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WO1993016091A1 - Nouveaux liponucleotides, leur fabrication ainsi que leur utilisation en tant que medicaments antiviraux - Google Patents

Nouveaux liponucleotides, leur fabrication ainsi que leur utilisation en tant que medicaments antiviraux Download PDF

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Publication number
WO1993016091A1
WO1993016091A1 PCT/EP1993/000294 EP9300294W WO9316091A1 WO 1993016091 A1 WO1993016091 A1 WO 1993016091A1 EP 9300294 W EP9300294 W EP 9300294W WO 9316091 A1 WO9316091 A1 WO 9316091A1
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WO
WIPO (PCT)
Prior art keywords
group
formula
hydrogen
halogen
alkyl
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP1993/000294
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German (de)
English (en)
Inventor
Dieter Herrmann
Alfred Mertens
Harald Zilch
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Roche Diagnostics GmbH
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Boehringer Mannheim GmbH
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Filing date
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Publication of WO1993016091A1 publication Critical patent/WO1993016091A1/fr
Anticipated expiration legal-status Critical
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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,
  • Rl is a straight-chain or branched, saturated or unsaturated alkyl chain with 1-20 carbon atoms, optionally one or more times by phenyl, halogen, Ci-Cg-alkoxy, Cx-Cö-alkyl mercapto, Ci-Cg-alkoxycarbonyl -, Ci-Cg-alkylsulfinyl or Cj-Cs-alkylsulfonyl groups can be substituted,
  • X represents a valence line, oxygen, sulfur, sulfinyl or sulfonyl,
  • Y has the same meaning as X, the two
  • Groups X and Y may be the same or different,
  • Z can be oxygen or sulfur
  • A can represent a methylene group or an oxygen atom
  • Nuc can be 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 antitumor effect and could be used in oncology.
  • Chem. Pharm. Bull. 1, 209 (1988) describes 5 '- (3-SN-phosphatidyl) nucleosides with antileukaemic activity and their enzymatic synthesis from the corresponding nucleosides and phosphocholines in the presence of phospholipase D with transferase activity .
  • the compounds of the present invention are new and 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 cytomegalovirus, 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 cytomegalovirus, 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 further medicaments include agents which can be used for the treatment and prophylaxis of HIV infections or diseases accompanying this disease, such as 3 'azido-3' deoxythymidine, 2 ', 3' dideoxynucleosides such as B. 2 ', 3'-dideoxycytidine, 2', 3 '-dideoxyadenosine and 2', 3 '-dideoxy-inosine, acyclic nucleosides (z. B. 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 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.
  • Rj preferably denotes a straight-chain Cg-C ⁇ alkyl group which can also be substituted by a C ⁇ -Cg alkoxy or a Ci-Cs-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.
  • Ci-Cs-alkyl mercapto residue this means in particular the methyl mercapto, ethyl mercapto, propyl mercapto, butyl mercapto and hexyl mercapto residues.
  • R2 preferably means a straight chain group, which can also be substituted by a Ci-Cg-alkoxy group or a C ⁇ ⁇ Cg-alkylraercapto group.
  • R 2 represents in particular 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.
  • R2 is substituted by a Ci-Cs-alkyl mercapto residue, this means in particular the methyl mercapto, ethyl mercapto, butyl mercapto and hexyl mercapto residue.
  • X and Y preferably represent an oxygen or sulfur atom
  • Z is preferably an oxygen atom
  • Nuc is a nucleoside derivative represented by the 5 1-position to the phosphonic acid of the lipophilic part of the Formula I is bound.
  • the following residues are suitable as nucleosides or nucleoside analogues:
  • R 3 is hydrogen or a hydroxyl group
  • R 5 each represent hydrogen or one of the radicals 4 and R 5 is halogen, a hydroxyl, a cyano or an azido group and, moreover, R 3 and R4 can represent a further bond between C-2 'and C-3',
  • Rg can be hydrogen, an alkyl chain with 1-4 carbon atoms or halogen
  • R 6 ' can be hydrogen or a benzyl or phenylthio radical
  • R 7 can be hydrogen, an alkyl chain with 1-4 carbon atoms or halogen
  • Rg 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
  • nucleosides or nucleoside analogues come into question for Nuc, which differ from the known antiviral acting connections, such as. B. carbovir, HEPT, gangciclovir, AZT or acyclovir.
  • Nuc of the formula II, 4 and R 5 are preferably each hydrogen or one of the two radicals is preferably cyano, azido or halogen, such as fluorine, chlorine, bromine or iodine.
  • R 3 and R4 represent a hydrogen atom and R5 is cyano, azido or fluorine, or R5 is hydrogen and R 3 / R 4 represent a further bond between C-2 'and C-3' are particularly preferred .
  • R or R 7 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.
  • the radical R 8 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.
  • Rio preferably means a hydrogen, fluorine, chlorine or bromine atom, a Ci-Cg-alkoxy group, in particular a methoxy-ethoxy, propoxy, butoxy or hexyloxy group, a C ⁇ 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, butyl or hexyl group, by a hydroxy-C2-C 6 alkyl group, such as. B.
  • hydroxyethyl, hydroxypropyl, hydrox - butyl or hydroxyhexyl group, by a C 3 -C 5 cycloalkyl rest such as B. the cyclopropyl, cyclopentyl or cyclohexyl radical, preferably by aryl phenyl, by an aralkyl radical, such as in particular benzyl, which may also have one or more hydroxyl or methoxy groups, by Ci-Cg-alkyl groups, such as.
  • the amino group can also be substituted by a heterarylalkyl or hetaryl radical, such as in particular z.
  • a heterarylalkyl or hetaryl radical such as in particular z.
  • the heterarylalkyl radical is preferably understood to mean the thienylmethyl, furylmethyl or pyridylmethyl radical.
  • Preferred coupled nucleosides in the claimed liponucleotides of the general formula I are:
  • the compounds of general formula I can be prepared by a compound of the general formula V,
  • R3 ' represents hydrogen or a hydroxy 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 4' and R5 'is a hydroxyl group protected by an oxygen protective group familiar to the person skilled in the art, or R3' and R4 'represent a further bond and B has the meanings given, in the presence of a condensing agent such.
  • B. an optionally substituted benzenesulfonic acid chloride, preferably 2,4,6-triisopropylbenzenesulfonic acid chloride and a tert.
  • Nitrogen base e.g.
  • pyridine or lutidine in an inert solvent such as. B. toluene, or reacted directly in pyridine and, after hydrolysis, optionally cleaves the oxygen-protecting groups in accordance with the methods customary in nucleoside chemistry, or
  • R, R2, X, Y, Z and A have the abovementioned meanings, with a compound of the general formula VI or Via, in which R 3 ', R4 •, Rs' and B have the meanings given, in Presence of phospholipase D in an inert solvent, such as.
  • an inert solvent such as.
  • chloroform brings in the presence of a suitable buffer to the reaction and, if appropriate, splits off the oxygen protecting group after the reaction, in accordance with the methods 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-dia-tetraacetic acid and their non-toxic salts, high-molecular polymers, such as liquid polyethylene oxide for crime regulation.
  • 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, animal and vegetable fats, solid high-molecular polymers, such as polyethylene glycols, etc.
  • Preparations suitable for oral applications can, if desired, contain flavoring or sweetening agents.
  • 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 phosphoric acid (3-dodecylmercapto-1-decyloxy) -2-propyl ester was converted from the corresponding alcohol (WO 91/05558) by reaction with POCI 3 and subsequent hydrolysis produced and used as a raw product in the above reaction.
  • 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 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)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

