WO1983002611A1 - Trisubstituted diazo compounds - Google Patents

Trisubstituted diazo compounds Download PDF

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Publication number
WO1983002611A1
WO1983002611A1 PCT/CH1982/000011 CH8200011W WO8302611A1 WO 1983002611 A1 WO1983002611 A1 WO 1983002611A1 CH 8200011 W CH8200011 W CH 8200011W WO 8302611 A1 WO8302611 A1 WO 8302611A1
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WO
WIPO (PCT)
Prior art keywords
pyridyl
phenyl
formula
carbon atoms
methyl
Prior art date
Application number
PCT/CH1982/000011
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German (de)
French (fr)
Inventor
Ag Ciba-Geigy
Original Assignee
Sallmann, Alfred
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
Publication date
Application filed by Sallmann, Alfred filed Critical Sallmann, Alfred
Priority to JP82500351A priority Critical patent/JPS59500055A/en
Priority to AU80037/82A priority patent/AU8003782A/en
Priority to GB08324692A priority patent/GB2123830A/en
Publication of WO1983002611A1 publication Critical patent/WO1983002611A1/en
Priority to FI833281A priority patent/FI833281A/en
Priority to NO833349A priority patent/NO833349L/en
Priority to DK4284/83A priority patent/DK428483D0/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/125—Saturated compounds having only one carboxyl group and containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms
    • 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
    • C07D233/64—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 substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to new substituted diaza compounds, in particular compounds of general formula I.
  • R 1 and R 2 independently of one another are carbocyclic aryl and / or heteroaryl, A is a divalent hydrocarbon radical and R 3 is formyl or acetalized formyl, their isomers and their salts, in particular pharmaceutically usable salts, processes for their preparation, pharmaceutical preparations which contain such compounds and their use, for example as active pharmaceutical ingredients or for the manufacture of pharmaceutical preparations.
  • Carbocyclic aryl is, for example, monocyclic carbocyclic aryl, such as optionally substituted phenyl.
  • Heteroaryl is, for example, monocyclic, preferably 5- or 6-membered heteroaryl, where at least one ring member represents a heteroatom, such as a nitrogen, oxygen or sulfur atom, it being possible for a nitrogen atom to also be present in oxidized form.
  • a heteroatom such as a nitrogen, oxygen or sulfur atom
  • Such 5-membered residues are e.g. Pyrrolyl, such as 2-pyrrolyl, furyl, such as 2-furyl, thienyl, such as 2- or 3-thienyl.
  • 6-membered heteroaryl examples include pyridyl, such as 2-, 3- or 4-pyridyl, 1-oxidopyridyl, such as 1-oxido-3-pyridyl or 1-oxido-4-pyridyl, and pyrimidyl, such as 2-pyrimidyl Question.
  • Halogen, lower alkyl, hydroxy, lower alkoxy and / or acyloxy are suitable as substituents of carbocyclic aryl, such as phenyl, or heteroaryl, such as pyridyl or 1-oxidopyridyl.
  • Acyloxy is derived, for example, from an organic carboxylic acid and means, for example, lower alkanoyloxy.
  • a hydrocarbon residue A is, for example, a divalent aliphatic, cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon residue.
  • divalent aliphatic hydrocarbon radicals are lower alkylene, lower alkylidene, lower alkenyl or lower alkenylidene.
  • Divalent cycloaliphatic hydrocarbons are, for example, monocyclic 3- to 8-membered cycloalkylenes or cycloalkylidenes.
  • Cycloaliphatic-aliphatic hydrocarbon radicals are, for example, those which have a monocyclic 3- to 8-membered cycloaliphatic radical as the cycloaliphatic radical and lower alkylidene as the aliphatic radical, such as cycloalkyl-nederalkylidene.
  • Acetalized formyl is understood to mean, for example, an aliphatic alcohol, such as lower alkenol, lower alkenediol or, in particular, lower alkanol, and lower alkanediol, acetalized formyl, for example dimethoxy-, methoxy-ethoxy-, diethoxyformyl or methylenedioxy-, ethylenedioxy-methyl.
  • an aliphatic alcohol such as lower alkenol, lower alkenediol or, in particular, lower alkanol, and lower alkanediol
  • acetalized formyl for example dimethoxy-, methoxy-ethoxy-, diethoxyformyl or methylenedioxy-, ethylenedioxy-methyl.
  • lower organic radicals and compounds are preferably to be understood as meaning those which contain up to and with 7, especially up to and with 4 carbon atoms (carbon atoms).
  • Halogen is, for example, halogen up to and including atomic number 35, such as fluorine, chlorine or bromine, and also iodine.
  • Lower alkyl is e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, furthermore a pentyl, hexyl or heptyl radical.
  • Lower alkoxy is e.g. Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec.-butyloxy or tert.-butyloxy.
  • Lower alkylthio is e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butylthio.
  • Phenyl lower alkoxy is e.g. Phenylmethoxy, phenylethoxy or phenylpropyloxy.
  • Phenyl lower alkylthio is e.g. Benzyl, phenylethyl or phenylpropylthio.
  • Hydroxy lower alkoxy is e.g. Hydroxyethoxy, hydroxypropyloxy or 1,2-dihydroxypropyloxy.
  • Lower alkoxy lower alkoxy is e.g. Methoxyethoxy, ethoxyethoxy, methoxypropyloxy or methoxybutyloxy.
  • Phenyl lower alkoxy lower alkoxy is e.g. 2-benzyloxyethoxy or 2- (2-phenylethoxy) ethoxy.
  • Lower alkanoyloxy is e.g. Acetyl, propionyl, butyryl, iso-sec or tert-butyryloxy.
  • Lower alkylene is, for example, straight-chain, such as methylene, ethylene, 1,3-propylene or 1,4-butylene, or branched, such as 1,2-propylene, 1,2- or 1,3- (2-methyl) propylene or 1 , 2-butylene.
  • Lower alkylidene has a tertiary or in particular a quaternary carbon atom and is, for example, ethylidene or 1,1- or 2,2-propylidene, furthermore 1,1- or 2,2-butylidene or 1,1-, 2,2- or 3,3-pentylidene.
  • Lower alkenylene is e.g. Ethenylene, 1,2- or 1,3-propenylene or 1,2-, 1,3-or 1,4-buten-2-ylene.
  • Lower alkenylidene is e.g. Ethenylidene, 1,1-propen-l-ylidene, 1,1-propen-2-ylidene, and also a butenylidene, such as 1,1-buten-3-ylidene.
  • Cycloalkyl is e.g. Cyclopropylene, 1,2- or 1,3-cyclobutylene, 1,2-, 1,3- or 1,4-cyclopentylene, also a cyclohexylene.
  • Cycloalkylidene is e.g. Cyclopropylidene, cyclobutylidene, cyclopentylidene or cyclohexylidene.
  • Cycloalkyl-lower alkylidene is e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexylmethylene, ethylidene or propylidene, and also a cyclohexylbutylidene.
  • Carboxy lower alkoxy is e.g. Carboxymethoxy, 2-carboxyethoxy, 2-, 3-carboxypropyloxy, 1-carboxy-2-propyloxy, 2-, 3- or 4-carboxy-n-butyloxy, 1-carboxy-2-methyl-propyl-3-oxy or 1 -Carboxy-2-methyl-propyl-2-oxy.
  • Lower alkoxycarbonyl-lower alkoxy contains, in each case independently of one another, the above under in the lower alkoxy part. Lower alkoxy listed meanings.
  • Salts of compounds of the formula I according to the invention are preferably pharmaceutically usable salts, such as pharmaceutically usable acid addition salts, for example salts with inorganic acids, such as mineral acid, with sulfamic acids, such as cyclohexylsulfamic acid, with organic carboxylic acids, such as lower alkane carboxylic acids, optionally unsaturated dicarboxylic acids, with by hydroxy and / or Oxo-substituted carboxylic acids or with sulfonic acids, for example sulfates or hydrohalides, such as hydrobromides or hydrochlorides, oxalates, malonates, fumarates or maleinates, tartrates, pyruvates or citrates, sulfonates, such as methane, benzene or p-toluenesulfonates.
  • the compounds of formula I and their pharmaceutically usable salts have valuable pharmacological properties. In particular, for example when used locally, they
  • This property can be detected, for example, according to the method developed by G. Tonelli, L. Thibault, Endocrinology 77, 625 (1965) by inhibiting the rat ear edema induced by croton oil in the normal rat in the dose range from about 1 to about 100 mg / ml.
  • an ED 50 value 18 mg / ml determined.
  • the compounds of the formula I which can be used according to the invention are therefore medicinal products, in particular external (topical) dermatological agents for the treatment of inflammatory dermatoses of any genesis, such as in the case of mild skin irritation, contact dermatitis, rashes, burns, and as mucosal phlogostatic agents for the treatment of mucosal inflammation, e.g. the eyes, nose, lips, mouth, genital, anal region.
  • the compounds can also be used as sunscreens.
  • the present invention also relates to the use of the compounds according to the invention and their salts for the treatment of inflammation, e.g. of inflammatory diseases of various origins, as well as for the manufacture of medicines.
  • the invention relates in particular to compounds of the formula I in which, on the one hand, R 1 and R 2 independently of one another are phenyl and / or phenyl substituted by halogen, lower alkyl, hydroxy, lower alkoxy and / or lower alkanoyl, or on the other hand one of the radicals R 1 and R 2 is pyrrolyl, Means furyl, thienyl, pyridyl, 1-oxidopyridyl or pyrimidyl, which in each case can be unsubstituted or substituted by halogen, lower alkyl, hydroxy, lower alkoxy and / or lower alkanoyloxy, and the other phenyl, pyrrolyl, furyl, thienyl, pyridyl, 1-oxidopyridyl or Pyrimidyl means which is in each case unsubstituted or by halogen, lower alkyl, hydroxy, lower alkoxy and / or lower alkan
  • the invention relates in particular to compounds of the formula I in which R 1 and R 2 independently of one another are phenyl and / or phenyl which is substituted by halogen, hydroxy, lower alkyl, lower alkoxy and / or lower alkanoyloxy,
  • A is lower alkylene having up to and with 4 carbon atoms, such as Methylene, lower alkylidene with up to and with 7 carbon atoms, such as 2,2-propylidene, lower alkenyl with up to and with 4 carbon atoms, such as 1,3-propen-2-ylene, lower alkenylidene with up to and with 7 carbon atoms, such as 1,1-butene 3-ylidene, 3- to 8-membered cycloalkylene, such as cyclopropylene, 3-to 8-membered cycloalkylidene, such as cyclopentylidene, or cycloalkyl-lower alkylidene with up to and with 7 carbon atom
  • the invention particularly relates to compounds of the formula I in which one of the radicals R 1 and R 2 is pyridyl or 1-oxidopyridyl, which are unsubstituted and / or each substituted by halogen, hydroxyl, lower alkyl, lower alkoxy and / or lower alkanoyloxy, and the other phenyl, pyridyl or 1-oxidopyridy1, which may be unsubstituted and / or substituted in each case by halogen, hydroxy, lower alkyl, lower alkoxy and / or lower alkanoyloxy, means A lower alkylene with up to and with 4 carbon atoms, such as methylene, lower alkylidene with up and with 7 C atoms, such as 2,2-propylidene, lower alkenyls with up to and with 7 C atoms, such as 1,3-propen-2-ylene, lower alkenylidene with up to and with 4 C atoms, such as
  • the invention relates in particular to compounds of the formula I in which R 1 and R 2 independently of one another are phenyl and / or by halogen with atomic numbers up to and including 35, such as chlorine, hydroxy, lower alkyl having up to and with 4 carbon atoms, such as methyl, and / or lower alkoxy with up to and with 4 carbon atoms, such as methoxy, substituted phenyl,
  • A is lower alkylene with up to and with 4 carbon atoms, such as methylene, lower alkylidene with up to and with 7 carbon atoms, such as 2,2-propylidene, lower alkenylidene with up to and with 7 carbon atoms, such as l, l-buten-3-ylidene, or 3- to 8-membered cyclo-lower alkylidene, such as 1, 1-cyclopentylidene, and R 3 formyl or diniederalkoxy-methyl each with up to and with 4 carbon atoms in the lower al
  • the invention relates in particular to compounds of the formula I in which one of the radicals R 1 and R 2 is phenyl or halogen with atom numbers up to and including 35, such as chlorine, hydroxy, lower alkyl having up to and 4 carbon atoms, such as methyl, and / or Lower alkoxy with up to and with 4 carbon atoms, such as methoxy, means substituted phenyl and the other pyridyl, such as 3-pyridyl, or 1-oxido-pyridyl, such as 1-oxido-3-pyridyl, each of which is unsubstituted or substituted by halogen with atomic numbers up to and including 35, such as chlorine, hydroxyl and / or lower alkoxy, can be substituted with up to and with 4 carbon atoms, such as methoxy,
  • the invention relates in particular to compounds of the formula I in which R 1 and R 2 independently of one another are phenyl and / or phenyl which is substituted by lower alkoxy having up to and with 4 carbon atoms, such as methoxy,
  • R 3 is formyl or diniederalkoxy-methyl, each with up to and with 4 C atoms in the lower alkoxy part, such as diethoxy-methyl, or lower alkylenedioxy methyl with up to 4 carbon atoms in the lower alkylene part, such as 1,3-dioxolan-2-yl, means their isomers and their salts, in particular pharmaceutically usable salts.
  • the invention relates primarily to compounds of the formula I in which one of the radicals R 1 and R 2 is phenyl or substituted by halogen with an atom number of up to and including 35, such as chlorine, hydroxy or lower alkoxy, with up to and including 4 C atoms, such as methoxy Is phenyl and the other is pyridyl, such as 3- or 4-pyridyl, or 1-oxidopyridyl, such as 1-oxido-3-pyridyl or 1-oxido-4-pyridyl, A is lower alkylidene with up to and with 4 carbon atoms, such as 2,2-propylidene, and R 3 is formyl or di-lower alkoxy-methyl, each with up to and with 4 carbon atoms in the lower alkoxy part, such as diethoxy-methyl, or lower alkylenedioxy-methyl with up to and 4 carbon atoms in the lower alkylene part, such as 1,3-dioxolan-2-yl
  • the invention relates primarily to compounds of the formula I in which one of the radicals R 1 and R 2 is phenyl or by halogen with an atomic number mer up to and including 35, such as chlorine, hydroxy or lower alkoxy with up to and with 4 carbon atoms, such as methoxy, substituted phenyl and the other pyridyl, such as 3- or 4-pyridyl, or 1-oxidopyridyl, such as 1-oxido 3- pyridyl or 1-oxido-4-pyridyl, A represents a quaternary carbon atom lower alkylidene with up to and with 4 carbon atoms, such as 2,2-propylidene, the quaternary carbon atom being directly attached to the imidazole ring, means, and R 3 is formyl or diniederalkoxy-methyl with up to and with 4 carbon atoms in each case in the lower alkyl part, such as diethoxy-methyl, their isomers and their salts, in particular pharmaceutically
  • the invention relates primarily to compounds of the formula I in which one of the radicals R 1 and R 2 is phenyl and the other pyridyl, such as 3-pyridyl, or 1-oxidopyridyl, such as 1-oxido-3-pyridyl, A 2, Represents 2-propylidene and R 3 means formyl or di-lower alkoxy-methyl, each having up to and with 4 carbon atoms in lower alkyl, such as diethoxy-methyl, their isomers and their salts, in particular pharmaceutically usable salts
  • the invention relates in particular to the new compounds mentioned in the examples and their salts, in particular pharmaceutically usable salts of such compounds having salt-forming groups, and to the topically administrable pharmaceutical preparations listed in the examples.
  • the invention also relates to processes for the preparation of compounds of the formula I and their salts, in particular pharmaceutically usable salts of such compounds with salt-forming groups, and to the preparation processes listed in the examples.
  • the compounds of formula I or their salts can be prepared in a manner known per se.
  • radicals Y 1 and Y 6 are hydroxyl or amino and the other and Y 2 is hydrogen and Y 3 together with Y 4 and Y 5 is one
  • Z is hydroxy or amino Y 1 or Y 6 , Y 3 or Y 4 or Y 5 or halogen or sulfonyloxy Y 4 or Y 5 .
  • Reactive esterified hydroxy is, for example, with an inorganic mineral acid, such as hydrohalic acid, or with an organic sulfonic acid, such as lower alkane or optionally Substituted benzenesulfonic acid, esterified hydroxy and primarily means halogen, for example chlorine or bromine, and sulfonyloxy, for example methane or p-toluenesulfonyloxy.
  • Tautomers of compounds of the formula II are, for example, those in which a partial enol or enamine grouping of the formula
  • Y 1 together with Y 6 represents an additional bond and Y 5 is hydroxy or amino, in the form of the corresponding tautomeric keto or ketimine form, wherein Y 1 is hydrogen and Y 5 together with Y 6 is oxo or imino and / or those in which a partial enol or enamine grouping of the formula
  • H - Z is split off from a compound of the formula II, a tautomer and / or salt thereof in a customary manner, in particular in the manner known from the literature for analogous reactions, if necessary with heating, such as in a temperature range from about 20 ° to about 250 ° C, under pressure and / or in the presence of a catalytic agent, preferably an acid.
  • a catalytic agent preferably an acid.
  • acids for example inorganic acids, such as mineral acids, for example sulfuric acid, polyphosphoric acid or hydrohalic acid, such as hydrochloric acid, or organic acids, such as lower alkane carboxylic acids, for example acetic acid.
  • an inert solvent for example an optionally halogenated hydrocarbon, such as chloroform, chlorobenzene, hexane or toluene, a lower alkanol, such as methanol or ethanol, a carboxamide, such as lower alkanecarboxamide, for example dimethylformamide or formamide, or a lower alkanecarboxylic acid, such as Formic or acetic acid, and / or under an inert gas such as nitrogen.
  • an optionally halogenated hydrocarbon such as chloroform, chlorobenzene, hexane or toluene
  • a lower alkanol such as methanol or ethanol
  • a carboxamide such as lower alkanecarboxamide, for example dimethylformamide or formamide
  • a lower alkanecarboxylic acid such as Formic or acetic acid
  • the starting materials of the formula II, their tautomers and / or salts are predominantly formed in situ by processes known per se and further reacted under the reaction conditions without isolation to the compound of the formula I.
  • the cleavage of H - Z can take place with direct cyclization or after an upstream cyclization.
  • an acylated ⁇ -amino ketone of the formula can be used
  • the starting materials of the formula (IIIa) are known or are prepared by processes known per se. For example, one starts from a compound of the formula (Illb) or a salt thereof and reacts them with an acid derivative of the formula R 3 -A-COOH (IIIc), for example a corresponding anhydride, such as a halocarbonyl compound.
  • reaction with an amidine of the formula (IIle) is usually carried out with heating, for example in a temperature range from about 50 ° to about 250 ° C.
  • reaction of the ammonium carboxylate of the formula (IIle) with a compound of the formula (IIld) is carried out with an at least 3-molar, or, if the compound of the formula (IIld) is in salt form, at least 4-molar excess of the ammonium salt of the compound of the formula (Ille), optionally with heating, for example in a temperature range from about 50 ° to about 250 ° C, preferably at 90 ° to 120 ° C, wherein the compound of formula (Ille) simultaneously as Solvent can serve.
  • This variant can, for example, also be modified in such a way that the ammonium salt of the formula IIle, in relation to the reactive ester Z, is used in an approximately equimolar amount and, in addition, ammonia, optionally in the form of a salt of an acid which is weaker than R 3 -COOH, in excess Amount, preferably in a 3 to 5-fold excess, is added.
  • a reactive esterified hydroxy group Z 1 is, for example, one which is preferably esterified by strong inorganic or organic acids, such as strong mineral acids, for example hydrohalic acids, such as chlorine or hydrobromic acid, or strong organic sulfonic acids, such as corresponding lower alkane or arylsulfonic acids, for example methane or an optionally substituted benzenesulfonic acid Hydroxy group and represents, for example, halogen, such as chlorine or bromine, lower alkylsulfonyloxy, for example methyl or ethylsulfonyloxy, or arylsulfonyloxy, for example p-toluene or benzenesulfonyloxy.
  • strong inorganic or organic acids such as strong mineral acids, for example hydrohalic acids, such as chlorine or hydrobromic acid, or strong organic sulfonic acids, such as corresponding lower alkane or arylsulfonic acids, for example methane or an optional
  • the ammonium salt of the formula (Ille) can also be formed in situ under the reaction conditions, for example by introducing the free acid of the formula (Ille) in the reaction mixture and adding liquid or gaseous ammonia.
  • the ammonia can also be added in the form of a salt with an acid which is weaker than R 1 -A-COOH, such as carbonic acid.
  • Suitable solvents are, for example, optionally halogenated hydrocarbons, such as optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbons, such as hexane, cyclohexane, toluene, chloroform, or chlorobenzene, alkanols, such as propanol, isopropanol, butanols, pentanols or octanols, ethers, such as dimethoxyethane, ethylene glycol monoethyl ether , Dioxane or tetrahydrofuran, lower alkanecarboxylic acids, such as formic or acetic acid or preferably acids of the formula (IIIc), amides, such as lower alkanecarboxamides, for example formamide or dimethylformamide, and lactams, for example N-methylpyrrolidone, sulfoxides, such as dimethyl sulfoxide, or water.
  • a preferred embodiment of this variant for the preparation of compounds of the formula I according to the invention via compounds of the formula II is that a compound of the formula IIId, in which Z is, for example, halogen, such as bromine, with an ammonium salt of the formula (III) at a reaction temperature of about 100 ° C.
  • the compound of the formula (III) is added in excess, for example in a ratio to the ester of the formula (IIld) of about 4: 1 to about 6: 1, and can be formed in situ by, for example, the corresponding acid among the Reacts reaction conditions with liquid ammonia.
  • the starting materials of the formula (IIld) are known or can be prepared by processes known per se.
  • (IIIf) is brominated, for example, and thus converted into a compound of the formula (IIld) or a salt thereof, for example hydrohalide, in which Z 1 denotes bromine.
  • an oxazole of the formula can also be used
  • the compounds of the formula (III) can be prepared by a process known per se, for example by reacting compounds of the formula
  • Z 1 is optionally reactive esterified hydroxy, with a carboxylic acid of the formula R 3 -A-COOH (IIIc), a functional derivative or salt thereof, such as a corresponding anhydride, for example a halocarbonyl derivative, optionally via a compound of the formula
  • a compound of the formula II is formed in each case, which according to the invention, in particular in situ, further reacts to a compound of the formula I.
  • a compound of the formula (II), for example one in which Y 1 is hydroxyl, Y 2 and Y 6 are hydrogen and Y 3 together with Y 4 and Y 5 is a group of the formula N -, for example
  • a compound of the formula II is in each case formed, which according to the invention, in particular in situ, further reacts to a compound of the formula I.
  • Some of the process variants described above can be carried out by using mild conditions so that the compounds of the formula II or their tautomers and / or salts can be isolated.
  • hydrogenation catalysts which can be used are elements of subgroup VIII and derivatives thereof, such as platinum, palladium or palladium chloride, which are optionally supported on a customary support material, such as activated carbon or alkaline earth metal compounds, for example barium carbonate, or Raney nickel.
  • the reduction can be carried out, if necessary, with cooling or heating, for example in a temperature range from about 0 ° to about 150 ° C, in an inert solvent such as a halogenated hydrocarbon, e.g. Chloroform, carbon tetrachloride or chlorobenzene, or an ether such as dimethoxyethane, diethyl ether, dioxane or tetrahydrofuran, and / or under inert gas, e.g. Perform nitrogen.
  • an inert solvent such as a halogenated hydrocarbon, e.g. Chloroform, carbon tetrachloride or chlorobenzene, or an ether such as dimethoxyethane, diethyl ether, dioxane or tetrahydrofuran, and / or under inert gas, e.g. Perform nitrogen.
  • Such groups R ' 3 are, for example, groups which can be reductively converted into the radical R 3 , such as functionally modified carboxy.
  • R 3 such as functionally modified carboxy.
  • carboxy, halocarbonyl, lower alkoxycarbonyl or carbamoyl R ' 3 are converted into formyl R 3 by reduction.
  • radicals R ' 3 mentioned are reduced in a manner known per se, for example using a suitable reducing agent in an inert solvent, if appropriate with cooling or heating.
  • halocarbonyl is reduced to formyl by hydrogen on noble metal catalysts, such as palladium, which are optionally bound to support materials, such as barium sulfate, while reduction of carboxy to formyl, for example with the help of formic acid.
  • noble metal catalysts such as palladium
  • support materials such as barium sulfate
  • carboxy to formyl for example with the help of formic acid.
  • optionally complex hydrides such as lithium aluminum hydride or lithium tri-tert-butoxy or lithium triethoxy aluminate, is reduced.
  • Lower alkoxycarbonyl or carbamoyl can likewise be reduced reductively to formyl with the aid of suitable optionally complex hydrides.
  • Esterified hydroxymethyl is, for example, hydroxymethyl esterified with a mineral acid, such as hydrohalic acid, such as hydrochloric acid, or a carboxylic acid, such as lower alkane carboxylic acid, for example acetic acid, or optionally substituted benzoic acid.
  • Etherified hydroxymethyl is etherified with a lower alkanol, for example.
  • the groups R ' 3 of this type are oxidized in a manner known per se, for example by reaction in a suitable oxidizing agent, for example in an inert solvent such as a lower alkyl carboxylic acid, for example acetic acid, a ketone, for example acetone, an ether, for example tetrahydrofuran, a heterocyclic aromatic, eg pyridine, or water or a mixture thereof, if necessary with cooling or heating, for example from about 0 ° to about 150 ° C.
  • suitable oxidizing agents are oxidizing transition metal compounds, in particular those with elements of sub-groups I, VI, VII, or VIII.
  • Examples include: silver compounds, such as silver nitrate, oxide or picolinate, chromium compounds, such as chromium trioxide or potassium dichromate, manganese compounds, such as tetrabutylammonium or benzyl (triethyl) ammonium permanganate, and also iron compounds, such as potassium ferrate.
  • selective oxidizing agents are used, such as pyridinium chlorochromate, a suitable ketone, such as cyclohexanone in the presence of aluminum tert-butoxide, or, if hydroxymethyl has been reactively esterified with p-toluenesulfonic acid, dirnethyl sulfoxide.
