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WO2003089421A1 - Lactones-urees antivirales - Google Patents

Lactones-urees antivirales Download PDF

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Publication number
WO2003089421A1
WO2003089421A1 PCT/EP2003/003981 EP0303981W WO03089421A1 WO 2003089421 A1 WO2003089421 A1 WO 2003089421A1 EP 0303981 W EP0303981 W EP 0303981W WO 03089421 A1 WO03089421 A1 WO 03089421A1
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WIPO (PCT)
Prior art keywords
alkyl
amino
compounds
aryl
substituted
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
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PCT/EP2003/003981
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German (de)
English (en)
Inventor
Tobias Wunberg
Ulrich Betz
Judith Baumeister
Axel Jensen
Susanne Nikolic
Jürgen Reefschläger
Holger Zimmermann
Franz Zumpe
Rolf Grosser
Gerald Kleymann
Wolfgang Bender
Kerstin Henninger
Guy Hewlett
Jörg Keldenich
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.)
Bayer AG
Original Assignee
Bayer AG
Bayer Healthcare AG
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.)
Filing date
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Priority to JP2003586142A priority Critical patent/JP2005529119A/ja
Priority to CA002482715A priority patent/CA2482715A1/fr
Priority to AU2003232476A priority patent/AU2003232476A1/en
Priority to EP03746829A priority patent/EP1499603A1/fr
Publication of WO2003089421A1 publication Critical patent/WO2003089421A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the invention relates to lactones and processes for their preparation and their use for the manufacture of medicaments for the treatment and / or prophylaxis of diseases, in particular for use as antiviral agents, in particular against cytomegaloviruses.
  • the present invention relates to compounds of the formula
  • D represents oxygen or sulfur
  • R 1 represents hydrogen or -CC 6 - alkyl, where alkyl can be substituted with 0, 1, 2 or 3 substituents independently of one another selected from the group consisting of halogen, hydroxy, Ci-C 6 alkoxy, C ⁇ -Cio- Aryl, amino and -CC 6 -alkylamino,
  • R 1 and R 4 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl ring, where the cycloalkyl ring can be substituted with 0, 1, 2 or 3 substituents independently selected from the Group consisting of halogen, hydroxyl, -CC 6 -alkyl, -C-C 6 -
  • R 2 represents C 3 -C ⁇ o-cycloalkyl or C 6 -C ⁇ o-aryl, where aryl can be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, nitro, cyano, Ci C 6 alkoxy,
  • R 3 represents hydrogen or -CC 6 - alkyl, where alkyl can be substituted with
  • substituents independently selected from the group consisting of fluorine, chlorine, hydroxy, -C-C 6 alkoxy, C 6 -C 10 aryl,. Amino and C 1 -C 6 -alkylamino,
  • R 3 and R 6 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl ring, where the cycloalkyl ring can be substituted with 0, 1, 2 or 3 substituents independently selected from the Group consisting of halogen, hydroxy, -CC 6 alkyl, -C 6 -alkoxy, Cg-do-aryl, amino and Ci-C ö alkylamino,
  • R 4 is hydrogen or Ci-C ö -alkyl, where alkyl may be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, C ⁇ -C 6 - alkoxy, Amino and C 1 -C 6 -alkylamino,
  • R 5 represents hydrogen, halogen, hydroxy, cyano, C 1 -C 6 -alkoxy, carboxy, CrC 6 - alkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, amino, C ds-alkylamino or C 1 -C 6 -alkyl.
  • R 6 represents hydrogen or C C ⁇ -alkyl, where alkyl can be substituted with 0, 1, 2 or 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, hydroxy, C 1 -C 6 alkoxy, C 6 -C ⁇ o Aryl, amino and C 1 -C 6 -AH **. Ylamino.
  • R 1 , R 3 , R 4 and R 6 are not simultaneously hydrogen.
  • the compounds according to the invention can also be in the form of their salts, solvates or
  • the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore relates to the enantiomers or diastereomers and their respective mixtures.
  • Such mixtures of enantiomers and / or diastereomers can isolate the stereoisomerically uniform constituents in a known manner.
  • the invention also relates to tautomers of the compounds.
  • preferred salts are physiologically acceptable salts of the compounds according to the invention.
