DE1961984A1 - Steroids of the estrogen series with long-term effects - Google Patents

Description

description
to the patent application

WAHNER ₁ -LAlIBERi PHARMACEUTICAL COMPANY
201 Tabor Road, Morris Plains, New Jersey »USA»

"concerning
Long-term steroids of the estrogen series

The invention relates to novel steroids of the
Long-term estrogen series. In particular, the invention relates to C ₇ to Cp ₀ -IT cycloalkenyl ethers of oestradiol-3-esters and novel preparations with long-lasting contraceptive and estrogenic effects, which _{contain the mentioned C 7} to Cpq-IT-cycloalkenyl ethers of oestradiol-3-esters as active ingredients.

The compounds according to the invention correspond to the general one Formula?

CH ₀ -CH,

c. c

(D,

009828/1903

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1A-5Z 228

- 2 - ""

wherein R is an unsubstituted alkanoyl group nit straight or branched chain, a Phenylalkanoylgruppe, a Cycloalkylalkanoylgruppe with "up to 10 carbon atoms or a lower optionally substituted by one Alkyigruppe, a lower Aikoxygruppe, a CycloallEoxygruppe _s represents a nitro group or a halogen atom substituted benzoyl group and η for is an integer from 1 to 23 inclusive.

Groups with 1 to 5 carbon atoms are considered to be "low" here referred to in the molecule.

Typical examples of the esters mentioned are: the acetyl, Propionyl, butyryl, isobutyryl, valeryl, isovaleryl, Trimethylacetyl-, caproyl-, önanthoy-, capryloyl-, phenylacetyl-, a-phenylpropionyl-, ß-phenylpropionyl-, a-phenylbutyryl-, ß-Phenylbutyf yl-, Cy c 1 op en tylacetyl-, Gycloliexylacetyl-, a-Cyclopentylpropionyl- ', ß-Cyclopentylpropioiiyl- and benzoyl esters.

Typical examples of substituents on BeBZolring, the are preferably in the para position: Ketliyl, Ethyl j Propyl, Hethoxy, Ethoxy, Propoxy, Gjclopentyloxy, Cyclohexyloxy, fluorine and chlorine.

It has been found that the compounds according to the invention interesting pharmacological properties on ^ eiseü, which they as uterotrophic (an enlargement of the uterus be>; irkeEde) / and contraceptives suitable for Farjablütlera do. They are suitable for both oral and parenteral e Administration suitable. Also, thanks to their good

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Solubility in oil can be administered in a single dose and then have a long-lasting effect.

According to the invention, the · new compounds which are a long-term contraceptive and estrogenic effects used as active ingredients in medicinal products in which they are mixed with an inert, solid or liquid, drug-usable carriers are available.

Such drugs contain the active ingredient in an amount of about 0.1 to about 100 mg, preferably from 0.5 * to 20 mg and can be in the form of tablets, powders, capsules, ampoules or sachets with several single doses or in other pharmaceutical forms suitable for oral or parenteral administration be.

The following tests were carried out to determine the pharmacological data:

A) Determination of the uterotrophic long-term effect

The compounds to be tested were dissolved in sesame oil and in a single dose of 0.05 / uHol rats, which after removal the ovaries weighed about 45 to 50 g, subcutaneously administered. At the end of the 4th, 8th and 12th weeks after administration the hats were killed and the uterine coviclit of the treated animals and the untreated comparison animals determined on a torsion spring balance. The increase in the weight of the uterus was regarded as an indication of the estrogenic effects. '.

1A-37 228 - 4. -

The results are compiled in Table I, in which the uterotrophic action of some representative compounds according to the invention is compared with that of estradiol-17-oenanthate, which is known as one of the estrogenic agents with the highest long-term effects.

TABLE I:

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TABEL

Uterus weight in mg after.

CD
CO
K »
OO

untreated Comparison animals oestraaiol-17-oenanthate

Estradiol 5-p-chlorobenzoate 17- (1'-cyclooctenyl) ether

Jp
"> 7- (i'-cyclooctenyl) ether estradiol-3-anisate-17- (1 ^! -Cyclooctenyl) ether Q * stradiol-3-" benzoate 17- (1'-cycloheptenyl) ether estradiol-3 "benzoate -I7-CI ^l -cyclooctenyl) ether estradiol-3-benzcat-17- (1'-cyclononenyl) ether estradiol-3- "benzoate-17- (1'-cyclodecenyl) ether

Qstradiol-3-benzoate

17- (1 ^l -cyclododecenyl) ether

4 weeks

S weeks

19.5 ± 6.3 23.0 ± 1.7

128.5 ~ 5.3 104.4 to 10.5

195.2 i 9.6 164.4 - 13.4

194.3 ^± 7.4 180.5 - 9.5 207.9 - 7.2 174.9 - 16.0

209.3 to 15.7 from 154.1 to 11.9

163.9 i 17.8 159.5 ± 14.6

208.0 t 9.0 162.0 ± 12.4

120.3 ~ 15.5 from 138.2 to 10.2

90.3 i 17.2 165.4 ± 16.6

Continued TABLE I:

- 12 weeks • - -37 228 196 22.5 - 2.01 I.
VJI 198 71.3 ^± 3.76 I. 142.1 ± 8.17 124.7 ± 8.97 118.4 ± 10.30 131.6 *
^± 8.34 * *

Forts, too

TABLE I.

