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WO1993016092A1 - Nouveaux conjugues acide lipophosphonique-nucleosides et leur utilisation en tant que medicaments antiviraux - Google Patents

Nouveaux conjugues acide lipophosphonique-nucleosides et leur utilisation en tant que medicaments antiviraux Download PDF

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Publication number
WO1993016092A1
WO1993016092A1 PCT/EP1993/000295 EP9300295W WO9316092A1 WO 1993016092 A1 WO1993016092 A1 WO 1993016092A1 EP 9300295 W EP9300295 W EP 9300295W WO 9316092 A1 WO9316092 A1 WO 9316092A1
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WIPO (PCT)
Prior art keywords
group
formula
compounds
hydrogen
halogen
Prior art date
Application number
PCT/EP1993/000295
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German (de)
English (en)
Inventor
Dieter Herrmann
Alfred Mertens
Harald Zilch
Original Assignee
Boehringer Mannheim Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication of WO1993016092A1 publication Critical patent/WO1993016092A1/fr

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Classifications

    • 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
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • 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
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/117—Esters of phosphoric acids with cycloaliphatic alcohols
    • 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
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • 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
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • the present invention relates to new phospholipid derivatives of nucleosides of the general formula I,
  • l is a straight-chain or branched, saturated or unsaturated alkyl chain with 1-20 carbon atoms, optionally one or more times by phenyl, halogen, C 1 -C 6 -alkoxy, C 1 -C 6 -alkyl mercapto, C 1 -C 6 -alkoxy carbonyl, Ci-Cg-alkylsulfinyl or Ci-Cg-alkylsulfonyl groups can be substituted,
  • R 2 is a straight-chain or branched, saturated or unsaturated alkyl chain with 1-20 carbon atoms, which may be substituted one or more times by phenyl, halogen, C] _- C 6 -alkoxy-, Ci-Cg-alkylmercapto-, Ci-Cs -Alkoxycarbon- yl- or Ci-Cg-alkylsulfonyl groups can be substituted.
  • X represents a valence line, oxygen, sulfur, the sulfinyl or the sulfonyl group,
  • Y is a valence line, an oxygen or sulfur atom
  • Z can be oxygen or sulfur
  • Nuc represents a residue derived from a nucleoside derivative
  • J. Med. Chem. 3_3, 1380 (1990) describes nucleoside conjugates of thioether lipids with cytidine diphosphate which have an antitu oral effect and could be used in oncology.
  • 5 '- (3-sn-phosphatidylcholine dyl) nucleoside described with antileukemic activity, as well as their enzymatic synthesis from the corresponding nucleosides and phosphocholines in the presence of phospholipase D with transferase activity.
  • J. Med. Chem. 3_4, 1408 (1991) likewise describes nucleoside conjugates with an anti-HIV-1 activity which are substituted in the sn-2 position of the lipid part by methoxy or ethoxy.
  • the compounds of the present invention also have valuable pharmacological properties. They are particularly suitable for the therapy and prophylaxis of infections caused by DNA viruses such as e.g. the herpes simplex virus, the cyto himie virus, papova viruses, the varicella zoster virus or epstein-barr virus or RNA viruses such as toga viruses or in particular retroviruses such as the oncoviruses HTLV-I and II , as well as the lentiviruses Visna and the human immunodeficiency virus HIV-1 and 2.
  • DNA viruses such as e.g. the herpes simplex virus, the cyto egalie virus, papova viruses, the varicella zoster virus or epstein-barr virus or RNA viruses such as toga viruses or in particular retroviruses such as the oncoviruses HTLV-I and II , as well as the lentiviruses Visna and the human immunodeficiency virus HIV-1 and 2.
  • 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
  • the compounds of the present invention and their pharmaceutical preparations can also be used in combination with other medicaments for the treatment and prophylaxis of the above-mentioned infections.
  • these other drugs include agents that are useful for the treatment and prophylaxis of HIV infections or diseases accompanying this disease, such as 3'-azido-3'-deoxythymidine, 2 ', 3'-dideoxynucleosides such as e.g. 2 ', 3'-dideoxycytidine, 2', 3'-dideoxyadenosine and 2 ', 3 • -dideoxy-inosine, acyclic nucleosides (e.g.
  • acyclovir or non-nucleoside RT inhibitors, such as. B. HEPT, nevirapine or L-697,661 and corresponding derivatives.
