CH628619A5 - Process for the preparation of a liquid mixture containing peroxide-, hydroperoxide- and/or sulphur-containing, unsaturated fatty acids and/or fatty acid esters - Google Patents

Description

628 619

2nd

PATENT CLAIMS

1. A process for the preparation of a liquid mixture containing peroxide, hydroperoxide and / or sulfur-containing, unsaturated fatty acids and / or fatty acid esters, characterized in that the fatty acids and / or the fatty acid esters are contacted with oxygen and / or sulfur, that the reaction mixture Temperatures between 110 and 250 ° C is heated and that the product is then cooled to room temperature.

2. The method according to claim 1, characterized in that the reaction takes place by contacting the starting products with air or oxygen.

3. The method according to claim 1, characterized in that the unsaturated fatty acids and / or fatty acid esters are vegetable or animal oils, especially fish oils.

4. The method according to claim 3, characterized in that said oils are contacted with oxygen in the presence of a radical initiator.

5. The method according to claim 4, characterized in that the reaction by heating the starting substance with the initiator, together with oxygen for a time between

15 minutes and 2 hours.

6. The method according to claim 3, characterized in that said oils are heated together with oxygen in the presence of sulfur.

7. The method according to claim 6, characterized in that the reaction by heating the starting substance with sulfur to temperatures between 120 and 130 ° C together with oxygen in a time between 30 min and 1 h, the oxygen in the form of air in the Mixture is blown.

8. The method according to claim 6, characterized by the following process steps:

- Feeding the oil with sulfur

- Warming the reaction mixture to temperatures between

120 and 130 ° C

- blowing in air for oxidation and stirring

- Keep the reaction mixture at the temperature mentioned for at least 30 min and

- Allow the product to cool to room temperature.

9. The method according to claim 8, characterized in that the sulfur which has precipitated again in the cooled mixture is filtered off from the mixture and partly added back into the mixture, whereupon it can be stirred further at room temperature in order to convert further sulfur into the product .

10. The method according to claim 1, characterized in that the sulfur is one or two times precipitated or sublimated sulfur (so-called sulfur flower).

11. The method according to claim 3, characterized in that the oil is a polyunsaturated fatty acid or a triglyceride.

12. The method according to claim 3, characterized in that the polyunsaturated fatty acid conjugated linolenic acid, conjugated electostearic acid, cottonseed oil or a mixture of different fatty acids, as they are obtained from fish liver, especially cod liver.

13. The method according to claim 3, characterized in that the oil is sesame seed oil.

14. The method according to claim 9, characterized in that the reaction mixture is heated to temperatures between 120 and 127CC and held there.

15. The method according to claim 14, characterized in that the temperature is between 125 and 127 ° C.

16. The method according to claim 1, characterized in that the reaction mixture is kept at the reaction temperature for 30 to 60 min.

17. The method according to claim 1, characterized in that the reaction mixture is stirred vigorously by blowing air.

18. The method according to claim 7, characterized in that the shorter the reaction time, the more intensely the mixture is stirred.

19. The method according to claim 6, characterized in that up to 5 wt.% Sulfur, based on the oil, are added.

20. The method according to claim 1, characterized in that the unsaturated group contains conjugated and / or non-conjugated double bonds and allylmethylene.

21. A liquid mixture containing peroxide, hydroperoxide and / or sulfur-containing, unsaturated fatty acids and / or fatty acid esters, produced by the process according to claim 1.

The invention described here relates to a method for producing a liquid mixture containing peroxide, hydroperoxide and / or sulfur-containing, unsaturated fatty acids and / or fatty acid esters and the liquid mixture obtained therewith.

Processes that can be compared with the method according to the invention are not known to the applicant from the prior art.

The inventive method for producing a liquid mixture containing peroxide, hydroperoxide and / or sulfur-containing, unsaturated fatty acids and / or fatty acid esters is characterized in claim 1.

By administering the products mentioned to humans, the patients treated in this way have a greatly reduced addiction to tobacco smoke. The product can be administered using known methods. Examples of this are injections or oral capsules.

