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WO1990009998A1 - Nouveaux analogues de nucleosides acycliques, leur procede de fabrication et leur utilisation en tant que medicaments antiviraux - Google Patents

Nouveaux analogues de nucleosides acycliques, leur procede de fabrication et leur utilisation en tant que medicaments antiviraux Download PDF

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Publication number
WO1990009998A1
WO1990009998A1 PCT/EP1990/000298 EP9000298W WO9009998A1 WO 1990009998 A1 WO1990009998 A1 WO 1990009998A1 EP 9000298 W EP9000298 W EP 9000298W WO 9009998 A1 WO9009998 A1 WO 9009998A1
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Prior art keywords
group
radical
alkyl
methyl
thymine
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PCT/EP1990/000298
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German (de)
English (en)
Inventor
Alfred Mertens
Harald Zilch
Bernhard Koenig
Edith Koch
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Roche Diagnostics GmbH
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Boehringer Mannheim GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • Novel acyclic nucleoside analogues processes for their preparation and use of these compounds as antiviral drugs.
  • the present invention relates to new acyclic nucleoside and nucleotide analogs of the general formula I
  • R is a hydrogen atom, an aliphatic C 1 -C 20 acyl radical, a monophosphate, diphosphate or
  • A represents the pyrimidine bases thymine, uracil or cytosine or purine bases adenine, hypoxanthine or guanine, which are substituted in the 1- or 7- or 9-position, and
  • R 1 a in the event that A is a thymine, uracil or
  • Cytosine group means an aryl radical, a saturated, unsaturated or aromatic heterocyclic five- or six-membered ring with one or more heteroatoms, a C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl radical, a straight-chain or branched C 2 -C 7 Alkynyl or C 2 -C 7 alkenyl radical, a C 4 -C 8 alkanedienyl radical, a formyl, cyano, azido, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylcarbonyl or Aminocarbonyl group, or the radical -CR 2 R 3 R 4, wherein R 2 and R 3 are independently hydrogen or a C 1 - C 6 alkyl group and R 4 is hydrogen, amino, azido, cyano, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylcarbonyl, aminocarbonyl, C 1
  • Heteroatoms a C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl radical, a straight-chain or branched C 2 -C 7 alkynyl or C 2 -C 7 alkenyl radical, a C 4 -C 8 alkanedienyl radical , a formyl, cyano, azido, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylcarbonyl or aminocarbonyl group, or the radical -CR 2 R 3 R 4 , where R 2 and R 3 are Hydrogen atom and R 4 is a cyano, C 1 -C 6 alkoxylcarbonyl, C 1 -C 6 alkylcarbonyl,
  • Aminocarbonyl-, haloalkyl or azido-C 1 -C 6 -alkyl mean their tautomers, optically active forms or physiologically tolerable salts of inorganic and organic acids.
  • the invention also relates to processes for the preparation of these compounds and medicaments containing these compounds.
  • the compounds according to the invention can be optically active or in the form of their racemates.
  • the stereoisomeric compounds can be prepared from the racemic mixtures by methods known per se using diastereomeric salts. For example, tartaric acid, malic acid or camphor-10-sulfonic acid can be used for the resolution.
  • Compounds with a similar structure are already known.
  • Guanine and hypoxanthine derivatives for the treatment of autoimmune diseases are also known from EP-A-0,249,247, in which R 1 includes a C 1 -C 8 alkyl group or a
  • Phenyl group and R can represent a hydrogen atom.
  • R 1 represents the methyl group and R represents a hydrogen atom is from Biochem. Pharmacol. 1981, 30, 3071 and Mol. Pharmacol. 1983, 24, 316 known.
  • the invention was based on the object of making available new compounds of the formula I which have increased activity compared to the compounds known from the prior art, and to make them available in the form of medicaments.
  • the compounds should have a lower level of side effects and the lowest possible toxicity.
