EP0000928A1 - Nitroimidazoles and pharmaceutical compositions containing them as well as their preparation - Google Patents

Nitroimidazoles and pharmaceutical compositions containing them as well as their preparation Download PDF

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EP0000928A1
EP0000928A1 EP78100690A EP78100690A EP0000928A1 EP 0000928 A1 EP0000928 A1 EP 0000928A1 EP 78100690 A EP78100690 A EP 78100690A EP 78100690 A EP78100690 A EP 78100690A EP 0000928 A1 EP0000928 A1 EP 0000928A1
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Prior art keywords
lower alkyl
aryl
nitro
methyl
hydroxy
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EP0000928B1 (en
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Carey Ernest Smithen
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F Hoffmann La Roche AG
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    • 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
    • C07D233/66—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to new nitroimidazoles, a process for their preparation and pharmaceutical preparations containing these compounds.
  • lower alkyl means a straight or branched chain alkyl group preferably having 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl.
  • hydroxy lower alkyl groups are hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl and 2-hydroxybutyl.
  • lower cycloalkyl means cycloalkyl groups, preferably having up to 6 carbon atoms, such as cyclopropyl, cyclopentyl and cyclohexyl.
  • aryl means the phenyl group or the mono- or polysubstituted, preferably mono- or polysubstituted phenyl group, where the substituents can be halogens (ie fluorine, chlorine, bromine or iodine) trifluoromethyl, lower alkyl, lower alkoxy, nitro and amino.
  • substituents can be halogens (ie fluorine, chlorine, bromine or iodine) trifluoromethyl, lower alkyl, lower alkoxy, nitro and amino.
  • substituted phenyl groups are 4-chlorophenyl, 2,4-dichlorophenyl, p-tolyl, 4-methoxyphenyl, 4-nitrophenyl and 4-aminophenyl.
  • aryl-lower alkyl denotes a lower alkyl radical substituted by an aryl group.
  • aryl-lower alkyl groups examples include benzyl, 4-chlorobenzyl, phenethyl and phenylpropyl.
  • saturated heteromonocyclic rings which are formed from the substituents R 1 and R 2 together with the nitrogen atom and which can carry a hydroxyl group on a C atom which is not directly adjacent to the nitrogen atom are pyrrolidino, piperidino, 3-hydroxypyrrolidino, 4- Hydroxy-piperidino and 3-hydroxy-hexahydro-1H-azepino.
  • saturated heteromonocyclic rings which are formed from the substituents R 1 and R 2 together with the nitrogen atom to which they are attached and which may contain another oxygen, sulfur or nitrogen atom which may optionally be substituted as indicated above are piperazino, N-methylpiperazino, N- (2-hydroxyethyl ⁇ piperazino, morpholino and thiamorpholino.
  • lower alkoxy means a straight or branched chain alkoxy group preferably having 1-6 carbon atoms, such as methoxy or ethoxy.
  • nitroimidazoles of the present invention are compounds of the formula I in which R 1 is hydrogen, lower alkyl, hydroxy-lower alkyl, aryl or aryl-lower alkyl, R lower alkyl, hydroxy-lower alkyl, aryl or aryl-lower alkyl or R1 and R 2 together with the nitrogen atom to which they are attached, a 5-, 6- or 7-membered saturated heteromonocyclic
  • Represent ring which may contain a further oxygen, sulfur or nitrogen atom, which may optionally be substituted by a lower alkyl, hydroxy-lower alkyl, aryl or aryl-lower alkyl group, and their acid addition salts.
  • a particularly interesting group of nitroimidazole derivatives of the present invention are those compounds of the formula I in which R 1 and R 2 together with the nitrogen atom to which they are attached represent a 6-membered heteromonocyclic ring which may contain another oxygen or nitrogen atom , which is optionally substituted by a lower alkyl group, and their acid addition salts.
  • the reaction of an epoxide of formula II with an amine of formula III according to process variant (a) can be carried out in the presence or absence of an inert organic solvent.
  • Suitable inert organic solvents are lower alkanols (e.g. methanol and ethanol), dimethylformamide or dimethylacetamide.
  • an excess of an amine of formula III can be used as a solvent.
  • Pressure and temperature during the reaction are not critical; the reaction can be carried out at room temperature and under atmospheric pressure or else at elevated temperature and / or elevated pressure. In a preferred embodiment, the reaction is carried out at a temperature of about 50 ° C. to the reflux temperature of the reaction mixture and under normal pressure.
  • the condensation of a compound of formula IV (azomycin) with an epoxide of formula V according to process variant (b) is carried out in the presence of a base.
  • Catalytic amounts of the base are preferably used, although larger amounts are also used can.
  • Preferred bases are alkali metal carbonates (e.g. sodium carbonate or potassium carbonate), although other bases such as alkali metal hydroxides (e.g. sodium hydroxide or potassium hydroxide) can also be used.
  • the condensation is expediently carried out in the presence of an inert organic solvent, for example a lower alkanol (for example methanol or ethanol). Although the condensation can also be carried out at room temperature and under higher pressure, it is preferably carried out at elevated temperature, in particular at the reflux temperature of the reaction mixture, and under atmospheric pressure.
  • a halohydrin of the formula VI is reacted with an amine of the formula III according to process variant (c), at least one mole of amine is advantageously used per mole of halohydrin.
  • the reaction is advantageously carried out in the presence of an acid-binding agent, such as an alkali metal carbonate (for example sodium carbonate or potassium carbonate) or a tertiary organic amine (for example pyridine) or, preferably, in the presence of excess amine of the formula III.
  • an acid-binding agent such as an alkali metal carbonate (for example sodium carbonate or potassium carbonate) or a tertiary organic amine (for example pyridine) or, preferably, in the presence of excess amine of the formula III.
  • an acid-binding agent such as an alkali metal carbonate (for example sodium carbonate or potassium carbonate) or a tertiary organic amine (for example pyridine) or, preferably, in the presence of excess amine of the formula III.
  • the reaction advantageously takes place in the presence of an inert organic solvent, for example a lower alkanol (for example methanol or ethanol).
  • an inert organic solvent for example a lower alkanol (for example methanol or ethanol).
  • the temperature and pressure during the reaction are not critical. It can be carried out at room temperature and under normal pressure or at elevated temperature and under pressure. In a preferred embodiment, the reaction is carried out at elevated temperature, in particular at the reflux temperature of the reaction mixture, and under normal pressure. Chlorohydrin is used as the preferred halohydrin of the formula VI.
  • the compounds of formula I can be converted into acid addition salts, for example by reaction with an inorganic cal acid, such as a hydrohalic acid (e.g. HCl or HBr), sulfuric acid, nitric acid or phosphoric acid or with an organic acid such as acetic acid, citric acid, maleic acid, malic acid, fumaric acid, succinic acid, methanesulfonic acid or paratoluenesulfonic acid.
  • Physiologically acceptable acid addition salts especially the hydrochlorides, are preferred.
  • Physiologically unacceptable acid addition salts can be converted into physiologically acceptable acid addition salts by treatment with a base and subsequent reaction with a physiologically acceptable acid.
  • the starting compounds of the formulas II to VI are known compounds.
  • the compounds of the formula I and their physiologically tolerated acid addition salts can be used as so-called "radiosensitizers" for sensitizing hypoxic cells to radiation, in particular in connection with the treatment of hypoxic tumor cells by radiation.
  • radiosensitizers for sensitizing hypoxic cells to radiation, in particular in connection with the treatment of hypoxic tumor cells by radiation.
  • the effectiveness of the compounds of the formula I and their physiologically tolerable acid addition salts as radiosensitizers for hypoxic cells can be determined in an in vitro experiment on hypoxic Chinese hamster V79 cells (cf.
  • the compounds of formula I and their physiologically tolerated acid addition salts can also be used to control infections caused by protozoa, in particular infections caused by Trichomonas vaginalis can be caused.
  • the compounds according to the invention can be used as pharmaceutical preparations with direct or delayed release of the active ingredient in a mixture with an organic or inorganic inert carrier material suitable for enteral, for example oral or parenteral administration, such as water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, Talc, vegetable oils, polyalkylene glycols or petroleum jelly can be used.
  • the preparations can be in solid form, for example as tablets, dragées, suppositories, capsules; in semi-solid form, for example as ointments; or in liquid form, for example as solutions, suspensions or emulsions.
  • compositions are sterilized and or or contain further adjuvants such as preservatives -, stabilizing, wetting or emulsifying agents, flavor-improving, salts for changing the osmotic pressure or buffering agents.
  • adjuvants such as preservatives -, stabilizing, wetting or emulsifying agents, flavor-improving, salts for changing the osmotic pressure or buffering agents.
  • the preparations can also contain other therapeutically valuable compounds.
  • the pharmaceutical preparations can be prepared in the manner familiar to any person skilled in the art by mixing one of the compounds according to the invention as an active ingredient with an inert, solid or liquid carrier suitable for therapeutic administration, and if appropriate bringing the mixture into a special galenic form.
  • the compounds according to the invention can be administered orally at a dosage of about 20 to 60 mg per kg of body weight and day. In general, however, the total dose administered during a treatment should not exceed about 200 mg per kg body weight and day.
  • the compounds according to the invention can also be administered orally at a daily dosage of about 20 to 60 mg per kg of body weight.
  • the dose ranges mentioned above are only guidelines and can be exceeded or undershot depending on the individual requirements.
  • the pharmaceutical preparation described above can be produced in a manner known per se, if possible with the exclusion of light, and should be kept in the dark.

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Abstract

Nitroimidazole der Formel <IMAGE> worin R¹ Wasserstoff, Niederalkyl, Hydroxy-niederalkyl, Niedercycloalkyl, Aryl oder Arylniederalkyl R² Niederalkyl. Hydroxy-niederalkyl, Niedercycloalkyl, Aryl, Aryl-niederalkyl oder ein Rest der Formel <IMAGE> mit m = 0 und n = 1 oder m = 1 und n = 0 und worin R³ Wasserstoff, Methyl, Hydroxy oder ein freies Oxylradikal oder R¹ und R² zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-, 6- oder 7gliedrigen gesättigten heteromonocyclischen Ring, der eine Hydroxygruppe an einem dem Stickstoffatom nicht direkt benachbarten C-Atom tragen kann und der ein weiteres Sauerstoff-, Schwefel- oder Stickstoffatom enthalten kann, das gebenenfalls durch eine Niederalkyl-, Hydroxy-niederalkyl-, Aryl- oder Aryl-niederalkylgruppe substituiert ist, darstellen, und deren Säureadditionssalze, sowie deren Herstellung nach an sich bekannten Methoden.Nitroimidazoles of the formula <IMAGE> wherein R¹ is hydrogen, lower alkyl, hydroxy-lower alkyl, lower cycloalkyl, aryl or aryl-lower alkyl R² lower alkyl. Hydroxy-lower alkyl, lower cycloalkyl, aryl, aryl-lower alkyl or a radical of the formula <IMAGE> with m = 0 and n = 1 or m = 1 and n = 0 and in which R³ is hydrogen, methyl, hydroxy or a free oxyl radical or R¹ and R² together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated heteromonocyclic ring which can carry a hydroxyl group on a carbon atom which is not directly adjacent to the nitrogen atom and which has another oxygen, sulfur or nitrogen atom May contain, which is optionally substituted by a lower alkyl, hydroxy-lower alkyl, aryl or aryl-lower alkyl group, and their acid addition salts, and their preparation by methods known per se.

