DE1812838A1 - Contraceptives - Google Patents

Description

Cologne, 22.11.1968 / Ax

EI du Pont de Nemours St Company,
Wilmington, Delaware 19898 (V.St.A.).

Contraceptives

The invention relates to methods of using 4-phenylbioyclo / 2 ~, 2,2 / octane and oot-2-ene-i-carboxylates as antifertility agents for warm-blooded animals and preparations that contain an effective amount of one or more these compounds contain.

Prior to the invention, some of the compounds within the scope of the invention were known. It is known, that these compounds are suitable intermediates in the synthesis of 4-phenyrbieyclo / 2 ~, 2,27ootan-1-amines and their salts are. These amines are powerful antidepressants. Such as the U.S. patent disclosure 3 308 16O shows the use of was within the scope of the Invention falling 4-phenylbicyclo / 2 ~, 2,27octane-1-carboxylic acids the only known use as an intermediate in the production of the corresponding amines.

Of the currently known anti-volatility agents apply the estrogens and progestin as the most effective pregnancy contraceptive agents. Of these pharmaceutical agents, the most common are mixtures of steroids estrogeneη and progestins applied. The application

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this drug causes a pseudo pregnancy and prevents ovulation. To induce this state of pseudopregnancy, these agents are administered orally during a regular part of each meetrual cycle. While they are very effective, this dosage regimen can cause side effects. The most common side effects are similar to the symptoms seen during pregnancy. These side effects include nausea, occasional vomiting, mild dizziness, headache, breast enlargement, and nipple pigmentation, especially during the first cycle that these drugs are taken.

It has been found that the compounds according to the invention in a completely different way for the prevention of Pregnancy can be used. While currently the most commonly used estrogen-progestin mixtures must be taken for a relatively long time prior to coitus, the compounds can be made according to Invention to be taken before or after coitus to prevent pregnancy The exact mechanism of action has not yet been fully clarified, but animal experiments show that most likely the Nidation is prevented in any way.

It thus appears that the compounds according to the invention have a mechanism of action that differs from that of the contraceptives used so far differs significantly.

This new mechanism of action has numerous practical advantages, e.g. ease of use, avoidance taking it for long periods of time, avoiding taking it according to a certain schedule and avoiding a constant one A state of sham pregnancy, which is responsible for numerous side effects.

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The invention relates to a method of prevention the pregnancy "in animals, which is characterized by the fact that the female animal is given an effective amount of a Compound of the following formula administered:

Stand in this formula

A for a single bond or a double bond, R ₁ for hydrogen, HO-, H ₃ CO-, H ₅ C ₂ O-, H ~ C ₃ O, HqC.O

η atom,

or R-C-O, in which R is hydrogen / or an alkyl radical having 1 to 12 carbon atoms, and

R _{9 stands} for -H, an alkyl radical with 1 to 6 carbon atoms or Me-%, where Me ^ is a non-toxic, pharmaceutically acceptable salt-forming cation, for example sodium, potassium, magnesium or ammonium.

Compounds of the above formula, in which A has the abovementioned meaning, R ₁ for hydrogen, HO ₁ H ₃ CO-, H ₅ C ₂ O- and O- are preferred

R-C-O-

stands, where R is an alkyl radical having 1 to 4 carbon atoms is, and Rp is hydrogen, methyl, ethyl, sodium, potassium or ammonium.

According to a further aspect, the invention comprises preparations in which one or more of the invention used 4-phenylbicyclo / 2 ~, 2,27octane or -oct-2-en-1-carboxylate in an amount sufficient to prevent pregnancy with suitable pharmaceutical carriers for the pursuit of warm-blooded animals are mixed.

