NO144151B - ANALOGY PROCEDURE FOR THE PREPARATION OF 2,3-EPOXYDES WITH THERAPEUTIC EFFECT - Google Patents

Description

The present invention relates to an analogue process

method for producing epoxides of formula I below. Haze-

see substances are useful therapeutics, especially in the treatment of difficulties with prostate secretion, and especially in the treatment of "prostate".

In British Patent Application No. 40568 (1973) it is shown

that higher alkanols than C-^g have beneficial therapeutic effects

nings to difficulties with prostate secretion, and especially prostate adenoma. It has now been found that 2,3-epoxyalkanes with general formula:

where A is an alkylene residue with 15-20 C atoms are compounds that are as active as the aforementioned higher alkanols.

The 2,3-epoxyalkanes of formula I are new and are attributed with interesting therapeutic properties. One only knows a one-

celted C^g-epoxyalkane from before, it concerns a pheromone of the butterfly species lépidoptera, namely cis-7,8-epoxy-2-methyl-octadeane which is emitted by the females of the species Porthetria dis-

pair to attract the males in order to pave the way for a favorable intraspecific mating. This pheromone is a laboratory curiosum. After extraction, the structure was found by Beroza in "Journal of Association of Official Analytical Chemist"(1971), 54, 251, and then confirmed by synthesis by Eiter in the journal "Angew. Chem. Internat.", (English edition),

(1972), 11, 60.

By "hydrocarbon residue" A is meant here an alkylene residue

with linear or branched carbon chain containing 15-20

C atoms. As will be seen later, the preferred hydrocarbon residues are those which contain a linear chain. The lower limit C^,. is determined by a statistical survey of connection activities, to which we will return.

The compounds of formula I are prepared according to

a method known in and of itself by reacting a corresponding alkene with a peracid. The method consists in reacting one mole of alkene with formula

where A has the previously stated meaning, with at least one mole of peracid, at room temperature (15-25°C).

Among usable peracids, one can particularly mention peracetic acid, perbenzoic acid, perphthalic acid, metachloroperbenzoic acid. These peracids are in principle equivalent, nevertheless it has been established that metachloroperbenzoic acid gives the best result from an industrial point of view, especially when it comes to the purity of the end product. Metachloroperbenzoic acid, formed during the reaction, can be removed more easily than the other acids.

To carry out this reaction, 1.1 mol of metachloroperbenzoic acid is reacted with 1 mol of alkene II in an inert solvent such as methylene chloride.

2-Alkenes of formula II can be especially prepared

a) from the corresponding 2-alkanols by treatment with H2S04 or b) by reacting an organomagnesium compound III

with l-chloro-2-butene IV according to the scheme:

where A' is an alkylene residue containing 14-19 C atoms.

Methods A and B below both illustrate a method for producing 2,3-epoxy-eicosane from 2-eicosene by oxidation with metachloroperbenzoic acid (method A) and with peracetic acid (method B). Methods C and D indicate the production of a starting alkene, namely 2-eicose.

Method A

6 g of 2-eicose are dissolved in 100 ml of methylene chloride and this solution is added to a bottle equipped with a cooler and a stirrer (the flask can optionally be placed in a cooling bath or heating bath).

4 g of metachloroperbenzoic acid is gradually added (within approx. 30 min), i.e. a molar excess of approx. 10% in relation to the stoichiometric amount. The mixture is stirred and kept at room temperature ((15-25°C) using a stream of water while the acid is added, and the mixture is then set aside overnight at room temperature, then heated at reflux for two hours to destroy the peracid.

After cooling, a large amount of metachloroperbenzoic acid precipitates. This is filtered out. The methylene chloride solution is washed with 100 ml of sodium sulphite, 100 g/litre, and then with 100 ml of sodium bicarbonate 100 g/litre, then with water to a pH above 6. The organic solution is dried over calcium chloride and distilled to remove the methylene chloride. You get 4.8 g of product, that is, a crude yield of 76%.

The purification takes place by column chromatography.

A glass column with a diameter of 3.5 cm is filled with 100 g of silica of chromatography quality suspended in petroleum ether. After the silica gel has been filled, the crude product is poured at the top of the column after dissolving it in a mini-scale amount of petroleum ether. The column is washed with petroleum ether and it collects in 1 liter of solvent 0.2 g of product which is discarded. Elution is continued in a mixture of petroleum ether and diethyl ether (90:10). 500 ml of eluate delivers 4.5 g of 2,3 epoxy-eicosane, m.p. = 40°C, b.p. 15 mm Hg = 200-210°C.

Method B

7 g of 2-eicone is dissolved in 20 g of peracetic acid. The oxidation of the ethylene function to epoxide takes place during cooling.

The acetic acid is neutralized in 10 ml of water with IN NaOH. The aqueous solution is extracted with ether. After evaporating the ether, 6 g of 2,3-epoxy-eicosane, which is purified as described above, syrup is obtained. 40°C, b.p. 15 mm Hg = 200-210°C.

