EP1339699A1 - Amidoalkyl-uraciles substitues et leur utilisation - Google Patents

Amidoalkyl-uraciles substitues et leur utilisation

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Publication number
EP1339699A1
EP1339699A1 EP01994632A EP01994632A EP1339699A1 EP 1339699 A1 EP1339699 A1 EP 1339699A1 EP 01994632 A EP01994632 A EP 01994632A EP 01994632 A EP01994632 A EP 01994632A EP 1339699 A1 EP1339699 A1 EP 1339699A1
Authority
EP
European Patent Office
Prior art keywords
formula
compounds
group
alkyl
meaning given
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.)
Withdrawn
Application number
EP01994632A
Other languages
German (de)
English (en)
Inventor
Barbara Albrecht
Michael Gerisch
Gabriele Handke
Axel Jensen
Thomas Krahn
Werner Nickl
Felix Oehme
Karl-Heinz Schlemmer
Henning Steinhagen
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
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Filing date
Publication date
Application filed by Bayer AG, Bayer Healthcare AG filed Critical Bayer AG
Publication of EP1339699A1 publication Critical patent/EP1339699A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C07D239/96—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D403/12—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 chain containing hetero atoms as chain links
    • 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
    • C07D405/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • D means -CH 2 -, -O- or -S-,
  • E denotes (CC ⁇ -alkylene or (C 3 -C 8 ) -cycloalkylene, which are optionally substituted one or more times, independently of one another, by substituents selected from the group consisting of (CrC 4 ) -alkoxy, hydroxy and amino,
  • T represents a methylene group
  • Y 2 is hydroxy
  • R 3 (C 6 -do) aryl or a 5- to 13-membered heterocycle with up to four
  • the compounds of the formula (I) according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
  • the invention relates to both the enantiomers or
  • hydrates or “solvates” refer to those forms of the compounds of the formula (I) which are in the solid or liquid state
  • Hydration with water or coordination with solvent molecules a molecule cool-Nerbinding or form a complex.
  • examples of hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates. Equally, the hydrates and / or solvates of salts of the compounds according to the invention are also suitable.
  • Mono- or di- (-CC 6 ) -alkylaminocarbonyl stands for an amino group linked via a carbonyl group with one or with two identical or different straight-chain or branched alkyl substituents, each having 1 to 6 carbon atoms.
  • the corresponding mono- or di-alkylaminocarbonyl groups with fewer carbon atoms, such as mono- or di- (C 1 -C 4 ) -alkylaminocarbonyl, which are preferred, are derived analogously from this definition.
  • Examples include: methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, t-butylaminocarbonyl, NN-D-unethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl-N-memyl-iminocarbonyl, N-methyl-Nn- propylamino-carbonyl, N-isopropyl-Nn-propylaminocarbonyl and Nt-buryl-N-methyl-iminocarbonyl.
  • (-C-C 6 ) alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • the corresponding alkoxy groups with fewer carbon atoms such as (dC 4 ) alkoxy and (C 1 -C 3 ) alkoxy, are derived analogously from this definition. In general, (dC 3 ) alkoxy is preferred.
  • (dC 4 ) alkanoyl is preferred.
  • (Cy-C ⁇ -alkanoyloxy stands for a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, which carries a double bonded oxygen atom in the 1 position and is linked via a further oxygen atom in the 1 position. Examples include: acetoxy, Propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy and n-hexanoyloxy.
  • Cg-doVAryl stands for an aromatic radical with 6 to 10 carbon atoms. Examples include: phenyl and naphthyl.
  • Examples include: thienyl, furyl, pyridyl, pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, quinoline, isoquinolinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, imidazopyridinyl, isoxazolyl, finidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl,
  • Ring size such as 5- to 10-membered, 5- to 7-membered or 6-membered heterocycles.