  • Physiologically acceptable salts of compounds (I) include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid. Naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • Physiologically acceptable salts of the compounds (T) also include salts of conventional bases, such as, for example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 C atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoelhanolamine, diethanolamine, triethanolamine, dicyclo-hexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, dehydroabietylamine and methylamine, arginine diamine, arginine diamine.
  • alkali metal salts for example sodium and potassium salts
  • alkaline earth metal salts for example calcium and magnesium salts
  • solvates are those forms of the compounds which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvate, in which coordination takes place with water. In the context of the present invention, unless otherwise specified, the substituents have the following meaning:
  • Alkylamino, alkylaminocarbonyl and alkoxycarbonyl represent a linear or branched alkyl radical with generally 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl , n-pentyl and n-hexyl.
  • Alkoxy is exemplary and preferably methoxy, ethoxy, n-propoxy,
  • Alkylamino stands for an alkylamino radical with one or two (independently of one another) alkyl substituents, for example and preferably for methylamino, ethylamino, n-propylamino, isopropylarnino, tert-butylamino, n-pentylamino, n-
  • Hexylamino NN-dimethylamino, NN-diethylamino, N-ethyl-N-methylamino, N- me yl-Nn-propylan-ino, N-isopropyl-Nn-propylamino, N-tert.-butyl-N-mefhylamino, N- Ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.
  • Alkylaminocarbonyl stands for an alkylarninocarbonyl radical with one or two (independently selected) alkyl substituents, by way of example and preferably for methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert.-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, n-hexylaminocarbonyl , N, N-Die1hylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-isopropyl-Nn-propylamino-carbonyl, N-tert.-butyl-N-methylaminocarbonyl, N-ethyl- Nn-pentylamino-carbonyl and N
  • Alkoxycarbonyl is exemplified and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.
  • Cycloalkyl stands for a cycloalkyl group with generally 3 to 10, preferably 5 to 10 carbon atoms, by way of example and preferably for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl.
  • Aryl stands for a mono- to tricyclic aromatic, carbocyclic radical with usually 6 to 14 carbon atoms; exemplary and preferably for phenyl, naphthyl and phenanthrenyl.
  • Heterocyclyl stands for a mono- or polycyclic, preferably mono- or bicyclic, non-aromatic heterocyclic radical with generally 4 to 10, preferably 5 to 8 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series N, O, S, SO, SO 2 .
  • the heterocyclyl residues can be saturated or partially unsaturated. 5- to 8-membered, monocyclic saturated heterocyclyl radicals having up to two heteroatoms from the are preferred
  • Halogen stands for fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
  • R 1 represents CrC 6 alkyl, where alkyl can be substituted by 0, 1 or 2
  • Substituents independently selected from the group consisting from fluorine, chlorine; Hydroxy, CrC ⁇ -alkoxy, Cö-Cio-aryl, amino and C ⁇ -C 6 - alkylamino,
  • R 2 represents C 3 -C ⁇ o-cycloalkyl or C 6 -C ⁇ o-aryl, where aryl can be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano and C ⁇ -C 6 - alkyl .
  • R 3 represents hydrogen or C 1 -C 6 -alkyl, where alkyl can be substituted with 0, 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, hydroxyl, C 1 -C 6 -alkoxy, Cö-Cio -Aryl, amino and
  • R 4 represents C 1 -C 6 -alkyl, where alkyl can be substituted with 0, 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, hydroxy, C 1 -C 6 -alkoxy, C 6 -C ⁇ o-aryl , Amino and C ⁇ -C 6 -
  • R 5 represents hydrogen, halogen, hydroxy, amino, C 1 -C 6 -alkylamino or C 1 -C 6 -alkyl
  • R 6 represents hydrogen or CrC 6 - alkyl, where alkyl can be substituted with 0, 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, hydroxy, C 1 -C 6 -alkoxy, C 6 -C ⁇ o-aryl , Amino and
  • R 1 represents d-Ce-alkyl
  • R represents phenyl or adamantyl, where phenyl can be substituted with 0, 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano and C 1 -C 6 -alkyl,
  • R represents hydrogen
  • R 4 represents Ci-C ⁇ -alkyl
  • R 5 represents hydrogen, hydroxy, fluorine, chlorine or methyl
  • R 6 represents hydrogen
  • R 5 stands for hydroxyl, fluorine, chlorine or methyl and is bound via the 6 position to the aromatics.