The compounds that are used in the method according to the invention include 4-hienyl and sub-

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Substituted phenylbicyclo / 2,2,2joctane-1-carboxylic acids and -carboxylic acid esters, 4-phenyl- and substituted Phenylbicyolo / 2 ", 2,2,7oct-2-en-1-carboxylic acids and -carboxylic acid esters and salts of these compounds« In the frame In this specification, the term "phenyl ¹¹ " denotes a phsnyl radical and a phenyl radical which is substituted in the p-position to the point of attachment to the bicyclooctane ring. These compounds have the formula

0-R,

Stand in it

A for a single bond or a double bond, R ₁ for hydrogen, HO-, H ₅ CO-, H ₅ O ₂ O-, H ₇ O ₅ O, H ₉ B ₄ O

or R-C-O-, in which R is hydrogen or an alkyl radical having 1 to 12 carbon atoms, and

R _{2 stands} for -H, an alkyl radical with 1 to 6 carbon atoms or Me ^, where Me ^ is a non-toxic, pharmaceutically acceptable salt-forming cation, for example sodium, potassium, magnesium or ammonium.

Generally these compounds are made from acetophenone or a substituted acetophenone. The desired acetophenone is made with diethyl ethoxymethylene malonate treated in ethyl alcohol in the presence of sodium ethoxide under a nitrogen atmosphere. Then can Bases and solvents can be used. An equivalent amount of sodium hydride, sodium ethoxide or potassium tert-butoxide can in anhydrous dimethylformamide, ethylene glycol dimethyl ether, Diethylene glycol dimethyl ether or Tetrahydrofuran can be used. The intermediate compound thus formed is by treatment with anhydrous Hydrogen fluoride is cyclized to a pyrone.

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1 I'TUP PISI) Il 1 I 111

IIIIIHIIIllllllllM · Wl

The pyrone is dissolved in an inert solvent such as benzene and heated with ethylene under a pressure from 50 to 3000 atmospheres to 150 to 200 ⁰ C, with the corresponding ethyl ester of 4-Phenylbicyolo / S ", 2.2 / oct ~ 2-en-1-carboxylic acid is formed and this ester can be isolated by evaporating the solvent.

If the corresponding bioyclooctane compound is desired, the 4-phenylbicyclo / 2 "', 2,27oct-2-en-1-carboxylic acid ethyl ester in the presence of a hydrogenation catalyst in a suitable solvent, for example in ethanol or a similar acid, to the corresponding 4- Phenylbicy- ä olo / ?, 2,27ootane-1-carboxylic acid aryl ester are reduced.

If the free carboxylic acid is desired, it can be prepared from the ester by alkaline hydrolysis will. The free acid can be precipitated from the solution by acidifying the reaction system and then according to customary methods Methods are isolated.

When the 4-phenylbicyclo / 2 ~, 2,2 / οοΐ-2-βη-1 -carboxylic acid isolated in this way and the octanoic acid is desired, this can be done by catalytic hydrogenation of the 4-Pfeenylbioyolo / ?, 2,27oot-2-enoic acid can be obtained.

The following examples illustrate how the compounds I used for the purposes of the invention fertilize can be produced.

example 1

3-carboethoxy-6-phenyl-2-pyrone

A mixture of 240 parts of acetophenone and 432 parts of diethyl ethoxymethylene malonate is under a nitrogen " atmosphere is added dropwise to a flask containing a solution of 50.6 parts of sodium metal in 2000 parts of absolute Contains alcohol. The mixture is heated under stirring for 2 hours under the reflux and allowed to cool. About 1000 to 1500 parts of alcohol are evaporated

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removed under reduced pressure, after which ether is added in such an amount that a granular or powdery yellow precipitate is formed. The precipitate is filtered off, washed with ether and dried.

The crude yellow precipitate is added to 692 parts of anhydrous hydrogen fluoride at from -60 to -70 ⁰ C. The mixture is allowed to warm to room temperature and the excess hydrogen fluoride is evaporated. Dichloromethane and water are added to the residue. The dichloromethane extract is washed with dilute NaHCO, solution, with anhydrous MgSO. dried and then evaporated. The residue is triturated with ethyl acetate to give the corresponding 3-carboethoxy-6-phenyl-2-pyrone of melting point 107 to 109 ⁰ C is obtained.