Uterus weight in mg after.

4> weeks

CD CO K> OO

Ostradiol J-benzoate 17-0'-cyclopentadecenyl) ether

Estradiol-3-acetate- (17- (1 ^l -cyclooctenyl) ether Estradiol-3-trimethylace'tat-17- (1'-cyclooctenyljether

Estradiol-3-isobutyrate-17- (1 ^f -cyclooctenyl) ether

Estradiol - ^ - o-chlorobenzoate- ^ 7- (i'-cyclooctenyl) ether

Octradiol 3-m-chlorobenzoate 17- (1'-cyclooctenyl) ether

171.5-12.4 199.3-9.4

181.2 - 27.1

194.3 ± 13.8 146.0 ±. 15.3 163.2 ± 5.2

8 weeks 12th Weeks * ± 19.9 I. 194.8 - 170.4 - ^: 15.2 - 8.1 cn 121.0 - 166.8 - * 148.9 - * 158.8: 157.7 165.0: 187.6 ^: 9.8 - 10.6 • 15.9 - 20.0 - 12.9 - 6.8

* no measurement ro ro

CD

1A «-37 228 - 7 -

From Table I it can be seen that the compounds according to the invention have a greater and longer estrogenic action exercise as the standard connection used for comparison.

In particular, it can be seen from the table that some the compounds according to the invention have uterotrophic activity even 12 weeks after the treatment, which corresponds at least to that which is exercised by the standard 'connection at the end of the 4th week.

B) determination; the contraceptive effectiveness

Contraceptive efficacy was determined in adult female Wistar rats which were approximately 150 to Weighed 170 g. The compounds to be tested were in sesame oil -Dissolved and subcutaneously in a single dose of 0.5 / µmol injected. The next day, the treated animals were caged together with fertile males held until pregnancy occurred and 15 lasted up to 18 days; then the females were transferred to individual cages.

The results of this investigation are summarized in Table II, which corresponds to the situation on the 160th day after administration.

TABLE II:

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TABLE II-

Number of rats

Compound administered

Treated on t60. Day
delt

(Day ^ Zero)

Comparison animals

Estradiol 3-p -chlorobenzoate - ^ - O '-cyclooctenyl) ether

estradiol-3-p-fluorobenzoate-17-0'-cyclooctenyl) ether

Estradiol-5-anisate-17-C ' ¹ ' -cyclooctenyl) ether

untradiol-3-benzoate-17- (1'-cycloheptenyl) -ether

Estradiol 3-benzoate

17- (1'-cyclooctenyl) ether Estradiol 3-benzoate

17- C ' ¹ ' -cyclononenyl) ether

, estradiol-3-bensoate-17 - ('i '-cyclodecenyl) ether

delivered * discarded perishes ** dead not

pregnant

(27.6)

(137.7)

(137

(153.0)

(139.5)

3
1
1
1

1
1

Continued TABLE II:

10 I. CO 6th Γ

5 7 8

ΓΌ Γ0 CD

Continued to TABLE-E II

r- J

Number of rats.

Compound Behan- administered on day 160

delt

(Day delivered * discarded perished ** dead, no
Zero) pregnant

estradiol-3-benzoato "7- (I'-cyclododecenyl) -
° ether 10 - - - 10

oo estradiol-3-acetate

»O 17- (1'-cyclooctenyl) - ^

® ether 10 4 (137.5) 4 - 1 1 ι

- »» estradiol-3-trimethyl-

^β acetate-17- (i'-cyclo-

° octenyl) ether 10 4 (147.5) - 2 1 3. - *

CJ p>

Estradiol-3-isobutyrate- ^ ₁

17_ (1'-cyclooctenyl) - -o

ether 10 3 (122.3). 2 113 i \>

* In brackets the mean number of days from treatment to delivery
** Because of difficult delivery

■ * - »

i. *

CD QD

1A-37 228

- 10 -

From Table II it can be seen that the invention "Compounds, when injected in a single dose of 0.5 / µmole, prevented the entry of one Prevented pregnancy for at least 15 weeks, while at. the control animals gave birth after 4 weeks.