Description

Die vorliegende Erfindung betrifft neue Nitroimidazole, ein Verfahren zu deren Herstellung und pharmazeutische Präparate mit einem Gehalt an diesen Verbindungen.The present invention relates to new nitroimidazoles, a process for their preparation and pharmaceutical preparations containing these compounds.

Die Nitroimidazole der vorliegenden Erfindung sind Verbindungen der allgemeinen Formel

Figure imgb0001

  • worin R1 Wasserstoff, Niederalkyl, Hydroxy-niederalkyl, Niedercycloalkyl, Aryl oder Aryl- niederalkyl
  • R 2 Niederalkyl, Hydroxy-niederalkyl, Niedercycloalkyl, Aryl, Aryl-niederalkyl oder ein Rest der Formel
    Figure imgb0002
    mit m = 0 und n = 1 oder
  • m = 1 und n = O und worin
  • R3 Wasserstoff, Methyl, Hydroxy oder ein freies Oxylradikal oder
  • R 1 und R 2 zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-, 6-oder 7-gliedrigen gesättigten heteromonocyclischen Ring, der eine Hydroxygruppe an einem dem Stickstoffatom nicht direkt benachbarten C-Atom tragen kann und der ein weiteres Sauerstoff-, Schwefel- oder Stickstoffatom enthalten kann, das ggf. durch eine Niederalkyl-, Hydroxy-niederalkyl-, Aryl- oder Aryl-niederalkyl-gruppe substituiert ist, darstellen, und deren Säureadditionssälze.
The nitroimidazoles of the present invention are compounds of the general formula
Figure imgb0001
  • wherein R 1 is hydrogen, lower alkyl, hydroxy-lower alkyl, lower cycloalkyl, aryl or aryl lower alkyl
  • R 2 lower alkyl, hydroxy-lower alkyl, lower cycloalkyl, aryl, aryl-lower alkyl or a radical of the formula
    Figure imgb0002
     with m = 0 and n = 1 or
  • m = 1 and n = O and where
  • R 3 is hydrogen, methyl, hydroxy or a free oxyl radical or
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated heteromonocyclic ring which can carry a hydroxyl group on a carbon atom which is not directly adjacent to the nitrogen atom and which contains further oxygen - Can contain sulfur or nitrogen atom, which is optionally substituted by a lower alkyl, hydroxy-lower alkyl, aryl or aryl-lower alkyl group, and their acid addition salts.

In der Beschreibung und den Ansprüchen bedeutet der Ausdruck "Niederalkyl" eine gerad- oder verzweigtkettige Alkylgruppe mit vorzugsweise 1-6 Kohlenstoffatomen, wie Methyl, Aethyl, Propyl, Isopropyl, Butyl, tert.Butyl, Pentyl und Hexyl. Beispiele von Hydroxyniederalkylgruppen sind Hydroxymethyl, 2-Hydroxyäthyl, 2-Hydroxypropyl, 3-Hydroxypropyl und 2-Hydroxybutyl. Der Ausdruck "Niedercycloalkyl" bedeutet Cycloalkylgruppen mit vorzugsweise bis zu 6 Kohlenstoffatomen,wie Cyclopropyl, Cyclopentyl und Cyclohexyl. Der Ausdruck Aryl bedeutet die Phenylgruppe oder die ein- oder mehrfach, vorzugsweise ein- oder zweifach substituierte Phenylgruppe, wobei die Substituenten Halogene (d.h. Fluor, Chlor, Brom oder Jod) Trifluormethyl, Niederalkyl, Niederalkoxy, Nitro und Amino sein können. Beispiele solcher substituierter Phenylgruppen sind 4-Chlorphenyl, 2,4-Dichlorphenyl, p-Tolyl, 4-Methoxyphenyl, 4-Nitrophenyl und 4-Aminophenyl. Der Ausdruck "Aryl-niederalkyl" bezeichnet einen durch eine Arylgruppe substituierten Niederalkylrest. Beispiele solcher Arylniederalkylgruppen sind Benzyl, 4-Chlorbenzyl, Phenäthyl und Phenylpropyl. Beispiele von gesättigten heteromonocyclischen Ringen, die aus den Substituenten R1 und R2 zusammen mit dem Stickstoffatom gebildet werden und die eine Hydroxygruppe an einem dem Stickstoffatom nicht_direkt benachbarten C-Atom tragen können, sind Pyrrolidino, Piperidino, 3-Hydroxy-pyrrolidino, 4-Hydroxy-piperidino und 3-Hydroxy-hexahydro-lH-azepino. Beispiele von gesättigten heteromonocyclischen Ringen,die aus den Substituenten R1 und R2 zusammen mit dem Stickstoffatom,an das sie gebunden sind,gebildet werden und die ein weiteres Sauerstoff-, Schwefel- oder Stickstoffatom enthalten können, das gegebenenfalls wie vorstehend angegeben substituiert sein kann, sind Piperazino, N-Methylpiperazino, N-(2-Hydroxyäthyl}piperazino, Morpholino und Thiamorpholino. Der Ausdruck "Niederalkoxy" bedeutet eine gerad- oder verzweigtkettige Alkoxygruppe mit vorzugsweise 1-6 Kohlenstoffatomen,wie Methoxy oder Aethoxy.In the description and claims, the term "lower alkyl" means a straight or branched chain alkyl group preferably having 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl. Examples of hydroxy lower alkyl groups are hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl and 2-hydroxybutyl. The term "lower cycloalkyl" means cycloalkyl groups, preferably having up to 6 carbon atoms, such as cyclopropyl, cyclopentyl and cyclohexyl. The term aryl means the phenyl group or the mono- or polysubstituted, preferably mono- or polysubstituted phenyl group, where the substituents can be halogens (ie fluorine, chlorine, bromine or iodine) trifluoromethyl, lower alkyl, lower alkoxy, nitro and amino. Examples of such substituted phenyl groups are 4-chlorophenyl, 2,4-dichlorophenyl, p-tolyl, 4-methoxyphenyl, 4-nitrophenyl and 4-aminophenyl. The term "aryl-lower alkyl" denotes a lower alkyl radical substituted by an aryl group. Examples of such aryl-lower alkyl groups are benzyl, 4-chlorobenzyl, phenethyl and phenylpropyl. Examples of saturated heteromonocyclic rings which are formed from the substituents R 1 and R 2 together with the nitrogen atom and which can carry a hydroxyl group on a C atom which is not directly adjacent to the nitrogen atom are pyrrolidino, piperidino, 3-hydroxypyrrolidino, 4- Hydroxy-piperidino and 3-hydroxy-hexahydro-1H-azepino. Examples of saturated heteromonocyclic rings which are formed from the substituents R 1 and R 2 together with the nitrogen atom to which they are attached and which may contain another oxygen, sulfur or nitrogen atom which may optionally be substituted as indicated above are piperazino, N-methylpiperazino, N- (2-hydroxyethyl} piperazino, morpholino and thiamorpholino. The term "lower alkoxy" means a straight or branched chain alkoxy group preferably having 1-6 carbon atoms, such as methoxy or ethoxy.

Eine interessante Gruppe von Nitroimidazolen der vorliegenden Erfindung sind Verbindungen der Formel I in denen R1 Wasserstoff, Niederalkyl, Hydroxy-niederalkyl, Aryl oder Aryl-niederalkyl, R Niederalkyl, Hydroxy-nieder alkyl, Aryl oder Aryl-niederalkyl oder R1 und R 2 zusammen mit dem Stickstoffatom,an das sie gebunden sind,einen 5-, 6- oder 7-gliedrigen gesättigten heteromonocyclischenAn interesting group of nitroimidazoles of the present invention are compounds of the formula I in which R 1 is hydrogen, lower alkyl, hydroxy-lower alkyl, aryl or aryl-lower alkyl, R lower alkyl, hydroxy-lower alkyl, aryl or aryl-lower alkyl or R1 and R 2 together with the nitrogen atom to which they are attached, a 5-, 6- or 7-membered saturated heteromonocyclic

Ring darstellen der ein weiteres Sauerstoff-, Schwefel-oder Stickstoffatom enthalten kann, das gegebenenfalls durch eine Niederalkyl-, Hydroxy-niederalkyl-, Aryl oder Aryl-niederalkyl-gruppe substituiert sein kann, sowie deren Säureadditionssalze.Represent ring which may contain a further oxygen, sulfur or nitrogen atom, which may optionally be substituted by a lower alkyl, hydroxy-lower alkyl, aryl or aryl-lower alkyl group, and their acid addition salts.

Eine besonders interessante Gruppe von Nitroimidazolderivaten der vorliegenden Erfindung sind solche Verbindungen der Formel I in denen R1 und R2 zusammen mit dem Stickstoffatom,an das sie gebunden sind,einen 6-gliedrigen heteromonocyclischen Ring darstellen, der ein weiteres Sauerstoff- oder Stickstoffatom enthalten kann, das gegebenenfalls durch eine Niederalkylgruppe substituiert ist, sowie deren Säureadditionssalze.A particularly interesting group of nitroimidazole derivatives of the present invention are those compounds of the formula I in which R 1 and R 2 together with the nitrogen atom to which they are attached represent a 6-membered heteromonocyclic ring which may contain another oxygen or nitrogen atom , which is optionally substituted by a lower alkyl group, and their acid addition salts.

