DE1470078A1 - Imidazole compounds and processes for their preparation - Google Patents

Description

Patent attorneys Pienzenauerstraße 28

Telephone 483225 and 486415 Telegrams! Chemindus Munich

March 24, 1969 8771 (M 62 024)

P 14 70 078 8
New documents

HKRCK A CO. «INC.
Rahway, New Jersey 07065 "V. St. A.

Imldazole compounds and processes for their preparation

Various nitro-mldazole compounds have already been reported « that they fair the oil disease Histomoniaais and / or brewable against the protozoenitis trichomoniasis are. Examples of such substances are l- (2-hydroxyethyl) -5-nltroimidazole, 1,2-Dimethyl-5-nitroimidazole, 1-Methy1-5-nltrolmidazole and 1- (2-hydroxyethyl) -2-methyl-5-nitroimidazole.

Hiatomoniasis is an oil disease caused by the protozoal parasite Histomonae meleagridls is caused · Dlesο Disease »that afflicts turkeys or turkeys, 1st auoh as turkey blackhead or aaterohepati-

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tls known. It is a serious economic problem in the turkey breeding industry because it is spreading rapidly among turkey flocks and the mortality rate can be as high as 80% . The compounds currently available for treating turkey head are beneficial, but none of them have been found to be completely satisfactory as they allow the development of resistant strains of the infecting organism or lead to undesirable lifting effects when fed to the poultry in the quantities required to treat the disease. So the search for new and improved compounds against historaoniasis has not stopped.

Triohoiaoniasis is another protozoal disease «caused by TrlGhomonas vaginalis is caused. T. vaginal! S infected mainly the vagina in humans and is the stiological marriage Cause of a very bothersome and common fora of vaginal inflammation known as T * vaginalis vaginitis is · The drugs currently available for the treatment of this disease have certain limitations and disadvantages » so that the search for improved substances against trichomoniasis has also continued in the field.

It is an object of the present invention to provide a new class of chemical compounds which are highly effective Possess effectiveness against histomoniasis and trichomoniaaic. Another object of the invention is to provide new 1-substituted 5-nitroimidazole-2-arboxamides and N-substituted carbozamides that have such Have effectiveness against protozoa. Another object of the invention are processes for making these new carboxamide compounds from 2-Hydroxymethylimidazole.

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The invention relates to compounds of the formula

O ₂ KO

N
-CXMR ₉ RZ (I)

₂ R ₃

where R denotes a lower alkyl radical or a group where η is a value from 2 to 4, R ₂ denotes a hydrogen atom or a lower AUqrlrest, IU denotes a hydrogen atom or a lower alkyl, hydroxyalkyl, aryl or amino radical and MR ₂ R ₃ together can also form a morpholine, piperazoline or pyrroline ring.

The substituent in the 1-position of the imldazole ring R can for example methyl, ethyl, propyl or butyl or a hydroxyalkyl group, for example 2-HydroxyKthyl or 3-Hydroxypropyl, be.

If R ₃ or R is a lower alkyl radical, this can be, for example, methyl, ethyl or butyl. If R. is an aryl group, this can be, for example, phenyl, tolyl or a functionally substituted phenyl group.

From the above discussion it can be seen that the invention is 1-lower-alky 1- (or 1-hydroxyalkyl) -

oarboxaiaide itself as well as compounds in which the AmIdtell is further substituted. If generally here reference is made to imidazole-2-oarboxamide, so should both the primary and substituted amides may be included.

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The new 1-lower-alkyl-5-nitroimidazole-2-arboxamides are the invention manufactured, invited nan

(A) a l-iiiederlg-alkyl-S-nitroimidarol ^ -carbonylhalogeriid with an amin of the formula H-NR ₂ R- to a compound of the formula I, for which R is a lower alkyl radical, or

(b) a Laotian of the formula

with an amine of the formula H-HRgR to form a compound of the formula I for which R is a group - (GHg) _n OH, or

(o) a hydrocarbon ester of a 1-lower alkyl-5-nitroimldazole-2-carboxylic acid nlt ammonia to a compound of the formula I, for which R. a lower alkylreet and R_ and R, hydrogen fatoae, where the symbols R and η have the meanings given above.

This is shown in the following scheme:

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rj N

O ₂ H-II ^ J-CH ₂ OH - ^ O ₂ N-1 ^^ - CH ₂ OH

II

«1 III

Ri

O ₂ N-

-COOH

IV

»1 VH

VI

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In the above formulas, R ₁ denotes a lower alkyl radical, H denotes a metal, "preferably an alkali metal, such as" for example sodium or potassium "or an alkaline earth metal such as calcium or barium," Y denotes a hydrocarbon radical with fewer than 9 carbon atoms and preferably a lower alkyl group and X represents a chlorine or bromine atom. R ₂ and R have the meanings given above.

The details of the inventive preparation of the 1-alkyl-5-nitroimidazole-2-arboxamide compounds are now given below. For the sake of simplicity, the following discussion will focus primarily on making connections directed «for which the 1-position of the Imidaxolringa with is substituted by a methyl group · However, it goes without saying « that corresponding reaction conditions for the invention Preparation of the other l-lower alkyl-5-nitroimidazole-2-oarboxamides can be applied and the description can also be applied to the synthesis of such substances.