It has been found that special allylic unsaturated compounds, when heated sufficiently high and long enough in the presence of oxygen, significantly increase their peroxide content. The incorporation of sulfur into the compounds mentioned during or before heating has proven to be very useful for the application mentioned. It has been shown that the combination of the two processes leads to products which show the best results among the compounds which can be produced in this way.

The process according to the invention thus leads to products which are obtained by means of oxidation of the fatty acids or fatty acid esters. For example, air can be blown through the corresponding reaction mixture. The unsaturated fatty acids or their esters advantageously comprise, as starting substance, either elemental sulfur and / or a conventional, free-radical initiator such as, for example, the tertiary-butyl peroxide during the heating process.

The starting substance with the allyl groups is advantageously a natural fatty acid ester, such as the vegetable or animal oils. A particularly suitable example of a vegetable oil is sesame oil, and fish oils are particularly suitable for animal oils. Sesame oil is a vegetable oil, which consists largely of triglycerides. As the starting substance for the method according to the invention, it is the most advantageous according to current knowledge.

The starting substance should contain a substantial proportion of allyl groups of the following two types:

. -CH = CH-CH2-CH = CH- and / or

-CH = CH-CH = CH-CH2-,

As can be seen from the formulas, the double bonds can be either conjugated or non-conjugated. The compound always contains allylmethylene hydrogen.

The starting substances specified in detail are warmed up and oxidized in the presence of oxygen. The temperature to be observed is between 110 and 150 ° C. The Zu5

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Oxygen can be conveyed by heating the starting substance in free air. Advantageously, however, the oxygen is blown through the warmed-up oil either in pure form or as air while the starting substance is being warmed up. The blowing through of the air always serves as stirring.

Various polyunsaturated fatty acids, oils or triglycerides can be used to react with the oxygen and with the sulfur in the process according to the invention in order to obtain the sulfurized reaction products according to the invention. These polyunsaturated fatty acids represent a known class of compounds and include fatty acids such as conjugated linolenic acid, conjugated electostearic acid, cottonseed oil and mixtures of various fatty acids such as those obtained from fish liver, especially cod liver. However, the oil preferred in the process according to the invention is sesame oil.

The sulfur used in the process according to the invention must be very pure. It can be sulfur precipitated once or twice or, preferably, sublimed sulfur. The latter is also called sulfur flowers.

If sulfur is added in the process according to the invention, for example to sesame oil, the reaction temperature should be between approximately 120 to 130 ° C. It is even better if the temperature in this special case is between 125 and 127 ° C. These reaction temperatures relate to a reaction time of approximately half an hour. The specific reaction temperature can be adjusted to the reaction time. For example, temperatures of 129 to 130.degree. C., even up to 140.degree. C., can be kept for very short times for a shorter reaction time of the special embodiment mentioned. Higher temperatures are not recommended since this degrades the product of the process according to the invention.

If no sulfur is present in the process according to the invention, the temperature can be between 110 and 150 ° C., but advantageously between 120 and 140 ° C.

Depending on the case, the heat treatment takes between 15 minutes and 2 hours. If sulfur is present, the best results are achieved with reaction times between 30 min and 1 h. If a free radical initiator is present, or if a special starting mixture contains such an inherent substance in sufficient amounts, the heat treatment can also be shorter.

It shows that there is a connection between compounds which lead to agents useful according to the invention and their assumed peroxide or hydroperoxide content. When checking the contents mentioned by means of conventional iodometric analysis, it has been shown that the contents of peroxides or hydroperoxides in the compounds mentioned are substantially increased in the method according to the invention. The results can be expressed, for example, in micro equivalents per gram.

In the case of triglycerides with the allylic groups mentioned, the oxidic products appear to be hydroperoxides of the following group formula:

- CH = CH - CH = ÇH - CH -

OOH

The structural formula mentioned is derived from spectroscopic analysis results and also from others.

Whatever the formula of the product of the process according to the invention, it seems to be certain that its content of peroxide or hydroperoxide groups can be determined by means of conventional iodometric analysis. This finding applies both to the products of the process according to the invention with and to those without sulfur.