Beispiele von erfindungsgemässen Verbindungen der Formel I sind:

  • 2-Nitro-α-(piperidino)-methyl-1-imidazol-äthanol,
  • a-(Morpholino)-methyl-2-nitro-l-imidazol-äthanol,
  • a-(4-Methylpiperazino)-methyl-2-nitro-l-imidazol- äthanol,
  • 2-Nitro-α-(pyrrolidino)-methyl-1-imidazol-äthanol,
  • α-(Diäthylamino)-methyl-2-nitro-1-imidazol-äthanol,
  • α-[Di-(2-hydroxyäthyl)-amino]-methyl-2-nitro-1-imidazol-äthanol,
  • α-(tert.Butylamino)-methyl-2-nitro-1-imidazol- äthanol,
  • a-(Benzylamino)-methyl-2-nitro-l-imidazol-äthanol,
  • a-[(4-Methoxyphenyl)-amino]-methyl-2-nitro-l-imidazol- äthanol,
  • α-(Dimethylamino)-methyl-2-nitro-1-imidazol-äthanol,
  • a-(Hexahydro-lH-azepino)-methyl-2-nitro-l-imidazol- äthanol,
  • 4-[2-Hydroxy-3-(2-nitro-l-imidazolyl)-propylamino]-2,2,6,6-tetramethylpiperidin-N-oxyl,
  • o-[(2,2,6,6-Tetramethyl-4-piperidinyl)-amino]-methyl-2-nitro-l-imidazol-äthanol,
  • α-(Cyclohexylamino)-methyl-2-nitro-1-imidazol- äthanol,
  • α-(Dicyclohexylamino)-methyl-2-nitro-1-imidazol- äthanol und
  • 1-[2-Hydroxy-3-(2-nitro-l-imidazolyl)-propyl]-3-pyrrolidinol.
Examples of compounds of the formula I according to the invention are:
  • 2-nitro-α- (piperidino) methyl-1-imidazole-ethanol,
  • a- (morpholino) methyl-2-nitro-l-imidazole-ethanol,
  • a- (4-methylpiperazino) methyl-2-nitro-l-imidazole ethanol,
  • 2-nitro-α- (pyrrolidino) methyl-1-imidazole ethanol,
  • α- (diethylamino) methyl-2-nitro-1-imidazole-ethanol,
  • α- [di (2-hydroxyethyl) amino] methyl-2-nitro-1-imidazole ethanol,
  • α- (tert-butylamino) methyl-2-nitro-1-imidazole ethanol,
  • a- (benzylamino) methyl-2-nitro-l-imidazole ethanol,
  • a - [(4-methoxyphenyl) amino] methyl-2-nitro-l-imidazole ethanol,
  • α- (dimethylamino) methyl-2-nitro-1-imidazole-ethanol,
  • a- (hexahydro-lH-azepino) methyl-2-nitro-l-imidazole ethanol,
  • 4- [2-hydroxy-3- (2-nitro-l-imidazolyl) propylamino] -2,2,6,6-tetramethylpiperidine-N-oxyl,
  • o - [(2,2,6,6-tetramethyl-4-piperidinyl) amino] methyl-2-nitro-l-imidazole-ethanol,
  • α- (cyclohexylamino) methyl-2-nitro-1-imidazole ethanol,
  • α- (Dicyclohexylamino) methyl-2-nitro-1-imidazole ethanol and
  • 1- [2-Hydroxy-3- (2-nitro-l-imidazolyl) propyl] -3-pyrrolidinol.

Die erfindungsgemässen Nitroimidazole und ihre Säureadditionssalze können dadurch hergestellt werden, dass man

  • (a) ein Epoxid der Formel
    Figure imgb0003
    mit einem Amin der Formel
    Figure imgb0004
    worin R1 und R2 wie vorstehend definiert sind, umsetzt oder
  • (b) eine Verbindung der Formel
    Figure imgb0005
    mit einem Epoxid der Formel
    Figure imgb0006
    worin R10 und R20 ebenso definiert sind wie R1 und R2 mit dem Unterschied, dass R10 nicht Wasserstoff ist, in Gegenwart einer Base umsetzt oder
  • (c) ein Halohydrin der Formel
    Figure imgb0007
    worin X Chlor oder Brom darstellt, mit einem Amin der Formel III umsetzt und gewünschtenfalls eine erhaltene Verbindung der Formel I in ein Säureadditionssalz überführt.
The nitroimidazoles according to the invention and their acid addition salts can be prepared by
  • (a) an epoxy of the formula
    Figure imgb0003
     with an amine of the formula
    Figure imgb0004
     wherein R 1 and R 2 are as defined above, or
  • (b) a compound of the formula
    Figure imgb0005
     with an epoxy of the formula
    Figure imgb0006
     wherein R 10 and R 20 are defined as R 1 and R 2 with the difference that R 10 is not hydrogen, or in the presence of a base
  • (c) a halohydrin of the formula
    Figure imgb0007
     wherein X represents chlorine or bromine, reacted with an amine of formula III and, if desired, converted a compound of formula I obtained into an acid addition salt.

Die Umsetzung eines Epoxids der Formel II mit einem Amin der Formel III gemäss Verfahrensvariante (a) kann in Gegenwart oder Abwesenheit eines inerten organischen Lösungsmittels durchgeführt werden. Geeignete inerte organische Lösungsmittel sind niedere Alkanole (z.B. Methanol und Aethanol), Dimethylformamid oder Dimethylacetamid. Andererseits kann ein Ueberschuss eines Amins der Formel III als Lösungsmittel verwendet werden. Druck und Temperatur während der Reaktion sind nicht kritisch; die Umsetzung kann bei Raumtemperatur und unter Atmosphärendruck oder aber bei erhöhter Temperatur und/oder erhöhtem Druck durchgeführt werden. In einer bevorzugten Ausführungsform wird die Reaktion bei einer Temperatur von etwa 50°C bis zur Rückflusstemperatur des Reaktionsgemisches und unter Normaldruck durchgeführt.The reaction of an epoxide of formula II with an amine of formula III according to process variant (a) can be carried out in the presence or absence of an inert organic solvent. Suitable inert organic solvents are lower alkanols (e.g. methanol and ethanol), dimethylformamide or dimethylacetamide. On the other hand, an excess of an amine of formula III can be used as a solvent. Pressure and temperature during the reaction are not critical; the reaction can be carried out at room temperature and under atmospheric pressure or else at elevated temperature and / or elevated pressure. In a preferred embodiment, the reaction is carried out at a temperature of about 50 ° C. to the reflux temperature of the reaction mixture and under normal pressure.

Die Kondensation einer Verbindung der Formel IV (Azomycin) mit einem Epoxid der Formel V gemäss Verfahrensvariante (b) wird in Gegenwart einer Base durchgeführt. Es werden vorzugsweise katalytische Mengen der Base verwendet, obgleich auch grössere Mengen verwendet werden können. Bevorzugte Basen sind Alkalimetallcarbonate (z.B. Natriumcarbonat oder Kaliumcarbonat), obgleich auch andere Basen,wie Alkalimetallhydroxide (z.B. Natriumhydroxid oder Kaliumhydroxid) ,verwendet werden können. Die Kondensation wird zweckmässigerweise in Gegenwart eines inerten organischen Lösungsmittels, z.B. eines niederen Alkanols (z.B. Methanol oder Aethanol), durchgeführt. Obgleich die Kondensation auch bei Raumtemperatur und unter höherem Druck durchgeführt werden kann,wird sie vorzugsweise bei erhöhter Temperatur, insbesondere bei der Rückflusstemperatur des Reaktionsgemisches, und unter Atmosphärendruck durchgeführt.The condensation of a compound of formula IV (azomycin) with an epoxide of formula V according to process variant (b) is carried out in the presence of a base. Catalytic amounts of the base are preferably used, although larger amounts are also used can. Preferred bases are alkali metal carbonates (e.g. sodium carbonate or potassium carbonate), although other bases such as alkali metal hydroxides (e.g. sodium hydroxide or potassium hydroxide) can also be used. The condensation is expediently carried out in the presence of an inert organic solvent, for example a lower alkanol (for example methanol or ethanol). Although the condensation can also be carried out at room temperature and under higher pressure, it is preferably carried out at elevated temperature, in particular at the reflux temperature of the reaction mixture, and under atmospheric pressure.

Bei der Umsetzung eines Halohydrins der Formel VI mit einem Amin der Formel III gemäss Verfahrensvariante (c) wird zweckmässigerweise mindestens ein Mol Amin pro Mol Halohydrin eingesetzt. Die Reaktion wird zweckmässigerweise in Gegenwart eines säurebindenden Mittels,wie eines Alkalimetallcarbonats (z.B. Natriumcarbonat oder Kaliumcarbonat) oder eines tertiären organischen Amins (z.B. Pyridin) oder, vorzugsweise, in Gegenwart von überschüssigem Amin der Formel III durchgeführt. Demgemäss werden in einer bevorzugten Ausführungsform mindestens 2 Mol eines Amins der Formel III pro Mol des Halohydrins der Formel VI eingesetzt. Die Umsetzung findet zweckmässigerweise in Gegenwart eines inerten organischen Lösungsmittels, beispielsweise eines niederen Alkanols (z.B. Methanol oder Aethanol),statt. Die Temperatur und der Druck während der Reaktion sind nicht kritisch. Es kann bei Raumtemperatur und unter Normaldruck oder aber bei erhöhter Temperatur und unter Druck gearbeitet werden. In einer bevorzugten Ausführungsform wird die Reaktion bei erhöhter Temperatur, insbesondere bei Rückflusstemperatur des Reaktionsgemisches, und unter Normaldruck ausgeführt. Als bevorzugtes Halohydrin der Formel VI wird Chlorhydrin verwendet.When a halohydrin of the formula VI is reacted with an amine of the formula III according to process variant (c), at least one mole of amine is advantageously used per mole of halohydrin. The reaction is advantageously carried out in the presence of an acid-binding agent, such as an alkali metal carbonate (for example sodium carbonate or potassium carbonate) or a tertiary organic amine (for example pyridine) or, preferably, in the presence of excess amine of the formula III. Accordingly, in a preferred embodiment, at least 2 moles of an amine of the formula III are used per mole of the halohydrin of the formula VI . The reaction advantageously takes place in the presence of an inert organic solvent, for example a lower alkanol (for example methanol or ethanol). The temperature and pressure during the reaction are not critical. It can be carried out at room temperature and under normal pressure or at elevated temperature and under pressure. In a preferred embodiment, the reaction is carried out at elevated temperature, in particular at the reflux temperature of the reaction mixture, and under normal pressure. Chlorohydrin is used as the preferred halohydrin of the formula VI.

