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WO1990009999A1 - Derives de seco-nucleosides et medicaments les contenant - Google Patents

Derives de seco-nucleosides et medicaments les contenant Download PDF

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Publication number
WO1990009999A1
WO1990009999A1 PCT/EP1990/000299 EP9000299W WO9009999A1 WO 1990009999 A1 WO1990009999 A1 WO 1990009999A1 EP 9000299 W EP9000299 W EP 9000299W WO 9009999 A1 WO9009999 A1 WO 9009999A1
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WO
WIPO (PCT)
Prior art keywords
group
compounds
alkyl
thymine
general formula
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/EP1990/000299
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German (de)
English (en)
Inventor
Alfred Mertens
Harald Zilch
Bernhard Koenig
Edith Koch
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Roche Diagnostics GmbH
Original Assignee
Boehringer Mannheim GmbH
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Filing date
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Application filed by Boehringer Mannheim GmbH filed Critical Boehringer Mannheim GmbH
Publication of WO1990009999A1 publication Critical patent/WO1990009999A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom

Definitions

  • the invention relates to seconucleoside derivatives, processes for the preparation of these compounds and medicaments containing them.
  • the present invention relates to seco-nucleoside or nucleotide derivatives of the general formula I
  • R denotes hydrogen, an aliphatic acyl group with 1-20 C atoms or a monophosphate, diphosphate or triphosphate group,
  • R 1 is a C 1 -C 7 alkyl, halo C 1 -C 7 alkyl, trifluoromethyl, C 2 -C 7 alkenyl, C 3 -C 7 alkanedienyl, C 2 -C 7 - Alkynyl, cyano, formyl, C 1 -C 7 alkylcarbonyl, C 1 -C 7 alkoxycarbonyl, aminocarbonyl, azido, C 3 -C 7 cycloalkyl, C 3 -C 7 Is cycloalkenyl or aryl group or a saturated, unsaturated or aromatic heterocycle, and
  • R 2 is a thymine, uracil, cytosine, adenine, hypoxanthine or guanine group, where a) R cannot be a hydrogen atom or an acyl group if R 1 is an alkyl, cycloalkyl or phenyl group and R 2 is an uracil or thymine group, and b) R cannot be a hydrogen atom or an acyl group if R 1 is an alkyl group and R 2 is an adenine, guanine or hypoxanthine group, their tautomers, optically active forms or physiologically acceptable salts of inorganic and organic acids and bases, and processes for their preparation and medicaments containing these compounds.
  • the invention also relates to the optically active forms and racemic mixtures of these compounds.
  • 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 camphoric acid can be used for the resolution.
  • EP-A-0,046,307 describes uracil and thymine derivatives in which R can be a hydrogen atom or an acyl group and R 1 can be an alkyl, cycloalkyl or phenyl group. These compounds have an anti-tumor effect as a drug. Such compounds are not covered by disclaimer a) from the definition given above with respect to formula I.
  • R 2 can mean an adenine, guanine or hypoxanthine group. These compounds have an antiviral effect. You are disclaimer b) of the above definition regarding.
  • Formula I does not include.
  • Chem.Pharm.Bull. 33, 1703 (1985) describes the synthesis of pyrimidine acyclonucleosides in which R 1 represents a methyl group and R 2 represents the uracil or thymine group.
  • seco-nucleosides such as acycloadenosine can be used as an inhibitor of adenosine deaminase (J.Med.Chem. 14, 367, 1971), acycloguanosine is active against herpes simplex (Lancet 243, 1979) and acyclonucleosides of pyrimidine have an inhibitory effect Have an effect on the enzyme uridine phosphorylase.
  • J.Med.Chem. 32, 73, 1989 describes acyclic nucleosides which have only a weak effect in HIV-infected cells.
  • the object of the present invention is to provide new compounds which are more effective than the known compounds.
  • the compounds of the present invention 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, papilloma 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 human immunodeficiency virus HIV-1 or -2, caused. They are therefore particularly suitable for the production of antiviral drugs.
  • PDL generalized lymphadenopathy
  • ARC AIDS-related complex
  • RNA viruses at the level of virus-specific DNA or RNA transcription.
  • the substances can influence the multiplication of retroviruses especially by inhibiting the enzyme reverse transcriptase (cf. Proc.Natl. Acad.Sci. USA 81, 1911, 1986 or Nature 325, 773 1987).
  • reverse transcriptase cf. Proc.Natl. Acad.Sci. USA 81, 1911, 1986 or Nature 325, 773 1987.
  • AIDS 3'-azido-3'-deoxythymidine
  • 3'-azido-3'-deoxythymidine (DE-A-3,608,606) is currently approved for the treatment of AIDS in AIDS patients.
  • toxic side effects of 3'-azido-3'-deoxythymidine on the bone marrow require blood transfusions in about 50% of the patients treated.
  • the compounds of the general formula I do not have these disadvantages. They have an antiviral effect without being cytotoxic in pharmacological
  • the aliphatic acyl radical in the definition of the substituent R in the general formula I can be saturated or unsaturated, straight-chain or branched and contain 1-20, preferably 1-10 or 1-6 carbon atoms.
  • acetyl, propionyl, isopropionyl and tert-butyryl radical is particularly preferred.
  • alkyl, haloalkyl, alkylcarbonyl and alkoxycarbonyl radicals occurring in the definition of the substituent R 1 of the general formula I can be saturated or unsaturated, straight-chain or branched and contain 1-7, preferably 1-4 carbon atoms.
  • the methyl, ethyl, propyl, isopropyl, trifluoromethyl, methyloxycarbonyl, ethyloxycarbonyl and halomethyl radical is particularly preferred, where halogen means fluorine, chlorine, bromine and iodine.
  • alkenyl, alkanedienyl and alkynyl radicals occurring in the definition of the substituent R 1 of the general formula I can be straight-chain or branched and contain 2-7, preferably 2-4, carbon atoms.
  • the vinyl, propenyl, 2-methylpropenyl, butadienyl, ethynyl and propynyl radical is particularly preferred.
  • the cycloalkyl and cycloalkenyl radicals occurring in the definition of the substituent R 1 of the general formula I can contain 3-7, preferably 3-6 carbon atoms.