  • hydroxymethyl R is, for example, 3 is oxidized with 4-dimethylamino-pyridine-N-oxide to formyl R 3 '3, while, for example esterified with hydrochloric acid bis-hydroxymethyl R tetrabutylammoniumdichromat with'.
  • R ' 3 which can be converted into R 3 are functionally modified formyl groups or formyl protected by protective groups.
  • Functional modified formyl has, for example, thioxo, optionally N-substituted imino, such as N-lower alkyl or N-phenyl-imino, hydroxyimino, optionally substituted hydrazono, such as N-tosyl- or N, N-di-lower alkyl-hydrazono, as the functionally modified oxo.
  • Functionally modified formyl of this type is converted into formyl R 3 in a conventional manner hydrolytically, if necessary in the presence of a protonic acid.
  • Protected formyl is, for example, acetalized formyl with a mercaptan, such as lower alkanediol or lower alkylene diol, or with a mercaptan and alcohol, such as lower alkanol and lower alkane thiol or mercapto lower alkanol.
  • a mercaptan such as lower alkanediol or lower alkylene diol
  • a mercaptan and alcohol such as lower alkanol and lower alkane thiol or mercapto lower alkanol.
  • Formyl can furthermore be used as di- or tetrahydro-1,3-oxazine, such as 3,3,5-trimethyl-1,3-oxazin-2-yl, or as imidazolidine, such as optionally N-mono- or N, N-disubstituted Imidazolidin-2-yl, and as a hemiacetal with an alcohol, such as lower alkanol, or with a mercaptan, such as lower alkane thiol.
  • Corresponding protective groups can be split off oxidatively, hydrolytically, if necessary in the presence of a protonic acid.
  • corresponding thioacetals or halfacetals become oxidative, for example under the action of N-bromosuccinimide, chloramine-T, thallium (III) nitrite, heavy metal compounds, for example mercury (II) oxide, copper (II) oxide bar chloride, or electrochemically in formyl are converted, while from the corresponding oxazine or imidazolidine derivatives and hemiacetals with lower alkanols, the rest of formyl is hydrolytically reacted in the presence of strong protonic acid, such as mineral acids, for example sulfuric acid, hydrohalic acids or phosphoric acids, such as sulfonic acids, for example p-toluenesulfonic acid, or for carboxylic acids, for example glacial acetic acid, to be released.
  • strong protonic acid such as mineral acids, for example sulfuric acid, hydrohalic acids or phosphoric acids, such as sulfonic acids, for example p-toluenesul
  • the starting materials of the formula V are prepared by processes known per se. For example, one starts from a diketone of the formula
  • the compounds of the formula (V) can be prepared, for example, by reacting 2-methyl-2,4-pentanediol with a nitrile of the formula R 3 -A-CN in the presence of sulfuric acid.
  • the correspondingly substituted dihydro-1,3-oxazine formed in this way is converted into the tetrahydro-1,3-oxazine of the formula V in a mixture of tetrahydrofuran and ethanol at -45 ° C. and a pH of about 7 under the action of sodium borohydride reduced.
  • ammonia which is predominantly added in excess, can also be used in the form of an ammonia-donating agent, the release taking place at elevated temperature and, if appropriate, under pressure.
  • suitable ammonia-releasing agents are ammonium salts of lower alkanecarboxylic acids, preferably ammonium acetate, or a carboxylic acid of the formula R 3 -A-COOH, and a suitable lower alkanecarboxamide, in particular formamide.
  • a compound obtainable according to the invention can be converted in a conventional manner into another compound of the formula I.
  • Suitable hydrolysis agents are, for example, protonic acids, such as mineral acids, for example hydrochloric acid or hydrobromic acid, sulfuric acid or phosphoric acid, or organic carboxylic or sulfonic acids, such as lower alkanoic acids, for example acetic acid, or lower alkyl or arylsulfonic acid, for example p-toluenesulfonic acid.
  • protonic acids such as mineral acids, for example hydrochloric acid or hydrobromic acid, sulfuric acid or phosphoric acid, or organic carboxylic or sulfonic acids, such as lower alkanoic acids, for example acetic acid, or lower alkyl or arylsulfonic acid, for example p-toluenesulfonic acid.
  • substituents R 1 , R 2 and R 3 contains hydroxy as additional substituents, this can be etherified in a manner known per se.
  • the reaction with an alcohol component e.g. with a lower alkanol, such as ethanol, in the presence of acids, e.g. mineral acid, such as sulfuric acid, or of dehydrating agents, such as dicyclohexylcarbodiimide, leads to lower alkoxy.
  • acids e.g. mineral acid, such as sulfuric acid
  • dehydrating agents such as dicyclohexylcarbodiimide
  • ethers can be split into alcohols.
  • aromatic alcohols are formed from alkoxyaryl compounds by ether cleavage using acids, such as mineral acids, for example hydrohalic acid, such as hydrobromic acid, or Lewis acids, for example halides of elements of main group 3, such as boron tribromide, or using bases, for example lower alkylamines, such as methylamine. carries out.
  • Hydroxy can also be converted to lower alkanoyloxy, for example by reaction with a desired lower alkanecarboxylic acid such as acetic acid or a reactive derivative thereof, for example in the presence of an acid such as a protonic acid e.g.
  • Chloric, hydrobromic, sulfuric, phosphoric or a benzenesulfonic acid in the presence of a Lewis acid, e.g. of boron trifluoride etherate, or in the presence of a water-binding agent.
  • a Lewis acid e.g. of boron trifluoride etherate
  • esterified hydroxy e.g. by base catalysis to be solvolysed to hydroxy.
  • Free compounds of the formula I obtained can be converted into salts in a manner known per se.
  • Hydroxy-containing groups R 1 or R 2 are converted with appropriate bases such as alkali metal hydroxides, into the salts with bases mentioned at the beginning, or by treatment with an acid addition salt forming acid addition salts as mentioned above.
  • Salts obtained can be converted into the free compounds in a manner known per se, for example by treatment with an acidic reagent, such as a mineral acid, or a base, for example alkali metal hydroxide.
  • the compounds of the formula (I) can be present in the form of one of the possible isomers or as mixtures thereof.
  • the compound of formula (I), including its salts, can also be obtained in the form of its hydrates or include other solvents used for crystallization.
  • the compounds of formula (I) can, depending on the choice of starting materials and procedures, in the form of one of the possible isomers or as mixtures thereof, e.g. depending on the number of asymmetric carbon atoms as pure optical isomers, such as antipodes, or as isomer mixtures, such as racemates, diastereoisomer mixtures or racemate mixtures, are also present as tautomers.
  • Diastereomer mixtures and racemate mixtures obtained can be separated into the pure isomers, diastereomers or racemates in a known manner on account of the physico-chemical differences in the constituents, for example by chromatography and / or fractional crystallization. Racemates obtained can furthermore be broken down into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, with the aid of microorganisms or by reaction of an acidic end product with an optically active base which forms salts with the racemic acid and separation of the salts obtained in this way, for example because of their different solubilities, into the diastereomers from which the antipodes can be released by the action of suitable agents. It is advantageous to isolate the more effective of the two antipodes.
  • the invention also relates to those embodiments of the process according to which one starts from a compound obtainable as an intermediate at any stage of the process and carries out the missing steps or uses a starting material in the form of a salt or in particular forms under the reaction conditions.
  • the pharmaceutical preparations according to the invention which contain the compound according to the invention or pharmaceutically usable salts thereof, are preferably those for topical application to warm breeders, the pharmacological active ingredient being contained alone or together with a pharmaceutically usable carrier material.
  • the daily dosage of the active ingredient depends on the age and individual condition as well as on the method of application.
  • Corresponding agents with a concentration range of about 1 to about 10% w / w, e.g. in the form of creams, ointments or solutions, for example, can be applied 2 to 3 times a day.
  • the topical pharmaceutical preparations that can be used are primarily creams, ointments, pastes, foams, tinctures and solutions which contain from about 0.1 to about 10% of the active ingredient.
  • Creams are oil-in-water emulsions that contain more than 50% water.
  • the main oils used are fatty alcohols, e.g. lauryl, cetyl or stearyl alcohol, fatty acids, e.g. palmitin or stearic acid, liquid to solid waxes, e.g. isopropyl myristate, wool wax or beeswax, and / or hydrocarbons, e.g. petroleum jelly (petrolatum) or paraffin oil .
  • Suitable emulsifiers are surface-active substances with predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens), furthermore polyoxyethylene fatty alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, or corresponding ionic fatty alcohols, or corresponding ionic emulsifiers, such as ionic emulsifiers, or corresponding ionic emulsifiers, such as ionic emulsifiers, or corresponding ionic emulsifiers, such as ionic emulsifiers, such as ionic emulsifiers , for example sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are
  • Additives to the water phase include agents which reduce the drying out of the cream, for example polyalcohols such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols, also preservatives, fragrances, etc.
  • polyalcohols such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols, also preservatives, fragrances, etc.
  • Ointments are water-in-oil emulsions that contain up to 70%, but preferably from about 20% to about 50%, water or aqueous phases.
  • the fatty phase is primarily hydrocarbons, e.g. Petroleum jelly, paraffin oil and / or hard paraffins in question, the hydroxyl compounds, such as fatty alcohols or esters thereof, which are preferably suitable for improving the water-binding capacity, e.g. Cetyl alcohol or wool wax alcohols or wool wax.
  • Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (spans), e.g. Sorbitan oleate and / or sorbitan isostearate.
  • Additions to the water phase include Humectants such as polyalcohols e.g. Glycerin, propylene glycol, sorbitol and / or polyethylene glycol, as well as preservatives, fragrances, etc.
  • Fatty ointments are water-free and contain in particular hydrocarbon, for example paraffin, petroleum jelly and / or liquid paraffins, also natural or partially synthetic fat, for example coconut fatty acid triglyceride, or preferably hardened oils, for example hydrogenated peanut or castor oil, furthermore fatty acid partial esters of glycerol, for example glycerol mono- and distearate, and for example the fatty alcohols and emulsifiers which increase the water absorption capacity, emulsifiers / or additives.
  • hydrocarbon for example paraffin, petroleum jelly and / or liquid paraffins
  • natural or partially synthetic fat for example coconut fatty acid triglyceride, or preferably hardened oils, for example hydrogenated peanut or castor oil, furthermore fatty acid partial esters of glycerol, for example glycerol mono- and distearate, and for example the fatty alcohols and emulsifiers which increase the water absorption capacity, emulsifiers / or
  • Pastes are creams and ointments with secretion-absorbing powder components, such as metal oxides, e.g. Titanium oxide or zinc oxide, also talc and / or aluminum silicates, which have the task of binding moisture or secretions.
  • metal oxides e.g. Titanium oxide or zinc oxide
  • talc and / or aluminum silicates which have the task of binding moisture or secretions.
  • Foams are e.g. administered from pressure vessels and are liquid oil-in-water emulsions in aerosol form, with halogenated hydrocarbons such as chlorofluoro-lower alkanes, e.g. Dichlorodifluoromethane and dichlorotetrafluoroethane can be used as blowing agents.
  • the oil phase used includes Hydrocarbons, e.g. Paraffin oil, fatty alcohols, e.g. Cetyl alcohol, fatty acid esters e.g. Isopropyl myristate, and / or other waxes.
  • the emulsifiers used include Mixtures of those with predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and those with predominantly lipophilic properties, such as sorbitan fatty acid esters (Spans).
  • Teweens polyoxyethylene sorbitan fatty acid esters
  • Spans sorbitan fatty acid esters
  • additives such as preservatives, etc.
  • Tinctures and solutions usually have an aqueous-ethanol base, which includes polyalcohols, e.g. glycerol, glycols and / or polyethylene glycol, as humectants to reduce evaporation, and refatting substances, such as fatty acid esters with low polyethylene glycols, ie lipophilic substances soluble in the aqueous mixture as a substitute for the fatty substances extracted from the skin with the ethanol, and, if necessary, other auxiliaries and additives are added.
  • the topically usable pharmaceutical preparations are prepared in a manner known per se, for example by dissolving or suspending the active ingredient in the base or in a part thereof, if necessary. When the active ingredient is processed as a solution, it is usually dissolved in one of the two phases before emulsification; when processed as a suspension, it is mixed with part of the base after emulsification and then added to the rest of the formulation.
  • the starting material can be prepared as follows: A mixture of 10.0 g of N- [ ⁇ - (3-pyridyl) phenacyl] malonaldehyde acid dimethylacetal amide, 30.0 g of ammonium acetate and 100 ml of glacial acetic acid is boiled under reflux for two hours and then poured into a mixture of 200 g of ice and 150 ml of concentrated aqueous ammonia solution with vigorous stirring. The crystal slurry is extracted twice with 150 ml of ethyl acetate each time and the organic phase is washed neutral with water, dried with magnesium sulfate and evaporated to dryness under 11 torr at 40 °. The residue is chromatographed on 500 g of silica gel.
  • the starting material is prepared as follows: 19.7 g of malonaldehyde acid dimethyl acetal (V.V. Shikina et al. J. Gen. Chem. U.S.S.R. 25, 723-725 (1955)) are dissolved in 300 ml of anhydrous ether. Ammonia gas is introduced into the solution at 0 ° for one hour. The mixture is then evaporated to dryness under reduced pressure. The ammonium salt of malonaldehyde acid dimethylacetal is present as an oil.
  • Example 2 A solution of 5.9 g of 2- [4 (5) -phenyl-5 (4) - (3-pyridyl) - imidazol-2-yl] acetaldehyde dimethylacetal in 120 ml of methylene chloride is made up to 0-5 ° cooled and mixed with 3.5 g of m-chloroperbenzoic acid. The mixture is stirred for 24 hours at room temperature. The yellow solution is then washed twice with 20 ml of 2N potassium hydrogen carbonate solution and with 30 ml of water, dried over magnesium sulfate and at 40 ° under reduced pressure. The residue is dissolved in a little methanol. After adding water kris the 2- [4 (5) -phenyl-5 (4) - (l-oxido-3-pyridyl) imidazol-2-yl] acetaldehyde dimethyl acetal.
  • Example 3 A suspension of 3.29 g of 2- [4 (5) -phenyl-5 (4) - (3-pyridyl) - imidazol-2-yl] -2-methyl-propionic acid sodium salt in 70 ml of anhydrous benzene 3.2 ml of oxalyl chloride are added dropwise with stirring at 5 ° for 10 minutes. The mixture is stirred for one hour at 5 ° and 15 hours at room temperature, cooled and evaporated to dryness under reduced pressure. The residue is mixed with 70 ml of anhydrous benzene and again concentrated to dryness under reduced pressure.
  • the 2- [4 (5) -phenyl-5 (4) - (3-pyridyl) imidazol-2-yl] -2-methyl-propionic acid chloride is present as an oil. The acid chloride is unstable and is implemented immediately.
  • the filtrate is adjusted to pH 8.0 with concentrated aqueous ammonia solution.
  • the mixture is shaken with 100 ml of methylene chloride. Filter the water-methylene chloride mixture through a layer of Hyflo Super Cd. The filtrate is extracted three times with 40 ml of methylene chloride. The organic extracts are combined, washed with 50 ml of water and concentrated to dryness under reduced pressure. The diethylene glycol dimethyl ether is then freed at 50 ° under 0.1 mm. The residue is chromatographed on a Lobar finished column (Grosse C, Merck) for low-pressure liquid chromatography.
  • Example 4 In an analogous manner to that described in Example 1-3 and in the manner shown in the description, one can obtain:
  • Example 5 An ointment containing 5% 2- [4 (5) -phenyl-5 (4) - (1-oxido3-pyridyl) -imidazol-2-yl] methylpropanal dimethyl acetal can be prepared as follows :
  • Sorbitan sesquioleate 5.0% p-hydroxybenzoic acid ester 0.2%
  • Example 6 A cream containing 10% 2- [4 (5) -phenyl-5 (4) - (3-pyridyl) imidazol-2-yl] acetaldehyde dimethyl acetal can be prepared as follows:
  • the acrylic acid polymer is suspended in a mixture of demineralized water and 1,2-propylene glycol. Then stir
  • Triethanolamine added, whereby a mucus is obtained.
  • a mixture of isopropyl palmitate, cetyl palmitate, silicone oil, sorbitan monostearate and polysorbate is heated to approximately 75 ° and incorporated into the mucus, which is likewise heated to approximately 75 °, with stirring.
  • the cream base cooled to room temperature is then used to produce a concentrate with the active ingredient.
  • the concentrate is homogenized by means of a continuous homogenizer and then added to the base as a proton.
  • Example 7 A cream containing 5% 2- [4 (5) -phenyl-5 (4) - (l-oxido-3-pyridyl) imidazol-2-yl] -2-methylpropanal dimethyl acetal can be as follows be preserved.
  • Triglyceride mixture of saturated medium-fat fatty acids 5.0%
  • Cetomacrogol 1000 1.0% microcrystalline cellulose 0.5%
  • Cetyl alcohol, cetyl palmitate, the triglyceride mixture, stearic acid and glycerol stearate are melted together.
  • the microcrystalline cellulose is dispersed in part of the water.
  • Cetomacrogol is dissolved in the remaining part of the water and the propylene glycol and the mucus are mixed with it.
  • the fat phase is then added to the water phase with stirring and stirred cold.
  • the active ingredient is rubbed with part of the base and the rubbing is then incorporated into the rest of the cream.
  • Example 8 A transparent hydrogel containing 5% 2- (4 (5) -phenyl-5 (4) - (4-pyridyl) -imidazol-2-yl] acetaldehyde dimethylacetal is prepared as follows. Composition: active ingredient 5%
  • the hydroxypropyl methyl cellulose is swollen in the water.
  • the active ingredient is dissolved in a mixture of isopropanol and propylene glycol.
  • the active ingredient solution is then mixed with a swollen cellulose derivative and, if desired, fragrances (0.1%) are added.
  • Example 9 A transparent hydrogel containing 5% 2- [4 (5) - phenyl-5 (4) - (l-oxido-3-pyridyl) -imidazol-2-yl] -2-methylpropanal-di methylacetal is used manufactured as follows.
  • Example 10 A foam spray containing 1% 2- [4 (5) -phenyl-5 (4) - (l-oxido-3-pyridyl) imidazol-2-yl] -2-methylpropanal dimethylacetal can be prepared as follows become:
  • Cetyl alcohol, paraffin oil, isopropyl myristate, cetomacrogol and sorbitan stearate are melted together. Methyl and propyl paraben are dissolved in hot water. The melt and the solution are then mixed. The active ingredient, suspended in propylene glycol, is incorporated into the base. Chemoderm is then added and water is added to the final weight.

Abstract

New substituted diazo compounds, particularly compound having the general formula I$(11,)$wherein R1? and R2? are, independently from each other, carbocyclic aryl and/or heteroaryl, A is a residual bivalent hydrocarbon and R3? is formyl or acetalised formyl, the isomers and salts thereof, particularly those which are pharmaceutically usable. The compounds having the formula (I) may be used as epidermic antiphlogistic and are produced according to known methods.

Description

Trisubstituierte Diaza-Derivate Trisubstituted diaza derivatives
Die Erfindung betrifft neue substituierte Diazaverbindungen, insbesondere Verbindungen der allgemeinen Formel IThe invention relates to new substituted diaza compounds, in particular compounds of general formula I.
(I),
Figure imgf000003_0001
worin R1 und R2 unabhängig voneinander carbocyclisches Aryl und/oder Heteroaryl bedeuten, A einen zweiwertigen Kohlenwasserstoffrest darstellt und R3 Formyl oder acetalisiertes Formyl bedeutet, ihre Isomeren und ihre Salze, insbesondere pharmazeutisch verwendbare Salze, Verfahren zu ihrer Herstellung, pharmazeutische Präparate, die solche Verbin dungen enthalten, und ihre Verwendung, z.B. als Arzneimittelwirkstoffe oder zur Herstellung pharmazeutischer Präparate.(I),
Figure imgf000003_0001
in which R 1 and R 2 independently of one another are carbocyclic aryl and / or heteroaryl, A is a divalent hydrocarbon radical and R 3 is formyl or acetalized formyl, their isomers and their salts, in particular pharmaceutically usable salts, processes for their preparation, pharmaceutical preparations which contain such compounds and their use, for example as active pharmaceutical ingredients or for the manufacture of pharmaceutical preparations.
Carbocyclisches Aryl ist beispielsweise monocyclisches carbocyclisches Aryl, wie gegebenenfalls substituiertes Phenyl.Carbocyclic aryl is, for example, monocyclic carbocyclic aryl, such as optionally substituted phenyl.
Heteroaryl ist beispielsweise monocyclisches, vorzugsweise 5- oder 6-gliedriges Heteroaryl, wobei mindestens ein Ringglied ein Heteroatom, wie ein Stickstoff-, Sauerstoff- oder Schwefelatom, darstellt, wobei ein Stickstoffatom auch gegebenenfalls in oxidierter Form vorliegen kann. Solche 5-gliedrigen Reste sind z.B. Pyrrolyl, wie 2-Pyrrolyl, Furyl, wie 2-Furyl, Thienyl, wie 2- oder 3-Thienyl.Heteroaryl is, for example, monocyclic, preferably 5- or 6-membered heteroaryl, where at least one ring member represents a heteroatom, such as a nitrogen, oxygen or sulfur atom, it being possible for a nitrogen atom to also be present in oxidized form. Such 5-membered residues are e.g. Pyrrolyl, such as 2-pyrrolyl, furyl, such as 2-furyl, thienyl, such as 2- or 3-thienyl.
Als 6-gliedriges Heteroaryl kommt z.B. Pyridyl, wie 2-, 3- oder 4-Pyridyl, 1-Oxidopyridyl, wie 1-Oxido-3-pyridyl oder 1-Oxido-4-pyridyl, und Pyrimidyl, wie 2-Pyrimidyl, in Frage. Als Substituenten von carbocyclischem Aryl, wie Phenyl, bzw. Heteroaryl, wie Pyridyl oder 1-Oxido-pyridyl, kommen beispielsweise Halogen, Niederalkyl, Hydroxy, Niederalkoxy und/oder Acyloxy in Betracht. Acyloxy ist beispielsweise von einer organischen Carbonsäure abgeleitet und bedeutet z.B. Niederalkanoyloxy.Examples of 6-membered heteroaryl include pyridyl, such as 2-, 3- or 4-pyridyl, 1-oxidopyridyl, such as 1-oxido-3-pyridyl or 1-oxido-4-pyridyl, and pyrimidyl, such as 2-pyrimidyl Question. Halogen, lower alkyl, hydroxy, lower alkoxy and / or acyloxy are suitable as substituents of carbocyclic aryl, such as phenyl, or heteroaryl, such as pyridyl or 1-oxidopyridyl. Acyloxy is derived, for example, from an organic carboxylic acid and means, for example, lower alkanoyloxy.
Ein Kohlenwasserstoffrest A ist beispielsweise ein zweiwertiger aliphatischer, cycloaliphatischer oder cycloaliphatisch-aliphatischer Kohlenwasserstoffrest.A hydrocarbon residue A is, for example, a divalent aliphatic, cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon residue.
Als zweiwertige aliphatische Kohlenwasserstoffreste kommen beispielsweise Niederalkylen, Niederalkyliden, Niederalkenylen oder Niederalkenyliden in Frage. Zweiwertige cycloaliphatische Kohlenwasserstoffe sind beispielsweise monocyclische 3- bis 8-gliedrige Cycloalkylene oder Cycloalkylidene. Cycloaliphatisch-aliphatische Kohlenwasserstoffreste sind beispielsweise solche, die als cycloaliphatischen Rest einen monocyclischen 3- bis 8-gliedrigen cycloaliphatischen Rest und als aliphatischen Rest Niederalkyliden aufweisen, wie Cycloalkyl-nie-deralkyliden.Examples of divalent aliphatic hydrocarbon radicals are lower alkylene, lower alkylidene, lower alkenyl or lower alkenylidene. Divalent cycloaliphatic hydrocarbons are, for example, monocyclic 3- to 8-membered cycloalkylenes or cycloalkylidenes. Cycloaliphatic-aliphatic hydrocarbon radicals are, for example, those which have a monocyclic 3- to 8-membered cycloaliphatic radical as the cycloaliphatic radical and lower alkylidene as the aliphatic radical, such as cycloalkyl-nederalkylidene.
Unter acetalisiertem Formyl ist beispielsweise mit einem aliphatischen Alkohol, wie Niederalkenol, Niederalkendiol oder insbesondere Niederalkanol sowie Niederalkandiol, acetalisiertes Formyl zu verstehen, beispielsweise Dimethoxy-, Methoxy-ethoxy-, Diethoxyformyl oder Methylendioxy-, Ethylendioxy-methyl.Acetalized formyl is understood to mean, for example, an aliphatic alcohol, such as lower alkenol, lower alkenediol or, in particular, lower alkanol, and lower alkanediol, acetalized formyl, for example dimethoxy-, methoxy-ethoxy-, diethoxyformyl or methylenedioxy-, ethylenedioxy-methyl.
In der vorliegenden Beschreibung sind unter "niederen" organischen Resten und Verbindungen vorzugsweise solche zu verstehen, die bis und mit 7, vor allem bis und mit 4 Kohlenstoffatome (C-Atome) enthalten.In the present description, “lower” organic radicals and compounds are preferably to be understood as meaning those which contain up to and with 7, especially up to and with 4 carbon atoms (carbon atoms).
Die vor- und nachstehend verwendeten Allgemeindefinitionen haben im Rahmen der vorliegenden Anmeldung in erster Linie die folgenden Bedeutungen: Halogen ist z.B. Halogen bis und mit Atomnummer 35, wie Fluor, Chlor oder Brom, ferner Iod.The general definitions used above and below have the following meanings in the context of the present application: Halogen is, for example, halogen up to and including atomic number 35, such as fluorine, chlorine or bromine, and also iodine.
Niederalkyl ist z.B. Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, Iso butyl, sec.-Butyl, tert.-Butyl, ferner ein Pentyl-, Hexyl oder Heptyl rest.Lower alkyl is e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, furthermore a pentyl, hexyl or heptyl radical.
Niederalkoxy ist z.B. Methoxy, Ethoxy, n-Propyloxy, Isopropyloxy, n-Butyloxy, Isobutyloxy, sec.-Butyloxy oder tert.-Butyloxy.Lower alkoxy is e.g. Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec.-butyloxy or tert.-butyloxy.
