DE3876925T2 - CONDENSATION PRODUCTS MADE FROM 2,2,4-TRIMETHYL-1,2-DIHYDRO-CHINOLINE AND OXO COMPOUNDS AND DERIVATIVES THEREOF. - Google Patents

Description

The present invention relates to novel condensation products of 2,2,4-trimethyl-1,2-dihydroquinoline and oxo compounds and derivatives thereof as well as a process for their preparation and feed and feed premixes containing these compounds as well as pharmaceutical compositions containing the novel compounds as active ingredient.

In recent decades, the importance of the use of antioxidants has increased all over the world in various fields, and accordingly the use of antioxidants is widespread. Antioxidants are most commonly used in the rubber and plastics industries; in these fields the most important requirement is the effectiveness of the antioxidants; additional, very important factors are their tolerability and their low tendency to migrate. The use of antioxidants in agriculture, the food industry and recently in veterinary science and human therapy has increased considerably. In the rubber and plastics industries, some amine and phenol type antioxidants are used, whereas for the stabilization of feedstuffs practically only 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (EMQ) and 2,6-di-tertiarybutylhydroxytoluene (BHT) have been used. Antioxidants suitable for stabilising feed mixtures must fulfil several essential requirements at the same time, such as having a broad spectrum of activity and low toxicity (if necessary zero toxicity). The last point is acknowledged in the recommendation of the WHO/FAO Nutrition Meeting Series No. 40 A, B, C, WHO/FOD AU 67.29, according to which only antioxidants should be used for the purposes mentioned. whose LD₅₀ value exceeds 5g/kg body weight. It is known that neither EMQ nor BHT fulfill this requirement. Despite this fact, these two compounds are widely accepted in the current state of the art. These two compounds are the best in meeting the complex requirements.

6,6'-methylene-bis(2,2,4-trimethyl-1,2-dihydroquinoline) is used in human therapy due to its radiosensitizing properties, but has not proven to be particularly suitable for stabilizing feedstuffs, as it often causes discoloration in the animals' fatty tissue due to the extreme sensitivity of its methyl group.

The antioxidant activity of 6,6'-ethylidene-bis-(2,2,4- trimethyl-1,2-dihydroquinoline) (called XAX-M) is suitable, its toxicity is low, but after oxidation, the ethylidene group is also oxidized and has a certain coloring effect.

Another disadvantage of XAX-M, which is produced according to Hungarian patent specification No. 162,358, is that the product is not chemically homogeneous, but according to page 4 of the Hungarian patent specification, its degree of polycondensation, i.e. the number of dihydroquinoline units, varies depending on the reaction conditions. The products obtained by condensation with acetaldehyde or a higher aldehyde form a mixture of condensed molecules containing 2 to 4 dihydroquinoline units. A uniform composition cannot easily be guaranteed, although this is required by the user.

To date, no economically viable process for its production has been found. DE-OS 35 40 105 concerns the same product and its property of increasing the coccidiostatic activity of known coccidiostats.

The present invention was directed to new To find compounds that not only have the good antioxidant activity of the known dihydroquinoline derivatives, but also have a chemically homogeneous structure, are suitable for human and veterinary use, increase the activity of coccidiostats and show low toxicity. The new compounds should be available in high purity via an economical process.

We have now found that new compounds fulfilling the above requirements can be prepared if 2,2,4-trimethyl-1,2-dihydroquinoline is condensed with lower ketones under special reaction conditions and, if desired, the resulting compounds are sulfonated and/or acylated.

According to the present invention, new compounds of general formula (I)

and acid addition salts thereof, wherein

R¹ represents optionally substituted C₁₋₄ alkyl and

R² represents optionally substituted C₁₋₂ alkyl,

X is hydrogen or SO₃Me, where

Me is hydrogen, an alkali or alkaline earth metal ion, and

Y stands for hydrogen or acyl.

The new compounds can be prepared by condensation of acetoanil-(2,2,4-trimethyl-1,2-dihydroquinoline) or salts thereof with an oxo derivative of the general formula R¹R²CO, wherein R¹ and R² are as defined above, in the presence of 1-5%, preferably 2-3%, of a nitrogen-containing base as cocatalyst, preferably Triethanolamine, pyridine or aniline, and in the presence of a mineral acid, preferably 0.9-2.5 mol, preferably 1.25-1.75 mol of hydrochloric acid as catalyst, based on the dihydroquinoline, in a solvent, and, if desired, converting the resulting product to an acid addition salt or releasing the free base from the salt, and, if desired, sulfonating and/or acylating the resulting base, e.g. with sulfuric acid or oleum.