  • A is a ring member -CH 2 -D- or -D-CH 2 -,
  • D means -CH 2 -, -O- or -S-,
  • E (dC 6 ) -alkylene means that optionally one or more, independently of one another, by substituents selected from the group of (-C-C 4 ) -
  • G (-CC) alkylene means that optionally one or more times, independently of one another, by substituents selected from the group of (-C-C 4 ) -
  • Row denotes N, O and or S, the ring systems being up to three times, independently of one another, selected by substituents from the group of nitro, cyano, fluorine, chlorine, (dC 6 ) alkyl, (C 3 -C 6 ) cycloalkyl , (dC 6 ) -
  • Alkoxy, trifluoromethyl, di- and trifluoromethoxy can be substituted
  • u means 0 or 1
  • v means 0 or 1
  • W -O-, -S-, -CO-O-, -O-CO- or -NR 4 - means
  • R 4 represents hydrogen or (dC 6 ) alkyl
  • Y 1 is hydrogen
  • Y 2 is hydroxy
  • Y 1 and Y 2 together represent O
  • R 1 is hydrogen or (dC 6 ) -alkyl, which can be substituted one or more times by halogen,
  • R 2 represents hydrogen
  • R 3 is phenyl, naphthyl or a 5- to 10-membered heterocycle having up to four heteroatoms from the series N, O and / or S, the ring systems being up to three times, independently of one another, selected by substituents from the group of nitro, Cyano, halogen, (dC 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, (dC 6 ) alkoxy, trifluoromethyl, di- and trifluoromethoxy,
  • A is a ring member -CH 2 -D- or -D-CH 2 -,
  • D means -CH 2 - or -S-
  • E represents a methylene or 1,2-ethylene group
  • G represents a methylene or 1,2-ethylene group
  • U denotes phenylene, pyridinediyl or piperazin-1,4-diyl,
  • u means 0 or 1
  • V means pyrimidinyl, v means 0 or 1,
  • W denotes -O-, -CO-O- or -O-CO-
  • w means 0 or 1
  • Y 1 and Y 2 together represent O
  • R 1 represents hydrogen
  • R 2 represents hydrogen
  • R 3 is phenyl, naphthyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, thienopyrimidinyl, isoxazolyl, 1,3-benzodioxolyl or pyrrolidinyl, the ring systems in each case up to two, independently of one another, being selected by substituents from the group of nitro, cyano , Bromine, chlorine, fluorine, hydroxy, (-C-C 3 ) alkoxy, (dC 3 ) -alkyl, (C 3 -C 6 ) -cycloalkyl, trifluoromethyl, amino and di- (dC 3 ) -alkylamino can be substituted .
  • the present invention also relates to a process for the preparation of the compounds of the formula (I) according to the invention, wherein Compounds of formula (II)
  • Z represents an alkyl or benzyl radical and E and X the above
  • Z represents an alkyl or benzyl radical and A, E and X are those given above
  • G, R 1 , T, U, V, Y 1 , Y 2 , t and u have the meaning given above, v is 1, w is 0 and V additionally as a substituent is a suitable leaving group such as halogen, preferably bromine or iodine, or contains triflate and which are optionally used in the form of their salts,
  • A, E, G, R ! , T, U, V, X, Y 1 , Y 2 , t and u have the meaning given above, v is 1, w is 0 and V additionally has a suitable leaving group as a substituent, such as halogen, preferably bromine or iodine, or Triflat contains
  • R 3 has the meaning given above and M represents an optionally substituted metallic or semi-metallic element such as zinc, magnesium, boron, lithium, copper or tin,
  • R 2 has the meaning given above but is not hydrogen and Q represents a leaving group
  • bases are suitable as bases.
  • bases preferably include alkali and alkaline earth metal hydroxides such as lithium, sodium or potassium hydroxide or alkali and alkaline earth metal carbonates such as sodium or potassium carbonate or sodium or potassium methoxide or sodium or potassium ethoxide or potassium tert-butoxide or amides such as sodium amide, lithium bis - (Trimethylsilyl) amide or lithium diisopropylamide or amines such as triethylamine, diisopropylethylamine, diisopropylamine, N-methylmorpholine, 4-dimethylamino-pyridine or pyridine.
  • alkali and alkaline earth metal hydroxides such as lithium, sodium or potassium hydroxide or alkali and alkaline earth metal carbonates such as sodium or potassium carbonate or sodium or potassium methoxide or sodium or potassium ethoxide or potassium tert-butoxide or amides