The substances estradiol-3-p-chlorobenzoate 17- (1'-cyclooctenyl) ether gave particularly clear results as well as estradiol-3-benzoate-17- (i'-cyclododecenyl) ether, after their administration, even on the 160th day, none of the 10 test animals was pregnant.

The compounds according to the invention can be prepared by reacting 3-ester estradiol intermediate products the formula:

OH

(II),

where R- has the above meaning with a functional Derivative of a cyclic ketone of the formula:

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(CH ₂ ) _n (III)

^ CH ₂ -CH ₂

where η has the above meaning at temperatures above 70 ^° C.

With "functional derivatives" here are the typical derivatives of the ketones according to formula III with lower, aliphatic ones Alcohols meant. Such functional derivatives are acetals or enol ethers of lower alcohols 1 "to 5 carbon atoms and mixtures thereof and are obtained by reacting the free ketone with a lower alkyl orthoformate, the methyl and ethylenol ether or the dimethyl and diethyl acetals are preferred.

The reaction is carried out under anhydrous conditions, preferably in the presence of an acidic catalyst and in an organic solvent such as benzene, toluene, xylene or dimethylformamide. After about 1 hour the reaction is complete and the end product can be isolated in the usual way, e.g. by neutralization of the catalyst, if present, evaporation of the solvent and recrystallization of the residue a suitable solvent.

The invention also includes novel estradiol-3-esters, the

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act as starting materials for some of the compounds of the invention, and a process for their preparation. These up to now not yet described estradiol-3-esters, namely the compounds of formula II in which R is a by a lower alkyl group, a lower alkoxy group, a cycloalkoxy group, a Nitro group or a halogen atom-substituted benzoyl group represents, are prepared in such a way that estrone is mixed with an esterifying agent derived from a substituted benzoic acid, e.g. with an anhydride or a chloride, treated under usual esterification conditions and the estrogen-3-ester thus obtained with an alkali hydride such as lithium, aluminum or sodium borohydride reduced to the 17-keto group in a 17ß-hydroxy group to convict. '

The examples explain the invention in more detail without restricting it. * '

Manufacturing process I

5 ml of p-chlorobenzoyl chloride are added to a solution of 10 g of estrone in 100 ml of pyridine, which has been cooled to 0 C. The reaction mixture is left to stand overnight at room temperature and then poured into ice water. The precipitate which separated out was filtered off and recrystallized from a mixture of methanol and ethylene chloride. There were 14.2 g of estrone-3-p-chlorobenzoate, mp 199 -. Gained 204 ⁰ C. A completely purified sample of the product melted at 2Λβ * ~ 217 ° C. ; ..-

In the same way, oestrone-3-m-chlorobenzoate, m.p. 212 -

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- 13 -

Erhalben 216 ⁰ C - ° C and estrone-3-o-chlorobenzoate, mp 214th.

Manufacturing process II

To a ⁰ to Q G-cooled solution of 5 g Ösbron in ^ Q ml of pyridine are added to 3 ml p-Pluorbenzoylchlorid. The keakblons mixture is left to stand at room temperature overnight and then poured into ice water. Oestrone-3-p-chlorobenzoate is obtained, which, after recrystallization from methanol / mebyl chloride, melts at 210 to 212.degree.

In the same way one obtains Ösbron-3-m-fluorobenzoate and Oestrone-3-o-fluorobeiizoab.

Manufacturing process III

A solution, cooled to 0 ° C., of 5 S oestrone in ^ O ml of pyridine

• A _y

is treated with 3 ml of p-methoxybenzoyl chloride. Working as above, one obtains oestrone-3-anisate from Pp. 229 231 ^O C.

Oestrone-3-m-methoxybenzoate and oil-trone-3-o-methoxybenzoate can be obtained in the same way.

Manufacturing process IV

By reacting oestrone with p-nitrobenzoyl chloride, p-Cyclopentyloxybenzoyl chloride and p-toluyl chloride are obtained when working as above, oestrone p-nitrobenzoate, oestrone pcyclopentyloxybenzoate or estrone p-toluate.

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Example 1_

A solution of 2 g of sodium borohydride in 10 ml of water is added to a solution of 10 g of estrone 3-p-chlorobenzoate in 320 ml of tetrahydrofuran while stirring. After stirring for a further 3 h, the mixture is treated with 10 ml of 10% acetic acid and evaporated in vacuo. The residue is taken up in water, filtered off and recrystallized from methylene chloride / diethyl ether; 6.3 g of estradiol-3-p-chlorobenzoate, melting point 183-185 ° C., / ~ « J ^ = + 52 ° (dioxane, c = 0.5%) are obtained.