  • the compounds of general formula I increase the DNA or. RNA viruses at the level of virus-specific DNA or. Inhibit RNA transcription.
  • the substances can specifically inhibit the multiplication of retroviruses (cf. Proc.
  • the compounds of general formula I according to the invention are suitable for the therapy and prophylaxis of infections caused by DNA viruses such as e.g. the herpes simplex virus, cytomegalo virus,
  • Papilloma virus, varicella zoster virus or Epstein-Barr virus - or RNA viruses - such as toga viruses or in particular retroviruses such as the onco viruses HTLV-I and II and the lentiviruses Visna, HIV-1 and -2 (HTLV-III and IV) - are caused.
  • the compounds of the formula I appear to be particularly suitable for the treatment of the clinical manifestations of retroviral HIV infection in humans, such as persistent generalized lymphadenopathy (PGL), the advanced stage of the AIDS-related complex (ARC) and the clinical picture of AIDS.
  • PDL persistent generalized lymphadenopathy
  • ARC advanced stage of the AIDS-related complex
  • AZT 3'-azido-3'-deoxythymidine, DE 3,608,606 AI
  • the compounds of the general formula I do not have these disadvantages. They have an antiviral effect without being cytotoxic in pharmacologically relevant concentrations.
  • R in the general formula I is an aliphatic acyl radical, this can be straight-chain or branched, saturated or unsaturated and contain 1-20, preferably 1-10 carbon atoms.
  • the acetyl, propionyl, isopropionyl and tert-butyryl radicals are particularly preferred.
  • R 1 is an aryl radical, it should preferably be understood to mean the phenyl radical.
  • the meaning of heterocyclic five or six rings for R 1 includes rings with 1- 4 or 1-5 heteroatoms, where the heteroatoms can be the same or different and mean oxygen, nitrogen or sulfur, and the heterocyclic five or six rings if desired on one or several nitrogen atoms can carry one oxygen atom.
  • Preferred heterocyclic five-membered rings are the furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,
  • R 1 is a heterocyclic six-membered ring, the pyridinyl, pyrimidinyl,
  • R 1 is a cycloalkyl or cycloalkenyl radical, then three to seven-membered rings are to be understood.
  • the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl radical are preferred.
  • alkynyl radicals for R 1 with 2-7 are straight-chain or branched and preferably represent the ethynyl and propynyl radical.
  • Straight-chain or branched alkenyl radicals having 2-7, preferably 2-4, carbon atoms, are preferably the vinyl, propenyl or 2-methylpropenyl radical.
  • Alkanedienyl radicals can contain 4-8 carbon atoms, with the butadienyl radical being particularly preferred.
  • R 1 or one of the radicals R 2 , R 3 or R 4 stands for a C 1 -C 6 alkoxycarbonyl or C 1 -C 6 alkylcarbonyl radical
  • the alkyl part can be straight-chain or branched and preferably 1-4 C- Have atoms.
  • the methyl, ethyl, isopropyl and isobutyl radicals are particularly preferred.
  • alkyl radicals occurring in the definition of the substituents R 2 , R 3 and R 4 as well as the "alkyl" parts of the alkyl mercapto, haloalkyl and
  • Azidoalkyl groups can also be straight-chain or branched, saturated or unsaturated and have 1-6, preferably 1-4 carbon atoms.
  • R 2 and R 3 are hydrogen and R 4 is formyl, cyano or amino, or methoxycarbonyl, ethoxycarbonyl, methylcarbonyl, ethylcarbonyl, aminocarbonyl, methylthio , Ethylthio, fluoromethyl, trifluoromethyl, azidomethyl or azidoethyl radical, b) compounds with R 2 being hydrogen, R 3 being the same
  • Methyl and R 4 are azido, cyano, amino or the methoxycarbonyl, ethoxycarbonyl, methylcarbonyl, ethylcarbonyl, aminocarbonyl, methylthio, ethylthio, ethyl, propyl, fluoromethyl, trifluorraethyl or azidomethyl radical, c)
  • Compounds with R 2 and R 3 are methyl and R 4 with the meaning given under b).
  • the bases A are preferably the pyrimidine bases, for example thymine.
  • R 1 means in particular a phenyl, C 5 -C 6 cycloalkyl, for example cyclohexyl, C 3 -C 5 alkenyl, for example 1-propen-2-yl; or the -CR 2 R 3 R 4 group, where R 2 and R 3 represent a hydrogen atom and R 4 represents a C 1 -C 4 alkyl group, for example the methyl group.
  • R is preferably a hydrogen atom and the triphosphate group.
