DE2011583A1 - New imidazolium compounds - Google Patents

Description

New imidazolium compounds

The present invention relates to new quaternary imidazolium salts, in particular quaternary 3- (2-lower digits 1-4-amino-5-pyrimidinylmethyl) -1,2-disubstituted Imidazolium salts and their manufacturing process.

In accordance with the present invention, it has been found that 3- (2-lower alkyl-4-amino-5-pyrimidinylmethyl) -1,2-di-lower alkylimidazolium quaternary salts have useful medicinal properties and particularly for use in treatment and contraception of coccidiosis in poultry.

The compounds of the present invention can be made by the following general Formula are represented: -

NO"

CH ₂ -th 2 '1

cX

- 1 -0098 ^ 0/2235

! 11825 β

Γ -

. wherein R is a lower alkyl radical,

^! Rf is a lower alkyl radical,.

j X is an anion and

b and c certain numbers with such values that the positive Charge of b-moles of cation by c-moles of anion X

ι neutralized,

mean «If, for example, X is a monovalent anion such as a halide is, then b is equal to 1 and c is equal to 2. As can be seen from the structural formula above, the compounds described here can can be regarded as substituted imidazoles. The imidazole ring is at the 3-position through a 2-lower alkyl ~ 4-amino-5-pyrimidinylmethyl radical substituted. It is also in the 1 and 2 positions through the same or different lower alkyl radicals substituted. The pyrimidine part also contains a low *

, alkyl group in the 2-position of the pyrimidine ring. The ones in the Pyrimidine and imidazole portions of these salts present need not, of course, be the same in any particular connection.

Furthermore, with reference to formula I, the anion (designated as X) can be an inorganic anion such as chloride, bromide, iodide, nitrate, sulfate, phosphate and the like or the anion of an organic acid such as citric acid, tartaric acid, acetic acid, picric acid, stearic acid, succinic acid, Benzoic acid, phthalic acid, phenoxyacetic acid, embonic acid, abietic acid, 2-naphthalenesulfonic acid or ethylenediamintotraonnigiiUuro ooln, Eu kunn auoh duo anion or polymorun prebonding soin, like polyphoaphate or polyatyrenesulfonate. The nature of the anion is not critical and any anion can be used as long as it is not inappropriate ₍ toxic Amino group, which in these compounds

fertilize is present, formed simultaneously with the quaternary salt will. This is supposed to mean that the expression "quaternary

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lisas; * ■■■ * ^iV \ ^

Salt ^{11 is used} in the present description and claims in the sense that the acid addition salt of such quaternary salts is meant. .

The compounds of the present invention are prepared by reacting an acid addition salt of an ester of a 2-lower alkyl-4-amino-5-hydroxymethylpyrimidine and a strong acid with a 1,2-di-lower alkylimidazole compound 2-Lower alkyl-4-amino-5-hydroxymethylpyrimidine and a hydrohalic acid reacted directly with the substituted imidazole · This process can be illustrated as follows t

2N "+ HX

wherein R is a lower alkyl radical, R * is a lower alkyl radical and X denotes a halogen such as chlorine or bromine.

Although the proportions of the reactants in the above equation are given as equimolar, such proportions are not critical, an excess of one of the reactants can also be converted appropriately. Preferably, however, an excess of substituted imidazole used

The reaction is preferably in the presence of an organic Solvent carried out, which under the reaction conditions

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It is inert, like acetonitrile and Ν, Ν-di-lower alkylalkanoamides · Ss

can also use other solvents such as methanol, ethanol, propanol j

and the like can be used. The reaction temperature is j

not critical and one prefers to continue the procedure at about,

To be carried out at room temperature. At room temperature the reaction is j

generally complete after 5 "to 20 hours or more, depending naoh | the concentration of the reactants and the specifically amplified [used reactants · Bs but are significant quantitative <gen of the product in a short time will receive the products j fall out of. Reaction mixture on standing at room temperature or with the addition of a suitable precipitating agent, such as ether, ethyl acetate and the like, and can be obtained by filtering off or by other customary procedures.