Niederalkylthio ist z.B. Methyl-, Ethyl-, n-Propyl-, Isopropyl-, n-Butyl-, Isobutyl-, sec.-Butyl oder tert.-Butylthio.Lower alkylthio is e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butylthio.
Phenylniederalkoxy ist z.B. Phenylmethoxy, Phenylethoxy oder Phenylpropyloxy.Phenyl lower alkoxy is e.g. Phenylmethoxy, phenylethoxy or phenylpropyloxy.
Phenylniederalkylthio ist z.B. Benzyl-, Phenylethyl- oder Phenylpropylthio.Phenyl lower alkylthio is e.g. Benzyl, phenylethyl or phenylpropylthio.
Hydroxyniederalkoxy ist z.B. Hydroxyethoxy, Hydroxypropyloxy oder 1,2-Dihydroxypropyloxy.Hydroxy lower alkoxy is e.g. Hydroxyethoxy, hydroxypropyloxy or 1,2-dihydroxypropyloxy.
Niederalkoxyniederalkoxy ist z.B. Methoxyethoxy, Ethoxyethoxy, Methoxypropyloxy oder Methoxybutyloxy.Lower alkoxy lower alkoxy is e.g. Methoxyethoxy, ethoxyethoxy, methoxypropyloxy or methoxybutyloxy.
Phenylniederalkoxyniederalkoxy ist z.B. 2-Benzyloxyethoxy oder 2-(2-Phenylethoxy)-ethoxy.Phenyl lower alkoxy lower alkoxy is e.g. 2-benzyloxyethoxy or 2- (2-phenylethoxy) ethoxy.
Niederalkanoyloxy ist z.B. Acetyl-, Propionyl-, Butyryl-, Iso- Sec-oder tert.-Butyryloxy.Lower alkanoyloxy is e.g. Acetyl, propionyl, butyryl, iso-sec or tert-butyryloxy.
Niederalkylen ist z.B. geradkettig, wie Methylen, Ethylen, 1,3-Propylen oder 1,4-Butylen, oder verzweigt, wie 1,2-Propylen, 1,2- oder 1,3-(2-Methyl)-propylen oder 1,2-Butylen. Niederalkyliden weist ein tertiäres oder insbesondere ein quartäres C-Atom auf und ist z.B. Ethyliden oder 1,1- oder 2,2-Propyliden, ferner 1,1- oder 2,2-Butyliden oder 1,1-, 2,2- oder 3,3-Pentyliden.Lower alkylene is, for example, straight-chain, such as methylene, ethylene, 1,3-propylene or 1,4-butylene, or branched, such as 1,2-propylene, 1,2- or 1,3- (2-methyl) propylene or 1 , 2-butylene. Lower alkylidene has a tertiary or in particular a quaternary carbon atom and is, for example, ethylidene or 1,1- or 2,2-propylidene, furthermore 1,1- or 2,2-butylidene or 1,1-, 2,2- or 3,3-pentylidene.
Niederalkenylen ist z.B. Ethenylen, 1,2- oder 1,3-Propenylen oder 1,2-, 1,3-oder 1,4-Buten-2-ylen.Lower alkenylene is e.g. Ethenylene, 1,2- or 1,3-propenylene or 1,2-, 1,3-or 1,4-buten-2-ylene.
Niederalkenyliden ist z.B. Ethenyliden, 1,1-Propen-l-yliden, 1,1-Propen-2-yliden, ferner ein Butenyliden, wie 1,1-Buten-3-yliden.Lower alkenylidene is e.g. Ethenylidene, 1,1-propen-l-ylidene, 1,1-propen-2-ylidene, and also a butenylidene, such as 1,1-buten-3-ylidene.
Cycloalkylεn ist z.B. Cyclopropylen, 1,2- oder 1,3-Cyclobutylen, 1,2-, 1,3- oder 1,4-Cyclopentylen, ferner ein Cyclohexylen.Cycloalkyl is e.g. Cyclopropylene, 1,2- or 1,3-cyclobutylene, 1,2-, 1,3- or 1,4-cyclopentylene, also a cyclohexylene.
Cycloalkyliden ist z.B. Cyclopropyliden, Cyclobutyliden, Cyclopentyliden oder Cyclohexyliden.Cycloalkylidene is e.g. Cyclopropylidene, cyclobutylidene, cyclopentylidene or cyclohexylidene.
Cycloalkyl-niederalkyliden ist z.B. ein Cyclopropyl-, Cyclobutyl-, Cyclopentyl- oder Cyclohexyl-methylen , -ethyliden oder -propyliden, ferner ein Cyclohexyl-butyliden.Cycloalkyl-lower alkylidene is e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexylmethylene, ethylidene or propylidene, and also a cyclohexylbutylidene.
Carboxyniederalkoxy ist z.B. Carboxymethoxy, 2-Carboxyethoxy, 2-, 3-Carboxypropyloxy, 1-Carboxy-2-propyloxy, 2-, 3- oder 4-Carboxy-n-butyloxy, 1-Carboxy-2-methyl-propyl-3-oxy oder 1-Carboxy-2-methyl-propyl-2-oxy.Carboxy lower alkoxy is e.g. Carboxymethoxy, 2-carboxyethoxy, 2-, 3-carboxypropyloxy, 1-carboxy-2-propyloxy, 2-, 3- or 4-carboxy-n-butyloxy, 1-carboxy-2-methyl-propyl-3-oxy or 1 -Carboxy-2-methyl-propyl-2-oxy.
Niederalkoxycarbonyl-niederalkoxy enthält jeweils im Nieder- alkoxyteil unabhängig voneinander die vorstehend unter. Niederalkoxy auff geführten Bedeutungen.Lower alkoxycarbonyl-lower alkoxy contains, in each case independently of one another, the above under in the lower alkoxy part. Lower alkoxy listed meanings.
Salze von erfindungsgemässen Verbindungen der Formel I sind vorzugsweise pharmazeutisch verwendbare Salze, wie pharmazeutisch verwendbare Säureadditionssalze, beispielsweise Salze mit anorganischen Säuren, wie Mineralsäure, mit Sulfaminsäuren, wie Cyclohexylsulfaminsäure, mit organischen Carbonsäuren, wie Niederalkancarbonsäuren, gegebenenfalls ungesättigte Dicarbonsäuren, mit durch Hydroxy und/oder Oxo substituierten Carbonsäuren oder mit Sulfonsäuren, beispielsweise Sulfate oder Hydrohalogenide, wie Hydrobromide oder Hydrochloride, Oxalate, Malonate, Fumarate oder Maleinate, Tartrate, Pyruvate oder Citrate, Sulfonate, wie Methan-, Benzol- oder p-Toluolsulfonate. Die Verbindungen der Formel I und ihre pharmazeutisch verwendbaren Salze weisen wertvolle pharmakologische Eigenschaften auf. Insbesondere besitzen sie, z.B. bei lokaler Anwendung, eine ausgeprägte antiinflammatorische Wirkung.Salts of compounds of the formula I according to the invention are preferably pharmaceutically usable salts, such as pharmaceutically usable acid addition salts, for example salts with inorganic acids, such as mineral acid, with sulfamic acids, such as cyclohexylsulfamic acid, with organic carboxylic acids, such as lower alkane carboxylic acids, optionally unsaturated dicarboxylic acids, with by hydroxy and / or Oxo-substituted carboxylic acids or with sulfonic acids, for example sulfates or hydrohalides, such as hydrobromides or hydrochlorides, oxalates, malonates, fumarates or maleinates, tartrates, pyruvates or citrates, sulfonates, such as methane, benzene or p-toluenesulfonates. The compounds of formula I and their pharmaceutically usable salts have valuable pharmacological properties. In particular, for example when used locally, they have a pronounced anti-inflammatory effect.
Diese Eigenschaft lässt sich beispielsweise nach der von G. Tonelli, L. Thibault, Endocrinology 77, 625 (1965) entwickelten Methode durch Hemmung des mit Crotonöl induzierten Rattenohroedems bei der Normalratte im Dosisbereich von etwa 1 bis etwa 100 mg/ml nachweisen. So wurde beispielsweise für die Verbindung 2-[4(5)-Phenyl-5(4)-(3-pyridyl)-imid azol-2-yl]-acetaldehyd-dimethylacetal im vorstehend beschriebenen Test ein ED50-Wert von 18 mg/ml ermittelt.This property can be detected, for example, according to the method developed by G. Tonelli, L. Thibault, Endocrinology 77, 625 (1965) by inhibiting the rat ear edema induced by croton oil in the normal rat in the dose range from about 1 to about 100 mg / ml. For example, for the compound 2- [4 (5) -phenyl-5 (4) - (3-pyridyl) imide azol-2-yl] acetaldehyde dimethyl acetal in the test described above, an ED 50 value of 18 mg / ml determined.
Die erfindungsgemäss anwendbaren Verbindungen der Formel I sind daher als Arzneimittel, insbesondere externe (topische) Hautphlogistatika für die Behandlung entzündlicher Dermatosen jeglicher Genese, wie bei leichten Hautirritationen, Kontaktdermatitis, Exanthemen, Verbrennungen, sowie als Schleimhautphlogostatika für die Behandlung von Mukosaentzündungen, z.B. der Augen, Nase, Lippen, Mund, Genital-, Analregion, geeignet. Ferner können die Verbindungen als Sonnenschutzmittel verwendet werden.The compounds of the formula I which can be used according to the invention are therefore medicinal products, in particular external (topical) dermatological agents for the treatment of inflammatory dermatoses of any genesis, such as in the case of mild skin irritation, contact dermatitis, rashes, burns, and as mucosal phlogostatic agents for the treatment of mucosal inflammation, e.g. the eyes, nose, lips, mouth, genital, anal region. The compounds can also be used as sunscreens.
Die vorliegende Erfindung betrifft ebenfalls die Verwendung der erfindungsgemässen Verbindungen und deren Salze zur Behandlung von Entzündungen, z.B. von entzündlichen Erkrankungen unterschiedlichster Genese, sowie zur Herstellung von Arzneimitteln.The present invention also relates to the use of the compounds according to the invention and their salts for the treatment of inflammation, e.g. of inflammatory diseases of various origins, as well as for the manufacture of medicines.
Die Erfindung betrifft insbesondere Verbindungen der Formel I, worin einerseits R1 und R2 unabhängig voneinander Phenyl und/oder durch Halogen, Niederalkyl, Hydroxy, Niederalkoxy und/oder Niederalkanoyl substituiertes Phenyl bedeuten oder worin andererseits einer der Reste R1 und R2 Pyrrolyl, Furyl, Thienyl, Pyridyl, 1-Oxidopyridyl oder Pyrimidyl bedeutet, welches jeweils unsubstituiert oder durch Halogen, Niederalkyl, Hydroxy, Niederalkoxy und/oder Niederalkanoyloxy substituiert sein können, und der andere Phenyl, Pyrrolyl, Furyl, Thienyl, Pyridyl, 1-Oxidopyridyl oder Pyrimidyl bedeutet, welches jeweils unsubstituiert oder durch Halogen, Niederalkyl, Hydroxy, Niederalkoxy und/oder Niederalkanoyloxy substituiert sein können, und jeweils A Niederalkylen, Niederalkyliden, Niederalkenylen, Niederalkenyliden, Cycloalkylen, Cycloalkyliden oder Cycloalkyl-niederalkyliden darstellen und R3 Formyl oder mit einem aliphatischen Alkohol acetalisiertes Formyl bedeutet, ihre Isomeren sowie ihre Salze, insbesondere pharmazeutisch verwendbare Salze.The invention relates in particular to compounds of the formula I in which, on the one hand, R 1 and R 2 independently of one another are phenyl and / or phenyl substituted by halogen, lower alkyl, hydroxy, lower alkoxy and / or lower alkanoyl, or on the other hand one of the radicals R 1 and R 2 is pyrrolyl, Means furyl, thienyl, pyridyl, 1-oxidopyridyl or pyrimidyl, which in each case can be unsubstituted or substituted by halogen, lower alkyl, hydroxy, lower alkoxy and / or lower alkanoyloxy, and the other phenyl, pyrrolyl, furyl, thienyl, pyridyl, 1-oxidopyridyl or Pyrimidyl means which is in each case unsubstituted or by halogen, lower alkyl, hydroxy, lower alkoxy and / or lower alkanoyloxy can be substituted, and each represent A lower alkylene, lower alkylidene, lower alkenyl, lower alkenylidene, cycloalkylene, cycloalkylidene or cycloalkyl lower alkylidene and R 3 means formyl or formyl acetalized with an aliphatic alcohol, their isomers and their salts, in particular pharmaceutically usable salts .
Die Erfindung betrifft insbesondere Verbindungen der Formel I, worin R1 und R2 unabhängig voneinander Phenyl und/oder durch Halogen, Hydroxy,- Niederalkyl, Niederalkoxy und/oder Niederalkanoyloxy substituiertes Phenyl bedeuten, A Niederalkylen mit bis und mit 4 C-Atomen, wie Methylen, Niederalkyliden mit bis und mit 7 C-Atomen, wie 2,2-Propyliden, Niederalkenylen mit bis und mit 4 C-Atomen, wie 1,3-Propen-2-ylen, Niederalkenyliden mit bis und mit 7 C-Atomen, wie 1,1-Buten 3-yliden, 3- bis 8-gliedriges Cycloalkylen, wie Cyclopropylen, 3-bis 8-gliedriges Cycloalkyliden, wie Cyclopentyliden, oder Cycloalkylniederalkyliden mit bis und mit 7 C-Atomen im Alkylidenteil und mit einem 3- bis 8-gliedrigem Cycloalkylteil, wie 2-Cyclohexyl-l,l-ethyliden, bedeutet und R3 Formyl oder mit einem Niederalkanol, Niederalkenol, Niederalkandiol oder Niederalkendiol acetalisiertes Formyl bedeutet, ihre Isomeren sowie ihre Salze, insbesondere pharmazeutisch verwendbare Salze.The invention relates in particular to compounds of the formula I in which R 1 and R 2 independently of one another are phenyl and / or phenyl which is substituted by halogen, hydroxy, lower alkyl, lower alkoxy and / or lower alkanoyloxy, A is lower alkylene having up to and with 4 carbon atoms, such as Methylene, lower alkylidene with up to and with 7 carbon atoms, such as 2,2-propylidene, lower alkenyl with up to and with 4 carbon atoms, such as 1,3-propen-2-ylene, lower alkenylidene with up to and with 7 carbon atoms, such as 1,1-butene 3-ylidene, 3- to 8-membered cycloalkylene, such as cyclopropylene, 3-to 8-membered cycloalkylidene, such as cyclopentylidene, or cycloalkyl-lower alkylidene with up to and with 7 carbon atoms in the alkylidene part and with a 3- to 8-membered cycloalkyl, such as 2-cyclohexyl-l, l-ethylidene, and R 3 is formyl or formalized with a lower alkanol, lower alkenol, lower alkanediol or lower alkenediol, their isomers and their salts, in particular pharmaceutically acceptable salts.
Die Erfindung betrifft insbesondere Verbindungen der Formel I, worin einer der Reste R1 und R2 Pyridyl oder 1-Oxido-pyridyl, die unsubstituiert und/oder jeweils durch Halogen, Hydroxy, Niederalkyl, Niederalkoxy und/oder Niederalkanoyloxy substituiert sein können, und der andere Phenyl, Pyridyl oder 1-Oxidopyridy1, die unsubstituiert und/oder jeweils durch Halogen, Hydroxy, Niederalkyl, Niederalkoxy und/oder Niederalkanoyloxy substituiert sein können, bedeutet, A Niederalkylen mit bis und mit 4 C-Atomen, wie Methylen, Niederalkyliden mit bis und mit 7 C-Atomen, wie 2,2-Propyliden, Niederalkenylen mit bis und mit 7 C-Atomen, wie l,3-Propen-2-ylen, Niederalkenyliden mit bis und mit 4 C-Atomen, wie l,l-Buten-3-yliden, 3- bis 8-gliedri ges Cycloalkylen, wie Cyclopropylen, 3- bis 8-gliedriges Cycloalkyliden, wie Cyclopentyliden, oder Cycloalkyl-niederalkyliden mit bis und mit 7 C-Atomen im Alkylidenteil und mit einem 3- bis 8-gliedrigem Cycloalkylteil, wie 2-Cyclohexyl-l,l-ethyliden, bedeutet und R3 mit einem Niederalkanol, Niederalkenol, Niederalkandiol oder Niederalkendiol acetalisiertes Formyl bedeutet, ihre Isomeren sowie ihre Salze, insbesondere pharmazeutisch verwendbare Salze.The invention particularly relates to compounds of the formula I in which one of the radicals R 1 and R 2 is pyridyl or 1-oxidopyridyl, which are unsubstituted and / or each substituted by halogen, hydroxyl, lower alkyl, lower alkoxy and / or lower alkanoyloxy, and the other phenyl, pyridyl or 1-oxidopyridy1, which may be unsubstituted and / or substituted in each case by halogen, hydroxy, lower alkyl, lower alkoxy and / or lower alkanoyloxy, means A lower alkylene with up to and with 4 carbon atoms, such as methylene, lower alkylidene with up and with 7 C atoms, such as 2,2-propylidene, lower alkenyls with up to and with 7 C atoms, such as 1,3-propen-2-ylene, lower alkenylidene with up to and with 4 C atoms, such as l, l- Buten-3-ylidene, 3- to 8-membered ges cycloalkylene, such as cyclopropylene, 3- to 8-membered cycloalkylidene, such as cyclopentylidene, or cycloalkyl-lower alkylidene with up to and with 7 carbon atoms in the alkylidene part and with a 3- to 8-membered cycloalkyl part, such as 2-cyclohexyl-l, l -ethylidene means and R 3 is acetalized with a lower alkanol, lower alkenol, lower alkanediol or lower alkenediol, their isomers and their salts, in particular pharmaceutically usable salts.
Die Erfindung betrifft insbesondere Verbindungen der Formel I, worin R1 und R2 unabhängig voneinander Phenyl und/oder durch Halogen mit Atomnummer bis und mit 35, wie Chlor, Hydroxy, Niederalkyl mit bis und mit 4 C-Atomen, wie Methyl, und/oder Niederalkoxy mit bis und mit 4 C-Atomen, wie Methoxy, substituiertes Phenyl bedeuten, A Niederalkylen mit bis und mit 4 C-Atomen, wie Methylen, Niederalkyliden mit bis und mit 7 C-Atomen, wie 2,2-Propyliden, Niederalkenyliden mit bis und mit 7 C-Atomen, wie l,l-Buten-3-yliden, oder 3- bis 8-gliedriges Cycloniederalkyliden, wie 1, 1-Cyclopentyliden, darstellen und R3 Formyl oder Diniederalkoxy-methyl jeweils mit bis und mit 4 C-Atomen im Nieder alkoxyteil, wie Dimethoxy-methyl, oder Niederalkendioxy-methyl mit bis und mit 4 C-Atomen im Niederalkylenteil, wie 1,3-Dioxolan-2-yl, bedeutet, ihre Isomeren sowie ihre Salze, insbesondere pharmazeutisch verwendbare Salze.The invention relates in particular to compounds of the formula I in which R 1 and R 2 independently of one another are phenyl and / or by halogen with atomic numbers up to and including 35, such as chlorine, hydroxy, lower alkyl having up to and with 4 carbon atoms, such as methyl, and / or lower alkoxy with up to and with 4 carbon atoms, such as methoxy, substituted phenyl, A is lower alkylene with up to and with 4 carbon atoms, such as methylene, lower alkylidene with up to and with 7 carbon atoms, such as 2,2-propylidene, lower alkenylidene with up to and with 7 carbon atoms, such as l, l-buten-3-ylidene, or 3- to 8-membered cyclo-lower alkylidene, such as 1, 1-cyclopentylidene, and R 3 formyl or diniederalkoxy-methyl each with up to and with 4 carbon atoms in the lower alkoxy part, such as dimethoxy-methyl, or lower alkenedioxy-methyl with up to and with 4 carbon atoms in the lower alkylene part, such as 1,3-dioxolan-2-yl, means their isomers and their salts, in particular those which can be used pharmaceutically Salts.
Die Erfindung betrifft insbesondere Verbindungen der Formel I, worin einer der Reste R1 und R2 Phenyl oder durch Halogen mit Atomnummer bis und mit 35, wie Chlor, Hydroxy, Niederalkyl mit bis und mit 4 C-Atomen, wie Methyl, und/oder Niederalkoxy mit bis und mit 4 C-Atomen, wie Methoxy, substituiertes Phenyl bedeutet und der andere Pyridyl, wie 3-Pyridyl, oder 1-Oxido-pyridyl, wie 1-Oxido-3-pyridyl, bedeutet, die jeweils unsubstituiert oder durch Halogen mit Atomnummer bis und mit 35, wie Chlor, Hydroxy und/oder Niederalkoxy mit bis und mit 4 C-Atomen, wie Methoxy, substituiert sein können, A Niederalkylen mit bis und mit 4 C-Atomen, wie Methylen, Niederalkyliden mit bis und mit 7 C-Atomen, wie 2,2-Propyliden, Niederalkenyliden mit bis und mit 7 C-Ato men, wie 1,1-Buten-3-yliden, oder 3- bis 8-gliedriges Cycloniederalkyliden, wie 1,1-Cyclopentyliden, dartellen und R3 Formyl oder Diniederalkoxymethyl jeweils mit bis und mit 4 C-Atomen im Niederalkylteil, wie Dimethoxymethyl, oder Niederalkyendioxy-methyl mit bis und mit 4 C-Atomen im Niederalkylenteil, wie 1,3-Dioxolan-2-yl, bedeutet, ihre Isomeren sowie ihre Salze, insbesondere pharmazeutisch verwendbare Salze.The invention relates in particular to compounds of the formula I in which one of the radicals R 1 and R 2 is phenyl or halogen with atom numbers up to and including 35, such as chlorine, hydroxy, lower alkyl having up to and 4 carbon atoms, such as methyl, and / or Lower alkoxy with up to and with 4 carbon atoms, such as methoxy, means substituted phenyl and the other pyridyl, such as 3-pyridyl, or 1-oxido-pyridyl, such as 1-oxido-3-pyridyl, each of which is unsubstituted or substituted by halogen with atomic numbers up to and including 35, such as chlorine, hydroxyl and / or lower alkoxy, can be substituted with up to and with 4 carbon atoms, such as methoxy, A lower alkylene with up to and with 4 carbon atoms, such as methylene, lower alkylidene with up to and including 7 carbon atoms, such as 2,2-propylidene, lower alkenylidene with up to and with 7 carbon atoms men, such as 1,1-buten-3-ylidene, or 3- to 8-membered cyclo-lower alkylidene, such as 1,1-cyclopentylidene, dartellen and R 3 formyl or diniederalkoxymethyl each with up to and with 4 carbon atoms in the lower alkyl part, such as dimethoxymethyl , or Niederalkyendioxy-methyl with up to and with 4 carbon atoms in the lower alkyl part, such as 1,3-dioxolan-2-yl, means their isomers and their salts, in particular pharmaceutically usable salts.
Die Erfindung betrifft insbesondere Verbindungen der Formel I, worin R1 und R2 unabhängig voneinander Phenyl und/oder durch Niederalkoxy mit bis und mit 4 C-Atomen, wie Methoxy, substituiertes Phenyl bedeuten, A Niederalkylen mit bis und mit 4 C-Atomen, wie Methylen, oder insbesondere Niederalkyliden mit bis und mit 4 C-Atomen, wie 2,2-Propyliden, darstellt und R3 Formyl oder Diniederalkoxy-methyl jeweils mitbis und mit 4 C-Atomen im Niederalkoxyteil, wie Diethoxy-methyl, oder Niederalkylendioxy-methyl mit bis und mit 4 C-Atomen im Niederalkylenteil, wie 1,3-Dioxolan-2-yl, bedeutet, ihre Isomeren sowie ihre Salze, insbesondere pharmazeutisch verwendbare Salze.The invention relates in particular to compounds of the formula I in which R 1 and R 2 independently of one another are phenyl and / or phenyl which is substituted by lower alkoxy having up to and with 4 carbon atoms, such as methoxy, A lower alkylene having up to and with 4 carbon atoms, such as methylene, or in particular lower alkylidene with up to and with 4 C atoms, such as 2,2-propylidene, and R 3 is formyl or diniederalkoxy-methyl, each with up to and with 4 C atoms in the lower alkoxy part, such as diethoxy-methyl, or lower alkylenedioxy methyl with up to 4 carbon atoms in the lower alkylene part, such as 1,3-dioxolan-2-yl, means their isomers and their salts, in particular pharmaceutically usable salts.
Die Erfindung betrifft in erster Linie Verbindungen der Formel I, worin einer der Reste R1 und R2 Phenyl oder durch Halogen mit Atomnummer bis und mit 35, wie Chlor, Hydroxy oder Niederalkoxy mit bis und mit 4 C-Atomen, wie Methoxy, substituiertes Phenyl bedeutet und der andere Pyridyl, wie 3- oder 4-Pyridyl, oder 1-Oxidopyridyl, wie 1-Oxido-3-pyridyl oder 1-Oxido-4-pyridyl, darstellt, A Niederalkyliden mit bis und mit 4 C-Atomen, wie 2,2-Propyliden, bedeutet, und R3 Formyl oder Diniederalkoxy-methyl jeweils mit bis und mit 4 C-Atomen im Niederalkoxyteil, wie Diethoxy-methyl, oder Niederalkylendioxy-methyl mit bis und mit 4 C-Atomen im Niederalkylenteil, wie 1,3-Dioxolan-2-yl, bedeutet, ihre Isomeren sowie ihre Salze, insbesondere pharmazeutisch verwendbare Salze.The invention relates primarily to compounds of the formula I in which one of the radicals R 1 and R 2 is phenyl or substituted by halogen with an atom number of up to and including 35, such as chlorine, hydroxy or lower alkoxy, with up to and including 4 C atoms, such as methoxy Is phenyl and the other is pyridyl, such as 3- or 4-pyridyl, or 1-oxidopyridyl, such as 1-oxido-3-pyridyl or 1-oxido-4-pyridyl, A is lower alkylidene with up to and with 4 carbon atoms, such as 2,2-propylidene, and R 3 is formyl or di-lower alkoxy-methyl, each with up to and with 4 carbon atoms in the lower alkoxy part, such as diethoxy-methyl, or lower alkylenedioxy-methyl with up to and 4 carbon atoms in the lower alkylene part, such as 1,3-dioxolan-2-yl means their isomers and their salts, in particular pharmaceutically usable salts.