  • the compounds of the present invention and the other medicament can each be administered individually, simultaneously, if appropriate in a single or two separate formulations or at different times.
  • Possible salts of the compounds of the general formula I are, in particular, alkali metal, alkaline earth metal and ammonium salts of the phosphate group.
  • Lithium, sodium and potassium salts are preferred as alkali salts.
  • 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 having 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 inorganic or organic acids.
  • suitable acids for this purpose are: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fu aric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulfonic acid.
  • Rj preferably denotes a straight-chain C 1 -C 4 -alkyl group which can also be substituted by a C 1 -C 6 -alkoxy or a C 1 -C 6 -alkyl mercapto group.
  • Ri represents in particular a decyl, undecyl, dodecyl, tridecyl or tetradecyl group.
  • Preferred Ci-Cg-alkoxy substituents of Ri are the methoxy, ethoxy, butoxy and the hexyloxy groups.
  • R 1 is substituted by a C 1 -C 6 -alkyl mercapto residue, this means in particular the methyl mercapto, ethyl mercapto, propyl mercapto, butyl mercapto and the hexyl mercapto residue.
  • R 2 preferably represents a straight chain C ⁇ o ⁇ c i 4 ⁇ Yl Alk "group which may be substituted by a Ci-C ⁇ -alkoxy group or a C ⁇ ⁇ Cg alkylmercapto group.
  • R 2 in particular represents a decyl, undecyl, dodecyl , Tridecyl or tetradecyl group.
  • the C 1 -C 6 alkoxy substituents of R 2 are preferably the methoxy, ethoxy, propoxy, butoxy and the hexyloxy group.
  • Is R 2 is substituted by a C 1 -C 6 alkyl mercapto group including in particular the methyl mercapto, ethyl mercapto, butyl mercapto and hexyl mercapto residues.
  • X is preferably sulfur, sulfinyl or sulfonyl and Y is oxygen.
  • Z is preferably an oxygen atom.
  • the Nuc radical stands for a nucleosidic radical which is bonded via the 5 'position to the phosphonic acid of the lipophilic part of the formula I.
  • the following residues derived from nucleosides or nucleoside analogs are suitable as nucleoside residues, for example:
  • R3 is hydrogen or a hydroxy group
  • R 4 are each hydrogen or one of the radicals R4 and R 5 is halogen, a hydroxyl, a cyano or an azido group and, moreover, R3 and R can represent a further bond between C-2 'and C-3' ,
  • B represents a basic group of the formula III from the series of the purine or pyrimidine bases
  • R 6 can be hydrogen, an alkyl chain with 1-4 carbon atoms or halogen, g 'can be a hydrogen atom or a benzyl or phenylthio radical,
  • R 7 can be hydrogen, an alkyl chain with 1-4 carbon atoms or halogen
  • R can be hydrogen, an alkyl chain with 1-4 carbon atoms, halogen, or a hydroxy or an amino group
  • Rg can be hydrogen or an amino group
  • Nuc can also be of the carbocyclic type
  • nucleoside analogs come into consideration for Nuc, which differ from the known antiviral compounds, such as. B. carbovir (carbocyclic cyclopentane derivative of 2 ', 3' -dideoxy-2 ', 3' -didehydro-guanosine), HEPT (1- [(2-hydroxyethoxy) methyl] -6-phenylthio-thymine) and the like Derive derivatives, ganciclovir, azidothymidine (AZT) or acyclovir.
  • Nuc means in particular the radical -CH 2 -CH (CH 2 0H) -0-CH 2 -B or -CH 2 -CH -0-CH 2 -B, where B is a group of the formula III c with R ⁇ - A ino represents.
  • R 4 and R5 are preferably each hydrogen or one of the two radicals is preferably a cyano or azido group or a halogen atom, such as fluorine, chlorine, bromine or iodine.
  • R 3 and R 4 represent a hydrogen atom and R5 is cyano, azido or fluorine, or R 5 is hydrogen and R 3 / R4 is a further bond between C-2 • and C-3 ' represent.
  • the radicals Rg or R7 preferably denote a hydrogen atom, a methyl, ethyl, propyl or butyl radical, or a halogen atom, such as fluorine, chlorine, bromine or iodine.
  • a hydrogen atom, the methyl or ethyl radical and a chlorine or bromine atom are particularly preferred for Rg or R7.
  • the radical Rg is preferably a hydrogen atom, a methyl, ethyl, propyl or butyl radical, an amino group or a halogen atom such as fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.
  • R o preferably denotes a hydrogen, fluorine, chlorine or bromine atom, a Ci-Cg-alkoxy group, in particular a methoxy, ethoxy, propoxy, butoxy or hexyloxy group, a Ci-Cg-alkyl mercapto group, in particular a methyl mercapto group, Ethylmercapto, butylmercapto or hexyl mercapto group, or an amino group which can be mono- or disubstituted by a C ⁇ Cg alkyl group, such as.
