EP0000928B1 - 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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EP0000928B1
EP0000928B1 EP78100690A EP78100690A EP0000928B1 EP 0000928 B1 EP0000928 B1 EP 0000928B1 EP 78100690 A EP78100690 A EP 78100690A EP 78100690 A EP78100690 A EP 78100690A EP 0000928 B1 EP0000928 B1 EP 0000928B1
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Prior art keywords
nitro
ethanol
methyl
aryl
imidazole
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EP0000928A1 (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 to 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.
  • aryl-lower alkyl denotes a lower alkyl radical substituted by an aryl group.
  • aryl-lower alkyl groups are 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-1 H-azepino.
  • saturated heteromonocyclic rings which are formed from the substituents R I and R 2 together with the nitrogen atom to which they are attached and which may contain a further 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 with preferably 1-6 carbon atoms, such as methoxy or ethoxy.
  • nitroimidazoles of the present invention are compounds of the formula I in which R I 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 2 together with the nitrogen atom to which they are attached represent a 5-, 6- or 7-membered saturated heteromonocyclic ring which may contain another oxygen, sulfur or nitrogen atom which may be replaced by a lower alkyl, hydroxy-lower alkyl , Aryl or aryl-lower alkyl group can be substituted, as well as their acid addition salts.
  • a particularly interesting group of nitroimidazole derivatives of the present invention are those compounds of the formula 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 a further 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 can also be used.
  • 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 conveniently carried out in the presence of an inert organic solvent, e.g. B. a lower alkanol (z. B. methanol or ethanol) performed.
  • 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 When a halohydrin of the formula VI is reacted with an amine of the formula 111 according to process variant (c), at least one mole of amine is advantageously used per mole of halohydrin.
  • the reaction is conveniently carried out in the presence of an acid-binding agent such as an alkali metal carbonate (e.g. sodium carbonate or potassium carbonate) or a tertiary organic amine (e.g. pyridine) or, preferably, in the presence of excess amine of the formula III.
  • an acid-binding agent such as an alkali metal carbonate (e.g. sodium carbonate or potassium carbonate) or a tertiary organic amine (e.g. pyridine) or, preferably, in the presence of excess amine of the formula III.
  • an acid-binding agent such as an alkali metal carbonate (e.g. sodium carbonate or potassium carbonate) or a tertiary organic amine (e.g
  • the reaction expediently 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, e.g. B. by reaction with an inorganic 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 be converted to a physiologically acceptable acid.
  • the starting compounds of the formulas II to VI are known compounds.
  • the compounds of the formula 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 and their physiologically tolerable acid addition salts as radiosensitizers for hypoxic cells can be demonstrated in an in vitro experiment on hypoxic Chinese hamster V 79 cells (cf.
  • the compounds of the formula and their physiologically acceptable acid addition salts can also be used to control infections caused by protozoa, in particular infections caused by Trichomonas vaginalis.
  • the compounds of the invention can be used as pharmaceutical preparations with direct or delayed release of the active ingredient in a mixture with one for enteral, e.g. B. oral or parenteral application of suitable organic or inorganic inert carrier material, such as.
  • suitable organic or inorganic inert carrier material such as.
  • water gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols or petroleum jelly
  • the preparations can be in solid form, e.g. B. as tablets, dragees, suppositories, capsules; in semi-solid form, e.g. B. as ointments; or in liquid form, e.g. B. present as solutions, suspensions or emulsions.
  • 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 necessary bringing the mixture into a special galenical 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 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.

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

  • Rl Wasserstoff, Niederalkyl, Hydroxy-niederalkyl, Niedercycloalkyl, Aryl oder Aryl-niederalkyl
  • R2 Niederalkyl, Hydroxy-niederalkyl, Niedercycloalkyl, Aryl, Aryl-niederalkyl oder ein Rest der Formel
    Figure imgb0002
    • mit m =0 und n = oder
    • m = 1 und n =0 und worin
  • R3 Wasserstoff, Methyl, Hydroxy oder ein freies Sauerstoffradikal oder
  • Rl 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 ggf. durch eine Niederalkyl-, Hydroxy-niederalkyl-, Aryl- oder Aryl-niederalkyl-gruppe substituiert ist, darstellen,

