DE2244265A1 - NEW IMIDAZOLE DERIVATIVES, THEIR MANUFACTURING AND THE MEDICAL COMPOSITIONS THAT CONTAIN THEM - Google Patents

Description

Dr. F. Zumetein Sr. - Dr. E. Assmann Dr. R. Koenigsbarger - Dipl. Phys. R. Holzbauer

Dr. F. Zumstsin jun.

Patent attorneys

8 Munich 2, Bräuhausstrasse Ai III

SC 3967 "

RHONE POULENC S.A. - Paris, France

New imidazole derivatives, their production and the medicinal ones

r

Compositions containing them

The present invention relates to new imidazole derivatives of the general formula

—N

J ¹ U

(D

⁰ A

CH -CH-O CO Ν ^Λ
CH ₂ - ^ HO-CO-N

CH ₃

their addition salts with acids, their preparation and the pharmaceuticals Compositions containing them in the form of bases and / or salts.

In the above general formula I, the symbols R ^ mean and Rp, which can be the same or different from one another, in each case a hydrogen atom or a straight-chain or branched one Alkyl radical with 1 to 4 carbon atoms, and R represents a hydrogen atom or a straight or branched chain

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Represents an alkyl radical with 1 to 4 carbon atoms.

According to the invention, the carbamates of the general formula I by reacting a compound of the general formula

fc - η '(Π)

in which the symbols R ₁ and R _{2 have} the meanings given above, with an imidazole derivative of the general formula

C ₂ Xj-.

CH ₂ -CH-O-CO-X

in which X is a halogen atom, preferably a chlorine atom, or a phenoxy or benzyloxy radical, preferably a phenoxy radical, means and R has the meaning given above, are prepared «

One can in an inert organic solvent, such as a hydrocarbon, e.g. benzene, or toluene, a chlorinated solvent, e.g. chloroform or dichloroethane, an ether, e.g. diethyl ether, isopropyl ether, tetrahydrofuran or dioxane, an amide, e.g. dimethylformamide, or a basic solvent such as pyridine. If X is a phenoxy or benzyloxy radical, it is advantageous as a solvent an aliphatic alcohol with a straight or branched chain and with 1 to 4 carbon atoms or itself to use an aqueous medium.

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It is generally carried out at a temperature between 20 ^° C. and the reflux temperature of the solvent used.

In addition, if X represents a halogen atom, optionally in Presence of an acid acceptor, such as an inorganic one Base, e.g., of an alkali or alkaline earth carbonate or bicarbonate, or in a basic solvent such as for example pyridine, work »

The compounds of general formula III for which X is a Represents chlorine atom, can in situ by the action of phosgene on a 1- [2-hydroxypropyl ~ (1)] - 5-nitrolmidazole derivative of the general formula

(IV)

CH i-CH-OH

² !

Ci

in which R has the meaning given above.

The compounds of general formula III for which X is a Means phenoxy or benzyloxy, can by the action of phenyl or Benzylehlorformiät on a 1- [2-hydroxypropyl- (i) ] ~ 5-nitroimidazole derivative of the general Ramel IV in the presence a tertiary organic base.

The 1- [2-hydroxypropyl- (1)] -5-nitroimidazole derivatives of the general Formula IV can, for example, by the action of propylene oxide on a 5-nitroimidazole derivative of the general

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formula

° 2 ^Ν -Ο- «(V)

in which R has the meaning given above, in an organic acidic medium according to that in the French patent 1 427 627 methods described.

The new products of the general formula I can, if appropriate, by physical methods (such as, for example, distillation, Crystallization, chromatography) or by chemical methods (such as formation of salts, crystallization the same and subsequent decomposition in an alkaline medium; The type of anion of the salt plays a role in these operations does not matter, the only condition is that the salt should be well defined and easily crystallizable) cleaned.

The new products prepared according to the invention can be converted into addition salts with acids.

The addition salts can by reacting the new compounds can be obtained with acids in suitable solvents. As • organic solvents are used, for example, alcohols, Ethers, ketones or chlorinated solvents. The salt formed precipitates, if necessary after concentrating its solution and is separated by filtration or decantation.

The new products according to the invention and their addition salts have interesting chemotherapeutic properties, associated with a low toxicity. In particular, they have a very good effectiveness against protozone, the has a particular effect against the pathogenic agents of amoebic diseases and Trichomonas diseases. Under the Products of general formula I represent those for

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which the symbol R represents an alkyl radical and R ₁ and R each represent hydrogen atoms, represent a preferred class of products. The product for which R represents a methyl radical and Rj and R ₂ each represent a hydrogen atom is particularly effective.

The test of the acute toxicity when administered orally to the mouse (one administration per day for three consecutive days) shows that "the animals tolerate doses of 1000 mg of active substance per kg (DL _Q ^ 100Q mg / kg / po).

The amoebicidal activity was demonstrated in the treatment of hepatic amoebiasis in hamsters by the oral route (DC ₁ -A about JQ mg / kg / p _e o, per day for 4 consecutive days).

The effectiveness against Trichomonas versus T, vaginalis was in vitro (minimum trichomonaeide concentration: 12yUg / ml) and in vivo in the mouse (DCc-q between 15 and 20 mg / kg / p.o. each Day for 5 consecutive days).

The new compounds are used for medical purposes in the form of bases or in the form of pharmaceutically usable, i.e. in the case of non-toxic addition salts.

