FI60001B - FOERFARANDE FOER FRAMSTAELLNING AV NYA EPOXALKANER VILKA AER TERAPEUTISKT ANVAENDBARA I SYNNERHET VID BEHANDLING AV SEKRETORISKA PROSTATABESVAER - Google Patents

Description

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Mj ^ (11) UTLÄGGNINGSSKRIFT 6U001 '(51) Kv.lk.3 / lnt.CI.3 c 07 D 303/04 FINLAND - FINLAND (21) •' «•" «“ »'' • mu.-Ι * Μ · η «** ΒΙ» ηΙη | 750692 (22) H> k «ml * pllvi - An * öknln (vd * g 11.03-75 (23) Alkuptlvi —Glltl {h« tsdtg 11.03.75 (41) Translators JulklMksI - Bllvlt offuntllf 12.09.75

Patent and Registration Office .,., , . . ., u „, _. . (44) Date of issue of the publication number .— .-, n- □,

Patent and registration authorities Ansöku utltgd och vcl.skriftan publtcarad 31. ϋ (. Öi (32) (33) (31) Pyydetty etuoikeus — Begird prloritet 11.03.7 ^

Engl anti-England (GB) 10683 (71) IRCEBA, 38, rue de Lisbonne, 75008 Paris, France-France (FR) (72) Jacques Debat, Paris, France-France (FR) (7 ^) Oy Kolster Ab ( 5U) A process for the preparation of novel epoxyalkanes which are therapeutically useful, in particular in the treatment of secretory disorders of the prostate

The invention relates to a process for the preparation of novel epoxy alkanes of formula (i) below. These compounds can be used in medicine, especially in secretory disorders of the prostate, especially in the treatment of adenoma.

GB 1 k59 233 discloses that upper alkanols having 16 carbon atoms or more can be used in the treatment of secretory disorders of the prostate and especially in the context of prostate adenoma. It has now been found that 1,2- and 2,3-epoxyalkanes of the formula CH 2 -CH-CH-R (I) 0 wherein R is H or CH 3 and R x is (CH 2) 2, (CH 2 g , (CH2) 19 or (CH2) 2Q, are as effective compounds as said upper alkanols.

60001 2

The compounds of formula (i) are prepared by a method known per se by reacting the corresponding alkene with peracid. The process is based on reacting one mole of an alkene of the formula CH 2 -R 1 -CH = CH-R (II) in which R 1 and R 2 have the same meaning as above, with more than one mole of peracid at room temperature (15-25 ° C). .

Suitable peracids for this purpose are, in particular, peracetic acid, perbenzoic acid, phthalic acid, metachloroperbenzoic acid. These peracids are equivalent, however, it has been found that the use of metachloroperbenzoic acid is most advantageous from an industrial point of view, especially in terms of the purity of the final product, as the metachlorobenzoic acid formed during the reaction is easier to remove than other mentioned acids.

In the process according to the application, 1.1 moles of metachloroperbenzoic acid and 1 mole of alkene II are reacted in an inert solvent, for example methylene chloride.

The 1-alkenes of formula (II) are commercial products. In particular, 2-alkenes of formula (II) may be prepared from (a) treatment of the corresponding 2-alkanols with HgSO 4, or (b) reaction of the organomagnesium compound III with 1-chloro-2-butene (IV) according to the following formula

Br-Mg-R'1-CH3 + C1-CH2-CH = CH-CH3 -> (III) (IV) ch3-ch = ch-ch2-r'1-ch3 wherein R '^ is a hydrocarbon residue containing at least 1 carbon atom.

The 1,2- and 2,3-epoxyalkanes of formula (i) are novel compounds and have interesting therapeutic properties. It is already known e.g.

19 Hydrocarbon-Containing Epoxy Time: A pheromone from the insect Lepidoptera, cis-7,8-epoxy-2-methyl-octadecane, secreted by Porthetria dysfarrows to attract dogs to a favorable scene for intra-species mating. This pheromone is a laboratory curiosity. After isolating it, Beroza has shown its structure in J. of the Association of Official Analytical 3 60001

Chemists (1971) »5 ^, 251, and Eiter has synthesized the structure by Angew. Chem. Internat., (English edition), (1972), 11, 60.