  • Possible salts of the compounds of the general formula I are, in particular, alkali metal, alkaline earth metal and ammonium salts of the phosphate groups.
  • alkali salts are, in particular, alkali metal, alkaline earth metal and ammonium salts of the phosphate groups.
  • Lithium, sodium and potassium salts are preferred.
  • Magnesium and calcium salts are particularly suitable as alkaline earth metal salts.
  • ammonium salts are understood to be salts which contain the ammonium ion, which can be substituted up to four times by alkyl radicals with 1-4 carbon atoms and / or aralkyl radicals, preferably benzyl radicals.
  • the substituents can be the same or different.
  • the compounds of the general formula I can contain basic groups, in particular amino groups, which can be converted into acid addition salts using suitable acids.
  • suitable acids for this purpose are: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulfonic acid.
  • the substances of the general formula I are mixed in a manner known per se with suitable pharmaceutical carriers, flavorings, flavors and colors and shaped, for example, as tablets or dragées or with the addition of appropriate auxiliaries in water or oil, such as, for. B. olive oil, suspended or dissolved.
  • suitable pharmaceutical carriers such as, for. B. olive oil, suspended or dissolved.
  • the new substances of general formula I according to the invention and their salts can be administered enterally or parenterally in liquid or solid form.
  • Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizers, solubilizers or buffers.
  • additives are z. B. tartrate and citrate buffer, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and their
  • non-toxic salts such as non-toxic salts
  • high molecular weight polymers such as liquid polyethylene oxide
  • Solid carriers are e.g. B. starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, high molecular fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols).
  • Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.
  • the compounds according to the invention are usually applied in amounts of 0.1-100 mg, preferably 0.2-80 mg per day and per kg of body weight. It is preferred to distribute the daily dose over 2 -5 applications, with 1 to 2 tablets with an active substance content of 0.5-1000 mg being administered for each application.
  • the tablets can also be delayed, which reduces the number of applications per day to 1-3.
  • the active substance content of the retarded tablets can be 2 - 2000 mg.
  • the active ingredient can also be given by injection one to eight times a day or by continuous infusion, with amounts of 5 to 4000 mg per day usually being sufficient.
  • the compounds of the general formula I according to the invention can be prepared by various methods known per se, suitable protective groups being introduced beforehand and being split off again later.
  • the purine and pyrimidine bases used as starting materials are known and commercially available.
  • R 5 is a suitable protective group such as, for example, the trityl, acetyl,
  • the pyrimidine or purine bases bis or trissilylated with hexamethyldisilazane are expediently reacted with a compound of the general formula II in which Z is chlorine
  • the trimethylsilyl protective groups are split off in a known manner to give the 9-position Substituted purine derivatives or the pyrimidine derivatives of formula I substituted in the 1-position.
  • a protective gas in the reaction vessel such as, for example, is recommended Nitrogen or argon.
  • the silyl protective group can be split off e.g.
  • a method is also advantageous in which a compound of the formula II in which R 1 , R 5 and Z have the meaning given above is reacted with a pyrimidine or purine base under phase transfer conditions.
  • phase transfer catalyst for example tris [2- (2-methoxyethoxy) ethyl] amine (TDA-1), and transported into the organic phase in which it reacts with the reactive compound of the formula II.
  • Another advantageous method for preparing the compounds of formula I is the solid-liquid phase transfer process using solid, powdered potassium hydroxide, the above-mentioned cryptand, and a compound of formula II and a pyrimidine or.