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, alconycarbonyle 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 sulfinyle ou le sulfonyle, Y a la même notation que X, les deux groupes X et Y pouvant être identiques ou différents, Z peut être l'oxygène ou le soufre, A peut représenter un groupe méthylène ou un atome d'oxygène, Nuc peut être un reste dérivé d'un dérivé nucléosidique, ainsi que leur 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, notamment pour le traitement des infections virales ou rétrovirales.
PCT/EP1993/000294 1992-02-12 1993-02-08 Nouveaux liponucleotides, leur fabrication ainsi que leur utilisation en tant que medicaments antiviraux Ceased WO1993016091A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19924204032 DE4204032A1 (de) 1992-02-12 1992-02-12 Neue liponucleotide, deren herstellunmg sowie deren verwendung als antivirale arzneimittel
DEP4204032.9 1992-02-12

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WO1993016091A1 true WO1993016091A1 (fr) 1993-08-19

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AU (1) AU3453993A (fr)
DE (1) DE4204032A1 (fr)
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WO1994028908A3 (fr) * 1993-06-10 1995-03-23 Univ Wake Forest (phospho)lipides contre l'infection a virus de l'hepatite b
WO1995032984A1 (fr) * 1994-05-28 1995-12-07 Boehringer Mannheim Gmbh Nouveaux esters lipidiques de monophosphates de nucleosides et leur utilisation comme medicaments immunosuppresseurs
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US7026469B2 (en) 2000-10-19 2006-04-11 Wake Forest University School Of Medicine Compositions and methods of double-targeting virus infections and cancer cells
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