Examples 2 and 3

The experiment described in Example 1 is repeated, but using an equivalent amount of that mentioned below substituted acetophenone is used in place of the acetophenone used in Example 1 and the said pyrons can be obtained.

Bei- Substituted P y r on

game acetophenone

2 p-methoxyaceto-3-carboethoxy-6- (p-methoxyphenone phenyl) -2-pyrone, melting point

112-114 C

3 p-Ethoxyaceto- 3 ~ carboethoxy-6- (p-ethoxyphenone phenyl) -2-pyrone, melting point

124.5 to 125 ⁰ C.

Example 4

A solution of 0.2 mol of 3-carboethoxy-6-phenyl-2-pyrone in 200 ml of benzene is heated under an ethylene pressure of 1000 atmospheres in a suitable pressure vessel at 200 ⁰ C for 16 hours. The mixture is cooled and the benzene evaporated. The residue consists of the 4-phenylbicyclo - / ^^, ^ / oct ^ -en-i-carboxylic acid ethyl ester with a boiling point of 192 ° C / 12 mm Hc.

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ORIGINAL WSPECTED

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Examples 5 and 6

The experiment described in Example 4 is repeated, wherein however, an equivalent amount of the pyrons mentioned below instead of the 3-carboethoxy-6-phenyl-2-pyrone used in Example 4- used and the bicyclooctenes mentioned are obtained.

Example P yr ο η Bioyoloocten

3-0arboethoxy-6- _i 4 ^. (P-methoxyphenyl) bioyolo-

(4-methc "~

2-pyrone

(4 - methoxyphenyl) - ßi, 2,27oot-2-en-1-carboxylic acid

Sthyleater, boiling point 172 ⁰ O /

0.6 mm Hg

6 3-carboethoxy-6- 4- (p-ethoxyphenyl) bioyolo / 2 ~ _t 2.27-

(4-ethoxyphenyl) oct-2-en-1-carboxylic acid ethyl-2-pyrone ester, boiling point 172 0 / 0.35 mm

Ed

Example 7

A mixture of 0.2 mol of 4-phenylblayolo / 2 ~, 2,27oct-2-en-1-carboxylic acid ethyl ester, 200 ml of glacial acetic acid and 3 f 10biger palladium carbon is at an initial pressure of 3 atmospheres hydrogenated in a shaker. When the uptake of hydrogen ceases, the catalyst is filtered off and the piltrate evaporated under reduced pressure, leaving 4-phenylbioyolo / 2 ", 2,27octane-1-carboxylic acid ethyl ester with a boiling point of 192 ° C / 12 mm Hg.

Example 8 and 9

The experiment described in Example 7 is repeated, but using an equivalent amount of that mentioned below Bicyclooctenes instead of the 4-phenylbicyclo / 2,2,27oct-2-en-1-carboxylic acid ethyl ester used in Example 7 used and the following are obtained Bcyclooctancarbonsäureäthylester.

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example

Bicyolooctene Bicyclooctane

Ethyl 4- (p-methoxyphenyl) bicyclo / 2.2 _f 27oot-2-en-1-carboxylate

Ethyl 4- (p-lthoxyphenyl) -bicyclo / 2.2 _f 2.7oct-2-en-1-carboxylate

4- (p-Methoxyphenyl) -bicyclo- / 2,2,2, / oc tan ~ 1 -carbonic acid ethyl ester, melting point
85-87 C

4- (p-lthoxyphenyl) -bicyclo- / 2,2,2_7oo tan-1 -carboxylic acid ethyl ester, boiling point
170-172 ° O / E.35 pn Hg

example

A mixture of 1.6 mol of 4-phenylbicyclo / f _i 2 _{t of} 27oct-2-en-1-carboxylic acid ethyl ester, 2.0 mol of sodium hydroxide and 1000 ml of diethylene glycol is heated ^{to 160 0 15 under nitrogen for 2 hours.} The mixture is cooled and poured into 4000 ml of water. The solution is acidified with 400 ml of 6N-H01 · The precipitate is filtered off, washed with water and dried, v / obei 4-phenylbicyclo / 2 "2, _27oct-2-en-1-carboxylic acid of melting point 249-250 ⁰ O obtained will.