und deren Säureadditionssalze.The nitroimidazoles of the present invention are compounds of the general formula
Figure imgb0001
 wherein
  • R l 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 = or
    • m = 1 and n = 0 and where
  • R 3 is hydrogen, methyl, hydroxy or a free oxygen 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 C atom which is not directly adjacent to the nitrogen atom and which has a further oxygen, May 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, Äthyl, Propyl, Isopropyl, Butyl, tert.Butyl, Pentyl und Hexyl. Beispiele von Hydroxyniederalkylgruppen sind Hydroxymethyl, 2-Hydroxyäthyl, 2-Hydroxypropyl, 3-Hydroxypropyl und 2-Hydroxybutyl.In the description and claims, the term "lower alkyl" means a straight or branched chain alkyl group preferably having 1 to 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.

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-1 H-azepino. Beispiele von gesättigten heteromonocyclischen Ringen, die aus den Substituenten RI 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 Äthoxy.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-1 H-azepino. Examples of saturated heteromonocyclic rings which are formed from the substituents R I and R 2 together with the nitrogen atom to which they are attached and which may contain a further 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 with preferably 1-6 carbon atoms, such as methoxy or ethoxy.

Eine interessante Gruppe von Nitroimidazolen der vorliegenden Erfindung sind Verbindungen der Formel I in denen RI Wasserstoff, Niederalkyl, Hydroxy-niederalkyl, Aryl oder Aryl-niederalkyl, R2 Niederalkyl, Hydroxy-niederalkyl, Aryl oder Aryl-niederalkyl oder R1 und R2 zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 5-, 6- oder 7-gliedrigen gesättigten heteromonocyclischen 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.An interesting group of nitroimidazoles of the present invention are compounds of the formula I in which R I 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 2 together with the nitrogen atom to which they are attached represent a 5-, 6- or 7-membered saturated heteromonocyclic ring which may contain another oxygen, sulfur or nitrogen atom which may be replaced by a lower alkyl, hydroxy-lower alkyl , Aryl or aryl-lower alkyl group can be substituted, as well as their acid addition salts.

Eine besonders interessante Gruppe von Nitroimidazolderivaten der vorliegenden Erfindung sind solche Verbindungen der Formel 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 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 a further oxygen or nitrogen atom, which is optionally substituted by a lower alkyl group, and their acid addition salts.

Beispiele von erfindungsgemäßen Verbindungen der Formel sind:Examples of compounds of the formula according to the invention are:

  • 2-Nitro-α-(piperidino)-methyl-1-imidazol-äthanol,2-nitro-α- (piperidino) methyl-1-imidazole-ethanol,
  • α-(Morpholino)-methyl-2-nitro-1-imidazol-äthanol,α- (morpholino) methyl-2-nitro-1-imidazole ethanol,
  • α-(4-Methylpiperazino)-methyl-2-nitro-1-imidazol-äthanol,α- (4-methylpiperazino) methyl-2-nitro-1-imidazole-ethanol,
  • 2-Nitro-α-(pyrrolidino)-methyl-1-imidazol-äthanol2-nitro-α- (pyrrolidino) methyl-1-imidazole ethanol
  • α-(Diäthylamino)-methyl-2-nitro-1-imidazol-äthanolα- (Diethylamino) methyl-2-nitro-1-imidazole-ethanol
  • α-[Di-(2-hydroxyäthyl)-amino]methyl-2-nitro-1-imidazol-äthanol,α- [di (2-hydroxyethyl) amino] methyl-2-nitro-1-imidazole ethanol,
  • α-(tert.Butylamino)-methyl-2-nitro-1-imidazol-äthanol,α- (tert-butylamino) methyl-2-nitro-1-imidazole-ethanol,
  • α-(Benzylamino)-methyl-2-nitro-1-imidazol-äthanol,α- (benzylamino) methyl-2-nitro-1-imidazole ethanol,
  • α-[(4-Methoxyphenyl)-amino]-methyl-2-nitro-1-imidazol-äthanol,α - [(4-methoxyphenyl) amino] methyl-2-nitro-1-imidazole-ethanol,
  • α-(Dimethylamino)-methyl-2-nitro-1-imidazol-äthanol,α- (dimethylamino) methyl-2-nitro-1-imidazole-ethanol,
  • α-(Hexahydro-1 H-azepino)-methyl-2-nitro-1-imidazol-äthanol,α- (hexahydro-1 H-azepino) methyl-2-nitro-1-imidazole-ethanol,
  • 4-[2-Hydroxy-3-(2-nitro-1-imidazolyl)-propylamino]-2,2,6,6-tetramethylpiperidin-N-oxyl,4- [2-hydroxy-3- (2-nitro-1-imidazolyl) propylamino] -2,2,6,6-tetramethylpiperidine-N-oxyl,
  • α-[(2,2,6,6-Tetramethyl-4-piperidinyl)-amino]-methyl-2-nitro-1-imidazol-äthanol,α - [(2,2,6,6-tetramethyl-4-piperidinyl) amino] methyl-2-nitro-1-imidazole-ethanol,
  • α-(Cyclohexylamino)-methyl-2-nitro-1-imidazol-äthanol,α- (cyclohexylamino) methyl-2-nitro-1-imidazole-ethanol,
  • α-(Dicyclohexylamino)-methyl-2-nitro-1-imidazol-äthanol undα- (Dicyclohexylamino) methyl-2-nitro-1-imidazole-ethanol and
  • 1-[2-Hydroxy-3-(2-nitro-1-imidazolyl)-propyl]-3-pyrrolidinol.1- [2-Hydroxy-3- (2-nitro-1-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 R2wie 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 RI 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 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,
    implements 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 I and R 2 with the difference that R 10 is not hydrogen, in the presence of a base or
  • (c) a halohydrin of the formula
    Figure imgb0007
     where X represents chlorine or bromine,
    reacted with an amine of the formula III and, if desired, converted a compound of the formula 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 Äthanol), Dimethylformamid oder Dimethylacetamid. Andererseits kann ein Überschuß 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 Äthanol), 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 can also be used. 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 conveniently carried out in the presence of an inert organic solvent, e.g. B. a lower alkanol (z. B. methanol or ethanol) performed. 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 111 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 111 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 Äthanol), 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 111 according to process variant (c), at least one mole of amine is advantageously used per mole of halohydrin. The reaction is conveniently carried out in the presence of an acid-binding agent such as an alkali metal carbonate (e.g. sodium carbonate or potassium carbonate) or a tertiary organic amine (e.g. 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 expediently 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. HCI oder HBr), Schwefelsäure, Salpetersäure oder Phosphorsäure oder mit einer organischen Säure, wie Essigsäure, Zitronensäure, Maleinsäure, Äpfelsäure, 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, e.g. B. by reaction with an inorganic 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 be converted to 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 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 und ihrer physiologisch verträglichen Säureadditionssalze als Radiosensitiser für hypoxische Zellen kann in einem in vitro-Versuch an hypoxischen chinesischen Hamster-V 79-Zellen (vergl. Adams et al., Radiation Research, 67, 9-20 (1976) gezeigt werden. So besitzen z. B. 2-Nitro-α-(piperidino)-methyl-1-imidazol-äthanol-hydrochlorid und α-(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 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 and their physiologically tolerable acid addition salts as radiosensitizers for hypoxic cells can be demonstrated in an in vitro experiment on hypoxic Chinese hamster V 79 cells (cf. Adams et al., Radiation Research, 67, 9-20 (1976 For example, 2-nitro-α- (piperidino) methyl-1-imidazole-ethanol hydrochloride and α- (benzylamino) methyl-2-nitro-1-imidazole-ethanol hydrochloride have two new nitroimidazoles according to the invention, an amplification factor of 1.6 (VF index 1.6) at concentrations of 30 μmol or 40 μmol. In order to achieve the same amplification with misonidazole or metronidazole, these two known nitroimidazoles would have to be used in a concentration of 300 μmol or 4000 µmol can be used.