Die Verbindungen der Formel I können in Säureadditionssalze übergeführt werden, z.B. durch Umsetzung mit einer anorganischen Säure,wie einer Halogenwasserstoffsäure (z.B. HCl oder HBr), Schwefelsäure, Salpetersäure oder Phosphorsäure oder mit einer organischen Säure,wie Essigsäure, Zitronensäure, Maleinsäure, Aepfelsäure, Fumarsäure, Bernsteinsäure, Methansulfonsäure oder Paratoluolsulfonsäure. Physiologisch verträgliche Säureadditionssalze, insbesondere die Hydrochloride, sind bevorzugt. Physiologisch nicht verträgliche Säureadditionssalze können in physiologisch verträgliche Säureadditionssalze durch Behandlung mit einer Base und anschliessende Umsetzung mit einer physiologisch verträglichen Säure übergeführt werden.The compounds of formula I can be converted into acid addition salts, for example by reaction with an inorganic cal acid, such as a hydrohalic acid (e.g. HCl or HBr), sulfuric acid, nitric acid or phosphoric acid or with an organic acid such as acetic acid, citric acid, maleic acid, malic acid, fumaric acid, succinic acid, methanesulfonic acid or paratoluenesulfonic acid. Physiologically acceptable acid addition salts, especially the hydrochlorides, are preferred. Physiologically unacceptable acid addition salts can be converted into physiologically acceptable acid addition salts by treatment with a base and subsequent reaction with a physiologically acceptable acid.

Die Ausgangsverbindungen der Formeln II bis VI sind bekannte Verbindungen.The starting compounds of the formulas II to VI are known compounds.

Die Verbindungen der Formel I und ihre physiologisch verträglichen Säureadditionssalze können als sogenannte "Radiosensitiser" zur Sensibilisierung hypoxischer Zellen gegenüber Strahlen verwendet werden, insbesondere im Zusammenhang mit der Behandlung von hypoxischen Tumorzellen durch Bestrahlung. Die Wirksamkeit der Verbindungen der Formel I und ihrer physiologisch verträglichen Säureadditionssalze als Radiosensitiser für hypoxische Zellen kann in einem in vitro-Versuch an hypoxischen chinesischen Hamster-V79-Zellen (vergl. Adams et al., Radiation Research, 67, 9-20 (1976) gezeigt werden. So besitzen z.B. 2-Nitro-a-(piperidino)-methyl-l-imidazol-äthanol-hydrochlorid und a-(Benzylamino)-methyl-2-nitro-1-imidazol-äthanol-hydrochlorid, zwei neue erfindungsgemässe Nitroimidazole, einen Verstärkungsfaktor von 1,6 (VF Index 1,6) bei Konzentrationen von 30 µMol bzw. 40 µMol. Um die gleiche Verstärkung mit Misonidazol oder Metronidazol zu erreichen, müssten diese beiden bekannten Nitroimidazole in einer Konzentration von 300 µMol bzw. 4000 µMol verwendet werden.The compounds of the formula I and their physiologically tolerated acid addition salts can be used as so-called "radiosensitizers" for sensitizing hypoxic cells to radiation, in particular in connection with the treatment of hypoxic tumor cells by radiation. The effectiveness of the compounds of the formula I and their physiologically tolerable acid addition salts as radiosensitizers for hypoxic cells can be determined in an in vitro experiment on hypoxic Chinese hamster V79 cells (cf. Adams et al., Radiation Research, 67, 9-20 (1976 For example, 2-nitro-a- (piperidino) methyl-l-imidazole-ethanol hydrochloride and a- (benzylamino) methyl-2-nitro-1-imidazole-ethanol hydrochloride have two new ones according to the invention Nitroimidazoles, an amplification factor of 1.6 (VF Index 1.6) at concentrations of 30 µmol or 40 µmol. To achieve the same amplification with misonidazole or metronidazole, these two known nitroimidazoles in a concentration of 300 µmol and 4000 respectively µMol can be used.

Die Verbindungen der Formel I und ihre physiologisch verträglichen Säureadditionssalze können auch zur Bekämpfung von durch Protozoen verursachten Infektionen verwendet werden, insbesondere von Infektionen, die durch Trichomonas vaginalis verursacht werden.The compounds of formula I and their physiologically tolerated acid addition salts can also be used to control infections caused by protozoa, in particular infections caused by Trichomonas vaginalis can be caused.

Die erfindungsgemässen Verbindungen können als pharmazeutische Präparate mit direkter oder verzögerter Freigabe des Wirkstoffs in Mischung mit einem für die enterale, z.B. orale, oder parenterale Applikation geeigneten organischen oder anorganischen inerten Trägermaterial, wie z.B. Wasser, Gelatine, Gummi arabicum, Milchzucker, Stärke, Magnesiumstearat, Talk, pflanzlichen Oelen, Polyalkylenglycolen oder Vaseline verwendet werden. Die Präparate können in fester Form, z.B. als Tabletten, Dragees, Suppositorien, Kapseln; in halbfester Form, z.B. als Salben; oder in flüssiger Form, z.B. als Lösungen, Suspensionen oder Emulsionen vorliegen. Gegebenenfalls sind sie sterilisiert und bzw. oder enthalten weitere Hilfsstoffe, wie Konservierungs-, Stabilisierungs-, Netz- oder Emulgiermittel, Mittel zur geschmacklichen Verbesserung, Salze zur Veränderung des osmotischen Druckes oder Puffersubstanzen. Die Präparate können auch andere therapeutisch wertvolle Verbindungen enthalten.The compounds according to the invention can be used as pharmaceutical preparations with direct or delayed release of the active ingredient in a mixture with an organic or inorganic inert carrier material suitable for enteral, for example oral or parenteral administration, such as water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, Talc, vegetable oils, polyalkylene glycols or petroleum jelly can be used. The preparations can be in solid form, for example as tablets, dragées, suppositories, capsules; in semi-solid form, for example as ointments; or in liquid form, for example as solutions, suspensions or emulsions. Optionally they are sterilized and or or contain further adjuvants such as preservatives -, stabilizing, wetting or emulsifying agents, flavor-improving, salts for changing the osmotic pressure or buffering agents. The preparations can also contain other therapeutically valuable compounds.

Die Herstellung der pharmazeutischen Präparate kann in der jedem Fachmann geläufigen Weise erfolgen, indem man eine der erfindungsgemässen Verbindungen als aktiven Bestandteil mit einem zur therapeutischen Verabreichung geeigneten, inerten, festen oder flüssigen Träger vermischt, und das Gemisch gegebenenfalls in eine besondere galenische ?orm bringt.The pharmaceutical preparations can be prepared in the manner familiar to any person skilled in the art by mixing one of the compounds according to the invention as an active ingredient with an inert, solid or liquid carrier suitable for therapeutic administration, and if appropriate bringing the mixture into a special galenic form.

Bei Verwendung als Radiosensitiser können die erfindungsgemässen Verbindungen oral bei einer Dosierung von etwa 20 bis 60 mg pro kg Körpergewicht und Tag verabreicht werden. Im allgemeinen sollte aber die während einer Behandlung verabreichte Gesamtdosis etwa 200 mg pro kg Körpergewicht und Tag nicht überschreiten. Bei Verwendung als Mittel gegen Protozoen, können die erfindungsgemässen Verbindungen ebenfalls bei einer täglichen Dosierung von etwa 20 bis 60 mg pro kg Körpergewicht oral verabreicht werden. Es versteht sich jedoch von selbst, dass die vorstehend genannten Dosisbereiche nur Richtlinien darstellen und je nach den individuellen Erfordernissen über- sowie unterschritten werden können.When used as a radiosensitiser, the compounds according to the invention can be administered orally at a dosage of about 20 to 60 mg per kg of body weight and day. In general, however, the total dose administered during a treatment should not exceed about 200 mg per kg body weight and day. When used as an agent against protozoa, the compounds according to the invention can also be administered orally at a daily dosage of about 20 to 60 mg per kg of body weight. However, it goes without saying that the dose ranges mentioned above are only guidelines and can be exceeded or undershot depending on the individual requirements.

Beispiel 1example 1

  • (a) Ein Gemisch aus 5,1 g 1-(2,3-Epoxypropyl)-2-nitroimidazol, 3,3 g Diäthylamin und 100 ml Methanol wurde 12 bis 18 Stunden unter Rückfluss erhitzt. Nach Abzug des Lösungsmittels unter vermindertem Druck wurden 8,1 g eines hellbraunen Rückstandes erhalten, der in 25 ml heissem Aethanol gelöst wurde. Die Lösung wurde mit Holzkohle entfärbt und filtriert. Nach Kristallisation wurden 5,2 g (72%) α-(Diäthylamino)-methyl-2-nitro-1-imidazol- äthanol in Form hellgelber Kristalle, F. 92-930C, erhalten.(a) A mixture of 5.1 g of 1- (2,3-epoxypropyl) -2-nitroimidazole, 3.3 g of diethylamine and 100 ml of methanol was heated under reflux for 12 to 18 hours. After removal of the solvent under reduced pressure, 8.1 g of a light brown residue were obtained, which was dissolved in 25 ml of hot ethanol. The solution was decolorized with charcoal and filtered. After crystallization, 5.2 g (72%) of α- (diethylamino) methyl-2-nitro-1-imidazole-ethanol obtained in the form of light yellow crystals, mp 92-93 0 C,.
  • (b) 3,6 g α-(Diäthylamino)-methyl-2-nitro-1-imidazol-äthanol wurden in einer minimalen Menge warmen Aethanols gelöst und mit einem geringen Ueberschuss von wasserfreiem ätherischem HCl behandelt. Das nach Abkühlung und Kristallisation erhaltene cremefarbene Hydrochloridsalz (4,0 g) wurde in ca. 40 ml heissem Aethanol gelöst, zur Entfärbung mit Holzkohle behandelt, filtriert und,falls nötig, mit einigen ml trockenem Diäthyläther zur Kristallisation gebracht. Es wurden so 4,0 g α-(Diäthylamino)-methyl-2-nitro-l-imidazol-äthanol-hydrochlorid in Form schwach cremefarbener Kristalle, F. 145-146°C (Zersetzung), erhalten.(b) 3.6 g of α- (diethylamino) methyl-2-nitro-1-imidazole-ethanol was dissolved in a minimal amount of warm ethanol and treated with a slight excess of anhydrous ethereal HCl. The cream-colored hydrochloride salt (4.0 g) obtained after cooling and crystallization was dissolved in about 40 ml of hot ethanol, treated with charcoal for decolorization, filtered and, if necessary, brought to crystallization with a few ml of dry diethyl ether. 4.0 g of α- (diethylamino) methyl-2-nitro-l-imidazole-ethanol hydrochloride were thus obtained in the form of slightly cream-colored crystals, melting point 145-146 ° C. (decomposition).
Beispiel 2Example 2

  • (a) In zu Beispiel l(a) analoger Weise wurde nach Kristallisation aus Isopropanol 2-Nitro-α-(pyrrolidino)-methyl-1-imidazol-äthanol in Form hellgelber Kristalle.F. 83-85°C, erhalten. Ausbeute 79%.(a) In a manner analogous to Example 1 (a), after crystallization from isopropanol, 2-nitro-α- (pyrrolidino) methyl-1-imidazole-ethanol was obtained in the form of pale yellow crystals . Mp 83-85 ° C. Yield 79%.
  • (b) In zu Beispiel l(b) analoger Weise wurde 2-Nitro-a-(pyrrolidino)-methyl-l-imidazol-äthanol-hydrochlorid in Form schwach cremefarbener Kristalle, F. 158-159°C (Zers.), erhalten. Ausbeute 87%.(b) In a manner analogous to Example 1 (b), 2-nitro-a- (pyrrolidino) methyl-l-imidazole-ethanol hydrochloride was obtained in the form of slightly cream-colored crystals, mp 158-159 ° C. (dec.), receive. Yield 87%.
Beispiel 3Example 3

In zu Beispiel l(a) analoger Weise wurde nach Kristallisation aus Aethanol 2-Nitro-α-(piperidino)-methyl-1-imidazol-äthanol in Form hellgelber Kristalle, F. 110-112°C, erhalten. Ausbeute 88%.In a manner analogous to Example 1 (a), crystallization from ethanol gave 2-nitro-α- (piperidino) methyl-1-imidazole-ethanol in the form of pale yellow crystals, mp 110-112 ° C. Yield 88%.