Die Erfindung betrifft in erster Linie Verbindungen der Formel I, worin einer der Reste R1 und R2 Phenyl oder durch Halogen mit Atomnum mer bis und mit 35, wie Chlor, Hydroxy oder Niederalkoxy mit bis und mit 4 C-Atomen, wie Methoxy substituiertes Phenyl bedeutet und der andere Pyridyl, wie 3- oder 4-Pyridyl, oder 1-Oxidopyridyl, wie 1-Oxido 3-pyridyl oder 1-Oxido-4-pyridyl, darstellt, A ein ein quartäres C-Atom aufweisendes Niederalkyliden mit bis und mit 4 C-Atomen, wie 2,2-Propyliden, wobei das quartäre C-Atom direkt an den Imidazolring geburden ist, bedeutet, und R3 Formyl oder Diniederalkoxy-methyl mit bis und mit 4 C-Atomen jeweils im Niederalkylteil, wie Diethoxy-methyl, darstellt, ihre Isomeren sowie ihre Salze, insbesondere pharmazeutisch verwendbare Salze.The invention relates primarily to compounds of the formula I in which one of the radicals R 1 and R 2 is phenyl or by halogen with an atomic number mer up to and including 35, such as chlorine, hydroxy or lower alkoxy with up to and with 4 carbon atoms, such as methoxy, substituted phenyl and the other pyridyl, such as 3- or 4-pyridyl, or 1-oxidopyridyl, such as 1-oxido 3- pyridyl or 1-oxido-4-pyridyl, A represents a quaternary carbon atom lower alkylidene with up to and with 4 carbon atoms, such as 2,2-propylidene, the quaternary carbon atom being directly attached to the imidazole ring, means, and R 3 is formyl or diniederalkoxy-methyl with up to and with 4 carbon atoms in each case in the lower alkyl part, such as diethoxy-methyl, their isomers and their salts, in particular pharmaceutically usable salts.
Die Erfindung betrifft in allererster Linie Verbindungen der Formel I, worin einer der Reste R1 und R2 Phenyl und der andere Pyridyl, wie 3-Pyridyl, oder 1-Oxidopyridyl, wie 1-Oxido-3-pyridyl, bedeutet, A 2,2-Propyliden darstellt und R3 Formyl oder Diniederalkoxy-methyl jeweils mit bis und mit 4 C-Atomen im Niederalkyl- wie Diethoxy-methyl, bedeutet, ihre Isomeren sowie ihre Salze, insbesondere pharmazeutisch verwendbare SalzeThe invention relates primarily to compounds of the formula I in which one of the radicals R 1 and R 2 is phenyl and the other pyridyl, such as 3-pyridyl, or 1-oxidopyridyl, such as 1-oxido-3-pyridyl, A 2, Represents 2-propylidene and R 3 means formyl or di-lower alkoxy-methyl, each having up to and with 4 carbon atoms in lower alkyl, such as diethoxy-methyl, their isomers and their salts, in particular pharmaceutically usable salts
Die Erfindung betrifft namentlich die in den Beispielen genannten neuen Verbindungen und ihre Salze, insbesondere pharmazeutisch verwendbare Salze von solchen Verbindungen mit salzbildenden Gruppen, sowie die in den Beispielen aufgeführten topisch applizierbaren pharmazeutischen Präparate.The invention relates in particular to the new compounds mentioned in the examples and their salts, in particular pharmaceutically usable salts of such compounds having salt-forming groups, and to the topically administrable pharmaceutical preparations listed in the examples.
Die Erfindung betrifft ebenso Verfahren zur Herstellung von Verbindungen der Formel I und ihrer Salze, insbesondere pharmazeutisch verwendbarer Salze von solchen Verbindungen mit salzbildenden Gruppen, sowie die in den Beispielen aufgeführten Herstellungsverfahren.The invention also relates to processes for the preparation of compounds of the formula I and their salts, in particular pharmaceutically usable salts of such compounds with salt-forming groups, and to the preparation processes listed in the examples.
Die Verbindungen der Formel I oder deren Salze lassen sich in an sich bekannter Weise herstellen.The compounds of formula I or their salts can be prepared in a manner known per se.
Eine Verfahrensweise besteht beispielsweise darin, dass man aus einer Verbindung der Formel (II)One procedure is, for example, that a compound of the formula (II)
Figure imgf000012_0001
worin einer der Reste Y1 und Y6 Hydroxy oder Amino und der andere sowie Y2 Wasserstoff darstellt und Y3 gemeinsam mit Y4 und Y5 eine
Figure imgf000012_0001
wherein one of the radicals Y 1 and Y 6 is hydroxyl or amino and the other and Y 2 is hydrogen and Y 3 together with Y 4 and Y 5 is one
Gruppe der Formel =N- bedeutet oder worin Y1 gemeinsam mit Y6 eineGroup of the formula = N- or wherein Y 1 together with Y 6 one
Bindung darstellt, Y2 Wasserstoff ist, Y3 Hydroxy oder Amino bedeutet und Y4 gemeinsam mit Y5 eine Gruppe der Formel -NH- darstellt oder worin Y1 gemeinsam mit Y6 eine Bindung darstellt, Y2 gemeinsam mit Y3 eine zusätzliche Bindung und einer der Reste Y4 und Y5 Amino und der andere Amino, Hydroxy oder reaktionsfähiges verestertes Hydroxy, insbesondere Halogen oder Sulfonyloxy, darstellt oder worin Y1 Hydroxy ist, Y2 sowie Y3 Wasserstoff bedeutet, Y4 Hydroxy oder Amino darstellt und Y5 gemeinsam mit Y6 eine Gruppe der Formel =NH oder, sofern Y4 Amino ist, Oxo oder Imino bedeutet, oder einem Tautomeren und/oder Salz davon, unter Einführung einer gegebenenfalls zusätzlichen Bindung H-Z abspaltet, und gewünschtenfalls die Verfahrensgemäss erhältliche Verbindung in eine andere Verbindung der Formel I, eine verfahrensgemäss erhältliche freie Verbindung in ein Salz oder ein verfahrensgemäss erhältliches Salz in die freie Verbindung oder in ein anderes Salz überführt und/oder, wenn erwünscht, ein erfindungsgemäss erhältliches Gemisch von isomeren Verbindungen der Formel I in die einzelnen Isomeren auftrennt.Binding is Y 2 is hydrogen, Y 3 is hydroxy or amino and Y 4 together with Y 5 is a group of the formula -NH- or wherein Y 1 together with Y 6 is a bond, Y 2 together with Y 3 is an additional bond and one of the radicals Y 4 and Y 5 is amino and the other is amino, hydroxy or reactive esterified hydroxy, in particular halogen or sulfonyloxy, or in which Y 1 is hydroxy, Y 2 and Y 3 are hydrogen, Y 4 is hydroxy or amino and Y 5 together with Y 6 cleaves a group of the formula = NH or, if Y 4 is amino, oxo or imino, or a tautomer and / or salt thereof, with the introduction of an optionally additional bond HZ, and if desired the compound obtainable according to the process into a convert another compound of formula I, a process-available free compound into a salt or a process-available salt into the free compound or another salt rt and / or, if desired, a mixture of isomeric compounds of the formula I obtainable according to the invention is separated into the individual isomers.
Dabei bedeutet Z Hydroxy oder Amino Y1 bzw. Y6 , Y3 oder Y4 bzw. Y5 oder Halogen bzw. Sulfonyloxy Y4 bzw. Y5.Z is hydroxy or amino Y 1 or Y 6 , Y 3 or Y 4 or Y 5 or halogen or sulfonyloxy Y 4 or Y 5 .
Reaktionsfähiges verestertes Hydroxy ist beispielsweise mit einer anorganischen Mineralsäure, wie Halogenwasserstoffsäure, oder mit einer organischen Sulfonsäure, wie Niederalkan- oder gegebenenfalls substituierte Benzolsulfonsäure, verestertes Hydroxy und bedeutet in erster Linie Halogen, z.B. Chlor oder Brom, sowie Sulfonyloxy, z.B. Methan- oder p-Toluolsulfonyloxy.Reactive esterified hydroxy is, for example, with an inorganic mineral acid, such as hydrohalic acid, or with an organic sulfonic acid, such as lower alkane or optionally Substituted benzenesulfonic acid, esterified hydroxy and primarily means halogen, for example chlorine or bromine, and sulfonyloxy, for example methane or p-toluenesulfonyloxy.
Tautomere von Verbindungen der Formel II sind beispielsweise solche, in denen eine partielle Enol- bzw. Enamin-Gruppierung der FormelTautomers of compounds of the formula II are, for example, those in which a partial enol or enamine grouping of the formula
(IIa)
Figure imgf000013_0001
(IIa)
Figure imgf000013_0001
worin Y1 gemeinsam mit Y6 eine zusätzliche Bindung darstellt und Y5 Hydroxy bzw. Amino bedeutet, in Form der entsprechenden tautomeren Keto- bzw. Ketiminform, worin Y1 Wasserstoff ist und Y5 gemeinsam mit Y6 Oxo bzw. Imino bedeutet, vorliegt und/oder solche, in denen eine partielle Enol- bzw. Enamingruppierung der Formelwherein Y 1 together with Y 6 represents an additional bond and Y 5 is hydroxy or amino, in the form of the corresponding tautomeric keto or ketimine form, wherein Y 1 is hydrogen and Y 5 together with Y 6 is oxo or imino and / or those in which a partial enol or enamine grouping of the formula
(IIb)
Figure imgf000013_0002
(IIb)
Figure imgf000013_0002
worin Y2 gemeinsam mit Y3 eine Bindung darstellt und Y4 Hydroxy bzw. Amino bedeutet, in Form der entsprechenden tautomeren Form vorliegt, worin Y2 Wasserstoff ist und Y3 gemeinsam mit Y4 Oxo bzw. Imino darstellt, vorliegt, wobei die genannten Tautomeren miteinander im Gleichgewicht stehen.wherein Y 2 together with Y 3 is a bond and Y 4 is hydroxy or amino, is in the form of the corresponding tautomeric form, in which Y 2 is hydrogen and Y 3 together with Y 4 is oxo or imino, the abovementioned Tautomers are in balance with each other.
Die Abspaltung von H - Z aus einer Verbindung der Formel II, einem Tautomeren und/oder Salz davon erfolgt in üblicher, insbesondere in der aus der Literatur für analoge Reaktionen bekannten Weise, erforderlichenfalls unter Erwärmen, wie in einem Temperaturbereich von etwa 20° bis etwa 250°C, unter Druck und/oder in Gegenwart eines katalycischen Mittels, vorzugsweise einer Säure. Als Säuren eignen sich beispielsweise anorganische Säuren, wie Mineralsäuren, z.B. Schwefelsäure, Polyphosphorsäure oder Halogenwasserstoffsäure, wie Chlorwasserstoffsäure, oder organische Säuren, wie Niederalkancarbonsäuren, z.B. Essigsäure. Dabei arbeitet man erforderlichenfalls in einem inerten Lösungsmittel, beispielsiv-isse einem gegebenenfalls halogenierten Kohlenwasserstoff, wie Chloroform, Chlorbenzol, Hexan oder Toluol, einem Niederalkanol, wie Methanol oder Ethanol, einem Carbσnsäureamid, wie Niederalkancarbonsäureamid, z.B. Dimethylformamid oder Formamid, oder einer Niederalkancarbonsäure, wie Ameisen- oder Essigsäure, und/oder unter Inertgas, wie Stickstoff.H - Z is split off from a compound of the formula II, a tautomer and / or salt thereof in a customary manner, in particular in the manner known from the literature for analogous reactions, if necessary with heating, such as in a temperature range from about 20 ° to about 250 ° C, under pressure and / or in the presence of a catalytic agent, preferably an acid. Are suitable as acids for example inorganic acids, such as mineral acids, for example sulfuric acid, polyphosphoric acid or hydrohalic acid, such as hydrochloric acid, or organic acids, such as lower alkane carboxylic acids, for example acetic acid. If necessary, the process is carried out in an inert solvent, for example an optionally halogenated hydrocarbon, such as chloroform, chlorobenzene, hexane or toluene, a lower alkanol, such as methanol or ethanol, a carboxamide, such as lower alkanecarboxamide, for example dimethylformamide or formamide, or a lower alkanecarboxylic acid, such as Formic or acetic acid, and / or under an inert gas such as nitrogen.
Die AusgangsStoffe der Formel II, ihre Tautomeren und/oder Salze werden nach an sich bekannten Verfahren zum überwiegenden Teil in situ gebildet und unter den Reaktionsbedingungen ohne Isolierung weiter zu der Verbindung der Formel I umgesetzt. Dabei kann die Abspaltung von H - Z unter direkter Cyclisierung oder im Anschluss an eine vorgelagerte Cyclisierung erfolgen.The starting materials of the formula II, their tautomers and / or salts are predominantly formed in situ by processes known per se and further reacted under the reaction conditions without isolation to the compound of the formula I. The cleavage of H - Z can take place with direct cyclization or after an upstream cyclization.
So kann man in einer bevorzugten Ausführungsform des vorstehenden Verfahren beispielsweise ein acyliertes α-Aminoketon der FormelFor example, in a preferred embodiment of the above process, an acylated α-amino ketone of the formula can be used
(lIla)(purple)
Figure imgf000014_0001
oder ein Salz davon mit Ammoniak umsetzen. Dabei arbeitet man beispielsweise unter Erwärmen, z.B. in einem Temperaturbereich von etwa 50° bis etwa 250°C, und unter inerten Bedingungen.
Figure imgf000014_0001
or react a salt thereof with ammonia. This is done, for example, with heating, for example in a temperature range from about 50 ° to about 250 ° C, and under inert conditions.
Die Ausgangsstoffe der Formel (lIla) sind bekannt oder werden nach an sich bekannten Verfahren hergestellt. Beispielsweise geht man von einer Verbindung der Formel (Illb)
Figure imgf000015_0002
oder einem Salz davon aus und setzt diese mit einem Säurederivat der Formel R3-A-COOH (IIIc), beispielsweise einem entsprechenden Anhydrid, wie einer Halogencarbonylverbindung, um.The starting materials of the formula (IIIa) are known or are prepared by processes known per se. For example, one starts from a compound of the formula (Illb)
Figure imgf000015_0002
or a salt thereof and reacts them with an acid derivative of the formula R 3 -A-COOH (IIIc), for example a corresponding anhydride, such as a halocarbonyl compound.
In einer weiteren, besonders bevorzugten Variante des eingangs beschriebenen Verfahrens setzt man eine Verbindung der FormelIn a further, particularly preferred variant of the process described at the outset, a compound of the formula is used
(llld)
Figure imgf000015_0001
worin Z 1gegebenenfalls reaktionsfähiges verestertes Hydroxy bedeutet, oder ein Salz davon mit einer Verbindung der Formel(llld)
Figure imgf000015_0001
wherein Z 1 is optionally reactive esterified hydroxy, or a salt thereof with a compound of the formula
R3 - A - Z2 (Ille), worin Z2 ein Amidinorest oder Ammoniumcarboxylat bedeutet, oder ein Salz davon gegebenenfalls mit Ammoniak um.R 3 - A - Z 2 (Ille), in which Z 2 represents an amidino radical or ammonium carboxylate, or a salt thereof, optionally with ammonia.
Die Umsetzung mit einem Amidin der Formel (Ille) erfolgt üblicherweise unter Erwärmen, beispielsweise in einem Temperaturbereich von etwa 50° bis etwa 250°C.The reaction with an amidine of the formula (IIle) is usually carried out with heating, for example in a temperature range from about 50 ° to about 250 ° C.
Die Reaktion des Ammoniumcarboxylats der Formel (Ille) mit einer Verbindung der Formel (llld) wird mit einem mindestens 3-molaren, oder, falls die Verbindung der Formel (llld) in Salzform vorliegt, mindestens 4-molaren Ueberschuss des Ammoniumsalzes der Verbindung der Formel (Ille), gegebenenfalls unter Erwärmen, z.B. in einem Temperaturbereich von etwa 50° bis etwa 250°C, vorzugsweise bei 90° bis 120°C, durchgeführt, wobei die Verbindung der Formel (Ille) gleichzeitig als Lösungsmittel dienen kann. Diese Variante kann beispielsweise auch dahingehend abgewandelt werden, dass man das Ammoniumsalz der Formel Ille, in bezug auf den reaktionsfähigen Ester Z , in etwa äquimolarer Menge einsetzt und zusätzlich Ammoniak, gegebenenfalls in Form eines Salzes einer gegenüber R3-COOH schwächeren Säure, in überschüssiger Menge, vorzugsweise in 3- bis 5-fachem Ueberschuss, zugibt.The reaction of the ammonium carboxylate of the formula (IIle) with a compound of the formula (IIld) is carried out with an at least 3-molar, or, if the compound of the formula (IIld) is in salt form, at least 4-molar excess of the ammonium salt of the compound of the formula (Ille), optionally with heating, for example in a temperature range from about 50 ° to about 250 ° C, preferably at 90 ° to 120 ° C, wherein the compound of formula (Ille) simultaneously as Solvent can serve. This variant can, for example, also be modified in such a way that the ammonium salt of the formula IIle, in relation to the reactive ester Z, is used in an approximately equimolar amount and, in addition, ammonia, optionally in the form of a salt of an acid which is weaker than R 3 -COOH, in excess Amount, preferably in a 3 to 5-fold excess, is added.
Eine reaktionsfähige veresterte Hydroxygruppe Z1 ist beispielsweise eine vorzugsweise durch starke anorganische oder organische Säuren, wie starke Mineralsäuren, z.B. Halogenwasserstoffsäuren, wie Chloroder Bromwasserstoffsäure, oder starke organische Sulfonsäuren, wie entsprechende Niederalkan- oder Arylsulfonsäuren, z.B. Methan- oder eine gegebenenfalls substituierte Benzolsulfonsäure, veresterte Hydroxygruppe und stellt z.B. Halogen, wie Chlor oder Brom, Niederalkylsulfonyloxy, z.B. Methyl- oder Ethylsulfonyloxy, oder Arylsulfonyloxy, z.B. p-Toluol- oder Benzolsulfonyloxy, dar.A reactive esterified hydroxy group Z 1 is, for example, one which is preferably esterified by strong inorganic or organic acids, such as strong mineral acids, for example hydrohalic acids, such as chlorine or hydrobromic acid, or strong organic sulfonic acids, such as corresponding lower alkane or arylsulfonic acids, for example methane or an optionally substituted benzenesulfonic acid Hydroxy group and represents, for example, halogen, such as chlorine or bromine, lower alkylsulfonyloxy, for example methyl or ethylsulfonyloxy, or arylsulfonyloxy, for example p-toluene or benzenesulfonyloxy.
Das Ammoniumsalz der Formel (Ille) kann auch unter den Reaktionsbedingungen in situ gebildet werden, beispielsweise indem man im Reaktionsgemisch die freie Säure der Formel (Ille) vorlegt und mit flüssigem oder gasförmigem Ammoniak versetzt. Bei dieser Ausführungsform kann das Ammoniak auch in Form eines Salzes mit einer gegenüber R1-A-COOH schwächeren Säure, wie Kohlensäure, zugegeben werden. Als geeignete Lösungsmittel kommen z.B. gegebenenfalls halogenierte Kohlenwasserstoffe, wie gegebenenfalls halogenierte aliphatische, cycloaliphatische oder aromatische Kohlenwasserstoffe, wie Hexan, Cyclohexan, Toluol, Chloroform, oder Chlorbenzol, Alkanole, wie Propanol, Isopropanol, Butanole, Pentanole oder Octanole, Ether, wie Dimethoxyethan, Ethylenglykolmonoethylether, Dioxan oder Tetrahydrofuran, Niederalkancarbonsäuren, wie Ameisen- oder Essigsäure oder vorzugsweise Säuren der Formel (IIIc), Amide, wie Niederalkancarbonsäureamide, z.B. Formamid oder Dimethylformamid, sowie Lactame, z.B. N-Methylpyrrolidon, Sulfoxide, wie Dimethylsulfoxid, oder Wasser in Frage. Eine bevorzugte Ausführung dieser Variante zur erfindungsgemässen Darstellung von Verbindungen der Formel I über Verbindungen der Formel II besteht darin, dass man eine Verbindung der Formel llld, worin Z beispielsweise Halogen, wie Brom, bedeutet, mit einem Ammoniumsalz der Formel (Elle) bei einer Reaktionstemperatur von etwa 100°C umsetzt. Die Verbindung der Formel (Ille) wird im Ueberschuss zugegeben, beispielsweise in einem Verhältnis gegenüber dem Ester der Formel (llld) von etwa 4:1 bis etwa 6:1, und lässt sich in situ bilden, indem man z.B. die entsprechende Säure unter den Reaktionsbedingungen mit flüssigem Ammoniak umsetzt.The ammonium salt of the formula (Ille) can also be formed in situ under the reaction conditions, for example by introducing the free acid of the formula (Ille) in the reaction mixture and adding liquid or gaseous ammonia. In this embodiment, the ammonia can also be added in the form of a salt with an acid which is weaker than R 1 -A-COOH, such as carbonic acid. Suitable solvents are, for example, optionally halogenated hydrocarbons, such as optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbons, such as hexane, cyclohexane, toluene, chloroform, or chlorobenzene, alkanols, such as propanol, isopropanol, butanols, pentanols or octanols, ethers, such as dimethoxyethane, ethylene glycol monoethyl ether , Dioxane or tetrahydrofuran, lower alkanecarboxylic acids, such as formic or acetic acid or preferably acids of the formula (IIIc), amides, such as lower alkanecarboxamides, for example formamide or dimethylformamide, and lactams, for example N-methylpyrrolidone, sulfoxides, such as dimethyl sulfoxide, or water. A preferred embodiment of this variant for the preparation of compounds of the formula I according to the invention via compounds of the formula II is that a compound of the formula IIId, in which Z is, for example, halogen, such as bromine, with an ammonium salt of the formula (III) at a reaction temperature of about 100 ° C. The compound of the formula (III) is added in excess, for example in a ratio to the ester of the formula (IIld) of about 4: 1 to about 6: 1, and can be formed in situ by, for example, the corresponding acid among the Reacts reaction conditions with liquid ammonia.
Die Ausgangsstoffe der Formel (llld) sind bekannt oder können nach an sich bekannten Verfahren hergestellt werden.The starting materials of the formula (IIld) are known or can be prepared by processes known per se.
So lassen sie sich beispielsweise durch Esterkondensation von veresterten Säuren der Formeln R1-CH2-COOH bzw. R2-CH2-COOH mit veresterten Säuren der Formeln R1-COOH bzw. R2-COOH, vorzugsweise in Gegenwart einer Base erhalten. Das resultierende α-Methylenketon der FormelThey can be obtained, for example, by ester condensation of esterified acids of the formulas R 1 -CH 2 -COOH or R 2 -CH 2 -COOH with esterified acids of the formulas R 1 -COOH or R 2 -COOH, preferably in the presence of a base . The resulting α-methylene ketone of the formula
(IIIf)
Figure imgf000017_0001
wird beispielsweise bromiert und somit in eine Verbindung der Formel (llld) bzw. ein Salz, z.B. Hydrohalogenid, davon überführt, worin Z1 Brom bedeutet.(IIIf)
Figure imgf000017_0001
is brominated, for example, and thus converted into a compound of the formula (IIld) or a salt thereof, for example hydrohalide, in which Z 1 denotes bromine.
Ausserdem kann man in einer weiteren bevorzugten Ausführungsform ein Oxazol der FormelIn a further preferred embodiment, an oxazole of the formula can also be used
(Illg)
Figure imgf000017_0002
mit Ammoniak über Verbindungen der Formel II zu Verbindungen der Formel I umsetzen. Diese Reaktion wird gegebenenfalls unter Druck, beispielsweise bei 185 atü, und/oder Erwärmen, z.B. auf etwa 100° bis etwa 250°C, durchgeführt.(Illg)
Figure imgf000017_0002
react with ammonia via compounds of the formula II to give compounds of the formula I. This reaction is optionally carried out under pressure, for example at 185 atm, and / or heating, for example at about 100 ° to about 250 ° C.
Die Verbindungen der Formel (Illg) ihrerseits lassen sich nach an sich bekanntem Verfahren herstellen, beispielsweise durch Umsetzung von Verbindungen der FormelFor their part, the compounds of the formula (III) can be prepared by a process known per se, for example by reacting compounds of the formula
(Illh),
Figure imgf000018_0001
worin Z1 gegebenenfalls reaktionsfähiges verestertes Hydroxy bedeutet, mit einer Carboπsäure der Formel R3-A-COOH (IIIc), einem funktionellen Derivat oder Salz davon, wie einem entsprechenden Anhydrid, z.B. einem Halogencarbonylderivat, gegebenenfalls über eine Verbindung der Formel(Illh),
Figure imgf000018_0001
wherein Z 1 is optionally reactive esterified hydroxy, with a carboxylic acid of the formula R 3 -A-COOH (IIIc), a functional derivative or salt thereof, such as a corresponding anhydride, for example a halocarbonyl derivative, optionally via a compound of the formula
R2-C(=0)-CH(R1)-O-C(=O)-A-R3 (Illi), und mit Ammoniak.R 2 -C (= 0) -CH (R 1 ) -OC (= O) -AR 3 (Illi), and with ammonia.
Dabei wird jeweils eine Verbindung der Formel II gebildet, die erfindungsgemäss, insbesondere in situ, zu einer Verbindung der Formel I weiterreagiert.A compound of the formula II is formed in each case, which according to the invention, in particular in situ, further reacts to a compound of the formula I.
In einer weiteren bevorzugten Ausführungsform des vorstehenden Verfahrens kann man beispielsweise das Diketon der FormelIn a further preferred embodiment of the above process, for example, the diketone of the formula
Figure imgf000018_0002
mit einem Aldehyd der Formel R3-A-C(=O)-H (Illl) oder einem Salz davon, und mit einem Ueberschuss an Ammoniak unter Erwärmen umsetzen. Dabei wird beispielsweise intermediär eine Verbindung der Formel (II), z.B. eine solche, worin Y1 Hydroxy, Y2 sowie Y6 Wasserstoff bedeuten und Y3 gemeinsam mit Y4 und Y5 eine Gruppe der Formel =N- darstellt, z.B.
