CS195690B2 - Method of producing novel derivatives of nitroimidazole - Google Patents

Description

The invention relates to a process for the preparation of novel nitroimidazole derivatives of the general formula I,

wherein one of R 1 and R 2 is hydrogen; and the other of these residues is low. group

R 5 represents a lower alkyl radical having 1 to 2 carbon atoms, ‘R 5 represents a lower alkylamino group, the lower alkyl group containing 1 'to 14 carbon atoms, and salts thereof.

Lower alkyl radicals are, for example, methyl, ethyl, n-propyl or isopropyl or straight or branched butyl, in particular methyl or ethyl.

Lower alkylamino is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or sep.-butylamino. . The new com- plexes have valuable corporate logistics. Thus, they have particular effects

195890

(Against bacteria, especially against gram, negative bacteria, protozoa) and worms such as whipworms (Trichomonas ©), shrimps (Šdhistosoma), and 'amoeba', as can be shown by experimenters , for example, in the liver of healthy hamsters, which have been artificially infected with the vertebrate ammonium (Entamoeha htstolytica), at doses ranging from about 10 to about 100 m./kg (orally). In addition, the novel imazazoles can be used as starting materials or as intermediates for the production of other, in particular therapeutically, leaching compounds.

The invention relates in particular to the production of compounds of the general formula Ia,

ΑΛ ti "

IKJI-C-RS lf ⁰ (Ia)

195890 in mulž

M 1 is hydrogen, R 5 and R 5 are as defined in formula I, and salts thereof.

In the same way, the invention also relates, in particular, to the preparation of the compounds of formula Ib,

in which ·

R2 is hydrogen,

R 3 and R 5 are as defined in formula I, and salts thereof.

Of particular interest are the compounds of formulas Ia, Ib, wherein R 1 and R 5, respectively, have the meanings given below under formula m or under formula. Ib, R 5 is methyl and R 5 is methylamino and salts thereof.

Of these novel imidazoles of Formula I, particular mention should be made

1- (Methylcarhamoyl) -2-oxo-3- [1-methyl- -5-nj) -throtimidazol-12-yl] -e^:trahydoimidimidazole, which in the liver of healthy hamsters, which have been artificially inthfied with Daphnia (Entomamoeba htstolyttca), causes an orally distinct uivolInsn abscess at doses of 10 to 100 mg / kg orally.

According to the invention, the novel nitroimide, azoles of formula I are obtained by converting to the imazole of formula U,

in which Mi, R? They have the above meaning, they cause lower

R-NGO ,, (III) wherein R is C 1 -C 4 alkyl.

. The following conversions may be performed singly or in combination and in any order. It is important to ensure that no other functional groups are attacked during individual operations.

The invention also relates to such process alternatives in which the starting material is used in a process. in the form of a salt and / or a racemate and / or optical antipodes.

Said reactions were. carried out in the usual manner in the presence of or. in the absence of diluents, condensing agents or catalysts, at room temperature, or at or below room temperature, optionally in a closed vessel. If appropriate, work in a larger dilution (dilution principle).

The starting materials are known or, if they are new, can be obtained by methods known per se.

Depending on the reaction conditions and the preferred materials, the reaction products are obtained in free form or in the form of acid addition salts. Thus, for example, isasadiates, neutral or mixed salts, and optionally also their hemihydrates, monohydrates, sesquids, wires or polyhydrides can be obtained. The acid addition salts of the novel compounds can be converted in a known manner into the free compound, for example by treatment with basic agents, such as alkali or Janto-exchangers. On the other hand, may form iie obtained throws ¹ Salts with organic or inorganic acids. In particular, those acids which are suitable for the formation of therapeutically useful salts are used for the preparation of acid addition salts. such acids can be used. (for example, include: hydrohalogenic, sulfuric, phosphoric, nitric, perchloric, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulphonic acids such as (formic, acetic, prop, ionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic or pyruvic acid, ttenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxyiheinzoic, salicyloic or p -aminosalicylic, embonic, methisulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid; ^;> ny halogěnbenzehsulfonové acid toluensuliřonóvá, naphthalenesulfonic acid. or sulIfanilová; methiobin, 'tryptdfah, lysine or terginin. / I These or other salts of the new sloučéíiiii such as pJIkráty, can also be used to purify the free bases obtained, by volné- bases are converted into salts which are separated from these salts from the Due to the close relationship between the new salts in the free form of their salts, both the preceding and the following parts are understood to include the free compounds according to the purpose and purpose, and possibly also the corresponding phalates, as well as quaternary salts which can be produced by quaternization of the compounds AND.

Depending on the number of asymmetric carbon atoms Ia according to the starting materials and processes selected, the novel compounds can be present in the form of mixtures of racerates, in the form of racemates or optical antipodes. The racemate mixtures can be separated into the pure racemates in known manner, for example by chromatography and / or traction crystallization, based on the physical-chemical differences of the individual components.

