Fig. 5).
  • TBAF tetrabutylammonium fluoride trihydrate
  • ⁇ R is the quantum yield of the reference
  • / and I R are the integrated emission intensities of the probe and the reference respectively
  • OD and OD R are the optical densities of the probe and the reference respectively
  • n and n R the refractive indexes of the solvent for the probe and the reference respectively.
  • 8-aryl substituted 2' deoxyguanosines show relatively high molar extinction coefficients and emission maxima well into the visible range (Fig. 6). Many of these compounds exhibit high quantum yields in acetonitrile and are quenched by water, highlighting the promising environmentally-sensitive emission and ability to act as chemosensors.
  • the medical utility i.e. cytotoxicities of selected 8-substituted 2'-deoxy- guanosines in cancer tissues
  • cytotoxicities of selected 8-substituted 2'-deoxy- guanosines in cancer tissues was assessed using a standard assay (for details see Liu, D. Bull. Environmental Contamination Toxicology, 1981 , 26, 145-149; Strotmann, U. J., Butz, B., Bias, W-R. Ecotoxicology Environmental Safety, 1993, 25, 79-89) that evaluates metabolic activity as a function of compound concentration.
  • the concentration of the compound needed to inhibit metabolic activity by 50% is defined as the EC50 value (Fig. 7).
  • selected 8-substituted 2'-deoxyguanosines in particular 8-(4-pyridyl)-2'-deoxyguanosine (20) and 8-(2-thiophyl)-2'-deoxyguanosine (22) were highly cytotoxic to cancer tissues.
  • Triphenylphosphine (685 mg, 2.60 mmoles) and diethyldiazocarboxylate (DEAD) 40% in toluene (1.24 ml_, 2.50 mmoles) were dissolved in anhydrous dioxane (20 ml_). The mixture was stirred at room temperature for 10 minutes and then 2-(trimethylsilyl)- ethanol (308.3 mg, 371.87 uL, 2.80 mmoles) was added. The mixture was stirred for 15 minutes at room temperature and 8-bromo-3',5 I -O-bis(te/t-butyldimethylsilyl)-2 l - deoxyguanosine (3) (1 g, 1.74 mmoles) was added.
  • DEAD diethyldiazocarboxylate
  • reaction mixture was degassed with argon for 30 minutes, and then tetrakis(triphenylphosphine) palladium (30.8 mg, 0.12 mmoles) was added, followed by an aqueous Na 2 CO 3 3M solution (222 uL) and toluene (2.7 ml_), both previously degassed with argon.
  • the reaction was stirred under argon at 80 0 C for 24 hours.
  • the reaction mixture was then diluted with DCM, washed with a saturated solution of Na 2 CO 3 twice, dried with Na 2 SO 4 , filtered and evaporated.
  • the crude material was purified by column chromatography (Hex:AcOEt 9:1) to yield 90 mg (87 %) of a yellow solid.
  • the solid residue was then washed in a glass tube by addition of a solvent, sonication, centrifugation and removal of the supernatant with a glass pipette. This operation was performed four times with hexane (ca. 1 mL) and twice with methanol (ca. 400 uL). The residue was then dried to yield 6 mg (27 %) of a white solid.
  • the solid residue was then washed in a glass tube by addition of a solvent, sonication, centrifugation and removal of the supernatant with a glass pipette. This operation was performed four times with water (ca. 500 uL) and four times with methanol (ca. 500 uL). The residue was then dried to yield 16 mg (14 %) of a yellowish solid.
  • the solid residue was then washed in a glass tube by addition of a solvent, sonication, centrifugation and removal of the supernatant with a glass pipette. This operation was performed four times with hexane (ca. 500 uL) and four times with water (ca. 500 uL). The residue was then lyophilized to yield 33 mg (44 %) of a yellowish solid.
  • the solid residue was then washed in a glass tube by addition of a solvent, sonication, centrifugation and removal of the supernatant with a glass pipette. This operation was performed twice with hexane (ca. 400 ⁇ l_), twice with acidic water (acetic acid, pH 4) (ca. 400 ⁇ l_) and twice with water (ca. 400 ⁇ L). The residue was then lyophilized to yield 45 mg (57 %) of a yellow solid.
  • the solid residue was then washed in a glass tube by addition of a solvent, sonication, centrifugation and removal of the supernatant with a glass pipette. This operation was performed twice with hexane (ca. 400 u L), twice with acidic water (acetic acid, pH 4) (ca. 500 ⁇ L) and twice with water (ca. 500 uL). After drying, the whole washing process was repeated a second time. The residue was then lyophilized to yield 47 mg (56 %) of a white solid.

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Abstract

La présente invention concerne de nouvelles 2'-désoxyguanosines 8-substituées (formule I) et 6,8-disubstituées (formule I) et des précurseurs pour préparer celles-ci ainsi que des procédés pour préparer lesdits composés et précurseurs. De plus, la présente invention concerne l’utilisation d’un ou plusieurs de ces composés pour préparer un médicament, de préférence un médicament pour le traitement et/ou la prévention de cancer, d’infections, de maladies auto-immunes, de maladies cardiovasculaires, de maladies génétiques héréditaires, de maladies de la peau et de maladies d’immunodéficience primaire. De plus, la présente invention concerne une composition pharmaceutique ou diagnostique comprenant les nouvelles 2'-désoxyguanosines 8-substituées et 6,8-disubstituées ainsi que des procédés diagnostiques et médicaux mettant en œuvre celles-ci.
PCT/EP2009/006423 2008-09-10 2009-09-04 2'-désoxyguanosines 8- et 6,8-substituées et utilisations de celles-ci WO2010028781A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110669346A (zh) * 2019-09-29 2020-01-10 四川科路泰交通科技有限公司 一种沥青复合型阻燃剂及其应用

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WO2002018404A2 (fr) * 2000-08-30 2002-03-07 F. Hoffmann-La Roche Ag Derives de nucleosides
WO2003072757A2 (fr) * 2002-02-28 2003-09-04 Biota, Inc. Mimetiques nucleotidiques et leurs promedicaments

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WO2002018404A2 (fr) * 2000-08-30 2002-03-07 F. Hoffmann-La Roche Ag Derives de nucleosides
WO2003072757A2 (fr) * 2002-02-28 2003-09-04 Biota, Inc. Mimetiques nucleotidiques et leurs promedicaments

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G. -X. HE ET AL: "N2- and C8-Substituted Oligonucleotides with Enhanced Thrombin Inhibitory Activity in Vitro and in Vivo", JOURNAL OF MEDICINAL CHMEISTRY, vol. 41, 1998, pages 2234 - 2242, XP002454913 *
K. KOHDA ET AL: "Synthesis, Miscoding Specificity, and Thermodynamic Stability of Oligonucleotide Containing 8-Methyl-2'-deoxyguanosine", CHEMISTRY RESEARCH IN TOXICOLOGY, vol. 9, 1996, pages 1278 - 1284, XP002551111 *
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Y. SAITO ET AL: "C8-alkynyl- and alkylamino substituted 2'-deoxyguanosines: a universal linker for nucleic acids modification", TETRAHEDRON, vol. 64, 2008, pages 3578 - 3588, XP022509610 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110669346A (zh) * 2019-09-29 2020-01-10 四川科路泰交通科技有限公司 一种沥青复合型阻燃剂及其应用

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