  • amides such as sodium amide, lithium bis - (
  • the compounds of the formula (I) according to the invention surprisingly show an unforeseeable, valuable pharmacological spectrum of action and are therefore particularly suitable for the prophylaxis and / or treatment of diseases.
  • They can preferably be used in drugs for the prevention and / or therapy of ischemia and reperfusion damage in the heart (after an acute infarction), in the brain
  • cardiovascular diseases such as unstable angina and arteriosclerosis, neuronal and neurodegenerative diseases such as Epilepsy, chronic pain, Alzheimer's disease and Parkinson's disease, traumatic brain injuries, septic shock as well as arthritis, diabetes, chronic colitis, sudden hearing loss, inflammatory diseases of the
  • Lungs such as asthma and chronic bronchitis and cancer can be used.
  • the present invention also relates to the use of the substances of the formula (I) for the production of medicaments and pharmaceutical compositions for the prophylaxis and / or treatment of the aforementioned clinical pictures.
  • the present invention further relates to a method for the prophylaxis and / or treatment of the aforementioned clinical pictures with the substances of the formula
  • the compounds according to the invention can also be used in the treatment of acute myocardial infarction in combination with one or more of the following medicaments which belong to the standard therapy for acute myocardial infarction: calcium channel blockers (such as, for example, nifedipine, diltiazem, verapamil), nitrovasodilators (such as, for example, isosorbide dinitrate , Glycerol trinitrate, isosorbide-5-mono-nitrate, molsidomine), beta-blockers (such as metoprolol,
  • calcium channel blockers such as, for example, nifedipine, diltiazem, verapamil
  • nitrovasodilators such as, for example, isosorbide dinitrate , Glycerol trinitrate, isosorbide-5-mono-nitrate, molsidomine
  • beta-blockers such as metoprolol
  • antiarrhythmics such as lidocaine, amiodarone
  • beta-adrenergic agonists such as dopamine, dobutamine
  • Inhibition of PARS activity can be expressed as a% of PARS inhibition when incubated with various substances or as the concentration at which 50% of the enzyme is inhibited, i.e. H. are shown as ICso value.
  • Tris-HCl and MgCl 2 are dissolved in water, DTT is added from a 100 mM aqueous starting solution (stored at -20 ° C) and the pH is adjusted to 7.4 with concentrated HC1.
  • DNA 1 mg / ml calf thymus DNA
  • Histones 10 mg / ml type HA histones, calf thymus
  • NAD + Mix 2 mM NAD + in buffer
  • TCA Trichloroacetic acid
  • the compounds to be tested are dissolved in a concentration of 10 mM in DMSO (dimethyl sulfoxide).
  • the assay is carried out in deep 96-hole plates. 70 ⁇ l buffer, 10 ⁇ l DNA, 10 ⁇ l histones, 10 ⁇ l NAD + / [ 14 C] -NAD + Mix and 0.5-5 ⁇ l PARS (approx. 10,000 cpm / test) with 1 ⁇ l of the compounds ( Final concentration 0.001-10 ⁇ M) combined in a total volume of approx. 110 ⁇ l. After 10 min.
  • MHEC5-T cells / hole DSM ACC 336; German coUection of microorganisms and cell cultures
  • DSM ACC 336 German coUection of microorganisms and cell cultures
  • the cells are incubated with 3 mM aqueous H 2 O 2 solution and various concentrations of the substances in the presence of 6 vol.% Alamar blue solution in the medium for 5 hours at 37 ° C.
  • 10 ⁇ M 1,5-dihydroxyisoquinoline (DHCH) solution is used as reference substance.
  • the fluorescence is measured at 530-560 nm excitation wavelength and 590 nm emission wavelength.
  • The% of cell protection is calculated as the difference between the living cells treated with H 2 O 2 only and the cells treated with HO 2 and PARS inhibitor. 10 ⁇ M DHCH is used as the internal standard and 100% protection is set. The values obtained for the other substances are related to this value.
  • EC50 values indicate the concentration at which 50% of the maximum cell protection is reached, the maximum protection being set as 100% value by 10 ⁇ M DHCH.
  • DHCH has an EC 50 value of 2 ⁇ M.