Examples 11 to

The experiment described in Example 10 is repeated, but using an equivalent amount of that mentioned below Ester instead of the 4-phenylbicyolo / 2 ", 2,27oct-2-en-1-carboxylic acid ethyl ester used in Example 10 25 is used and the acids mentioned below can be obtained.

example

Ester

acid

4-phenylbicyclo / 2 ", 2,27-octane-1-carboxylic acid alkyl ester

4- (p-methoxyphenyl) bicyclo / 2 ", Aryl 2,2 / oct-2-en-1-carboxylate

13 4- (p-Methoxyphenyl) bicyclo / 2,2,2 / octane-1-carboxylic acid ethyl ester

4-phenylbicyclo / ?, 2,2 / -octane-1-carboxylic acid, ""
Melting point 287-289 0

4- (p-Methoxyphenyl) -bicyolo / 2 " _t 2,2 / oct-2-en-1-carboxylic acid, melting point 299-30O ⁰ C

4- (p-methoxyphenyl) bicyclo / 2% 2.27octane ~ 1 -carboxylic acid, Sehmelzp, 275-276 C

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Example ester acid

14 4- (pA "thoxyphenyl) bi- 4- (pA" thoxyphenyl) bicyolocyclo / 2,2,2 / oct-2-en-1 - JjL _t 2,2joct-2-en-1 -oarbon-

aryl carboxylate acid "*

15 4- (p-A "thoxyphenyl) bi- 4- (p-A" thoxyphenyl) bioyclocyclo / 2 ~, 2.2 / octane-1 - / 2 ", 2.27ootane-1-carboxylic acid aryl carboxylate of melting point 286-287 ° C

The bicyclooctenic acids can by catalytic hydrogenation easily converted to the bicyclooctanoic acids in the manner described below.

Example 16 ^

A mixture of 0.2 mol of 4-Phenylbioyclo _j / ~? ', 2,27oct-2-en ~ 1-carboxylic acid, 200 ml glacial acetic acid and 3 g 10biger palladium carbon is hydrogenated at 60 ⁰ C and 3 atmospheres in a shaker for 16 hours . The reaction product is placed in the thimble of a Soxhlet apparatus and the catalyst is continuously extracted. The acetic acid solution is then left to cool, the 4-phenylbicyclo / 2 ~, 2,27octane-1-carboxylic acid crystallizing. The crystals are filtered off and dried. Melting point 287-289 ⁰ C.

Example 17

A mixture of 0.03 mol of 4- (p-methoxyphenyl) bicyclo / ?, 2.27- ^ octane-i-carboxylic acid ethyl ester, 100 ml of glacial acetic acid and 50 ml of 48 # hydrobromic acid is refluxed for 16 hours. The mixture is left to cool, whereupon crystals separate out. The crystals are filtered off, washed with water and dried, the acetic acid monobolvate of 4- (p-hydroxyphenyl) bioyolo /!?, 2.27 ~ octane-1-carboxylic acid having a melting point 299-30O ⁰ C is obtained

If the experiment described in Example 17 with an equivalent amount of 4- (p-methoxyphenyl) bioyclo / ?, 2,27oot-2-35. aryl en-1-carboxylate is repeated, becomes 4- (p-HydroxyphenylJbioyolo / ?, 2,2JoOt-2-en-1-carboxylic acid obtain·