Die Verbindungen der Formel 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 the formula and their physiologically acceptable acid addition salts can also be used to control infections caused by protozoa, in particular infections caused by Trichomonas vaginalis.

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 Ölen, 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 Drucks oder Puffersubstanzen. Die Präparate können auch andere therapeutisch wertvolle Verbindungen enthalten.The compounds of the invention can be used as pharmaceutical preparations with direct or delayed release of the active ingredient in a mixture with one for enteral, e.g. B. oral or parenteral application of suitable organic or inorganic inert carrier material, such as. 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, e.g. B. as tablets, dragees, suppositories, capsules; in semi-solid form, e.g. B. as ointments; or in liquid form, e.g. B. present as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain further auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, agents for improving the taste, salts for changing the osmotic pressure or buffer substances. 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 Form 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 necessary bringing the mixture into a special galenical 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.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.

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.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 Äthanol gelöst wurde. Die Lösung wurde mit Holzkohle entfärbt und filtriert. Nach Kristallisation wurden 5,2g (72%) α-(Diäthylamino)-methyl-2-nitro-1-imidazoläthanol in Form hellgelber Kristalle, F. 92-93° C, 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-imidazoleethanol were obtained in the form of pale yellow crystals, melting point 92-93 ° C.
  • (b) 3,6 g a-(Diäthylamino)-methyl-2-nitro-1-imidazol-äthanol wurden in einer minimalen Menge warmen Äthanols gelöst und mit einem geringen Überschuß von wasserfreiem ätherischem HCI behandelt. Das nach Abkühlung und Kristallisation erhaltene cremefarbene Hydrochloridsalz (4,0 g) wurde in ca. 40 ml heißem Äthanol gelöst, zur Entfärbung mit Holzkohle behandelt, filtriert und, falls nötig, mit einigen ml trockenem Diäthyläther zur Kristallisation gebracht. Es wurden so 4,0 g 1X-(Diäthylamino)-methyl-2-nitro-1-imidazol-äthanol-hydrochlorid in Form schwach cremefarbener Kristalle, F. 145-146°C (Zersetzung), erhalten.(b) 3.6 g of a- (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 1X- (diethylamino) methyl-2-nitro-1-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 1 (a) analoger Weise wurde nach Kristallisation aus Isopropanol 2-Nitro-α-(pyrrolidino)-methyl-1-imidazol-äthanol in Form hellgelber Kristalle, F. 83­85°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, melting point 8385 ° C. Yield 79%.
  • (b) In zu Beispiel 1 (b) analoger Weise wurde 2-Nitro-α-(pyrrolidino)-methyl-1-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-α- (pyrrolidino) methyl-1-imidazole-ethanol hydrochloride was obtained in the form of slightly cream-colored crystals, mp 158-159 ° C. (dec.), receive. Yield 87%.
Beispiel 3Example 3

  • (a) In zu Beispiel 1 (a) analoger Weise wurde nach Kristallisation aus Äthanol 2-Nitro-α-(piperidino)-methyl-1-imidazol-äthanol in Form hellgelber Kristalle, F. 110-112° C, erhalten. Ausbeute 88%.(a) In a manner analogous to Example 1 (a), after crystallization from ethanol, 2-nitro-α- (piperidino) methyl-1-imidazole-ethanol was obtained in the form of pale yellow crystals, melting point 110-112 ° C. Yield 88%.
  • (b) In zu Beispiel 1 (b) analoger Weise wurde 2-Nitro-α-(piperidino)-methyl-1-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-1-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 1 (a) analoger Weise wurde nach Kristallisation aus Äthanol, 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 1 (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 1 (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 1 (a) analoger Weise wurde nach Kristallisation aus Äthanol, α-(4-Methylpiperazino)-methyl-2-nitro-1-imidazol-äthanol in Form schwach gelber Kristalle, F. 144-145°C, erhalten. Ausbeute 62%.(a) In a manner analogous to Example 1 (a), after crystallization from ethanol, α- (4-methylpiperazino) methyl-2-nitro-1-imidazole-ethanol in the form of pale yellow crystals, mp 144-145 ° C. , receive. Yield 62%.
  • (b) In zu Beispiel 1 (b) analoger Weise wurde α-(4-Methyl-piperazino)-methyl-2-nitro-1-imidazol-äthanol-dihydrochlorid in Form fast farbloser Kristalle, F. 215-216°C, (Zers.), erhalten. Ausbeute 93%.(b) In a manner analogous to Example 1 (b), α- (4-methyl-piperazino) methyl-2-nitro-1-imidazole-ethanol-dihydrochloride was obtained in the form of almost colorless crystals, mp 215-216 ° C., (Dec.). Yield 93%.
Beispiel 6Example 6