  • Purine base in an aprotic solvent see Seela et al., Helv. Chim. Acta 1988, 71.1;
  • the chloromethyl ethers of the general formula II with Z equal to chlorine can also be reacted directly using tetrabutylammonium iodide as phase transfer catalyst with the pyrimidine or purine base in an inert solvent (cf. Helv.Chim. Acta 1987. 70, 220) or after being mixed with Sodium acetate are reacted with di- or triacetylated pyrimidine or purine bases (see J.Med.Chem. 1986, 29, 1384) or are condensed in a mercury-cyanide-catalyzed reaction with the silylated base (see J.Med .Chem.
  • reaction times are depending on the reactant and
  • the reactions are generally carried out at temperatures between 0 and 150 ° C, preferably room temperature and 100 ° C.
  • R 1 and R 5 have the meaning given above, are reacted with paraformaldehyde or 1,3,5-trioxane in the presence of gaseous hydrogen chloride or adsorbed on silica gel and the reaction products are used in the next reaction without further purification (cf. Helv.Chim Acta 1987, 70, 219; J.Med.Chem. 1988, 31, 144 and 1986, 29, 1384).
  • the phosphate groups are introduced in a known manner in compounds of the general formula I in which R is hydrogen.
  • the monophosphates are obtained, for example, by phosphorylating compounds of the formula I where R is hydrogen with phosphorus oxychloride in trialkyl phosphate, preferably trimethyl phosphate.
  • the triethylammonium salts obtained in this way can be converted into other salts by salting in a known manner.
  • the di- or triphosphates of the general formula I are prepared by activating a trialkylammonium salt of the monophosphate of the formula I and then using a trialkylammonium phosphate or diphosphate is condensed. Tributylammonium ions are preferably used as trialkylammonium ions.
  • the activation is advantageously carried out under anhydrous conditions using 1,1'-carbonyldiimidazole at room temperature in a polar, aprotic solvent, such as, for example, dimethylformamide.
  • the condensation is also carried out at room temperature in a polar, aprotic solvent.
  • Dimethylformamide is preferred.
  • the reaction times for activation and condensation reaction are 3 hours to 3 days each.
  • the success of the phosphorylation can be checked by thin layer chromatography, electrophoresis and 31 P NMR spectroscopy.
  • the phosphorylation is lower
  • reaction time is 5 hours to 1 day, preferably 7-15 hours.
  • the various salts of the di- and triphosphates can also be prepared by known methods.
  • Formula I can also be carried out as a one-pot variant.
  • the presentation follows the rules of Ludwig (Acta Biochim. Biophys. Acad. Sei. Hung. 1981, 16, 131), Ruth / Cheng (Mol. Pharmcol. 1981, 20, 415) and Kovacs / ötvös (Tetrahedron Lett. 1988, 29, 4525).
  • Ludwig Acta Biochim. Biophys. Acad. Sei. Hung. 1981, 16, 131
  • Ruth / Cheng Mol. Pharmcol. 1981, 20, 415)
  • Kovacs / ötvös Tetrahedron Lett. 1988, 29, 4525.
  • 2-benzyloxy-1-phenylethanol was prepared by reacting benzyloxyacetaldehyde with phenyllithium at -80 ° C. in 59% yield. Chloromethylation and reaction with bis- (trimethylsilyl) thymine yielded 1 - [(2-benzyloxy-1-phenylethoxy) methyl] thymine as a white solid from the mp. After column chromatography on silica gel with ethyl acetate / heptane 1/1 as eluent in 53% yield. 104-106 ° C. The hydrogenation on palladium on carbon led to the 1 - [(2-hydroxy-1-phenylethoxy) methyl] thymine (mp. 114-116 ° C.) in 74% yield.
  • 2-Benzyloxy-1-cyclohexylethanol was prepared analogously to Example 1 from benzyloxyacetaldehyde and cyclohexylmagnesium chloride and purified by column chromatography on silica gel with ethyl acetate / heptane 1/5 as the eluent (68% yield, colorless oil). Chloromethylation and reaction with bis- (trimethylsilyl) thymine led to 1 - [(2-benzyloxy-1-cyclohexylethoxy) methyl] -thymine after column chromatography on silica gel with ethyl acetate / heptane 2/1 as eluent in 83% yield.
  • the 4- (t-butyldiphenylsilyloxy) -3-hydroxy-2-methylbutene-1 was prepared by reacting t-butyldiphenylsilyloxyacetaldehyde with 2-propenylmagnesium bromide at RT and then heating to 60 ° C. in 42% yield .
  • Example 3 obtained from