The acid addition salts can be formed with an acid such as hydrochloric acid, hydrogen bromide or sulfuric acid, preferably hydrochloric acid.

In the meaning of R¹, the alkyl groups can be straight-chain or branched and represent an optionally substituted C₁₋₄ alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. butyl, preferably methyl, ethyl or isobutyl. The substituents can be selected from hydroxyl, halogen, C₁₋₄ alkoxy, carboxyl and C₁₋₄ alkoxycarbonyl. R² can preferably represent C₁₋₂, preferably methyl, ethyl, which can be substituted with the same groups as indicated for R¹. X preferably represents hydrogen or SO₃Me, where Me represents an alkali or alkaline earth metal ion, preferably sodium, potassium or calcium ion. Y preferably represents hydrogen or an acyl group, preferably acetyl, formyl, benzoyl, in particular acetyl.

Surprisingly, the use of a nitrogen-containing base leads to rapid condensation and, accordingly, the formation of side products is excluded.

During the condensation, the reaction medium is preferably the ketone itself in an amount of 0-40%, which preferably contains 10-20% water.

The sulfonation can be carried out using the known processes using oleum or sulfuric acid. The acetylation can be carried out using the known acetylating agents such as acetic anhydride, acetyl chloride, benzoyl chloride, formyl chloride, etc.

The reaction mixture can be worked up by filtration of the salt, preferably the hydrochloride, and by centrifugation and its conversion into a free base. A product with a purity higher than 95% can be obtained. According to another method, the product is worked up with the mother liquor, after which the unreacted starting material is distilled off in vacuo and accordingly a product of 60-80% purity can be obtained. It turns out that a pure product is obtained without crystallization. The reaction is carried out at a temperature ranging from room temperature to the boiling point of the mixture, optionally under pressure.

Acetone, methyl ethyl ketone or methyl isobutyl ketone, especially acetone, is preferably used as a ketone. The molar ratio of the ketone to acetoanil is generally in the range of 0.5 mol to a multiple excess. A tenfold excess is preferably used.

The other starting material used according to the invention is 2,2,4-trimethyl-1,2-dihydroquinoline and this compound is known from Bayer, J. Prakt. Chem. 2/33, 401/1886, and Combes, Bull. Soc. Chim. Fr. 49, 89 (1888).

The ketone condensation products of the invention are new compounds. Due to their chemical structure, they show no coloring effect and can be widely used as oxidizing agents in industry, in particular in the food and feed industry as well as in the field of therapy and veterinary science. The property of the new compounds to increase the activity of known coccidiostatics is particularly significant.

For example, we have found that 2,2-di(2',2',4'-trimethyl-1',2'-dihydroquinolin-6'-yl)-propane has excellent anti-aging activity of rubber and does not cause discoloration. Similarly, 2,2-di(2',2',4'-trimethyl-1',2'-dihydroquinolin)-butane can be used as a non-staining anti-aging agent of rubber, as it dissolves extremely well in rubber compounds and can be used up to 5% in Products that can come into contact with food.

2,2-Di(2',2'-dimethyl-4'sodium methanesulfonate-1',2'- dihydroquinolin-6'-yl)-propane is easily soluble in water and can be used accordingly for injections in human therapy. The compound protects against harmful reactions of free radicals. This is important in the case of poisoning, radiation injuries and circulatory disorders. In veterinary therapy, encelophalomalatia in poultry can be treated by administering the compound in drinking water.

Among the tested new antioxidant active ingredients, the toxicity of 2,2-di(2',2',4'-trimethyl-1',2'-dihydroquinoline)-propane is very low and it can be used usefully in the feed and food industry and for therapeutic purposes and for stabilizing substances, as well as in animal feed, especially as antioxidants in poultry, rabbit and pig feed to increase the activity of coccidiostatics. Even under extreme conditions (in the presence of iron, copper compounds or halides) no discoloration occurs in the nutrient or fatty tissues. To demonstrate the coccidiostatic activity-enhancing effect of the compound of Example 3, it was compared with salinomycin and monensin. The degree of infection of the animals was evaluated as 0, 1, 2, 3 crosses (+, ++, +++). The oocyst index is the sum of the crosses in relation to the total number of animals. Table 1 Diet Oocyst index Death Body weight Standard deviation Infection control Compound according to Example 3 Compound according to Example 3, Salinomycin Compound according to Example 3, Monensinxx x Hoechst xx Eli Lilly

The table shows that in the case of salinomycin the compound of Example 3 at a dose of 15 ppm and in the case of monensin the compound of Example 3 at a dose of 30 ppm provide the same protection as the known compounds when administered alone at a dose recommended by the manufacturer.