However, it must be pointed out that the oxidized products mentioned need not be the only active components of the products. It can be assumed that other products of the process according to the invention also have a smoke-reducing effect. Other possible compounds are, for example, radicals which originate from the decomposition of triglyceride oils or from sulfur-containing olefinic polymerization products. Decomposition products of lower molecular weight of the oils mentioned or of the addition products with sulfur, such as, for example, sulfides, disulfides, hydropersulfides, etc., can likewise be present in the action mentioned.

A preferred embodiment of the process according to the invention is that in which elemental sulfur is added during the oxidation of sesame oil. The addition and incorporation into the product are approximately one percent by weight sulfur, based on the sesame seed oil. The addition of sulfur seems to increase the amount of sesame oil oxidation products. Such oxidation products can include, for example, conjugated hydroperoxides, dienes, trienes, unsaturated carbonyls, etc. The stated effect also seems to be optimal at around 127 ° C. The latter result is inferred from investigations using UV spectroscopic analyzes. In the absence of sulfur, the temperature around 127 ° C also appears to be optimal for the production of oxidation products of the starting substance.

As has been said above, it appears that the most effective products are those that have a relatively high peroxide content. A comparison of the preferred starting substances and products, i.e. a comparison of sesame seed oil that has been oxidized or treated with air in the presence of sulfur with other triglycerides or oils containing triglyceride, such as cereal oil, cottonseed oil and triols, in terms of their peroxide levels indicates peroxide levels , which corresponds to the observed bioactivities of the compounds in alcoholics. An indication of such a connection of bioactivity is generally correct with the results of the peroxide analysis of the abovementioned compounds both in their untreated state and after oxidation with the presence of sulfur under the same conditions. The corresponding results are summarized in the following table:

(Table on the next page above.)

The lower bioactivity and the lower peroxide content of cottonseed oil is attributed to the presence of natural antioxidants in the raw material. The elimination of these antioxidants from natural oils such as cereal or cottonseed oil or the use of relatively pure, allylic unsaturated compounds or mixtures thereof leads to products which have a significantly increased peroxide content after treatment in accordance with the process according to the invention. Triolein contains only oleic acid groups, which are characterized by the allylic unsaturated group - CH = CH — CH2— and are therefore difficult to oxidize. This is especially true if the compound with the preferred starting substance, i.e. sesame seed oil. In the case of sesame seed oil, an end product was obtained which had a peroxide content of 35.7 meq / kg * in the case of the oil-sulfur-air reaction, while the same starting product had a corresponding value of 63.3 meq / kg * at 137 ° C. without the addition of sulfur . The corresponding increase in the process with sulfur is 16.9 meq / kg *, for those without sulfur at 137 ° C 53.1 meq / kg *.

In general, it can be stated that the increase in the peroxide content when sulfur is stored can be defined as 3 to approximately 100 and in the case of oxidation without sulfur from 3 to approximately 400.

The analysis procedure for determining the peroxide content is as follows:

2 g of liquid to be examined are placed in a flask. During the addition, the flask is continuously nitrogen

* Journal Be. fd agric. 1975.26, pages 1353-1356.

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628 619 4

Peroxide levels (maeq / kg)

Used as starting substance

oil

(Peroxide content)

a

Oil saturated with sulfur b *

Oil treated with air in the presence of sulfur b-a

Difference in the peroxide content

Sesame seed oil

18.8

35.7

16.9

(10.2)

Cereal oil

11.3

14.9

3.6

(6.8)

Cottonseed oil

10.9

10.2

-0.7 »*

(7.3)

olive oil

12.4

13.8

1.4

(5.9)

Triolein

8.6

8.5

-0.1 **

(7.2)

* Warmed to 127 ° C for 30 minutes, addition of 90 1 / min air and quick, mechanical stirring; Mixture contains 1.0% by weight of elemental sulfur.

