DE1926043C3 - New estrogen ethers and methods of making them - Google Patents

Description

in which R for a 4 '- (lower) -alkoxytetrahydropyran-4'-yloxy or a 5', 6'-dihydro-2H-pyran-4'-yloxy group and R ₁ for hydroxy, acyloxy (with 1 to ^ carbon atoms ), lower alkoxy, lower cycloalkoxy or tetrahydropyran-2'-yloxy.

2. Process for the preparation of the compounds of the formula I according to claim 1, characterized in that that he

a) estrone is alkylated or acylated in a manner known per se in the 3-position corresponding to the meaning of R ₁ , then the ketogen group in the 17-position is stirred into a 17 ^ -hydroxy group in a manner known per se and this is in the presence of an acidic catalyst and an inert solvent is reacted with a 4'-alkoxy-5 ', 6'-dihydro-2H-pyran, whereupon an existing 3-acyl group is optionally saponified, or

b) estradiol in a manner known per se selectively on the hydroxyl group in the 3-position corresponding to the meaning of R ₁ vathei t or esterified and then, as indicated under a), introduces the radical R in the 17-position and optionally an ester group present in the 3-position saponified.

3. Medicinal product containing a compound of formula 1 according to claim 1.

The new estrogen ethers possess the general one formula

in which R stands for a 4 '- (lower) -alkoxytetrahydropyran-4'-yloxy- or a 5 ', 6'-dihydro-2H-pyran-4'-yloxy group and R, for hydroxy, acyloxy (with up to 12 carbon atoms), lower alkoxy, lower Cycloalkoxy or tetrahydropyran ^ '- yloxy stand. where R 'is lower alkyl.

(I) The term "lower alkoxy" refers to

Radicals having 1 to 6 carbon atoms, e.g. B methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy or amyloxy, hexaloxy, and the term "lower alkyl" for methyl, ethyl, Propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, amyl or hexyl,

The acyloxy groups that may be present are those which differ from those usually used in steroid technology Derive the acids used. These hydrocarbyl carboxylic acids are both substituted and also unsubstituted acids that are completely saturated or have a different degree of unsaturated Bonds (including aromatic bonds)

can have. They can be straight, branched or cyclic and contain 1 to 12 carbon atoms. Furthermore, they can by functional groups, such as. B. hydroxyl groups, alkoxy groups with up to 6 carbon atoms, acyloxy groups with up to 12 carbon atoms, nitro groups, amino groups, Halogen atoms, etc., bonded to the hydrocarbon main chain. Typical hydrolyzable esters thus include acetate, propionate, butyrate, valerate, caproate, oenanthate, Caprylate, pelargonate, acrylate, undecanoate, phenoxyacetate, benzoate, phenyl acetate, diphenyl acetate, Diethyl acetate, trimethyl acetate, tert-butyl acetate, trimethyl hexanoate, methyl neopentyl acetate, cyclohexyl acetate, Cyclopentyl propionate, adamantoate, glycolate, methoxyacetate, hemisuccinate, hemiadipate, hemi- / ty> -dimethyl glutarate, acetoxyacetate. 2-chloro-4-nitrobenzoate, aminoacetate, diethylaminoacetate, piperidinoacetate, / i-chloropropionate, trichloroacetate or / i-chlorobutyrate.

The new steroid ethers have high oral anti-fertility and estrogenic potency. the Compounds can be used parenterally in the same manner and dosage as estradiol; at When administered orally, they are used in the same way as ethinyl estradiol. The invention Compounds can be in any conventional pharmaceutical form, especially in a for oral administration suitable form. z. B. solid, as pills, powder, capsules, tablets etc., or liquid, administered as a syrup, emulsion, suspension, etc.

One of the most effective estrogenic agents known is estradiol, a natural hormone. Because this connection however, has very little oral efficacy, its use has been other than by parenteral administration impractical. Oral estrogenic agents known to date have been compounds with a structure other than estradiol (e.g. ethinyl estradiol) that the body do not use a natural hormone such as estradiol. In contrast, the new connections orally effective and, when administered orally, deliver estradiol to the body.