The oocyst index is determined by a well-known method: the oocysts are counted microscopically. 25 visible fields are examined at the same time. If the number of oocysts counted per field is less than 1, the value is marked by +, if it is between 1-10, it is marked by ++, above 10 the value is marked by +++.

Antioxidant activity

Based on the active oxygen method (AOM)

1. Description of the procedure

Under thermostatic conditions, a uniform air flow is passed over the samples containing antioxidant or not containing antioxidant. The change in the Lea number over time is measured.

2. Materials used

Glycerol trioleate purum C₅₇₇H₁₀₄O₆ LOBA Fine Chemicals

K.J. p.a.

chloroform

Glacial acetic acid

Na₂S₂O₃ 0.002 N solution

Strength indicator

3. Test procedure

30 g of glycerol trioleate in which 20 mg (0.02%) of test antioxidant has been dissolved are weighed into 4 thermostated test cuvettes. The cuvettes are kept at 70ºC and air is passed through the test oil at a rate of 9.6-10 l/hour. A sample is taken hourly from the control and every 4 hours from the antioxidant sample and the Lea number is determined as follows:

To about 1 g of sample, add 30 ml of a solution of 1:1 chloroform and glacial acetic acid and 1 g of solid potassium iodide, boil for 60 seconds, cool quickly and add 15 ml of a 5% aqueous potassium iodide solution.

It is titrated in the presence of 0.002N Na₂S₂O₃ solution in the presence of a starch indicator. The results are calculated using the formula:

(Consumption/ml 0.002 N Na₂S₂O₃) Blind test x factor/weight (g) 4. Results Control Time (h) Lea Number Samples MTDQ Comparison 6,6'-methylenebis-derivative (melting point degrees Celsius) Material according to example Acetyl derivative according to example

In the case of X=SO₃Na, a water-soluble antioxidant is obtained, which is tested in the following heterogeneous system:

30 ml water, neutralized with 1 ml phosphate buffer of pH=7.

20 g glycerol trioleate, 1.5 g 30% fatty alcohol sulfonate.

20 g of the tested antioxidant are added to the emulsion thus prepared. The amount of antioxidant and the Lea numbers are related to the oil content. Lea number/time Control SO₃⊃min;Na⊃plus; derivative Glutathione 1-ascorbic acid

EXAMPLES example 1

In a four-necked flask equipped with a stirrer, a thermometer, an addition funnel and a reflux condenser, 150 parts by weight of acetone containing 10% water, 105 parts by weight of acetoanil and 2.5 parts by weight of pyridine are placed, and 100 parts by weight of concentrated hydrochloric acid are added dropwise. The mixture is heated to boiling point and stirred at this temperature for 22 hours. The mixture is cooled, after which 110 parts by weight of 40% sodium hydroxide are added. The mixture is stirred under reflux, acetone is separated, and 40 parts by weight of unreacted acetoanil are distilled off in vacuo. The bottom product is (60 parts by weight) 2,2-di(2',2',4'-trimethyl-1',2'-dihydroquinol- 6'-yl)-propane with 80% purity. Melting point: 125-135 ºC.

Example 2

In an autoclave that can be heated by steam and cooled by water and is equipped with a thermometer, stirrer and an addition opening, 100 parts by weight of acetoanil, 2 parts by weight of triethanolamine, 280 parts by weight of anhydrous acetone and 106 parts of concentrated hydrochloric acid are added. The unit is closed and the contents are stirred under pressure for 12 hours at 72-75ºC, cooled to 40ºC and neutralized by adding 100 parts by weight of 40% sodium hydroxide solution. The aqueous phase is removed and acetone is distilled off from the organic phase, after which acetoanil is distilled off in vacuo. Yield: 62 parts by weight of 76% 2,2-di(2',2',4'-trimethyl-1',2'-dihydroquinol-6'-yl)-propane. Melting point 120-135ºC.

Example 3

From the antioxidant according to Examples 1 and 2, a product is obtained in good yield, which can be recrystallized from benzene and then from isopropanol and which melts at 156ºC, is completely white and has a purity of 96% by HPLC chromatography. The product shows a biological activity similar to that of the product with a purity of 80%. After evaporation of the mother liquor, an excellent ageing inhibitor for rubber is obtained.