2-Hydroxymethylimidazole is used to prepare the starting compound with formation of 2-hydroxyraethyl-5-nitroi «idazole (Compound II in the above scheme) nitrated · This conversion stage is carried out «by adding the hydroxyraethyl compound brought into contact with a suitable filtering agent The preferred nitrating agent is nitric acid in the presence of boron trifluoride. Acetyl nitrate however, sulfur trioxide-nitric acid are also satisfactory. To achieve the best results, it is useful massive «that the hydroxymethyl substituent by esterification or hardening is slit before nitriding. Bs 1st ZweokmKsalg, a lower AlkarsKureester, such as

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wise to produce the acetic acid ester by reacting the hydroxymethyl compound with acetic anhydride. Other esters can of course be used provided the starting material is treated with the appropriate esterifying agents, never for example propionic anhydride and the like. The nitration is carried out. By treating the ester of 2-hydroxyinethyliraidazole with the nitrating agent in an anhydrous reaction medium. The reactants can be mixed in the cold and then allowed to warm slowly to room temperature. The nitration reaction mixture is then heated at temperatures in the range from 60 to 100 ^° C. for a short period of time. When aoetyl nitrate is used as the nitrating agent, the reaction is usually less than

Practically completed 1 hour, during reaction tents of about

2 to 8 hours are preferred at Salpetera & ure-Bortrifluorld. The reaction times and temperatures are not particularly critical and can be varied within reasonable limits. It can be seen that the reaction finishes faster at higher temperatures. At the end of the nitration it will Reaction mixture neutralized with a base and the nitrated Imldazole in an organic solvent, such as Chloroform, methyl ethyl acetone, butanol or ethyl acetate, extracted. If an esterified hydroxymethyl group is present 1st, it is hydrolyzed, and the 2-hydroxyethyl-5-nitroimidazole is extracted and purified.

Then α-hydroxymethyl-S-nitroolmldazole becomes in the 1-position duroh reaction alkylated with a lower alkylating agent. Suitable alkylating agents are the Di-nledrlg-alkyl sulfates, such as dimethyl sulfate, diethyl sulfate and the like, or sulfonates of duroh methylbenzenesulfonate, Xthyl p-toluenesulfonate and propylbenzenesulfonate Type.

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It is a critical feature of this stage that anionization of the imidazole is reduced to a minimum and preferably practically completely suppressed. Otherwise, other undesirable alkylated imidazoles will be formed. In order to achieve the desired purpose, the alkylation is carried out according to the invention in the absence of a solvent. If a solvent is deemed necessary or of two kinds for any reason, inert solvents such as diphenyl oxide, tetramethyl sulfone, hexachlorobenzene, naphthalene, or diphenyl ether can be used. Satisfactory results are obtained using approximately equimolar amounts of the xmidazole compound and the alkylating agent. However, an excess of up to about 50 % of the alkylating agent may optionally be used without adversely affecting the reaction. The alkylation reaction 1st in 5 minutes to 1 hour at temperatures in the range of about 75 to 225 ⁰ C and preferably 100 to 175 ends praktisoh ⁰ C. After this period of time, any remaining alkylating agent is neutralized with a base such as sodium hydroxide, and the 1-lower alkyl-2-hydroxymethyl-5-nitroimidazole compound is recovered by extraction with an organic solvent. In this way, using the appropriate alkylating agents, 1-methyl-2-hydroxymethyl-5-nitroimidazole and the corresponding 1-ethyl-, 1-propyl- and 1-butyimidazoles are obtained.

The next stage is the l-nledrig-alkyl-2-hydroxymethyl-5-nitroimidazoles of the formula XII by suitable oxidation reaction into the corresponding 2-carboxylic acid compounds (IV) convicted. This oxidation is preferably carried out by the 2-hydroxymethylimidazole compound with the oxidizing agent is brought into contact in an alkaline medium.

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Alkali permanganates, such as sodium or potassium permanganate, are the preferred oxidizing agents. Oxidation with fermanganate will take place at room temperature or below carried out in a solvent medium that is itself resistant to oxidation. Examples of suitable solvents that can be mentioned are aoetone, methyl ethyl ketone, Cyclopentanone and dimethyl sulfone. In addition to alkali permanganate, the oxidation reaction can also be carried out with oxidizing agents, such as sodium hypochlorite or nickel peroxide, be performed. An alkali chromate, for example xalium diohrate, can also be used, but it is difficult because of the formation of metal complexes are to be separated from the desired product, not preferred. The l-nledrig-alkyl-S-nitroimidazole ^ -carfeonic acids themselves are unstable Compounds that tend to decarboxylate almost spontaneously. Because of this, the product comes in the form of a Salt, such as an alkali salt, for example the sodium or potassium salt, isolated. These salts can if desired can be cleaned, but it has been found that they can be cleaned in the method according to the invention without excessive cleaning are quite satisfactory in the following synthesis steps. In this way the sodium or potassium salts of 1-methyl-5-nitroimidazole ~ 2-carboxylic acid, l-ethyl-5-nitroimidazole- ^ 2-carboxylic acid and 1-propyl-5-nitroimidazole-2-carboxylic acid were obtained.

In the next reaction, the salt of 1-nledrig-alkyl-5-nitroialdasol-2-carboxylic acid Converted into the corresponding acid halide or the corresponding ester. The acid halide can be either the acid chloride or the acid bromide. The output connections for the production of the new compounds used esters are preferably low

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ge alkyl esters such as methyl, ethyl, propyl or isopropyl esters, but aryl or aralkyl esters such as benzyl or phenyl esters can also be used. From the above scheme it can be seen that the acid salt can be converted into either an acid halide or an ester. In addition, the esters and acid halides can be mutually converted into one another. This is sometimes useful as a means of producing a compound which can be purified without undue difficulty. For example, in many cases the esters are more easily purified than the acid halides. Either an acid halide or an ester can be converted directly into the terminal amides. If one wishes to prepare tertiary amides, ie those compounds of the formula VII for which both R ₂ and R have meanings other than hydrogen atoms, it is preferable and in some cases In some cases it is necessary to use the acid chloride as the starting material, since the tertiary amines only react sohwer with 1-lower-alkyl-5-methyl-methyl-2-carboxylic acid esters. This will be discussed further later.