  • R 1 represents methyl
  • R 2 stands for adamantyl or phenyl, where phenyl can be substituted with 0, 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, cyano and methyl.
  • R 4 represents methyl
  • R 4 represents benzyl
  • R 6 represents hydrogen
  • R 1 and R 4 are methyl.
  • radical definitions specified in detail in the respective combinations or preferred combinations of radicals are also replaced by radical definitions of a different combination, regardless of the respectively specified combinations of the radicals. Combinations of two or more of the preferred ranges mentioned above are very particularly preferred.
  • the invention further relates to processes for the preparation of the compounds of
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 have the meaning given above, and
  • R 7 represents alkyl, preferably methyl or ethyl
  • -NH 2 is bound to the aromatics via one of the positions 2, 3, 5 or 6, and
  • R 1 , R 3 , R 4 , R 5 and R 6 have the meaning given above, '
  • the reaction according to Verfaliren [A] is generally carried out in a solvent, preferably in a temperature range from ⁇ l0 ° C to room temperature at normal pressure.
  • Solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-
  • Butanol or tert-butanol, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine preferred are methanol, diethyl ether or mixtures of methanol and diethyl ether or ethanol and tetrahydrofuran.
  • Reducing agents are, for example, sodium borohydride, lithium borohydride, tetrabutylammonium borohydride or sodium cyanoborohydride, preferably sodium borohydride.
  • reaction according to process [B] is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from room temperature to the reflux of the solvents at atmospheric pressure.
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran or diethylene dimethyl ether - Glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 2-butanone, dimethyl sulfoxide, acetonitrile or pyridine, tetrahydrofuran, methylene chloride or eth
  • Bases are, for example, alkali carbonates such as cesium carbonate, sodium or potassium carbonate, or potassium tert-butoxide, or other bases such as sodium hydride,
  • DBU triethylamine or diisopropylethylamine, preferred are diisopropylethylamine and triethylamine.
  • the compounds of the formula (TV) are known or can be synthesized from the corresponding starting materials by known processes.
  • the compounds of formula (II) can be prepared by compounds of formula (II).
  • NH 2 is bound to the aromatics via one of the positions 2, 3, 5 or 6, and
  • the reaction is generally carried out under the conditions described in process [B].
  • the compounds of formula (III) can be prepared by compounds of formula (III).
  • N0 2 is bound to the aromatics via one of the positions 2, 3, 5 or 6, and
  • R 1 , R 3 , R 4 , R 5 , R 6 and R 7 have the meaning given above,
  • tin (II) chloride tin in hydrochloric acid or hydrogen with palladium on carbon.
  • the reaction is generally carried out in inert solvents, preferably in a temperature range from room temperature to the reflux of the solvents at atmospheric pressure to 3 bar.
  • Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, iso-
  • hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions
  • solvents such as dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate or pyridine, ethanol, isopropanol, ethyl acetate or im are preferred Case of tin dichloride in dimethylformamide
  • the compounds of formula (V) can be prepared by compounds of the formula
  • NO 2 is bound to the aromatics via one of the positions 2, 3, 5 or 6, and
  • R 1 , R 3 , R 4 , R 5 and R 6 have the meaning given above,
  • R 7 has the meaning given above, are implemented.
  • reaction is generally carried out in inert solvents or in compounds of the formula (VII), if appropriate in the presence of an acid, preferably in a temperature range from room temperature to the reflux of the solvents at atmospheric pressure.
  • Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate or pyridine, ethanol being preferred or methanol.
  • ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate or pyridine, ethanol being preferred or methanol.
  • Acids are, for example, hydrochloric acid, sulfuric acid or p-toluenesulfonic acid, sulfuric acid is preferred.
  • the compounds of the formula (VII) are known or can be synthesized from the corresponding starting materials by known processes.
  • the compounds of formula (VI) can be prepared by compounds of the formula
  • R 1 , R 3 , R 4 , R 5 and R 6 have the meaning given above,
  • the compounds of formula (VIII) can be prepared by compounds of formula (VIII).