  • (a) In zu Beispiel 1 (a) analoger Weise, aber unter Verwendung äquimolekularer Mengen der Reagentien, wurde, nach Kristallisation aus Isopropanol, α-[Di-(2-hydroxyäthyl)-amino]-methyl-2-nitro-1-imidazol-äthanol in Form hellgelber Kristalle, F. 92-93° C, erhalten. Ausbeute 79%.(a) In a manner analogous to Example 1 (a), but using equimolecular amounts of the reagents, after crystallization from isopropanol, α- [di- (2-hydroxyethyl) amino] methyl-2-nitro-1- imidazole-ethanol in the form of light yellow crystals, mp 92-93 ° C, obtained. Yield 79%.
  • (b) In zu Beispiel 1 (b) analoger Weise wurde α-[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), α- [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 1 (a) analoger Weise, aber unter Verwendung von 2 Moläquivalenten von tert.-Butylamin, wurde, nach Kristallisation aus Äthanol, α-(tert.-Butylamino)-methyl-2-nitro-1-imidazol-äthanol in Form hellgelber Kristalle, F. 114―115° C, erhalten. Ausbeute 36%.(a) In a manner analogous to Example 1 (a), but using 2 molar equivalents of tert-butylamine, after crystallization from ethanol, α- (tert-butylamino) methyl-2-nitro-1-imidazole -Ethanol in the form of light yellow crystals, mp 114-115 ° C, obtained. Yield 36%.
  • (b) In zu Beispiel 1 (b) analoger Weise wurde x-(tert.-Butylamino)-methyl-2-nitro-1-imidazol-äthanol-hydrochlorid in Form schwach cremefarbener Kristalle, F.198-199°C (Zers.), erhalten. Ausbeute 87%.(b) In a manner analogous to Example 1 (b), x- (tert-butylamino) methyl-2-nitro-1-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 1 (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 1 (a), but using equimolecular amounts of the reagents, α- (benzylamino) methyl-2-nitro-1-imidazole-ethanol was obtained in the form of a light yellow gum which was uniform according to thin layer chromatography, receive.
  • (b) 4,5 g α-(Benrylamino)-methyl-2-nitro-1-imidazoläthanol wurden in einer minimalen Menge warmen Äthanols gelöst und mit einer äquivalenten Menge äthanolischer 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 Äthanol gelöst, mit Holzkohle entfärbt, filtriert und, soweit nötig, mit einigen ml trockenem Diäthyläther zur Kristallisation gebracht. Es wurden so 3,6g α-(Benzylamino)-methyl-2-nitro-1-imidazol-äthanolmaleat in Form schwach cremefarbener Kristalle, F. 153-154° C (Zers.), erhalten.(b) 4.5 g of α- (benrylamino) 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). The mixture was allowed to cool and crystallize over 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 α- (benzylamino) methyl-2-nitro-1-imidazole-ethanol maleate were thus obtained in the form of slightly cream-colored crystals, melting point 153-154 ° C. (dec.).
  • (c) In analoger Weise wurde, nach Kristallisation aus Äthanol, α-(Benzylamino)-methyl-2-nitro-1-imidazol-äthanoloxalat 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 1 (a) analoger Weise, aber unter Verwendung äquimolarer Mengen der Reagentien wurde, nach Kristallisation aus Äthanol, α-[(4-Methoxyphenyi)-amino]-methyi-2-nitro-1 -imidazoi-äthanol in Form brauner Nadeln, F. 162-163°C, erhalten. Ausbeute 80%.(a) In a manner analogous to Example 1 (a), but using equimolar amounts of the reagents, after crystallization from ethanol, α - [(4-methoxyphenyi) amino] methyi-2-nitro-1-imidazo-ethanol was obtained in the form of brown needles, mp 162-163 ° C. Yield 80%.
  • (b) In zu Beispiel 1 (b) analoger Weise wurde α-[(4-Methoxyphenyl)-amino]-methyl-2-nitro-1-imidazol-äthanolhydrochlorid 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, melting point 156-157 ° C. (Dec.). Yield 97%.
Beispiel 10Example 10