In the same way, estradiol-3-ia-chlorobenzoate is obtained, melting point 166-169 ° C, / "a7f = + 53.5 ° (dioxane, c = 0.5 %) and Öbdil3hlbt F 168 172 ° C / ~ 7 ^ 5

Mp. 166-169C, / a7f = + 53.5 (dioxane, c = 0.5 %) and oesbradiol-3-o-chlorobenzoate, mp. 168-172 ° C, / ~ oc_7 ^ = + 55.5 ( Dioxane, c = 0.5%).

An anhydrous mixture of 2 g of estradiol-3-p-chlorobenzoate and 20 mg of p-töluenesulfonic acid in 700 ml of toluene is mixed with. 2 ml of cyclooctanonmethyleneol ether are added and the mixture is then distilled for 40 minutes. After adding a few drops of pyridine to neutralize the acid catalyst, the mixture is evaporated in vacuo, and the solid residue is taken up in methanol and filtered. After recrystallization from methylene chloride / methanol, 2.13 g of estradiol 3-p-chlorobenzoate-17- (1'-cyclooctenyl) ether, melting point 172-174 ° C., ^ = + 4-7 ° (dioxane, c = 0.5 %) .

In the same manner, estradiol-3-m-chlorobenzoate-17- (i'-cyciöoctenyl) ether, mp. 150 - 152 ⁰ C, / ~ A_7 _D = + 49.8 ° (dioxane, c - 0.5% ) and estradiol-3-c-chlorobenzoate-17- (i'-cyclooctenyl) ether, mp 151 -. 153 ⁰ C / faj- ⁷ ^ ⁴ = + 51 ° (dioxane, c = 0.5 #).

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1A-37 228

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Oestradiol uses / 3-oenanthate or oestradiol-3-caprylate

or estradiol-3-phenylethyl acetate, one obtains estradiol-3-enanthate-17-O'-cyclooctenyl ether, / ~ a_7 _D = + 37-5 ° (dioxane, c = 0.5 / ») or estradiol -3-caprylate-17- (1'-cyclooctenyl) ether, / ~ a_7 _D = + 43 ° (dioxane, c = 0.5%) or estradiol-3-phenylethyl acetate-17-O'-cyclooctenyl) ether , / ~ a_7 _D = + 48.1 ° (dioxane, c = 0.5%).

Example 2

An anhydrous mixture of 2 g of estradiol 3-p-chlorobenzoate, 3 ml of cycloheptanone dimethylacetal, 20 mg of pyridine tosylate and 700 ml of toluene is distilled for 40 minutes. The acidic catalyst is then neutralized with a few drops of pyridine and the mixture is evaporated to dryness in vacuo. After · Recording with methylene chloride / methanol, the residue yields the estradiol-3-p-chlorobenzoate-17- (1'-cycloheptenyl) · ether, Pp 1 $ β -. 158 ° C / "A_7 _D - + 53 ° (dioxane , c = 1 ^c , b).

Example 3

An anhydrous mixture of 2 g estradiol 3-p-chlorobenzoate, 3 ml of cyclononanone methyleneol ether, 20 mg of p-toluenesulfonic acid and 800 ml of toluene is distilled for 40 minutes. The acid catalyst is then with a few drops Pyridine neutralized and the mixture evaporated to dryness in vacuo. The taken up with methylene chloride / ethanol The residue is estradiol 3-p-chlorobenzoate 17- (1'-cyclononenyl) ether.

In the same way one obtains estradiol - ^ - p-chlorobenzoate - "^ - '(1 ^l -cyclododecenyl) ether, m.p. 145-147 ° C, /" a 7 ^ = + 4> °

- 16 009828/1903

1A-3? 228 - 16 -

(Dioxane, c = 0.5%).

7 / ld /

UV: λ 241 -

Max

example

G To a well stirred solution of 10 oestrone-3-p-fluorobenzoate in 320 ml of tetrahydrofuran is added with stirring a solution of 2 g of sodium borohydride in 10 ml of v / ater to _r. After stirring for a further 3 hours, 10 ml of 10% acetic acid are added to the mixture and the mixture is evaporated in vacuo. The residue taken up in water, filtered and recrystallized from methylene chloride / diethyl ether is estradiol-3-p-fluorobenzoate, melting point 210-212 ° C., / ~ oc_7§ ⁴ = + 56 ° (dioxane, c «0.5 %).

Estradiol 3-m-fluorobenzoate is obtained in the same way and oestradipl-3-o-fluorobenzoate.

An anhydrous mixture of 2 g of otradiol-3-p-fluorobenzoate and 20 mg of p-toluenesulfonic acid in 700 ml of toluene is mixed with 2 ml of cyclooctanone methyleneol ether and distilled for 40 minutes. After neutralizing the acid catalyst with a few drops of pyridine, the mixture is evaporated in vacuo and the residue is taken up in methanol and filtered. After crystallization from methylene chloride / methanol one obtains the estradiol-3-p-fluorbe.nzoa.t-17- (i'-cyclooctenyl) ether, Pp 141 -. 144 ⁰ C, / ~ A_7 ^ ⁴ = + 48 ° (dioxane , c '= 0.5 %).