  • B. the methyl, ethyl, propyl, butyl or hexyl group or by halogen atoms such as fluorine, chlorine or bromine may be substituted.
  • the amino group can also be substituted by a heterarylalkyl or hetaryl radical, such as, in particular, e.g. B. the thienyl, furyl or pyridyl.
  • a heterarylalkyl radical is preferably understood to mean the thienylmethyl, furylmethyl or pyridylmethyl radical.
  • nucleosides are particularly suitable as coupling components for the preparation of the lipid-nucleotide conjugates of the formula I:
  • R3 represents hydrogen or a hydroxyl group protected by an oxygen protective group familiar to the person skilled in the art and R 4 'u.
  • R5 'in each case represents hydrogen, halogen, an azido, a cyano or one of the radicals R4' and R5 'is a hydroxyl group protected by an oxygen protective group familiar to the person skilled in the art, or R 3 ' and R4 'represent a further bond and B is the has the meanings given above,
  • a condensing agent such as. B. an optionally substituted benzenesulfonic acid chloride, preferably 2,4,6-triisopropylbenzenesulfonic acid chloride, and a tert.
  • Nitrogen base e.g. As pyridine or lutidine, in an inert solvent such as. B. toluene, or directly in abs. Brings pyridine to the reaction and, after hydrolysis has taken place, optionally cleaves the oxygen protecting groups in accordance with the methods customary in nucleoside chemistry, or
  • R 1, R 2 , X, Y and Z have the meanings given above, with a compound of the general formula VI or.
  • R 3 ', R4', R5 1 and B have the meanings given, in the presence of phospholipase D in an inert solvent, such as z. B. chloroform, in the presence of a suitable buffer and after the reaction, if appropriate, splits off the oxygen protecting group in accordance with the processes customary in nucleoside chemistry.
  • the medicaments containing compounds of the formula I for the treatment of viral infections can be administered enterally or parenterally in liquid or solid form.
  • the usual forms of application are possible, such as tablets, capsules, dragees, syrups, solutions or suspensions.
  • Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizers, solubilizers and buffers.
  • additives are, for example, tartrate and citrate buffers, ethanol, complexing agents, such as ethylene-diaminetetraacetic acid and their non-toxic salts, high molecular weight polymers, such as liquid polyethylene oxide, for regulating the viscosity.
  • Liquid carriers for injection solutions must be sterile and are preferably filled into ampoules.
  • Solid carriers are, for example, starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicic acids, higher molecular fatty acids, such as stearic acid, gelatin, agar agar, calcium phosphate, magnesium stearate, _
  • Preparations suitable for oral applications can, if desired, contain flavorings or sweeteners.
  • the dosage can depend on various factors, such as the mode of application, species, age or individual condition.
  • 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, 1-2 tablets with an active ingredient content of 0.5-500 mg being administered with 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 - 1000 mg.
  • the active ingredient can also be given by continuous infusion, the amounts of 5-1000 mg per day normally being sufficient.
  • the 4-dodecylmercapto-3-decyloxybutanephosphonic acid was obtained from diethyl 3-epoxybutanephosphonic acid (Synth. Commun. 487, 1979) by reaction with dodecyl mercaptan, subsequent reaction of the alcoholate of 4-dodecyl-mercapto-3-hydroxybutane phosphonodisylphosphonic acid with desylphosphonate made with trimethylsilyl bromide and water.
  • mice Female Balb / c mice, 6-8 weeks old (Iffa Credo), were given 0.2 ml of a virus-containing spleen supernatant per day i.p. inoculated. The animals were i.p. daily from day 0 (start: 1 h after virus inoculation) to day 13. treated with the substance to be examined in doses of 6.25 mg, 12.5 mg, 25 mg and 50 mg per kg.
  • the parameters body weight and small blood count (WBC, RBC, Hb, Hkt, Plt) and on day 14 after killing the animals, the individual spleen weights were determined as parameters for viremia.
  • the substances according to the invention are investigated according to the same scheme as for AZT.
  • the results obtained show that the substances examined have a dose-dependent effect on virus-related splenomegaly and can therefore be used in the therapy of retroviral infections.
  • MT2 cells were pre-incubated with the substance to be examined and infected with HIV-1 (HTLV-III-B, MOI 0.03). The supernatant was removed, replaced with medium (including substance) and incubated for 7 days.
  • HIV-1 HTLV-III-B, MOI 0.03