Figure imgf000018_0002
with an aldehyde of the formula R 3 -AC (= O) -H (III) or a salt thereof, and with an excess of ammonia with heating. For example, a compound of the formula (II), for example one in which Y 1 is hydroxyl, Y 2 and Y 6 are hydrogen and Y 3 together with Y 4 and Y 5 is a group of the formula = N -, for example
(IIlm) oder eine tautomere Form
Figure imgf000019_0001
davon gebildet, die unter den Reaktionsbedingungen erfindungsgemäss weiterreagiert.(IIlm) or a tautomeric form
Figure imgf000019_0001
formed thereof, which continues to react according to the invention under the reaction conditions.
Dabei wird j eweils eine Verbindung der Formel II gebildet, die erfindungsgemäss, insbesondere in situ, zu einer Verbindung der Formel I weiterreagiert.In this case, a compound of the formula II is in each case formed, which according to the invention, in particular in situ, further reacts to a compound of the formula I.
Einige der vorstehend beschriebenen Verfahrensvarianten lassen sich durch Anwendung milder Bedingungen so durchführen, dass die Verbindungen der Formel II bzw. ihre Tautomeren und/oder Salze isoliert werden können.Some of the process variants described above can be carried out by using mild conditions so that the compounds of the formula II or their tautomers and / or salts can be isolated.
Verbindungen der Formel I oder Salze davon kann man weiterhin herstellen, indem man beispielsweise eine Verbindung der FormelCompounds of the formula I or salts thereof can also be prepared by, for example, a compound of the formula
(IV)
Figure imgf000019_0002
oder ein Salz davon zu einer Verbindung der Formel I reduziert und gewünschtenfalls die verfahrensgemäss erhältliche freie Verbindung in ein Salz oder ein verfahrensgemäss erhältliches Salz in die freie Verbindung oder in ein anderes Salz überführt. Die Reduktion erfolgt nach an sich bekannten Verfahren. So behandelt man Verbindungen der Formel (IV) oder deren Salze mit Wasserstoff in Gegenwart eines Hydrierungskatalysators oder mit einem Dithionit, z.B. Natriumdithionit, oder mit einem Phosphorhalogenid, z.B. Phosphortrichlorid. Als Hydrierungskatalysatoren lassen sich beispielsweise Elemente der VIII. Nebengruppe sowie Derivate davon, wie Platin, Palladium oder Palladiumchlorid, die gegebenenfalls auf einem üblichen Trägermaterial, wie Aktivkohle oder Erdalkalimetallverbindungen, z.B. Bariumcarbonat, aufgezogen sind, oder Raney-Nickel, verwenden.(IV)
Figure imgf000019_0002
or a salt thereof is reduced to a compound of formula I and, if desired, the process-available free compound is converted into a salt or a process-available salt into the free compound or into another salt. The reduction takes place according to methods known per se. Thus, compounds of the formula (IV) or their salts are treated with hydrogen in the presence of a hydrogenation catalyst or with a dithionite, for example sodium dithionite, or with a phosphorus halide, for example phosphorus trichloride. Examples of hydrogenation catalysts which can be used are elements of subgroup VIII and derivatives thereof, such as platinum, palladium or palladium chloride, which are optionally supported on a customary support material, such as activated carbon or alkaline earth metal compounds, for example barium carbonate, or Raney nickel.
Die Reduktion lässt sich erforderlichenfalls unter Kühlen oder Erwärmen, beispielsweise in einem Temperaturbereich von etwa 0° bis etwa 150°C, in einem inerten Lösungsmittel, wie einem halogenierten Kohlenwasserstoff, z.B. Chloroform, Tetrachlorkohlenstoff oder Chlorbenzol, oder einem Ether, wie Dimethoxyethan, Diethylether, Dioxan oder Tetrahydrofuran, und/oder unter Inertgas, z.B. Stickstoffdurchführen.The reduction can be carried out, if necessary, with cooling or heating, for example in a temperature range from about 0 ° to about 150 ° C, in an inert solvent such as a halogenated hydrocarbon, e.g. Chloroform, carbon tetrachloride or chlorobenzene, or an ether such as dimethoxyethane, diethyl ether, dioxane or tetrahydrofuran, and / or under inert gas, e.g. Perform nitrogen.
Das vorstehend beschriebene Herstellungsverfahren wird in erster Linie mit solchen Verbindungen der Formel (IV) durchgeführt, worin R3 acetalisiertes Formyl darstellt.The preparation process described above is carried out primarily with those compounds of the formula (IV) in which R 3 is acetalized formyl.
Die Ausgangsstoffe der Formel IV oder deren Salze sind in an sich bekannter Weise erhältlich, beispielsweise in dem eine Verbindung der FormelThe starting materials of the formula IV or their salts are obtainable in a manner known per se, for example in that of a compound of the formula
((IIaa),
Figure imgf000020_0001
ein Tautomeres oder ein Salz davon in situ mit einem Ueberschuss an Ammoniak und einem Aldehyd der Formel R3-A-C(=O)-H (IIll) bei erhöhter Temperatur umsetzt. Verbindungen der Formel I lassen sich ferner herstellen, indem man in einer Verbindung der Formel((IIaa),
Figure imgf000020_0001
a tautomer or a salt thereof is reacted in situ with an excess of ammonia and an aldehyde of the formula R 3 -AC (= O) -H (IIll) at elevated temperature. Compounds of formula I can also be prepared by in a compound of formula
(v),
Figure imgf000021_0001
worin R' einen im R überführbaren Rest bedeutet, den Rest R' in einen Rest R überführt und gewünschtenfalls die verfahrensgemäss erhältliche freie Verbindung in ein Salz oder ein verfahrensgemäss erhältliches Salz in die freie Verbindung oder in ein anderes Salz überführt.(v),
Figure imgf000021_0001
wherein R 'denotes a radical which can be converted into R, converts the radical R' into a radical R and, if desired, converts the free compound obtainable according to the process into a salt or a salt obtainable according to the process into the free compound or into another salt.
Derartige Gruppen R'3 sind beispielsweise reduktiv in den Rest R3 überführbare Gruppen, wie gegebenenfalls funktionell abgewandeltes Carboxy. Insbesondere werden Carboxy, Halogencarbonyl, Niederalkoxycarbonyl oder Carbamoyl R'3 durch Reduktion in Formyl R3 überführt.Such groups R ' 3 are, for example, groups which can be reductively converted into the radical R 3 , such as functionally modified carboxy. In particular, carboxy, halocarbonyl, lower alkoxycarbonyl or carbamoyl R ' 3 are converted into formyl R 3 by reduction.
Die Reduktion der genannten Reste R'3 erfolgt in an sich bekannter Weise, beispielsweise unter Verwendung eines geeigneten Reduktionsmittels in einem inerten Lösungsmittel, gegebenenfalls unter Kühlen oder Erwärmen. So wird beispielsweise Halogencarbonyl durch Wasserstoff an Edelmetallkatalysatoren, wie Palladium, welche gegebenenfalls an Trägermaterialien, wie Bariumsulfat, gebunden sind, zu Formyl reduziert, während Reduktion von Carboxy zu Formyl beispielsweise mit Hilfe von Ameisensäure. oder gegebenenfalls komplexen Hydriden, wie Lithiumaluminiumhydrid oder Lithyium-tri-tert.-butoxy- oder Lithium-triethoxy-aluminat, reduziert wird. Ebenso kann Niederalkoxycarbonyl bzw. Carbamoyl mit Hilfe von geeigneten gegebenenfalls komplexen Hydriden reduktiv zu Formyl reduziert werden.The radicals R ' 3 mentioned are reduced in a manner known per se, for example using a suitable reducing agent in an inert solvent, if appropriate with cooling or heating. For example, halocarbonyl is reduced to formyl by hydrogen on noble metal catalysts, such as palladium, which are optionally bound to support materials, such as barium sulfate, while reduction of carboxy to formyl, for example with the help of formic acid. or optionally complex hydrides, such as lithium aluminum hydride or lithium tri-tert-butoxy or lithium triethoxy aluminate, is reduced. Lower alkoxycarbonyl or carbamoyl can likewise be reduced reductively to formyl with the aid of suitable optionally complex hydrides.
Weitere in R3 überführbare Gruppen sind beispielsweise oxidativ in diesen überführbare Reste, wie gegebenenfalls verestertes oder verethertes Hydroxymethyl. Verestertes Hydroxymethyl ist beispielsweise mit einer Mineralsäure, wie Halogenwasserstoff-, wie Chlorwasserstoffsäure, oder einer Carbonsäure, wie Niederalkancarbonsäure, z.B. Essigsäure, öder gegebenenfalls substituierten Benzoesäure verestertes Hydroxymethyl. Verethertes Hydroxymethyl ist beispielsweise mit einem Niederalkanol verethert.Further groups which can be converted into R 3 are, for example, residues which can be converted into them oxidatively, such as, if appropriate, esterified or etherified hydroxymethyl. Esterified hydroxymethyl is, for example, hydroxymethyl esterified with a mineral acid, such as hydrohalic acid, such as hydrochloric acid, or a carboxylic acid, such as lower alkane carboxylic acid, for example acetic acid, or optionally substituted benzoic acid. Etherified hydroxymethyl is etherified with a lower alkanol, for example.
Die Oxidation derartiger Gruppen R'3 erfolgt in an sich bekannter Weise, beispielsweise durch Umsetzung in einem geeigneten Oxidationsmittel, beispielsweise in einem inerten Lösungsmittel, wie einer Niederalkylcarbonsäure z.B. Essigsäure, einem Keton, z.B. Aceton, einem Ether, z.B. Tetrahydrofuran, einem heterocyclischen Aromaten, z.B. Pyridin, oder Wasser oder einem Gemisch davon, erforderlichenfalls unter Kühlen oder Erwärmen, z.B. von etwa 0° bis etwa 150°C. Als Oxidationsmittel kommen beispielsweise oxidierende Uebergangsmetallverbindungen, insbesondere solche mit Elementen der I., VI., VII., oder VIII. Nebengruppe, in Frage. Als Beispiele seien genannt: Silberverbindungen, wie Silbemitrat, -oxid oder picolinat, Chromverbindungne, wie Chromtrioxid oder Kaliumdichromat, Manganverbindungen, wie Tetrabutylammonium- oder Benzyl(triethyl)-ammoniumpermanganat, ferner Eisenverbindungen, wie Kaliumferrat. Insbesondere werden selektive Oxidationsmittel verwendet, wie Pyridiniumchlorochromat, ein geeignetes Keton, wie Cyclohexanon in Gegenwart von Aluminium-tert.-butylat, oder, wenn Hydroxymethyl mit p-Toluolsulfonsäure reaktionsfähig verestert ist, Dirnethylsulfoxid.The groups R ' 3 of this type are oxidized in a manner known per se, for example by reaction in a suitable oxidizing agent, for example in an inert solvent such as a lower alkyl carboxylic acid, for example acetic acid, a ketone, for example acetone, an ether, for example tetrahydrofuran, a heterocyclic aromatic, eg pyridine, or water or a mixture thereof, if necessary with cooling or heating, for example from about 0 ° to about 150 ° C. Examples of suitable oxidizing agents are oxidizing transition metal compounds, in particular those with elements of sub-groups I, VI, VII, or VIII. Examples include: silver compounds, such as silver nitrate, oxide or picolinate, chromium compounds, such as chromium trioxide or potassium dichromate, manganese compounds, such as tetrabutylammonium or benzyl (triethyl) ammonium permanganate, and also iron compounds, such as potassium ferrate. In particular, selective oxidizing agents are used, such as pyridinium chlorochromate, a suitable ketone, such as cyclohexanone in the presence of aluminum tert-butoxide, or, if hydroxymethyl has been reactively esterified with p-toluenesulfonic acid, dirnethyl sulfoxide.
So wird beispielsweise Hydroxymethyl R'3 mit Bis-tetrabutylammoniumdichromat, während z.B. mit Chlorwasserstoffsäure verestertes Hydroxymethyl R'3 mit 4-Dimethylamino-pyridin-N-oxid zu Formyl R3 oxidiert wird.Thus hydroxymethyl R is, for example, 3 is oxidized with 4-dimethylamino-pyridine-N-oxide to formyl R 3 '3, while, for example esterified with hydrochloric acid bis-hydroxymethyl R tetrabutylammoniumdichromat with'.
Weitere, in R3 überführbare Gruppe R'3 sind funktionell abgewandelte Formylgruppen oder durch Schutzgruppen geschütztes Formyl. Funktionell abgewandeltes Formyl weist als funktionell abgewandeltes Oxo beispielsweise Thioxo, gegebenenfalls N-substituiertes Imino, wie N-Niederalkyl oder N-Phenyl-imino, Hydroxyimino, gegebenenfalls substituiertes Hydrazono, wie N-Tosyl- oder N,N-Diniederalkyl-hydrazono, auf. Derartig funktionell abgewandeltes Formyl wird in üblicher Weise hydrolytisch, erforderlichenfalls in Gegenwart einer Protonsäure, in Formyl R3 übergeführt. Durch Schutzgruppen geschütztes Formyl ist beispielsweise mit einem Mercaptan, wie Niederalkandiol oder Niederalkylendiol, oder mit einem Mercaptan und Alkohol, wie Niederalkanol und Niederalkan thiol oder Mercaptoniederalkanol, acetalisiertes Formyl. Weiterhin kann Formyl als Di- oder Tetrahydro-1,3-oxazin, wie 3,3,5-Trimethyl-1,3- oxazin-2-yl, oder als Imidazolidin, wie gegebenenfalls N-mono- oder N,N-disubstituiertes Imidazolidin-2-yl, sowie als Halbacetal mit einem Alkohol, wie Niederalkanol, oder mit einem Mercaptan, wie Niederalkan thiol, vorliegen. Entsprechende Schutzgruppen können oxidativ, hydrolytisch, erforderlichenfalls in Gegenwart einer Protonsäure abgespaltet, werden. Insbesondere werden entsprechende Thioacetale, bzw. -halbacetale oxidativ, beispielsweise unter Einwirkung von N-Bromsuccinimid, Chloramin-T, Thallium-(III)-nitrit, Schwermetallverbindungen, z.B. Quecksilber(II) oxid, Kuρfer(II)oxidbarchlorid, oder elektrochemisch in Formyl übergeführt werden, während aus entsprechenden Oxazin- bzw. ImidazolidinDerivaten sowie Halbacetalen mit Niederalkanolen der Rest Formyl hydrolytisch in Gegenwart von starken Protonsäure, wie Mineralsäuren, z.B. Schwefelsäure, Halogenwasserstoffsäuren oder Phosphorsäuren, wie Sulfonsäuren, z.B. p-Toluolsulfonsäure, oder wie Carbonsäuren, z.B. Eisessig, freigesetzt werden.Further groups R ' 3 which can be converted into R 3 are functionally modified formyl groups or formyl protected by protective groups. Functional modified formyl has, for example, thioxo, optionally N-substituted imino, such as N-lower alkyl or N-phenyl-imino, hydroxyimino, optionally substituted hydrazono, such as N-tosyl- or N, N-di-lower alkyl-hydrazono, as the functionally modified oxo. Functionally modified formyl of this type is converted into formyl R 3 in a conventional manner hydrolytically, if necessary in the presence of a protonic acid. Protected formyl is, for example, acetalized formyl with a mercaptan, such as lower alkanediol or lower alkylene diol, or with a mercaptan and alcohol, such as lower alkanol and lower alkane thiol or mercapto lower alkanol. Formyl can furthermore be used as di- or tetrahydro-1,3-oxazine, such as 3,3,5-trimethyl-1,3-oxazin-2-yl, or as imidazolidine, such as optionally N-mono- or N, N-disubstituted Imidazolidin-2-yl, and as a hemiacetal with an alcohol, such as lower alkanol, or with a mercaptan, such as lower alkane thiol. Corresponding protective groups can be split off oxidatively, hydrolytically, if necessary in the presence of a protonic acid. In particular, corresponding thioacetals or halfacetals become oxidative, for example under the action of N-bromosuccinimide, chloramine-T, thallium (III) nitrite, heavy metal compounds, for example mercury (II) oxide, copper (II) oxide bar chloride, or electrochemically in formyl are converted, while from the corresponding oxazine or imidazolidine derivatives and hemiacetals with lower alkanols, the rest of formyl is hydrolytically reacted in the presence of strong protonic acid, such as mineral acids, for example sulfuric acid, hydrohalic acids or phosphoric acids, such as sulfonic acids, for example p-toluenesulfonic acid, or for carboxylic acids, for example glacial acetic acid, to be released.
Die AusgangsStoffe der Formel V werden nach an sich bekannten Verfahren hergestellt. Beispielsweise geht man von einem Diketon der FormelThe starting materials of the formula V are prepared by processes known per se. For example, one starts from a diketone of the formula
R1 - C = 0R 1 - C = 0
R2 - C = 0 <IIIk>R 2 - C = 0 <IIIk>
aus und setzt dieses mit Ammoniak und einem Aldehyd der Formel R'3-A-C(=O)-H in einem inerten Lösungsmittel und unter Erwärmen in die in situ gebildete Verbindung der Formel V ohne Isolierung weiter um.and sets this with ammonia and an aldehyde of the formula R ' 3 -AC (= O) -H in an inert solvent and with heating in the compound of formula V formed in situ without isolation.
Der Aldehyd der Formel R3-A-C(=O)-H (III1) kann in den vorstehend beschriebenen Herstellungsverfahren für Verbindungen der Formeln II und IV beispielsweise auch unter den Reaktionsbedingungen aus einem Oxazinderivat der FormelThe aldehyde of the formula R 3 -AC (= O) -H (III1) can also be prepared, for example, under the reaction conditions from an oxazine derivative of the formula in the preparation processes for compounds of the formulas II and IV described above
Figure imgf000024_0001
freigesetzt werden. Die Verbindungen der Formel (V) lassen sich beispielsweise herstellen, indem man 2-Methyl-2,4-pentandiol mit einem Nitril der Formel R3-A-CN in Gegenwart von Schwefelsäure umsetzt. Das dabei gebildete, entsprechend substituierte Dihydro-1,3-oxazin wird in einem Gemisch aus Tetrahydrofuran und Ethanol bei -45°C und einem pH-Wert von etwa 7 unter Einwirkung von Natriumborhydrid zu dem Tetrahydro-1,3-oxazin der Formel V reduziert.
Figure imgf000024_0001
to be released. The compounds of the formula (V) can be prepared, for example, by reacting 2-methyl-2,4-pentanediol with a nitrile of the formula R 3 -A-CN in the presence of sulfuric acid. The correspondingly substituted dihydro-1,3-oxazine formed in this way is converted into the tetrahydro-1,3-oxazine of the formula V in a mixture of tetrahydrofuran and ethanol at -45 ° C. and a pH of about 7 under the action of sodium borohydride reduced.
In den vorstehend beschriebenen Verfahren zur Herstellung von Verbindungen der Formeln II, IV und V kann das Ammoniak, welches überwiegend im Ueberschuss zugegeben wird, auch in Form eines Ammoniak abgebenden Mittels eingesetzt werden, wobei die Freisetzung bei erhöhter Temperatur und gegebenenfalls unter Druck erfolgt. Als Ammoniak abgebende Mittel kommen z.B. Ammoniumsalze von Niederalkancarbonsäuren, vorzugsweise Ammoniumacetat, oder einer Carbonsäure der Formel R3-A-COOH, ferner ein geeignetes Niederalkancarbonsäureamid, insbesondere Formamid, in Frage.In the processes for the preparation of compounds of the formulas II, IV and V described above, the ammonia, which is predominantly added in excess, can also be used in the form of an ammonia-donating agent, the release taking place at elevated temperature and, if appropriate, under pressure. Examples of suitable ammonia-releasing agents are ammonium salts of lower alkanecarboxylic acids, preferably ammonium acetate, or a carboxylic acid of the formula R 3 -A-COOH, and a suitable lower alkanecarboxamide, in particular formamide.
Eine erfindungsgemäss erhältliche Verbindung kann in üblicher Weise in eine andere Verbindung der Formel I überführt werden. Ein verfahrensgemäss erhältliches Acetal der Formel I (R'3 = acetalisiertes Formyl) kann in üblicher Weise, erforderlichenfalls in Gegenwart eines geeigneten Hydrolysemittels zu einem Aldehyd der Formel I (R'3 = gegebenenfalls hydratisiertes Formyl) hydrolysiert werden. Geeignete Hydrolysemittel sind beispielsweise Protonensäuren, wie Mineralsäuren, z.B. Chlor- oder Bromwasserstoffsäure, Schwefelsäure oder Phosphorsäure, oder organische Carbon- oder Sulfonsäuren, wie Nieder alkansäuren, z.B. Essigsäure, oder Niederalkyl- bzw. Arylsulfonsäure, z.B. p-Toluolsulfonsäure. Umgekehrt kann man einen verfahrensgemäss erhältlichen Aldehyd (I, R'3 = Formyl) in üblicher Weise, z.B. durch Umsetzung mit dem entsprechenden Alkohol in Gegenwart eines sauren Kondensationsmittels, wie einer Mineralsäure oder organischen Sulfonsäure, vorteilhaft unter destillativer bzw. azeotrop-destillativer Entfernung des Reaktionswassers, oder durch Umsetzung mit einem Orthocarbonsäureester, z.B. einem Orthoameisensäureniederalkylester, oder mit einem Acetal, bzw. Ketal einen z.B. mit Benzaldehyddiniederalkylacetal bzw. -niederalkylenacetal bzw. einem Acetophenon-diniederalkylketal bzw.-niederalkylenketal, vorteilhaft in Gegenwart katalytischer Mengen einer Mineral- oder Sulfonsäure, z.B. von Chlorwasserstoff- oder p-Toluolsulfonsäure, in Acetale (I, Rl = acetalisiertes' Formyl) überführen.A compound obtainable according to the invention can be converted in a conventional manner into another compound of the formula I. An acetal of the formula I (R ' 3 = acetalized formyl) obtainable according to the process can be hydrolyzed in a customary manner, if necessary in the presence of a suitable hydrolysis agent, to give an aldehyde of the formula I (R' 3 = optionally hydrated formyl). Suitable hydrolysis agents are, for example, protonic acids, such as mineral acids, for example hydrochloric acid or hydrobromic acid, sulfuric acid or phosphoric acid, or organic carboxylic or sulfonic acids, such as lower alkanoic acids, for example acetic acid, or lower alkyl or arylsulfonic acid, for example p-toluenesulfonic acid. Conversely, an aldehyde (I, R ' 3 = formyl) obtainable according to the process can be used in the customary manner, for example by reaction with the corresponding alcohol in the presence of an acidic condensing agent, such as a mineral acid or organic sulfonic acid, advantageously with the distillative or azeotropic-distillative removal of the Water of reaction, or by reaction with an orthocarboxylic acid ester, for example a lower alkyl orthoformate, or with an acetal or ketal, for example with benzaldehyde din-lower alkyl acetal or lower alkylene acetal or an acetophenone-lower alkyl ketal or lower alkylene ketal, advantageously in the presence of catalytic amounts of a mineral or sulfonic acid , for example from hydrochloric acid or p-toluenesulfonic acid, into acetals (I, Rl = acetalized 'formyl).
Enthält mindestens einer der Substituenten R1, R2 und R3 als zusätzlichen Substituenten Hydroxy, so lässt sich dieser nach an sich bekannter Weise verethern. Die Umsetzung mit einer Alkoholkomponente, z.B. mit einem Niederalkanol, wie Ethanol, in Gegenwart von Säuren, z.B. Mineralsäure, wie Schwefelsäure, oder von Dehydratisierungsmitteln, wie Dicyclohexylcarbodiimid, führt zu Niederalkoxy.Phenole bzw. deren Salze lassen sich z.B. in Gegenwart von Basen, wie Alkalimetallhydroxiden oder -carbonaten, z.B. Natriumhydroxid oder Kaliumcarbonat, mit Hilfe von Diniederalkylsulfaten, Diazoniederalkanen oder Alkyl- bzw. Arylhalogeniden in entsprechende Niederalkylphenylether bzw. Arylphenylether überführen. Umgekehrt kann man Ether in Alkohole spalten. So entstehen z.B. aus Alkoxyarylverbindungen aromatische Alkohole, indem man die Etherspaltung mittels Säuren, wie Mineralsäuren, z.B. Halogenwasserstoffsäure, wie Bromwasserstoffsäure, oder wie Lewissäuren, z.B. Halogeniden von Elementen der 3. Hauptgruppe, wie Bortribromid, oder mittels Basen, z.B. Niederalkylaminen, wie Methylamin, durchführt.If at least one of the substituents R 1 , R 2 and R 3 contains hydroxy as additional substituents, this can be etherified in a manner known per se. The reaction with an alcohol component, e.g. with a lower alkanol, such as ethanol, in the presence of acids, e.g. mineral acid, such as sulfuric acid, or of dehydrating agents, such as dicyclohexylcarbodiimide, leads to lower alkoxy.Phenols or their salts can be used, for example, in the presence of bases, such as alkali metal hydroxides or carbonates, e.g. Sodium hydroxide or potassium carbonate, with the aid of di-lower alkyl sulfates, diazo-lower alkanes or alkyl or aryl halides, convert into corresponding lower alkyl phenyl ether or arylphenyl ether. Conversely, ethers can be split into alcohols. For example, aromatic alcohols are formed from alkoxyaryl compounds by ether cleavage using acids, such as mineral acids, for example hydrohalic acid, such as hydrobromic acid, or Lewis acids, for example halides of elements of main group 3, such as boron tribromide, or using bases, for example lower alkylamines, such as methylamine. carries out.
Weiterhin lässt sich Hydroxy in Niederalkanoyloxy umwandeln, beispielsweise durch Umsetzung mit einer gewünschten Niederalkancarbonsäure, wie Essigsäure oder einem reaktionsfähigen Derivat davon, beispielsweise in Gegenwart einer Säure, wie eine Protonsäure, z.B.Hydroxy can also be converted to lower alkanoyloxy, for example by reaction with a desired lower alkanecarboxylic acid such as acetic acid or a reactive derivative thereof, for example in the presence of an acid such as a protonic acid e.g.