^λ max ²²⁸ -

- 17 -

0 0 9 8 2dB / 1 9 03., _BA d ORIGINAL

1A-37 228

- 17 -

In the same manner, estradiol-3-p-fluorbenzoab-17i (T_ _cyc lodecenyl) ether, mp. 164- 166 ⁰ C, / ~ oc_7jf = + (dioxane, c = 0.5%) and estradiol-3-p -fluorobenzoab-17- (1'-cyclododecenyl) ether, pp. 152 - 154- ⁰ C, Γ ^ -ΐψ = + 48.5 ° (dioxane, c = 0.5 %)

Example 5

To a solution of 10 g of Ösbron-3-anisat in 320 ml of tebrahydrofuran, a solution of 2 g of sodium borohydride in 10 ml of water is added without stirring. After the mixture has been stirred for 3 hours, 10 ml of 10% acetic acid are added and the mixture is evaporated in vacuo. The absorbed in water, filtered and recrystallized from methylene chloride / Diäbhyläther residue is the Ösbradiol-3-anisate, mp 195 -. 197 ⁰ C, / _ ~ <χ_7ψ = + 53 ° (dioxane, c = 0.5%).

In the same way, estradiol 3-m-methoxybenzoate is obtained and estradiol 3-o-methoxybenzoate.

An anhydrous mixture of 2 g of 3-anisate and 20 mg of p-toluenesulfonic acid in 700 ml of toluene is mixed with 2 ml of cyclooctanonemebhylenol ether and distilled for 40 minutes. After adding a few drops of pyridine to the Neubralisabion of the acid catalyst, the mixture is evaporated in vacuo and the solid residue is taken up in methanol and filtered. After recrystallization from methylene chloride / methanol, the ösbradiol-3-anisat-17- (1 '~ cycloocberiyl) ether is obtained, melting point 149 - 151 ° C, / ~ a_7 ^ = f48 ° (dioxane, c = 0.5 %) .

UV: λ 260-261 m / i; E ^ = 461. r '%

max / 1cm ^

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009828/190 3

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1Δ-37 228 - 18 -

In the same way one obtains Üstradiol-3-anisat-17-

(1'-cyclododecenyl) ether, mp. 119 - 121 ⁰ C, / ~ A_7 _D = + 46.8 °

(Dioxane, c = 0.5%).

According to the procedure described above, except that esfcron-3-p-nitrobenzoate is reduced with sodium borohydride is obtained, estradiol-3-p-nitrobenzoate, which with cyclooctanonmethylenoläther is converted to estradiol-3-p-nibrobenzoate-17- (i'-cycloocbenyl) ether, Mp. 220-223 ° C,

/ ~ a 7 = + 44 ° (dioxane, c = 1 %) .

Similarly, estrone ~ 3-p-cyclopentyloxybenzoate is reduced to estradiol-3-p-cyclopentyloxybenzoate, which is converted into estradiol-J-pcyclopentyloxybenzoate 17- (i'-cyclooctenyl) ether, pp. 200 202 ⁰ C, / ~ a_7 _D = + 44 ° (dioxane, c = 1%) is transferred.

In the same manner may be estradiol-3-p-toluate (obtained by reduction of estrone-p-toluate with NaBH ^) with Cyclooctanonmethylenoläther to convert estradiol-3-p-toluate-17- (i'-cyclooctenyl) ether, Pp. 164 - 166 ° C, / ~ a_7 _D = + 5 ^, 5 ° (dioxane, c = 1%) converted.

Example 6

A mixture of 1.5 g of Exalton (cyclopentanedecanone), 2 methanol, 1.5 cm ^ -methyl orthoformate and 15 mg of p-toluenesulfonic acid ;% drd heated to 60 to 70 ° C for 30 minutes. That The reaction mixture, which contains a mixture of methylenol ether and dimethyl acetal from Exalton, is treated with 5 cm- '' dimethylformamide and 2.2 g estradiol-3-p-chloro-

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1A-37 228 - 19 -

benzoate and then kept at about 160 ^° C. for 1 hour under a nitrogen atmosphere. After adding a few drops of pyridine to neutralize the acid catalyst, the mixture is evaporated; after recrystallization of the residue from methanol / IIethylene chloride, the estradiol 3-pchlorobenzoate 17-0'-cyclopentadecenyl ether is obtained.

17-0'-Cyclotridecenyl) ether is obtained in the same way, the 17- (1'-cycloheptadecenyl) ether, the 17- (1'-cycloheneicosenyl) ether and the 17-0'-cyclononacosenyl) ether of estradiol-3-p-chlorobenzOate.