  • the present invention furthermore relates to medicaments and pharmaceutical compositions which comprise at least one compound of the formula (I), 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 manner, such as, for example, orally, parenterally, pulmonally, nasally, sublingual, lingual, buccal, rectal, transdermal, conjunctival, otic or as an implant.
  • 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. enteric coatings), capsules, dragees, granules, pellets, powders, emulsions, suspensions and solutions.
  • Tablets non-coated and coated tablets, e.g. enteric coatings
  • capsules dragees, granules, pellets, powders, emulsions, suspensions and solutions.
  • Parenteral administration can be done by bypassing a resection step (intravenously, intraarterially, intracardially, intraspinally or intralumbally) or by engaging absorption (intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resection step intravenously, intraarterially, intracardially, intraspinally or intralumbally
  • absorption intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • application forms are a. 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., nasal drops / solutions, sprays; tablets or capsules to be administered lingually, sublingually or buccally, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), 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. These include 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 or cyclodextrins), stabilizers (eg antioxidants such as ascorbic acid), dyes (eg inorganic pigments such as iron oxides) or taste and / or smell corrections.
  • 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.
  • the therapeutically active compounds should be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95% by weight of the total mixture, ie. H. the active substance should be present in amounts sufficient to achieve the dosage range indicated.
  • the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.
  • the active compound (s) according to the invention in total amounts of from about 0.01 to about 100, preferably 0.05 to 50 mg / kg of body weight per 24 hours in the form of several single doses to achieve the desired results.
  • a single dose contains the active ingredient (s) according to the invention preferably in amounts of about 0.01 to 50, in particular 0.1 to 10 mg / kg body weight.
  • heteroaryl-piperazines required as starting compound for some synthesis examples can be prepared by reacting corresponding chloro-heteroaromatics with piperazine.
  • 2-chloroethylglycinate can be obtained from H. Kunz, M. Buchholz, Chem. Ber. 1979, 112, 2145-2157.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux dérivés amidoalkyl-uraciles de formule (I), un procédé de production de ces dérivés, ainsi que leur utilisation comme substances actives médicamenteuses pour la prophylaxie et/ou le traitement de maladies.
EP01994632A 2000-11-14 2001-11-02 Amidoalkyl-uraciles substitues et leur utilisation Withdrawn EP1339699A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10056312 2000-11-14
DE10056312A DE10056312A1 (de) 2000-11-14 2000-11-14 Substituierte Amidoalkyluracile und ihre Verwendung
PCT/EP2001/012694 WO2002040455A1 (fr) 2000-11-14 2001-11-02 Amidoalkyl-uraciles substitues et leur utilisation en tant qu'inhibiteurs de la poly(adp-ribose)-synthetase (pars)

Publications (1)

Publication Number Publication Date
EP1339699A1 true EP1339699A1 (fr) 2003-09-03

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EP01994632A Withdrawn EP1339699A1 (fr) 2000-11-14 2001-11-02 Amidoalkyl-uraciles substitues et leur utilisation

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US (1) US7125995B2 (fr)
EP (1) EP1339699A1 (fr)
AU (1) AU2002224825A1 (fr)
CA (1) CA2428335A1 (fr)
DE (1) DE10056312A1 (fr)
WO (1) WO2002040455A1 (fr)

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US7615556B2 (en) * 2006-01-27 2009-11-10 Bristol-Myers Squibb Company Piperazinyl derivatives as modulators of chemokine receptor activity
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DE10056312A1 (de) 2002-05-16
US7125995B2 (en) 2006-10-24
WO2002040455A1 (fr) 2002-05-23
US20050075347A1 (en) 2005-04-07
AU2002224825A1 (en) 2002-05-27
WO2002040455A8 (fr) 2002-07-18

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