  • the cyclopropyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl radical is particularly preferred.
  • the aryl and hetaryl radicals occurring in the definition of the substituent R 1 of the general formula I are preferably phenyl, heterocyclic five-membered rings with 1-4 heteroatoms and heterocyclic six-membered rings with 1-2 heteroatoms, the heteroatoms of the aforementioned five- and six-membered rings being identical or different can mean oxygen, sulfur and nitrogen.
  • pyridyl pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl radical, as well as their di and tetrahydro derivatives.
  • the group R 1 is in particular a C 1 -C 4 alkyl group, for example methyl or ethyl group; a halogen-C 1 - C 4 -alkyl-, for example the chloroethyl group; a
  • Cycloalkyl for example cyclopentyl or cyclohexyl group; a phenyl, furyl, pyridyl or triazolyl group, it being possible for the heterocyclic radical to be bonded via the 1-, 2-, 3- or 4-position, such as, for example, 2-furyl, 3-furyl, 2-pyridyl , 4-triazolyl or 4-pyridyl.
  • R 2 is preferably the thymine group.
  • the group R preferably denotes a hydrogen atom, a C 1 -C 4 -alkylcarbonyl group, for example the acetyl group, or the mono- or 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.
  • 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 compounds of general formula I are new compounds. They can be prepared analogously to known, related compounds (cf. Chem. Pharm.Bull. 33, 1703, 1985). It has proven particularly expedient to prepare the compounds of the general formula I by using a compound of the general formula II
  • R 1 has the meaning given
  • R 3 is hydrogen or an easily removable oxygen protective group, such as, for example, the trityl, acetyl, benzoyl, benzyl or trialkylsilyl group
  • X is a leaving group, such as chlorine, bromine or iodine , Tosylate, mesylate or acetate, with thymine, uracil, cytosine, adenine, hypoxanthine, guanine or a silyl-protected derivative of these bases, and after splitting off any protective groups, compounds of the general formula I
  • R 1 and R 2 have the meaning given and R 3 is hydrogen
  • R 1 and R 2 have the meaning given and R 3 is hydrogen
  • compounds of the general formula I in which R 1 and R 2 have the meaning given and R 3 is hydrogen, in a known manner into the mono -, Di- or triphosphates or the corresponding acyl derivatives
  • reaction of the compounds of the general formula II is advantageously carried out using silyl-protected thymine, uracil, cytosine, adenine, hypoxanthine or guanine in an aprotic solvent, such as, for example, diethyl ether, tetrahydrofuran, toluene, dimethylformamide, dichloromethane or chloroform at temperatures between 0 ° C.
  • an aprotic solvent such as, for example, diethyl ether, tetrahydrofuran, toluene, dimethylformamide, dichloromethane or chloroform
  • the Reaction mixture advantageously catalytic amounts of a Lewis acid, such as aluminum trichloride, zinc bromide, zinc iodide, boron trifluoride, titanium tetrachloride or tin tetrachloride, or molar amounts of trimethylsilyl chloride, bromide or iodide can be added.
  • a Lewis acid such as aluminum trichloride, zinc bromide, zinc iodide, boron trifluoride, titanium tetrachloride or tin tetrachloride, or molar amounts of trimethylsilyl chloride, bromide or iodide can be added.
  • organic or inorganic acids e.g. Hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, or by acidic ion exchange, e.g. Amberlite IR-120 or Amberlist 15.
  • organic or inorganic acids e.g. Hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, or by acidic ion exchange, e.g. Amberlite IR-120 or Amberlist 15.
  • the silyl-protected bases R 2 can according to known
  • Processes are obtained, such as reaction of the respective base R 2 with hexamethyl disilazane.
  • reaction of compounds of general formula III with thymine, uracil, cytosine, adenine, hypoxanthine, guanine or a silyl-protected derivative of these bases is advantageously carried out in a protic or aprotic solvent at temperatures between -25 ° C and 150 ° C, preferably between 25 ° C and 75 ° C carried out, whereby conditions of phase transfer catalysis can be used in particular, in which the above-mentioned bases are converted into a corresponding anion, for example by 50 percent.
  • aqueous sodium hydroxide solution and the anion formed in this way are hydrophobized by a phase transfer catalyst, for example tris [2- (2-methoxyethoxy) ethyl] amine, and are transported into the organic phase in which it reacts with the reactive compound of the formula III.
  • 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 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 are obtained by known methods, preferably from the monophosphates by reaction with o-phosphates or pyrophosphates. Their various salts can also be prepared by known methods.
  • Such additives are, for example, tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts) and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation.
  • Solid carriers are, for example, starch, lactose, mannitol, methyl cellulose, Talc, highly disperse silicas, high-molecular fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high-molecular polymers (such as polyethylene glycols).
  • Preparations suitable for oral administration can, if desired, 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, 1-2 tablets with an active ingredient content of 0.5-1000 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 2-2000 mg.
  • the active ingredient can also be given by injection one to eight times a day or by continuous infusion, with amounts of 5-4000 mg per day usually being sufficient.
  • the mixture was stirred in an ice bath for a further 15 minutes and then added dropwise to a solution of 0.5 mmol bis-tributylammonium pyrophosphate, 2 ml DMF, 2 ml pyridine and 0.2 ml tributylamine while cooling with ice. After 5 minutes, 2 ml of a 0.2 molar aqueous triethylammonium hydrogen carbonate solution were added to stop the reactions, the mixture was diluted with water after 30 minutes, applied to a Sephadex DEAE column and with a 0.1-0.5 molar linear gradient eluted from triethylammonium bicarbonate.