Example 4

Example 1 can be followed, but acetone is replaced by methyl ethyl ketone. Yield: 45 parts by weight of 2,2-di(2',2',4'-trimethyl-1',2'-dihydroquinol-6'- yl)-propane, purity: 55%. After recrystallization from hexane, followed by isopropanol, a product with 96-97% purity is obtained, melting at 117-118ºC. The product is an excellent antioxidant and its synergistic effect makes a saving of 80% possible when used together with coccidiostats. From the mother liquor a non-staining antioxidant for the rubber industry can be obtained.

Example 5

The procedure described in Example 1 can be followed, but methyl isobutyl ketone is used as the ketone. Yield: 20 % 2,2-di(2',2',4'-trimethyl-1',2'-dihydroquinol-6'-yl)- isohexane. Purity: 50%, melting point after recrystallization 120-126ºC. The product can be used in a similar way to the product of Example 4.

Example 6

100 parts by weight of a 96% product according to Example 3 are dissolved in 400 parts by weight of 96% sulphuric acid, after which the mixture is slowly heated to 80°C and the reaction is carried out at this temperature for 2 to 3 hours. The sulphonated product is added dropwise to a mixture of 1000 parts by weight of water and 1000 parts by weight of ice, and the precipitated sulphonic acid is filtered off. It is recrystallised from hot water in the form of the free acid and then converted into its sodium salt. The colourless, crystalline product thus obtained is dried to constant weight.

Yield: 100 parts by weight

Analysis of the product dried at 120ºC:

C 55.1 % (54.91); H 5.4 % (5.42); N4.56% (4.75); 0 16.34 % (16.27) S 10.9 % (10.85); Na 7.7% (7.8).

The product is suitable for therapeutic purposes.

Example 7

The product of Example 3 is used. 100 parts by weight of the product are dissolved in 600 parts by weight of acetic anhydride and the solution is refluxed for 2 hours. Acetic acid and the excess of anhydride are distilled off from the crude product and it is recrystallized from 600 parts by weight of hot acetone. Yield: 114 parts by weight, melting point 120-121°C, and the product is obtained in the form of pale yellowish crystals.

Claims (10)

1. Compounds of the general formula I and acid addition salts thereof, wherein R¹ represents optionally substituted C₁₋₄ alkyl and R² represents optionally substituted C₁₋₂ alkyl, X is hydrogen or SO₃Me, where Me is hydrogen or an alkali or alkaline earth metal ion, Y stands for hydrogen or acyl. 2. Compounds according to claim 1 wherein R¹ represents optionally substituted C₁₋₄ alkyl and R² represents optionally substituted C₁₋₂ alkyl, X stands for hydrogen, and Y stands for hydrogen. 3. A process for the preparation of the compounds of general formula I and the acid addition salts thereof, which comprises the condensation of 2,2,4-trimethyl-1,2-dihydroquinoline or a salt thereof with a ketone of general formula R₁R₂CO, wherein R₁ and R₂ are as defined above, in the presence of a catalyst such as a mineral acid (preferably hydrochloric acid) and a cocatalyst such as a nitrogen-containing base, preferably triethanolamine, pyridine or aniline, in a solvent, and, if desired, Conversion of the product thus obtained into an acid addition salt or release of the base from the salt and, if desired, sulfonation and/or acetylation of the base obtained. 4. A process according to claim 3, which comprises carrying out the condensation in 0-40%, preferably 10-20% of the ketone. 5. A process according to claim 3, which comprises using the acid, preferably hydrochloric acid, in a molar ratio of 0.9-2.5 moles, preferably 1.25-1.75 moles, relative to the weight of the dihydroquinoline. 6. Pharmaceutical composition comprising as active ingredient a compound according to claim 1 or 2. 7. A feed or feed premix for the treatment of coccidiosis, which comprises a compound according to claim 1 or claim 2 in addition to ionophoric polyether antibiotics or salts thereof, preferably sodium salts. 8. A method for preserving substances against oxidation, e.g. rubber, plastics, food, animal feed or pharmaceutical or veterinary compositions, which comprises incorporating a compound according to claim 1 or 2 into the substance. 9. Substances, e.g. rubber, plastics, food, animal feed or pharmaceutical or veterinary substances, containing a compound according to claim 1 or claim 2. 10. Use of the compounds according to claim 1 or claim 2 for the manufacture of a medicament for the treatment of poisoning, avian celophalomalatia, radiation injuries and circulatory insufficiency or for the manufacture of a medicament with coccidiostatic activity which also comprises a contains a coccidiostatic agent.