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Example .18

In a Soxhlet extraction apparatus with Linde molecular sieve 5A with a grain size of 1.6 m in the extraction sleeve a mixture contained in the flask of 0.1 mol of 4-phenylbicyclo / 2 ~, 2.27oct-2-en-1-carboxylic acid, 0.5 g p-toluenesulfonic acid and 250 ml of methyl alcohol for 16 hours heated to reflux. The solution is cooled and. evaporated "The residue is dissolved in dichloromethane" The Solution is washed with NaHCO, solution, with anhydrous MgSO. dried and evaporated, whereby the 4-phenylbicyclo / 2 ", 2,27oct-2-en-1-carboxylic acid ^ thylester is obtained.

Examples 19 to 21

The experiment described in Example 18 is repeated, but using a 40 percent amount of the amounts mentioned below "Acids" in place of the 4-phenylbicyclo / 2 ", 2,27oct-2-en-1-carboxylic acid used in Example 18 and the corresponding alcohol can be used in place of the methanol used in Example 18 and those below called "esters" are obtained.

Example acid ester

19 4-phenylbicyclo / 2,2,27- 4-phenylbicycldi / 2 ", 2,2.7-

octane-1-carboxylic acid "" octane-1-carboxylic acid methyl

ester

20 4- (p-hydroxyphenyl) - 4- (p-hydroxyphenyl)

bicyclo / 2,2,2,7octane-1-blcyclo / 2,2,2,7octane-1-carboxylic acid carboxylic acids ^ thyl esters

21 4- (p-methoxyphenyl) - 4- (p-methoxyphenyl) bicyclo-

bicyclo / ^, 2.27octane-1- / 2 ~ »2.27octane-1-carboxylic acid

carboxylic acid ~~ butyl ester

Example 22

A mixture of 0.010 mol of 4- (p-hydroxyphenyl) bicyclo / 2 ~, 2,27-octane-1-carboxylic acid, 50 ml of acetic anhydride and 4 g (0.050 mol) of anhydrous sodium acetate is 1 hour on

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C. 6th H 70 81 7th .99 71 05 .01

1812U38

Heated to reflux. The mixture is cooled, 20 ml of water are added and the mixture is stirred overnight. The product is evaporated under reduced pressure. The residue is dissolved in a mixture of water and chloroform. The chloroform extract is washed with water, dried with anhydrous MgSO ^ and evaporated. The residue is recrystallized from nitromethane, giving 4- (p-acetoxyphenyl) bicyclo- / 2,2,27octane-1-carboxylic acid with a melting point of 290-30O ⁰ C (decomp.).

Elemental analysis:

Calculated for 0. | γΗ ₂₀ 0, ί
Found:

Examples 23 to 26

Esters of longer chain acids can be prepared in the manner described in Example 21, but it is usually preferable to use an inert high boiling solvent such as xylene and one molar equivalent or greater amount of acid anhydride per mole of 4- (p-hydroxyphenyl) bicyclo / 2 ", 2,2_7octane-1-carboxylic acid to be used. Good results are also obtained if 4- (p-hydroxyphenyl) bicyclo / 2,2,2_7oct-2-en-1-carboxylic acid instead of 4- ( p-Hydroxyphenyl) bicyclo / 2 ", 2, 2 _pl 7octane-1-carboxylic acid is used. If the fatty acid anhydrides mentioned below of higher molecular weight are used in place of the acetic anhydride used in Example 21, the esters mentioned below are conveniently separated off by column chromatography.