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

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

In zu Beispiel 1 (a) analoger Weise wurde in 62%iger Ausbeute, nach Chromatographie an Aluminiumoxid (Elution mit Dichlormethan), 4-[2-Hydroxy-3-(2-nitro-1-imidazolyl)-propylami- no]-2,2,6,6-tetramethylpiperidin-N-oxyl in Form orangefarbener Kristalle, F. 150-151°C, erhalten.In a manner analogous to Example 1 (a), 4- [2-hydroxy-3- (2-nitro-1-imidazolyl) propylamino] was obtained in 62% yield, after chromatography on aluminum oxide (elution with dichloromethane). 2,2,6,6-tetramethylpiperidine-N-oxyl in the form of orange crystals, melting point 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-1-imidazol-äthanol in Form cremefarbener Kristalle, F. 151-153° C, 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-1-imidazole-ethanol was used in Form of cream-colored crystals, mp 151-153 ° C, obtained. Yield 60%.

Beispiel 14Example 14

  • (a) In zu Beispiel 1 (a) analoger Weise wurde, nach Umkristallisation aus Isopropanol, α-(Cyclohexylamino)-methyl-2-nitro-1-imidazol-äthanol in Form cremefarbener Kristalle, F. 66-68°C, erhalten. Ausbeute 90%.(a) In a manner analogous to Example 1 (a), after recrystallization from isopropanol, α- (cyclohexylamino) methyl-2-nitro-1-imidazole-ethanol was obtained in the form of cream-colored crystals, melting point 66-68 ° C. . Yield 90%.
  • (b) In zu Beispiel 1 (b) analoger Weise wurde, nach Umkristallisation aus Äthanol/Diäthyläther, α-(Cyclohexylamino)-methyl-2-nitro-1-imidazol-äthanol-hydrochlorid in Form farbloser Kristalle, F. 192-193° C (Zers.), erhalten.(b) In a manner analogous to Example 1 (b), after recrystallization from ethanol / diethyl ether, α- (cyclohexylamino) methyl-2-nitro-1-imidazole-ethanol hydrochloride in the form of colorless crystals, mp 192-193 ° C (dec.).
Beispiel 15Example 15

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

In zu Beispiel 1 (a) analoger Weise wurde, nach Umkristallisation aus Äthanol, 1-[2-Hydroxy-3-(2-nitro-1-imidazolyl)-propyl]-3-pyrrolidinol in Form cremefarbener Kristalle, F. 126-127°C, erhalten.In a manner analogous to Example 1 (a), after recrystallization from ethanol, 1- [2-hydroxy-3- (2-nitro-1-imidazolyl) propyl] -3-pyrrolidinol in the form of cream-colored crystals, m.p. 126- 127 ° C.