  • R 5 has the meaning given above
  • the reaction is generally carried out in merten solvents, optionally in the presence of a Lewis acid, preferably in a temperature range from -10 ° C to room temperature at normal pressure.
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran or glycol Diethylene glycol dimethyl ether, hydrocarbons such as hexane or cyclohexane, or others
  • halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene
  • ethers such as diethyl ether, methyl tert-butyl ether,
  • Solvents such as ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 2-butanone, dimethyl sulfoxide, acetonitrile or pyridine, 1,2-dichloroethane is preferred.
  • Lewis acids are, for example, aluminum trichloride or titanium tetrachloride, and aluminum trichloride is preferred.
  • R 1 , R 4 and R 5 have the meaning given above,
  • L 1 represents halogen, preferably bromine or iodine
  • the reaction is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from -78 ° C. to room temperature at atmospheric pressure.
  • Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, ethylbenzene, xylene, toluene, preferably tetrahydrofuran or toluene.
  • ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether
  • hydrocarbons such as benzene, ethylbenzene, xylene, toluene, preferably tetrahydrofuran or toluene.
  • Bases are, for example, amides such as sodium amide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, or other bases such as sodium hydride, DBU or diisopropylethylamine, preferably sodium amide, lithium hexamethyldisilazide, potassium hexamethyldisilazide or lithium diisopropylamide.
  • amides such as sodium amide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide.
  • R 6 represents hydrogen
  • R 1 , R 3 , R 4 , R 5 and R 7 have the meaning given above,
  • the reaction is generally carried out in inert solvents, preferably in a temperature range from 0 ° C. to room temperature at atmospheric pressure.
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol
  • hydrocarbons such as benzene, xylene, tol
  • the compounds of formula (XU) can be prepared by compounds of the formula in which
  • R 5 has the meaning given above
  • the reaction is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from -78 ° C. to room temperature at atmospheric pressure.
  • Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, ethylbenzene, xylene, toluene, hexane, heptane, cyclohexane or petroleum fractions , or other solvents such as dimethylformamide or dimethylacetamide, or mixtures of the solvents, diethyl ether, tetrahydrofuran, heptane and / or ethylbenzene are preferred.
  • ethers such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol di
  • Bases are, for example, sodium or potassium methoxide, or sodium or potassium ethoxide or potassium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsilyl) amide, lithium diisopropylamide, or organometallic compounds such as butyllithium or phenyllithium, or other bases such as sodium hydride , DBU, triethylamine or diisopropylethylamine, lithium diisopropylamide is preferred.
  • amides such as sodium amide, lithium bis (trimethylsilyl) amide, lithium diisopropylamide, or organometallic compounds such as butyllithium or phenyllithium, or other bases such as sodium hydride , DBU, triethylamine or diisopropylethylamine, lithium diisopropylamide is preferred.
  • the compounds of the formula (XTV) are known or can be synthesized from the corresponding starting materials by known processes.
  • the compounds of formula (XIII) can be prepared by compounds of the formula
  • the reaction is optionally carried out in inert solvents, preferably in a temperature range from room temperature to 100 ° C. at normal pressure.
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclo- hexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile or pyridine, preferably tetrahydrofuran or methylene chloride.
  • halogenated hydrocarbons such as methylene chloride,
  • the compounds of formula (XVI) can be prepared by compounds of the formula
  • -NO 2 is bound to the aromatics via one of the positions 2, 3, 5 or 6, and
  • R 1 , R 3 , R 4 , R 5 and R 6 have the meaning given above,
  • tin (II) chloride or tin in hydrochloric acid may be reduced, e.g. with tin (II) chloride or tin in hydrochloric acid.
  • the compounds of formula (XVII) can be prepared by reacting compounds of formula (V) according to the conditions described in process [A].
  • compounds of formula (EU) can be prepared by using compounds of formula
  • N-diallyl is bonded to the aromatics via one of the positions 2, 3, 5 or 6, and
  • R 1 , R 3 , R 4 , R 5 , R 6 and R 7 have the meaning given above,
  • the reaction is generally carried out in inert solvents, preferably in a temperature range from room temperature to the reflux of the solvents at atmospheric pressure.