At-

game anhydride ester

23 Propionic acid 4- (p-propionoxyphenyl) bioyclo / 2 ", 2, g7-anhydride octane-1-carboxylic acid "~

24 Butyric acid 4- (p-butyroxyphenyl) bicyclo / 2,2,2 / anhydride 2-en-1-carboxylic acid ~

25 isobutyric acid 4- (p-isobutyroxyphenyl) bicyclo / 2 ~, 2,2-7-anhydride oct-2-en-1-carboxylic acid "~

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For example anhydride ester

26 Dodecanoic acid 4- (pI ⁾ odeoanoyloxyphenyl) bieyclQ-anhydride / 2,2,27ootaE-1-carboxylic acid

The 4- (p-hydroxyphenyl) "bicyclo / 2", 2.27oci; an-1-oarT3onsäuremethylester and ethyl esters can also be attached to the p-hydroxyl group esterified by the methods described in Examples 21 to 25 and the modifications described there will·

Salts of the 4-arylbicyclo / 2 ", 2,27ootylcarboxylic acids can easily be prepared in the manner described below". A mixture of 0.1 mol of arylbicyclo / 2 ₉ 2 "27oct-2-en-1-carboxylic acid and 0.1 equivalent of alkali hydroxide, alkaline earth carbonate or ammonium hydroxide in 250 ml of water is heated until all of the acid is dissolved. The use of an excess of HELOH is advantageous because NE * is easily lost during heating. The solution is left to cool, the salt crystallizing. The crystals are filtered off, washed with the minimum amount of cold water and dried to give, for example, the following salts :

Sodium salt of 4- (p-methoxyphenyl) bicgrclo / 2 _i> 2.2 _A 7'ootane-1-carboxylic acid

Potassium salt of 4- (p-ethoxyphenyl) bicyclo / 2% 2,27oct-2-en-1-carboxylic acid

Ammonium salt of 4- (p-hydroxyphenyl) bicyolo / 2 ~, 2,27octane-1-carboxylic acid

Magnesium salt of 4- (p-hydroxyphenyl) bicyclo / 2 ", 2.27oct-2-en-1-carboxylic acid

The compounds of the invention may ζυχ preventing pregnancy by the method according to the inventions · dung be administered in any suitable manner. "For example, the administration may be by parenteral, d _# ku effected subcutaneously or intramuscularly ,, oral or rectal

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SiW TSh: ':. ■ "" ■■:%

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Presentation is also possible. These compounds can be administered in single doses or in divided doses in time 15 days after coitus. Preferably the compounds are administered in a single dose after coitus, but before the estimated time of implantation of the fertilized egg in the uterine lining.

The dose given depends on age, state of health and the weight of the recipient as well as the frequency of administration. Generally, with an on one or more days given a dose of 0.001 to 50 mg of active ingredient per kilogram per day achieved the desired result. A dose of 0.005 to 10 mg / kg / day is used preferred and a dose in the range from 0.01 to 5 mg / kg / day particularly preferred.

These compounds have had excellent results in preventing the pregnancy of rats. The method according to the invention can therefore be used in addition to the previously known methods of controlling rodents or used as a substitute for these methods.

Example 27

In immature rats (28 days old), premature puberty is prevented with a single dose of the serum from pregnant mares, Gonadotropin, whereupon the animals are mated with normal male rats. A suspension of 4- (p-hydroxyphenyl) bioyclo / 2 ~, 2,2_7ootan-1 -carboxylic acid in sesame oil is administered orally daily for a period of 6 days, starting on the day sperm or a vaginal plug is detected. One week after mating, the Animals killed and their uteri examined for implantation sites. If these spots are found, that is true Animal as viable. Comparison animals have an average of 8 implantation sites

909827/1559

When a series of graduated doses is given, it is found that the dose at which 50% of the animals show no sign of pregnancy, the ED ₅₀ , 0.31 mg / kg / day,

The experiment described in Example 27 is repeated, but using 4- (p-methoxyphenyl) bicyclo / 2,2,2 / octane-1-carboxylic acid instead of the compound used in the experiment described above. It is found that the ED ₁ -Q is between 0.31 and 1.2 mg / kg / day.