In anti-fertility experiments, rats smoke according to the procedure in "Journal of Reproduction and Fertility «, 10, 105 (1965) (with the modification of Use of sesain oil instead of an aqueous one Carrier), gives a daily oral dose of less than 6.2 μg 17 / f- (4'-methoxytetrahydropyran-4'-yloxy) -östra-1,3,5 (10) -trien-3-ol 100% inhibition; an oral dose is required to achieve the same effect from at least 200 to 400 μg estradiol necessary, what the much greater effectiveness of i7 / i- (4 ' - Methoxytetrahydropyran - 4 '- yloxy) - estral, 3,5 (10) -trien-3-ol to an orally active source of estradiol.

estrogenic experiments according to the method described in "Endocrinology", 55, 65 (1954) (with the modification the use of corn oil in place of an aqueous vehicle, treatment 3, and not 4 days) gave the following oral activities for 17 / ¥ - (4'-methoxytetrahydropyran-4'-yloxy) -estra-1,3,5 (10) -trien-3-ol compared to estradiol:

Medium Average uterine ratio

Total dose, g

Kon- 44 ± 0.02

troll

B 0.56 i 0.04 0.5

A 0.67 ± 0.04 0.2

B 0.94 ± 0.15 1.0

A 1.11 ± 0.08 0.4

B 1.11 ± 0.10 2.0

A 1.48 ± 0.13 0.8

B 1.10 ± 0.14 4.0

A 2.16 ± 0.10 1.6

These data show that 17 / f- (4'-methoxytetrahydropyran - 4 '- yloxy) - oestra -1,3,5 (10) - triene - 3 - oil about 500% more effective than estradiol when used as an oral estrogen. Oral anti-fertility effects of 17 / H4'-methoxytetrahydropyran-4'-yloxy) -estra-1,3,5 (10) -trien-3-ol is even more remarkable, with oral efficacy at least 32 times greater than the oral potency of estradiol.

The new 4 '- (low) -alkoxytetrahydropyran-4'-yl ethers according to the invention and 5 ', 6'-dihydro-2H-pyran-4'-yl ethers are prepared by reacting the steroid nucleus with a reactive hydroxyl group in the 17ß-position with an overburden a 4 '- (lower) alkoxy - 5', 6 '- dihydro - 2 H - pyran. Free basic compounds containing hydroxyl groups, which are stable under acidic conditions can, under practically anhydrous conditions, with a Excess of the alkoxydihydropyran in the presence of a small amount of an acidic catalyst such as Hydrogen chloride, p-toluenesulfonic acid, boron trifluoroetherate etc., alone or together with an inert, organic solvent such as benzene, diethyl ether, Methyl chloride, etc., at a temperature from 0 ° C to about 50 ° C, preferably at room temperature (about 25 C) reacted for about 1 to 72 hours will.

Then the alkoxy tetrahydropyranyl ether steroid isolated in the usual way. After the reaction has ended, the reaction mixture is z. B. with a Treated a small amount of pyridine and then in a dilute 10% aqueous sodium bicarbonate solution poured with stirring, and the product is extracted with an organic, with water Immiscible solvents, such as diethyl ether, methylene chloride, hexane, etc., isolated. The organic one Extract is made by removing the organic solvent under reduced pressure at a Concentrated temperature below 40 ° C. The ether product can be obtained by recrystallization or chromatography be cleaned on neutral clay.

The implementation of the 17 / i-hydroxy compounds described with 4 '- (lower) -alkoxy-5', 6'-dihydro-2H-pyran according to the methods given for formation of the 4 '- (lower) -alkoxytetrahydropyran-4'-yl ether according to the invention can also use a second series of ethers, i.e. 5 ', 6'-dihydro-2H-pyran-4'-yl ether of the starting materials. This second ether group corresponds to the compounds of formula 1, in which R sees for a 5 ', 6'-dihydro-2 H-pyran-4'-yloxy group. Hydrocarbon solvents as reaction medium, higher catalyst concentrations and longer reaction times increase the yield the 5 \ 6'-dihydro-2 H-pyran-4'-yloxy compounds; the use of ether or tetrahydrofuran solvents, lower catalyst concentrations and shorter reaction times increase the yield of 4 '- (low) -alkoxytetrahydropyran-4'-yloxy compounds. This second group of compounds can be separated from the reaction products by conventional chromatographic methods.