(b) In zu Beispiel l(b) analoger Weise wurde 2-Nitro-α-(piperidino)-methyl-l-imidazol-äthanol-hydrochlorid in Form schwach cremefarbener Kristalle, F. 144-145°C (Zers.), erhalten. Ausbeute 90%.(b) In a manner analogous to Example 1 (b), 2-nitro-α- (piperidino) methyl-l-imidazole-ethanol hydrochloride was obtained in the form of slightly cream-colored crystals, mp 144-145 ° C. (dec.), receive. Yield 90%.

Beispiel 4Example 4

  • (a) In zu Beispiel l(a) analoger Weise wurde nach Kristallisation aus Aethanol, α-(Morpholino)-methyl-2-nitro-1-imidazol-äthanol in Form hellgelber Kristalle, F. 112-113°C, erhalten. Ausbeute 88%.(a) In a manner analogous to example l (a), after crystallization from ethanol, α- (morpholino) methyl-2-nitro-1-imidazole-ethanol was obtained in the form of pale yellow crystals, mp 112-113 ° C. Yield 88%.
  • (b) In zu Beispiel l(b) analoger Weise wurde α-(Morpholino)-methyl-2-nitro-1-imidazol-äthanol-hydrochlorid in Form schwach cremefarbener Kristalle, F. 196-197°C (Zers.),erhalten. Ausbeute 93%.(b) In a manner analogous to Example 1 (b), α- (morpholino) methyl-2-nitro-1-imidazole-ethanol hydrochloride was obtained in the form of slightly cream-colored crystals, mp 196-197 ° C. (dec.), receive. Yield 93%.
Beispiel 5Example 5

  • (a) In zu Beispiel l(a) analoger Weise wurde nach Kristallisation aus Aethanol, α-(4-Methylpiperazino)-methyl-2-nitro-l-imidazol-äthanol in Form schwach gelber Kristalle, F. 144-145°C, erhalten. Ausbeute 62%.(a) In a manner analogous to example l (a), after crystallization from ethanol, α- (4-methylpiperazino) methyl-2-nitro-l-imidazole-ethanol in the form of pale yellow crystals, mp 144-145 ° C. , receive. Yield 62%.
  • (b) In zu Beispiel l(b) analoger Weise wurde α-(4-Methylpiperazino)-methyl-2-nitro-l-imidazol-äthanol-dihydrochlorid in Form fast farbloser Kristalle, F. 215-216°C, (Zers.), erhalten. Ausbeute 93%.(b) In a manner analogous to example l (b), α- (4-methylpiperazino) methyl-2-nitro-l-imidazole-ethanol dihydrochloride was obtained in the form of almost colorless crystals, mp 215-216 ° C., (dec .), receive. Yield 93%.
Beispiel 6Example 6

  • (a) In zu Beispiel l(a) analoger Weise, aber unter Verwendung äquimolekularer Mengen der Reagentien, wurde, nach Kristallisation aus Isopropanol, α-[Di-(2-hydroxyäthyl)-amino]-methyl-2-nitro-l-imidazol-äthanol in Form hellgelber Kristalle, F. 92-93°C, erhalten. Ausbeute 79%.(a) In a manner analogous to example l (a), but using equimolecular amounts of the reagents, after crystallization from isopropanol, α- [di- (2-hydroxyethyl) amino] methyl-2-nitro-l- imidazole-ethanol in the form of light yellow crystals, mp 92-93 ° C, obtained. Yield 79%.
  • (b) In zu Beispiel l(b) analoger Weise wurde a-[Di-(2-hydroxyäthyl)-amino]-methyl-2-nitro-1-imidazol-äthanol- hydrochlorid in Form schwach cremefarbener Kristalle, F. 151-152°C (Zers.), erhalten. Ausbeute 75%.(b) In a manner analogous to Example 1 (b), a- [di- (2-hydroxyethyl) amino] methyl-2-nitro-1-imidazole-ethanol hydrochloride was obtained in the form of slightly cream-colored crystals, F. 151-152 ° C (dec.). Yield 75%.
Beispiel 7Example 7

  • (a) In zu Beispiel l(a) analoger Weise, aber unter Verwendung von 2 Moläquivalenten von tert.-Butylamin, wurde, nach Kristallisation aus Aethanol, a-(tert.-Butylamino)-methyl-2-nitro-l-imidazol-äthanol in Form hellgelber Kristalle, F. 114-115°C, erhalten. Ausbeute 36%.(a) In a manner analogous to Example l (a), but using 2 molar equivalents of tert-butylamine, a- (tert-butylamino) methyl-2-nitro-l-imidazole was obtained after crystallization from ethanol -ethanol in the form of light yellow crystals, mp 114-115 ° C. Yield 36%.
  • (b) In zu Beispiel l(b) analoger Weise wurde a-(tert.-Butylamino)-methyl-2-nitro-l-imidazol-äthanol-hydrochlorid in Form schwach cremefarbener Kristalle, F. 198-199°C (Zers.), erhalten. Ausbeute 87%.(b) In a manner analogous to example l (b), a- (tert-butylamino) methyl-2-nitro-l-imidazole-ethanol hydrochloride was obtained in the form of slightly cream-colored crystals, melting point 198-199 ° C. (dec .), receive. Yield 87%.
Beispiel 8Example 8

  • (a) In zu Beispiel l(a) analoger Weise, aber unter Verwendung äquimolekularer Mengen der Reagentien wurde α-(Benzylamino)-methyl-2-nitro-1-imidazol-äthanol in Form eines hellgelben Gummis, der gemäss Dünnschichtchromatographie einheitlich war, erhalten.(a) In a manner analogous to example l (a), but using equimolecular amounts of the reagents, α- (benzylamino) methyl-2-nitro-1-imidazole-ethanol was in the form of a light yellow gum which was uniform according to thin layer chromatography, receive.
  • (b) 4,5 g α-(Benzylamino)-methyl-2-nitro-1-imidazol- äthanol wurden in einer minimalen Menge warmen Aethanols gelöst und mit einer äquivalenten Menge aethanolischer Maleinsäure (1,9 g) behandelt. Man liess das Gemisch abkühlen und während mehreren Stunden auskristallisieren. Das erhaltene cremefarbene Maleinsäuresalz (5,2 g) wurde in 50 ml heissem Aethanol gelöst, mit Holzkohle entfärbt, filtriert und, soweit nötig, mit einigen ml trockenem Diäthyläther zur Kristallisation gebracht. Es wurden so 3,6 g a-(Benzylamino)-methyl-2-nitro-l-imidazol-äthanol- maleat in Form schwach cremefarbener Kristalle, F. 153-154°C (Zers.), erhalten.(b) 4.5 g of α- (benzylamino) methyl-2-nitro-1-imidazole ethanol was dissolved in a minimal amount of warm ethanol and treated with an equivalent amount of ethanolic maleic acid (1.9 g). M left the mixture cool and crystallize for several hours. The cream-colored maleic acid salt obtained (5.2 g) was dissolved in 50 ml of hot ethanol, decolorized with charcoal, filtered and, if necessary, brought to crystallization with a few ml of dry diethyl ether. 3.6 g of a- (benzylamino) methyl-2-nitro-l-imidazole-ethanol maleate were thus obtained in the form of slightly cream-colored crystals, mp 153-154 ° C. (dec.).
  • (c) In analoger Weise wurde, nach Kristallisation aus Aethanol, α-(Benzylamino)-methyl-2-nitro-1-imidazol-äthanol- oxalat in Form farbloser Kristalle, F. 197-198°C (Zers.), erhalten.(c) In an analogous manner, after crystallization from ethanol, α- (benzylamino) methyl-2-nitro-1-imidazole-ethanol-oxalate was obtained in the form of colorless crystals, melting point 197-198 ° C. (dec.) .
Beispiel 9Example 9

  • (a) In zu Beispiel l(a) analoger Weise, aber unter Verwendung äquimolarer Mengen der Reagentien wurde, nach Kristallisation aus Aethanol, α-[(4-Methoxyphenyl)-amino]-methyl-2-nitro-l-imidazol-äthanol in Form brauner Nadeln, F. 162-163°C, erhalten. Ausbeute 80%.(a) In a manner analogous to example l (a), but using equimolar amounts of the reagents, after crystallization from ethanol, α - [(4-methoxyphenyl) amino] methyl-2-nitro-l-imidazole-ethanol was obtained in the form of brown needles, mp 162-163 ° C. Yield 80%.
  • (b) In zu Beispiel l(b) analoger Weise wurde α-[(4-Methoxyphenyl)-amino]-methyl-2-nitro-1-imidazol-äthanol- hydrochlorid in Form sehr schwach rosagefärbter Kristalle, F. 156-157°C (Zers.), erhalten. Ausbeute 97%.(b) In a manner analogous to Example 1 (b), α - [(4-methoxyphenyl) amino] methyl-2-nitro-1-imidazole-ethanol hydrochloride was obtained in the form of very weakly pink-colored crystals, m. 156-157 ° C (dec.). Yield 97%.
Beispiel 10Example 10