The acid halides of the formula VI are obtained from the corresponding acid salts of the formula IV or from the esters of the formula V. by bringing these compounds into close contact with a halogenating agent, examples of suitable halogenating agents are obtained are oxalyl chloride, oxalyl bromide, thionyl chloride, Phosphorus oxychloride, phosphorus penta chloride and phosphorus pentabromide. The oxalyl halides are preferred. The reaction can be carried out in an inert organic solvent are, and for this purpose solvents such as benzene, toluene, xylene and dimethyl sulfoaid, suitable. Alternatively, an excess of a liquid halogenating agent can be used be used as a reactive solution Dl formation of the l-lower-alkyl-S-nitroimldazole-S-carbo-

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The nyl halide occurs rapidly and the reaction is ordinary Practically finished in 5 to 90 minutes at elevated temperatures. To ensure that the reaction is complete, there will normally be an excess of Oxaly! halide used. The crude 1-lower alkyl-5-nitroimidazole-2-carbonyl halide thus obtained Is for conversion to a lower alkyl ester or without further purification for the direct production of an imidazole-2 ° carboxamlds satisfactory. If desired, the imidazole-2-carbony halide but by recrystallization from an inert organic solvent such as benzene or toluene, getting cleaned.

Examples of compounds obtained in this way are 1-methyl-5-nltroimldazol-2 = carbonyl chloride, l-methyl-5-nitroimld azole-2-earbonylbroinide, 1 ° ethyl ~ 5-nitroimida2: ol «2-carbonyl chloride, 1-n-propyl-S-nitroimidazole-S-carbonylchloride and 1-butyl-5-nitroimidazole-2-carbonyl bromide. These 1-lower alkyl-5-nitroimidazole-2-carbonyl halides when treated with a suitable Arain result in the corresponding l ° lower-alkyl-5-nitroolmidazole carboxamides. This is how the reaction of an XmIdazole-2-carbonyl chloride takes place with ammonia to the corresponding xmidazole-2-earboxaroid itself. Are substituted amines at used in the reaction, the correspondingly substituted l-lower alkyl-S-nitroiisidazole ^ -carboxamides are formed.

Lower alkyl esters of 1-nledrig-alkyl-5 "nitroimidazole-2-car» Organic acids can easily be obtained from the corresponding 2-carbonyl halide by reaction with a lower alkanol in the presence of a base such as pyridine. Preferably this esterification reaction is carried out in an anhydrous or practically anhydrous reaction medium and, whether-

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even it is not necessary, carried out in the presence of a base, which serves as an acid-binding agent. Satisfactory Results are obtained when putting the acid halide in a lower alkenol in the presence of a small amount a base for 15 minutes to about 2 hours at room temperature. The reaction conditions are not critical and can be varied.

Alternatively, the esters of the 1-lower alkyl-5-nitroiraidazole-2-carboxylic acids can be prepared directly from the carboxylic acid salts by reacting such salts with an esterifying agent in a suitable solvent medium. For example, the salts of the Imidazolsäuren with esterifying agents, such as dimethyl or diethyl sulfate, in Lösungemitteln such as acetonitrile, dimethylformamide or dimethylsulfoxide are treated at temperatures from about room temperature to about 75 ⁰ C for short periods of time. Under these conditions the corresponding lower alkyl ester is produced in good yield and in considerable purity.

Typical examples of esters which can be prepared according to the invention are ethyl-l-methyl-5 = nitroiraidazole-2-carboxylate, methyl-1-methyl-5-nitroimidazole-2-carboxylate, Propyl 1-ethyl-5-nitroimidazole-2-carboxylate, Benzyl 1-methyl-5-nitroimidazole-2-oeurboxylate and ethyl 1-propyl-S-nitroimidazole ^ -carboxylate.

As mentioned earlier, those are used against histomoniasis and triohomoniasis effective l-lower-alkyl-5-nitroimidazole-2-carboxamides according to the invention in good yield during treatment a l-lower alkyl ^ -nltroimldazol-S-oarbcnylchloride or of a lower alkyl ester of a l-lower-alkyl-5-nitroiraid-

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obtained azole-2-carboxylic acid with an amine. Is ammonia called Amine reaction components used are 1-lower alkyl-5-nitroimldazole-2-carboxamides get yourself. Substituted amines, of course, provide the correspondingly substituted amides. The reaction conditions required to prepare these imidazole carboxamides are not unduly critical and include essentially that the amine with the l-lower alkyl = 5 ~ nitroimidazole-2-carbonyl halide or carboxylic acid ester in a suitable solvent medium is brought into intimate contact. The solvent should be a solohes that is not reactive under the conditions used, and organic Solvents such as benzene, toluene, lower alkenols such as methanol, ethanol or isopropanol, and substances such as dimethylformamide or tetrahydrofuran have been found to be quite satisfactory. The reaction proceeds rapidly at room temperature using an excess of the amine reactant completely. The amide obtained is obtained and purified according to methods known per se.