Pure racemates can be obtained by known methods 185690, for example by recrystallization. from an optically active solvent, by means of microorganisms or by reaction with an optically active acid, which forms a racemic salt compound and decomposes the salts thus obtained, for example on account of their different solubilities, into diastereomers, from which they can be released reagents. Particularly useful optically active acids are, for example, the D- and L-forms of tartaric, dl-o-toluyltartaric, malic, mandelic, camphorsulphonic or cholineic acids. Preferably, it is isolated more effectively from oipou Antipodes.

According to the invention, however, it is also possible to obtain racemic products in the form of pure racemates or optical antipodes by using starting lacquers which contain one or (several asymmetric carbon atoms in the form of pure racemates or in the form of an optical antipode). According to their antimicrobial properties, compounds of formula (I), their addition of salts with acid (and quaternary salts) may serve to protect hydrophobic or other high-molecular-weight organic substances which are subject to decomposition by bacteria or other rhoots. The compounds of the present invention are also used as additives that support livestock and which are added to the feed in a ratio of from 5 to 5%. up to 500 ppm,) Correspondingly The therapeutic composition consists of an antimicrobially active moiety (compounds of formula I (v, i) from above) or an acid addition salt or a high-quality salt (and some pharmacologically usable pastry carrier or liquid diluents).

The pharmaceutical preparations contain at least one compound of formula (I) (see above) as active ingredient together with a conventional pharmaceutical carrier. The type of carrier depends mainly on the area of application for external use, for example disinfection of healthy skin as well as disinfection • oral cavity and for the treatment of dermatoses and affection • Bacteria-related sores are particularly suitable • ointments, powders, tinctures • Ointment bases may be anhydrous, for example from mixtures of fat • sheep wool and petrolatum, or may also be (o aqueous emulsions in which the active ingredient is (suspended). Suitable powders are, for example, starches, such as rice starch, (the specific weight of which may optionally be reduced, for example by adding highly disperse silicic acid or vice versa (increase). Tinctures contain at least one active ingredient in aqueous, especially 45-75% ethanol, to which optionally 10 to 20% glycriine is added, especially in the case of decomposition of healthy skin, solutions which are prepared with polyethylene glycol and other customary solutions are contemplated. The active substance content of the pharmaceutical preparations for external application is preferably between 0.1 and 5%. Gargling water or concentrates for preparing the oral cavity and larynx are suitable for disinfecting the oral cavity and larynx, in particular alcoholic beverages. solutions containing 1 to 5% of the active ingredient, to which glycerin and / or flavoring agents may be added, and on the other hand lozenges, i.e. solid dosage forms, preferably with a relatively (high sugar or similar content) and a relatively low active ingredient content , for example 0.2 to 20%, as with other ingredients such as binders and (flavoring agents).

dez Disinfection of sfaev and κ orainimu treatment (urinary tract infections are possible (especially solid dosage forms such as toablets, dragees and capsules) containing, preferably between 10 and 90% of the active ingredient swollen in formula I (see above), to allow administration of daily doses of between 0.1 and 12.5 g for adult patients or suitably reduced doses for children To prepare tablets and dragee cores, the compounds of formula I are combined with solid, powdered (carriers such as lactose, sucrose: (for, sorbitol, maize starch, potato Bkirob or amylopectin, cellulose derivatives (or gelatin), preferably with the addition of lubricants such as magnesium stearate or calcium stearate or polyether ethylene glycols of suitable molecular weight. , for example, concentrated sugar solutions which still contain, for example, gum arabic, talc, and / or titanium dioxide or a lacquer which is dissolved in readily volatile organic roles in solvents or in a solvent mixture. Dyestuffs may be added to these coatings, for example to distinguish different doses of active ingredient. Soft gelatin capsules and other sealed capsules are, for example, a mixture of gelatin and glycerin and may contain, for example, mixtures of a compound of formula I with a poly. ethylene glycol. The push-fit capsules contain, for example, the active ingredient granules with solid, powdered excipients such as lactose, sucrose, sorbitol, mannitol; starches such as potato starch, corn starch or amylopectin, cellulose derivatives and gelatin, as well as magnesium stearate or stearic acid.

In all dosage forms, the compounds of formula (I) may be present as the sole active compounds or may be combined with other known pharmacologically active substances, in particular antibacterial, or / or antifungal, or otherwise amtimicirobial active substances, for example to extend the application possibilities. Thus, they may be combined with, for example, 5,7-dichloro-2-methyl-8-quinolinol or other 8-quinolinol derivatives, sulfamerazine or sul195690 iafurazolam - or other sulfanilamide derivatives, chloramlfentcol or tetracycline or other antibiotics, with 3,4 ', 5' -tribramsaliicylanilides or with other halogenated benzoxazoles or benzoxazolones, with polyhydroxyhydroxydifeethylmethane, with halogen-dihydroxy-diphenylsulfides, with 4,4'-dichloro-2-hyidiroxydiphenylether or with 2 ', 4,4'-triichror-2-hydroxydiphenyl ether or other polyhalogenated hydroxy ethers or others. polyhalohydroxy-diphenyl ethers or with a bactericidally active quaternary, compounds thereof or certain dithiocarbamic acid derivatives such as tetramethylthiuram disulfide. ^Further they can also use carriers which themselves have a 'favorable pharmacological properties, such as sulfur powder, or · zineičnatý stearate, as components excipients. An appropriate way of protecting organic substances that are exposed to bacteria or other microbes assumes that such substances are treated with a compound of formula I. The organic substance may be, for example, a natural or synthetic polymeric material, a protein or carbohydrate containing material or natural or synthetic fiber or a textile material made from these substances.