  • Inert solvents are, for example, hydrocarbons such as benzene, ethylbenzene, xylene, toluene, or other solvents such as ethyl acetate, dimethylformamide or dimethylacetamide or mixtures of these solvents, preferably dimethylformamide, toluene or a mixture of dimethylformamide and toluene.
  • the compounds of the formula (XX) can be synthesized from the corresponding NN-diallylamino-substituted starting materials by the alternative synthetic process described for the formula (VIII) or known processes.
  • the compounds of the general formula (I) according to the invention show an unforeseeable surprising spectrum of action. They show an antiviral effect against representatives of the group of herpes viridae, especially against the human cytomegalovirus (HCMV). They are therefore suitable for the treatment and prophylaxis of diseases caused by herpes viridae, in particular diseases caused by human cytomegaloviruses.
  • HCMV human cytomegalovirus
  • the compounds of the general formula (I) can be used for the production of medicaments which are suitable for the prophylaxis or treatment of diseases, in particular viral diseases.
  • the compounds according to the invention are valuable active substances for the treatment and prophylaxis of human cytomegalovirus infections and diseases caused thereby. Examples of indications which may be mentioned are:
  • HCMV infections Treatment and prophylaxis of HCMV infections in AIDS patients (retinitis, pneumonitis, gastrointestinal infections).
  • the new active ingredients can be used alone and, if necessary, in combination with other antiviral active ingredients such as Gancyclovir or Acyclovir.
  • the present invention further relates to medicaments which contain at least one compound according to the invention, preferably together with one or more pharmacologically acceptable auxiliaries or excipients, and to their use for the purposes mentioned above.
  • the active substance can act systemically and / or locally.
  • it can be applied in a suitable way, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, topical or as
  • the active ingredient can be administered in suitable administration forms for these administration routes.
  • Known application forms which release the active ingredient quickly and / or modified such as e.g. Tablets (non-coated and coated tablets, e.g. tablets or film-coated tablets provided with enteric coatings), capsules, dragees, granules, pellets, powders, emulsions, suspensions, solutions and aerosols.
  • Tablets non-coated and coated tablets, e.g. tablets or film-coated tablets provided with enteric coatings
  • capsules dragees, granules, pellets, powders, emulsions, suspensions, solutions and aerosols.
  • Parenteral administration can be done by bypassing an absorption step (intravenously, intraarterially, intracardially, intraspinally or intralumbally) or by switching on absorption (intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • absorption step intravenously, intraarterially, intracardially, intraspinally or intralumbally
  • absorption intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration the following are suitable form injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.
  • Inhaled drug forms e.g. powder inhalers, nebulizers
  • nasal drops / solutions, sprays e.g., aqueous suspensions (lotions, shake mixes), lipophilic suspensions, ointments, creams, milk, pastes, powder or implants.
  • the active compounds can be converted into the administration forms mentioned in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable excipients.
  • Carriers e.g. microcrystalline cellulose
  • solvents e.g. liquid polyethylene glycols
  • emulsifiers e.g. sodium dodecyl sulfate
  • dispersants e.g. polyvinylpyrrolidone
  • synthetic and natural biopolymers e.g. albumin
  • stabilizers e.g. antioxidants such as ascorbic acid
  • dyes e.g. inorganic pigments
  • iron oxides e.g. inorganic pigments
  • the dosage is about 0.01 to 25 mg / kg, preferably 0.1 to 10 mg / kg body weight.
  • Dilution ratios and concentration details of liquid / liquid solutions each relate to the volume.
  • Pillar packing material KBD 6371 (250 * 20); Temperature: 23 ° C; Eluent: ethyl acetate; Compound dissolved in ethyl acetate.
  • Method 3 Column: packing material 6371 (250 * 20); Temperature: 23 ° C; Eluent: ethyl acetate; Compound dissolved in ethyl acetate / tetrahydrofuran (1: 1 (v / v)).
  • Examples 12A to 21A are produced according to general working procedure A.
  • the LDA solution required to carry out this reaction is freshly prepared.
  • 21.4 ml (153 mmol) of diisopropylamine are dissolved in 25 ml of dry THF under an argon atmosphere and cooled to -20 ° C.
  • 61.2 ml (153 mmol) of n-butyllithium are added dropwise as a 2.5 molar solution.