Typical examples of the 1-lower alkyl-5-nitroimldazole-2-carboxamld compounds which can be prepared according to the invention are 1-methyl-5-ntroimidazole-2-arboxamld, 1-ethyl-5-nitroimldazole-2-carboxamld, ln-propyl ~ 5 ~ nitroimidazole-2-carboxamide, 1,1T-dimethyl-5-nitrolmidazole-2-arboxamide, N * ~ phenyl-1-methyl-5-nitroimidazole-2-oarboxamide, N ^l - (2-hydroxyethyl) -l- methyl-5-nitroimidazole-2-oarboxanld, l-methyl-S-nltrolmldazol ^ -carbonylhydrazine, M- (l-ethyl-5-nitroimidazole-2-carbonyl) -morpholine, N ^f , N ^f -di (2- hydroxyethyl) -l-methyl-5-nitroimidazole-2-carboxamide, N '- (2-HydroxyKthyl) -1, N ¹ -dimethyl-5-nitroimidazole-2-earboxamld, N * - (2-hydroxyethyl) -l- ethyl-5 = nitroimidazole-2-oarboxamide and N *, N * -diethyl-1-ethyl-S-nitroimidazole ^ -arboxamide.

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The 1- (hydroxyalkyl) -5-nitroimidazole-2-arboxamides can according to the invention from 1- (hydroxyalkyl) ~ 2- (β-phenylvinyl) -5 ° nitro itnidazole can be produced. Applied to the synthesis of l- (2-Hydroxyäth3X) -5 ~ nitroimidazole-2-carboxaraid, can be represent the procedure as follows.

-CH = CH-CgHc

CH ₂ CH ₂ OSO, - (2)

₂ Ν-Ιί Jl-CONR ₂ R ₃ CH ₂ CH ₂ OH

(5)

In these formulas, R ₂ and R 1 have the meanings given above.

In the first stage of this process, the 1-hydroxyalkyl substituent is used "blocked" by the formation of a sulfonate such as methanesulfonate, p-toluenesulfonate or the like. The sulfonyloxy compound is then oxidized with a suitable oxidizing agent, and for this purpose alkali or Brdalkallpermanganate preferred. The O-phenylvinyl group

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in the 2-position of the xmidazole ring becomes a carboxylic acid group oxidizes. This oxidized product is not stable. The 7-lactone of the above formula (5) forms in the Reaction mixture and is isolated as such. The oxidation of 1- (sulfonyloxyalkyl) -2- (ß-phenylvinyl) -5-ni troiraidazols and the reaction of the lactone obtained with .einem amine are carried out under practically the same conditions made «as previously for the oxidation of 1-lower-alkyl-2-hydroxymethyl-5-nltrolmidazoles with alkali permanganate and for the production of l «lower-alkyl-5-nitroimidazole-2-carboxamides of formula VII have been described. When the lactone reacts with ammonia or with a secondary amine becomes the 1- (2-hydroxyalkyl) -5-nitroimidazole-2-carboxarald compound of the above formula (4).

Examples of the! - (hydroxyalkyl) -5-nitrolmldazole-2-carboxamide compounds obtainable in this way include 1- (2-hydroxyethyl) -5-nitroimidazole-2-carboxamide, N ¹ -methyl-1- (2-hydroxyethyl) -5-nitrolau.dazol-2-carboxamid, 1- (3-hydroxypropyl) -5-nltroimidazol-2-oarboxamid, N *, l-Dl- (2-hydroxyethyl) -5-nltroimidazole-2-carboxamide and N, N ^f -Dlmethyl-1- (2-hydroxyethyl) -5-nitroimidazole-2-carboxamide. The corresponding 1- (aeyloxyalkyl-5-nitroimldazole-2-carboxamide compounds are obtained in two ways by esterifying the 1- (hydroxyalkyl) -imidazoles according to known procedures * For example, the reaction of the 1-hydroxyalkyl compound with a lower alkanoylochloride or benzoylchloride in the presence a base such as pyridine, to the corresponding 1- (lower-alkanoyloxyalkyl) or! - (benzoyloxyalkyl) derivatives.

The available according to the invention in! -Position substitute-

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th 3 ^< -nitroimidazole-2-oarboxamld compounds are effective in controlling enterohepatitis in turkeys. For this purpose, they are administered to the turkeys and the turkeys mixed with a component of their food, for example the feed or the drinking water. Good disease control is achieved when the imidazole compounds according to the invention are incorporated into a turkey feed ration in amounts of from about 0.005 to about 0.05 wt. # And preferably from 0.0125 to 0.04 wt.% Of the putter. The optimal concentration will depend largely on the age of the birds, the severity of the infection, and the particular substance used. With these feed contents, a good control of the disease is achieved with practically no undesirable side effects or an inhibition of the growth of the turkeys. If the turkey feed or the turkey ration is used as a carrier for the 1-substituted 5-nitroimidazole-2-arboxamide compounds obtainable according to the invention, it is expedient for the substance to be mixed uniformly through the feed. This is accomplished by first preparing a premix or feed additive or feed in which the active ingredient is present in concentrations of from about 1 to about 40 weight percent and the carrier or diluent is a non-toxic orally ingestible carrier. The carrier is preferably a nutrient, for example dried corn grains, wheat meal, wheat pulp, soybean meal, fermentation residues and corn meal. Such feed supplements, supplementary feedstuffs or premixes are then mixed uniformly through the turkey feed ration according to conventional working methods, for example grinding or rolling.