Pharmaceutical compositions are prepared which, when combined with a physiologically acceptable diluent, contain a therapeutically effective amount of at least one compound of formula (i). Physiologically acceptable liquid or solid carriers can be used to prepare these pharmaceutical compositions containing the upper epoxyalkanes prepared in accordance with the invention. Of the solid preparations, mention may be made in particular of powders, compresses, granules, capsules, dragees, gels and suppositories.

The solid carrier used may be one or more substances which act as diluents, perfumes, solubilizers, lubricants, melting agents, surfactants, or compression disintegrants. The solid carrier can also contain one or more encapsulating agents.

The compound active as a powder is incorporated into a solid finely divided carrier. To prepare extrudates, the active compound is mixed in suitable proportions with a carrier having suitable melting properties. Powders and compacts contain from 1 to 90% by weight of active ingredient. Solid carriers which may be mentioned are, in particular, magnesium carbonate, magnesium stearate, talc, sucrose, glucose, lactose, pectin, dextrin, starch, gelatin, dragant gum, methylcellulose, sodium carboxymethylcellulose, low melting waxes and cocoa butter.

Liquid form preparations include solutions, suspensions, and emulsions. The carrier in this case may be an aqueous solution of polyethylene glycol or a mixture of polypropylene glycol on the one hand and an oil, in particular olive oil, on the other.

Aqueous suspensions for oral use are prepared by dispersing the active compound in finely divided water in water to which is added a viscous substance, natural rubber or synthetic rubber, resin, etc., e.g., gum arabic, ion exchange resin, methylcellulose, carboxymethylcellulose, or any of the foregoing.

The results of the pharmacological tests performed are summarized below. The histological transformations induced in the epithelium of adult rats were examined. It was found that the products according to the invention are able to stimulate the prostate function of adult rats when the rats have been treated with the new substances orally for 15 days to 3 months at relatively low doses, as a significant improvement can be observed e.g. per kg of animal weight per day.

60001 ι »

The compounds prepared according to the invention were denoted by the numbers I-IV; in addition, two reference compounds A-1 (1,2-epoxydodecane) and A-2 (1,2-epoxyhexadecane) were studied. The chemical and physical properties of the tested compounds are shown in Table 1.

Methodology of Pharmacological Experiments Adult rats of about 9 months of age were administered the epoxyalkane to be tested daily at the above dose in a diluent such as olive oil for the above time period. Control rats were given diluent only.

In the experiment, animals were treated 6 days a week for 7 weeks. Each epoxyalkane was administered as a solution of 0.1 ml / 100 g animal weight, i.e. at a concentration of 0.5 g product / liter oil.

At the end of the experiment, control and treated animals were sacrificed, the abdominal portion of the prostate was isolated, fixed in alcohol, and examined histologically.

Prostate circumferential surgeries were rated according to the following scale:

Epithelium + 1

The peripheral epithelial growth of the key glands appears cubic and covers more than half of the outer surface of the prostate.

Epithelium + 2

Epithelial growth is particularly cylindrical in nature.

Epithelium + 3

Epithelium similar throughout to the peripheral glands.

Epithelium +

Epithelial overgrowth and hypersecretion (this "degree" was not observed in the experiments performed).

The results for the abdominal prostate after the animals of the control group and the treated animals were killed after receiving the above-mentioned doses of Compounds I-IV according to the invention and Reference Compounds A-1 and A-2 are shown in Table II.

In summary, examination of the prostate circumference from the abdominal section of the prostate reveals that Reference Compounds A-1 and A-2, in which A contains 9 and 13 carbon atoms, are ineffective because they give a similar result to the animals in the control group.

Compounds I-IV prepared according to the invention are significantly active.

The following Examples 1 and 2 each illustrate the preparation of 2,3-epoxyecosanane from 2-eicosene by oxidation with metachloroperbenzoic acid.