The acid addition salts of the 5-hydroxymethylpyrimidine esters with hydrochloric acids, ie the halomethylpyrimidine dihydro- ⁱ halides, are preferably used for the reaction with the substituted imidazoles. The quaternization can, however, also be carried out using the acid addition salt of the 5-hydroxymethylpyrimidine esters with strong organic acids, such as with the methylsulfinate, p-toluenesulfonate, benzenesulfonate and naphthalenesulfonate esters.

The quaternization can be carried out in such a way that the specifically desired salt is obtained directly, or the quaternary salt obtained from the reaction medium can expediently according to known methods Working methods can be converted into the desired salt

The quaternary 3- (2-lower alkyl-4-amino-5-pyrimidinylmethyl) -1-substituted Imidazolium salts which can be prepared according to the present invention include the 3- (2-methyl-4-amino-5-pyrimidinylmethyl) -1,2-dimethylimidazollum saltsj the 3- (2-methyl-4-amino-5-pyrimidinylmethyl) -1,2-diethylimidazolium salts | 3- (2-ethyl-4-amino-5-pyrimidinylmethyl) -1,2-dimethylimidazolium

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ί 11625 '·''■ V ^ ■ ^: -''>

j "salts; the 3- (2-ethyl-4-amino-5-pyrimidinylmethyl) -1,2-diä1shyl-J imidazolium salts; the 3- (2-n-propyl-4-amino-5-pyrimidinylmethyi) ^ - 1,2-dimethylimidazolium aces and the 3- (2-n-butyl-4-amino-5-pyrimidinylmethyl) -1 | 2-diethylimidazolium salts ·; ..- ■■

. ί As "already mentioned above, the compounds of the present invention for the treatment and prevention of Coceidiose in poultry are; useful These compounds are suitably used as ingredients * - fed j ~ i of the feed of the animals and parts of the poultry, though. j. they can also be administered dissolved or suspended in drinking water. A composition can also be given to the animals.

be that the quaternary salts are intimately dispersed in or mixed with an inert carrier or diluent. ; By an inert carrier is meant a carrier which, in view of ι is not reactive to the quaternary salt and is safe I can be administered to the animals. The carrier or diluent is preferably a substance that is a component of animal feed j is or can be. Composition formulations ranging from about 1 to ; about 40% by weight and preferably about 2 to 25% by weight of active ingredient are particularly useful as an additive to poultry feed ■ suitable and compositions containing about 5 to 15 wt .- ^ des Coocidiostatic agents are very satisfactory.

Examples of typical putter additives that make a quaternary imidazo? ·? • The lium salt dispersed in a solid, inert carrier contains: '

(lbs.) kg ▲ 3- (2-methyl-4-amino-5-pyrimidinylmethyl) -

■! 1, ^ - dimethylimidazoiiumbromid-hydrobromid (6.0) 2.72

("Wheat standard middlings») Middle "'] j Wheat quality '"' ■. (94.0) 42.6

B · 3- (2-iithyl-4-amino-5-pyrimidinylmethyl) - ^! ': 1, ^^ JjaethyliMda ^ oliumbromid-hydrobromid - (10,0) 4 «54:. "Corn distillers" dried grains "(9O _r O)

-5-

(lbs.) kg C. 3- (2-n-Propyl-4-amino-5-pyrimidinylmethyl) -

1,2-dimethylimidazolium chromide hydrobromide (12.0) 5.49

Soluble molasses (88.0) 39.9

These and similar feed additives are made by using the quaternary imidazolium salt uniformly mixed with the carrier or carriers.

The feed additives of the above type are usually further diluted with materials such as corn meal or soybean meal before they are incorporated into the animal feed. In this intermediate stage of processing the content of coccidiostatic agent in the carrier to about 0.1? S is reduced to about 1.0 wt. -4>. This dilution is used to facilitate the uniform distribution of the substance in the finished feed. The finished feed contains a source of fat, protein, carbohydrate, minerals, vitamins and other nutritional factors.