A second route of administration is via drinking water of birds. This is preferred when the turkeys are heavy

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are infected, as the birds usually become solid after stopping Eat food, keep drinking. Slightly higher dosage levels are achieved for the route via the drinking water than for the method of administration used via solid feed, and contents of the nitroimidazole-2-carboxaml compounds im Drinking water from about 0.025 to about 0.1 weight pounds is quite satisfactory . Some of the amides obtainable according to the invention are not highly water soluble and it is useful when using such compounds. Suspension or Use emulsifier or convert the compound into a water-soluble Transfer form.

Turkey feed contents at which typical members of the invention Compounds available that are effective in controlling turkey blackhead disease are the following:

Verbin dung Qew.g in F utter

1-methyl-5-nitroimidazole-2-oarbox-

amld 0.006-0.008

1-N'-Diraethyl-S-nitroimidazole-S-

carhoxamide 0.0125

1-methyl-5-nitroimidazole-2-carbonyl-

hydrazine 0.025

N * -Phenyl-1-methyl-5-nitroimidazole-

2-carboxamide 0.0125

1, N *, N ¹ -Triinethyl-S-nitroimidaaol ^ -

oarboxamide 0.006

N- (I-methyl-5-nitroiniidazole-2-carbonyl) morpholine 0.025

The 1-substituted 5-nitroiraidazole-2-carboxanid compounds also show a considerable degree of effectiveness against triohomoniaais. When used to treat the protozoal

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Trlchomoniasis Disease They are administered orally in unit dosage form, usually in tablets or capsules. Tablets or capsules containing from about 100 to about 500 mg of active ingredient against Trichomoniasls are quite satisfactory and are manufactured according to methods known in the pharmaceutical field. Thus, these dosage forms contain the normal diluents / excipients, lubricants and excipients normally used in the preparation of orally administrable solid dosage forms. Alternatively, the compounds can be suspended or dissolved in liquid carriers for oral administration. The preferred compounds for use against T. fetus and the in vivo activity of such compounds in the mouse are given below. The activity is expressed in ragAg according to the method described by Cuckler, Kupferberg and Mlllman in "Chemotherapeutic and Tolerance Studies on Amino-nltro Thiazoles ¹ * (Antibiotics ft Chemotherapy, % 540-530, 1955).

Connection activity

l-Methyl-S-nitroimidazole-S-oarboxamid 10 1, N * -Dimefchyl-5-nltroiniida2: ol-2-carboxaraid 10 1, N ¹ , N * -Triiaethyl-S-nitroimidazole-S-carb-

oxamide 10

N * - (2-hydroxyethyl) -1-methyl-5-nitrolmidazole-2-carboxamide 20th

N- (I-methyl-5-nitroimidazole-2-carbonyl) morpholine 40

1 - (2-Hydroxyethyl) ~ 5-Ni troiinidazol-2-oarb-

oxanld 20

N- (2,3-dihydroxypropyl) -1-raethyl-5-nitro-

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In addition, it was found that certain of the 1-substituted 5-nitroimidazole compounds obtainable according to the invention have a surprising degree of antibacterial activity, in particular against the Gram-positive staphylococci and streptococci and the Gram-negative Salmonella Schottmullerl. This is shown in the following _f where the numerical fourth indicates the concentration in r / ral at which the compounds are effective in tests in vitro.

Connection S. Schott. Staph. Strep.

1.N ¹ -Dimethyl-N ¹ -phenyl-5-nitroi, iiiaazol-2-carboxamide 200

1-methyl-S-nitroimidazole-S-carbo-

nylhydrazine 50 25

1-methyl-5-nitroimidazole-2-carb-

oxamid 50 200

N '- (2,3-dihydroxypropyl) -1-methyl-5-nitroimidazole-2-carboxamide . 200 25

1- (2-hydroxyethyl) -5-nitroimide-

azole-2-carboxamide 200 50

1, N'-di- (2-hydroxyethyl) -5-nitro-

imidazole-2-carboxamide 50 25

The following examples illustrate the invention without representing it restrict.

example

0 g (0.86 ^ mol) of 2-hydroxymethylimidazole are in 200 ml Acetic anhydride dissolved. The solution is left to stand overnight at room temperature. The acetate of 2-acetoxymethylimidazole crystallizes out. This crystalline solid substance is well sucked up with Xther and filtered, and the crystals are washed with Xther until the smell of

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Acetic acid no longer detectable left. Dae 2-Acetoxymethyllmldazol-esslgsäuresalz melts at 80 ⁰ C. The 2-acetoxymethylimidazole-acetic acid salt is dissolved in 10 # Lgera Natriumbioarbonat, and the 2-Acetoxymethylimldazol is "extracted with ethyl acetate Evaporation of the ethyl acetate extracts in vacuo and recrystallizing the residue from ethyl acetate one obtains 2-Acetoxymethyllmldazole from P = 82 to 85 ⁰ C.

B * 176 _# 6 g (0.882 mol) of 2-acetoxymethyllmldazole acetic acid salt are added in small amounts to 165 ml of cold, fuming 90% nitric acid. This solution is slowly added with stirring and cooling to 150 ml of cold, fuming 90 # Lger nitric acid containing 90.1 g of gaseous BF. The reaction mixture is heated on a steam bath for 5 hours.

After cooling to room temperature, the reaction mixture is poured onto ice and neutralized with sodium hydroxide. The resulting solution is then extracted with ethyl acetate and the ethyl acetate evaporated to dryness in vacuo · The residue is 1 hour in a solution of 100 ml of 2.5N sodium hydroxide and 100 ml of methanol are kept under reflux. The solution is then neutralized with hydrochloric acid and extracted with ethyl acetate. The extracts are evaporated to dryness and the residue is dissolved in methanol dissolved and chromatographed over activated charcoal.