  • the solution obtained is then stirred for a further 30 min with heating to 0.degree.
  • 12.4 g (51 mmol) of l- [3- (diallylamino) phenyl] -2-methyl-l-propanone are also dissolved in 10 ml of dry THF under an argon atmosphere. After cooling to -78 ° C, the freshly prepared LDA solution is slowly added dropwise. It will be at 1 hour
  • a fresh LDA solution is prepared from 1.15 g (11.38 mmol) of diisopropylamine and 4.55 ml of a 2.5 molar n-butyllithium solution in 15 ml of dry THF under an argon atmosphere.
  • 3.16 g (10.35 mmol) are dissolved in 30 ml THF under an argon atmosphere and the solution obtained is cooled to -78 ° C.
  • the Irish-made LDA solution is slowly added dropwise to this solution at -78 ° C.
  • the mixture is stirred for a further hour at -78 ° C. before 4.75 g (31 mmol) of methyl bromoacetate in 15 ml of THF are added dropwise.
  • reaction mixture is allowed to warm up slowly to room temperature and is stirred for a further 4 hours at RT. Then 14 ml of 1N hydrochloric acid, 70 ml of water and 100 ml of methylene chloride are added. The phases are separated and the aqueous phase is extracted 3 times with methylene chloride. The combined organic phases are dried over magnesium sulfate. After filtration and evaporation of the solvent, the residue is purified by column chromatography (silica gel: cyclohexane / methylene chloride 2: 1 then 1: 1 and finally with pure methylene chloride). 1.17 g (28% of theory) of product are obtained.
  • Examples 1 to 10 are produced according to general working procedure B.
  • Anti-HCMV anti-human cytomegalo virus cytopathogenicity tests
  • test compounds are used as 50 millimolar (mM) solutions in dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • Ganciclovir, foscarnet and cidofovir serve as reference compounds. After adding 2 ⁇ l each of the 50, 5, 0.5 and 0.05 mM
  • DMSO stock solutions with 98 ⁇ l cell culture medium in the 2 AH series in duplicate are carried out 1: 2 dilutions with 50 ⁇ l medium each up to the 11 series of the 96-well plate.
  • the wells in rows 1 and 12 each contain 50 ⁇ l medium.
  • Row 12 (without substance) serves as a virus control.
  • the final test concentrations are 250 - 0.0005 ⁇ M.
  • the plates are incubated for 6 days at 37 ° C / 5% CO 2 , ie until all cells in the virus controls are infected (100% cytopathogenic effect [CPE]).
  • CPE cytopathogenic effect
  • the wells are then fixed by adding a mixture of formalin and Giemsa's dye and colored (30 minutes), with aqua bidest. washed and dried in a drying cabinet at 50 ° C. Then the plates are visually evaluated with an overhead microscope (plaque multiplier from Technomara).
  • CC 50 (NHDF) substance concentration in ⁇ M at which no visible cytostatic effects on the cells can be seen compared to the untreated cell control
  • EC50 (HCMV) substance concentration in ⁇ M that inhibits the CPE (cytopathic effect) by 50% compared to the untreated virus control
  • SI selective index
  • mice 3-4 week old female immunodeficient mice (16-18 g), Fox Chase SCID or Fox Chase SCID-NOD or SCID-beige are obtained from commercial breeders (Bomholtgaard, Jackson). The animals are kept in isolators under sterile conditions (including litter and feed).
  • HCMV Human cytomegalovirus
  • NHDF cells human embryonic foreskin fibroblasts
  • NHDF cells with an infection multiplicity (MOI) of 0.01 the virus-infected cells are harvested 5-7 days later and in the presence of Minimal Essential Medium (MEM), 10% Fetal Calf Serum (FCS) with 10% DMSO at -40 ° C stored. After serial dilution of the virus-infected cells in steps of ten, the titer is determined on 24-well plates of confluent NHDF cells after vital staining with neutral red.
  • MOI infection multiplicity
  • the infected sponges are incubated with 25 ⁇ l PBS / 0.1% BSA / 1 mM DTT with 5 ng / ⁇ l basic fibroblast growth factor (bFGF).