The amount of quaternary imidazolium salt required for optimal control of avian coccidiosis will, of course, vary somewhat with the particular compound or compounds used. In general, the compounds of the formula I are effective when administered in concentrations of about 0.001 μl to 0.003 # in the feed.

The anticoccidial effectiveness of the quaternary imidazolium salts is determined by feeding groups of common white Leghorn chicks a ration that has graduated concentrations of quaternary Contains imidazolium compound and the birds orally inoculated with spore-forming oocysts of coccidia on the second day of the test. 50,000 B. tenella oocysts are used. The birds are medicated for a period of days (5 to 8) Food fed, then weighed and sacrificed and examined for oocyst and / or coccidiosis damage. The effectiveness of the quaternary Imidazolium salt is expressed as the concentration in the feed ixt

009840/223

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J percent by weight that provides the desired infection control. '■. : ■ ■ ^; - ... .- ■■. ■ - ■ ■ i - - ψ - ..- ·

The anticoccidial activity of representative compounds of the present invention against E *. Tenella. Is the following compound E • tenella

3- (4-Amino-S-propyl-S-pyrimidinyl- «

- 'methyl) -ί _t 2-dimethylimidazolium bromide-
'-. hydrobromide, 0.0015

3- (4 «-j | mino-2-methyl-5-pyrimidinyl- ·.

_; methyl) -1,2-dimethylimidazolium chloride'- ■.: ■■ - ■■ -

hydrochloride 0.0015.

3- (4-Amino-2-ethyl-5-pyrimidinyl methyl) -

1, S ^ imethylimidazolium bromide hydrobromide 0.0015 ",

■ '■■■■ ■■ -.- .. "' ■ ■ ■ - AC: - '; / -

Many of the quaternary imidazolium salts of the present invention will be.

desirably or advantageously to the poultry with the drinking water administered to birds, · This method of treatment is often used applied in the therapeutic use of the present compounds, since poultry with goccidiosis tend to have less solid feed than normal birds to consume. The water-soluble quater- natural salts can be added directly to the drinking water

^: water-soluble powders can be produced natively, in which the coccidiostatic agent is intimately mixed with a suitable carrier, such as dextrose or sucrose, and these powders are added to the poultry drinking water as soon as it is necessary

; ge water soluble powders may be of any desired Zonzen * - concentration of Coooidiostatikum contain and preparations with a fetched from 1 to 25 wt .- 4 of active compound are suitable?.

The following examples are intended to illustrate the invention without, however, restricting it.

0098A0 / 2235. - -

V:

example 1

3- (4 ^ Amino-2-propyl-5-pyrimidinylmethyl) -1,2-dimethylimidazolium bromide hydrobromide

20 g of 1,2-dimethylimidazole are added with stirring to a suspension of 20 g of 4-amino-5-bromomethyl-2-propylpyrimidine dihydrobromide in 100 ml of acetonitrile. After standing for several hours at room temperature, a small portion of 1,2-dimethylimidazole hydrobromide is removed Resin is triturated with acetone, which is also decanted. The resin is dissolved in 25 ml of 48% hydrobromic acid, then diluted with acetone until the product, 3- (4-amino-2-propyl) -5-pyrimidinylmethyl, crystallizes ) -1,2-dimethylimidazolium bromide hydrobromide, begins · The product weighs 9.8 g and can be purified in methanol / acetone · Mp ■ 269 ⁰ C (decomposition) ·
Analysis: (C.-H ₂₀ N ₅ Br * HBr)

'• C H N Br Ber.i' 38.34, 5.20 17.20, 39.26 # Found: 38.95, 5.31, 17.38, 39.76 *.

Example 2

3- (4-Amino-2-methyl-5-pyrimidinylmethyl) -1,2-dimethyl imidazolium chloride hydrochloride.

The reaction is carried out with 4-amino-5-chloromethyl-2-methylpyrimidine dihydrochloride and 1,2-dimethylimidazole in acetonitrile. The procedure used is similar to Example 1 except that hydrochloric acid is used in place of hydrobromic acid. The pure product, 3- (4-amino-2-methyl ~ 5-pyrimidinylmethyl) -1,2-dimethylimidazolium chloride hydrochloride, melting at 271 ⁰ C (decomposition), crystallized from methanol / Aoeton analyzed · dihydrate.