As examples of pharmaceutically acceptable addition salts one can use the salts of mineral acids (such as; for example the Hydrochlorides, sulfates, nitrates, phosphates) or of organic Acids (such as acetates, propionates, succinates, Benzoates, fumarates, maleates, tartrates, theophylline acetates, Salicylates, phenolphthalinates, methylene-bis-'ß-oxynaphtoate) or. name of substitution derivatives of these acids *

The following examples serve to further explain the Invention.'

example 1

A suspension of 30 g of 1- [2-Phenoxycarbonylo3iy-propyl- (1)] - 2-methyl-5-nitroimidazole in 85 cnr ammonia (dl · · = 0.89) is added with stirring 30 minutes at 60 ^e C to the Dissolution heated, then the reaction mixture is ^{allowed to cool to 25 °} C. and the crystals formed are filtered off and dried. 16 g of a solid product are obtained in this way. After Itakristallisation 90 cnr acetonitrile is obtained 14.8 g of 1- [2-Aminocarbonyloxypropyl- (i) J-2-methyl-5-nitroimidazole P "158 ⁰ C.

The 1 - [2-phenoxycarbonyloxy-propyl- (1)] -2Hnethyl-5-nitroimidaJSOl can be prepared by adding 88 g of phenyl chloroformate to a solution of 100% within 1 hour while maintaining a temperature of about 6 * 0 add g 1-f2-hydroxypropyl- (i)] -2-methyl-5-nitroimidazole in 800 cnr anhydrous pyridine. It is left to stand overnight and then the reaction mixture is poured into 5000 cnr water. After filtering the crystals formed, and drying is obtained 145 g of 1- [2-phenoxycarbonyloxy-propyl ~ (1)] ^ - methyl-S-nitroimidazole from 132 to 134 m P ^O C.

Example 2

To 25 g of 1- [2-Phenoxycarbonyloxypropyl- (1)] -2-methyl-5- * nitroimidazole is added with stirring at 20 ⁰ C to 66 cnr an ethanolic 5-n-methylamine solution. The substance of the plague dissolves quickly. The solution obtained is stirred for 30 minutes at a temperature of about 25 ^° C. and then concentrated under reduced pressure (30 mm Hg). The residue is then taken up in 300 ml of methylene chloride and the organic phase is washed three times with 100 ml of sodium hydroxide solution each time and dried over sodium sulfate. After filtering, the solvent is evaporated off under reduced pressure (20 mm Hg). 16.6 g of solid are obtained in this way

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Product that melts at around 96 ^{° C.} Recrystallization from 280 cnr an acetonitrile isopropyl ether mixture (10; 90 volumes) to obtain 11 g * 9 1 ~ [2-methylaminocarbonyloxy-propyl (i) 3-2-methyl-5-nitroimidazole by F = 102 ⁰ C. .

The pharmaceutical compositions containing the derivatives of the general formula I and / or salts thereof in pure form or in the presence of a diluent or coating agent, constitute a further object of the present invention These compositions can be used by the oral, rectal or parenteral routes or by topical application will.

As solid compositions for oral administration, tablets, pills, powders or granules can be used. In In these compositions, the active product according to the invention is with one or more inert diluents, such as sucrose, lactose or starch ^, mixed. These compositions can also contain other substances as the diluent, such as a lubricant, e.g. magnesium stearate.

The liquid compositions for oral administration can be pharmaceutically acceptable emulsions, solutions, suspensions, Use syrups and elixirs that contain inert diluents such as water or paraffin oil. These compositions can also contain substances other than the diluents, such as wetting agents, sweeteners, contain health-enhancing substances or flavorings.

The compositions according to the invention for parenteral administration can be aqueous or non-aqueous sterile solutions, suspensions or emulsions. As a solvent or Carriers can be propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters,

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such as ethyl oleate. These compositions can also use adjuvants, especially wetting agents, Emulsifiers and dispersants. The sterilization can be done in different ways, for example by means of a bacteriological filter * by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions that can be dissolved in sterile water or any other injectable sterile medium at the time of use.

The compositions for rectal administration are suppositories, which, in addition to the active substance, can contain excipients such as cocoa butter or soup wax.

The topical treatment compositions can take various forms. The most commonly used are vaginal tablets or ovules, which, in addition to the active product or products, also contain inert diluents and lubricants that contain the in the compositions for oral administration contained are comparable, or may contain products that allow better diffusion of the drug in situ, such as sodium bicarbonate *

In human therapy, the doses depend on the desired effect and the duration of treatment. They generally lie between 0.25 and 2 g per day for oral administration for an adult and between 0.25 and 1 g per day for vaginal administration.

example

Tablets containing 100 mg of active substance are prepared according to the usual technique the following composition:

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22U265

1- [2-aminocarbonyloxy-propyl- (1) J -2-

methyl-5-nitroimidazole O, 100 g

Grain starch 0.090 g

colloidal silica 0.008 g

Magnesium stearate. 0.002 g

These tablets can be used in human therapy "by administration." by the oral route, for example in an amount of 3 to 5 Tablets per day for one adult.

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Claims (1)

- ίο - Claims Imidazole derivatives of the general formula CH ₀ -CH-O-CO-N '* I>. in which the symbols R ₁ and R ₂ , which can be the same or different, each represent a hydrogen atom or a straight-chain or branched alkyl radical with 1 to 4 carbon atoms and R represents a hydrogen atom or a straight-chain or branched alkyl radical with 1 to 4 carbon atoms , and their addition salts with acids. 2. A method for producing the products according to claim 1, characterized in that one is a product of the general formula in which R ^ and Rg have the meaning given above, with an imidazole derivative of the general formula 309811/1150 GH ₀ -GH-O-GO-X ² I. CH ₃ in which X is a halogen atom or a phenoxy or benzyloxy group and R has the meaning given above, converts and optionally converts the product obtained into a Addition salt converted with an acid, 5. Pharmaceutical compositions that can be used in therapy, characterized by a content of at least one product according to claim 1 as active substance. ORIGINAL INSPECTED