  • (a) In zu Beispiel l(a) analoger Weise wurde, nach Umkristallisation aus Isopropanol, a-(Dimethylamino)-methyl-2-nitro-l-imidazol-äthanol in Form hellgelber Kristalle, F. 78-79°C, erhalten. Ausbeute 40%.(a) In a manner analogous to example l (a), after recrystallization from isopropanol, a- (dimethylamino) methyl-2-nitro-l-imidazole-ethanol was obtained in the form of pale yellow crystals, melting point 78-79 ° C. . Yield 40%.
  • (b) In zu Beispiel l(b) analoger Weise wurde, nach Umkristallisation aus Methanol/Diäthyläther, α-(Dimethyl- amino)-methyl-2-nitro-1-imidazol-äthanol-hydrochlorid in Form farbloser Kristalle, F. 202-203°C (Zers.), erhalten.(b) In a manner analogous to Example 1 (b), after recrystallization from methanol / diethyl ether, α- (dimethylamino) methyl-2-nitro-1-imidazole-ethanol hydrochloride in the form of colorless crystals, m.p. 202 -203 ° C (dec.).
Beispiel 11Example 11

  • (a) In zu Beispiel l(a) analoger Weise wurde, nach Umkristallisation aus Isopropanol, α-(Hexahydro-1H-azepino)-methyl-2-nitro-l-imidazol-äthanol in Form hellgelber Kristalle, F. 102-103°C, erhalten.(a) In a manner analogous to example l (a), after recrystallization from isopropanol, α- (hexahydro-1H-azepino) methyl-2-nitro-l-imidazole-ethanol in the form of light yellow crystals, mp 102-103 ° C.
  • (b) In zu Beispiel l(b) analoger Weise wurde, nach Umkristallisation aus Aethanol/Diäthyläther, α-(Hexahydro-1H-azepino)-methyl-2-nitro-l-imidazol-äthanol-hydrochlorid in Form farbloser Kristalle, F. 133-134°C (Zers.), erhalten.(b) In a manner analogous to example l (b), after recrystallization from ethanol / diethyl ether, α- (hexahydro-1H-azepino) methyl-2-nitro-l-imidazole-ethanol hydrochloride in the form of colorless crystals, F 133-134 ° C (dec.).
Beispiel 12Example 12

In zu Beispiel l(a) analoger Weise wurde in 62%-iger Ausbeute, nach Chromatographie an Aluminiumoxid (Elution mit Dichlormethan),4-[2-Hydroxy-3-(2-nitro-l-imidazolyl)-propylamino]-2,2,6,6-tetramethylpiperidin-N-oxyl in Form orangefarbener Kristalle, F. 150-151°C, erhalten.In a manner analogous to example l (a), 4- [2-hydroxy-3- (2-nitro-l-imidazolyl) propylamino] -2. In 62% yield, after chromatography on aluminum oxide (elution with dichloromethane) , 2,6,6-tetramethylpiperidine-N-oxyl in the form of orange crystals, mp 150-151 ° C.

Beispiel 13Example 13

In zu Beispiel 1(a) analoger Weise wurde, nach Umkristallisation aus Isopropanol, α-[(2,2,6,6-Tetramethyl-4-piperidinyl)-amino]-methyl-2-nitro-l-imidazol-äthanol in Form cremefarbener Kristalle, F. 151-1530C, erhalten. Ausbeute 60%.In a manner analogous to Example 1 (a), after recrystallization from isopropanol, α - [(2,2,6,6-tetramethyl-4-piperidinyl) amino] methyl-2-nitro-l-imidazole-ethanol was used in Form of cream-colored crystals, F. 151-153 0 C, obtained. Yield 60%.

Beispiel 14Example 14

  • (a) In zu Beispiel l(a) analoger Weise wurde, nach Umkristallisation aus Isopropanol, a-(Cyclohexylamino)-methyl-2-nitro-l-imidazol-äthanol in Form cremefarbener Kristalle, F. 66-68°C, erhalten. Ausbeute 90%.(a) In a manner analogous to Example l (a), after recrystallization from isopropanol, a- (cyclohexylamino) methyl-2-nitro-l-imidazole-ethanol was obtained in the form of cream-colored crystals, mp 66-68 ° C. . Yield 90%.
  • (b) In zu Beispiel l(b) analoger Weise wurde, nach Umkristallisation aus Aethanol/Diäthyläther, a-(Cyclohexyl- amino)-methyl-2-nitro-l-imidazol-äthanol-hydrochlorid in Form farbloser Kristalle, F. 192-193°C (Zers.), erhalten.(b) In a manner analogous to example l (b), after recrystallization from ethanol / diethyl ether, a- (cyclohexylamino) methyl-2-nitro-l-imidazole-ethanol hydrochloride was added in Form of colorless crystals, mp 192-193 ° C (dec.).
Beispiel 15Example 15

  • (a) In zu Beispiel l(a) analoger Weise wurde, nach Umkristallisation aus Aethanol, α-(Dicyclohexylamino)-methyl-2-nitro-l-imidazol-äthanol in Form orangegelber Kristalle, F. 149-150°C, erhalten. Ausbeute 31%.(a) In a manner analogous to example l (a), after recrystallization from ethanol, α- (dicyclohexylamino) methyl-2-nitro-l-imidazole-ethanol was obtained in the form of orange-yellow crystals, mp 149-150 ° C. . Yield 31%.
  • (b) In zu Beispiel l(b) analoger Weise wurde, nach Umkristallisation aus Aethanol/Diäthyläther, α-(Dicyclo- hexylamino)-methyl-2-nitro-l-imidazol-äthanol-hydrochlorid in Form cremefarbener Kristalle, F. 208-2090C (Zers.), erhalten.(b) In a manner analogous to Example 1 (b), after recrystallization from ethanol / diethyl ether, α- (dicyclo-hexylamino) methyl-2-nitro-l-imidazole-ethanol hydrochloride in the form of cream-colored crystals, F. 208 -209 0 C (dec.).
Beispiel 16Example 16

In zu Beispiel l(a) analoger Weise wurde, nach Umkristallisation aus Aethanol, 1-[2-Hydroxy-3-(2-nitro-l-imidazolyl)-propyl]-3-pyrrolidinol in Form cremefarbener Kristalle, F. 126-130°C, erhalten.In a manner analogous to Example l (a), after recrystallization from ethanol, 1- [2-hydroxy-3- (2-nitro-l-imidazolyl) propyl] -3-pyrrolidinol in the form of cream-colored crystals, m.p. 126- 130 ° C, obtained.

Beispiel 17Example 17

  • (a) Ein Gemisch aus 5,65 g 2-Nitroimidazol und 250 mg wasserfreiem Kaliumcarbonat in 150 ml Aethanol wurde 15 Minuten unter Rückfluss erhitzt. Nach Zusatz von 7,05 g frisch destilliertem 3-Piperidino-propylen-oxid in einer minimalen Menge Aethanol wurde das Gemisch weitere 3 Stunden unter Rückfluss erhitzt und anschliessend filtriert. Das Filtrat wurde unter vermindertem Druck zur Trockene eingeengt und lieferte 13 g eines gelben Oeles, das zwischen 100 ml Aethylacetat und 100 ml Wasser verteilt wurde. Die wässrige Phase wurde abgetrennt, einmal mit 50 ml Aethylacetat gewaschen und die vereinigten organischen Phasen wurden dann 4 mal mit jeweils 50 ml 2N HCl extrahiert. Der vereinigte wässrige Extrakt wurde durch Zusatz von überschüssigem festen Natriumcarbonat basisch gemacht und 3 mal mit jeweils 100 ml Dichlormethan extrahiert. Der organische Extrakt wurde über wasserfreiem Natriumcarbonat getrocknet und filtriert. Das Filtrat wurde unter vermindertem Druck zur Trockene eingeengt und lieferte 6,5 g eines hellgelben Feststoffes, der in 25 ml heissem Aethanol gelöst wurde. Die Lösung wurde durch Behandlung mit Holzkohle entfärbt, filtriert und lieferte nach Kristallisation 1,4 g (11%) 2-Nitro-a-(piperidino)-methyl-l-imidazol- äthanol in Form hellgelber Kristalle, F. 108-109°C.(a) A mixture of 5.65 g of 2-nitroimidazole and 250 mg of anhydrous potassium carbonate in 150 ml of ethanol was heated under reflux for 15 minutes. After the addition of 7.05 g of freshly distilled 3-piperidino-propylene oxide in a minimal amount of ethanol, the mixture was heated under reflux for a further 3 hours and then filtered. The filtrate was evaporated to dryness under reduced pressure and gave 13 g of a yellow oil which was partitioned between 100 ml of ethyl acetate and 100 ml of water. The aqueous phase was separated, washed once with 50 ml of ethyl acetate and the combined organic phases were then extracted 4 times with 50 ml of 2 N HCl. The combined aqueous extract was made basic by adding excess solid sodium carbonate and extracted 3 times with 100 ml of dichloromethane each time. The organic extract was dried over anhydrous sodium carbonate and filtered. The filtrate was concentrated to dryness under reduced pressure and gave 6.5 g of a light yellow solid which was dissolved in 25 ml of hot ethanol. The solution was decolorized by treatment with charcoal, filtered and, after crystallization, gave 1.4 g (11%) of 2-nitro-a- (piperidino) methyl-l-imidazole-ethanol in the form of pale yellow crystals, mp 108-109 ° C.
  • (b) 1,27 g 2-Nitro-a-(piperidino)-methyl-l-imidazol- äthanol wurden in 25 ml warmem Aethanol gelöst und mit einem geringen Ueberschuss an wasserfreiem ätherischem HC1 behandelt. Man liess das Gemisch abkühlen und während mehreren Stunden kristallisieren. Es wurden so 1,4 g 2-Nitro- a-(piperidino)-methyl-l-imidazol-äthanol-hydrochlorid in Form schwach cremefarbener Kristalle erhalten, die mit dem gemäss Beispiel 3(b) erhaltenen Material identisch waren.(b) 1.27 g of 2-nitro-a- (piperidino) methyl-l-imidazole-ethanol were dissolved in 25 ml of warm ethanol and treated with a slight excess of anhydrous ethereal HC1. The mixture was allowed to cool and crystallize for several hours. 1.4 g of 2-nitro-a- (piperidino) methyl-l-imidazole-ethanol hydrochloride were thus obtained in the form of slightly cream-colored crystals which were identical to the material obtained according to Example 3 (b).
Beispiel 18Example 18