«· 8« ■ »

009840/2235

example (O ₁₁ H _{1 6} N ₅ C1. HCl 9 N »47 σ .2H ₂ O). 21 , 76 11825 40, 49, H 21 _, ·
Analyzes 40, 13, 6.49, "· '' · 5 5.54,. [Bar·: - i ;

3- (4-Amino-2-ethyl-5-pyrimidinylmethyl) -1,2-dimethylimidazoli \ am- ! bromide-hydrobromide

i The same reaction conditions were used as in Example I game 1, with the exception that ^ -A
<imidazole in acetonitrile represent the reactants »Das ■ ;. Product, 3- (4-r'mino-2-ethyl-5 ^ yrimidinylmethyl) -i, 2-dimethylimid- [azolium'bromid-hydro "bromide, is purified from methanol / acetone and melts at 279 ° C (decomposition), .

; Analyzes (O ₁₂ H ₁₈ N ₅ Br ^ HBr) "'

C H N Br "

j Ber, j ^; 36.66, 4.87, 17 ^ 82, 40.66 fi

Found: 36.45, 4.93, 18.06, 40.69? Δ.

' Example 4

■ If the procedure described in Example 1 is repeated using of 1,2-diethylimidazole, which with 4-amino-5-broramethyl-2-

! propylpyrimidine dihydrobromide, 4-amino-5-bromomethyl-2-methylpyri-

■ midine dihydrobromide or 4-amino-5-bromomethyl-2-ethylpyrimidine dihydrobromide is implemented, you get the following products »

• 3- (4-Amino-2-propyl-5-pyrimidinylmethyl j -1,2-diethylimidazolium- ; bromide-hydrobromide; 3 ~ (4-Amino-2-methyl-5-pyrimidinylmethyl) -1,2-diethylimidazolium bromide hydrobromide, or 3- (4-Amino-2-ethyl-5-pyrimidinylmethyl) -1,2-diethylimidazolium bromide hydrobromide.

i - '■

¹ example 5 '.

If the procedure of Example 4 is repeated using 1-methyl-2-ethylimidazole, the following products are obtained:

¹¹⁸²⁵ "

3- (4-amino-2-propyl-5-pyrimidinylmethyl) -1-methyl-2-ethylimidazolium bromide hydrobromide; 3- (4-Amino-2-methyl-5-pyrimidinylmethyl) -1-ynethyl-2-ethyliinidazolium bromide hydrobromide; or 3- (4-Amino-2-ethyl-5-pyrimidinylmethyl) -1 «Fflethyl-2-ethylamidazolium bromide hydrobromide. ». ·.

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Claims (5)

where R is a lower alkyl radical, R ^{1 is} a lower alkyl radical, X is an anion and b and c "denote certain numbers, where b and c have such numerical values that b-4 ole cations are neutralized by c moles of anion X ^ 2. As a compound according to claim 1; 3- (2 "4lethyl-4-amino-5-pyrimidinylmethyl) -1 ^^ - dimethylimidazolium halide hydrohalide. 3. As a compound according to claim 1: 3 ~ (2-ethyl-4-aniino-5-pyrimidinylmethyl) -1,2-dimethylimidazolium halide hydrohalide. 4. As a compound according to claim Ij 3- (2-n-propyl ~ 4-3ΐϋίηο-5-pyrimidinylmethyl) -1,2-diethylimidazolium halide hydrohalide. - ti - ·. '■■■■■■' ■ / '■. 009840/2235 5. Process for the preparation of the compounds according to claim 1, characterized in that an acid addition salt of a strong acid and a 2-i \ ^r lower alkyl-4-araino-5-hydroxymethylpyrimidine ester-'with a 1,2-di-lower alkylimidazo! is reacted to form a quaternary 3- (2-i-lower alkyl-4-amino-5-pyrimidinylmethyl) -1,2-di-lower alkylimidazolium salt. - 12 009840/2235