Method C

35 g of 60% sulfuric acid solution is filled into a 100 ml flask equipped with a cooler, stirrer and heated in an oil bath. 7 g of 2-eicosanol (0.0234 mol) are introduced into the flask and heated under reflux (100-110°C) for 16 hours.

After cooling, extract with 200 ml of chloroform, wash twice with 150 ml of sodium carbonate, 100 g/litre, and several times with water until you have a pH above 6 in the wash water. The chloroform solution is dried over calcium chloride, the chloroform is evaporated by distillation and the evaporation residue is distilled up to 180°C under 15 mm pressure. You get 6 g of 2-eicose, that is, a yield of 85%.

Method D

Dissolve 61 g of 1-bromohexadecane in 100 ml of ether. 4.86 g of magnesium shavings are added. The amount is stoichiometric.

The Grignard reaction is started as usual with an iodine crystal and when the reaction becomes lively, it is regulated from the outside with an ice bath and kept under reflux. It stops by itself after a few minutes.

When this step is finished, lime is added to a solution containing 18 g of 1-chloro-2-butene in 20 ml of dry ether.

The exothermic reaction is kept under its own reflux, which decreases after approx. 15 min.

The cold solution is washed with water containing an excess of hydrochloric acid to dissolve the formed magnesium oxide. The ether solution is decanted off and dried. The ethylene compound, namely 2-eicosene, is obtained quantitatively. This is purified by distillation in vacuum at 160°C, 1 mm Hg.

After discarding the run-on and run-off, one has 7 g of product whose composition and purity can be easily confirmed by NMR analysis.

In the following table 1, some epoxyalkanes with formula I and two comparison products A-I have been listed

and A-2, as all these products are produced according to method A. 2,3-epoxyeicosane according to methods A and B can also be found in

the table (example 1).

The following summarizes the results of the pharmacological trials that have been carried out.

The histological changes seen in the epithelium of adult rats have been investigated. It has been found that the product manufactured according to the invention is able to

stimulate prostate function in adult rats treated orally from 15 days to 3 months with very small doses, until a clear improvement occurred, e.g. at a dose of 0.5 mg/kilogram body weight/day, for products according to examples 1-3.

Method.

Adult rats, approximately 9 months old, received daily

in the specified period of time the epoxyalkane to be examined in the specified dose, in a draining agent such as e.g. consisted of olive oil e.

Control rats only received a laxative (olive oil).

In the examples described, the animals are treated six days/week for seven weeks. Each oxyalkane is given as a solution in a volume of 0.1 mm/100 g body weight in the rats, or a concentration of 0.5 g product/litre of oil.

After the experiments have ended, test animals and control animals are killed, the ventral part of the prostate gland is removed. placed in alcohol and examined histologically.

The appearance of the incisions around the periphery of the prostate is noted according to the following assessment scale:

Epithelium + 1

An enlargement of the marginal epithelium of the central glands assumes a square appearance and occupies more than half of the external surface of the prostate.

Epithelium + 2

The growth of the epithelium assumes more of a cylindrical character.

Epithelium + 3

The epithelium is almost identical to the epithelial cells in the marginal glands.

Epithelium + 4

Papillary hyperlasia of the epithelium with hypersecretion (this condition has not been observed during the experiments carried out).

Table II contains results regarding the prostate gland examined after the control animals and the treated animals have been killed, the treated animals receiving the specified dose of epoxy alkanes according to examples 1-3 and comparative examples A-I and A-2.

Table II also contains results from statistical

2 2

tical tests using the method chi (x ) and the EPP index. The chi 2 method makes it possible to find the probability "p". The EPP index (examination of the prostate periphery) is defined as the ratio between the sum of all cases classified within "epithelium 1+" multiplied by the coefficient 1, the class "epithelium 2+" multiplied by the coefficient 2 and individuals classified within "epithelium 3 +" multiplied by the coefficient 3 divided by the number of animals, and this index makes it possible to confirm the statistical result. As shown in Table II, it is established that the compound is inactive if the EPP is below 1.80, and activity towards the prostate if the EPP is equal to or greater than 1.80.

In conclusion, investigations of the prostate periphery show that the comparison compounds A-I and A-2, which respectively have a C^- and C^^h<y>chlorocarbon residue, are inactive because they give a result which is analogous to the control results. This lack of activity for the products A-I and A-2 is confirmed by the statistical examination in relation to control animals according to the chi 2 method. Within the series of epoxyalkanes with formula I, it is further seen that the activity at prostate level begins to become apparent when the hydrocarbon residue A comprises at least 15 C atoms» The products according to examples 1-3 are significantly active.

Claims (1)

Analogous process for the preparation of epoxyalkanes with therapeutic effect, in particular for the treatment of prostate hypertrophy, with general formula where A denotes an alkylene residue with 15-20 C atoms, characterized by reacting the alkene with the formula where A has the meaning as indicated above, with a peracid in excess in relation to the stoichiometric ratio, at a temperature between 15 and 25°C.