Chlor-, Bromwasserstoff-, Schwefel-, Phosphor- oder einer Benzolsulfonsäure, in Gegenwart- einer Lewissäure, z.B. von Bortrifluorid Etherat, oder in Gegenwart eines wasserbindenden Mittels. Umgekehrt, kann verestertes Hydroxy, z.B. durch Basen-Katalyse, zu Hydroxy solvolysiert werden.Chloric, hydrobromic, sulfuric, phosphoric or a benzenesulfonic acid, in the presence of a Lewis acid, e.g. of boron trifluoride etherate, or in the presence of a water-binding agent. Conversely, esterified hydroxy, e.g. by base catalysis to be solvolysed to hydroxy.
Erhaltene freie Verbindungen der Formel I können in an sich bekannter Weise in Salze überführt werden. Hydroxy aufweisende Gruppen R1 bzw. R2 werden mit entsprechenden Basen wie Alkalimetallhydroxiden, in die eingangs aufgeführten Salze mit Basen, oder durch Behandeln mit einer wie vorstehend aufgeführten, Säureadditionssalze bildenden Säureadditionssalze umgewandelt werden. Erhaltene Salze können in an sich bekannter Weise in die freien Verbindungen umgewandelt werden, z.B. durch Behandeln mit einem sauren Reagenz, wie einer Mineralsäure, bzw. einer Base, z.B. Alkalihydroxid.Free compounds of the formula I obtained can be converted into salts in a manner known per se. Hydroxy-containing groups R 1 or R 2 are converted with appropriate bases such as alkali metal hydroxides, into the salts with bases mentioned at the beginning, or by treatment with an acid addition salt forming acid addition salts as mentioned above. Salts obtained can be converted into the free compounds in a manner known per se, for example by treatment with an acidic reagent, such as a mineral acid, or a base, for example alkali metal hydroxide.
Infolge der engen Beziehung zwischen der neuen Verbindung in freier Form und in Form ihrer Salze sind im vorausgegangenen und nachfolgend unter der freien Verbindung oder ihren Salzen sinn- und zweck gemäss gegebenenfalls auch die entsprechenden Salze bzw. die freie Verbindung zu verstehen.As a result of the close relationship between the new compound in free form and in the form of its salts, the preceding compound and the following are also to be understood as meaning and purpose according to the free compound or its salts, if appropriate also the corresponding salts or the free compound.
Die Verbindungen der Formel (I) kann, je nach der Wahl der Ausgangsstoffe und Arbeitsweisen, in Form eines der möglichen Isomeren oder als Gemische derselben vorliegen.Depending on the choice of starting materials and procedures, the compounds of the formula (I) can be present in the form of one of the possible isomers or as mixtures thereof.
Die Verbindung der Formel (I) einschliesslich ihre Salze kann auch in Form ihrer Hydrate erhalten werden oder andere zur Kristallisation verwendete Lösungsmittel einschliessen.The compound of formula (I), including its salts, can also be obtained in the form of its hydrates or include other solvents used for crystallization.
Die Verbindungen der Formel (I) können, je nach der Wahl der Ausgangsstoffe und Arbeitsweisen, in Form eines der möglichen Isomeren oder als Gemische derselben, z.B. je nach der Anzahl der asymmetrischen Kohlenstoffatome als reine optische Isomere, wie Antipoden, oder als Isomerengemische, wie Racemate, Diastereoisomerengemische oder Racematgemische, ferner als Tautomere vorliegen.The compounds of formula (I) can, depending on the choice of starting materials and procedures, in the form of one of the possible isomers or as mixtures thereof, e.g. depending on the number of asymmetric carbon atoms as pure optical isomers, such as antipodes, or as isomer mixtures, such as racemates, diastereoisomer mixtures or racemate mixtures, are also present as tautomers.
Erhaltene Diastereomerengemische und Racematgemische können auf Grund der physikalisch-chemischen Unterschiede der Bestandteile in bekannter Weise in die reinen Isomeren, Diastereomeren oder Racemate aufgetrennt werden, beispielsweise durch Chromatographie und/oder fraktionierte Kristallisation. Erhaltene Racemate lassen sich ferner nach bekannten Methoden in die optischen Antipoden zerlegen, beispielsweise durch Umkristallisation aus einem optisch aktiven Lösungsmittel, mit Hilfe von Mikroorganismen oder durch Umsetzung eines sauren Endstoffes mit einer mit der racemischen Säure Salze bildenden optisch aktiven Base und Trennung der auf diese Weise erhaltenen Salze, z.B. auf Grund ihrer verschiedenen Löslichkeiten, in die Diastereomeren, aus denen die Antipoden durch Einwirkung geeigneter Mittel freigesetzt werden können, zerlegt. Vorteilhaft isoliert man den wirksameren der beiden Antipoden.Diastereomer mixtures and racemate mixtures obtained can be separated into the pure isomers, diastereomers or racemates in a known manner on account of the physico-chemical differences in the constituents, for example by chromatography and / or fractional crystallization. Racemates obtained can furthermore be broken down into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, with the aid of microorganisms or by reaction of an acidic end product with an optically active base which forms salts with the racemic acid and separation of the salts obtained in this way, for example because of their different solubilities, into the diastereomers from which the antipodes can be released by the action of suitable agents. It is advantageous to isolate the more effective of the two antipodes.
Die Erfindung betrifft auch diejenigen Ausführungsformen des Verfahrens, nach denen man von einer auf irgendeiner Stufe des Verfahrens als Zwischenprodukt erhältlichen Verbindungen ausgeht und die fehlenden Schritte durchführt oder einen Ausgangsstoff in Form eines Salzes verwendet oder insbesondere unter den Reaktionsbedingungen bildet.The invention also relates to those embodiments of the process according to which one starts from a compound obtainable as an intermediate at any stage of the process and carries out the missing steps or uses a starting material in the form of a salt or in particular forms under the reaction conditions.
Die Ausgangsstoffe der Formeln II, IV und V, die speziell für die Herstellung der erfindungsgemässen Verbindungen entwickelt wurden, die Verfahren zu ihrer Herstellung sowie ihre Verwendung bilden ebenfalls einen Gegenstand der Erfindung.The starting materials of the formulas II, IV and V, which were specially developed for the preparation of the compounds according to the invention, the processes for their preparation and their use likewise form a subject of the invention.
Bei den erfindungsgemässen pharmazeutischen Präparaten, welche die erfindungsgemässe Verbindung oder pharmazeutisch verwendbaren Salze davon enthalten, handelt es sich vorzugsweise um solche zur topischen Anwendung an Warmbrüter(n), wobei der pharmakologische Wirkstoff allein oder zusammen mit einem pharmazeutisch anwendbaren Trägermaterial enthalten ist. Die tägliche Dosierung des Wirkstoffs hängt von dem Alter und dem individuellen Zustand sowie von der Applicationsweise ab. Entsprechende Mittel mit einem Konzentrationsbereich von etwa 1 bis etwa 10 % G/G, z.B. in Form von Cremen, Salben oder Lösungen, können beispielsweise 2 bis 3 x täglich appliziert werden.The pharmaceutical preparations according to the invention, which contain the compound according to the invention or pharmaceutically usable salts thereof, are preferably those for topical application to warm breeders, the pharmacological active ingredient being contained alone or together with a pharmaceutically usable carrier material. The daily dosage of the active ingredient depends on the age and individual condition as well as on the method of application. Corresponding agents with a concentration range of about 1 to about 10% w / w, e.g. in the form of creams, ointments or solutions, for example, can be applied 2 to 3 times a day.
Als topisch anwendbare pharmazeutische Präparate kommen in erster Linie Cremen, Salben, Pasten, Schäume, Tinkturen und Lösungen in Frage, die von etwa 0,1 bis etwa 10 % des Wirkstoffs enthalten. Cremen sind Oel-in-Wasser Emulsionen, die mehr als 50 % Wasser aufweisen. Als ölige Grundlage verwendet man in erster Linie Fettalkohole, z.B. Lauryl-, Cetyl- oder Stearylalkohol, Fettsäuren, z.B. Palmitin oder Stearinsäure, flüssige bis feste Wachse, z.B. Isopropylmyristat, Wollwachs oder Bienenwachs, und/oder Kohlenwasserstoffe, z.B. Vaseline (Petrolatum) oder Paraffinöl. Als Emulgatoren kommen oberflächenaktive Substanzen mit vorwiegend hydrophilen Eigenschaften in Frage, wie entsprechende nichtionische Emulgatoren, z.B. Fettsäureester von Polyal koholen oder Ethylenoxidaddukte davon, wie Polyglycerinfessäureester oder Polyoxyethylensorbitanfettsäureester (Tweens), ferner Polyoxy ethylenfettalkoholether oder -fettsäureester, oder entsprechende ionische Emulgatoren, wie Alkalimetallsalze von Fettalkoholsulfaten, z.B. Natriumlaurylsulfat, Natriumcetylsulfat oder Natriumstearylsulfat, die man üblicherweise in Gegenwart von Fettalkoholen, z.B. Cetyl alkohol oder Stearylalkohol, verwendet. Zusätze zur Wasserphase sind u.a. Mittel, welche die Austrocknung der Creme vermindern, z.B. Poly alkohole, wie Glycerin, Sorbit, Propylenglykol und/oder Polyethylen glykole, ferner Konservierungsmittel, Riechstoffe, etc.The topical pharmaceutical preparations that can be used are primarily creams, ointments, pastes, foams, tinctures and solutions which contain from about 0.1 to about 10% of the active ingredient. Creams are oil-in-water emulsions that contain more than 50% water. The main oils used are fatty alcohols, e.g. lauryl, cetyl or stearyl alcohol, fatty acids, e.g. palmitin or stearic acid, liquid to solid waxes, e.g. isopropyl myristate, wool wax or beeswax, and / or hydrocarbons, e.g. petroleum jelly (petrolatum) or paraffin oil . Suitable emulsifiers are surface-active substances with predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens), furthermore polyoxyethylene fatty alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, or corresponding ionic fatty alcohols, or corresponding ionic emulsifiers, such as ionic emulsifiers, or corresponding ionic emulsifiers, such as ionic emulsifiers, such as ionic emulsifiers , for example sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are usually used in the presence of fatty alcohols, for example cetyl alcohol or stearyl alcohol. Additives to the water phase include agents which reduce the drying out of the cream, for example polyalcohols such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols, also preservatives, fragrances, etc.
Salben sind Wasser-in-Oel-Emulsionen, die bis zu 70 %, vorzugsweise jedoch von etwa 20 % bis etwa 50 % Wasser oder wässrige Phasen enthalten. Als Fettphase kommen in erster Linie Kohlenwasserstoffe, z.B. Vaseline, Paraffinöl und/oder Hartparaffine in Frage, die zur Verbesserung des WasserbindungsVermögens vorzugsweise geeignete Hydroxyverbindungen, wie Fettalkohole oder Ester davon, z.B. Cetylalkohol oder Wollwachsalkohole bzw. Wollwachs, enthalten. Emulgatoren sind entsprechende lipophile Substanzen, wie Sorbitanfettsäureester (Spans), z.B. Sorbitanoleat und/oder Sorbitanisostearat. Zusätze zur Wasserphase sind u.a. Feuchthaltungsmittel, wie Polyalkohole, z.B. Glycerin, Propylenglykol, Sorbit und/oder Polyethylenglykol, sowie Konservierungsmittel, Riechstoffe, etc.Ointments are water-in-oil emulsions that contain up to 70%, but preferably from about 20% to about 50%, water or aqueous phases. The fatty phase is primarily hydrocarbons, e.g. Petroleum jelly, paraffin oil and / or hard paraffins in question, the hydroxyl compounds, such as fatty alcohols or esters thereof, which are preferably suitable for improving the water-binding capacity, e.g. Cetyl alcohol or wool wax alcohols or wool wax. Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (spans), e.g. Sorbitan oleate and / or sorbitan isostearate. Additions to the water phase include Humectants such as polyalcohols e.g. Glycerin, propylene glycol, sorbitol and / or polyethylene glycol, as well as preservatives, fragrances, etc.
Fettsalben sind wasserfrei und enthalten als Grundlage insbesondere Kohlenwasserstoff, z.B. Paraffin, Vaseline und/oder flüssige Paraffine, ferner natürliches oder partialsynthetisches Fett, z.B. Kokosfettsäuretriglycerid, oder vorzugsweise gehärtete Oele, z.B. hydriertes Erdnuss- oder Rizinusöl, ferner Fettsäurepartialester des Glycerins, z.B. Glycerinmono- und -distearat, sowie z.B. die im Zusammenhang mit den Salben erwähnten, die Wasseraufnahmefähigkeit steigernden Fettalkohole, Emulgatoren und/oder Zusätze.Fatty ointments are water-free and contain in particular hydrocarbon, for example paraffin, petroleum jelly and / or liquid paraffins, also natural or partially synthetic fat, for example coconut fatty acid triglyceride, or preferably hardened oils, for example hydrogenated peanut or castor oil, furthermore fatty acid partial esters of glycerol, for example glycerol mono- and distearate, and for example the fatty alcohols and emulsifiers which increase the water absorption capacity, emulsifiers / or additives.
Pasten sind Cremen und Salben mit sekretabsorbierenden Puderbestandteilen, wie Metalloxiden, z.B. Titanoxid oder Zinkoxid, ferner Talk und/oder Aluminiumsilikate, welche die Aufgabe haben, vorhandene Feuchtigkeit oder Sekrete zu binden.Pastes are creams and ointments with secretion-absorbing powder components, such as metal oxides, e.g. Titanium oxide or zinc oxide, also talc and / or aluminum silicates, which have the task of binding moisture or secretions.
Schäume werden z.B. aus Druckbehältern verabreicht und sind in Aerosolform vorliegende flüssige Oel-in-Wasser-Emulsionen, wobei halogenierte Kohlenwasserstoffe, wie Chlorfluorniederalkane, z.B. Dichlordifluormethan und Dichlortetrafluorethan, als Treibmittel verwendet werden. Als Oelphase verwendet man u.a. Kohlenwasserstoffe, z.B. Paraffinöl, Fettalkohole, z.B. Cetylalkohol, Fettsäureester,z.B. Isopropylmyristat, und/oder andere Wachse. Als Emulgatoren verwendet man u.a. Gemische von solchen mit vorwiegend hydrophilen Eigenschaften, wie Polyoxyethylen-sorbitan-fettsäureester (Tweens), und solchen mit vorwiegend lipophilen Eigenschaften, wie Sorbitan fettsäureester (Spans). Dazu kommen die üblichen" Zusätze, wie Konservierungsmittel, etc.Foams are e.g. administered from pressure vessels and are liquid oil-in-water emulsions in aerosol form, with halogenated hydrocarbons such as chlorofluoro-lower alkanes, e.g. Dichlorodifluoromethane and dichlorotetrafluoroethane can be used as blowing agents. The oil phase used includes Hydrocarbons, e.g. Paraffin oil, fatty alcohols, e.g. Cetyl alcohol, fatty acid esters e.g. Isopropyl myristate, and / or other waxes. The emulsifiers used include Mixtures of those with predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and those with predominantly lipophilic properties, such as sorbitan fatty acid esters (Spans). In addition, there are the usual "additives, such as preservatives, etc.
Tinkturen und Lösungen weisen meistens eine wässerig-äthanolische Grundlage auf, der u.a. Polyalkohole, z.B. Glycerin, Glykole und/oder Polyethylenglykol, als Feuchthaltemittel zur Herabsetzung der Verdunstung, und rückfettende Substanzen, wie Fettsäureester mit niedrigen Polyethylenglykolen, d.h. im wässrigen Gemisch lösliche, lipophile Substanzen als Ersatz für die der Haut mit dem Aethanol entzogenen Fettsubstanzen, und, falls notwendig, andere Hilfs- und Zusatzmittel beigegeben sind. Die Herstellung der topisch verwendbaren pharmazeutischen Präparate erfolgt in an sich bekannter Weise, z.B. durch Lösen oder Suspendieren des Wirkstoffs in der Grundlage oder in einem Teil davon, falls notwendig. Bei Verarbeitung des Wirkstoffs als Lösung wird dieser in der Regel vor der Emulgierung in einer der beiden Phasen gelöst; bei Verarbeitung als Suspension wird er nach der Emulgierung mit einem Teil der Grundlage vermischt und dann dem Rest der Formulierung beigegeben.Tinctures and solutions usually have an aqueous-ethanol base, which includes polyalcohols, e.g. glycerol, glycols and / or polyethylene glycol, as humectants to reduce evaporation, and refatting substances, such as fatty acid esters with low polyethylene glycols, ie lipophilic substances soluble in the aqueous mixture as a substitute for the fatty substances extracted from the skin with the ethanol, and, if necessary, other auxiliaries and additives are added. The topically usable pharmaceutical preparations are prepared in a manner known per se, for example by dissolving or suspending the active ingredient in the base or in a part thereof, if necessary. When the active ingredient is processed as a solution, it is usually dissolved in one of the two phases before emulsification; when processed as a suspension, it is mixed with part of the base after emulsification and then added to the rest of the formulation.
Die nachfolgenden Beispiele illustrieren die oben beschriebene Erfindung, sie sollen jedoch diese in ihrem Umfang in keiner Weise einschränken. Temperaturen sind in Celsiusgraden angegeben.The following examples illustrate the invention described above, but are not intended to limit the scope thereof in any way. Temperatures are given in degrees Celsius.
Beispiel 1:Example 1:
Eine Mischung von 30,0 g α-Brom-benzyl-(3-pyridyl)-keton-hydrobromid und 50,0 g Ammoniumsalz des Malonaldehydsäure-dimethylacetals in 180 ml wasserfreiem Dimethylformamid werden unter Rühren und Einleiten von Stickstoffgas während vier Stunden auf 100° erhitzt. Dann wird die Mischung abgekühlt und bei 70° unter 11 Torr zur Trockene eingedampft. Den Rückstand versetzt man mit 100 ml Wasser und 400 ml Ethyl acetat. Durch Zugabe von konzentrierter wässriger Ammoniaklösung wird der pH auf 8,0 gestellt. Die organische Phase wird abgetrennt, mit 50 ml Wasser gewaschen, über Magnesiumsulfat getrocknet und unter 11 Torr zur Trockene eingedampft. Den Rückstand chromatographiert man an 500 g Silikagel. Die Fraktionen 1-4, eluiert mit je 600 ml Chloroform, werden verworfen. Die Fraktionen 5-16, eluiert mit je 600 mlA mixture of 30.0 g of α-bromo-benzyl- (3-pyridyl) ketone hydrobromide and 50.0 g of ammonium salt of malonaldehyde acid dimethylacetal in 180 ml of anhydrous dimethylformamide are stirred at 100 ° for four hours with nitrogen gas heated. The mixture is then cooled and evaporated to dryness at 70 ° under 11 torr. The residue is mixed with 100 ml of water and 400 ml of ethyl acetate. The pH is adjusted to 8.0 by adding concentrated aqueous ammonia solution. The organic phase is separated off, washed with 50 ml of water, dried over magnesium sulfate and evaporated to dryness under 11 torr. The residue is chromatographed on 500 g of silica gel. Fractions 1-4, eluted with 600 ml of chloroform each, are discarded. Fractions 5-16, eluted with 600 ml each
Chloroform-Methanol (98:2), werden vereinigt und unter vermindertem Druck zur Trockene eingedampft. Der Rückstand, das N-[α-(3-Pyridyl)phenacyl]-malonaldehyd-säure-dimethylacetal-amid liegt als gelbes Oel vor.Chloroform-methanol (98: 2) are combined and evaporated to dryness under reduced pressure. The residue, the N- [α- (3-pyridyl) phenacyl] malonaldehyde acid dimethylacetal amide, is present as a yellow oil.
Die Fraktionen 19-24, eluiert mit je 600 ml Chloroform-Methanol (97:3), werden vereinigt und unter vermindertem Druck zur Trockene eingedampft. Der Rückstand wird auf Ether-Petrolether kristallisiert. Das 2-[4-(5)-Phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-acetaldehyd-dime thylacetal schmilzt bei 142-145°.Fractions 19-24, eluted with 600 ml each of chloroform-methanol (97: 3), are combined and evaporated to dryness under reduced pressure. The residue is crystallized from ether-petroleum ether. The 2- [4- (5) -phenyl-5 (4) - (3-pyridyl) imidazol-2-yl] acetaldehyde dime thylacetal melts at 142-145 °.
Das Ausgangsmaterial kann wie folgt hergestellt werden: Ein Gemisch von 10,0 g N-[α-(3-Pyridyl)-phenacyl]-malonaldehyd-säuredimethylacetal-amid, 30,0 g Ammoniumacetat und 100 ml Eisessig wird zwei Stunden unter Rückfluss gekocht und anschliessend unter kräftigem Rühren in ein Gemisch aus 200 g Eis und 150 ml konzentrierter wässriger Ammoniaklösung gegossen. Der Kristallbrei wird zweimal mit je 150 ml Ethylacetat extrahiert und die organische Phase mit Wasser neutral gewaschen, mit Magnesiumsülfat getrocknet und unter 11 Torr bei 40° zur Trockene eingedampft. Den Rückstand chromatographiert man an 500 g Silikagel. Die Fraktionen 1-4, eluiert mit je 500 ml Chloroform-Methanol (99:1), werden verworfen. Die Fraktionen 5-15, eluiert mit je 500 ml Chloroform-Methanol (99:2), werden vereinigt und unter vermindertem Druck zur Trockene eingedampft. Den Rückstand kristallisiert man aus Ether-Petrolether. Das 2-[4(5)-Phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-acetaldehyd-dimethylacetal schmilzt bei 142-145°..The starting material can be prepared as follows: A mixture of 10.0 g of N- [α- (3-pyridyl) phenacyl] malonaldehyde acid dimethylacetal amide, 30.0 g of ammonium acetate and 100 ml of glacial acetic acid is boiled under reflux for two hours and then poured into a mixture of 200 g of ice and 150 ml of concentrated aqueous ammonia solution with vigorous stirring. The crystal slurry is extracted twice with 150 ml of ethyl acetate each time and the organic phase is washed neutral with water, dried with magnesium sulfate and evaporated to dryness under 11 torr at 40 °. The residue is chromatographed on 500 g of silica gel. Fractions 1-4, eluted with 500 ml each of chloroform-methanol (99: 1), are discarded. Fractions 5-15, eluted with 500 ml each of chloroform-methanol (99: 2), are combined and evaporated to dryness under reduced pressure. The residue is crystallized from ether-petroleum ether. The 2- [4 (5) -phenyl-5 (4) - (3-pyridyl) imidazol-2-yl] acetaldehyde dimethylacetal melts at 142-145 °.
Der Ausgangsstoff wird wie folgt hergestellt: 19,7 g Malonaldehyd säure-dimethylacetal (V.V. Shikina et al. J. Gen. Chem. U.S.S.R. 25, 723-725 (1955)) werden in 300 ml wasserfreiem Ether gelöst. In die Lösung wird bei 0° während einer Stunde Ammoniakgas eingeleitet. Anschliessend wird die Mischung unter vermindertem Druck zur Trockene eingedampft. Das Ammoniumsalz des Malonaldehyd-säure-dimethylacetals liegt als Oel vor.The starting material is prepared as follows: 19.7 g of malonaldehyde acid dimethyl acetal (V.V. Shikina et al. J. Gen. Chem. U.S.S.R. 25, 723-725 (1955)) are dissolved in 300 ml of anhydrous ether. Ammonia gas is introduced into the solution at 0 ° for one hour. The mixture is then evaporated to dryness under reduced pressure. The ammonium salt of malonaldehyde acid dimethylacetal is present as an oil.
Beispiel 2: Eine Lösung von 5,9 g 2-[4(5)-Phenyl-5(4)-(3-pyridyl)- imidazol-2-yl]-acetaldehyd-dimethylacetal in 120 ml Methylenchlorid wird auf 0-5° abgekühlt und mit 3,5 g m-Chlorperbenzoesäure versetzt.Die Mischung wird 24 Stunden bei Raumtemperatur gerührt.Die gelbe Lösung wird anschliessend zweimal mit je 20 ml 2 N Kaliumhydrogenkarbonatlösung und mit 30 ml Wasser gewaschen, über Magnesiumsulfat getrocknet und bei 40° unter vermindertem Druck eingeengt. Der Rückstand wird in wenig Methanol gelöst. Nach Zusatz von Wasser kris siert der 2-[4(5)-Phenyl-5(4)-(l-oxido-3-pyridyl)-imidazol-2-yl]- acetaldehyd-dimethylacetal.Example 2: A solution of 5.9 g of 2- [4 (5) -phenyl-5 (4) - (3-pyridyl) - imidazol-2-yl] acetaldehyde dimethylacetal in 120 ml of methylene chloride is made up to 0-5 ° cooled and mixed with 3.5 g of m-chloroperbenzoic acid. The mixture is stirred for 24 hours at room temperature. The yellow solution is then washed twice with 20 ml of 2N potassium hydrogen carbonate solution and with 30 ml of water, dried over magnesium sulfate and at 40 ° under reduced pressure. The residue is dissolved in a little methanol. After adding water kris the 2- [4 (5) -phenyl-5 (4) - (l-oxido-3-pyridyl) imidazol-2-yl] acetaldehyde dimethyl acetal.
Beispiel 3: Eine Suspension von 3,29 g 2-[4(5)-Phenyl-5(4)-(3-pyridyl)- imidazol-2-yl]-2-methyl-propionsäure-Natriumsalz in 70 ml wasserfreiem Benzol wird unter Rühren während 10 Minuten bei 5° 3,2 ml Oxalyl chlorid zugetropft. Die Mischung wird eine Stunde bei 5° und 15 Stunden bei Raumtemperatur gerührt, abgekühlt und unter vermindertem Druck zur Trockene eingeengt. Den Rückstand versetzt man mit 70 ml wasserfreiem Benzol und engt wieder unter vermindertem Druck zur Trockene ein. Das 2-[4(5)-Phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-2-methyl-propionsäure- chlorid liegt als Oel vor. Das Säurechlorid ist unstabil und wird sofort umgesetzt.Example 3: A suspension of 3.29 g of 2- [4 (5) -phenyl-5 (4) - (3-pyridyl) - imidazol-2-yl] -2-methyl-propionic acid sodium salt in 70 ml of anhydrous benzene 3.2 ml of oxalyl chloride are added dropwise with stirring at 5 ° for 10 minutes. The mixture is stirred for one hour at 5 ° and 15 hours at room temperature, cooled and evaporated to dryness under reduced pressure. The residue is mixed with 70 ml of anhydrous benzene and again concentrated to dryness under reduced pressure. The 2- [4 (5) -phenyl-5 (4) - (3-pyridyl) imidazol-2-yl] -2-methyl-propionic acid chloride is present as an oil. The acid chloride is unstable and is implemented immediately.