Ein Gemisch aus 4,1 g 3-Chlor-1-(2-nitro-1-imidazolyl)-2-propanol, 3,4 g Piperidin und 75 ml Methanol wurde 12 bis 18 Stunden unter Rückfluss erhitzt. Unter vermindertem Druck wurde das Lösungsmittel abgezogen und der cremefarbene Rückstand (7,3 g) wurde in 75 ml Wasser unter Zusatz eines geringen Ueberschusses von 2N HC1 suspendiert. Die homogene Lösung wurde 3 mal mit je 25 ml Dichlormethan gewaschen, mit einem geringen Ueberschuss einer 2N NatriumhydroxidLösung behandelt und 3 mal mit jeweils 75 ml Dichlormethan extrahiert. Die vereinigten Dichlormethanextrakte wurden über wasserfreiem Magnesiumsulfat getrocknet, filtriert und unter vermindertem Druck zur Trockene eingeengt. Es wurden 4,3 g eines cremefarbenen Feststoffes erhalten, der in 25 ml heissem Aethanol gelöst wurde. Die Lösung wurde mittels Holzkohle entfärbt, filtriert und lieferte nach Kristallisation 3,3 g (65%) 2-Nitro-o-(piperidino)-methyl-l-imidazol- äthanol in Form hellgelber Kristalle, F. 110-112°C. Dieses Produkt war mit dem gemäss Beispiel 3(a) erhaltenen identisch und wurde in zu Beispiel l(b) analoger Weise in das Hydrochlorid übergeführt.A mixture of 4.1 g of 3-chloro-1- (2-nitro-1-imidazolyl) -2-propanol, 3.4 g of piperidine and 75 ml of methanol was heated under reflux for 12 to 18 hours. The solvent was removed under reduced pressure and the cream-colored residue (7.3 g) was suspended in 75 ml of water with the addition of a slight excess of 2N HCl. The homogeneous solution was washed 3 times with 25 ml of dichloromethane, treated with a slight excess of a 2N sodium hydroxide solution and extracted 3 times with 75 ml of dichloromethane in each case. The combined dichloromethane extracts were dried over anhydrous magnesium sulfate, filtered and evaporated to dryness under reduced pressure. 4.3 g of an off-white solid were obtained, which was dissolved in 25 ml of hot ethanol. The solution was decolorized using charcoal, filtered and, after crystallization, gave 3.3 g (65%) of 2-nitro-o- (piperidino) -methyl-l-imidazole- ethanol in the form of light yellow crystals, mp 110-112 ° C. This product was identical to that obtained in Example 3 (a) and was converted into the hydrochloride in a manner analogous to Example 1 (b).

Beispiel AExample A

Figure imgb0008
Figure imgb0008

Das vorstehend beschriebene pharmazeutische Präparat kann in an sich bekannter Weise, möglichst unter Lichtausschluss, hergestellt werden und sollte im Dunkeln aufbewahrt werden.The pharmaceutical preparation described above can be produced in a manner known per se, if possible with the exclusion of light, and should be kept in the dark.

Claims (25)

1. Verfahren zur Herstellung von Nitroimidazolen der Formel
Figure imgb0009
 worin R1 Wasserstoff, Niederalkyl, Hydroxy-niederalkyl, Niedercycloalkyl, Aryl oder Aryl- niederalkyl R 2 Niederalkyl, Hydroxy-niederalkyl, Niedercycloalkyl, Aryl, Aryl-niederalkyl oder ein Rest der Formel
Figure imgb0010
mit m = 0 und n = 1 oder m = 1 und n = 0 und worin R3 Wasserstoff, Methyl, Hydroxy oder ein freies Oxylradikal oder R1 und R2 zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-, 6-oder 7-gliedrigen gesättigten heteromonocyclischen Ring, der eine Hydroxygruppe an einem dem Stickstoffatom nicht direkt benachbarten C-Atom tragen kann und der ein weiteres Sauerstoff-, Schwefel- oder Stickstoffatom enthalten kann, das ggf. durch eine Niederalkyl-, Hydroxy-niederalkyl-, Aryl- oder Aryl-niederalkyl-gruppe substituiert ist, darstellen und von deren Säureadditionssalzen, dadurch gekennzeichnet, dass man (a) ein Epoxid der Formel
Figure imgb0011
mit einem Amin der Formel
Figure imgb0012
worin R 1 und R2 wie oben definiert sind, umsetzt oder (b) eine Verbindung der Formel
Figure imgb0013
mit einem Epoxid der Formel
Figure imgb0014
worin R10 und R20 ebenso definiert sind wie oben R1 und R2 mit dem Unterschied, dass R10 nicht Wasserstoff ist,
in Gegenwart einer Base umsetzt oder (c) ein Halohydrin der Formel
Figure imgb0015
worin X Chlor oder Brom darstellt,
mit einem Amin der Formel III umsetzt und gewünschtenfalls eine erhaltene Verbindung I in ein Säureadditionssalz überführt. 1. Process for the preparation of nitroimidazoles of the formula
Figure imgb0009
 wherein R 1 is hydrogen, lower alkyl, hydroxy-lower alkyl, lower cycloalkyl, aryl or aryl-lower alkyl R 2 lower alkyl, hydroxy-lower alkyl, lower cycloalkyl, aryl, aryl-lower alkyl or a radical of the formula
Figure imgb0010
 with m = 0 and n = 1 or m = 1 and n = 0 and where R 3 is hydrogen, methyl, hydroxy or a free oxyl radical or R 1 and R 2 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated heteromonocyclic ring which can carry a hydroxy group on a carbon atom which is not directly adjacent to the nitrogen atom and which can contain a further oxygen, sulfur or nitrogen atom which may be replaced by a lower alkyl, hydroxy-lower alkyl, Aryl or aryl-lower alkyl group is substituted, and their acid addition salts, characterized in that (a) an epoxy of the formula
Figure imgb0011
 with an amine of the formula
Figure imgb0012
 wherein R 1 and R 2 are as defined above, or (b) a compound of the formula
Figure imgb0013
 with an epoxy of the formula
Figure imgb0014
 wherein R 10 and R 20 are as defined as R 1 and R 2 above, with the difference that R 10 is not hydrogen,
in the presence of a base or (c) a halohydrin of the formula
Figure imgb0015
 where X represents chlorine or bromine,
is reacted with an amine of the formula III and, if desired, a compound I obtained is converted into an acid addition salt. 2. Verfahren gemäss Anspruch 1, dadurch gekennzeichnet, dass man eine Verbindung der Formel I oder ein Säureadditionssalz davon herstellt, in der R1 Wasserstoff, Niederalkyl, Hydroxy-niederalkyl, Aryl oder Aryl- niederalkyl ist; R2 Niederalkyl, Hydroxy-niederalkyl, Aryl oder Aryl-niederalkyl ist oder R1 und R zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-, 6- oder 7-gliedrigen gesättigten heteromonocyclischen Ring, der eine Hydroxygruppe an einem dem Stickstoffatom nicht direkt benachbarten C-Atom tragen kann und der ein weiteres Sauerstoff-, Schwefel- oder Stickstoffatom enthalten kann, das ggf. durch eine Niederalkyl-, Hydroxy-niederalkyl-, Aryl- oder Aryl-niederalkyl-gruppe substituiert ist, darstellen.2. The method according to claim 1, characterized in that a compound of formula I or an acid addition salt thereof is prepared in which R 1 is hydrogen, lower alkyl, hydroxy-lower alkyl, aryl or aryl-lower alkyl; R 2 is lower alkyl, hydroxy-lower alkyl, aryl or aryl-lower alkyl or R 1 and R together with the nitrogen atom to which they are attached is a 5-, 6- or 7-membered saturated heteromonocyclic ring which has a hydroxy group on one of the Nitrogen atom can not carry directly adjacent C atom and which can contain a further oxygen, sulfur or nitrogen atom which is optionally substituted by a lower alkyl, hydroxy-lower alkyl, aryl or aryl-lower alkyl group. 3. Verfahren gemäss Anspruch 1, dadurch gekennzeichnet, dass man eine Verbindung der Formel I oder ein Säureadditionssalz davon herstellt, in der R1 und R 2 ge- meinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 6-gliedrigen heteromonocyclischen Ring, der ein . weiteres Sauerstoff- oder Stickstoffatom enthalten kann, das ggf. durch eine Niederalkylgruppe substituiert ist, darstellen.3. The method according to claim 1, characterized in that one produces a compound of formula I or an acid addition salt thereof, in which R 1 and R 2 g e - together with the nitrogen atom to which they are attached, a 6-membered heteromonocyclic ring who a. can contain further oxygen or nitrogen atom, which is optionally substituted by a lower alkyl group. 4. Verfahren zur Herstellung pharmazeutischer Präparate, dadurch gekennzeichnet, dass man eine in Anspruch 1 definierte Verbindung der Formel I, wie in Anspruch 1 definiert als aktiven Bestandteil mit einem.zur therapeutischen Verabreichung geeigneten, inerten, festen oder flüssigen Träger vermischt und dem Gemisch ggf. eine besondere galenische Form gibt.4. A process for the preparation of pharmaceutical preparations, characterized in that a compound of the formula I as defined in claim 1, as defined in claim 1, is mixed as an active ingredient with an inert, solid or liquid carrier suitable for therapeutic administration and, if necessary, the mixture gives a special galenic form. 5. Pharmazeutische Präparate auf der Basis einer Verbindung der Formel I, wie in Anspruch 1 definiert.5. Pharmaceutical preparations based on a compound of formula I as defined in claim 1. 6. Nitroimidazole der Formel
Figure imgb0016
 worin R 1 Wasserstoff, Niederalkyl, Hydroxy-niederalkyl, Niedercycloalkyl, Aryl oder Aryl- niederalkyl R2 Niederalkyl, Hydroxy-niederalkyl, Niedercycloalkyl, Aryl, Aryl-niederalkyl oder ein Rest der Formel
Figure imgb0017
mit m = O und n = 1 oder m = 1 und n = 0 und worin R3 Wasserstoff, Methyl, Hydroxy oder ein freies Oxylradikal oder R1 und R2 zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-, 6-oder 7-gliedrigen gesättigten heteromonocyclischen Ring, der eine Hydroxygruppe an einem dem Stickstoffatom nicht direkt benachbarten C-Atom tragen kann und der ein weiteres Sauerstoff-, Schwefel- oder Stickstoffatom enthalten kann, das ggf. durch eine Niederalkyl-,Hydroxy-niederalkyl-, Aryl- oder Aryl-niederalkyl-gruppe substituiert ist, darstellen und deren Säureadditionssalze. 6. Nitroimidazoles of the formula
Figure imgb0016
 wherein R 1 is hydrogen, lower alkyl, hydroxy-lower alkyl, lower cycloalkyl, aryl or aryl-lower alkyl R 2 lower alkyl, hydroxy-lower alkyl, lower cycloalkyl, aryl, aryl-lower alkyl or a radical of the formula
Figure imgb0017
 with m = O and n = 1 or m = 1 and n = 0 and where R 3 is hydrogen, methyl, hydroxy or a free oxyl radical or R 1 and R 2 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated heteromonocyclic ring which can carry a hydroxyl group on a carbon atom which is not directly adjacent to the nitrogen atom and which contains further oxygen - Can contain sulfur or nitrogen atom, which is optionally substituted by a lower alkyl, hydroxy-lower alkyl, aryl or aryl-lower alkyl group, and their acid addition salts. 7. Verbindungen gemäss Anspruch 6, dadurch gekennzeichnet, dass in Formel I R1 Wasserstoff, Niederalkyl, Hydroxy-niederalkyl, Aryl oder Aryl-niederalkyl ist; R2 Niederalkyl, Hydroxy-niederalkyl, Aryl oder Aryl- niederalkyl ist oder R1 und R2 zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-, 6- oder 7- gliedrigen gesättigten heteromonocyclischen Ring, der eine Hydroxygruppe an einem dem Stickstoffatom nicht direkt benachbarten C-Atom tragen kann und der ein weiteres Sauerstoff-, Schwefel- oder Stickstoffatom enthalten kann, das ggf. durch eine Niederalkyl-, Hydroxy-niederalkyl-, Aryl- oder Aryl-niederalkyl-gruppe substituiert ist, darstellen.7. Compounds according to claim 6, characterized in that in formula IR 1 is hydrogen, lower alkyl, hydroxy-lower alkyl, aryl or aryl-lower alkyl; R 2 is lower alkyl, H ydroxy-lower alkyl, aryl or aryl lower alkyl, or R 1 and R 2 together with the nitrogen atom to which they are attached, a 5-, 6- or 7-membered saturated heteromonocyclic ring, a hydroxy group on can carry a carbon atom not directly adjacent to the nitrogen atom and which can contain a further oxygen, sulfur or nitrogen atom which may be replaced by a lower alkyl, hydroxy-lower alkyl, Aryl or aryl-lower alkyl group is substituted. 8. Verbindungen gemäss Anspruch 6, dadurch gekennzeichnet, dass in Formel I R1 und R2 gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen 6-gliedrigen heteromonocyclischen Ring, der ein weiteres Sauerstoff- oder Stickstoffatom enthalten kann, das ggf. durch eine Niederalkylgruppe substituiert ist, darstellen.8. Compounds according to claim 6, characterized in that in formula IR 1 and R 2 together with the nitrogen atom to which they are attached, a 6-membered heteromonocyclic ring which may contain a further oxygen or nitrogen atom, which may be by is a lower alkyl group. 9. 2-Nitro-α-(piperidino)-methyl-1-imidazol-äthanol.9. 2-nitro-α- (piperidino) methyl-1-imidazole ethanol. 10. α-(Morpholino)-methyl-2-nitro-1-imidazol-äthanol.10. α- (Morpholino) methyl-2-nitro-1-imidazole ethanol. 11. a-(4-Methylpiperazino)-methyl-2-nitro-l-imidazol- äthanol.11. a- (4-Methylpiperazino) methyl-2-nitro-l-imidazole ethanol. 12. 2-Nitro-α-(pyrrolidino)-methyl-1-imidazol-äthanol.12. 2-Nitro-α- (pyrrolidino) methyl-1-imidazole ethanol. 13. a-(Diäthylamino)-methyl-2-nitro-l-imidazol-äthanol13. a- (diethylamino) methyl-2-nitro-l-imidazole-ethanol 14. α-[Di-(2-hydroxyäthyl)-amino]-methyl-2-nitro-1-imidazol-äthanol.14. α- [di (2-hydroxyethyl) amino] methyl-2-nitro-1-imidazole ethanol. 15. α-(tert.-Butylamino)-methyl-2-nitro-1-imidazol- äthanol.15. α- (tert-Butylamino) methyl-2-nitro-1-imidazole ethanol. 16. α-(Benzylamino)-methyl-2-nitro-1-imidazol-äthanol16. α- (Benzylamino) methyl-2-nitro-1-imidazole-ethanol 17. α-[(4-Methoxyphenyl)-amino]-methyl-2-nitro-1-imidazol-äthanol.17. α - [(4-methoxyphenyl) amino] methyl-2-nitro-1-imidazole-ethanol. 18. a-(Dimethylamino)-methyl-2-nitro-l-imidazol- äthanol.18. a- (Dimethylamino) methyl-2-nitro-l-imidazole ethanol. 19. α-(Hexahydro-1H-azepino)-methyl-2-nitro-1-imidazol-äthanol.19. α- (Hexahydro-1H-azepino) methyl-2-nitro-1-imidazole-ethanol. 20. 4-[2-Hydroxy-3-(2-nitro-l-imidazolyl)-propyl- amino]-2,2,6,6-tetramethylpiperidin-N-oxyl.2 0 . 4- [2-Hydroxy-3- (2-nitro-l-imidazolyl) propylamino] -2,2,6,6-tetramethylpiperidine-N-oxyl. 21. α-[(2,2,6,6-Tetramethyl-4-piperidinyl)-amino]-methyl-2-nitro-l-imidazol-äthanol.21. α - [(2,2,6,6-Tetramethyl-4-piperidinyl) amino] methyl-2-nitro-l-imidazole-ethanol. 22. α-(Cyclohexylamino)-methyl-2-nitro-1-imidazol- äthanol.22. α- (Cyclohexylamino) methyl-2-nitro-1-imidazole ethanol. 23. α-(Dicyclohexylamino)-methyl-2-nitro-1-imidazol- äthanol.23. α- (Dicyclohexylamino) methyl-2-nitro-1-imidazole ethanol. 24. 1-[2-Hydroxy-3-(2-nitro-l-imidazolyl)-propyl]-3-pyrrolidinol.24. 1- [2-Hydroxy-3- (2-nitro-l-imidazolyl) propyl] -3-pyrrolidinol. 25. Verwendung einer in Anspruch 1 definierten Verbindung der Formel I zur Sensibilisierung hypoxischer Zellen gegen Bestrahlung und zur Bekämpfung von durch Protozoen verursachten Infektionen.25. Use of a compound of formula I defined in claim 1 for sensitizing hypoxic cells to radiation and for combating infections caused by protozoa.
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Cited By (15)