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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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux dérivés de séco-nucléosides de formule (I), où R est hydrogène, un groupe acyle aliphatique avec 1 à 20 atomes de C ou un groupe monophosphate, diphosphate ou triphosphate, R1 est un groupe alkyle C¿1?-C7, halogène-alkyle C1-C7, trifluorométhyle, alkényle C2-C7, alkanediényle C3-C7, alkinyle C2-C7, cyano, formyle, alkyle C1-C7-carbonyle, alkoxycarbonyle C1-C7, aminocarbonyle, azido, cycloalkényle C3-C7 ou aryle ou bien un hétérocycle saturé, insaturé ou aromatique, et R?2¿ est un groupe thymine, uracyle, cytosine, adénine, hypoxanthine ou guanine; a) R ne peut être un atome d'hydrogène ou un groupe acyle si R1 est un groupe alkyle, cycloalkyle ou phényle et R2 est un groupe uracile ou thimine, et b) R ne peut être un atome hydrogène ou un groupe acyle si R1 est un groupe alkyle et R2 est un groupe adénine, guanine ou hypoxanthine. L'invention concerne également leurs tautomères, des formes optiquement actives ou des sels physiologiquement compatibles d'acides et de bases inorganiques et organiques, ainsi que des procédés pour les fabriquer et des médicaments contenant ces composés.
PCT/EP1990/000299 1989-02-24 1990-02-22 Derives de seco-nucleosides et medicaments les contenant Ceased WO1990009999A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP3905725.9 1989-02-24
DE3905725A DE3905725A1 (de) 1989-02-24 1989-02-24 Seco-nucleosid-derivate, verfahren zu deren herstellung sowie deren verwendung als antivirale mittel

Publications (1)

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WO1990009999A1 true WO1990009999A1 (fr) 1990-09-07

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0046307A1 (fr) * 1980-08-19 1982-02-24 Chugai Seiyaku Kabushiki Kaisha Dérivés de l'uracile, leur procédé de préparation et une composition pharmaceutique les contenant

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0046307A1 (fr) * 1980-08-19 1982-02-24 Chugai Seiyaku Kabushiki Kaisha Dérivés de l'uracile, leur procédé de préparation et une composition pharmaceutique les contenant

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Journal of Medicinal Chemistry, Band 32, 1989, American Chemical Society, (Washington, US), P. SCHEINER et al.: "Acyclic Analogues of 3'-Azido-3'-Deoxythymidine as Potential Antiviral Agents. Nucleoside Synthesis by Michael Addition", seiten 73-76 *

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DE3905725A1 (de) 1990-09-06

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