Example 7

An anhydrous mixture of 2 g of estradiol-3-benzoate and * 20 mg p-toluenesulfonic acid in 700 ml T / oluene becomes ty mixed with -2 ml of Cyclooctanmetliylenoläther and 40 minutes distilled. After adding a few drops of pyridine to neutralize the acid catalyst, the mixture becomes evaporated in vacuo and the solid residue taken up in methanol and filtered. After recrystallization from ethylene chloride / methanol one obtains the estradiol-3-benzoate-17-

° C / ~ a7 ⁴ = + 52 °

(1 ^l -cyclooctenyl) ether, m.p. 174-176 ° C, / ~ α_7 ^ = + 52 ^C (dioxane, c «0; 5 ^c / ä).

Example 8

An anhydrous mixture of 2 g of estradiol-3-benzoate, 3 ml Cycloheptanone dimethyl acetal, 20 ms pyridine tosylate and 700 ml. Toluene is distilled for 40 minutes. The acid catalyst is nexitralized with a few drops of pyridine and the genicch

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BATH ORIGINAL

1A-37 228

- 20 -

evaporated to dryness in vacuo. The recorded in methylene chloride / methanol yields the residue üstradiol-3-benzoate-17- (1'-cycloheptenyl) ether, mp 14-9 -. 151 ⁰ C, / ~ α_7 ^ ⁴ = + 57 ° (dioxane, c = 0 , 5%).

In the same way, oestradiol-3-acetate or oestradiol-3-isobutyrate gives oestradiol-3-acetate-17- (1'-cycloheptenyl) ether, / ~ a 7 _π = f 69.7 ° (dioxane, c = 0.5 %) ψ or the estradiol-3-isobutyrate-17- (1'-cycloheptenyl) ether and correspondingly the estradiol-3-benzoate-17- (1'-cyclononenyl) -ether, melting point 151-155 ° C, / "a_7 | ⁴ = + 52.5 ° (dioxane, c = 0.5%), estradiol-3-benzoate-17- (1'-cyclodecenyl) ether, ip. 149 151 ⁰ C, ΓαJ ^ = + 57 ° (dioxane, c = 0.5%), estradiol-3-benzoate-17- (1 ^l -.cyclododecenyl) ether, m.p. 163-166 ° C, / '"a J ^ = + 51 ° (dioxane, c = 0.5%) and estradiol-3-benzoate-17- (i'-cyclodocosenyl) ether, mp IO7 -. 110 ⁰ C, '/' «_ 7d = + 3 °> ⁶ ° ( Dioxane, c = 1%).

Example 9

A mixture of 1.5 g Exalton (cyclopentadecanone), 2 cm '' methanol, 1.5 cm ^ methyl orthoformate and 15 mg p-toluenesulfonic acid is kept at 60 to 70 ° C for 50 minutes. The reaction mixtures containing a mixture of Methylenoläther and exaltonee dimethylacetal is estradiol benzoate 3-mixed with 5 cnr dimethylformamide and 2.2 g, and heated under a nitrogen atmosphere for 1 hour at about 160 ⁰ C. After adding a few drops of pyridine to neutralize the acid catalyst, the mixture is evaporated in vacuo and the residue, after recrystallization from methanol / methylene chloride, gives estradiol-3-benzoate-17- (1'-cyclopentadecenyl) ether, melting point 136-139 ° C, / ~ a_7 ^ = + 40.5 ° (dioxane,

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1A-37 228 - 21 -

The 17 ~ (1'-cyclobridecenyl) -abher is obtained in the same way, the 17- ('' - Cycloheptadecenyl) ether, the 17- (1'-Cycloheneicosen; / l) ether and the 17- (1 '-cyclorioriacosenyl) -abher of Üsbradiol-p-benzoate.

Example 10

An anhydrous mixture of 2 g of estradiol-3-trimebhylacebate and 20 mg of p-toluenesulfonic acid in 700 ml of toluene is desbilled for 40 minutes with 2 ml of cyclooctanone methyleneol ether. After adding a few drops of pyridine to neutralize the acid test laboratory, the mixture is evaporated in vacuo and the solid residue is taken up in hebhanol and filtered. After recrystallization from methylene chloride / methanol, 2.3 g of estradiol - ^ - trimethylacetate-17- (i'-cyclooctenyl) ether, m.p. 155-157 ° C> C * -J ^ = + 56 ° (dioxane, c = 0.5%).