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Example 1 6 g of 2-eicosene was dissolved in 100 cm of methylene chloride, and this solution was poured into a flask equipped with a condenser and a stirrer (the flask can be immersed in either a cooling or heating bath, as the case may be).

1 * g of metachloroperbenzoic acid was added gradually over a period of about 30 minutes, i.e. in a molar excess of about 10% over the stoichiometric amount. The mixture was kept under stirring at room temperature (15-25 ° C) with a stream of water during the addition step, after which it was allowed to stand for ten hours at room temperature. Finally, it was refluxed for 2 hours to remove peracid.

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100 g / l solution of sodium sulphite, then 100 g of a 100 g / l solution of sodium bicarbonate and finally with water until the pH was above 6. The organic solution was dried over calcium chloride and then distilled to remove methylene chloride. 1.8 g of product were obtained, i.e. crude yield = j6%.

The product was purified by column chromatography. A glass column 3.5 cm in diameter was charged with 100 g of silica gel for chromatography suspended in petroleum ether. The crude product from the end of the column dissolved in a minimum volume of petroleum ether was then added. The column was then washed with petroleum ether to recover 0.2 g of discarded product from 1 liter of wash solvent. It was then eluted with a 90:10 mixture of petroleum ether and diethyl ether. 500 g of this eluate gave 1.5 g of 2,3-epoxyecosanane. Melting point 10 ° C. Boiling point / 15 mm Hg = 200-210 ° C.

Example 2 7 g of 2-eicosene were dissolved in 20 g of peracetic acid. The ethylene group was oxidized to the epoxide in the cold. The acetic acid formed was neutralized in 10 ml of water with 1N NaOH solution. The aqueous solution thus obtained was extracted with ether. The ether was removed to give 6 g of 2,3-epoxy-eicosan, which was purified as described above. Melting point 10 ° C. Boiling point / 15 mm Hg = 200-210 ° C.

Example 3 A 100 ml flask equipped with a condenser and a stirrer heated in an oil bath was charged with 25 g of a 60 wt% solution of sulfuric acid. To the flask was added 7 g of 2-eicosanol (0.0231 moles) and refluxed at 100-110 ° C for 16 hours.

7 60001

After the reaction mixture was cooled, 200 ml of chloroform was extracted, the chloroform solution was washed twice with 150 ml of 100 g / l sodium carbonate solution and then several times with water until the pH was above 6. The chloroform solution was dried over calcium chloride, then the chloroform was removed by distillation, and finally, the residue was distilled at about 180 ° C and 15 mm Hg under reduced pressure. Thus 6 g of 2-eicosene were obtained, i.e. a yield of 85% *

Example H

61 g of 1-bromohexadecane were dissolved in 100 ml of dry ether. To the flask was added 1+, 86 g of magnesium turnings. These amounts are stoichiometric.

The Grignard reaction was started in the usual manner with an iodine crystal, and when the reaction was started, it was externally controlled by means of an ice bath so that the reaction took place at reflux temperature. The reaction ended spontaneously after a few minutes.

After completion of the reaction, a cold solution of 18 g of 1-chloro-2-butene in 20 ml of dry ether was added. The exothermic reaction was maintained at natural reflux temperature, and the reaction was complete after about a quarter of an hour.

The cooled solution was washed with water containing excess hydrochloric acid to dissolve the magnesium oxide formed. The ether solution was collected by decantation and dried. The ethylene compound, namely 2-eicosene, was obtained quantitatively and purified by distillation at 160 ° C and 1 mm Hg under reduced pressure.

After removal of the initial and post-distillates, 7 g of product were recovered, the composition and purity of which are readily ascertained by nuclear magnetic resonance spectroscopy.

The following Table I lists a few epoxyalkanes of formula (i) as well as, for comparison, the two compounds A-1 and A-2. All of these compounds were prepared using the method of Example 1. For memory, 2,3-epoxyecosanane (Examples 1 and 2) is also shown in this table (Compound II).

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