Elution of the activated carbon with 50 pounds of ether-acetone first removes a small amount of imidazole-2-carboxaldehyde. The substance eluted on-βohllessend is 2-hydroxyoethyl-4 (5) -nitrolmidazole. After recrystallization from acetone, the product melts at I56 to 158 ⁰ C.

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C. 12.6 grams of dimethyl sulfate become 11.1 grams of 2-hydroxymethyl-4- (5) -nitroimidazole added, and the mass is mixed thoroughly. Then the mass is on a steam bath for 2 hours heated and cooled to room temperature.

A small amount of ice is added and the remaining dimethyl sulfate and methyl hydrogen sulfate are neutralized by the slow addition of concentrated ammonium hydroxide. The resulting solution is extracted with chloroform. The chloroform extracts are separated and evaporated to dryness to give a residue consisting of 1-methyl-2-hydroxymethyl-5-nitrolmidazole. Obtained pure l-methyl ^ Umkrlstalllsation from acetone receives virtually -hydroxyraethyl-S-nltroimidazol P * 117 to 119 ⁰ C.

D · 5 * 0 g (0.0318 mol) of 1-methyl-S-hydroxymethyl-S-nitroiraidazole are suspended in 75 ml of cold acetone. Under maintenance "maintaining a temperature of 0 to -5 ⁰ C are added under vigorous stirring 6.65 g (0.048 mol) Kaliumpermsnganat in small portions. After the last addition of permanganate, the reaction mixture is allowed to warm slowly to room temperature.

The reaction mixture is filtered and the solid material extracted with water. The aqueous extracts are in vacuo evaporated to dryness and give a residue of crystalline Kaliura-l-methyl-S-nitroimidezol ^ -oarboxylate, mixed with potassium hydroxide. This imidazole can be used without further purification in the further stages of the process be used.

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E. A sample of 1.0 g of the crude potassium l-raethyl-5-nitro imidazole-2-carboxylate is added to 40 ml with rapid stirring Oxalylehlorid added, and the reaction mixture is 1 Refluxed for hour.

The reaction mixture is then evaporated to dryness in vacuo. A small amount of benzene is added to the residue and the benzene is removed from the resulting suspension removed by evaporation in vacuo. The 1-methyl-5-nitroimidazole-2-carbonyl chloride obtained is reduced in vacuo dried and stored · It is not free from inorganic salts «but can go directly into« purulent stages of the Procedure can be used without further purification.

P. 470 mg crude potassium l-met] iyl-5-nitroimidazole-2-capbox5late are refluxed for half an hour with 5 ml of oxalyle chloride. Most of the excess oxalyl chloride is then removed by concentration in vacuo. The last traces of oxalyle chloride are obtained by adding 2 to 4 ml of benzene to the residue and appropriate evaporation of the benzene removed. The solid residue of salts and Acid chlorides is then very much in a mixture of 5 ml dissolved in dry ethanol and 1 ml of dried pyridine. After 1/2 hour standing at room temperature, the Mixture diluted with 40 to 50 ml of methylene dichloride and once with excess dilute HCl for removal of the pyridine extracted. After extraction with dilute sodium bicarbonate, the organic phase is dried over sodium sulfate dried and evaporated in vacuo »whereby an oil is obtained which partially crystallizes on standing.

S ORIGINAL

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This oil is dissolved in about 5 ml of ether and about 5 ml of petroleum ether are added. Most of the ether is then removed by boiling, leaving a cloudy solution which is applied to a 3 g Al ₂ O (Merck, basic) column, made in petroleum ether. The height of the column is roughly the same as its diameter to facilitate rapid flow. The column is eluted with about 40 ml of petroleum ether to remove most of the ethyl benzoate and then with about 40 ml of ether methylene dichloride (4: 1) to remove the ethyl 1-methyl-5-nitroimidazole-2-carboxylate. By evaporating this latter ether fraction, 136 mg of the desired product are obtained. This is recrystallized by dissolving in 2 ml of ether, adding 2 ml of petroleum ether and concentrating until the solution becomes slightly cloudy up to 81 ⁰ C.

Q. 0.86 g of crude 1 <41ethyl "> 5-nitroimidazole-2-carbonyl chloride are suspended in 5 ml of benzene. The suspension obtained is filtered to remove inorganic salts. An excess of anhydrous ammonia is introduced into the benzene solution with gentle stirring. The benzene is then removed in vacuo and the residue of 1-methyl-5-nitroimidazole-2-oarboxamide is dissolved in a minimal amount of ethyl acetate. The ethyl acetate solution is filtered and the filtrate is concentrated to dryness. 2-carboxamide is recrystallized from acetone and yields practically pure material from F = 222-224 ⁰ C (sublimation); A _011X 302 mu, e% 613 (CH ₅ OH).

ORIGINAL BATHROOM - 23 -

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l-ethyl-S-nitroimidazole ^ -carboxamide and l-propyl-5-nitroimidazole-2-carboxamide are obtained when l-ethyl-5-nitroimldazol-2-oarbonylohlorid and 1-propyl-5-nitrolmidazole-2-oarbonylochloride can be reacted with ammonia in accordance with the working conditions described above »

H. If gaseous dimethylamine is used instead of ammonia in the above procedure, Ι, Ν ', Ν ¹ trimethyl-5-nitrolmidazole ~ 2-carboxainide from F - 125 to 127 ⁰ C, J) _ΏΆχ 302.5, E % 500 (CH ₅ OH) after recrystallization from ether.