3,4 g g frisch hergestelltes 2-[4(5)-Phenyl-8(4)-(3-pyridyl)-imidazol 2-yl]-2-methyl-propionsäurechlorid werden in 60 ml Diethylenglykol dimethylester gelöst. Die Lösung wird auf -75° abgekühlt und unter Rühren und Einleiten von Stickstoffgas während 30 Minuten mit einer Suspension von 2,54 g Lithium-tri-tert.butoxy-aluminiumhydrid versetzt. Die Suspension wird nach beendetem Zutropfen noch 30 Minuten bei -70° und eine Stunde ohne Kühlung gerührt, wobei die Innentemperatur auf 0° ansteigt. Man giesst die Mischung auf 500 ml Eiswasser und filtriert durch eine Schicht Hyflo Super Cd. Das Filtrat wird mit konzentrierter wässriger Ammoniaklösung auf pH 8,0 gestellt. Das Gemisch wird mit 100 ml Methylenchlorid geschüttelt. Man filtriert die Wasser-Methylenchloridmischung durch eine Schicht Hyflo Super Cd. Das Filtrat wird dreimal mit je 40 ml Methylenchlorid extrahiert. Man vereinigt die organischen Extrakte, wäscht mit 50 ml Wasser und engt unter vermindertem Druck zur Trockene ein. Anschliessend wird bei 50° unter 0,1 mm vom Diethylenglykoldimethylether befreit. Der Rückstand chromatographiert man an einer Lobar Fertigsäule (Grosse C, Merck) für Niederdruck-Flüssigkeits-Chromatographie. Die Fraktionen 1-14, eluiert mit je 10 ml Chloroform-Isopropanol (95:5), werden verworfen. Die Fraktionen 15-29, eluiert mit je 10 ml Chloroform-Isopropanol (85:15) werden vereinigt und unter vermindertem Druck zur Trockene eingedampft. Der Rückstand, der 2-[4(5)-Pheny1-5 (4)-(3-pyridyl)-imidazol-2-yl]-2-methy1-propionaldehyd liegt als Oel vor.3.4 g of freshly prepared 2- [4 (5) -phenyl-8 (4) - (3-pyridyl) imidazol 2-yl] -2-methyl-propionic acid chloride are dissolved in 60 ml of diethylene glycol dimethyl ester. The solution is cooled to -75 ° and, while stirring and introducing nitrogen gas, a suspension of 2.54 g of lithium tri-tert-butoxy aluminum hydride is added for 30 minutes. After the dropwise addition has ended, the suspension is stirred for a further 30 minutes at -70 ° and for one hour without cooling, the internal temperature rising to 0 °. The mixture is poured onto 500 ml of ice water and filtered through a layer of Hyflo Super Cd. The filtrate is adjusted to pH 8.0 with concentrated aqueous ammonia solution. The mixture is shaken with 100 ml of methylene chloride. Filter the water-methylene chloride mixture through a layer of Hyflo Super Cd. The filtrate is extracted three times with 40 ml of methylene chloride. The organic extracts are combined, washed with 50 ml of water and concentrated to dryness under reduced pressure. The diethylene glycol dimethyl ether is then freed at 50 ° under 0.1 mm. The residue is chromatographed on a Lobar finished column (Grosse C, Merck) for low-pressure liquid chromatography. Fractions 1-14 eluted with 10 ml each of chloroform-isopropanol (95: 5) are discarded. Fractions 15-29, eluted with 10 ml each of chloroform-isopropanol (85:15), are combined and evaporated to dryness under reduced pressure. The residue, the 2- [4 (5) -Pheny1-5 (4) - (3-pyridyl) -imidazol-2-yl] -2-methy1-propionaldehyde, is present as an oil.
Figure imgf000034_0001
Figure imgf000034_0001
NMR (CDCl3): 9,70 (s, CHO) , 8,68 (br, H-2'), 8,34 (dbr, H-6'), 7,85 (dm, H-4'), 7,1-7,5 (m, übrige arom. H), 1,60 (s, CH3) .NMR (CDCl 3 ): 9.70 (s, CHO), 8.68 (br, H-2 '), 8.34 (dbr, H-6'), 7.85 (dm, H-4 ') , 7.1-7.5 (m, other aromatic H), 1.60 (s, CH 3 ).
Beispiel 4: In analoger Weise wie in Beispiel 1-3 beschrieben sowie entsprechend der in der Beschreibung aufgezeigten Weise kann man erhalten:Example 4: In an analogous manner to that described in Example 1-3 and in the manner shown in the description, one can obtain:
2-[4 (5)—Pheny1-5(4)-(3-pyridyl)-imidazol-2-yl]-propanoldimethylacetal, Oel, NMR (CDCl3), 8,72 (br. H-2'), 8,45 (dbr, H-6'), 7,84 (dm, H-4'), 7,1-7,5 (m, übrige Arom. H) , 4,61 (d, CH-0) , 3,4 (OCH3), 3,51 (dq, CH-CH3), 1,63 (d, C-CH3);2- [4 (5) —Pheny1-5 (4) - (3-pyridyl) imidazol-2-yl] propanoldimethylacetal, oil, NMR (CDCl 3 ), 8.72 (br. H-2 '), 8.45 (dbr, H-6 '), 7.84 (dm, H-4'), 7.1-7.5 (m, other aroma H), 4.61 (d, CH-0) , 3.4 (OCH 3 ), 3.51 (dq, CH-CH 3 ), 1.63 (d, C-CH 3 );
2-[4(5)-Phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-2-methyl-propanol-dimethylacetal, Oel, NMR (CDCl3) : 8,73 (br, H-2'), 8,41 (dbr, H-6'), 7,85 (dm, H-4f), 7,1-7,5 (m, übrige Arom. H), 4,60 (s, CH) , 3,47 (s, OCH3), 1,65 (CCH3 );2- [4 (5) -phenyl-5 (4) - (3-pyridyl) imidazol-2-yl] -2-methyl-propanol-dimethylacetal, oil, NMR (CDCl 3 ): 8.73 (br, H-2 '), 8.41 (dbr, H-6'), 7.85 (dm, H-4f), 7.1-7.5 (m, other aroma H), 4.60 (s , CH), 3.47 (s, OCH 3 ), 1.65 (CCH 3 );
2-[4(5)-Pheny1-5(4)-(l-oxido-3-pyridyl)-imidazol-2-yl]-propanol-dimethylacetol, Oel;2- [4 (5) -Pheny1-5 (4) - (l-oxido-3-pyridyl) imidazol-2-yl] propanol-dimethylacetol, oil;
2-[4(5)-Pheny1-5(4)-(l-xoido-3-pyridyl)-imidazol-2-yl]-2-methy1-ρropanol-dimethylacetol, Oel;2- [4 (5) -pheny1-5 (4) - (l-xoido-3-pyridyl) imidazol-2-yl] -2-methy1-ρropanol-dimethylacetol, oil;
2-[4(5)-Pheny1-5(4)-(3-pyridyl)-imidazol-2-yl]-2-methy1-1,1-methylendioxypropan, Oel; 2-[4(5)-Phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-2-methyl-l,l-ethylen dioxypropan, Oel;2- [4 (5) -pheny1-5 (4) - (3-pyridyl) imidazol-2-yl] -2-methy1-1,1-methylenedioxypropane, oil; 2- [4 (5) -phenyl-5 (4) - (3-pyridyl) imidazol-2-yl] -2-methyl-l, l-ethylene dioxypropane, oil;
2-[4(5)-Phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-butyraldehyd, Oel;2- [4 (5) -phenyl-5 (4) - (3-pyridyl) imidazol-2-yl] butyraldehyde, oil;
2-[4(5)-Phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-acetaldehyd, Oel,2- [4 (5) -phenyl-5 (4) - (3-pyridyl) imidazol-2-yl] acetaldehyde, oil,
NMR (CDCl3): 9,70 (s, CHO) , 8,71 (br, H-2'), 8,35 (dbr, H-6'), 7,84NMR (CDCl 3 ): 9.70 (s, CHO), 8.71 (br, H-2 '), 8.35 (dbr, H-6'), 7.84
(dm, H-4'), 7,1-7,5 (m, übrige Arom. H) , 4,03 (s, CH2) ;(dm, H-4 '), 7.1-7.5 (m, remaining aroma H), 4.03 (s, CH 2 );
2-[4 (5)-Pheny1-5 (4)-(3-pyridyl)-imidazol-2-y1]-propionaldehyd, Oel, NMR (CDCl3): 9,72 (s, CHO), 8,73 (br, H-2'), 8,40 (br, H-6'), 7,852- [4 (5) -Pheny1-5 (4) - (3-pyridyl) imidazol-2-y1] propionaldehyde, oil, NMR (CDCl 3 ): 9.72 (s, CHO), 8.73 (br, H-2 '), 8.40 (br, H-6'), 7.85
(dbr, H-4'), 7,1-75, (m, übrige Arom. H) , 3,97 (q, CHCH3) , 1,65 (d,(dbr, H-4 '), 7.1-75, (m, remaining aroma H), 3.97 (q, CHCH 3 ), 1.65 (d,
CH3) ;CH3);
2- [ 4 (5) -Phenyl-5 (4) - (l-oxido-3-pyridyl)-imidazol-2-yl ]-acetaldehyd,2- [4 (5) -phenyl-5 (4) - (l-oxido-3-pyridyl) imidazol-2-yl] acetaldehyde,
Oel;Oil;
2- [ 4 (5) -Phenyl-5 (4) - (l-oxido-3-ρyridyl)-imidazol-2-yl ]-propionaldehyd,2- [4 (5) -phenyl-5 (4) - (l-oxido-3-pyridyl) imidazol-2-yl] propionaldehyde,
Oel;Oil;
2-[4 (5)-Phenyl-5 (4)- (l-oxido-3-pyridyl)-imidazol-2-yl] -2-methyl-pro pionaldehyd, Oel ;2- [4 (5) -phenyl-5 (4) - (l-oxido-3-pyridyl) imidazol-2-yl] -2-methyl-pro pionaldehyde, oil;
2- [ 4 (5) -Pheny 1-5 (4 ) - ( l-oxido-3-pyridyl)-imidazo1-2-yl]-butyraldehyd,2- [4 (5) -pheny 1-5 (4) - (l-oxido-3-pyridyl) imidazo1-2-yl] butyraldehyde,
Oel, ausgehend aus dem entsprechenden Natriumsalz der j eweiligen Säure über das j eweilige Säurechlorid.Oil, starting from the corresponding sodium salt of the respective acid via the respective acid chloride.
Beispiel 5: Eine Salbe, enthaltend 5 % 2- [4 (5)-Phenyl- 5(4)- (1-oxido3-pyridy l)-imidazol-2-yl]--methylpropanal-dimethylacetal, kann wie folgt hergestellt werden:Example 5: An ointment containing 5% 2- [4 (5) -phenyl-5 (4) - (1-oxido3-pyridyl) -imidazol-2-yl] methylpropanal dimethyl acetal can be prepared as follows :
Zusammensetzung:Composition:
Wirkstoff 5 , 0 %Active ingredient 5.0%
Vaseline 45 ,0 %Vaseline 45.0%
Paraffinöl 19 , 6 %Paraffin oil 19.6%
Cetylalkohol 5 , 0 %Cetyl alcohol 5.0%
Bienenwachs 5 , 0 %Beeswax 5.0%
Sorbitan-sesquioleat 5 , 0 % p-Hydroxybenzoesäureester 0, 2 %Sorbitan sesquioleate 5.0% p-hydroxybenzoic acid ester 0.2%
Wasser , entmineralisiert bis zu 100, 0 % Die Fettstoffe und Emulgatoren werden zusammengeschmolzen. Das Konservierungsmittel wird in Wasser gelöst, und die Lösung in die Fettschmelze bei erhöhter Temperatur einemulgiert. Nach dem Erkalten wird eine Suspension des Wirkstoffs in einem Teil der Fettschmelze in die Emulsion eingearbeitet.Water, demineralized up to 100.0% The fatty substances and emulsifiers are melted together. The preservative is dissolved in water and the solution is emulsified into the fat melt at elevated temperature. After cooling, a suspension of the active ingredient is incorporated into part of the fat melt in the emulsion.
Beispiel 6: Eine Creme, enthaltend 10 % 2-[4(5)-Phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-acetaldehyd-dimethylacetal, kann wie folgt hergestellt werden:Example 6: A cream containing 10% 2- [4 (5) -phenyl-5 (4) - (3-pyridyl) imidazol-2-yl] acetaldehyde dimethyl acetal can be prepared as follows:
Zusammensetzung:Composition:
Wirkstoff 10,0 %Active substance 10.0%
Isopropylpalmitat 8,0 %Isopropyl palmitate 8.0%
Cetylpalmitat 1,5 %Cetyl palmitate 1.5%
Siliconöl 100 0,5 %Silicone oil 100 0.5%
Sorbitanmonostearat 3,0 %Sorbitan monostearate 3.0%
Polysorbat 60 3,5 %Polysorbate 60 3.5%
1,2-Propylenglykol PH 20,0 %1,2-propylene glycol PH 20.0%
Acrylsäurepolymerisat 0,5 %Acrylic acid polymer 0.5%
Triethanolamin 0,7 %Triethanolamine 0.7%
Wasser, entmineralisiert bis zu 100,0 %Water, demineralized up to 100.0%
Das Acrylsäurepolymerisat wird in einem Gemisch aus entmineralisiertem Wasser und 1,2-Propylenglykol suspendiert. Unter Rühren wird hieraufThe acrylic acid polymer is suspended in a mixture of demineralized water and 1,2-propylene glycol. Then stir
Triethanolamin zugegeben, wodurch ein Schleim erhalten -wird. Ein Gemisch aus Isopropylpalmitat, Cetylpalmitat, Siliconöl, Sorbitanmonostearat und Polysorbat wird auf ca. 75° erwärmt und unter Rühren in den gleichfalls auf ca. 75° erwärmten Schleim eingearbeitet. Die auf Raumtemperatur abgekühlten Creme-Grundlage wird hierauf zur Herstellung eines Konzentrates mit dem Wirkstoff verwendet. Das Konzentrat wird mittels eines Durchlaufhomogenisators homogenisiert und dann protionsweise der Grundlage hinzugefügt. Beispiel 7: Eine Creme, enthaltend 5 % 2-[4(5)-Phenyl-5(4)-(l-oxido- 3-ρyridyl)-imidazol-2-yl]-2-methylpropanal-dimethylacetal, kann wie folgt erhalten werden.Triethanolamine added, whereby a mucus is obtained. A mixture of isopropyl palmitate, cetyl palmitate, silicone oil, sorbitan monostearate and polysorbate is heated to approximately 75 ° and incorporated into the mucus, which is likewise heated to approximately 75 °, with stirring. The cream base cooled to room temperature is then used to produce a concentrate with the active ingredient. The concentrate is homogenized by means of a continuous homogenizer and then added to the base as a proton. Example 7: A cream containing 5% 2- [4 (5) -phenyl-5 (4) - (l-oxido-3-pyridyl) imidazol-2-yl] -2-methylpropanal dimethyl acetal can be as follows be preserved.
Zusammensetzung:Composition:
Wirkstoff 5,0 %Active ingredient 5.0%
Cetylpalmitat PH 2,0 %Cetyl palmitate PH 2.0%
Cetylalkohol PH 2,0 %Cetyl alcohol PH 2.0%
Triglyceridgemisch gesättigter mittelfettiger Fettsäuren 5,0 %Triglyceride mixture of saturated medium-fat fatty acids 5.0%
Stearinsäure 3,0 %Stearic acid 3.0%
Glycerinstearat PH 4,0 %Glycerol stearate pH 4.0%
Cetomacrogol 1000 1,0 % mikrokristalline Cellulose 0,5 %Cetomacrogol 1000 1.0% microcrystalline cellulose 0.5%
1,2-Propylenglykol, dest. 20,0 %1,2-propylene glycol, dist. 20.0%
Wasser, entmineralisiert, bis zu 100,0 %Water, demineralized, up to 100.0%
Cetylalkohol, Cetylpalmitat, das Triglyceridgemisch, Stearinsäure und Glycerinstearat werden zusammengeschmolzen. Die mikrokristalline Cellulose wird in einen Teil des Wassers dispergiert. Im restlichen Teil des Wassers wird Cetomacrogol gelöst und das Propylenglykol sowie der Schleim dazu gemischt. Die Fettphase wird anschliessend unter Rühren zu Wasserphase gegeben und kaltgerührt. Schliesslich wird der Wirkstoff mit einem Teil der Grundlage angerieben und hierauf die Anreibung in den Rest der Creme eingearbeitet.Cetyl alcohol, cetyl palmitate, the triglyceride mixture, stearic acid and glycerol stearate are melted together. The microcrystalline cellulose is dispersed in part of the water. Cetomacrogol is dissolved in the remaining part of the water and the propylene glycol and the mucus are mixed with it. The fat phase is then added to the water phase with stirring and stirred cold. Finally, the active ingredient is rubbed with part of the base and the rubbing is then incorporated into the rest of the cream.
Beispiel 8 : Ein transparentes Hydrogel, enthaltend 5 % 2-(4(5)-Phenyl-5(4)-(4-pyridyl)-imidazol-2-yl]-acetaldehyd-dimethylacetal, wird wie folgt hergestellt. Zusammensetzung: Wirkstoff 5 %Example 8: A transparent hydrogel containing 5% 2- (4 (5) -phenyl-5 (4) - (4-pyridyl) -imidazol-2-yl] acetaldehyde dimethylacetal is prepared as follows. Composition: active ingredient 5%
Propylenglykol 10 - 20 %Propylene glycol 10 - 20%
Isopropanol 20 %Isopropanol 20%
Hydroxypropyl-methylcellulose 2 %Hydroxypropyl methyl cellulose 2%
Wasser ad 100 %Water ad 100%
Die Hydroxypropyl-methylcellulose wird im Wasser gequollen. Der Wirkstoff wird in einem Gemisch aus Isopropanol und Propylenglykol gelöst. Anschliessend wird die Wirkstofflösung mit einem gequollenen Cellulose Derivat vermischt und, wenn erwünscht, mit Riechstoffen (0,1 %) versetzt.The hydroxypropyl methyl cellulose is swollen in the water. The active ingredient is dissolved in a mixture of isopropanol and propylene glycol. The active ingredient solution is then mixed with a swollen cellulose derivative and, if desired, fragrances (0.1%) are added.
Beispiel 9 : Ein transparentes Hydrogel, enthaltend 5 % 2-[4(5)- Phenyl-5(4)-(l-oxido-3-pyridyl)-imidazol-2-yl]-2-methylpropanal-di methylacetal, wird wie folgt hergestellt.Example 9: A transparent hydrogel containing 5% 2- [4 (5) - phenyl-5 (4) - (l-oxido-3-pyridyl) -imidazol-2-yl] -2-methylpropanal-di methylacetal is used manufactured as follows.
Zusammensetzung:Composition:
Wirkstoff 5 %Active ingredient 5%
Propylenglykol 20 %Propylene glycol 20%
Isopropanol 20 %Isopropanol 20%
Acrylsäurepolymerisat 2 %Acrylic acid polymer 2%
Triethanolamin 3 % Wasser ad 100 %Triethanolamine 3% water ad 100%
Acrylsäurepolymerisat und Wasser werden dispergiert und mit Triethanolamin neutralisiert. Der Wirkstoff wird in einem Gemisch aus Isopropanol und Propylenglykol gelöst. Anschliessend wird die Wirkstofflösung mit dem Gel vermischt, wobei, wenn erwünscht, Riechstoff (0,1 %) zugegeben werden kann. Beispiel 10: Ein Schaumspray, enthaltend 1 % 2-[4(5)-Phenyl-5(4)-(l-oxido-3-pyridyl)-imidazol-2-yl]-2-methylpropanal-dimethylacetal, kann folgendermassen hergestellt werden:Acrylic acid polymer and water are dispersed and neutralized with triethanolamine. The active ingredient is dissolved in a mixture of isopropanol and propylene glycol. The active ingredient solution is then mixed with the gel, it being possible, if desired, to add fragrance (0.1%). Example 10: A foam spray containing 1% 2- [4 (5) -phenyl-5 (4) - (l-oxido-3-pyridyl) imidazol-2-yl] -2-methylpropanal dimethylacetal can be prepared as follows become:
Zusammensetzung:Composition:
Wirkstoff 1,00 %Active substance 1.00%
Cetylalkohol PH 1,70 %Cetyl alcohol PH 1.70%
Paraffinöl, dickflüssig 1,00 %Paraffin oil, viscous 1.00%
Isopropylmyristat 2,00 %Isopropyl myristate 2.00%
Cetomacrogol 1000 2,40 %Cetomacrogol 1000 2.40%
Sorbitanmonostearat 1,50 %Sorbitan monostearate 1.50%
1,2-Propylenglykol PH 5,00 %1,2-propylene glycol pH 5.00%
Methylparaben 0,18 %Methyl paraben 0.18%
Propylparaben 0,02 %Propylparaben 0.02%
Chemoderm 314 0,10 %Chemoderm 314 0.10%
Wasser, entmineralis iert, bis zu 100,00 %Water, demineralized, up to 100.00%
Cetylalkohol, Paraffinöl, Isopropylmyristat, Cetomacrogol und Sorbitanstearat werden zusammengeschmolzen. Methyl- und Propylparaben werden in heissem Wasser gelöst. Die Schmelze und die Lösung werden anschliessend vermischt. Der Wirkstoff, in Propylenglykol suspendiert, wird in die Grundlage eingearbeitet. Anschliessend wird Chemoderm zugeführt und mit Wasser auf das Endgewicht ergänzt.Cetyl alcohol, paraffin oil, isopropyl myristate, cetomacrogol and sorbitan stearate are melted together. Methyl and propyl paraben are dissolved in hot water. The melt and the solution are then mixed. The active ingredient, suspended in propylene glycol, is incorporated into the base. Chemoderm is then added and water is added to the final weight.
Abfüllung:Bottling:
20 ml des Gemisches wird in eine Aluminiumblockdose eingefüllt. Die Dose wird mit einem Ventil versehen, und das Treibgas wird unter Druck eingefüllt. 20 ml of the mixture is poured into an aluminum block can. The can is fitted with a valve and the propellant is filled under pressure.

Claims

Patentansprüche Claims
1. Neue substituierte Diazaverbindungen der allgemeinen Formel1. New substituted diaza compounds of the general formula
(I),
Figure imgf000040_0001
worin R1 und R2 unabhängig voneinander carbocyclisches Aryl und/oder Heteroaryl bedeuten, A einen zweiwertigen Kohlenwasserstoffrest darstellt und R3 Formyl oder acetalisiertes Formyl bedeutet, ihre Isomeren und ihre Salze.(I),
Figure imgf000040_0001
wherein R 1 and R 2 independently of one another are carbocyclic aryl and / or heteroaryl, A is a divalent hydrocarbon radical and R 3 is formyl or acetalized formyl, their isomers and their salts.
2. Verbindungen der Formel (I) gemäss Anspruch 1, worin einerseits R1 und R2 unabhängig voneinander Phenyl und/oder durch Halogen, Niederalkyl, Hydroxy, Niederalkoxy und/oder Niederalkanoyl substituiertes Phenyl bedeuten oder worin andererseits einer der Reste R1 und R2 Pyrrolyl, Furyl, Thienyl, Pyridyl, l-Oxidopyridyl oder Pyrimidyl bedeutet, welche jeweils unsubstituiert oder durch Halogen, Niederalkyl, Hydroxy, Niederalkoxy und/oder Niederalkanoyloxy substituiert sein können, und der andere Phenyl, Pyrrolyl, Furyl, Thienyl, Pyridyl, 1-Oxidopyridyl oder Pyrimidyl bedeutet, welches jeweils unsubstituiert oder durch Halogen, Niederalkyl, Hydroxy, Niederalkoxy und/oder Niederalkanoyloxy substituiert sein können, und jeweils A Niederalkylen, Niederalkyliden, Niederalkenylen, Niederalkenyliden, Cycloalkylen, Cycloalkyliden oder Cycloalkyl-niederalkyliden darstellen und R3 Formyl oder mit einem aliphatischen Alkohol acetalisiertes Formyl bedeutet, ihre Isomeren sowie ihre Salze.2. Compounds of formula (I) according to claim 1, wherein on the one hand R 1 and R 2 independently of one another are phenyl and / or phenyl substituted by halogen, lower alkyl, hydroxy, lower alkoxy and / or lower alkanoyl or on the other hand one of the radicals R 1 and R 2 means pyrrolyl, furyl, thienyl, pyridyl, l-oxidopyridyl or pyrimidyl, which in each case can be unsubstituted or substituted by halogen, lower alkyl, hydroxy, lower alkoxy and / or lower alkanoyloxy, and the other phenyl, pyrrolyl, furyl, thienyl, pyridyl, 1 -Oxidopyridyl or pyrimidyl, which can in each case be unsubstituted or substituted by halogen, lower alkyl, hydroxy, lower alkoxy and / or lower alkanoyloxy, and each represent A lower alkylene, lower alkylidene, lower alkenyl, lower alkenylidene, cycloalkylene, cycloalkylidene or cycloalkyl lower alkylidene and R 3 is formyl or formyl acetalized with an aliphatic alcohol means their isomers and their salts.