The experiment described above is repeated again, but the compounds according to the invention are administered to female rats in a single oral dose on the third day about 53 hours after mating. 2.2,2_7oct-2-en ™ 1-carboxylic acid is administered in this way, an ED ₁ -Q of 0.86 mg / kg / day is found »

The compounds according to the invention can be used with equally good results for the prevention of pregnancy in other test animals, e.g. mice, guinea pigs, rabbits, monkeys and chimpanzees and are also effective in preventing pregnancy in domestic animals such as pigs, Cows, sheep and horses. In small animals it is usually convenient to use the compounds according to the invention to be administered in the form of a capsule or to be added to the feed of the animals. In large animals, however, it is common more expedient to administer them parenterally.

The active substances for the process according to the invention can be used in customary inventive preparations, for _e B, in the form of tablets, capsules, powder packets, or liquid solutions, suspensions or elixirs for oral administration or in the form of liquid solutions for parenteral treatment and in certain Cases in the form of suspensions for parenteral use are used «In these acces-

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- 15 -

In preparations, the active ingredient is usually always present in an amount of at least 0.01% by weight and not more than 90% by weight , based on the total weight of the preparation.

In addition to the material according to the invention, the preparation contains a solid or liquid non-toxic pharmaceutical carrier for the active ingredient.

In one embodiment of a pharmaceutical preparation according to the invention, a capsule, which can be an ordinary gelatin capsule, serves as the solid carrier. The capsule contains about 0.1 to 75% by weight of a ^ -phenylbicyclo ^^^ octane or -oct-2-en-1-carboxylate according to the invention and 99.5 to 25 % of a carrier. In a further embodiment, the active ingredient is tabletted with or without excipients. In another embodiment, the active ingredient is incorporated into powder packs and used. These capsules, tablets and powders generally consist of about 0.5 to 95%, preferably 1 to 50% by weight of the active ingredient. These formulation forms preferably contain about 0.5 to 250 mg of the active ingredient, with about 1 to 50 mg being particularly preferred.

As already mentioned, sterile liquids, e.g. water and oils from petroleum and oils, are suitable as pharmaceutical carriers of animal, vegetable or synthetic origin, e.g. peanut oil, soybean oil, mineral oil and sesame oil. In general water, saline solution, aqueous dextrose (glucose) and related sugar solutions and glycols, e.g. propylene glycol or polyethylene glycol, the preferred liquid carrier, especially for injection solutions. Sterile injection solutions, e.g., in saline, usually contain about 0.05 to 25%, preferably about 0.1 to 5% by weight of the active Ingredients.

As already mentioned, the oiale administration can be carried out in a suitable suspension, in a syrup or an elixir. In these vehicles, the active ingredient is common in an amount of about 0.01 to 5 # * preferably

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Contains about 0.05 "to $ 1 wt. · The pharmaceutical carrier In such preparations, an aqueous carrier, e.g. an aromatic water, a syrup or a pharmaceutical one Be slime.

Suitable pharmaceutical carriers are in "Remington's Pharmaceutical Sciences "by E.W. Martin, a well-known handbook in the field.

In addition to the above examples, one aspect of the invention is further illustrated by the following examples.

Example 28

Sine large number of unit capsules are for oral use Administration prepared by adding conventional two-part hard gelatin capsules with 10 mg of powdered 4 (p-methoxyphenyl) bicyclo / 2,2,27oct-2-en-1-carboxylic acid as the sodium salt, 342 mg of lactose, 8 mg of magnesium stearate and 40 mg of talc be filled.

Example 29

A large number of unit capsules are manufactured for oral administration by using soft gelafcine capsules a solution of 4- (p-ethoxyphenyl) bicyclo / 2,2,2_7οοΐ-2-βη-1-carboxylic acid aryl ester be filled in sesame oil.

Example 30

A large number of tablets are prepared by conventional methods so that the dosage unit is 5 mg of active Ingredients, 82.9 mg of anhydrous lactose, 2 mg of magnesium stearate and 10 mg of microcrystalline cellulose and 0.1 mg Contains fumed silica. Tablets with slow release of the active ingredient can be made by applying more suitable Coatings are also made.