** within the experimental inaccuracy.

rinses. 2 ml of concentrated acetic acid and 0.5 g of potassium iodide are added to the sample. The mixture is then sealed in flasks to prevent air from entering. The flask is kept in the dark for 30 minutes. The reaction takes place completely during this time. The flask is then opened and the side walls are washed down with as little water as possible. 1 to 2 ml of a 2% starch solution are then added to the solution. The solution is then titrated directly to the end point with 0.007 normal Na2S202 solution. At the end point, the solution is white when there are only a few peroxides; it is slightly yellow when there are large amounts of the group mentioned.

The products of the method according to the invention should be administered as soon as possible after production. It has been shown that prolonged storage of the same leads to reduced activity of the products, possibly due to degradation reactions.

Preferred products can be made by adding sulfur to the oil, for example sesame oil, and heating the mixture with stirring at temperatures not exceeding 130 ° C. In this case it is advantageous to heat the mixture to temperatures between 120 and 127 ° C and to keep it there. When the mixture is heated to temperatures above 130 ° C. for a certain time, the mixture becomes discolored, and at the same time the products required for the use according to the invention also appear to be degraded. The given temperatures refer to the process with the addition of sulfur. They specifically refer to the treatment of sesame oil with sulfur. The treatment temperatures depend on the starting material, but are generally always above 120 ° C, advantageously between 125 and 127 ° C. As I said, this information only applies to oils to which sulfur has been added.

If oil-sulfur mixtures are not heated above 90 ° C, it is difficult to incorporate the sulfur into the product only by heating and stirring. If the temperatures given above are observed, the sulfur is incorporated into the product to a sufficient extent in times between 30 minutes and 1 hour. During this time the mixture is stirred. It is even necessary to stir relatively violently. This can be done, for example, by blowing the air into the reaction mixture, which allows both the supply of oxygen and the stirring. It also appears that vigorous stirring affects the reaction time, i.e. the length of time that the product must be kept at the above temperatures is reduced.

After the reaction is complete, the product is left to cool to room temperature. In this case, sulfur crystals in turn precipitate out of the mixture. These settle on the ground, where there may still be sulfur, which has not been included in the reaction. These settled sulfur crystals can then easily be removed from the product mixture by filtration. The filtrate is then ready for the appropriate sterilization. It can then be administered, for example by means of injections or installed in capsules. The capsules can contain, for example, gelatin 30 and are suitable for oral administration of the product according to the invention.

The amount of sulfur which is incorporated into the oil in this way is advantageously between 0.1 and 2.5% by weight, based on the oil. If higher amounts of sulfur are used, they usually fail again when they cool down. In addition, it does not seem to be an advantage to use products that have a higher sulfur content. In addition, since the amount of sulfur administered depends primarily on the number of injections or capsules, the content of the individual capsule or injection is not critical.

40 From the examples described below it follows that the upper limit of the sulfur incorporated into the products by means of the method according to the invention is approximately one percent by weight. '

However, the sulfur content can also be much less than 1%, 45 if so desired. With injection solutions in particular, it is advantageous if the sulfur content is lower. If in the product for oral administration, i.e. in capsules, the sulfur content is lower, it simply means that more such capsules have to be taken.

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Expenmente indicate that the optimal sulfur content for oral administration is approximately 1% by weight, for injections the corresponding content is between 0.1 and 0.3% by weight, always based on the oil.

55 The dosage for the individual patient naturally depends on the patient himself and on the number of cigarettes that the corresponding person smokes per day. A daily dose of 3 to 5 capsules, which contains about 1 ml of the sulfurized oil, is usually sufficient for the first three days. Then the dosage 60 is gradually reduced. For a particularly heavy smoker, however, it may also be advantageous, for example, to take 8 capsules of 1 ml of one to two percent oil for the first three days and three to four such capsules for the next four days. In general, this is enough to greatly reduce or even eliminate the addiction to smoking. The addiction to tobacco mentioned above generally disappears after 2 to 3 days of treatment. The individual treatment can of course take months. It has proven to be right to leave the patient with individual capsules at their disposal,

which he should take whenever he feels a special desire to smoke.