Corresponding formulations for the treatment of animals contain, in sufficient amounts, 5-nitroimidazole of formula (I), which, according to the invention, contains a compound of formula (I). it promotes the growth of animals fed with this preparation.

The following Examples (a) to (d) illustrate the preparation of several typical dosage forms, but are by no means the only forms of such formulations.

(a) 250.0 g of the active substance are mixed with 550.0 g of lactose and 292.0 g of potato starch, the mixture is moistened; alcohol solution 8 g of gelatin and granulated with a sieve. After drying, 60.0 g of potato starch, 60.0 g of talc, 10.0 g of magnesium stearate and 20.0 g of colloidal silica are admixed with the granulate and the mixture. is compressed into 10,030 tablets of 125 mg each containing 25 mg of active ingredient. The tablets are optionally provided with indentations for finer dose adjustment.

(ib) From 100.0 g of active substance, 379.0 g of lactose and alcoholic solution of 6.0 g of gelatin, a granulate is prepared which, after drying, is mixed with ¹ 10.0 g of colloidal silica, 40.0 g of talc, 60 g, 0 g of potato starch and 5.0 g of magnesium stearate and the mixture is pressed into 10,000 dragee cores. The dragee cores were then coated with concentrated, 533.5 g crystalline sucrose syrup, 20.0 g shellac, 75.0 g arabic gum, 250.0 g talc, 20.0 g colloidal silica and 1.5 g dyes and dried. The dragees obtained weigh 150 mg and contain 10 mg of active ingredient.

(c) 25.0 g of the active ingredient and 1975 g of finely divided suppository bases (for example cocoa butter) are intimately mixed and the mixture melted. 1000 suppositories weighing 2.0 g are poured from the melt, which is kept homogeneous by stirring. These suppositories each contain 25 mg of active ingredient. .

d) For the preparation of a syrup containing 0.25% of active ingredient, it is dissolved in 3 liters of distilled water, 1.5 liters of glycerin, 42 g of methyl p-hydroxybenzoate, 18 g of n-propyl p-hydroxybenzoate and mild přiidá warming with 25.0 g of active ingredient, 4 liters of 70% sorbitol solution, 1000 · ig crystallized saccharose, ¹ g of glucose 350, and a flavoring substance, the resulting solution was filtered and the filtrate SE- up with distilled water to a volume of 10 liters.

The following example illustrates the preparation of the novel compounds of formula (I) but does not limit the invention in any way. Temperatures are given in degrees Celsius.

example

To a suspension of 0.1 g of 50% sodium hydride in 2 rol of absolute dimethylformamide was added dropwise a solution of 0.4 g of 2-oxo-3- [l-Methyl-5-nitroimld azo ^l l-2-yl] tetrahydroimidazol in 8 ml absOlutníto The reaction mixture was stirred at room temperature for 15 minutes. A solution of 0.2 g of methyl isocyanate in 2 ml of absolute dimethylformamide was added thereto, followed by heating at 100 ° C for 3 hours. The reaction mixture is then evaporated in vacuo, the residue is triturated with 50 ml of water, extracted with ethylene dichloride and the extract is dried over sodium sulfate. The residue is chromatographed on a silica gel column. The fraction was eluted with 2% imethathiol in chloroform. There was thus obtained 1-N-methylcarbabyoyl-2-oxo-3-f-methyl-5'-nitroimidazol-2-yl-triethyimidazole which melts at 176-177 °. Yield 70%.

Claims (3)

-SUBJECT 1. A process for the preparation of novel nitroleol derivatives of the general formula I: Wherein ^{1 is} one of R 1 and R 2 is hydrogen and the other is nitro, ¹ R 3 is a lower alkyl radical having 1 to 2 carbon atoms, R 5 is a lower alkylamino group, wherein the lower alkyl group contains 1 to 4 carbon atoms, and their acid addition and quaternary salts, characterized in that the imidafeol of the formula II is wherein R 1, R 2 and R 3 are as defined above, act with a lower alkyl isocyanate of general formula III. . R-NCO, (III) wherein R is C 1 -C 4 alkyl, whereupon any racemate mixtures obtained are separated into pure racemates, or the racemates obtained are separated into optical antipodes, or / and the salts obtained are converted the free compounds or other salts ha ^<or 'free compounds obtained are converted into their salts. 2. A method according to claim 1 wherein SG is treated with a compound of formula II wherein R1 is hydrogen, R2 is nitro, and R3 is methyl with a compound of formula III wherein R is methyl or ethyl. 3. The method of item 1, wherein 11a 3 '- (1-methyl-5-nitroimidazol-2-yl) 2-oxoteirahydroimidazzole is treated with methyl isocyanate.