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US4581368A (en) * 1982-05-27 1986-04-08 National Research Development Corporation Aziridino containing nitro imidazoles and pharmaceutical compositions
US4596817A (en) * 1982-05-27 1986-06-24 National Research Development Corporation Imidazole compounds useful in radiotherapy or chemotherapy and compositions
US4631289A (en) * 1982-05-27 1986-12-23 National Research Development Corporation Useful in radiotherapy of chemotherapy 4-aziridino-1-nitroimidazol-1-yl-2,3-butanediols
US4757148A (en) * 1982-05-27 1988-07-12 National Research Development Corporation Intermediate 1-(2-nitro-1-imidazolyl)-3-substituted amino-2-propanols and the corresponding 2,3-butanediols
EP0095906A1 (en) * 1982-05-27 1983-12-07 National Research Development Corporation Improvements relating to compounds useful in radiotherapy or chemotherapy
US4927941A (en) * 1987-06-10 1990-05-22 Yasunori Nishijima & Daikin Industries Ltd. Fluorine-containing nitroazole derivatives and radiosensitizer comprising the same
EP0294847A1 (en) * 1987-06-10 1988-12-14 Kyoto University Fluorine-containing nitroazole derivatives and radiosensitizer comprising the same
US5304654A (en) * 1987-06-10 1994-04-19 Yasunori Nishijima Fluorine-containing nitroimidazole compounds
EP0316967A1 (en) * 1987-06-24 1989-05-24 Nishijima, Yasunori Fluorine-containing nitroimidazole derivatives and radiosensitizer comprising the same
EP0302416A1 (en) * 1987-07-31 1989-02-08 Warner-Lambert Company 2-nitroimidazole derivatives useful as radiosensitizers for hypoxic tumor cells
EP0319329A3 (en) * 1987-12-04 1990-03-07 National Research Development Corporation Nitro-substituted aromatic or hetero-aromatic compounds nitro-substituted aromatic or hetero-aromatic compounds for use in cancer treatment for use in cancer treatment
US5098921A (en) * 1987-12-04 1992-03-24 National Research Development Corporation Nitro-substituted aromatic or hetero-aromatic compounds for use in cancer treatment
EP0319329A2 (en) * 1987-12-04 1989-06-07 Btg International Limited Nitro-substituted aromatic or hetero-aromatic compounds for use in cancer treatment
EP0375951A1 (en) * 1988-11-25 1990-07-04 Warner-Lambert Company A new process for the synthesis of novel and known nitroimidazoles which are useful as sensitizing agents
US20160145139A1 (en) * 2013-07-16 2016-05-26 Corning Incorporated System and method for bending thin glass

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JPS5444671A (en) 1979-04-09
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IT1098042B (en) 1985-08-31
AR218325A1 (en) 1980-05-30
FI70576B (en) 1986-06-06
US4241060A (en) 1980-12-23
CA1104133A (en) 1981-06-30
DK366678A (en) 1979-02-20
AT364829B (en) 1981-11-25
ES472661A1 (en) 1979-02-16
AU516443B2 (en) 1981-06-04
IT7826792A0 (en) 1978-08-16
AR220216A1 (en) 1980-10-15
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DK155367B (en) 1989-04-03
ATA601078A (en) 1981-04-15
IL55351A0 (en) 1978-10-31
FR2400512A1 (en) 1979-03-16
AU3891578A (en) 1980-02-21
JPS6220187B2 (en) 1987-05-06
NO151240B (en) 1984-11-26
IE781453L (en) 1979-02-19
NO782813L (en) 1979-02-20
HU179983B (en) 1983-01-28
FI70576C (en) 1986-09-24
DE2836073A1 (en) 1979-03-01
GR73055B (en) 1984-01-26
AR218553A1 (en) 1980-06-13
DK155367C (en) 1989-08-14
IL55351A (en) 1982-07-30
GB2003154A (en) 1979-03-07
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DE2860546D1 (en) 1981-04-16
FR2400512B1 (en) 1980-07-04
NL7808597A (en) 1979-02-21
IE47132B1 (en) 1983-12-28
YU41317B (en) 1987-02-28
ES478052A1 (en) 1979-10-16
EP0000928B1 (en) 1981-03-18
MC1210A1 (en) 1979-05-18
SE7808773L (en) 1979-02-20
NZ188140A (en) 1981-01-23
PH16364A (en) 1983-09-08

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