If the sulfurized oil is injected, this can be done intermuscularly or intraperitoneally. It is advantageous if the product has a sulfur content below 0.5% by weight, based on the oil. This content is advantageously between 0.1 and 0.3% by weight. Between 0.5 and 3 ml of this solution are injected. Such individual injections are given for 2 to 5 days. It has been shown that the injection of sulfurized oil, which contains more than 0.5% by weight of sulfur, causes pain in some cases. Administration by means of injections is of course not necessary, but this type of administration has the advantage that the effect can occur faster. A patient who is injected with the product mentioned can, of course, also use oral capsules. For example, after the specified number of injections, 3 to 4 capsules can be taken daily for a week.

Example I. An sulfurized oil was prepared by the method of the present invention by adding 50 g of sublimed sulfur from Fisher Scientific Co. to 11 sesame seed oils. The mixture was brought to a temperature of 127 ° C. with vigorous stirring by blowing in air. It was kept at this temperature until all of the sulfur had been incorporated into the sesame oil. The reaction mixture was then left to stand; when cooling to room temperature, a small amount of sulfur crystals precipitated, which accumulated on the bottom of the container. The crystals were filtered off from the mixture and approximately half were returned to the solution, whereupon they slowly dissolved.

After suitable sterilization, 1 ml each of this sulfurized oil was enclosed in gelatin capsules.

Four patients, who stated that they had previously smoked 3 to 4 Päck's cigarettes a day, received 5 of the capsules mentioned during the treatment in the first three days. During the following four days, they took 3 such capsules. All patients indicated that after the third day they no longer had a strong desire to smoke tobacco and that they only smoked 3 to 4 cigarettes a day. This is said to have happened without nervous disorders or other withdrawal symptoms.

Another patient, who had smoked 60 to 80 cigarettes a day for the past 20 years, took 8 capsules with 1 ml of sulfurized oil (1% by weight) on the first three days of treatment. During this time, her condition was relatively normal. The entire treatment lasted 10 days with progressively reduced doses. When writing down this report, the patient did not smoke for 4 months and did not notice any desire to smoke tobacco.

Different other people who were chronic smokers to different degrees received the same dosage. 80% of all of these people quit smoking during treatment, while 50% of the rest of the population experienced a sharp reduction in smoking addiction during treatment or aftercare.

628619

lung. The remaining treated patients apparently did not lose their smoking addiction.

Example 2:

4 g of sulfur were weighed into an Erlenmeyer flask. 200 ml of sesame seed oil were added. The mixture was heated to 125 ° C with stirring and kept at this temperature until the sulfur was completely dissolved. The flask was then left to stand; cooling to room temperature took 5 hours. During cooling, sulfur crystals precipitated, which were filtered off on a Büchner filter. The precipitated sulfur crystals were washed on the filter with hexane so as to wash out residual oil sticking to the crystals. The dried sulfur crystals were then weighed. This was repeated three times. The sulfur intake was determined absolutely and as a percentage from the data obtained. The corresponding results are summarized in the following table:

Sulfur absorption in sesame seed oil

Weight of sulfur: 4.00 g

Sulfur absorption

% Sulfur absorption

(G)

(Weight per volume)

Trial 1

2.05

1.02

Trial 2

2.00

1.00

Trial 3

1.92

0.96

medium

0.99%

It can be deduced from these results that the product of the process according to the invention, when sesame seed oil and sulfur is present, contains approximately 1% by weight of sulfur.

The product obtained in this way can be used in the same way as in Example 1.

Neither in the treated patients nor in animal experiments have any toxic or other side effects of the product of the method according to the invention been found.

In addition, it has also been found that colloidal sulfur also reduces smoking addiction in humans when administered in high doses of 5 to 50 mg 3 to 10 times a day for 3 to 5 days with progressively increasing doses.

The process according to the invention can also include the addition of selenium instead of sulfur. If selenium is used, it is also incorporated into the allylic residue, as happens with sulfur. However, the reaction temperature is higher, in the range from 230 to 250 ° C. A reaction time of 15 minutes to 1 hour at approximately 240 ° C. is advantageous. This also significantly increases the peroxide content of the product. However, the use of selenium-containing products has not yet been secured and clarified in the same way as those with or without sulfur.

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