Those used to form the ethers of the invention 4 '- (lower) -alkoxy-5', 6'-dihydro-2H-pyrans can be prepared by known processes will. So z. B. Tetrahydro-4'-pyrone with a primary or secondary alkanol under acidic conditions implemented to form the intermediate product 4 ', 4'-di- {low) -alkoxytetrahydropyran be that after distillation with an acid such as toluenesulfonic acid or mesitylenesulfonic acid, the Provides 4 '- (lower) -alkoxy-5', 6'-dihydro-2H-pyran product. One such procedure is in Joarn. At the. Chem. Soc., 89, 3367 (1967). The lower alk anol is preferably methanol, but other lower alcohols such as ethanol, propanol can also be used. isopropanol, Butanol, isobutanol, pentanol, amyl alcohol, hexanol, etc., to form the corresponding Pyrans such as 4'-methoxy-5 ', 6'-dihydro-2H-pyran, 4'-ethoxy-5', 6'-dihydro-2H-pyran, etc. are used will.

The new ethers are expediently made from oestrone. This can first be known in itself Way to be etherified or esterified at the 3-hydroxy group.

The etherification can, for. B. be done by the estrone with sodium hydride and then z. B. with cyclopentyl bromide in benzene under reflux for Treated formation of 3-cyclopentyl ether, or by the oestrone is reacted in a potassium hydroxide solution containing dimethyl sulfate, and then neutralized with acetic acid to give the 3-methoxyestrone. The products received can then be converted into the corresponding 17 // hydroxy derivative by the usual methods.

The oestrone can also be used to protect the free hydroxy group at C-3 by conventional methods

acylate. The acylation can e.g. B. after treatment with an appropriate acylating agent, such as acetic anhydride or another anhydride in Pyridine, to form the corresponding acylated products, whereupon the 17-keto group in the 17 / i-hydroxy group is converted.

The corresponding 17 / i-hydroxy compounds can then be mixed with an excess of 4 '- (low) -alkoxydihydro-2H-pyran in the presence of an acidic catalyst to form the corresponding 1 1 (1 - (4' - low - alkoxytetrahyuropyran - 4 '- yloxy) - and 17 / i- (5', 6'-dihydro-2H-pyran-4'-yloxy) steroids of the formula I. For example, estral, 3 , 5 (10) -trien-3-ol-17-one (estron) are etherified to 3-methoxyestral, 3,5 (10) -trien-17-one, whereupon with sodium borohydride in aqueous tetrahydrofuran to 3'-methoxyestra- 1,3,5 (10) -trien-17 / i-ol and 4'-methoxy-5 ', 6'-dihydro-2H-pyran to form 3 - methoxy - 1 1 / i - (4 '- methoxyteirahydropyran-4' - yloxy) - oestra - 1,3,5 (10) - triene and 3 - methoxy- \ l (i - (5 ', 6' - dihydro - 2H - pyran - 4 '- yloxy) - Oestral, 3,5 (10) -triene is converted, oestra-1,3,5 (10) -triene-3,17-diol (oestradiol) can also be mixed with one molar equivalent of acetic anhydride to form a mixture of the 3- Acetoxy and 17 / <- acetoxy compounds acylated w earth. The 3-acetoxy compound can be separated off by conventional chromatography on neutral clay and then with 4'-ethoxydihydro-2 H-pyran z. B. in the presence of an acidic catalyst, such as hydrochloric acid, to form 3-acetoxy-17 / i - (4 '- ethoxytctrahydropyran - 4' - yloxy) - oestra-1.3.5 (1O) -triene and 3-aretoxy-17 / f- (5 \ 6'-dihydro-2H-pyran-4'-yl <' ¹ > y) -östra-1,3,5 (10) -triene can be converted.

The ester groups in the 3-position of the compounds obtained can be hydrolyzed into the corresponding hydroxyl groups by customary processes.

The following examples illustrate the present invention without restricting it.

example 1

40

a) 2 ecm dihydropyran became a solution from Ig östra-1,3,5 (10) -trien-3-ol-17-one in 15 cm Benzene added. To remove moisture, about 1 ecm was distilled off, then it was cooled down. Solution added 0.4 g of p-toluenesulfonic acid. This mixture was allowed to stand for 4 days at room temperature and then with an aqueous sodium carbonate solution and water, dried and evaporated. The residue became more neutral Clay chromatographs eluting with hexane; so one obtained S-tetrahydropyran ^ '- yloxyöstra-1.3,5 (10) -trien-17-one. which was recrystallized from pentane.