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Abstract

Nouveaux analogues de nucléosides et nucléotides acycliques correspondant à la formule (I), où R représente un atome d'hydrogène, un résidu acyle aliphatique C1-C20, un groupe monophosphate, diphosphate ou triphosphate; A représente les bases-pyrimidine thymine, uracile ou cytosine ou les bases-purine adénine, hypoxanthine ou guanine, substituées en position 1, et 7 ou 9, respectivement; R1 représente un résidu aryle, un anneau hétérocyclique, un résidu cycloalkyle, un résidu alkylène, un résidu alkinyle, (a), -CN, -N¿3?, un groupe alcoxycarbonyle, un groupe alkylcarbonyle ou aminocarbonyle ou le résidu -CR?2R3R4, R2 et R3¿ représentant hydrogène ou alkyle. La présente invention porte également sur les tautomères, formes optiquement actives ou sels physiologiquement tolérés de ces composés, ainsi que sur un procédé pour obtenir ces composés et sur des médicaments qui les contiennent.
PCT/EP1990/000298 1989-03-01 1990-02-22 Nouveaux analogues de nucleosides acycliques, leur procede de fabrication et leur utilisation en tant que medicaments antiviraux Ceased WO1990009998A1 (fr)

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DEP3906357.7 1989-03-01
DE3906357A DE3906357A1 (de) 1989-03-01 1989-03-01 Neue acyclische nucleosid-analoga, verfahren zu ihrer herstellung und verwendung dieser verbindungen als antivirale arzneimittel

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2119722B1 (fr) 2002-08-23 2016-10-26 Illumina Cambridge Limited Nucléotides étiquetées
US10995111B2 (en) 2003-08-22 2021-05-04 Illumina Cambridge Limited Labelled nucleotides
CN112778363A (zh) * 2019-11-05 2021-05-11 华创合成制药股份有限公司 一种硝基咪唑类唑衍生物及其制备方法和用途

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6057305A (en) * 1992-08-05 2000-05-02 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Antiretroviral enantiomeric nucleotide analogs

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0049072A1 (fr) * 1980-09-16 1982-04-07 Syntex (U.S.A.) Inc. Dérivés de guanine et leur utilisation pour la préparation d'agents anti-viraux
EP0167385A2 (fr) * 1984-07-03 1986-01-08 The Wellcome Foundation Limited Composés antiviraux, traitement et formulations
EP0217207A1 (fr) * 1985-09-24 1987-04-08 Hoechst Aktiengesellschaft Amino-2 purines substituées en position 6 et 9, leur application, médicaments contenant ces purines et procédés pour leur préparation
EP0249247A2 (fr) * 1983-10-31 1987-12-16 Warner-Lambert Company Dérivés de purine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0049072A1 (fr) * 1980-09-16 1982-04-07 Syntex (U.S.A.) Inc. Dérivés de guanine et leur utilisation pour la préparation d'agents anti-viraux
EP0249247A2 (fr) * 1983-10-31 1987-12-16 Warner-Lambert Company Dérivés de purine
EP0167385A2 (fr) * 1984-07-03 1986-01-08 The Wellcome Foundation Limited Composés antiviraux, traitement et formulations
EP0217207A1 (fr) * 1985-09-24 1987-04-08 Hoechst Aktiengesellschaft Amino-2 purines substituées en position 6 et 9, leur application, médicaments contenant ces purines et procédés pour leur préparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Journal of Medicinal Chemistry, Band 29, Nr. 8, 1986, American Chemical Society, (Washington, US), J.C. MARTIN et al.: "Synthesis and Antiherpes-Virus Activity of Acyclic 2'-Deoxy-Guanosine Analogues Related to 9- (1,3-Dihydroxy-2-Propoxy) Methyl Guanine", seiten 1384-1389 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2119722B1 (fr) 2002-08-23 2016-10-26 Illumina Cambridge Limited Nucléotides étiquetées
US11008359B2 (en) 2002-08-23 2021-05-18 Illumina Cambridge Limited Labelled nucleotides
US10995111B2 (en) 2003-08-22 2021-05-04 Illumina Cambridge Limited Labelled nucleotides
US11028115B2 (en) 2003-08-22 2021-06-08 Illumina Cambridge Limited Labelled nucleotides
US11028116B2 (en) 2003-08-22 2021-06-08 Illumina Cambridge Limited Labelled nucleotides
CN112778363A (zh) * 2019-11-05 2021-05-11 华创合成制药股份有限公司 一种硝基咪唑类唑衍生物及其制备方法和用途
CN112778363B (zh) * 2019-11-05 2024-03-15 华创合成制药股份有限公司 一种硝基咪唑类唑衍生物及其制备方法和用途

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