*. *
In the same way, from oestradiol-J-acetate, oesbradiol-3-propionab or oesbradiol-3-isobutyrab, as starting material, oesbradiol-3-acebab-17- (1'-cyclooctenyl) ether, pp. 118 - 120 ⁰ G, / . ~ A_7 ^ = + 64 ° (dioxane, c = 0.5%) and Öctradiol-3-propionate-17 ~ (1'-cycloocbenyl) äbher, mp. 80 - 82 ⁰ G, / "^ = + a__7 61 ° (dioxane, c = 0.5%) or Ösbradiol-3-isobubyrate-17- (i'-cycloocbenyl) ether, m.p. 131 - ^ 33 ° G, Γα.J ^ = + (dioxane, c = 0.5%)

Example 11

An anhydrous mixture of 2 g of estradiol 3-propionate, 3 ml Cyclohexjbanondimethylacetal, 20 mg Pyridinbosylat and 700 ml of toluene is distilled for 40 minutes. The acid catalyst

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BATH ORIGINAL 009323/1903

1A-37 228 - 22 -

The generator is neutralized with a few drops of pyridine and the mixture is evaporated to dryness in vacuo. The residue taken up in methylene chloride / Ilethanol is estradiol-3-propionate-17- (1'-cycloheptenyl) ether.

Example Ί 12

An anhydrous mixture of 2 g of estradiol 3-propionate and 20 mg of p-toluenesulfonic acid in 700 ml of toluene is mixed with 2 ml of cyclododecanone dimethyl acetal and distilled for 40 minutes. Working according to Example 1 gives the estradiol 3-propionate 17- (1'-cyclododecenyl) ether, pp. 117-119 ° C, / ~ ol_7 ^ _{= +} 56.7 ° (dioxane.c = 0.5 %).

In the same way, from oestradiol-3-ananthate, oestradiol-3-caprylate or oestradiol-3-p-toluate as starting material, oestradiol-3-oenanthate-17- (i'-cyclododecenyl) ether or oestradiol-3-caprylate 17- (i'-cyclododecenyl) ether or estradiol-3-p-toluate-17- (i'-cyclododecenyl) ether, melting point 139 142 ⁰ G, / ~ a_7 _D = + 46.3 ° (dioxane, c = 1 %).

Example 13

500 mg of estradiol 3-p-chlorobenzoate 17- (i'-cyclooctenyl) ether are dissolved in 100 ml of sesame oil and the solution is poured into 1 ml ampoules so that each ampoule is 5 mg / ml contains the active ingredient.

Example 14

A solution of 200 mg of estradiol-3-p-chlorobenzoate-17-

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(i'-cyclooctenyl) ether in 100 ml of sesame oil is in ampoules of 1ml filled so that each ampoule contains 2 mg / ml of the active ingredient.

Example 15

500 mg estradiol-3-t> enzoate-17- (1'-cyclooctenyl) ether dissolved in 100 ml of sesame oil and filled the solution into ampoules of 1 ml so that each ampoule contains 5 mg / ml of active ingredient.

Example 16

A solution of 200 mg estradiol-3-t> enzoate-17- (i'-cyclododecenyl) ether 100 ml of sesame oil is filled into 1 ml ampoules so that each ampoule contains 2 mg / ml of active ingredient.

Example 12

500 mg estradiol-3-trimethylacetate-17- (i'-cyclooctenyl) ether are dissolved in 100 ml of sesame oil and the solution is poured into ampoules of 1 ml, so that each ampoule 5 mg / ml "active ingredient contains.

Example 1f3

A solution of 200 mg estradiol 3-isobutyrate 17- (i'-cyclododecenyl) ether in ^"1 OO ml Sesaaöl is filled into vials of 1 ml so that each vial 2 mg / ial active ingredient.

PATENT CLAIMS:

0 098 2 8/1903

Claims (1)