Example 2

5.0 g (0.02 Hol) 1-methyl-S-ntroimidazole ^ -oarbonyl chloride are dissolved in 100 ml of warm benzene. This solution is then, with rapid stirring, to 15 ml of N-methyl aniline in 100 ml of ether admitted. The solution becomes warm due to the heat of reaction. It is filtered warm to remove any solid N-Methylanllinhydroohlorld to remove.

The benzene filtrate is evaporated almost to dryness in vacuo. The residue is triturated with ether. The crystallization of 1, N * -dimethyl-N · -phenyl ^ -nitrolmldazole-S-carboxamide begins and is allowed to continue in the cold until it is complete. The crystalline product is then filtered off and washed with cold ether. The solid substance is recrystallized from acetone-ether and gives practically pure Ι, Ν'-dimethyl-N'-phenyi-S-nitroimidazole - ^ - carboxamide from F »106 to 108 ⁰ C; S _{mBX 506.0} rap, E % 567 (CH3OK).

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This working visa is used for the production of the following Table I listed amides from 1-methyl-5-nitroiraidazol-2 ~ carbonyl chloride and ethereal solutions of the appropriate amine are used.

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Tabel End product

CH ^ OH h max

Reaction component

σ
oo
co

. N- (1-methyl ~ 5-n ± trcimidazcl-2-carbonyl) - »orpholln 148 - 150 (

192 to 194 ⁰ C

2. N'-phenyl-1- «ethyl-5-nitroimidazole-2-arboxaoid

3. N '- (2-Thia «olyl) -1-methyl-5-nitroimidatzol-2-earboxainide 275-285 C.

4. 1-Methyl-4- (1-methyl-5-nitroimidazole-2-carbonyl) perazine 114 -II5 C

5. 1-Phenyl-2- (1-methyl-5-nitroimidazole-2-carbonyl) -1: hydrazine 206-207 C.

6. N'-Cs

CyyyJy 5-nitroimidazol-2 ~ oarboxarald 87 -

7. 1, N ¹ , N ¹ -Trlraethyl-5-nltroimidazole-2-car-

125.5-127 ° c

301.0

317.0 246.0

321, 270, £ 20

301.0

295.0 223.0

305.0 222.0

302.5

432

532
355

Morpholene aniline

339 »145, 2-amino-226 thlazcl

N-methyl-415 piperazine

175 phenyl-468 hydrazine

Ethanolamine

Dlmethylanln 425 (gaseous)

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The specified solvents are indicated as recrystallization solutions used: Compound 1: Aceton-Xther; Compound 2: Methylenohlorld; Compound 3: dimethylformamide; link 4 and 7: ether; Compound 5: dimethylformamide Xther; Connection 6s Aueton

Example 3

2.00 g (0.01 mol) of ethyl <-l-methyl-5-nitroimidazole-2-carboxylate Earth dissolved in 20 ml of warm 95% ethanol. This solution becomes 40 ml of chilled concentrated ammo all at once » sodium hydroxide was added with thorough stirring. The reaction mixture obtained is kept in the cold until crystallization has ended ditched·

The crystalline 1-methyl-5-nitroimidazole-2-earboxamide is filtered off and washed with water. Then it is recrystallized from warm 95% ethanol. F * m receives 1-methyl-5-nitroimldazole-2-carboxamld from P = 218 to 221 ⁰ C (Zera.) J _max 301 mp, E % 493 (CH ₃ OH).

Repeat this procedure using (1) aqueous hydrazine or (2) aqueous methylamine in place of of ammonium hydroxide, the following products are obtained:

(1) l-methyl-5-nitroimidazole-2-oarbony hydrazine P "155-156 ⁰ C!; h "ax 306 πιμ, E % 581 (CH-jOH), after recrystallization from ethanol-ether;

(2), N'-dimethyl-S-nitroimidazole-a-carboxaraid from F «109-110 ⁰ C!; h _mtaL 303.0, E % 571 (CH ₅ OH), after crystallization from acetone-ether.

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8771 example 4

10.28 g of a mixture of raw potassium-l-methyl-5-nitroiinidazol-2-oarboxylat are stirred at about 50 ⁰ C for 10 minutes in 40 ml Dim © sulfoxide. 6.7 ml of dimethyl sulfate are then added to the mixture with stirring. The reaction mixture is maintained for 1 1/4 hours at 60 to 65 ⁰ C * The reaction vessel is vented through a Sillconölwasohflasche.

After the heating time, the mixture is cooled to room temperature and filtered. The salts on the filter flask who «· the washed with small portions of acetonitrile and the washing liquid added to the filtrate.

The Flltrat is concentrated in vacuo (120 ⁰ C, 1.5 mm) to an oily-solid residue. The residue is partially dissolved in 40 ml of water and the whole mixture is extracted six times with 40 ml of ether. The ether extracts are combined, dried over magnesium sulfate and filtered to remove any solid material present.

The ether solution is gassed with triethylamine for 15 minutes to react with any remaining dimethyl sulfate. The ether is then removed in vacuo at room temperature. 5.76 g of solid crude methyl 1-methyl-S-nitroimidazole-S-carboxylate are obtained. The product is purified by slurrying in 20 ml of ether at room temperature for about 20 minutes. The slurry is filtered and the solid methyl 1-methyl-5-nitrolmidazol-2-carboxylate dried in vacuo at 50 ⁰ C; F »107 to 110 ⁰ C.

l-Metnyl-S-nltroimldazol ^ -carboxamld is obtained by dissolving 2 g of the above ester in 60 ml of ethanol, warm the solution

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to 45 ⁰ C and treatment of the warm solution with gaseous ammonia for about 20 minutes. The amide crystallizes out and is filtered off ; F * 218 to 219 ⁰ C.