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Example 31

A parenteral preparation administered by injection is prepared by stirring 0.5 wt .- # 4- (p-hydroxyphenyl) bicyclo / 2 ~, 2.27octane-1-carboxylic acid methyl ester in sesame oil and sterilization of the solution

Example 32

Suppositories for rectal use can be prepared by stirring together 0.25% by weight of methyl 4- (p-hydroxyphenyl) -bicyolo / 2,2,2,7octane-1-carboxylate in melted theobroma oil and shaping the mass into 2 g suppositories.

The most varied of preparations according to the invention can thus easily be made using other compounds according to Invention are prepared, which have been specifically mentioned above, but without being limited thereto is intended. The compounds are used in the specified amounts by known methods, which are described in the above mentioned manual by Martin are described.

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Claims (8)

Ί 8 1 ζ β 3 8-18 - claims 1.) Containing contraception agents: a) an effective amount of one or more compounds of the general formula wherein A is a single or a double bond, R _{1 is} hydrogen, -OH, -OCH ,, -OC ₂ H ₅ , -OC ₃ H ₇ , -OC ₂ ^ H ₉ or RCO is where R is hydrogen or an alkyl radical of 1 to 12 carbon atoms, and R _{0 is} H, an alkyl radical of 1 to 6 carbon atoms or vPi to Me, where Me ^{w is} a non-toxic pharmaceutically acceptable salt-forming cation, and b) a pharmaceutically acceptable diluent or carrier. 2.) Containing contraception agents: a) an effective amount of one or more compounds of the general formula ORIGINAL. INSPECTED 909827/1559 - 19 in which A is a single or a double bond, R _{1 is} H, -OH, -OCH ,, -OC ₂ H ₅ and RC ^, where R is an alkyl radical having 1 to 4 carbon atoms and R _{2 is} H, CH ,, C ₂ H ₅ or Me ¹ * ' , where Me * ^{0 is} a non-toxic pharmaceutically acceptable salt-forming cation, and b) a pharmaceutically acceptable diluent or a harmless carrier. 3.) Containing contraception agents: a) an effective amount of one or more compounds of the general formula wherein A and R _{1 are} as defined in claim 2 and R _{2 is} hydrogen, methyl, ethyl, sodium, potassium, magnesium or ammonium, and b) a pharmaceutically acceptable diluent or carrier. 4.) A method for preventing pregnancy in animals, characterized in that an effective amount of a compound of the general formula _{N is given to the female animals} 909827/1559 - 2ο - administered, in which A is a single or a double bond,
R ₁ H, -OH, -OCH ^, -OC ₂ H ₅ , -OC ₃ H ₇ , -OC ₄ H ₉ or R- is wherein R is hydrogen or an alkyl radical of 1 to carbon atoms, and R ₂ H, alkyl of 1 to 6 carbon atoms or Me ⁵ ^ iSt, where Me ^ is a non-toxic pharmaceutically acceptable salt-forming cation. 5.) The method according to claim 4, characterized in that R _{1 is} H, -OH, -OCH ,, -OC ₂ H ₅ or RC ^, wherein R is an alkyl radical of 1 to 4 carbon atoms, and R _{2 is} H, CH ^, C ₂ H ₅ or Me ^, where Me ^ is a non-toxic pharmaceutically acceptable salt-forming cation. 6.) Process according to claims 4 and 5 * characterized in that A and R. are as defined in claim 5 and R _{2 is} H, CH ^, CgH ₁ -, sodium, potassium, magnesium or ammonium. 7.) Process according to Claims 4 to 6, characterized in that the active compound is 4- (p-hydroxyphenyl) bicyclo _< / 2,2,27octane-1-carboxylic acid. 8.) Process according to claims 4 to 6, characterized in that the active compound 4- (p-methoxyphenyl) bicyclo / ~ 2,2,27octane-1-carboxylic acid. 1SSÖ