3. Verbindungen der Formel (I) gemäss Anspruch 1, worin R1 und R2 unabhängig voneinander Phenyl und/oder Halogen, Hydroxy, Niederalkyl, Niederalkoxy und/oder Niederalkanoyloxy substituiertes Phenyl bedeutet, A Niederalkylen mit bis und mit 4 C-Atomen, wie Methylen, Niederalkyliden mit bis und mit 7 C-Atomen, wie 2, 2-Propyliden, Niederalkenylen mit bis und mit 4 C-Atomen, wie 1,3-Propen-2-ylen, Nieder alkenyliden mit bis und mit 7 C-Atomen, wie 1, l-Buten-3-yliden, 3- bis 8-gliedriges Cycloalkylen, wie Cyclopropylen, 3- bis 8-gliedriges Cycloalkyliden, wie Cyclopentyliden, oder Cycloalkylniederalkyliden mit bis und mit 7 C-Atomen im Alkylidenteil und mit einem 3- bis 8-gliedrigen Cycloalkylteil, wie 2-Cyclohexyl-l,l-ethyliden, bedeutet und R3 Formyl oder mit einem Niederalkanol, Niederalkenol, Niederalkandiol oder Niederalkendiol acetalisiertes Formyl bedeutet, ihre Isomeren sowie ihre Salze.3. Compounds of the formula (I) according to Claim 1, in which R 1 and R 2 independently of one another are phenyl and / or halogen, hydroxyl, lower alkyl, lower alkoxy and / or lower alkanoyloxy-substituted phenyl, A is lower alkylene with up to and with 4 C atoms, such as methylene, lower alkylidene with up to and with 7 C atoms, such as 2,2-propylidene, lower alkenyl with up to and with 4 C atoms, such as 1,3-propen-2-ylene, Nieder alkenylidene with up to and with 7 carbon atoms, such as 1, l-buten-3-ylidene, 3- to 8-membered cycloalkylene, such as cyclopropylene, 3- to 8-membered cycloalkylidene, such as cyclopentylidene, or cycloalkyl-lower alkylidene with up to and with 7 C atoms in the alkylidene part and with a 3- to 8-membered cycloalkyl part, such as 2-cyclohexyl-l, l-ethylidene, and R 3 is formyl or formalized with a lower alkanol, lower alkenol, lower alkanediol or lower alkenediol, their isomers and theirs Salts.
4. Verbindungen der Formel (I) gemäss Anspruch 1, worin einer der Reste R1 und R2 Pyridyl oder 1-Oxido-pyridyl, die unsubstituiert und/oder jeweils durch Halogen, Hydroxy, Niederalkyl, Niederalkoxy und/oder Niederalkanoyloxy substituiert sein können, und der andere Phenyl, Pyridyl oder 1-Oxidopyridyl, die unsubstituiert und/oder jeweils durch Halogen, Hydroxy, Niederalkyl, Niederalkoxy und/oder Niederalkanoyloxy substituiert sein können, bedeutet, A Niederalkylen mit bis und mit 4 C-Atomen, wie Methylen, Niederalkyliden mit bis und mit 7 C Atomen, wie.2, 2-Propyliden, Niederalkenylen mit bis und mit 7 C-Atomen, wie 1,3-Propen-2-ylen, Niederalkenyliden mit bis und mit 4 C-Atomen, wie l,l-Buten-3-yliden, 3- bis 8-gliedriges Cycloalkylen, wie Cyclopropylen, 3- bis 8-gliedriges Cycloalkyliden, wie Cyclopentyliden, oder Cycloalkyl-niederalkyliden mit bis und mit 7 C-Atomen im Alkylidenteil und mit einem 3- bis 8-gliedrigem Cycloalkylteil, wie 2-Cyclohexyl-l,l-ethyliden, bedeutet und R3 Formyl oder mit einem Niederalkanol, Niederalkenyl, Niederalkandiol oder Niederalkendiol acetalisiertes Formyl bedeutet, ihre Isomeren sowie ihre Salze.4. Compounds of formula (I) according to claim 1, wherein one of the radicals R 1 and R 2 pyridyl or 1-oxido-pyridyl, which may be unsubstituted and / or substituted by halogen, hydroxy, lower alkyl, lower alkoxy and / or lower alkanoyloxy , and the other phenyl, pyridyl or 1-oxidopyridyl, which can be unsubstituted and / or substituted in each case by halogen, hydroxy, lower alkyl, lower alkoxy and / or lower alkanoyloxy, means A lower alkylene with up to and with 4 carbon atoms, such as methylene, Lower alkylidene with up to and with 7 C atoms, such as 2,2-propylidene, lower alkenyls with up to and with 7 C atoms, such as 1,3-propen-2-ylene, lower alkenylidene with up to and with 4 C atoms, such as l , l-buten-3-ylidene, 3- to 8-membered cycloalkylene, such as cyclopropylene, 3- to 8-membered cycloalkylidene, such as cyclopentylidene, or cycloalkyl-lower alkylidene with up to and with 7 C atoms in the alkylidene part and with a 3- to 8-membered cycloalkyl part, such as 2-cyclohexyl-l, l-ethylidene, and R 3 Formyl or acetalized with a lower alkanol, lower alkenyl, lower alkanediol or lower alkenediol means their isomers and their salts.
5. Verbindungen der Formel (I) gemäss Anspruch 1, worin R1 und R2 unabhängig voneinander Phenyl und/oder durch Halogen mit Atomnummer bis und mit 35, wie Chlor, Hydroxy, Niederalkyl mit bis und mit. 4 C-Atomen, wie Methyl, und/oder Niederalkoxy mit bis und mit 4 C-Atomen, wie Methoxy, substituiertes Phenyl bedeuten, A Niederalkylen mit bis und mit 4 C-Atomen, wie Methylen, Niederalkyliden mit bis und mit 7 C-Atomen, wie 2,2-Propyliden, Niederalkenyliden mit bis und mit 7 C-Atomen, wie 1,1-Buten-3-yliden, oder 3- bis 8-gliedriges Cycloniederalkyliden, wie 1,1-Cyclopentyliden, darstellen und R3 Formyl oder Diniederalkoxy-methyl jeweils mit bis und mit 4 C-Atomen im Niederalkoxyteil, wie Dimethoxy-methyl, oder Niederalkendioxy-methyl mit bis und mit 4 C-Atomen im Niederalkylenteil, wie 1,3-Dioxolan-2-yl, bedeutet, ihre Isomeren sowie ihre Salze.5. Compounds of formula (I) according to claim 1, wherein R 1 and R 2 independently of one another phenyl and / or by halogen with atomic number up to and including 35, such as chlorine, hydroxy, lower alkyl with up to and including. 4 carbon atoms, such as methyl, and / or lower alkoxy with up to 4 carbon atoms, such as methoxy, substituted phenyl, A lower alkylene with up to 4 carbon atoms, such as methylene, lower alkylidene with up to 7 carbon atoms Atoms such as 2,2-propylidene, lower alkenylidene with up to and with 7 carbon atoms, such as 1,1-buten-3-ylidene, or 3- to 8-membered cyclo-lower alkylidene, such as 1,1-cyclopentylidene, and R 3 is formyl or diniederalkoxy-methyl each with up to and with 4 C- Atoms in the lower alkoxy part, such as dimethoxy-methyl, or lower alkenedioxy-methyl with up to and with 4 carbon atoms in the lower alkylene part, such as 1,3-dioxolan-2-yl, mean their isomers and their salts.
6. Verbindungen der Formel (I) gemäss Anspruch 1, worin einer der Reste R1 und R2 Phenyl oder durch Halogen mit Atomnummer bis und mit 35, wie Chlor, Hydroxy, Niederalkyl mit bis und mit 4 C-Atomen, wie Methyl, und/oder Niederalkoxy mit bis und mit 4 C-Atomen, wie Methoxy, substituiertes Phenyl bedeutet und der andere Pyridyl, wie 3-Pyridyl, oder 1-Oxido-pyridyl, wie l-0xido-3-pyridyl, bedeutet, die jeweils unsubstituiert oder durch Halogen mit Atomnummer bis und mit 35, wie Chlor, Hydroxy und/oder Niederalkoxy mit bis und mit 4 C-Atomen, wie Methoxy, substituiert sein können, A Niederalkylen mit bis und mit6. Compounds of formula (I) according to claim 1, wherein one of the radicals R 1 and R 2 is phenyl or by halogen with atomic numbers up to and including 35, such as chlorine, hydroxy, lower alkyl having up to and 4 carbon atoms, such as methyl, and / or lower alkoxy with up to and with 4 carbon atoms, such as methoxy, is substituted phenyl and the other is pyridyl, such as 3-pyridyl, or 1-oxido-pyridyl, such as l-0xido-3-pyridyl, each of which is unsubstituted or by halogen with atomic numbers up to and including 35, such as chlorine, hydroxy and / or lower alkoxy with up to and including 4 carbon atoms, such as methoxy, A lower alkylene with up to and including
4 -C-Atomen, wie Methylen, Niederalkyliden mit bis und mit 7 C-Atomen, wie 2,2-Propyliden, Niederalkenyliden mit bis und mit 7 C-Atomen, wie l,l-Buten-3-yliden, oder 3- bis 8-gliedriges Cycloniederalkyliden, wie 1,1-Cyclopentyliden, darstellen und R3 Formyl oder Diniederalkoxymethyl, jeweils mit bis und mit 4 C-Atomen im Niederalkylteil, wie Dimethoxymethyl, oder Niederalkylendioxy-methyl mit bis und mit 4 C-Atomen im Niederalkylenteil, wie 1,3-Dioxolan-2-yl, bedeutet, ihre Isomeren sowie ihre Salze.4 -C atoms, such as methylene, lower alkylidene with up to and with 7 C atoms, such as 2,2-propylidene, lower alkenylidene with up to and with 7 C atoms, such as l, l-buten-3-ylidene, or 3- represent up to 8-membered cyclo-lower alkylidene, such as 1,1-cyclopentylidene, and R 3 formyl or diniederalkoxymethyl, each with up to and with 4 carbon atoms in the lower alkyl part, such as dimethoxymethyl, or lower alkylenedioxy-methyl with up to 4 carbon atoms in the lower alkyl part , such as 1,3-dioxolan-2-yl, means their isomers and their salts.
7. Verbindungen der Formel (I) gemäss Anspruch 1, worin R1 und R2 unabhängig voneinander Phenyl und/oder durch Niederalkoxy mit bis und mit 4 C-Atomen, wie Methoxy, substituiertes Phenyl bedeuten, A Niederalkylen mit bis und mit 4 C-Atomen, wie Methylen, oder insbesondere Niederalkyliden mit bis und mit 4 C-Atomen, wie 2,2-Propyliden, darstellt und R3 Diniederalkoxy-methyl jeweils mit bis und mit 4 C-Atomen im Niederalkoxyteil, wie Diethoxy-methyl, oder Niederalkylendioxy-methyl mit bis und mit 4 C-Atomen im Niederalkylenteil, wie 1,3-Dioxolan-2-yl, bedeutet, ihre Isomeren sowie ihre Salze. 7. Compounds of formula (I) according to claim 1, wherein R 1 and R 2 independently of one another are phenyl and / or phenyl which is substituted by lower alkoxy with up to and with 4 carbon atoms, such as methoxy, A lower alkylene with up to and with 4 C. -Atoms, such as methylene, or in particular lower alkylidene with up to and with 4 C atoms, such as 2,2-propylidene, and R 3 is diniederalkoxy-methyl, each with up to and with 4 C atoms in the lower alkoxy part, such as diethoxy-methyl, or Lower alkylenedioxy-methyl with up to and with 4 carbon atoms in the lower alkylene part, such as 1,3-dioxolan-2-yl, means their isomers and their salts.
8. Verbindungen der Formel (I) gemäss Anspruch 1, worin einer der8. Compounds of formula (I) according to claim 1, wherein one of the
Reste R1 und R2 Phenyl oder durch Halogen mit Atomnummer bis und mitR 1 and R 2 are phenyl or halogen with atomic numbers up to and including
35, wie Chlor, Hydroxy oder Niederalkoxy mit bis und mit 4 C-Atomen, wie Methoxy, substituiertes Phenyl bedeutet und der andere Pyridyl, wie 3- oder 4-Pyridyl, oder 1-Oxidopyridyl, wie 1-Oxido-3-pyridyl oder 1Oxido 4-pyridyl, darstellt, A Niederalkyliden mit bis und mit 4 C-Atomen, wie 2,2-Propyliden, bedeutet, und R3 Formyl oder Diniederalkoxy-methyl jeweils mit bis und mit 4 C-Atomen im Niederalkoxyteil, wie Diethoxy methyl, oder Niederalkylendioxy-methyl mit bis und mit 4 C-Atomen im Niederalkylenteil, wie 1,3-Dioxolan-2-yl, bedeutet, ihre Isomeren sowie ihre Salze.35, such as chlorine, hydroxy or lower alkoxy with up to 4 carbon atoms, such as methoxy, substituted phenyl and the other pyridyl, such as 3- or 4-pyridyl, or 1-oxidopyridyl, such as 1-oxido-3-pyridyl or 1Oxido represents 4-pyridyl, A is lower alkylidene with up to 4 carbon atoms, such as 2,2-propylidene, and R 3 formyl or diniederalkoxy-methyl, each with up to 4 carbon atoms in the lower alkoxy part, such as diethoxy methyl , or lower alkylenedioxy-methyl with up to and with 4 carbon atoms in the lower alkylene part, such as 1,3-dioxolan-2-yl, means their isomers and their salts.
9. Verbindungen der Formel (I) gemäss Anspruch 1, worin einer der Reste R1 und R2 Phenyl oder durch Halogen mit Atomnummer bis und mit 35, wie Chlor, Hydroxy oder Niederalkoxy mit bis und mit 4 C-Atomen, wie Methoxy, substituiertes Phenyl bedeutet und der andere Pyridyl, wie 3- oder 4-Pyridyl, oder 1-Oxidopyridyl, wie l-Oxido-3-pyridyl oder l-Oxido-4-pyridyl, darstellt, A ein ein quartäres. C-Atom aufweisendes Niederalkyliden mit bis und mit 4 C-Atomen, wie 2,2-Propyliden, wobei das quartäre C-Atom direkt an den Imidazolring gebunden ist, bedeutet, und R3 Formyl oder Diniederalkoxy-methyl mit bis und mit 4 C-Atomen jeweils im Niederalkylteil, wie Diethoxy-methyl, darstellt, ihre Isomeren sowie ihre Salze.9. Compounds of formula (I) according to claim 1, wherein one of the radicals R 1 and R 2 is phenyl or by halogen with atomic numbers up to and including 35, such as chlorine, hydroxyl or lower alkoxy having up to and including 4 carbon atoms, such as methoxy, is substituted phenyl and the other is pyridyl, such as 3- or 4-pyridyl, or 1-oxidopyridyl, such as l-oxido-3-pyridyl or l-oxido-4-pyridyl, A is a quaternary. Lower alkylidene containing up to 4 carbon atoms, such as 2,2-propylidene, where the quaternary carbon atom is bonded directly to the imidazole ring, and R 3 is formyl or diniederalkoxy-methyl with up to and with 4 C -Atoms each in the lower alkyl part, such as diethoxy-methyl, represents their isomers and their salts.
10. Verbindungen der Formel (I) gemäss Anspruch 1, worin einer der Reste R1 und R2 Phenyl und der andere Pyridyl, wie 3-Pyridyl, oder 1-Oxido pyridyl, wie 1-Oxido-3-pyridyl, bedeutet, A 2,2-Proρyliden darstellt und R3 Formyl oder Diniederalkoxymethyl jeweils mit bis und mit 4 C-Atomen im Niederalkoxy, wie Diethoxymethyl, bedeutet, ihrer Isomeren sowie ihre Salze.10. Compounds of formula (I) according to claim 1, wherein one of the radicals R 1 and R 2 is phenyl and the other pyridyl, such as 3-pyridyl, or 1-oxido pyridyl, such as 1-oxido-3-pyridyl, A 2,2-propylidene and R 3 is formyl or diniederalkoxymethyl, each having up to and with 4 carbon atoms in lower alkoxy, such as diethoxymethyl, their isomers and their salts.
11. 2-[4(5)-Phenyl-5(4)-(3-ρyridyl)-imidazol-2-yl]-acetaldehyd-dimethylacetal. 11. 2- [4 (5) phenyl-5 (4) - (3-pyridyl) imidazol-2-yl] acetaldehyde dimethyl acetal.
12. 2-[4-(5)-Phenyl-5(4)-(1-oxido-3-pyridyl)-imidazol-2-yl]-acetaldehyd-dimethylacetyl.12. 2- [4- (5) -phenyl-5 (4) - (1-oxido-3-pyridyl) imidazol-2-yl] acetaldehyde dimethylacetyl.
13. 2-[4(5)-Phenyl-5-(4)-(3-pyridyl)-imidazol-2-yl]-propandimethylacetal.13. 2- [4 (5) -phenyl-5- (4) - (3-pyridyl) imidazol-2-yl] propanedimethyl acetal.
14. 2-[4-(5)-Phenyl-5(4)-(3-pyfidyl)-imidazol-2-yl]-methyl-propanaldimethylacetal.14. 2- [4- (5) -phenyl-5 (4) - (3-pyfidyl) imidazol-2-yl] methyl propanaldimethylacetal.
15. 2-[4(5)-Phenyl-5(4)-(l-oxido-3-pyridyl)-imidazol-2-yl]-propanaldimethylacetal.15. 2- [4 (5) -phenyl-5 (4) - (l-oxido-3-pyridyl) imidazol-2-yl] propanaldimethylacetal.
16. 2-[4(5)-Phenyl-5 (4)-(l-oxido-3-pyridyl)-imidazol-2-y1]-2-methy1- propanaldimethylacetal.16. 2- [4 (5) -phenyl-5 (4) - (l-oxido-3-pyridyl) imidazol-2-y1] -2-methyl-propanaldimethylacetal.
17. 2-[4(5)-Phenyl-5 (4)-(3-pyridyl)-imidazol-2-yl]-2-methy1-1,1-methylendioxypropan.17. 2- [4 (5) -phenyl-5 (4) - (3-pyridyl) imidazol-2-yl] -2-methy1-1,1-methylenedioxypropane.
18. 2-[4(5)-Phenyl-5 (4)-(3-pyridyl)-imidazol-2-y1]-2-methy1-1,1-ethylendioxypropan.18. 2- [4 (5) -phenyl-5 (4) - (3-pyridyl) imidazol-2-y1] -2-methy1-1,1-ethylenedioxypropane.
19. 2-[4(5)—Phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-2-methy1-propionaldehyd.19. 2- [4 (5) —phenyl-5 (4) - (3-pyridyl) imidazol-2-yl] -2-methyl-propionaldehyde.
20. 2-[4(5)-Phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-2-methyl-butyraldehyd.20. 2- [4 (5) -phenyl-5 (4) - (3-pyridyl) imidazol-2-yl] -2-methylbutyraldehyde.
21. 2-[4(5)-Phenyl-5 (4)-(3-pyridyl)-imidazol-2-yl]-propionaldehyd.21. 2- [4 (5) -phenyl-5 (4) - (3-pyridyl) imidazol-2-yl] propionaldehyde.
22. 2-[4(5)-Phenyl-5 (4)-(1-oxido-3-pyridyl)-imidazol-2-yl]-acetaldehyd.22. 2- [4 (5) -phenyl-5 (4) - (1-oxido-3-pyridyl) imidazol-2-yl] acetaldehyde.
23.2-(4(5)-Phenyl-5 (4)—(l-oxido-3-pyridy1)-imidazol-2-yl]-propionaldehyd, 2-[4(5)-Phenyl-5 (4)-(1-oxido-3-pyridyl)-imidazol-2-y1]-2- methyl-propionaldehyd, 2-[4(5)-Phenyl-5(4)-(l-oxido-3-pyridyl)-imi dazol-2-yl]-butyraldehyd.23.2- (4 (5) -phenyl-5 (4) - (l-oxido-3-pyridy1) -imidazol-2-yl] -propionaldehyde, 2- [4 (5) -phenyl-5 (4) - ( 1-oxido-3-pyridyl) imidazol-2-y1] -2- methyl-propionaldehyde, 2- [4 (5) -phenyl-5 (4) - (l-oxido-3-pyridyl) -imidol-2-yl] butyraldehyde.
24. Eine Verbindung gemäss einem der Ansprüche 11 bis 23 in Form eines Säureadditionssalzes.24. A compound according to any one of claims 11 to 23 in the form of an acid addition salt.
25. Verbindung gemäss einem der Ansprüche 1-24 mit Wirkung als externe Hautphlogistika.25. A compound according to any one of claims 1-24 with effect as external dermatological agents.
26. Pharmazeutische Präparate, enthaltend mindestens eine Verbindung gemäss einem der Ansprüche 1-25.26. Pharmaceutical preparations containing at least one compound according to one of claims 1-25.
27. Verfahren zur Herstellung von Verbindungen der Formel (I) gemäss Anspruch 1, dadurch gekennzeichnet, dass man aus einer Verbindung der Formel27. A process for the preparation of compounds of formula (I) according to claim 1, characterized in that from a compound of formula
(Il) ,
Figure imgf000045_0001
worin einer der Reste Y1 und Y6 Hydroxy oder Amino und der andere sowie Y2 Wasserstoff darstellt und Y3 gemeinsam mit Y4 und Y5 eine(Il),
Figure imgf000045_0001
wherein one of the radicals Y 1 and Y 6 is hydroxyl or amino and the other and Y 2 is hydrogen and Y 3 together with Y 4 and Y 5 is one
Gruppe der Formel =N- bedeutet oder worin Y1 gemeinsam mit Y6 eineGroup of the formula = N- or wherein Y 1 together with Y 6 one
Bindung darstellt, Y2 Wasserstoff ist, Y3 Hydroxy oder Amino bedeutet und Y4 gemeinsam mit Y5 eine Gruppe der Formel -NH- darstellt oder worin Y1 gemeinsam mit Y6 eine Bindung darstellt, Y2 gemeinsam mit Y3 eine zusätzliche Bindung oder reaktionsfähiges verestertes Hydroxy, insbesondere Halogen oder Sulfonyloxy, darstellt oder worin Y1 Hydroxy ist, Y2 sowie Y3 Wasserstoff bedeutet, Y4 Hydroxy oder Amino darstellt und Y5 gemeinsam mit Y6 eine Gruppe der Formel =NH oder, sofern Y4 Amino ist, Oxo oder Imino bedeutet, oder einem Tautomeren und/oder Salz davon, unter Einführung einer gegebenenfalls zusätzlichen Bindung H-Z abspaltet, oder eine Verbindung der FormelBinding is Y 2 is hydrogen, Y 3 is hydroxy or amino and Y 4 together with Y 5 is a group of the formula -NH- or wherein Y 1 together with Y 6 is a bond, Y 2 together with Y 3 is an additional bond or reactive esterified hydroxy, especially halogen or sulfonyloxy, or wherein Y 1 is hydroxy is, Y 2 and Y 3 are hydrogen, Y 4 is hydroxy or amino and Y 5 together with Y 6 is a group of the formula = NH or, if Y 4 is amino, is oxo or imino, or a tautomer and / or salt thereof , with the introduction of an optionally additional bond HZ, or a compound of the formula
(IV)
Figure imgf000046_0001
oder ein Salz davon zu einer Verbindung der Formel I reduziert, in einer Verbindung der Formel(IV)
Figure imgf000046_0001
or a salt thereof reduced to a compound of formula I in a compound of formula
Figure imgf000046_0002
worin R'3 einen in R3 überführbaren Rest bedeutet, oder in einem Salz davon R'3 in R3 überführt und gewünschtenfalls die verfahrensgemäss erhältliche Verbindung in eine andere Verbindung der Formel I, eine verfahrensgemäss erhältliche Verbindung in ein Salz oder ein verfahrensgemäss erhältliches Salz in die freie Verbindung oder in ein anderes Salz überführt und/ oder, wenn erwünscht, ein erfindungsgemäss erhältliches Gemisch von isomeren Verbindungen der Formel I in die einzelnen Isomeren auftrennt.
Figure imgf000046_0002
wherein R ' 3 is a residue convertible to R 3 , or in a salt thereof, R' 3 is converted to R 3 and, if desired, the process-available compound into another compound of formula I, a process-available compound into a salt or a process-available salt converted into the free compound or into another salt and / or, if desired, a mixture of isomeric compounds of the formula I obtainable according to the invention is separated into the individual isomers.
28. Verfahren gemäss Anspruch 27, dadurch gekennzeichnet, dass man von einer auf irgendeiner Stufe des Verfahrens als Zwischenprodukt erhältlichen Verbindung ausgeht und die fehlenden Schritte durchführt, oder einen Ausgangsstoff in Form eines Salzes, Isomeren und/oder Racemates bzw. Antipoden verwendet oder unter den Reaktionsbedingungen bildet.28. The method according to claim 27, characterized in that one starts from a compound obtainable as an intermediate at any stage of the process and carries out the missing steps, or uses a starting material in the form of a salt, isomers and / or racemates or antipodes or among the Forms reaction conditions.
29. Verfahren zur Herstellung pharmazeutischer Präparate, dadurch gekennzeichnet, dass man mindestens eine Verbindung gemäss einem der Ansprüche 1-25 mit üblichen pharmazeutischen Hilfs- und Trägerstoffen vermischt.29. Process for the preparation of pharmaceutical preparations, thereby characterized in that at least one compound according to one of claims 1-25 is mixed with conventional pharmaceutical auxiliaries and carriers.
30. Verbindung gemäss einem der Ansprüche 1-25 zur therapeutischen Behandlung des menschlichen oder tierischen Körpers.30. A compound according to any one of claims 1-25 for the therapeutic treatment of the human or animal body.
31. Verwendung von Verbindung gemäss einem der Ansprüche 1-25 in einem Verfahren zur Behandlung entzündlicher Dermatosen.31. Use of compound according to any one of claims 1-25 in a method for the treatment of inflammatory dermatoses.
32. Die in den Beispielen 1-4 genannten neuen Verbindungen.32. The new compounds mentioned in Examples 1-4.
33. Das Verfahren der Beispiele 1-10 und die danach erhältlichen Verfahrensprodukte.33. The process of Examples 1-10 and the process products obtainable thereafter.
34. Die in dem Verfahren gemäss Anspruch 27, 28 und 32 verwendeten neuen Ausgangsstoffe und Zwischenprodukte. 34. The new starting materials and intermediates used in the process according to claims 27, 28 and 32.
PCT/CH1982/000011 1981-07-20 1982-01-25 Trisubstituted diazo compounds WO1983002611A1 (en)

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