b) A solution of 1 g of 3- (Te: rahydropyran-2'-yloxy) -östra-1,3,5 (10) -trien-17-one in 50 ecm tetrahydrofuran was stirred within 30 minutes added to a suspension of 1 g of lithium aluminum hydride in 50 ecm of anhydrous tetrahydrofuran and this mixture was heated to reflux for 2 hours. 5 ecm of ethyl acetate were carefully added to the mixture and added 2 ecm of water. Sodium sulfate was then added, the mixture filtered and the like obtained solid washed with hot ethyl acetate. The combined organic solutions were then evaporated and gave 3- (tetrahydropyran-2'-yloxy) -östra-1,3,5 (10) -trien-17 // - ol, which was further purified by recrystallization from acetone / hexane.

c) Was the method according to a) with the compound obtained according to b) using 4'-methoxy-5 ', 6'-dihydro-2H-pyran repeated, -o received one 3- {tetrahydropyran-2'-yloxy) -17f> '- (4'-methoxytetrahydropyran - 4 - yloxy) - östra -1,3.5 (10) - triene, oil.

Example 2

a) Was the procedure of Example 1 a) using 4'-methoxy-5 ', 6'-dihydro-2H-pyran and 3-acetoxy-oestra-1,3,5 (10) -triene-17f; -ol carried out (prepared according to Example 1 b) from the corresponding 17-one), the 3-aceloxy- 1 7β - (4 '- methoxytetrahydropyran - 4' - yloxy) - öslral, 3.5 (10} - trien.

b) Becomes a refluxing solution of 1 g of this compound in 30 ecm of methanol within a solution of 0.57 g of potassium hydroxide for 30 minutes in 0.2 ecm of water and 2.5 ecm of methanol were added under nitrogen and the reaction mixture for 2 hours heated to reflux, then cooled, neutralized with dilute acetic acid and reduced under reduced pressure Concentrated under pressure, a solid is obtained after adding water, which is filtered off and dried will. It is 17fi- (4'-methoxytetrahydropyran-4'-yloxy-1,3,5 (10) -trien-3-ol. F. = 224 to 226 C.

Example 3

If the process according to Example 2a) was carried out using the corresponding 3-propionyloxy compounds, the 3-propionyloxy -1 T [i - (4 '- methoxytetrahydropyran - 4' - y lox γ) -östra-U, 5 (10Mrien . F. = 100 to 101 C.

Example 4

Example 3 using the 3- [4'-methylbicyclo - (2 \ 2 ', 2') - oct - 2 '- en - yl - carboxylates] are used, the corresponding 17,; - ether is obtained. F. = 152 to 154 ° C.

Example 5

a) A solution of 1 chemical equivalent oestral, 3,5 (10) -trien-3-ol-17-one in 30 ecm benzene was heated to reflux, with removal of moisture about 2 ecm were distilled off. The mixture was cooled to room temperature, then were 2 chemical equivalents of sodium hydride added followed by 2 chemical equivalents of cyclopentyl bromide dripped into 10 ecm benzene within 20 minutes. The mixture was 20 hours heated to reflux, whereupon the precipitate of sodium bromide is filtered off and the organic phase dried and evaporated; so obtained 3-Cyclopentoxyöstra-1,3,5 (10) -trien-17-one, the by Recrystallization from pentane was further purified.

b) Was this compound reduced as in Example 1 b) and then according to Example 1 a) with 4'-methoxy-5 ', 6'-dihydro-2H-pyran reacted, so one obtained oestr-1,3,5 (10) -triene-3-cyclopentyloxy-17fi- (4'-methoxytctrahydropyran - 4 '- yl) - ether. F. = 100.5 to 101.5 ° C.

Example 6

2 ecm of 4'-methoxy-5 ', 6'-dihydro-2H-pyran were added to a solution of 1 g of 3-propionyloxy-estral, 3,5 (10) -lrien-17-ol in 15 ecm of benzene added. To remove moisture, about 1 ecm was

distilled, then 0.4 g of residue was added to the cooled solution on neutral clay

p-Toluenesulfonic acid added. This mixture was graphed, eluting with hexane

Let stand for 4 days at room temperature and one \ l (i - (5 ', 6' - dihydro - 2H - pyran ->

then with aqueous sodium carbonate solution and Was-3-propionylDxy-oestra-1,3,5 (10) -triene, the a

scr washed, dried and evaporated. The 5 was recrystallized. F. = 108 to 110 ° <I.

Claims (1)

Patent claims:
1. New estrogenic ther of the general formula The new compounds thus contain a
\ OR ' or -Group