  • the immunodeficient mice are anesthetized with avertine, the dorsal coat removed with the help of a dry razor, the epidermis opened 1-2 cm, relieved and the moist sponges transplanted under the dorsal skin.
  • the surgical wound is closed with tissue glue. 24 hours after the transplant the mice were treated orally with substance three times a day for 8 days (7 a.m. and 2 p.m. and 7 p.m.).
  • the dose is 7 or 15 or 30 or 60 mg / kg body weight, the application volume 10 ml / kg body weight.
  • the substances are formulated in the form of a 0.5% tylose suspension with 2% DMSO. 9 days after the transplant and 16 hours after the last one
  • the virus-infected cells are released from the sponge by collagenase digestion (330 U / 1.5 ml) and stored at -140 ° C. in the presence of MEM, 10% fetal calf serum, 10% DMSO.
  • the evaluation takes place after serial dilution of the virus-infected cells in steps of ten by titer determination on 24-well plates of confluent NHDF cells after vital staining with Neutrahot. The number of infectious virus particles after substance treatment compared to the placebo-treated control group is determined.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • the mixture of active ingredient, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are dried with the magnesium stearate for 5 min. mixed.
  • This mixture is compressed with a conventional tablet press (tablet format see above).
  • a pressing force of 15 kN is used as a guideline for the pressing.
  • Rhodigel is suspended in ethanol, the active ingredient is added to the suspension. The water is added with stirring. The swelling of the Rhodigel is stirred for about 6 hours.

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  • Organic Chemistry (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
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  • Communicable Diseases (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

L'invention se rapporte à des lactones, à leur procédé de production ainsi qu'à leur utilisation pour générer des médicaments qui servent à traiter et/ou prévenir des maladies et qui sont en particulier utilisés en tant qu'agents antiviraux dont l'action est en particulier dirigée contre des cytomégalovirus.
PCT/EP2003/003981 2002-04-19 2003-04-16 Lactones-urees antivirales Ceased WO2003089421A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2003586142A JP2005529119A (ja) 2002-04-19 2003-04-16 抗ウイルス性ラクトン−ウレア
CA002482715A CA2482715A1 (fr) 2002-04-19 2003-04-16 Lactones-urees antivirales
AU2003232476A AU2003232476A1 (en) 2002-04-19 2003-04-16 Antiviral lactone-ureas
EP03746829A EP1499603A1 (fr) 2002-04-19 2003-04-16 Lactones-urees antivirales

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10217518.7 2002-04-19
DE10217518A DE10217518A1 (de) 2002-04-19 2002-04-19 Lactone

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WO2003089421A1 true WO2003089421A1 (fr) 2003-10-30

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PCT/EP2003/003981 Ceased WO2003089421A1 (fr) 2002-04-19 2003-04-16 Lactones-urees antivirales

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JP (1) JP2005529119A (fr)
AU (1) AU2003232476A1 (fr)
CA (1) CA2482715A1 (fr)
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WO (1) WO2003089421A1 (fr)

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JP5408415B2 (ja) * 2009-06-10 2014-02-05 Ｊｓｒ株式会社 １位置換３，５−ジアミノベンゼンの製造方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998045259A2 (fr) * 1997-04-10 1998-10-15 Pharmacia & Upjohn Company Compositions antivirales polyaromatiques
WO2000034238A1 (fr) * 1998-12-09 2000-06-15 American Home Products Corporation Thio-urees inhibitrices des virus de l'herpes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998045259A2 (fr) * 1997-04-10 1998-10-15 Pharmacia & Upjohn Company Compositions antivirales polyaromatiques
WO2000034238A1 (fr) * 1998-12-09 2000-06-15 American Home Products Corporation Thio-urees inhibitrices des virus de l'herpes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CASTRO A ET AL: "NOVEL AGENTS FOR THE TREATMENT OF HUMAN CYTOMEGALOVIRUS INFECTION", EXPERT OPINION ON THERAPEUTIC PATENTS, ASHLEY PUBLICATIONS, GB, vol. 10, no. 2, 2000, pages 165 - 177, XP001145677, ISSN: 1354-3776 *

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DE10217518A1 (de) 2003-11-06
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AU2003232476A1 (en) 2003-11-03
EP1499603A1 (fr) 2005-01-26

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