Example 5

St SSS

To 5.54 g of l- (2-p-toluenesulfonyloxy) -ethyl-2-styryl-5-nitroimidazole in 130 ml of acetone 3 * 56 g of potassium permanganate are added in small portions while cooling with an ice bath within 45 minutes. The mixture is then ^{stirred for 45 minutes at 0 °} C. and filtered to remove manganese dioxide. The acetone filtrate is concentrated to a semi-solid residue which is purified by sublimation. One obtains 1- (2-hydroxyethyl) -S-nitroimidazole - ^ - oarbonsäurs-rl & e * · on -κ: ~ P = 185-199 ⁰ C. By crystallization from Kthylacetat ^ is obtained practically pure material from F = 200 to 201.5 ⁰ C; ^X max ²²² ' ⁵ "P ^(E * ^{225) j} 297" au (E {δ 155); 365 mu (E % 290);

144 mg l- (2-HydroxySthyl) -5-nitroimidazole ° 2-carboxylic acid-7-lactone are dissolved in 20 ml of methanol, and the resulting solution is kept for 15 minutes at 50 ⁰ C, wHhrend trookene? Ammonia is introduced into the solution. The solution is then concentrated to dryness in vacuo and the residue is recrystallized from ethyl acetate. L- obtained (2-hydroxyethyl) -5-nitroimidazole-2-carboxamide from F ■ »I60 to 162 ⁰ C. After recrystallization from acetone, melts the product at 163.5 to 164.5 ⁰ C.

Example 6

200 1H31 (1.09 BiMoI) 1- (2-HydroxyHthyl) ~ 5-nitroimidazole-2-carboxylic acid-7-laoton are added to 0.5 ml of pyrrolidine. That

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The mixture becomes warm and the Laoton dissolves. The mixture is heated on a steam bath for about 10 seconds, then cooled and diluted with 5 ml of water. The aqueous solution is made weakly acidic with 2.5N HCl and extracted three times with 5 ml of ethyl acetate each time. These extracts are combined, dried over sodium sulfate and then concentrated in vacuo to an almost colorless syrup. This syrup is crystallized by cooling and scratching in the presence of a drop of ethyl acetate. The crystalline N- ^ I- (2-hydroxyethyl) «^ -nitroimidazole-a-earbonyl7-pyrrolidine is recrystallized from ethyl acetate and then from ether. This gives the pure material from F - 83 to 85 ^° C .; A _raax 304 mu (E % 409), 217 rough (E # 474); (CH ₅ OH).

example

0.3 g of methyl-l-methyl-5-nitrolmidazole 2-earboxylate and 0.5 g of aminoglynerol are mixed and heated on a steam bath for 20 minutes. The reaction mixture is then cooled and 6 ml of water are added. The solution is extracted six times with 6 ml of ethyl acetate each time. The ethyl acetate extracts are combined, dried over sodium sulfate and concentrated to dryness in vacuo, N ^l - (2,3-dihydroxyprapyl) »l-methyl-5-nitroimidazole-2-carboxamide being obtained as a yellow-brown solid. The material is recrystallized from Xthylacetat to give purified Ämld from F "119 is to 126 ⁰ C.

0.5 g of l- {2-HydroxySthyl) -5-nitrolmldazol-2-carboxylic acid-r * = lactone are added to 0.75 ml of aminoethanol. The resulting mixture is stirred thoroughly and then left to stand at room temperature for about 20 minutes. 12 ml of water are then added to s and the resulting mixture is stirred until complete dissolution. The solution obtained is four times with each

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10 nil ethyl acetate extracted. The ethyl acetate extracts are combined, dried over sodium sulfate and evaporated in vacuo to dryness to give a crystalline product is obtained "This material is uracristallisiert twice from ethyl acetate to give crystals of l, N ^l-di- (2-hydroxy & thyl) -5-nitroimidazole 2-carboxatnid from P «100 to 108 ⁰ C can be obtained.

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Claims (2)

Claims where R denotes a lower alkyl radical or a group in which η is a value from 2 to 4, R ₂ denotes a hydrogen atom or a lower alkyl radical, R- * denotes a hydrogen atom or a lower alkyl, hydroxyalkyl, aryl or amino radical and ! 3RgR-Z together can also form a morpholine, piperazinyl or pyrrole dinyl ring. 2. Process for the preparation of compounds according to claim 1, characterized in that one (A) a l-lower alkyl-S-nitroimidazole ^ -oarbonyl halide with an atom of the formula H-NR ₂ RX to a compound of the formula I, for which R is a lower alkyl radical, or (b) a lactone of the formula BATH ORIGINAL 8771 with an AmIn of the formula H-NRgR- to form a compound of the formula I for which R is a group - (CHg) _n OH, «or (c) a hydrocarbon ester of a l-lower-alkyl-5-nitroimidazole-2-carboxylic acid with ammonia to form a compound of the formula I for which R is a lower alley and R and R are hydrogen atoms, where the symbols -NRgR, and η those given above
Have meanings. 3 · One compound antiparasitic agent
according to claim 1. - 33 909839/1539 BATH ORIGINAL