Beispiel 17Example 17

  • (a) Ein Gemisch aus 5,65 g 2-Nitroimidazol und 250 mg wasserfreiem Kaliumcarbonat in 150 ml Äthanol wurde 15 Minuten unter Rückfluß erhitzt. Nach Zusatz von 7,05 g frisch destilliertem 3-Piperidino-propylen-oxid in einer minimalen Menge Äthanol 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 Öles, das zwischen 100 ml Äthylacetat und 100 ml Wasser verteilt wurde. Die wäßrige Phase wurde abgetrennt, einmal mit 50 ml Äthylacetat gewaschen und die vereinigten organischen Phasen wurden dann 4mal mit jeweils 50 ml 2 N HCI extrahiert. Der vereinigte wäßrige Extrakt wurde durch Zusatz von überschüssigem festen Natriumcarbonat basisch gemacht und 3mal 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 Äthanol gelöst wurde. Die Lösung wurde durch Behandlung mit Holzkohle entfärbt, filtriert und lieferte nach Kristallisation 1,4g (11%) 2-Nitro-α-(piperidino)-methyl-1-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 2N HCl each time. 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-α- (piperidino) methyl-1-imidazole-ethanol in the form of light yellow crystals, mp 108-109 ° C. .
  • (b) 1,27 g 2-Nitro-α-(piperidino)-methyl-1-imidazol-äthanol wurden in 25 ml warmem Äthanol gelöst und mit einem geringen Überschuß an wasserfreiem ätherischem HCI behandelt. Man ließ das Gemisch abkühlen und während mehreren Stunden kristallisieren. Es wurden so 1,4 g 2-Nitro-α-(piperidino)-methyl-1-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-α- (piperidino) methyl-1-imidazole-ethanol was dissolved in 25 ml of warm ethanol and treated with a slight excess of anhydrous ethereal HCl. The mixture was allowed to cool and crystallize for several hours. 1.4 g of 2-nitro-α- (piperidino) methyl-1-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-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 Überschusses von 2 N HCI suspendiert. Die homogene Lösung wurde 3mal mit je 25 ml Dichlormethan gewaschen, mit einem geringen Überschuß einer 2 N Natriumhydroxid-Lösung behandelt und 3mal 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 Äthanol gelöst wurde. Die Lösung wurde mittels Holzkohle entfärbt, filtriert und lieferte nach Kristallisation 3,3 g (65%) 2-Nitro-α-(piperidino)-methyl-1-imidazoläthanol in Form hellgelber Kristalle, F. 110―112°C. Dieses Produkt war mit dem gemäß Beispiel 3 (a) erhaltenen identisch und wurde in zu Beispiel 1 (b) analoger Weise in das Hydrochlorid übergeführt.A mixture of 4.1 g of 3-chloro-1- (2-nitro-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 dichloromethane each time, with a slight excess of a 2 N sodium hydroxide solution treated and extracted 3 times with 75 ml of dichloromethane each time. 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-α- (piperidino) methyl-1-imidazoleethanol in the form of pale yellow crystals, melting point 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

Kapseln enthaltend:

Figure imgb0008
Capsules containing:
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 (24)