DR. IWG. F. AVUKSTIIOFF DIPU ING. G. PULSE DR-Kr. PBCHMANN DR. ING. D. BEHRENS PATENT Attorney 8 MUNICH8O SCHWEIGEnSTRASSE S TELKFOK 9380 81 mOwchkn 1A-37 PATENT CLAIMS: Compounds of the general formula: CH 0-C EO CH ₂ -CH ₂ (D wherein R is an uncubstituted alkanoyl group with straight or delayed chain, a phenyl alkanoyl group, a Cycloalkylalkanoyl group with up to 10 carbon atoms or a lower alkyl, lower alkoxy, Substituted cycloalkoxy or ITitro group or a halogen atom Is benzoyl group and η is an integer from 1 to 25 inclusive. Compound according to claim Λ , characterized draws that the substituent on the Benaol ring is in para-Stellun.fr. 009828/1903 «If 1A-37 228 3) "Compound according to claim 1 or 2, characterized in that g e k e η η indicates that the substituent on the benzene ring is chlorine, fluorine or the methoxy group. 4) estradiOl 3-p-chlorobenzoate 17- (1'-cyclooctenyl) ether. 5) estradiol 3-m-chlorobenzoate 17 - ('l' -cyclooctenyl) ether. 6) Estradiol 3-o-chlorobenzoate 17- (1'-cyclooctenyl) ether. 7) estradiol 3-p-chlorobenzoate 17 - ('1'-cycloheptenyl) ether. 8) Estradiol-3-p-chlorobenzoate 17- (i'-cyclononenyl) ether. 9) Estradiol 3-p-chlorobenzoate 17 - ('1' -cyclododecenyl) ether. 10) estradiol-3-p-fluorobenzoate-17 - ('1' -cyclooctenyl) - ether. 11) estradiol-3-p-fluorobenzoate-17- (i'-cyclodecenyl) - · ether" 12) Estradiol 3-p-fluorobenzoate 17- (i'-cyclododecenyl) ether. 13) Estradiol-3-anisate-17- (1'-cyclooctenyl) ether. 009828/1903 228 14} üstradiol-3-anisat-17- (1'-cyclododeceny ether. 15) estradiol-3-p-nitrobenzoate-17- (i'-cycloocteiiyl) -ether. 16) estradiol-J-p-cyclopentyloxybenzoate-i? - (1'-cyclooctenyl) ätlier. 17) Estradiol 3 ~ p-toluate 17- (1 ^l -cyclooctenyl) ether. 18) * estradiol-3-p-clilort> enzoate-17- (i'-cyclopentadecenyl) -ether. 19) ößtradiol-3-p -chlorobenzoate-17- (1'-cyclotridecenyl) ethers. 20) Oestradiol-3-p-chlorobenzoate 17- (1 '-cycloiieptadecenyl) -ether. 21) estradiol-3-p-chlorobenzoate-17- (1'-cycloheneicosenyl) -ätüer. 22) estradiol-3-p-ch.lorobenzoate-17- (1'-cyclononacosenyl) -ether. 23) estradiol 3-benzoate 17- (1'- 24) estfadiol-3-benzoate-17- (i ^r -cycloh.eptenyl) -ether. 25) estradiol 3-benzoate 17- (1'-cyclononenyl) ethers. 26) estradiol-3-benzoate 17- ('" ¹ ' -cyclodecenyl) ethers. 009828/1903 ÖRIGHNÄL INSPECTED 1A-37 228 2?) Estradiol-3-t> enzoate-17-0'-cyclododecenyl) ether. 28) estradiol 3-benzoate 17- (1'-cyclopentadecenyl) ether 29) Estradiol 3-benzoate 17- (1'-cyclotridecenyl) ether. 30) estradiol 3-benzoate 17- (' ¹ ' -cycloheptadecenyl O-ether 31) estradiol-3-'benzoate-17- (' ¹ ' -cycloheneicosenyl) -ätlier. 32) estradiol 3-benzoate 17- ( ^y "-cyclononacosenyl) ether. 33) estradiol-3-triethyl acetate 1? - (1'-cycloocteiiyl) ether. . estradiol-3-acetate-17-O'-cyclooctenyl) ether. 35) estradiol 3-propionate 17 - (^ '- cyclooctenyl) ether. 36) estradiol-3-iso "butirate- ^ 7- (i'-cyclooctenyl) ether. 37) estradiol-3-propionate-'i7- (' ⁱ ' -cycloheptenyl) -ether. 38) estradiol-3-propionate ~ ^{17- ('i l} -cyclododecenyl) -ether 39) estradiol-3-enanthate-17- (' ¹ '-c;,'clododecenyl) -ether. 40) estradiol-3-caprylate- ^ 7 - (^ ^f -cyclododecenyl) ether. 41) estradiol-3-acetate-17- (' ¹ ' -cycloheptenyl) -ether. ? 4) estradiol-5-isobxitirat - '! 7- ^{(y' l} -cycloheptenyl) ether. 009828/1903 a * 1A-37 228 43) Estradiol-3-Oenant ^ iat-17- (1'-cyclooctenyl) -ether. 44-) estradiol-3-caprylate-17- (1'-cyclooctenyl) -ether. 45) Estradiol 3-phenylethyl acetate 17- (i'-cyclooctenyl) ether. 46) estradiol 3-p-toluate 17- (1'-cyclododecenyl) ether. 47) estradiol-3-benzoate-17- (1'-cyclodocosenyl) -ät ^ er. · 48) Process for the preparation of the compounds according to to the preceding claims, characterized labeled in drawing net 1 which comprises reacting a compound of the formula: OH (II), wherein E has the meaning given in claim 1, at a temperature above 70 ° C is reacted with a functional derivative of a cyclic ketone of the formula: 009828/1903 1A-37 228 CH OH ₀ - CH, 2 in which η is a number from 1 to 23. 49) Use of the compounds according to one of claims 1 to 47 as active ingredients in agents with long-lasting estrogen and contraceptive effect. 86XXIV47 009828/1903