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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Abstract

L'invention concerne de nouveaux dérivés phospholipidiques de nucléosides de la formule générale (I), dans laquelle R1 représente une chaîne alkyle linéaire ou ramifiée, saturée ou non, avec 1 à 20 atomes de carbone, qui peut être éventuellement substituée une ou plusieurs fois par des groupes phényle, halogène, alcoxy C1-C6, alkylmercapto C1-C6, alcoxycarbonyle C1-C6, alkylsulfinyle C1-C6 ou alkylsulfonyle C1-C6, R2 représente une chaîne alkyle linéaire ou ramifiée, saturée ou non, avec 1 à 20 atomes de carbone, qui peut être éventuellement substituée une ou plusieurs fois par des groupes phényle, halogène, alcoxy C1-C6, alkylmercapto C1-C6, alcoxycarbonyle C1-C6 ou alkylsulfonyle C1-C6, X représente un trait de valence, l'oxygène, le soufre, le groupe sulfinyle ou sulfonyle, Y est un trait de valence, un atome d'oxygène ou un atome de soufre, Z peut être l'oxygène ou le soufre, et Nuc est un reste dérivé d'un dérivé nucléosidique, ainsi que leurs tautomères et leurs sels physiologiquement tolérables d'acides ou de bases inorganiques et organiques, ainsi que le procédé pour leur fabrication et les médicaments contenant ces composés.
PCT/EP1993/000295 1992-02-12 1993-02-08 Nouveaux conjugues acide lipophosphonique-nucleosides et leur utilisation en tant que medicaments antiviraux WO1993016092A1 (fr)

Applications Claiming Priority (2)

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DEP4204031.0 1992-02-12
DE19924204031 DE4204031A1 (de) 1992-02-12 1992-02-12 Neue lipidphosphonsaeure-nucleosid-konjugate sowie deren verwendung als antivirale arzneimittel

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