1. A process for the manufacture of nitroimidazoles of the formula
Figure imgb0016
wherein RI represents hydrogen, lower alkyl, hydroxy- (lower alkyl), lower cycloalkyl, aryl or aryl-(Iower alkyl), R2 represents lower alkyl, hydroxy-(Iower alkyl), lower cycloalkyl, aryl or aryl-(lower alkyl) or a grouping of the formula
Figure imgb0017
in which m = 0 and n = 1 or m = 1 and n=0, R3 represents hydrogen, methyl, hydroxy or a free oxygen radical, or R1 and R2 together with the nitrogen atom to which they are attached represent a 5-, 6- or 7membered saturated heteromonocyclic ring, which may carry a hydroxy group on a carbon atom not adjacent to the nitrogen atom and which may contain a further oxygen, sulphur or nitrogen atom, which may be substituted by a lower alkyl, hydroxy-(Iower alkyl), aryl or aryl-(lower alkyl) group, and of acid addition salts thereof, characterized in that
(a) an epoxide of the formula
Figure imgb0018
is reacted with an amine of the formula
Figure imgb0019
wherein R1 and R2 have the significance given above,
(b) a compound of the formula
Figure imgb0020
is reacted with an epoxide of the formula
Figure imgb0021
wherein R10 and R20 have any of the values accorded to R1 and R2 above except that R10 does not represent hydrogen,
in the presence of a base, or
(c) a halohydrin of the formula
Figure imgb0022
wherein X represents chlorine or bromine,
is reacted with an amine of formula III and, if desired, a compound of formula I obtained is converted into an acid addition salt.
2. A process according to claim 1, characterized in that there is manufactured a compound of formula I, or an acid addition salt thereof, in which R1 represents hydrogen, lower alkyl, hydroxy-(lower alkyl), aryl or aryl-(Iower alkyl); R2 represents lower alkyl, hydroxy-(lower alkyl), aryl or aryl-(Iower alkyl) or R1 and R2 together with the nitrogen atom to which they are attached represent a 5-, 6- or 7membered saturated heteromonocyclic ring, which may carry a hydroxy group on a carbon atom not adjacent to the nitrogen atom and which may contain a further oxygen, sulphur or nitrogen atom, which may be substituted by a lower alkyl, hydroxy-(Iower alkyl), aryl or aryl-(Iower alkyl) group.
3. A process according to claim 1, characterized in that there is manufactured a compound of formula I or an acid addition salt thereof, in which R1 and R2 together with the nitrogen atom to which they are attached represent a 6membered heteromonocyclic ring, which may contain a further oxygen or nitrogen atom, which may be substituted by a lower alkyl group.
4. A process for the manufacture of pharmaceutical preparations, characterized in that a compound of the formula I as defined in claim 1, as the active ingredient, is mixed which an inert, therapeutically compatible solid or liquid carrier and that the mixture is given a suitable galenic form.
5. Pharmaceutical preparations containing a compound of the formula I as set forth in claim 1.
6. Nitroimidazoles of formula I given in claim 1 and their acid addition salts.
7. Compounds according to claim 6, characterized in that in formula I R1 represents hydrogen, lower alkyl, hydroxy-(Iower alkyl), aryl or aryl-(Iower alkyl); R2 represents lower alkyl, hydroxy-(Iower alkyl), aryl or aryl-(lower alkyl) or R' and R2 together with the nitrogen atom to which they are attached represent a 5-, 6- or 7membered saturated heteromonocyclic ring, which may carry a hydroxy group on a carbon atom not adjacent to the nitrogen atom and which may contain a further oxygen, sulphur or nitrogen atom, which may be substituted by a lower alkyl, hydroxy-(lower alkyl), aryl or aryl-(Iower alkyl) group.
8. Compounds of formula I given in claim 6, characterized in that in formula I R1 and R2 together with the nitrogen atom to which they are attached represent a 6membered heterocyclic ring which may contain a further oxygen or nitrogen atom, which may be substituted by a lower alkyl group.
9. 2-Nitro-α-(piperidino)methyl-1-imidazole-ethanol.
10. α-(Morpholino)methyl-2-nitro-1-imidazole-ethanol.
11. α-(4-Methyipiperazino)methyl-2-nitro-1 -imidazole-ethanol.
12. 2-Nitro-α-(pyrrolidino)methyl-1-imidazole-ethanol.
13. α-(Diethylamino)methyl-2-nitro-1-imidazole-ethanol.
14. α-(Di-(2-hydroxyethyl)amino]methyl-2-nitro-1-imidazole-ethanol.
15. α-(Tert.-butylamino)methyl-2-nitro-1-imidazole-ethanol.
16. α-(Benzylamino)methyl-2-nitro-1-imidazole-ethanol.
17. α-[(4-Methoxyphenyl)amino]methyl-2-nitro-1-imidazole-ethanol.
18. α-(Dimethylamino)methyl-2-nitro-1-imidazole-ethanol.
19. α-(Hexahydro-1 H-azepino)methyl-2-nitro-1-imidazole-ethanol.
20. 4-[2-Hydroxy-3-(2-nitro-1-i m idazolyl) propylamino]-2,2,6,6-tetra methylpiperid i n-N-oxyl.
21. α-[(2,2,6,6-Tetramethyl-4-piperidinyl)amino]methyl-2-nitro-1-imidazole-ethanol.
22. α-(Cyclohexylamino)methyl-2-nitro-1-imidazole-ethanol.
23. α-(Dicyciohexyiamino)methyl-2-nitro-1 -imidazole-ethanol).
24.1 -[2-Hydroxy-3-(2-nitro-1 -imidazolyl)propyl]-3-pyrrolidinol.
EP78100690A 1977-08-19 1978-08-17 Nitroimidazoles and pharmaceutical compositions containing them as well as their preparation Expired EP0000928B1 (en)

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